*Disclaimer: There are many ongoing investigations to determine more about this outbreak. The information below was accurate as of 5/1/20. Please check the CDC website for the most up-to-date information about COVID-19.
In this podcast interview, Drs. Ilene Claudius and Mohsen Saidinejad discuss MIS-C with COVID-19. Get answers to questions such as: What is available as treatment for MIS-C? Why IVIG? What are the complications of the disease? How might MIS-C change your practice of testing children? Is there utility in testing for COVID-19 infection or antibodies in these cases?
The COVID-19 pandemic has had a unique impact on pediatric emergency departments. This survey report, “COVID-19: The Effects on the Practice of Pediatric Emergency Medicine,” summarizes and reviews the results of a survey of 65 pediatric emergency department leaders in the U.S. and Canada. The informal survey, which was conducted in April 2020, gathered information about the effects of the COVID-19 pandemic on the practice of pediatric emergency medicine. The report is accompanied by an infographic highlighting key survey results.
Although there is still much that is not understood, experience with previous coronavirus outbreaks and available data on COVID-19 indicate a reduced propensity to affect children. Nonetheless, serious complications— although rare—are being seen in pediatric patients. Our new review, “COVID-19: The Impact on Pediatric Emergency Care,” is written for emergency medicine clinicians and describes the epidemiology, clinical features, and management implications for COVID-19 in pediatric patients. It includes a discussion of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, as well as other aspects of the COVID-19 pandemic that are affecting children and families, such as poisonings, childhood immunizations, mental health, nonaccidental trauma, and neglect.
In late March, a statement released by the American College of Otolaryngology – Head and Neck Surgery (AAO-HNS) proposed that the symptoms of anosmia (loss or lack of the sense of smell) and dysgeusia (distortion in the sense of taste) be added to the list of screening tools for possible COVID-19 infection.1 In a volunteer sample of 2428 surveys of self-diagnosed anosmia, approximately 1 in 6 did not report any other symptom of COVID-19. While this study suffers from various methodological shortcomings, including the lack of confirmed diagnosis of COVID-19 in survey responders, the isolated presentation of anosmia may be a helpful tool in the future to identify asymptomatic carriers or to trigger targeted testing.2
The pathophysiology of COVID-19 is notably distinct from classically recognized lung pathologies; however, a definitive understanding remains elusive. While several pathophysiological mechanisms for this have been proposed, the quality of current literature supporting the leading theories varies greatly.
Our early understanding of the hypoxemic respiratory failure state seen in COVID-19 was the development of ARDS, a finding that has been supported by histological findings in autopsied patients.1-3 However, normal lung compliance is seen in these patients even as they become hypoxemic, a distinct pattern from the typical low-compliance state seen in ARDS.4 There is increasing suspicion among clinicians that other pathophysiological phenomena are at play; 2 hypotheses and an associated review of literature supporting them are discussed below.
A leading theory for the origins of ventilation/perfusion (V/Q) mismatch in critically ill COVID-19 patients, supported by laboratory evaluation of coagulation markers and autopsy findings, is the development of a prothrombotic coagulopathy leading to diffuse microthrombi formation in vital organs and increased pulmonary dead space ventilation.5-7
A retrospective observational study carried out at 3 hospitals in the Netherlands examined the incidence of a thrombotic complication composite outcome in 184 ICU-level COVID-19 patients. 31% of the enrolled patients suffered from a thrombotic complication; 81% of those complications were symptomatic acute pulmonary embolism. While the retrospective design and use of a composite outcome may artificially elevate these percentages (a limitation that is acknowledged by the authors), a remarkably high frequency of thrombotic events in critically ill COVID-19 patients is apparent. Of note, all enrolled patients received standard dosing of thromboprophylaxis throughout the observational period.8
A case series of autopsies performed on 4 patients in New Orleans, all of whom had acute respiratory decompensation and abnormal coagulation markers, found evidence of microthrombi in peripheral lung parenchyma, areas of diffuse alveolar damage, and a notable absence of evidence for secondary lung infection.5 (Note: This was derived from a symposium on the pathology of COVID-19 decedents, and is as yet unpublished. Of note, one of the cases of “classic myocarditis” was in a patient with an influenza coinfection.)
An analysis of lung and skin tissue in 5 patients with SARS-CoV-2 infection and severe respiratory failure, 3 of whom also had dermatologic features consistent with a systemic procoagulant state, found “…a pattern of cutaneous and pulmonary pathology involving microvascular injury and thrombosis, consistent with activation of the alternative pathway (AP) and lectin pathway (LP) of complement. Co-localization of SARS-CoV-2-specific spike glycoproteins with complement components in the lung and skin was also documented… suggest[ing] that at least a subset of severe COVID-19 infection involves a catastrophic, complement-mediated thrombotic microvascular injury syndrome with sustained activation of the AP and LP cascades.”9 Of note, “diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic ARDS, were not prominent.”9
Histological examination of kidney tissue in 26 patients who died of COVID-19 found endothelial injury patterns, with evidence for direct parenchymal tubular epithelial and podocyte viral infection, as well as “prominent erythrocyte aggregates obstructing the lumen of capillaries without platelet or fibrinoid material.”10
Furthermore, 3 large medical centers in the United States are preparing to publish data noting an unusually high rate of cerebrovascular accidents in the context of COVID-19 infection, often affecting a much younger demographic than typical stroke patients.11
A retrospective analysis of 449 patients found that in patients with a sepsis-induced coagulopathy (SIC) score ≥ 4 or D-dimer > 6-fold of the upper limit of normal, the 28-day mortality of heparin users was lower than nonusers. For heparin users versus nonusers: the 28-day mortality rate for patients with SIC score ≥ 4: 40% vs 64.2%, respectively, P = .029. The 28-day mortality rate for patients with D-dimer > 6-fold upper limit of normal: 32.8% vs 52.4%, respectively, P = .017.12 A definition and diagnostic calculator for the SIC score can be found in Table 1 of this 2019 article published in the Journal of Thrombosis and Haemostasis and seen below.13
Marcel Levi, Tom Poll, Jecko Thachill, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. Journal of Thrombosis and Haemostasis. 2019;17(11):1989-1994. Used with permission of John Wiley and Sons.
When determining the choice of anticoagulant, there is significant literature to support the use of heparins over the direct oral anticoagulant (DOAC) class of medications. Heparins have been shown to bind to SARS-CoV-2 spike proteins while also downregulating IL-6 and dampening immune response.14,15 Controlled studies are needed to see if these theoretical benefits translate to clinical outcomes.
Due to the propensity for unfractionated heparin to bind to various blood proteins (such as von Willebrand factor and others that proliferate in acute inflammation), frequent blood draws are needed to track achievement of therapeutic anticoagulation. Given the resource-intensive nature of monitoring these drips and the need to minimize repeated exposures to these patients, the authors recommend the use of once-daily dosing with-low-molecular-weight heparin in patients with sufficient renal function. For patients with renal insufficiency, monitoring unfractionated heparin drips with anti-Xa assays is recommended, where possible. Anti-Xa assays have been shown to be a better indicator of actual heparin level, associated with fewer bleeding complications, blood transfusions, and faster time to therapeutic range, while its higher price tag has been shown to be mitigated by a lessened need for monitoring tests and dosage changes.16-18 Alternatively, the use of accessible blood drawing ports (see Figures 1 and 2) will allow for the traditional coagulation profile analysis with activated partial thromboplastin times (aPTT).
There is a dearth of quality literature on the use of fibrinolytic therapy in COVID-19 patients at this time. A 3-patient case series discussing the application of tPA in hypoxemic COVID-19 patients demonstrated transient benefit in oxygenation in a setting with no comparator arm. Multiple study authors disclosed significant potential conflicts of interest with pharmaceutical and technology companies involved in producing coaguloactive therapies.19
Notwithstanding this, there is an ongoing clinical application of tPA at the Mount Sinai Hospital in New York City, led by Dr. Hooman Poor, whose critical care team has developed a treatment protocol for the use of tenecteplase in severely ill patients in what many view as a last-ditch attempt at resuscitating a severely critical patient. The treatment dose is 0.25 mg/kg (half the standard dose given in pulmonary embolism) with a maximum of 25 mg, in bolus form, over 1 minute. The inclusion and exclusion criteria are as follows:
Inclusion Criteria – Requires ALL of the Following to Receive
Exclusion Criteria – ANY of the Following Precludes Treatment With Tenecteplase
Procedural Considerations
It is too early to determine the efficacy of this treatment protocol, but data are being collected and analyzed and will be reported on when in sufficient quantity.
ACE2, the receptor by which SARS-CoV-2 gains entry into cells, is highly expressed in both human lungs and the heart. A meta-analysis of studies publishing laboratory markers in COVID-19 found a rate of acute cardiac injury (as defined by elevation of cardiac troponin) in 8%-12% of patients, though the etiology for this is still poorly understood.20
There is speculation that SARS-CoV-2 may be causing direct toxicity to myocardium; however, the literature to support this hypothesis is limited to case reports.21-23 A recently published case report in JAMA describes a patient with no previous cardiac history who presented 1 week after onset of cough and fever with elevated troponin, biventricular hypokinesis, circumferential pericardial effusion, nonobstructive coronary angiography, and cardiac MRI showing diffuse interstitial edema in the myocardium, all consistent with a diagnosis of acute myopericarditis. Of note, this patient did not have any typical respiratory symptoms or findings of COVID-19 on imaging.22 A review of 21 critically ill nursing home patients in Washington state found the development of cardiomyopathy in 7 (33%) of the patients.24
Whether the cause of the phenomena behind these case reports and the high rate of acute cardiac injury is due to direct myocardial toxicity from the virus or from other causes, such as a hyperinflammatory syndrome, is a question that requires more powerful and focused analysis. The phenomenon in which cytokines such as TNF-alpha and IL-1 directly suppress cardiomyocyte contractility has been well documented in other inflammatory conditions, such as sepsis.25
As published in the European Heart Journal and echoed by the American College of Cardiology, patients with heart failure and coronary artery disease are at increased risk of plaque rupture secondary to viral inflammation; therefore, use of plaque-stabilizing agents such as aspirin, statins, beta blockers, and angiotensin-converting enzyme inhibitors is recommended.26
A recent management guideline published in The Journal of the American College of Cardiology gives concrete recommendations for the care of patients diagnosed with acute myocardial infarction.27 The key takeaways are:
The Intensive Care National Audit and Research Centre (ICNARC) in London conducted a retrospective study comparing outcomes in COVID-19 patients to those with viral pneumonias between 2017-2019, and found that patients requiring advanced respiratory support (invasive mechanical ventilation, BiPAP or CPAP via endotracheal tube, tracheostomy, or ECMO) are dying at much higher rates in the COVID-19 subgroup than in the viral pneumonia group (66.3% vs 35.1%, respectively). While the sample of COVID-19 patients is biased toward those requiring shorter durations of care (because a portion of that group was still receiving care in the hospital at time of publication), such a stark difference in survival rates of advanced respiratory support patients demands an examination of whether the current management of patients in respiratory distress is optimal. Updated ventilatory management recommendations by Hickey et al can be viewed here.
The potential efficacy of hydroxychloroquine in the treatment of COVID-19 has been an issue of global public debate. While as many as 34 clinical trials are ongoing in China studying hydroxychloroquine in management of COVID-19, peer-reviewed publications are still lacking at this time. Comments made by French virologist Didier Raoult in support of using hydroxychloroquine in COVID-19 reference patients whose data have not been made public for peer review.1,2 Raoult’s French cohort of 1061 patients had no control arm for comparison, and there is concern for an anchoring bias in Raoult’s claims, given his prominent role in revealing the efficacy of hydroxychloroquine in treating intracellular bacterial infections.3,4
A parallel, double-blinded, randomized, phase 2b clinical trial aiming to assess the safety and efficacy of 2 different chloroquine dosages as adjunctive therapy of hospitalized patients with COVID-19 in Brazil prematurely closed the high-dose chloroquine treatment arm due to a trend toward increased lethality and QTc prolongation.5 A retrospective analysis of data from 368 patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers found an association of increased overall mortality in patients treated with hydroxychloroquine alone, in comparison to no treatment.6
At this time, there are no placebo-controlled, randomized, double-blinded prospective clinical trials that have been conducted supporting the efficacy and routine use of this medicine in COVID-19.
Convalescent plasma, whereby donor plasma bolstered with anti-SARS-CoV-2 antibodies is isolated and injected into critically ill COVID-19 patients, has been a subject of great academic interest. While this treatment method rests on theoretical understanding of human antiviral immunology, it has yet to be studied on the basis of clinical outcomes. An uncontrolled case series from Shenzen, China published in JAMA in late March 2020 described improvement in various clinical and laboratory markers in 5 critically ill COVID-19 patients after being given convalescent plasma infusions.7 However, confounders such as the administration of methylprednisolone and antiviral agents to all patients in the study, a low number of subjects, and lack of a control group preclude recommendations based on this study. No adverse events were mentioned in this case series.
As institutions across the United States begin offering SARS-CoV-2 antibody testing, the role of antibodies may go beyond therapy to directly impact epidemiological surveillance and public health policy. This is discussed further in the updated “Epidemiology” section below.
As communities face either the specter of a pandemic capable of overwhelming health systems or the uncertainty that follows the downswing of infections following the proverbial “peak,” it becomes imperative to understand the community penetration as well as the epidemiological and immunological characteristics of SARS-CoV-2.
A Stanford University study sampled 3330 adults and children and concluded that there was community antibody prevalence of up to 50 to 85 times greater than the number of confirmed cases in the community at that time.1 (The sample was recruited utilizing Facebook ads to find a “representative sample of the [Santa Clara] county by demographic and geographic characteristics.”) The locally developed test kit’s performance statistics were independently verified against controls and are critical drivers of this reported range; any meaningful deviation in the reported sensitivity and specificity of 80.3% (95% confidence interval [CI]; 72.1%-87.0%) and 99.5% (95% CI, 98.3%-99.9%), respectively, would result in vastly different epidemiologic extrapolations.
Taken at face value, this study’s findings signify far greater penetration of SARS-CoV-2 into the community than is indicated by confirmed cases. Santa Clara County also recently announced autopsy results concerning for COVID-19 from 2 patients who died on February 6 and February 17, 2020, indicating community transmission in California, and likely in the rest of the United States, may have begun earlier than previously postulated.2
Unique geographic characteristics may alter an R0 value in any particular locale; for example, the subway system in New York City likely portends a much higher R0 value due to ease of transmission. News media recently announced preliminary findings from antibody testing done on 3000 residents of New York State (chosen randomly at grocery stores), which estimated 13.9% of the population having been infected with SARS-CoV-2, with ranges from 11.6% to 21.2% in different locales. These data and testing parameters on the kits used in the study have yet to be published formally.3
Therefore, the authors recommend urgent repeat studies in impacted communities, with careful attention paid to test performance and control. On April 17, 2020, the University of Washington School of Medicine Virology Lab issued a press release noting an internal study using a new antibody test from Abbott Laboratories that ran 1200 samples and achieved 100% sensitivity and 99.6% specificity. If the data, when published, are deemed trustworthy, a test with these parameters would bode well for communities aiming to track seroprevalence into the future.4
It is still too early to tell what, if any, protection is conferred by SARS-CoV-2 antibodies, though much of the foundations of human immunology has a theoretical basis in the potential for these antibodies being able to prevent re-infection. The pertinent questions are: To what degree are antibody carriers protected, and for how long? SARS-CoV-1 (the related betacoronavirus that caused the 2002-2004 outbreak and shares genetic similarities with SARS-CoV-2) was found to develop and maintain high levels of SARS-specific antibodies in survivors for an average of 2 years, with a significant drop in IgG titers in the third year.5
Suppressing the R0 value in order to unburden overwhelmed healthcare systems will require an understanding of community penetration of SARS-CoV-2 as well as immunity conferred by prior infection and subsequent recovery, and both of these will require that widespread antibody testing and analysis become available. In communities still naïve to SARS-CoV-2 spread, aggressive and early testing may be able to mitigate the rapid spread of disease, as was done in South Korea in the early days of the pandemic.6
A transmission model for SARS-CoV-2 based on known data (and allowing for unknown data such as duration of immunity and degree of cross-immunity with other coronaviruses) projects the capability of SARS-CoV-2 to produce an outbreak at any time of year, with autumn/winter being susceptible to more acute outbreaks. If immunity to SARS-CoV-2 is not permanent, the virus will likely enter into regular circulation with outbreak cycles depending on the length of the period of conferred immunity.7
As tensions grow between communities facing economic collapse and healthcare systems calling for complete shutdowns, the need for a reasoned approach to lifting restrictions based on current data is needed. The American Enterprise Institute has formed a 4-phase framework for this process, from slowing the spread today to rebuilding readiness for the next pandemic in the future, which can be found here.8 A similar statement was released by the Infectious Diseases Society of America which can be found here.9 A general consensus in both of these documents emphasizes the following necessities prior to reopening an impacted community:
While both of these guidelines supply a useful framework to approach the important factors that need to be considered prior to lifting shutdowns, the authors stress that a single approach may not fit every community, and local leaders should make decisions based on real-time consultation with local public health experts and frontline providers facing the pandemic. Other vital considerations will be the prevailing epidemiologic data, forthcoming evidence for conferred immunity by antibodies, and a sector-based reopening approach, with attention paid to physical distancing capabilities.
There is growing experience that mechanical ventilation may not always be indicated in COVID-19-infected patients, and that ARDSnet strategies may sometimes be harmful to hypoxic patients. The unique pathophysiology of the novel coronavirus SARS-CoV-2 has led to a renewed interest in alternative ventilator strategies such as airway pressure release ventilation (APRV). APRV is a form of continuous positive airway pressure (CPAP) that is characterized by a timed pressure release while allowing for spontaneous breathing.1 (See Figure 1.) While previously considered a rescue strategy, APRV has recently gained acceptance as a primary ventilatory mode. Its indications for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), multifocal pneumonia, and severe atelectasis make it a very attractive ventilatory option.
Airway pressure release ventilation (APRV) is a form of continuous positive airway pressure (CPAP). The P-high is equivalent to a CPAP level; T-high is the duration of P-high. The CPAP phase (P-high) is intermittently released to a P-low for a brief duration (T-low) re-establishing the CPAP level on the subsequent breath. Spontaneous breathing may be superimposed at both pressure levels and is independent of time-cycling.2
Reprinted with permission from ICON Educational Supplement, 2004.
APRV provides continuous pressure to keep the lungs open with a timed release to a lower set pressure.2,3 The continuous-pressure phase of APRV transmits pressure to the chest wall, which allows for the recruitment of both proximal and distal alveoli. The prolonged continuous-pressure phase with the short release phase avoids the continuous cycles of recruitment-derecruitment that occur in pressure/volume control vent settings.4 This helps to avoid atelectrauma, barotrauma, and resulting ventilator-induced lung injury. (See Figure 2.) The timed release allows for passive exhalation and improved clearance of CO2. Since APRV relies upon spontaneous ventilation, it requires less sedation compared to conventional modalities, thus mitigating adverse events due to sedation. Spontaneous breathing has the benefit of increasing end-expiratory lung volume, decreasing atelectasis, and improving ventilation to dependent lung regions.4 Furthermore, spontaneous breathing improves the hemodynamic profile by decreasing intrathoracic pressure, thus improving preload and cardiac output.
Ventilation during airway pressure release ventilation (APRV) is augmented by release volumes and is associated with decreasing airway pressure and lung distension. Conversely, tidal volumes during conventional ventilation are generated by increasing airway pressure and lung distension.2
Reprinted with permission from ICON Educational Supplement, 2004.
Setting up APRV requires the adjustment of 4 main variables: (1) P-high, (2) P-low, (3) T-high, and (4) T-low.2,3 P-high is the continuous pressure that is set, while P-low is the pressure release part of the cycle. T-high is how long the continuous pressure is set to last, while T-low is the duration of the release phase. The patient should initially be set on assist control/volume control (AC/VC) immediately post intubation until paralysis wears off. Then, an inspiratory hold should be performed to determine the plateau pressure. This plateau pressure becomes the P-high and should generally be around 27-29 cm H2O, though obese patients may require a higher pressure. The P-low is generally set to 0; however, there is generally intrinsic PEEP, as full exhalation does not occur. The T-high is generally set to 4 to 6 seconds, while the T-low is set to .2 to .8 seconds in restrictive lung disease and .8 to 1.5 seconds in obstructive lung disease. To properly set the T-low, you should examine the flow-time waveform on the ventilator. The T-low should be set to approximately 75% of the peak expiratory flow rate (PEFR).2,4 The T-low needs to be continuously readjusted to 75% of the PEFR, as lung recruits over time. (See Figure 3.) FIO2 should be titrated downward once the patient is on APRV and comfortable.
A patient with a lung that initially has low compliance has a steeper expiratory flow curve (30°) and will require a short release phase (T-low) (0.3 s in this example) to terminate the expiratory flow rate at 75% of the peak expiratory flow. As the lung recruits and becomes more compliant, the slope decreases to 45°, requiring an extension in the T-low time, in this example to 0.5 s. With alveolar recruitment and increasing compliance, the lung is able to accommodate larger tidal volumes. Thus, airway pressure release ventilation allows for mechanical ventilation that is time controlled and adaptive to the patient's respiratory system mechanics (time-controlled adaptive ventilation).
Source: Kollisch-Singule M, Andrews P, Satalin J, et al. The time-controlled adaptive ventilation protocol: mechanistic approach to reducing ventilator-induced lung injury. European Respiratory ReviewEuropean Respiratory Review. 2019; Volume 28, Issue 152. Used under the Creative Commons Attribution-NonCommercial 4.0 licence ("CC-BY-NC").
An APRV rescue protocol for COVID-19 patients has been developed by Nader Habashi, Medical Director of the Multi-Trauma Critical Care Unit of the Adams Crowley Shock Trauma Center at the University of Maryland Medical Center in Baltimore Maryland. The protocol shortens the T-high to allow for more bulk ventilation until lung is recruited. This helps avoid excessive air hunger and work of breathing. Sedation should be utilized to control the respiratory drive, if needed. When transitioning from AC/VC, use this formula to calculate the T-high: (60/current rate)−T-low = T-high. For example: (if RR 20 and T-low is .5s), then T-high = (60/20)−.5s = 2.5s. T-high can be increased by .5 to 2s in order to maintain normocapnia.5
Spontaneous breathing is paramount in APRV; thus, a small amount of pressure support or automatic tube compensation should be added to account for the endotracheal tube’s intrinsic resistance.2 Hypoxemia can be corrected by increasing the P-high and T-high.2 Hypoxemia can also be corrected by shortening the T-low. Permissive hypercapnia is allowed in APRV; however, hypercapnia can be corrected, if needed, by decreasing sedation and/or by increasing P-high and T-high. It can be further corrected by increasing the T-low. Increasing the T-low can be problematic, however, as APRV relies upon intrinsic PEEP (iPEEP) to keep the lungs open during P-low. If the T-low increases, the iPEEP will decrease, thus risking derecruitment of alveoli.
Authors: Sean Hickey, MD, Icahn School of Medicine at Mount Sinai; Al Giwa, MD, Associate Professor of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
References
As the understanding of COVID-19 increases, more therapeutic measures have become utilized. Positioning the patient in the prone position (aka, “proning”) has long been touted for its benefits in the treatment of patients with ARDS, as noted in Guérin et al's 2013 PROSEVA study (PMID: 23688302). Proning has since become recommended by most critical care societies around the world for patients with a Pa02-to-Fi02 (P/F) ratio of ≤ 100. Given COVID-19’s frequent resemblance to ARDS in its pathophysiology, many are recommending proning these patients. For a concise review on proning and its use in the awake patient, please see this article by David Gordon, MD at Scott Weingart’s blog, EMcrit.org.
Los Coronavirus llevan su nombre por las peculiares partículas virales con forma de corona que recubren su superficie. Esta familia de virus infecta un amplio rango de vertebrados, particularmente mamíferos y aves, y son considerados una causa importante de infecciones respiratorias en todo el mundo.3,4 Con la reciente detección del Novel Coronavirus 2019 (SARS-CoV-2), y la enfermedad resultante a la que le ha dado su nombre: Enfermedad por Coronavirus (COVID-19), se suman un total de 7 coronavirus con la capacidad de infectar al ser humano:
Previo a la epidemia de SARS-CoV en 2003, HCoV-229E and HCoV-OC43 eran los únicos coronavirus conocidos capaces de infectar al ser humano. Luego de la epidemia de SARS fueron descubiertos 5 nuevos coronavirus en humanos, el más reciente el SARS-CoV-2, probablemente originado en Wuhan, provincia de Hubei, China. SARS-CoV-1 y MERS-CoV son particularmente infecciosos en humanos, y se asocian a una alta mortalidad. En este artículo serán revisados la epidemiología, fisiopatología y manejo del COVID-19, con un enfoque especial en las prácticas recomendadas y las implicancias en salud pública.
Se obtuvieron recursos de PubMed, ISI Web of Knowledge, y Cochrane Database of Systematic Reviews resources desde el 2012 al 2020 usando las palabras claves: emergency department, epidemic, pandemic, coronavirus, SARS-CoV-2, and COVID-19. También se accedió a los Sitios Web del Centro de Control y Prevención de Enfermedades de los Estados Unidos (CDC), la Organización Mundial de la Salud (OMS), Ministro de Salud, Trabajo y Bienestar de Japón, y EMCrit.
Hasta el 22 de Marzo de 2020 han sido reportados 328.275 casos de COVID-19 globalmente, con la mayoría de los nuevos casos ocurriendo fuera de China continental. Han habido 14.366 muertes confirmadas.1 Para números actualizados de casos confirmados y muertes por COVID-19 a nivel global acceda al rastreador en línea de la Universidad Johns Hopkins. Al momento de la publicación, los casos confirmados abarcan 169 países alrededor de todos los continentes, excepto Antártida, lo que llevó a que la Organización Mundial de la Salud (OMS) declarara a la infección por COVID-19 como pandemia. De las muertes, más de la mitad ocurrieron fuera de China, con Italia (5.476),e Irán (1.685) encabezando la lista. La letalidad actual es de 4,38%. La coincidencia de la epidemia de COVID-19 con el Año Nuevo Lunar Chino a fines de enero de 2020, con aproximadamente 15 millones de visitantes en la ciudad de Wuhan, los esfuerzos de contener la epidemia en China continental no fueron exitosos. Los reportes iniciales de poblaciones de pacientes afectados en hospitales de China, indican que la mayoría de los pacientes de gravedad y con mal pronóstico (determinados por el requerimiento de Terapia Intensiva y mortalidad) tieFnden a ser pacientes con comorbilidades como hipertensión, diabetes, obesidad, asma, enfermedad pulmonar obstructiva crónica, o edad avanzada. 2,6
En epidemiología, el valor R0 o número básico de reproducción (r sub-cero) de una infección es el número promedio de casos nuevos que genera un caso dado a lo largo de un período infeccioso, cuando todos los individuos son susceptibles. Estudios epidemiológicos iniciales sobre COVID-19 estiman un valor R0 de 2,2 (90% high density interval: 1,4-3,8), este valor es similar al SARS-CoV y la influenza pandémica, sugiriendo el potencial de trasmisión sostenida de humano a humano y la posibilidad de una pandemia global.7 Como será discutido en la sección “Prevención”, R0 es el reflejo tanto de la virulencia del virus como del comportamiento humano, por lo que con las adecuadas intervenciones sociales y de comportamiento, este valor R0 puede ser reducido.
Con solo pocos meses del primer caso, la mortalidad total por SARS-CoV-2 ya ha excedido ampliamente al MERS-CoV y SARS-CoV-1 combinados. Se cree que la mortalidad real es menor al reporte de letalidad por casos, debido a sesgos de selección, ya que solo aquellos con sintomatología lo suficientemente severa para ser evaluados en servicios de emergencias y/o que requieren hospitalización están siendo sometidos a pruebas diagnósticas para COVID-19.8 Los datos provenientes del crucero Diamond Princess nos ofrecen una muestra única de la mortalidad y sintomatología de esta enfermedad, dado que todas las personas a bordo fueron sometidas a pruebas diagnósticas para COVID-19, más allá de los síntomas. Basados en esta información no publicada, análisis de la Facultad de Higiene y Medicina Tropical de Londres han estimado una mortalidad ajustada por edad del 0,5%; esto todavía mostraría una mortalidad mayor que la Influenza pandémica, manteniendo un perfil infeccioso similar.9 Además, de acuerdo con el Ministerio de Salud, Trabajo y Bienestar de Japón, 327 de las 697 personas a bordo del barco con resultado positivo para COVID-19 nunca presentaron síntomas, incluso un mes después de la prueba.10
Tenemos la suerte de proporcionar una perspectiva en primera persona acerca de la crisis por COVID-19 en Italia, que comenzó unas semanas después del primer caso reportado en el Estado de Washington (21 de Enero), y lo que los epidemiólogos estiman que está 2 o 3 semanas adelantado del brote en el área metropolitana de Nueva York. El Dr. Andrea Duca es un Médico especialista en Emergencias y miembro del Consejo Editorial de Emergency Medicine Practice con sede en el Norte de Italia, el área que soportó el peso inicial del brote de COVID-19. Él informa que la rápida diseminación inicial de SARS-CoV-2 sobrepasó a la mayoría de los hospitales, los cuales no estaban preparados para lidiar con un influjo súbito de pacientes que requieren soporte ventilatorio. Al 18 de Marzo de 2020, Italia tiene una letalidad del 8,37%, lo que debe servir como una alarma para otros sistemas de salud alrededor del mundo que se están preparando para tratar pacientes con infección severa por COVID-19 en las próximas semanas. En la Tabla 1 se puede ver el resúmen del Dr Andrea Duca de las lecciones aprendidas sobre el manejo del brote epidémico de SARS-CoV-2 en su Departamento de Emergencias (DE) en Bérgamo, Italia. Datos adicionales de ese hospital se incluyen en las Figuras 1, 2, 3 y 4. La Figura 1 muestra una línea de tiempo de los casos de COVID-19 en la región de Lombardía, desde el 20 de Febrero al 17 de Marzo de 2020; la Figura 2 muestra el porcentaje de ingresos y altas del censo diario de pacientes con COVID-19, del 29 de Febrero al 10 de Marzo de 2020; la Figura 3 presenta el total de admisiones y egresos del censo diario de pacientes con COVID-19; la Figura 4 muestra día a día el destino de los pacientes con COVID-19, del 29 de Febrero al 10 de Marzo de 2020.
Los Coronavirus pertenecen al orden de los Nidovirales, la familia Coronaviridae, y subfamilia Orthocoronavirinae. Son virus envueltos con ARN positivo de simple cadena, y poseen el genoma de mayor tamaño dentro de todos los virus ARN. Dos tercios del genoma de los Coronavirus en el extremo 5’ terminal codifican proteínas virales involucradas en la transcripción viral y replicación, mientras que el tercio restante en el extremo 3’ terminal codifica proteínas estructurales y proteínas accesorias específicas de cada grupo.4 El conocimiento actual resalta 4 proteínas principales en los coronavirus: S (spike), E (envoltura), M (membrana), y N (nucleocápside). Estos biomarcadores juegan un rol fundamental no solamente en el diagnóstico de la enfermedad, sino también en cómo entendemos el perfil patogénico, y finalmente acerca de las opciones para una vacuna y/o tratamiento antiviral directamente dirigido a interrumpir el ciclo vital del virus. (Ver Figura 5).
Se cree que ambos virus SARS-CoV-1 y MERS-CoV son producto de la transmisión zoonótica desde la población de murciélagos.11 Nombrar al virus causante de la actual pandemia “SARS-CoV-2” es debido a su similitud genética con el virus causante de la epidemia en 2003, ahora conocido como “SARS-CoV-1”. Mientras que probablemente los Coronavirus han evolucionado a los largo de miles de años, permaneciendo confinados a poblaciones de murciélagos; huéspedes mamíferos intermediarios, (como civetas en el caso de SARS-CoV, y camellos dromedarios en el caso de MERS-CoV), han sido implicados y probablemente cumplan un rol en la transmisión final de Coronavirus a los humanos.12,13 Se sospecha que el brote de COVID-19 ha sido originado en el Mercado Mayorista de Mariscos Huanan, en la ciudad de Wuhan; sin embargo, otros investigadores sugieren que esté podría no haber sido la fuente original de transmisión a humanos.2,14 Los murciélagos raramente se comercializan en los mercados en China, pero son cazados y vendidos directamente a los restaurantes como alimento.15
Los Coronavirus infectan principalmente el tracto respiratorio superior y gastrointestinal de aves y mamíferos. La glicoproteína de superficie Spike (proteína-S) es un factor clave en la virulencia de los Coronavirus, ya que permite su adherencia a las células del huésped. Se ha demostrado que el MERS-CoV se adhiere a la dipeptidil-peptidasa 4 (DPP4), una proteína muy conservada a través de las especies. Mientras que la mayoría de los virus respiratorios afectan células ciliadas, el receptor DPP4 se expresa exclusivamente en células no ciliadas de la vía respiratoria del humano, por lo que se cree que es un importante factor de transmisión zoonótica y alta letalidad.16 En el caso de SARS-CoV-1, la enzima convertidora de angiotensina 2 (ECA2) es el principal receptor celular al cual estos virus se adhieren, por lo que se cree que juegan un rol en la habilidad de SARS-CoV-1 en producir infecciones respiratorias tanto altas como bajas, contribuyendo a su infectividad y letalidad.17
Estudios previos sugieren que la inmunopatogenia, también llamada “tormenta de citoquinas”, se relaciona con el deterioro de los pacientes en distintas enfermedades infecciosas, incluyendo SARS-CoV-1 y la gripe aviar.18,19 Varios estudios en la actualidad están investigando la posibilidad de que el deterioro de los pacientes infectados por COVID-19 sea producido por inmunopatogénesis, en donde la liberación de marcadores inflamatorios inicia un ciclo de retroalimentación positiva que conduce al distress respiratorio, la falla multiorgánica, y la muerte.20 Un cohorte de 41 casos confirmados por laboratorio de COVID-19 en China encontró que los pacientes en UTI tenían valores significativamente más altos de marcadores inflamatorios (IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1 y TNF-alfa).21 Un estudio reciente realizado en China provee un informe detallado de la inmunopatología del SARS-CoV-2, sugiriendo que los pacientes con infecciones severas por COVID-19 expresan una “... excesiva activación de la respuesta inmune… llevada a cabo por células Th1 patogénicas y monocitos inflamatorios,” hallazgos que son apoyados por el análisis inmunohistoquímico en biopsias pulmonares postmortem de pacientes COVID-19.22,23 Un creciente volumen de bibliografía sugiere la presencia de linfohistiocitosis hemofagocítica (HLH) secundaria, o inducida por el virus. Este síndrome hiper inflamatorio, sería la causa subyacente del deterioro de los pacientes, ya que el proceso de esta enfermedad muestra un patrón similar de citoquinas que en los pacientes con COVID-19, e incluye características clínicas cardinales como fiebre que no remite, citopenias, hiperferritinemia, y compromiso pulmonar. 24,25 Terapias inmunomoduladores están siendo consideradas para el tratamiento del COVID-19, y serán discutidas en la sección “Abordaje Terapéutico”.
SARS-CoV-2 ingresa a los neumonocitos tipo 2 en humanos a través del mismo receptor de ECA2 que SARS-CoV-1.26 Un estudio multicéntrico, retrospectivo, de cohortes, que estudió el riesgo de muerte intrahospitalaria, encontró que la hipertensión es la comorbilidad más frecuente en pacientes con COVID-19 que requieren admisión (30%), seguido de diabetes (19%).27
Mucho se ha dicho en las últimas semanas de la potencial conexión entre los antihipertensivos comúnmente usados, IECAs y ARA2, y un aumento del riesgo de infección severa por COVID-19, basados en la unión del SARS-CoV-2 al receptor de ECA2. Al momento, la recomendación colectiva de la Sociedad Europea de Cardiología, el Colegio Americano de Cardiología, la Sociedad Americana de Insuficiencia Cardíaca, y la Sociedad de Insuficiencia Cardíaca de América, es que los pacientes en tratamiento con IECAs y ARA2 deben continuar con su tratamiento. La Sociedad Europea de Cardiología declaró que “no hay evidencia clínica ni científica que sugiera que el tratamiento con IECAs o ARA2 deba ser discontinuado debido a la infección por COVID-19,”28 y la declaración conjunta de HFSA/ACC/AHA es que “no hay evidencia experimental o clínica que demuestre resultados favorables o perjudiciales en los pacientes con COVID-19 que utilizan IECAs o ARA2”.29
Preocupaciones similares acerca del uso de antiinflamatorios no esteroideos (AINES), como el ibuprofeno, ya que se postulan distintas interacciones entre el SARS-CoV-2 y la unión a los receptores de ECA2. Actualmente no hay evidencia científica que sugiera que la utilización de AINES empeore el curso del COVID-19. Se requieren estudios prospectivos multicéntricos para investigar más a fondo este asunto. Una discusión teórica acerca de los posibles beneficios o daños de estas medicaciones puede seguirse en "nephjc".
Mucho hemos aprendido a partir del cambio en la dinámica de transmisión luego de la implementación de estrictas restricciones de viajes y a las medidas de cuarentena en China continental. Un modelo matemático publicado en The Lancet, estima que la mediana del número básico de reproducción diario (Rt) en Wuhan declinó de 2,35 (95% intervalo de confianza CI 1.15-4.77) 1 semana antes de las restricciones a los viajes el 23 de Enero de 2020, a 1,05 (0.41-2.39) 1 semana después.30 La efectividades de las medidas gubernamentales e intervenciones sociales que han sido documentadas por análisis basados en datos, y debería instar a todos los gobiernos a actuar en consecuencia para priorizar la detección precoz, el aislamiento y el tratamiento; asegurar los suministros médicos adecuados; y establecer un sistema en el cual los pacientes sean internados en los hospitales designados con una estrategia terapéutica exhaustiva.30,31 Utilizando un modelo estocástico de transmisión parametrizado a la epidemia de COVID-19, Hellewell et al. concluyeron que “un rastreo altamente efectivo de contactos y aislamiento de casos es suficiente para controlar un nuevo brote de COVID-19 dentro de los 3 meses.”32
Un estudio publicado el 16 de Marzo de 2020 por el Imperial College of London y la OMS, compara 2 estrategias fundamentales para reducir la velocidad de diseminación del SARS-CoV-2: “(a) Mitigación, que se enfoca en disminuir, pero no necesariamente detener la diseminación epidémica - disminuyendo el pico de demanda al sistema de salud, protegiendo a aquellos con mayor riesgo de enfermedad severa, y (b) Supresión, en el cual se intenta revertir el crecimiento epidémico, reduciendo el número de casos a niveles bajos y manteniendo esta situación en forma indefinida.” El estudio encontró que “... políticas óptimas de Mitigación (combinando aislamiento domiciliario de los casos sospechosos, cuarentena domiciliaria de aquellos viviendo en la misma propiedad que los casos sospechosos, y distanciamiento social de los ancianos y personas con riesgo de enfermedad severa) puede reducir el pico de demanda de atención médica en dos tercios y las muertes a la mitad. Sin embargo, la resultante epidemia mitigada seguiría produciendo cientos de miles de muertes y los sistemas de salud (particularmente unidades de cuidados intensivos) resultarían saturados ampliamente”.35 Esto explica y brinda apoyo a las medidas agresivas tomadas recientemente por ciertos países para combatir la diseminación de la pandemia por SARS-CoV-2.
Los reportes de Italia sugieren que hasta un 20% de los profesionales de la salud lidiando con el COVID-19 resultaron infectados por el virus, y algunos fueron reportados muertos.34 Perder trabajadores de la salud debido a enfermedad en el momento en que son más necesitados puede ser el punto de inflexión para sistemas de salud que ya han sido llevados hasta el punto de quiebre debido al gran volumen de pacientes. El reconocimiento de la crisis en Italia subraya la importancia de fortalecer las estrictas medidas preventivas para todos los profesionales de la salud. Esto ha sido logrado en algunos sistemas de salud al asignar una persona que controle permanentemente la adherencia a las medidas en el Departamento de Emergencia.
Basado en las especificaciones del modo de transmisión de los Coronavirus como clase, y los patrones de transmisión documentados en las epidemias de SARS-CoV-1 y MERS-CoV, la transmisión de SARS-CoV-2 se presume que es principalmente a través de gotas y fomites, aunque también se han encontrado partículas virales en la materia fecal de pacientes seropositivos. Un artículo preimpreso publicado en The New England Journal of Medicine por investigadores del Instituto Nacional de Salud de los Estados Unidos, la Universidad Princeton, y la Universidad de Los Angeles California, estimó la vida media del virus SARS-CoV-2 en distintas superficies: 1,1 horas en aerosoles, 0,77 horas en cobre, 3,46 horas en cartón, 5,46 horas en acero, y 6,81 horas en plástico. Estos resultados indican la posible transmisión a través de aerosoles y fomites del SARS-CoV-2, brindan credibilidad al alto rango de diseminación reportado.35
Tanto la OMS como las guías del CDC hacen similar énfasis en la importancia de la estricta higiene de manos para restringir la transmisión del SARS-CoV-2. Esto proviene de la incertidumbre acerca de los vectores de transmisión a bordo del crucero Diamond Princess, en cuarentena en las costas de Japón, así como los informes crecientes alrededor del mundo del contagio de COVID-19 a personas que no han tenido contacto directo con casos sospechosos o conocidos, ni han viajado a zonas endémicas.36,37 Dados los reportes del CDC de China que informan haber hallado SARS-CoV-2 virus en las heces de pacientes seropositivos, la posibilidad de la transmisión fecal-oral y, por lo tanto, la transmisión a través de las manos es muy alta.38 Los profesionales de la salud y los pacientes deben seguir técnicas estándar de lavado de manos: lavar manos con agua y jabón durante por lo menos 20 segundos, especialmente luego de ir al baño; antes y después de comer; luego de sonarse la nariz, toser, o estornudar. Si no hay disponibilidad de agua y jabón, se puede utilizar desinfectante para manos con al menos 60% de alcohol.5
Pautas adicionales para aquellos con contacto cercano y sospecha de exposición incluyen “fuertes recomendaciones” para la atención médica inmediata, período de observación de 14 días, usar barbijo / mascarilla si se presenta tos o síntomas de infección del tracto respiratorio superior, priorizar el transporte privado sobre el público, notificar con anticipación previo a la llegada del paciente al centro de atención, higienizar el vehículo de transporte con desinfectante que contenga al menos 500 mg/L de cloro, con ventilación abierta.39 El período de incubación puede ser modificado pronto, debido a recientes reportes y estudios que sugieren un período de incubación de entre 0 a 24 días.40,41
Dado al reciente faltante de mascarillas/ barbijos N95 y otros EPP, se recomienda seguir las sucesivas recomendaciones para tener en cuenta la disponibilidad cambiante de los suministros necesarios. Esto puede y deber ser seguido en tiempo real, usando los links provistos en la Tabla 3. Adicionalmente, recientes consideraciones incluyen recomendaciones para designar unidades completas dentro de los centros de atención, con personal de salud dedicado al cuidado de los casos confirmados o sospechosos de COVID-19, con la necesidad de contar con habitaciones con aislamiento respiratorio.2
Quitarse el Equipo de Protección Personal (EPP) es a menudo el procedimiento de mayor riesgo durante la interacción médico-paciente, en términos de diseminación del COVID-19. A continuación se muestra un sencillo ejemplo, creado por Médicos de Emergencias de EMCrit acerca de como quitarse adecuadamente el EPP luego de evaluar un caso sospechoso o confirmado de COVID-19.42 (Ver Tabla 2.)
Un video con este procedimiento está disponible en youtube aquí
La experiencia de Bergamo, en la región de Lombardía en el Norte de Italia, provee un modelo de respuesta que puede ayudar a otros Sistemas de Salud a prepararse. Los DEs fueron expuestos a un volumen abrumador de pacientes con distress respiratorio severo en un corto período de tiempo. Fueron requeridos ajustes drásticos a la circulación de pacientes y a la eficiencia en el trabajo, un resumen de esos cambios y recomendaciones se muestran en la Tabla 1. Muchos de estos datos son estimados y de carácter preliminar.
El personal del DE debe mantener un alto índice de sospecha al evaluar a estos pacientes, especialmente aquellos con fiebre, tos, disnea, o signos de cualquier enfermedad respiratoria. Inicialmente el CDC enfocó las advertencias de viajes y riesgo epidemiológico a aquellos que recientemente viajaron, o tuvieron contacto con un viajero de la ciudad de Wuhan,provincia de Hubei, China; sin embargo, habiendo alcanzado la condición de pandemia, y la demostración de transmisión local, la conexión con China ya no es relevante como criterio para descartar la infección por SARS-CoV-2.
A fines de Enero de 2020, fueron publicados en The Lancet los primeros datos detallando las características clínicas, curso y pronóstico de la infección por SARS-CoV-2, comparada con las dos epidemias previas por Coronavirus (MERS-CoV y SARS-CoV-1).21,43 A continuación, un análisis multicéntrico retrospectivo de cohorte de 1.009 pacientes fue publicado en The New England Journal of Medicine, y permite vislumbrar en forma actualizada las características demográficas y clínicas del COVID-19.41 La tabla 3 permite diferenciar la sintomatología entre pacientes con enfermedad severa vs. no severa, definida por las guías de la Sociedad Americana de Tórax para neumonía adquirida en la comunidad.44 Los pacientes con enfermedad severa eran más ancianos que aquellos con enfermedad no severa con una media de 7 años, y tenían tasas más altas de comorbilidades, como hipertensión (23.7% vs 13.4%, respectivamente) y diabetes (16.2% vs 5.7%, respectivamente). Esta tabla y artículo pueden ser visualizados en forma completa en The New England Journal of Medicine. La Tabla 3 muestra un resúmen de las características iniciales del SARS-CoV-2 comparado con MERS-CoV y SARS-CoV-1.
El 18 de Marzo de 2020, el American Journal of Gastroenterology publicó un nuevo estudio del Grupo de Expertos en Tratamiento Médico de COVID-19 de Wuhan China, mostrando que los síntomas gastrointestinales (GI) como diarrea, son comunes en la infección por SARS-CoV-2.46 de 204 pacientes confirmados, 99 (48,5%) tuvieron síntomas GI, y 7 pacientes con síntomas GI no tuvieron ningún síntoma respiratorio. Esto es claramente algo distintivo a la enfermedad puramente respiratoria que las guías actuales han mostrado, pero es consistente con el patrón de transmisión fecal-oral observado en los estudios de China previamente citados. Además, el pronóstico de los pacientes con síntomas digestivos fue peor que aquellos con síntomas puramente respiratorios. Se encontró que los pacientes sin síntomas digestivo eran más propensos a curarse e irse de alta que los pacientes con síntomas digestivos asociados (60% vs 34,3%). Los autores no lograron comprobar la etiología que explique la diferencia entre la mortalidad y morbilidad en los pacientes con COVID-19 con síntomas respiratorios vs GI, y enfatizan que se requieren más estudios.46
Cabe notar, que en los datos oficiales de Bergamo, Italia, reportados por el Dr Andrea Duca, muestran una relación entre la obesidad y la severidad de la enfermedad y la necesidad de intubación y cuidados intensivos. De esta misma muestra, el porcentaje de pacientes con requerimiento de VNI o intubación en el DE fue similar a los datos de Wu et al,45 siendo hasta el 31% de los pacientes ingresados al hospital con sospecha de COVID-19. Es todavía muy temprano para saber cuántos de los pacientes que iniciaron VNI en el DE requerirán ventilación invasiva durante la hospitalización, y cuántos de los pacientes con oxígeno requerirán asistencia ventilatoria mecánica debido a su deterioro clínico. Esta información todavía está siendo recolectada y analizada, y pronto estará disponible para su publicación.
Dentro del primer mes de los reportes iniciales del brote de SARS-CoV-2, el CDC desarrolló una prueba de reacción en cadena de polimerasa de transcripción inversa en tiempo real (rRT-PCR) para el diagnóstico de SARS-CoV-2. Mientras que en los Estados Unidos esta prueba solamente estaba disponible a través del CDC, ahora está siendo disponible a nivel estatal a través del Recurso Internacional de Reactivos (IRR). El IRR fue establecido inicialmente por el CDC para el estudio y detección de Influenza, pero se ha expandido para incluir las nuevas cepas de Influenza y Coronavirus.47,48 Cabe destacar que los paneles virales ampliamente distribuidos solamente diagnóstican los Coronavirus humanos previamentes conocidos 229E, NL63, y HKU1.49 Las cepas SARS-CoV-1, MERS-CoV, y el SARS-CoV-2 requieren pruebas especializadas que están teniendo cada vez mayor disponibilidad. Lamentablemente, los esfuerzos iniciales para proveer pruebas diagnósticas en Estados Unidos se vieron obstaculizados por fallas en los equipos (kits) iniciales (debido a problemas con el reactivo), y hubo falta en la disponibilidad del en la mayoría del país debido a esto. La Tabla 4 resume las recomendaciones actuales acerca la administración de pruebas diagnósticas para SARS-CoV-2.
Esto se ha vuelto un punto controvertido a medida que la epidemia continúa en los Estados Unidos. Hay una pequeña desviación de las guías previas que indicaban testear a cualquier persona, incluyendo personal de salud, que haya tenido contacto con paciente sospechoso o confirmado de COVID-19, o que hayan viajado a zona endémica dentro de los últimos 14 días. Al momento de esta publicación, la recomendación es no testear al personal de salud que se encuentre asintomático que hayan tenido un contacto conocido, ni a otros individuos asintomáticos con exposiciones probables y/o historia de viaje. Al momento no está claro si estas recomendaciones volverán a cambiar.
Hay factores epidemiológicos que pueden guiar a la decisión de testear SARS-CoV-2. La presencia de COVID-19 a nivel local con transmisión comunitaria documentada puede ayudar a establecer el riesgo epidemiológico y guiar la toma de decisiones. Sin embargo, la inhabilidad de suplir la demanda de testeo de muchos hospitales ha llevado a dar marcha atrás con esta recomendación. Dada la preocupación creciente acerca de la disponibilidad y confiabilidad de la prueba para SARS-CoV-2, existen una amplia variedad de recomendaciones a nivel federal, estatal y local. Sin embargo, cuando los médicos decidan testear, deben recordar que basados en la experiencia de China (así como la reportada por el Dr Duca en Italia), se requieren dos pruebas negativas separadas por 24 hs (3 días en Italia), para descartar el diagnóstico de COVID-19.51
En el inicio del brote de SARS-CoV-2 en Estados unidos, muchos médicos fueron incitados a realizar pruebas de otros patógenos respiratorios (ej. Influenza), basado en recomendaciones de los servicios de enfermedades infecciosas y prevención de enfermedades. Sin embargo, se encuentra en debate la prueba y evaluación de COVID-19 en relación a coinfección por otros virus.
Luego de una exhaustiva búsqueda de bibliografía, entrevistas con varios especialistas en Enfermedades Infecciosas, consultas en diferentes foros a nivel nacional e internacional dedicados tanto a la Medicina de Emergencias como al COVID-19, solo pudimos encontrar un solo estudio Chino, no revisado por pares, con 8.274 especímenes recolectados y analizados para SARS-CoV-2 y otras especies virales. (El editor declara que, “Este es un artículo preimpreso y no ha sido revisado por pares. Muestra investigación médica que todavía no ha sido evaluada y no debería usarse para guiar la práctica clínica.”) En este estudio, encontraron que 5,8% de los pacientes con COVID-19 presentaban además otras coinfecciones virales, y que el 18,4% de infecciones virales distintas a COVID-19 presentaron también otros co-infectantes.52 Los autores reconocen la poca fidelidad de estas pruebas tanto para SARS-CoV-2 como para otros virus, lo cual puede subdiagnosticar el porcentaje real de coinfección. Además, en muestras preliminares reportadas por los científicos de Stanford Medicine Data, que se encuentran disponibles de libre acceso online a través del departamento de Salud Pública de California, encontraron que de 49 resultados positivos para SARS-CoV-2, 11 (22,4%) presentaban además coinfección con otros virus.53 Prevemos que un gran estudio validado ayudará a develar el ritmo de co-infección con SARS-CoV-2. Mientras tanto, recomendamos que los médicos mantengan un alto índice de sospecha de COVID-19, más allá de la presencia de otros virus.
Dada esta información, los médicos de emergencias deben transmitir en forma enfática al público general lo que ya sabemos de las infecciones respiratorias virales: que acudir al hospital ante la presencia de síntomas leves, fiebre, diarrea leve, o tos aislada, probablemente acarree un riesgo alto, tanto para sí mismo como para los pacientes vulnerables a su alrededor. Los pacientes que experimenten síntomas severos como dificultad para respirar, fiebre alta (>39°C), o intolerancia a la vía oral deben solicitar evaluación en forma urgente. Aquellos pacientes preocupados acerca de sus síntomas, o el riesgo de diseminación a sus familiares vulnerables, el cuidado debería enfocarse en practicar el distanciamiento social, la auto-cuarentena, la utilización de sistemas de telemedicina, y la utilización de clínicas de atención y testeo rápido, minimizando el riesgo de diseminación de la infección. Aunque se encuentre más allá del alcance de este artículo, es necesario continuar con discusiones que pongan en peso la necesidad de mantener el cuidado de los pacientes y a la vez la necesidad de minimizar la diseminación originada en los trabajadores de salud asintomáticos.
De acuerdo con la Tabla 1 en un artículo recientemente publicado en The Lancet, análisis univariados de las siguientes características de los pacientes y marcadores de laboratorio se asociaron a mayor mortalidad: edad avanzada, linfopenia, leucocitosis, elevación de ALT, LDH, Troponina I de alta sensibilidad, CPK, Dímero-D, ferritina sérica, Il-6, Tiempo de protrombina, creatinina y procalcitonina. 29 Modelos de regresión multivariada mostraron aumento de la mortalidad hospitalaria asociado con la edad (odds ratio [OR]. 1,10; intervalo de confianza [CI], 1,03-1,17, por año de incremento; P= 0,0043), falla orgánica determinada por puntaje de SOFA (5,65, 2,61-12,23; P<0,0001), y dímero-D mayor a 1µg/mL (18,42, 2,64-128,55: P= 0,0033) al ingreso.27 Esta tabla resume estos hallazgos y puede ser visualizada en The Lancet.
Un metaanálisis recientemente publicado, acerca de procalcitonina en pacientes con COVID-19, sugiere que los niveles de procalcitonina deberían permanecer dentro del rango de referencia en los pacientes con infección por SARS-CoV-2 no complicada, y que la elevación de procalcitonina puede reflejar la coinfección bacteriana en pacientes que desarrollan una severa forma de enfermedad por COVID-19.54 Un meta-análisis acerca del recuento de plaquetas en pacientes COVID-19, encontró que la trombocitopenia se asocia a un mayor riesgo de enfermedad severa, y que un descenso sustancial en el recuento de plaquetas debería servir como indicador de empeoramiento en los pacientes hospitalizados por COVID-19.55 Ver Tabla 5 para una correlación entre marcadores de laboratorio, severidad y manejo clínico para pacientes con neumonía por COVID-19.
Datos recientes publicados por el CDC el 17 de Marzo de 2020 muestran una tendencia llamativa en los porcentajes de hospitalización en poblaciones más jóvenes. La tabla 6 muestra los últimos porcentajes de internación, con hasta un 20% de hospitalización en individuos de 20 a 44 años, lo cual resulta alarmante. Las buenas noticias para la población pediátrica es que no se han registrados muertes en los Estados Unidos hasta el momento de esta publicación. (Ver apartado “Población Pediátrica”.)
Los hallazgos en las imágenes de tórax de COVID-19 han sido similares a los hallazgos vistos en años previos en epidemias de SARS-CoV-1 y MERS-CoV. Un análisis de un cohorte de 41 pacientes con infección por COVID-19 encontró compromiso pulmonar bilateral en 40 de los pacientes.21,59 Un estudio utilizando Tomografía Computada (TC) de 21 pacientes con infección por COVID-19 mostró 12 (57%) solo con opacidades en vidrio esmerilado; 6 (29%) con opacidades en vidrio esmerilado y consolidación al ingreso, y curiosamente 3 (14%) con CT normal al momento del diagnóstico. 15 pacientes (71%) tenían compromiso de dos o más lóbulos, y 16 (76%) mostraban enfermedad bilateral.60 De los 18 pacientes con hallazgos positivos en tomografía de tórax, todos tenían infiltrados en vidrio esmerilado, con 12 de los 18 presentando además consolidación lobar.60
Datos de 101 casos de neumonía por COVID-19 analizados retrospectivamente en 4 instituciones en Hunan, China, encontraron que las lesiones presentes en TC de tórax presentaban más frecuentemente una distribución periférica (87,1%), compromiso bilateral (82,2%), predominio en campos inferiores (54,5%), y compromiso multifocal (54,5%).61 Estos hallazgos, especialmente la disposición periférica de las lesiones, refleja la capacidad de la ecografía en detectar la neumonía por COVID-19.
Dada la diseminación nosocomial del virus, la cantidad de recursos necesarios para obtener una TC en estos pacientes, y el riesgo de transportar pacientes inestables e hipoxémicos, no se recomienda la realización de TC en forma rutinaria en pacientes con COVID-19, ya que raramente modifica el manejo. El Colegio Americano de Radiología apoya el uso limitado de la TC, reservándose para pacientes sintomáticos hospitalizados, quienes puedan sufrir otras patologías y deban ser evaluadas.62 La Figura 6 muestra un esquema diagnóstico para pacientes con sospecha de neumonía por COVID-19.
Literatura reciente así como la experiencia Italiana apoya el uso del Ultrasonido como una forma de examinar a los pacientes con sospecha de neumonía por COVID-19. Para la evaluación de neumonía o distress respiratorio del adulto (SDRA), la Ecografía Pulmonar muestra resultados similares a la TC de tórax y superiores a la radiografía (Rx) de tórax tradicional, con la ventaja adicional de su disponibilidad en el sitio de cuidado del paciente, posibilidad de repetirse, ausencia de radiación, y bajo costo.63 La Tabla 7 detalla los hallazgo en Ecografía Pulmonar y su correlato con la TC de tórax, con presencia de hallazgos principalmente en los campos posteriores.64 En Italia ha demostrado ser una herramienta de screening muy útil. (Ver Tabla 1.)
Con la progresión de la enfermedad, se puede ver una secuencia de cambios ecográficos64 (Ver Figura 7.)
En el siguiente link de Youtube se puede ver el video de un paciente con Neumonía por COVID-19 [Courtesía de Giovanni Volpicelli, MD]
Aquellos profesionales de la Salud que quieran recibir entrenamientos en los cambios característicos del parénquima pulmonar en los pacientes con COVID-19 pueden acudir a un artículo recientemente publicado por Huang et al, en cual contiene múltiples ejemplos de US correlacionados con hallazgos de TC de alta resolución.65 Esté artículos y las imágenes se encuentran en Research Square
El artículo, “A Rapid Advice Guideline for the Diagnosis and Treatment of 2019 Novel Coronavirus (2019-nCoV)-Infected Pneumonia (standard version),” publicado en el journal of Military Medical Research, provee guías rápidas de diagnóstico y varias imágenes de distintos casos.39 La Figura 8 muestra una Radiografía de Tórax (RxTx) y TC de Tórax típicas de un paciente con COVID-19.
El artículo, “Evolution of CT Manifestations in a Patient Recovered from 2019 Novel Coronavirus (2019-nCoV) Pneumonia in Wuhan, China,” publicado en el journal Radiology, publicó las imágenes de la evolución de un paciente de 42 años con infección por COVID-19 que se recuperó luego de 31 días.67
Al momento no existe tratamiento aprobado para el tratamiento específico de ninguna cepa de Coronavirus. En un estudio reciente de JAMA muchos pacientes con neumonía confirmada por COVID-19 recibieron tratamiento antibiótico de amplio espectro (moxifloxacina, 89 [64,4%]; ceftriaxona, 34 [24,6%]; azitromicina, 25 [18,1%]), y la mayoría recibió tratamiento para la Influenza [oseltamivir, 124 [89.9%]), algunos recibieron en forma adicional corticoides (glucocorticoides, 62 [44,9%]).2 Dada la naturaleza evolutiva de esta pandemia, es útil para los médicos buscar orientación en las guías que naciones, o sistemas de salud que hayan implementado protocolos de manejo y tratamientos aprobados. Una de estas guías de Bélgica, titulada “Guía Clínica Provisoria para casos Sospechosos/Confirmados de Covid-19 en Bélgica”. Recomendaciones de la Sociedad Italiana de Infecciones y Enfermedades Tropicales pueden encontrarse aquí (publicadas en italiano)
Para un ejemplo adicional,ver la Figura 9, del protocolo de tratamiento para COVID-19 del Boston Medical Center’s COVID-19.
Considerando la falta de evidencia directa respecto al tratamiento del COVID-19, las guías recientemente propuestas se basan en gran medida sobre las guías de tratamiento de las infecciones por SARS-CoV-1, MERS-CoV, e Influenza. Actualmente, hay recomendaciones débiles para el uso de interferón alfa inhalado dos veces al día, y lopinavir/ritonavir en forma oral dos veces al día; sin embargo, la evidencia que apoya esta indicación, para disminuir la mortalidad por SDRA en pacientes con SARS-CoV-1 y MERS-Cov, se limita a series y reportes de casos.39 Una reciente revisión sistemática mostró que el efecto anti coronavirus de lopinavir/ritonavir fue visto principalmente con el uso precoz, y no se demostró efecto significativo con el uso tardío de esta tapia.67 Un estudio randomizado controlado recientemente publicado en The New England Journal of Medicine con 199 pacientes hospitalizados con COVID-19 no encontró beneficio en mortalidad o tiempo de mejoría clínica con el tratamiento con lopinavir/ritonavir. Se notaron tendencias positivas en resultados no primarios, como complicaciones de falla renal aguda, infecciones severas, requerimiento de ventilación mecánica no invasiva o invasiva; sin embargo, el estudio finalizó el reclutamiento debido a que otro estudio que utiliza remdesivir entró en vigencia.68 Al momento, el uso de terapia combinada para el tratamiento de COVID-19 con antivirales es controversial, ya que no existen estudios controlados randomizados que apoyen su uso.69,70
Recientemente se ha reconocido a la droga Remdesivir como una terapia antiviral prometedora contra un amplio espectro de virus ARN, incluyendo SARS-CoV-1 y MERS-CoV tanto en modelos in vitro como en primates no humanos.71 Estudios recientes in vitro, encontraron que remdesivir y cloroquina inhiben la replicación viral de SARS-CoV-2 con concentraciones micromolares bajas y un alto índice de selectividad.72 Hay ensayos clínicos en curso, en varios países, evaluando la eficacia de remdesivir, aunque hasta el momento esta droga no se encuentra disponible comercialmente, y sólo está aprobada para uso compasivo en casos severos de COVID-19.
Un estudio de control abierto no randomizado reciente, comparó el tratamiento con favipiravir e interferón alfa (grupo tratamiento) vs. lopinavir/ritonavir e interferón alfa (grupo control), encontró una diferencia significativa en el tiempo de aclaramiento viral (mediana 4 versus 11 días, P < 0,001) y una tasa de mejoría de tomografía computarizada (TC) de tórax al día 14 (91,4% a 62,2%, P = 0,004); se destaca que pacientes críticamente enfermos fueron excluídos de este estudio.73
En una revisión sistemática en la literatura China, acerca del tratamiento para SARS-CoV-1, se identificaron 14 estudios en los cuales fueron usados corticoides. Doce estudios fueron inconcluyentes, y 2 mostraron daño potencial. Un estudio reportó diabetes secundaria al tratamiento con metilprednisolona.74 Otro estudio retrospectivo no controlado de 40 pacientes con SARS reportó necrosis avascular y osteoporosis dentro del grupo de pacientes tratados con corticoides.59 Un ensayo clínico controlado, randomizado, doble ciego, contra placebo, midió la carga viral a través del tiempo desde el inicio del cuadro febril, y demostró que el uso de corticoides dentro de la primer semana de enfermedad se asocia a un retraso en la disminución de la carga viral.75
Sin embargo, un estudio reciente realizado en China, evaluó los factores de riesgo para el desarrollo de SDRA en pacientes infectados por COVID-19, y encontró que el tratamiento con metilprednisolona disminuye el riesgo de muerte en el grupo de pacientes con SDRA (Hazard ratio 0,38; 95% IC, 0,20-0,72).45 Esta información apoya la teoría de que el deterioro de los pacientes con COVID-19 pueda ocurrir secundario a la inmunopatogenia y el desarrollo de la tormenta de citoquinas, la cual puede reducirse con la administración de corticoides en pacientes con SDRA severo.
La tormenta de citoquinas está siendo examinada como la culpable del rápido deterioro de los pacientes con COVID-19 que ocurre algunos días o semanas luego de la infección inicial por SARS-CoV-2. Esto plantea la posibilidad de utilizar terapia antiinflamatoria, como bloqueantes de receptores celulares, y terapia con células madres como potenciales agentes terapéuticos. Ensayos clínicos multicéntricos están investigando el uso de tocilizumab (bloqeuantes del receptor de IL-6) en el tratamiento de neumonía por COVID-19.20 Una lista descriptiva de las actuales investigaciones en agentes terapéuticos contra SARS-CoV-2 puede encontrarse en el Monthly Prescribing Reference.
Una considerable cantidad de publicaciones le han atribuído propiedades antivirales y efectos antiinflamatorios a la cloroquina; incluyendo la supresión de la IL-6, que se cree que cumple un rol significativo en la progresión de los pacientes con COVID-19 a SDRA severo.20,76 La cloroquina además a demostrado actuar como un efectivo antiviral en modelos animales infectados con Influenza aviar y SARS-CoV-1.77,78 Ciertos datos sin publicar de China, sugieren que la cloroquina ha sido estudiada para el tratamiento de COVID-19, con resultados favorables.79 El Departamento Provincial de Ciencia y Tecnología de Guangdong, y la Comisión Provincial de Salud de Guangdong, recientemente publicaron un consenso de expertos que recomienda el tratamiento de la neumonía secundaria a Novel Coronavirus con cloroquina 500 mg dos veces al día, vía oral, en pacientes sin contraindicaciones.80 Un estudio reciente publicado en Clinical Infectious Diseases, usando modelos fisiológicos basados en modelos farmacocinéticos, encontró un aumento de la potencia de hidroxicloroquina sobre cloroquina en tejido pulmonar (EC50 = 0,72 µM vs 5,47 µM, respectivamente). Este estudio recomienda un dosis de carga de 400 mg dos veces al día el primer día, seguido de una dosis de mantenimiento de 200 mg dos veces al día por 4 días.81 Estudios clínicos están en marcha para investigar formalmente el uso de estas dos medicaciones tanto como agentes terapéuticos y profilácticos contra COVID-19 en humanos.82 Un ensayo clínico no aleatorio reciente de 20 pacientes, encontró que el tratamiento con hidroxicloroquina se asocia a una reducción de la carga viral en pacientes con COVID-19, y este efecto es aumentado por la azitromicina. Usando hidroxicloroquina 600 mg por día, y azitromicina 500 mg el primer día seguido de 250 mg los siguientes 4 días.83 (Tenga en cuenta que el editor declara, “este artículo preimpreso no ha sido revisado por pares. Informa investigación médica que no ha sido evaluada todavía y por lo tanto no debería ser usado como guía clínica.”) Ensayos clínicos están siendo desarrollados para investigar formalmente el uso de estas medicaciones con fines terapéuticos y profilácticos contra COVID-19 en humanos.
Al momento no existen publicaciones significativas acerca del manejo, óptimo de fluidos en pacientes con COVID-19, tampoco publicaciones que describan el desarrollo en forma aguda de insuficiencia cardíaca congestiva secundaria al virus. Como se describió previamente, la principal teoría actualmente explica que la fisiopatología del rápido deterioro de los pacientes con SDRA severo (edema pulmonar no cardiogénico) secundario a COVID-19, es secundario a un estado hiperinflamatorio. Dado que esta no es una forma de shock distributivo o hipovolémico como se ve en el cuadro de sepsis bacteriana, y que la principal causa de muerte es el edema pulmonar, los autores recomiendan un abordaje juicioso de la resucitación con fluidos, evaluando caso por caso.
En aquellos pacientes que sufren deterioro clínico y requieren cuidados intensivos, se debe considerar la Ventilación mecánica No Invasiva, Invasiva, o el soporte vital extracorpóreo de ser necesario.39 El desarrollo de SDRA y la descompensación respiratoria cumple un rol principal en la patogénesis del COVID-19. En este sentido, los siguientes principios de tratamiento son claves en el manejo de pacientes con COVID-19:
Datos preliminares todavía no publicados del Dr Andrea Duca, Médico de Emergencias en Bergamo, Italia, muestran que del 29 de Febrero al 10 de Marzo de 2020, el porcentaje de pacientes que ingresó al DE con sospecha de infección por COVID-19 que requirió internación y oxigenoterapia aumentó un 138%. Dentro de esos pacientes internados, 31% continuaban hipóxicos a pesar de oxigenoterapia máxima y requirieron soporte ventilatorio en el DE (81% CPAP, 7% VNI, 12% Ventilación Invasiva), y el 82% presentó criterios de SDRA moderado a severo.
Datos desde China e Italia sugieren que los pacientes con COVID-19 que están hipoxémicos responden bien a PEEP, indicando un rol fundamental de la VNI como medida terapéutica y como recurso provisional para evitar la intubación.45 Las estadísticas de los estudios retrospectivos de China, indican que hasta un 30% de los pacientes internados requieren VNI,49 mientras que reportes precoces de Italia indican porcentajes cercanos al 31%.84 Dadas las tendencias epidemiológicas actuales, estos requerimiento probablemente sobrepasen la capacidad de la mayoría, cuando no de todos, los hospitales si no se toman masivas medidas de preparación. Basados en la información actual de China e Italia, recomendamos lo siguiente:
Las Figuras 10, 11 y 12 muestran dispositivos de VNI de una sola rama y Cascos de CPAP con filtros virales antes de la válvula de PEEP, y demostraciones de su uso
En aquellos pacientes que presentan dificultad respiratoria severo o que fallan a la prueba con VNI, se debe preparar la intubación endotraqueal para Ventilación Invasiva. Ver Tabla 8 para los pasos de la Secuencia de Intubación Rápida (SIR)
Actualmente existe controversia acerca del rol de la preoxigenación en la diseminación de partículas virales con la utilización de las técnicas clásicas. Una revisión de este tema se puede encontrar en EMcrit. Mientras tanto, las opciones comúnmente utilizadas son:
Para una breve sinopsis de las indicaciones, principios y diferentes tipo de ventilación invasiva, acceda a Hickey et al. Para paciente con COVID-19, se debe tener especial atención la sección de “Ventilación Protectiva Pulmonar”, basada en ARDSnet trials, que mostraron que en pacientes con SDRA la ventilación con bajo volumen corriente mejoran la mortalidad.85 Brevemente:
El volumen corriente (VC o Tidal Volume) debe colocarse inicialmente a 6ml/kg, basado en el peso ideal. A medida que los pacientes desarrollan lesión pulmonar aguda y progresan a SDRA, el compromiso pulmonar aumenta y desarrollan shunts, lo cual disminuye el volumen pulmonar funcional. El volumen corriente no debe ser ajsutado en base a los objetivos de ventimlación minuto. La frecuencia respiratoria debe ser ajustada a los objetivos de volumen minuto y el equilibrio ácido base del paciente. Una frecuencia respiratoria de 16/min suele ser apropiada inicialmente para la mayoría de los pacientes en los cuales se busca la normocapnia.86
En situación de catástrofe, cuando el número de pacientes que requiere ventilación mecánica supera el número de ventiladores disponibles, estos pueden ser alterados para dividir flujo de aire a varios pacientes. Haga click aqui para ver un video tutorial de cómo lograr esto.
Los puntos claves a tener en cuenta incluyen los siguientes:
Los niños impresionan estar relativamente a salvo de las complicaciones más severas y mortalidad, como ha sido mostrado en la Tabla 6 el índice de hospitalización por grupos de edad del CDC. A la fecha en los Estados Unidos, y por la experiencia de nuestro co-autor en el Norte de Italia, no han sido reportadas muertes en niños. Sin embargo, en una pre-publicación del 16 de Marzo de 2020 en el Journal of Pediatrics, Dong et al. analizador 2.143 niños en China con infección por SARS-CoV-2 sospechada o confirmada y encontraron que casi “4% de los niños permanecieron asintomáticos, 51% sufrieron enfermedad leve, y 39% enfermedad moderada. Cerca de 6% padecieron patología severa o crítica, comparada con 18,5% de adultos. Un niño, de 14 años murió.”87 Este estudio encontró que los lactantes tienen porcentajes más altos de enfermedad severa comparados con niños mayores. Aproximadamente 11% de los lactantes padecieron enfermedad severa o crítica comparado con 7% de los niños entre 1-5 años, 4% entre 6-10 años, 4% entre 11-15 años, y 3% de 16 años o más. Existen muchas teorías que especulan acerca de la diferencia entre adultos y niños, desde “niveles mayores de anticuerpos contra virus o diferencias en la respuesta del sistema inmune en desarrollo”.87 Otra teoría se relaciona con la falta de desarrollo de los receptores de ACE2 en niños, lo que previene que el virus se adhiera de la misma manera a sus células. Wu et al. informaron en su Resumen de Reporte de 72.314 Casos del Centro de para el Control y Prevención de Enfermedades de China aproximadamente 1000 casos en niños menores de 19 años, sin ninguna muerte reportada en menores de 9 años.84 En una correspondencia reciente con el New England Journal of Medicine, investigadores de China reportaron dentro un grupo de 171 casos confirmados de SARS-CoV-2, la muerte de un infante de 10 meses con múltiples comorbilidades.88
En un pequeño estudio retrospectivo en China, con 20 casos pediátricos confirmados de COVID-19, los pacientes fueron estudiados con TC de tórax y marcadores de laboratorio, incluyendo procalcitonina. Los autores encontraron que la procalcitonina se encontraba elevada en 16/20 pacientes, y las TC de tórax mostraron consolidación con signos de halo alrededor en 10/20 pacientes, y 12/20 mostraron opacidades en vidrio esmerilado. Este estudio sugiere que la coinfección es niños es más prevalente (8/20), y que la consolidación con signo de halo es un signo típico en esta población.58 Aunque la población pediátrica pueda estar a salvo de la morbilidad y mortalidad vista en los adultos, se debe tener en cuenta que pueden infectar a poblaciones más vulnerables, y se debe promover el distanciamiento social. Futuras investigaciones en la población pediátrica de Estados Unidos puede ayudar a comprender el comportamiento y manejo de presentaciones severas en niños.
La información acerca de mujeres embarazadas con COVID-19 es escasa.89 En general las pacientes embarazadas con infección por COVID-19 comparten las mismas características que las mujeres no embarazadas. En un estudio retrospectivo de 9 pacientes, Chen et al. analizaron el riesgo de transmisión materno fetal de SARS-CoV-2 y encontraron que la transmisión intrauterina de madres SARS-CoV-2 positivo es poco probable.90 Además, en ese grupo de pacientes, encontraron muy pocas complicaciones relacionadas con el embarazo, a diferencia de lo conocido en infecciones por SARS-CoV-1.91,92 Claramente, se necesitan estudios más grandes para evaluar el riesgo de transmisión vertical de la madre al feto del virus SARS-CoV-2.
La toma de decisiones compartidas es un proceso colaborativo, en el cual pacientes y médicos tratantes toman decisiones en conjunto acerca del cuidado de la salud, tomando en cuenta evidencia científica, experiencia clínica, así como los valores y preferencias del pacientes. Aunque la evidencia científica acerca del diagnóstico y tratamiento es nueva y evoluciona rápidamente, la extrapolación de cierto conocimiento proveniente de otras enfermedades infecciosas está justificado. Existen al menos dos escenarios clínicos relacionados al COVID-19 que son apropiados para la Toma de Decisiones Compartidas: 1) El testeo para SARS-CoV-2 en pacientes con síntomas leves y 2) La discusión del tratamiento en los pacientes críticamente enfermos.
Dado que al momento no existe tratamiento que haya demostrado beneficio para el COVID-19, realizar el diagnóstico de la enfermedad en pacientes con síntomas leves probablemente no cambie el manejo clínico. El tratamiento de soporte estándar, como usualmente es indicado en las enfermedades virales de vía aérea superior, pueden ser recomendadas para estos pacientes, sin la necesidad de realizar el análisis de SARS-CoV-2. Este tratamiento incluye antipiréticos de venta libre, antitusivos, descongestivos, analgésicos, fluidos por vía oral, y descanso. Los pacientes además deben ser instruidos en la práctica del auto aislamiento, para prevenir la diseminación a otros individuos. Las pruebas actuales, usando RT-PCR, tienen una sensibilidad de entre el 60-90% y pueden generar falsos positivos o falsos negativos. Dada la posibilidad real del agotamiento de los recursos para realizar las pruebas, podría ser razonable evitar el testeo, asumir la presencia del virus, y tomar las medidas de precaución social indicadas. Otros pacientes pueden expresar un fuerte preferencia de realizar la prueba para potencialmente reducir la ansiedad en caso de resultar negativo, o justificar mayor aislamiento social de ser positivo. Si nuevas terapias son halladas, esto podría cambiar la utilidad de las pruebas en los pacientes leves.
Otro escenario clínico donde sería apropiado la Toma de Decisiones Compartidas sería la intubación endotraqueal en pacientes con falla respiratoria y mal pronóstico, sea por su avanzada edad o por severas comorbilidades. Esta decisión será frecuentemente afrontada debido a que el SDRA es el camino final de muchos pacientes con COVID-19. Estudios precoces muestran la alta tasa de mortalidad en pacientes ancianos particularmente mayores de 80 años. En este escenario, los médicos podrían potencialmente favorecer la Toma de Decisiones Compartidas con los pacientes o sus representantes en forma colaborativa para decidir si la intubación está o no justificada. Esto es similar a la discusión de otros objetivos de cuidados en pacientes de edad avanzada y/o enfermedad terminal
En nuestra primera versión, especulamos acerca del futuro, cuando todavía no era una pandemia. Lamentablemente el futuro está aquí, y nos encontramos en el medio de una pandemia creciente que cierra ciudades, naciones, y continentes. Es mejor mirar los eventos pasados para aprender de los errores de otros y buscar oportunidades para mejorar en las regiones que todavía no se han inundado de COVID-19.
“Diseminación comunitaria,” “transmisión silenciosa,””distanciamiento social,”y äplanamiento de la curva” se han vuelto de uso habitual a la vez que el público y las sociedades médicas intentan comprender y controlar al COVID-19. Con un R0 similar a la influenza pandémica, la diseminación y contención del SARS-CoV-2 enfrenta desafíos sin precedentes.93 Continuamos encontrando que la información (y desinformación) que cambia constantemente , nos ha sumado un nuevo desafío con el público en general y la comunidad médica. The Lancet publicó una editorial online que apela a la comunidad médica y al público en general a buscar información verificada a través del CDC o la OMS. y evitar acudir a la redes sociales y otras fuentes de información no verificada. Muchos pacientes preocupados que se encuentran bien acudirán a los DE, congestionando sistemas ya sobrecargados. Esta es una oportunidad para que los servicios de salud desarrollen y/o expandan sus sistemas de telemedicina, para minimizar la saturación de los DE con pacientes de bajo riesgo.
Actualmente hay varias compañías de biotecnología y farmacéutica en carrera por el desarrollo de la vacuna contra el SARS-CoV-2, y aunque los estudios son prometedores, la disponibilidad y uso se encuentran al menos a 18 meses de distancia (mitad de 2021). Una vacuna de ADN candidata para SARS-CoV-2 que ha comenzado los ensayos clínicos en humanos, mientras que dos vacunas basadas en vectores pronto entrarán a ensayos clínicos en humanos; las vacunas basadas en proteínas todavía están en estadíos preclínicos.72 Los desafíos para el desarrollo de las vacunas incluyen el incompleto conocimiento de la transmisión viral, patogénesis y respuesta inmune; la falta de modelos animales óptimos para pruebas y estudios inmunológicos estandarizados.
Creamos que China, el estado de Washington, Italia, y ahora el área metropolitana de Nueva York deberían servir de ejemplos para el resto del mundo que todavía no han sido inundados de SARS-CoV-2. Estar preparados para una embestida de pacientes es el primer paso que todos los sistemas de salud tienen que aceptar. Probar y aislar personas infectados o sospechosos en forma temprana ha mostrado beneficio en China, Corea del Sur, y en cualquier otro lugar, y los locales como en Nueva York pueden atestiguar acerca del efecto negativo de no estar preparados para probar en masa y realizar una contención expeditiva de la diseminación en la población.
En el evento de influjo masivo de pacientes con exposición a SARS-CoV-2 o síntomas sospechosos de COVID-19 está indicado el aislamiento inmediato. Si una persona infectada se presenta a al DE hay un alto riesgo de diseminación y contaminación potencial de otras personas. El CDC recomienda color amplia cantidad de suministro de sanitizante para manos y ofrecer de forma accesible una máscara quirúrgica (barbijos / mascarilla) a la entrada del hospital y del DE. También recomiendan colocar carteles que alerten a toda persona que ingrese al establecimiento que se “coloque un barbijo (mascarilla) inmediatamente al ingresar y lo mantenga puesto durante toda la evaluación; cubrir nariz y boca al toser o estornudar; usar cuidadosamente pañuelos descartables; y realizar correcta higiene de manos luego del contacto con secreciones.”94 Los autores recomiendan a los administradores hospitalarios las siguientes directivas:
La mejor manera de salvar a la mayoría de las personas y reducir la morbilidad es ser proactivo y no reactivo. Aquellos de nosotros en medio de esta crisis desearíamos haber hecho las cosas de manera diferente y implementar las recomendaciones anteriores desde el momento en que encontramos al paciente cero. Nuestra falta de pruebas tempranas y aislamiento estricto va en contra de lo que recomiendan los epidemiólogos para controlar los brotes infecciosos. Por favor, aprenda de nuestros errores.
| Table 9. Helpful Resources for COVID-19 | ||
|---|---|---|
| Organization | Link | |
| United States Centers for Disease Control and Prevention | Coronavirus Disease 2019 (COVID-19) | |
| World Health Organization | Coronavirus disease (COVID-19) outbreak | |
| Johns Hopkins University | COVID-19 Global Case Tracker | |
| United States Department of Labor, Occupational Safety and Health Administration | COVID-19 Additional Resources | |
| American College of Emergency Physicians | COVID-19 Clinical Alert | |
| The Lancet | COVID-19 Resource Centre | |
La medicina basada en la evidencia requiere una apreciación crítica de la literatura, basada en la metodología de los estudios y número de casos. No todas las referencias son igual de robustas. Los hallazgos de grandes ensayos prospectivos, randomizados, y ciegos, acarrean mayor peso que el reporte de un caso. Para ayudar al lector a juzgar la fortaleza de cada referencia, será incluído en letra negrita información pertinente acerca del estudio, como tipo de estudio y cantidad de pacientes.
COVID-19患者に対しては機械的換気療法が必ずしも良い適応とならないことがあり、ARDSnet戦略が低酸素血症患者に対して有害となることがしばしば経験されている。 新規コロナウイルスSARS-CoV-2の独特な病態生理は、気道内圧開放換気（APRV）などのさらなる人工呼吸器戦略への関心を新たに高めている。 APRVは、持続気道陽圧法（CPAP）の一形態であり、自発呼吸を可能にしながら、一定の時間で圧力を解放することを特徴とします1（図1参照）。APRVはこれまで追加戦略として考えられていたが、最近では初期の人工呼吸器設定としても受け入れられるようになってきた。APRVは急性肺損傷（ALI）/急性呼吸窮迫症候群（ARDS）、多巣性肺炎、重度の無気肺などへ適応があるため、非常に魅力的な換気オプションとなっている。
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図 １.自発呼吸を温存したAPRV圧力サイクル |
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APRVは、CPAPの一形態である。P-highはCPAPレベルに相当し、T-highはP-highの持続時間である。CPAP相（P-high）は、短時間（T-low）の間、断続的にP-lowに解放され、その後の呼吸でCPAPレベルを再確立する。自発呼吸は両方の圧レベルにおいてもみられ、時間サイクルに依存しない2。
ICON Educational Supplement, 2004.から許可を得て転載。
APRVは、低い設定圧へ開放される際にも肺（胞）が虚脱しないために、圧を持続させる2,3。APRVの持続圧相は、胸壁まで圧を伝え、中枢と末梢の両方で肺胞のリクルートメントを可能にする。長い持続圧相と短い圧開放相を組み合わせることで、従圧式/従量式といった人工呼吸器設定で発生する肺胞の膨張と虚脱の連続サイクルを回避することができる4。これにより、虚脱性損傷や圧損傷を避けることができ、結果的に人工呼吸器による肺損傷を回避することができる。（図2を参照） 決まった時間で開放することで、受動的な呼気が生まれ、二酸化炭素の排出を改善することができる。APRVは自発換気に依存しているため、従来の方法に比べて必要とされる鎮静はより浅く、鎮静による有害事象を軽減することができる。自発呼吸には、呼気終末の肺容量の増加、無気肺の減少、下位肺領域への換気の改善といった効果がある4。さらに、自発呼吸は胸腔内圧を低下させることで血行動態を改善し、前負荷と心拍出量を向上させる。
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図２. APRVと従来の換気での一回換気量の比較 |
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APRVモードによる換気は高圧相からの開放した際の呼気によって行われ、換気時の気道内圧を低下させたり、肺の過膨張を抑制させたりすることとも関連している。一方で、従来の換気による換気では、気道内圧の上昇と肺の過膨張を引き起こしてしまう2。
ICON Educational Supplement, 2004の許可を得て転載
APRVの設定では以下の4つの値の設定が必要である2,3。
(1)P-high (2)P-low (3)T-high (4)T-low
P-highは高圧相で持続させる設定圧を指し、P-lowは換気サイクルにおける開放相における圧のことを指す。T-highは高圧相を持続させる時間であり、T-lowは開放相の時間のことである。挿管直後、筋弛緩の効果が切れるまでは、まず患者の呼吸器を従量式・補助/調節換気（AC/VC）モードにセットしておく。次に、プラトー圧を同定するために、吸気ホールドを行う。このプラトー圧がP-highに相当し、一般的に27-29cmH2O程度となるが、肥満患者ではより高い圧を要することもある。P-lowは0に設定する。ただし、一般的に内因性PEEPが存在しているため、呼気の終了（訳注：息を吐ききること）は生じない。T-highは通常4-6秒に設定する。一方で、T-lowは拘束性肺疾患で0.2-0.8秒、閉塞性肺疾患で0.8-1.5秒に設定する。適切なT-low値を設定するためには、人工呼吸器の流量波形を確認する必要がある。T-lowは呼気流速が呼気最大流速（PEFR）の約75%になるように設定する2,4。 経時的に肺がリクルートされるので、T-lowを呼気最大流速の75%となるように継続して調整し続ける必要がある。（表3） 患者がAPRVに同調し快適な呼吸ができていれば、FiO2は漸減させていくべきである。
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図３. 呼気フローカーブの図解 |
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コンプライアンスの低い肺を有する患者は、急峻な呼気流量曲線（30°）を描き、呼気流速が呼気最大流速の75%となるように開放相の時間を短くする（本例では0.3秒）必要がある。肺のリクルートメントがなされ、コンプライアンスが改善すると、直線の傾きは緩やか（45°）になり、T-lowの時間を延長させる（本例では0.5秒）必要が出てくる。肺胞のリクルートメントとコンプライアンスの改善が進行すれば、一回換気量の増大につながる。このように、気道内圧開放換気（APRV）では時間による制御と患者の呼吸器系力学に適した機械的換気（時間制御適応換気：time-controlled adaptive ventilation）を考慮する。
出典：Kollisch-Singule M, Andrews P, Satalin J, et al. The time-controlled adaptive ventilation protocol: mechanistic approach to reducing ventilator-induced lung injury. European Respiratory Review. 2019; Volume 28, Issue 152. the Creative Commons Attribution-NonCommercial 4.0 license ("CC-BY-NC") の下で使用
メリーランド州ボルチモアにあるThe Multi-Trauma Critical Care Unit of the Adams Crowley Shock Trauma Center at the University of Maryland Medical CenterのメディカルディレクターであるNader Habashi氏により、COVID-19患者に対するAPRVレスキュープロトコルが開発された。このプロトコルは、肺が再拡張されるまで、安定した換気を可能にするためにT-highを短縮するというものである。これは、過度の呼吸困難感と呼吸努力を避けるのに役立つ。鎮静剤は、必要に応じて、呼吸ドライブを制御するために使用する。AC/VCからの移行時には、次の式を用いてT-highを計算する。{(60/現在の呼吸数-T-low = T-high｝ 例えば、以下のように計算できる。(呼吸回数＝20/分およびT-lowが0.5秒である場合)、T-high = (60/20)−0.5秒 = 2.5秒。T-Highは正常な血中二酸化炭素濃度を維持するために0.5から2秒増加可能である5。
APRVでは自発呼吸が最も重要である。したがって、挿管チューブの内在性抵抗を考慮して、少量の圧サポートまたは自動チューブ補正（automatic tube compensation：ATC）を追加すべきである2。低酸素血症は、P-highとT-highを増加させることで修正可能である。また、低酸素血症はT-lowを短くすることで改善することが可能である。APRVでは許容的な高炭酸ガス許容人工換気法（Permissive hypercapnia）が認められているが、これは必要に応じて、鎮静を減少させること、および／またはP-highおよびT-highを増加させることによって、是正可能である。T-lowを増加させることによってさらに修正することができる。しかしながら、APRVはP-lowの間、肺を開き続けるために内因性PEEP（iPEEP）に依存しているため、T-lowを増加させることは問題となり得る。T-lowが増加した場合、iPEEPは減少し、このように肺胞の再虚脱の危険性がある。
Authors: Sean Hickey, MD, Icahn School of Medicine at Mount Sinai; Al Giwa, MD, Associate Professor of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
References
COVID-19への理解が深まるにつれ、より多くの治療法が行われるようになった。 Guérinet らの2013 PROSEVA研究（PMID：23688302）で述べられているように、患者を腹臥位にすること（別名「腹臥位療法」）は、ARDS患者の治療においてベネフィットがあるため、長い間、推奨されてきた。それ以来、世界中のほとんどの集中治療学会でPF比 (PaO2/FIO2)が100以下の患者に対しての腹臥位療法を推奨している。COVID-19の病態生理がARDSによく似ていることを踏まえ、多くの専門家が腹臥位療法を推奨している。覚醒しているCOVID-19患者の腹臥位についてとその使用に関する簡潔なレビューについては、Scott Weingart’s blog「EMcrit.org」にあるDavid Gordon医師の記事を参照するとよい。
新型コロナウイルスSARS-CoV-2、その感染症であるCOVID-19は、急速に健康、旅行、商業に対する世界的な脅威となった。 前例のない医療従事者と病院システムへの負担をマネジメントするために、救急医がこの感染流行についてできるだけ学ぶことが重要である。 このレビューではCOVID-19の疫学、予防、および治療に関する世界中の研究と経験から情報を分析し、この公衆衛生的問題のマネジメントに役立つ、信頼性の高いリソースへのリンクを提供する。 この感染流行が米国を席巻する中、早期に感染の中心となった地域、特にニューヨークと北イタリアから学ぶ教訓は、各地域の備えに役立つはずである。
42歳男性。1週間にわたる高熱（39.6℃ [103.3°F]）、咳嗽、疲労感であなたの救急外来に受診した。その前の週に、彼はニューヨーク市の救急医学会に参加しており、地下鉄に乗るとひどい咳をする人が幾人かいたと言った。トリアージナースはすぐに感染のリスクを察知し、患者にマスクをかけ、陰圧室に案内、診察の準備を整え、あなたに知らせた。この患者がトリアージ待ちをしている間に近くに座っていたであろう他の患者10人をどうするか？さて、次のアクションはどうしよう・・・？あなたの仕事時間も後半戦にさしかかったころ、程度はさまざまであるが上気道症状、下気道症状のある患者が途切れることなく受診してくる。さらには、程度は様々だが暴露したからとCOVID-19の検査を希望する「心配性な」無症状の患者も数人いる。彼らに何を伝えればいいのだろうか？また、多くの高感染リスク患者達をどう扱うべきだろうか？
コロナウイルスは、その粒子表面に点在する特徴的な王冠状のウイルス粒子（ビリオン）からその名を得ている。このウイルスファミリーは、脊椎動物、特に哺乳類や鳥類の広範囲に感染し、世界中でウイルス性呼吸器感染症の主な原因と考えられている3,4。最近、2019年の新型コロナウイルス（SARS-CoV-2）が検出され、その結果、コロナウイルス病2019（COVID-19）という名前が付けられた。人間に感染すると確認されているコロナウイルスは7種類存在する。
2003 年に SARS-CoV-1 が世界的に大流行するまでは、人間に感染するコロナウイルスは HCoV-229E と HCoV-OC43 だけであったが、2003 年の SARS-CoV-1 の世界的なアウトブレイク後は、さらに 5 種類のコロナウイルスが人間で発見されており、最近では、中国湖北省武漢市で発生したと考えられている新規コロナウイルスSARS-CoV-2が発見された。SARS-CoV-1とMERS-CoVは特に人間での病原性が高く、高い致死率を示している。本稿では、COVID-19の疫学、病態生理、管理について、最適な取り組みと公衆衛生的意義を中心にレビューする。
PubMed、ISI Web of Knowledge、Cochrane Database of Systematic Reviewsの2012年から2020年までのリソースに、救急部門、エピデミック、パンデミック、コロナウイルス、SARS-CoV-2、COVID-19をキーワードに検索した。また、米国疾病予防管理センター（CDC）、世界保健機関（WHO）、日本の厚生労働省、EMCritのウェブサイトにもアクセスした。
2020年3月27日時点で、全世界でCOVID-19の確定症例は566,269人に達しており、その大部分は中国本土以外で発生している。25,423人の死亡が確認されている1。 COVID-19による世界の確定症例数／死亡者数の最新情報は、ジョンズ・ホプキンス大学のオンライン・トラッカーで参照可能である。この記事を掲載している時点で、確認された症例は南極を除く全大陸の176カ国に及び、WHOがSARS-CoV-2感染症をパンデミックと宣言するまでになっている。死者数のうち、半数以上が中国以外の国で発生しており、イタリア8215人）、イラン（2378人）を筆頭としている。現在の世界の症例致死率は4.38％である。COVID-19の発生が2020年1月下旬の旧正月のお祝いと重なり、武漢市への訪問者数が約1,500万人となったことから、中国本土への感染を封じ込めようとする努力は最終的には失敗に終わった。中国の病院で感染した患者集団からの初期報告によると、（集中治療室（ICU）レベルのケアや死亡率を物差しとして）重症化し予後不良となった感染者の大半は、高血圧、糖尿病、肥満、喘息、慢性閉塞性肺疾患、高齢などの併存疾患を持つ患者である傾向があった2,6。
疫学では、R0値（「R-naught」と発音する）は基本再生産数として知られており、すべての個体が感染しうる集団において、1症例から直接感染すると予想される症例数と考えることができる。COVID-19の初期の疫学研究では、R0値は2.2（90%信頼区間：1.4-3.8）と推定されており、これはSARS-CoV-1やパンデミックインフルエンザと同様の値で、持続的なヒトからヒトへの感染と世界的なパンデミックの可能性を示唆している7。「予防」のセクションでより詳細に議論されるように、R0はウイルスの活動と人間の活動の両方を反映しているので、正しい社会的・行動的介入があれば、このR0の値を下げることが可能である。
最初の症例からわずか数カ月で、SARS-CoV-2による死亡者数は、MERS-CoVとSARS-CoVの両方を合わせた数をはるかに上回っている1。 真の致死率は症例致死率よりも低いと考えられているが、これは緊急の評価や入院を促すほど重篤な症状のある人だけがCOVID-19の検査を受けているという選択バイアスのためである 8。ダイヤモンド・プリンセス・クルーズ船のアウトブレイクからのデータは、症状に関係なく、船内の全員が検査を受けたことを考えると、この疾患の真の致死率と症状についての特別なデータセットとなる。このデータに基づいて、ロンドン衛生熱帯医学大学院からの未発表の分析では、年齢調整症例死亡率は0.5％と推定されている。これでもCOVID-19はパンデミックインフルエンザよりも致死性が高いとされる一方で、感染性像は類似している9。さらに、日本の厚生労働省によると、COVID-19が陽性だった乗船者697人のうち327人は、最初の検査陽性から1ヶ月経っても症状が出なかったという10。
私たちは幸運にもワシントン州の最初の報告例 (1 月 21 日) の数週間後に発生したイタリアの COVID 19 の危機から直接的な展望を得ることができ、疫学者の推定では、ニューヨーク都市圏のアウトブレイクは約 2 ～ 3 週間後である。Andrea Duca医師 は救急医であり、COVID-19 の最初の直撃を受けた地域である北イタリアにおけるEmergency Medicine Practiceの編集委員会のメンバーである。彼によると、SARS-CoV-2 の急速な広がりは、ほとんどの病院を圧倒しており、人工呼吸器を必要とする患者の突然の増加に対処する準備ができていなかった。2020年3月18日現在、イタリアの症例致死率は8.37％であり、今後数週間で重度のCOVID-19の患者に対応する準備をしている世界中の他の医療システムへの警告と受け取られるべきである。イタリアのベルガモでのSARS-CoV-2の発生を管理したAndrea Duca医師のまとめは、表1を参照。その病院からの追加データを図1、2、3、4に示している。図1はロンバルディア地方におけるCOVID-19症例時系列表（2020年2月20日～3月17日）、図2はCOVID-19患者の1日の入退院の割合（2020年2月29日～3月10日）、図3はCOVID-19患者の1日の入退院の合計（2020年2月29日～3月10日）、図4は日ごとのCOVID-19患者転帰を図示している（2020年2月29日～3月10日）。
コロナウイルスはニドウイルス目（Nidovirales） コロナウイルス科（Coronaviridae） オルトコロナウイルス亜科（Orthocoronavirinae）に属する。コロナウイルスは一本鎖プラス鎖RNAを持ち、そのゲノムサイズはRNAウイルスの中でも最大である。コロナウイルスのゲノムにおいて、約2/3の5'末端にはRNAウイルスの転写と複製に関わるウイルス蛋白がコードされており、残りの約1/3の3’末端にはウイルスの構造タンパク質と特異的なアクセサリータンパク質がコードされている4。現在、コロナウイルスには4種類の主要なタンパク質（S:スパイクタンパク質 E:エンベロープタンパク質 M:膜タンパク質 N:ヌクレオカプシド）が存在していることが明らかになっている。これらのバイオマーカーは“疾患をどのように診断するか”だけでなく、病原性の理解、ひいてはワクチンやウイルスの生活環を解体するような抗ウイルス薬の選択に関しても、中心的な役割を担っている。（表5を参照）
SARS-CoV-1およびMERS-CoVはいずれも、コウモリからの人畜共通感染症によるものであると考えられていた11。 今回のパンデミックを引き起こしたウイルス“SARS-CoV-2”は“SARS-CoV-1”と現在呼ばれている2003年にアウトブレイクを引き起こしたウイルスに遺伝的類似性から命名された。コウモリの群れの中だけでコロナウイルスは何千年もかけて進化してきた。しかし、中間宿主となる哺乳類（SARS-CoV-1の場合はジャコウネコ、MERS-CoVの場合はヒトコブラクダ）が関与することで、最終的なヒトへの新型コロナウイルス感染に寄与している可能性が高いのではないかと考えられている12,13。COVID-19のアウトブレイクは武漢市の華南海鮮卸売市場から生じたと考えられているが、この市場が元々のウイルス感染源ではない可能性があると考える研究者もいる2,14。中国ではコウモリを市場で見かけるのは稀であり、捕まえられたコウモリは食用として直接レストランに売られることのほうが多い15。
コロナウイルスは主に、鳥類や哺乳類の上気道もしくは消化管に感染する。ウイルス表面に発現しているスパイク糖タンパク質（Sタンパク）がコロナウイルスの病原性の決定に重要な鍵となる。これはSタンパクの存在によって宿主の細胞への結合が可能となるためである。MERS-CoVはジペプチジルペプチダーゼ4（DPP4）と結合することが知られている。DPP4とは、コロナウイルス株の受容体として知られており、哺乳類や鳥類の間に存在するタンパク質の一種である。ほとんどの呼吸器ウイルスは線毛細胞に感染するが、DPP4はヒトの気道では非線毛細胞に発現しており、このことが人畜共通感染症であることや高い致死率であることの重要な要因であると考えられている16。SARS-CoV-1においてはヒトアンジオテンシン変換酵素2（ACE2）がウイルスの結合する主要な細胞受容体であり、このACE2がSARS-CoV-1が持つ上下気道への感染性、SARS-CoV-1の感染力や致死性に寄与していると考えられている17。
“サイトカインストーム”とも呼ばれる免疫学的機序がSARS-CoV-1や鳥インフルエンザなどの様々な呼吸器ウイルスに罹患した患者の状態悪化につながることがこれまでの研究によって示唆されている18,19。免疫学的機序によってCOVID-19患者が急速な悪化を来し、また炎症性マーカーの放出がARDSや多臓器不全、死亡につながる正のフィードバックループを起こすという理論は数多くの研究から示唆されている20。検査によって確定診断された中国のCOVID-19患者41人のコホート研究では、ICU患者は非ICU患者と比べ、炎症性マーカー（IL-2,IL-7,IL-10,G-CSF,IP-10,MCP-1,MIP-1,TNF-α）が有意に高いことが明らかになった21。中国で最近行われた研究では、SARS-CoV-2における詳細な免疫病理学的な報告がされており、重症なCOVID-19患者は「病原性Th1細胞や炎症性単球による（略）過剰に活性化された免疫反応」を呈すとされている。またこの知見は、COVID-19患者の献体から採取した肺生検標本の免疫組織学化学分析によっても支持されている22,23。二次性もしくはウイルス誘発性の血球貪食性リンパ組織球症（HLH）や過炎症症候群がこれらの患者の状態悪化の根底にある原因であると、示唆する文献が次々と発表されている。この疾患の経過はCOVID-19患者でも同様の様相を呈し、臨床的な特徴としては解熱しない発熱、血球減少、高フェリチン血症、肺病変などが挙げられる24,25。COVID-19患者で考慮されている免疫制御による治療は“マネージメント”で取り上げる。
SARS-CoV-2はSARS-CoV-1と同様のACE2受容体を通して、ヒトの2型肺胞上皮細胞に侵入する26。 多施設後向きコホート研究によると、COVID-19と診断された入院を要する患者において、院内死亡と関連するリスク因子は高血圧が最も多く（30%）、続いて糖尿病が挙げられる（19%）27。
SARS-CoV-2がACE2受容体に結合することから、一般的に使用される降圧薬の一種であるACE阻害剤（ACE-I）やアンジオテンシン受容体拮抗薬（ARB）とCOVID-19の重症化リスク上昇との潜在的な関連性があるのではないかとここ数週間で指摘されている。現時点では、European Society of Cardiology・American College of Cardiology・American Heart Failure Society・Heart Failure Society of Americaの公式勧告によると、ACE-IやARBを服用している患者はその内服を継続するべきであると取りまとめられている。European Society of Cardiologyでは「COVID-19感染のために、ACE-IやARBによる治療を中断するべきという臨床的・科学的根拠は存在しない」と述べている28。また、HFSA/ACC/AHAによる共同声明でも「COVID-19患者にACE-IやARBを使用することに対して利益・不利益を示す実験的・臨床的データは存在しない」と述べている29。
ACE2受容体に結合したSARS-CoV-2との相互作用が生じるという仮説に基づけば、イブプロフェンのようなNSAIDsの使用に関しても同様の懸念が生じる。現状ではNSAIDsの使用がCOVID-19を増悪させることを示唆する科学的根拠は存在しない。この問題を調査するために前向き多施設研究が行われなければいけないことは明らかである。これらの薬剤の使用における理論的な利点と害に関する議論は“Nephrology Journal Club”で見ることができる。
中国本土における厳格な渡航制限と検疫措置の実施に伴う感染拡大の動的変化から、我々は多くのことを学ぶことができる。Lancet誌に掲載された数理統計学モデルによると、武漢における1日当りの再生産数（Rt）の中央値は渡航制限が開始される1週間前の2.35（95%信頼区間:1.15-4.77）から渡航制限開始1週間後の1.05（95%信頼区間:0.41-2.39）まで減少したと試算された30。広い範囲に及ぶ、政府による介入や社会的な介入の効果は、複数のデータドリブン分析によって示されており、このことによって全ての政府は「早期発見・隔離・治療を最優先とすること」「十分な医療資源を供給すること」「包括的な治療戦略を持ちながら指定病院へ入院させるシステムを確立すること」を進めていくに違いないであろう30,31。HellewellらはCOVID-19の発生をパラメータ化した確率的感染拡大モデルを使用することで、「非常に効果的な症例追跡と隔離によって3ヶ月以内のCOVID-19における新規アウトブレイクを十分制御できる」と結論づけている32。
インペリアル・カレッジ・ロンドンとWHOは2020年3月16日に研究を発表し、SARS-CoV-2の感染拡大速度を低下させる2つの基本的戦略を比較した。(1)“緩和：これは流行の拡大を遅らせることに焦点を当てているが、必ずしも流行を阻止することに焦点を当てているわけではない。重症化のリスクが高い人々を感染から守りながら医療需要のピークを減らすことに主眼をおいている。”(2)“抑圧：感染の拡大を抑制することで感染者数を低いレベルまで減らし、それをずっと維持させること”である。この研究によると、「理想的な緩和政策（つまり、疑い症例の自宅隔離と、高齢者やその他重症化のリスクが高い人々への社会的距離戦略）によって、ピーク時の医療需要を3分の2、死亡者数を半減できる」ことが明らかになっている。しかし緩和された流行が生じた場合、それでも何十万人もの死者が生じ、医療システム（特に集中治療室）は逼迫するであろう33。このことはSARS-CoV-2の蔓延に対して、現在各国が講じている積極的な措置を説明・支持するものである。
イタリアからの報告によると、COVID-19患者のケアに携わる医療従事者の最大20%がウイルスに感染するとされている。また時に死亡するとも報告されている34。最も必要とされている時に、病気に罹ることで医療従事者を失ってしまうということは、大量の患者によってすでに限界にまで達している医療システム崩壊の臨界点となるかもしれない。イタリアでの危機を認識することによって、全ての医療従事者に感染予防策を徹底することの重要性が強調される。これは、救急外来における感染予防のコンプライアンスを常に監視する人を決め、いくつかのシステムを用いることで達成される。
コロナウイルス属の感染の仕組みや、SARS-CoV-1やMERS-CoVアウトブレイクにおける感染パターンの記録から考えると、SARS-CoV-2の感染経路は主に飛沫感染と接触感染であると推測される。ただし、血清学的検査が陽性の患者の糞便からもウイルスが検出されている。米国国立衛生研究所（NIH）、プリンストン大学、カリフォルニア大学ロサンゼルス校の研究者らによる、New England Journal of Medicine誌に発表されたプレプリント論文によると、様々な物質の表面におけるSARS-CoV-2の半減期は以下のように推定されている。エアロゾル：1.1時間 銅：0.77時間 厚紙：3.46時間 鉄：5.46時間（訳注：原著では5.63時間） プラスチック：6.81時間35。これらの結果はSARS-CoV-2の感染経路がエアロゾルおよび接触感染である可能性が高いことを示唆し、SARS-CoV-2の高い感染率が報告されていることを裏付けている。
WHOもCDCも、感染制御ガイドラインで、SARS-CoV-2のウイルスを減らす際に徹底した手指衛生が重要であると強調している。これは、日本の沿岸海域で検疫措置を受けていたクルーズ船 ダイアモンド・プリンセス号に乗船していた無症候性キャリアの存在によって発生した懸念事項である。同様に、病原体保有者（確定例・疑い例）や流行地からの旅行者との直接的な接触のないCOVID-19患者に関する報告が世界中で増加している36,37。血清学的検査陽性の患者の糞便からSARS-CoV-2が検出されたという中国CDCからの報告から考えると、糞口感染、ひいては手指からの感染の可能性は極めて高いと言える38。患者・医療従事者は標準的な手指衛生の方法（特にトイレの後、食事の前後、鼻をかんだ後、咳やくしゃみをした後などに最低でも20秒、石鹸と流水で手を洗う）に準拠するべきである。もし石鹸や流水が使用できない場合は60%以上の濃度のアルコール含有消毒液を使用するべきである5。
濃厚接触および曝露した疑いがある人に対するガイドラインの追補には、即時の受診・14日間の経過観察・咳や上気道症状がある場合のフェイスマスク着用・公共交通機関ではない交通手段を可能な限り使用する・患者が来院する前に事前に告知しておく・換気している環境下で500mg/Lの濃度の塩素配合された消毒剤での輸送車両の消毒が記載されています39。ただし、直近の症例報告や研究によると潜伏期間が0-24日であるため、推奨される観察期間は容易に変更されるということに留意すること40,41。
N95マスクやその他の個人防護具が不足していることを考えると、必要な医療物資の在庫状況が変化することを考慮している現在の推奨事項に従う必要が高まっている。これらは表9に記載されているリンクを利用することでリアルタイムで状況のフォローができる。また、直近の空気感染隔離室だけではなく、施設内のユニット策定とCOVID-19疑い患者や確定患者を診療する専任スタッフの確保に対する推奨がされている2。
個人防護具（PPE）の脱着は、SARS-CoV-2の感染拡大の観点から見ても、医療者-患者間で接触する際、最も危険性の高い行為であることが多い。COVID-19を疑う患者もしくは確定患者の診察が終了した後のPPEの適切な脱着について、EMCritの救急医がまとめた簡単な手順を下記に記載する42。（表2を参照）
加えて、ビデオへのリンクは以下である
PPEの装着・脱着に関しての正しい手順のビデオはYouTubeから参照できる。
ベルガモ市での経験より、他の医療機関でのCOVID-19患者対応のシステム作成に役立つモデルが提唱された。同地域の救急外来では、短期間に重症呼吸不全の患者が多数発生したため、迅速な対応が必要となった。推奨事項の要約を表1に示した。なお、推奨事項は現時点でのデータ収集に基づくものである。
救急外来のスタッフは、すべての患者、特に発熱、咳、呼吸困難、呼吸器症状のある患者を診察する際には、SARS-CoV-2感染を強く疑って診察をするべきである。CDCは当初は武漢市への渡航警告を発表し、同地域への渡航歴、または渡航患者との接触歴をリスクと考えていた。しかし、現在は武漢市以外でもパンデミックの状態となり、SARS-CoV-2感染の除外基準として中国への渡航歴・接触歴はもはや重要ではなくなった。
2020年1月下旬、SARS-CoV-2感染の臨床的特徴、経過、予後について、過去の致命的なコロナウイルス感染（MERS-CoVおよびSARS-CoV-1）と比較したデータがThe Lancet
2020年3月18日、SARS-CoV-2感染症では下痢などの消化器症状が多いという研究が武漢市のグループによりAmerican Journal of Gastroenterology誌に発表された46。SARS-CoV-2患者204人のうち、99人（48.5%）で消化器症状があり、7人が呼吸器症状はなく消化器症状のみだった。これは単なる呼吸器疾患として捉えるという現在の定説と食い違っており、前述したように中国で観察された糞口感染パターンと一致している消化器症状のある患者は、呼吸器症状のみの患者よりも予後は悪く、消化器症状のない患者の方が消化器症状のある患者よりも治癒して退院する割合が高かった（60％ vs 34.3％）。著者らは消化器症状の有無により死亡率と罹患率に関与した因子を特定することができず、今後のさらなる研究が必要と考えている46。
Andrea Ducaらはベルガモのデータを用いて、肥満と重症度や挿管/集中治療の関連性を報告した。またその報告では、救急外来でNIVまたは気管挿管が必要になった患者の割合が、Wuら45の報告と同程度であり、COVID-19の疑いで入院した患者の最大31％を占めている。救急外来でNIVを開始した患者のうち、入院中に挿管が必要となる患者がどれくらいいるのか、また酸素を使用している患者のうち、どれくらいの患者が悪化して挿管が必要になるのかは現時点では分かっていない。これらのデータは現在収集・解析中であり、間もなく公表されるだろう。
SARS-CoV-2 のアウトブレイクの最初の報告から 1 か月以内に、CDC は SARS-CoV-2 を検出するためのリアルタイム逆転写ポリメラーゼ連鎖反応（rRT-PCR）検査を開発した。当初は米国での診断検査はCDCのみが行っていたが、International Reagent Resource（IRR）により、州レベルでも検査が可能となった。IRRはインフルエンザの研究と検出を目的に CDC により設立されたが、現在では新型インフルエンザとコロナウイルスまで対象を拡大している47,48。ウイルスパネルテストで検査可能なのは、ヒトコロナウイルスの初期型、すなわちヒトコロナウイルス 229E、NL63、OC43、および HKU1 のみである49。SARS-CoV-1、MERS-CoV、およびSARS-CoV-2は特殊なアッセイが必要である。残念ながら、米国では検査キットの欠陥（試薬の問題が原因）により、米国内の大半で利用可能であった検査ができなかった。表4にSARS-CoV-2検査に関する現在の推奨事項をまとめた。
アメリカでのアウトブレイクの拡大に伴い、検査の政策についての議論が絶えない。当初は、COVID-19が疑われるもしくは陽性患者との接触歴のある医療従事者、または症状発症から14日以内に流行地域への滞在歴のあるすべての人を検査するというのがこれまでの推奨であった。この時点では、曝露歴のある無症候性の医療従事者、または曝露および/または旅行歴のあるその他の無症候性の患者へは検査しないことが推奨されていた。また、入院する必要のない患者は検査する必要がないという推奨は撤回された。これらの推奨事項が再び変更されるかどうかは現時点では不明である。
疫学的要因はSARS-CoV-2検査を行うかどうかの判断の一助となりうる。コミュニティでのCOVID-19感染拡大が判明している地域においては、検査をするかどうかの判断に役立つかもしれない。しかし、多くの地域や病院ではすべての人を検査することができないため、このような推奨は撤回されることになった。SARS-CoV-2検査へのアクセスと信頼性への懸念が高まり、連邦、州、地方レベルでは推奨は異なっている。ただし、検査を考慮する時には、中国での初期の研究でも報告されているように、少なくとも24時間間隔（イタリアでは3日間）で2回の陰性を確認することがCOVID-19を除外するために必要であることを忘れてはならない51。 これらから、軽い症状、発熱、軽度の下痢、咳があるだけで病院に受診をすることは、自分自身や周囲の患者にとってデメリットの方が大きい可能性が高いということを救急医は一般市民に再度アナウンスすべきである。呼吸困難、高熱（39℃以上）、経口摂取困難などの重篤な症状がある場合は、病院を受診すべきである。また，症状に懸念がある人、増悪リスクの高い家族に映さないか心配な人については，感染拡大のリスクを最小限に抑えつつ，社会的距離の取り方，自己隔離，電話相談、ドライブスルー型のスクリーニングクリニックの利用（必要に応じて）などを実践するように留意すべきである。このレビューの範囲を超えているが、医療スタッフの健康および患者のケアの必要性と、無症候性の医療従事者からの院内感染の拡大を最小限に抑える必要性を天秤にかける機関や部門の方針については、今後も議論を続けていく必要があるだろう。
アメリカでSARS-CoV-2がアウトブレイクした当初は、感染症/感染予防当局の推奨に基づいて、他の呼吸器感染症（インフルエンザなど）の検査を実施することが推奨された。しかし、他のウイルスとの共感染の有無がCOVID-19の検査・評価に与える影響については現在も議論されている。
感染症専門医らへのインタビュー、救急医療とCOVID-19双方に特化したいくつかの国内/国際フォーラムの協議などの文献を徹底検索したところ、SARS-CoV-2と他のウイルスについて分析した中国のピュアレビューされていない研究（n=8274）を1件だけ見つけることができた。(「この論文は出版前であり、査読を受けていない医学的研究であるため、臨床の指針とすべきではない」と出版社は注意書きをしている。) この研究では、COVID-19患者の5.8％が他のウイルスと合併感染しており、非SARS-CoV-2感染の18.4％が他のウイルスと合併感染を起こしていた52。さらに、カリフォルニア州公衆衛生局の要請により、スタンフォード・メディシン・データの科学者が報告したデータでは、SARS-CoV-2陽性者49人のうち、11人（22.4％）が他のウイルスとの合併感染していた53。すなわち、他のウイルスの感染の有無にかかわらず、臨床医はSARS-CoV-2を強く疑う必要がある。
The Lancet
最近発表されたCOVID-19患者のプロカルシトニンに関するメタアナリシスでは、プロカルシトニンは合併症のないCOVID-19患者では正常範囲内であり、プロカルシトニンの上昇はCOVID-19が重症化し細菌感染を反映している可能性があることを示唆した54。COVID-19患者のメタアナリシスでは、血小板減少は重症化と関連しており、血小板数の大幅な減少は状態悪化の予測因子であることが明らかになった55。表5にCOVID-19患者の血液検査と重症度およびマネージメントについて示した。
2020年3月17日に発表されたCDCのデータによると、若年層の入院率が想定より多いことが明らかとなった。表6は最新の入院率を示しており、20～44歳で最大20％の入院率であることが分かった。発表時点でアメリカでは1例の小児死亡例が報告されている。（「小児」のセクションを参照のこと。
COVID-19患者の胸部画像所見は、過去のSARS-CoV-1およびMERS-CoVアウトブレイク時に見られた所見と類似している。41例のCOVID-19におけるコホート分析では、1人を除くすべての患者に両側の肺病変を認めた21,59。COVID-19患者21人のコンピュータ断層撮影（CT）スキャンの研究では、CTスキャンが正常であったのは3人（14 ％）であり、診断時のCTスキャン所見でスリガラス状陰影のみを認めたものが12人（57％）、スリガラス状陰影とコンソリデーション双方が認められたのは6人（29％） であった。15人(71％)の患者は2葉以上に病変があり、16人(76％)が両側性であった60。つまり、胸部CTで陽性所見を示した18人の患者すべてにスリガラス状陰影が認められ、18人中12人に小葉のコンソリデーションが認められた60。
中国湖南省の4施設から後ろ向きに分析されたCOVID-19肺炎101例のデータによると、CT上の病変は、末梢分布（87.1％）、両側病変（82.2％）、下肺優位（54.5％）、多巣性（54.5％）を示す可能性が高いことが分かった61。これらの所見、特に病変の末梢分布はCOVID-19肺炎を検出する肺超音波検査の能力を反映している。
マネジメントの変更につながることはほとんどないので、ウイルスの院内拡散する確率、CTスキャン撮像には資源がかかるというその性質、不安定な低酸素血症患者を搬送するリスクを考慮するとCOVID-19患者のルーチンでのCTスキャンは推奨されていない。The American College of Radiologyは、主に入院を要する有症状の患者で、他の病態を有する可能性を考慮する場合には控えめにCT検査を行うことを支持している62。図６にCOVID-19肺炎が疑われる患者における画像検査のスキーマを示す。
最近の文献やイタリアの事例報告では、COVID-19肺炎が疑われる患者をスクリーニングする方法として肺超音波検査を使用することが支持されている。肺炎および／または急性呼吸窮迫症候群（ARDS）の評価に対し、肺超音波検査は胸部CTと同等の結果を得られ、ポイントオブケアでの使いやすさ、繰り返しやすさ、放射線被曝がないこと、低コストという点で標準的な胸部X線検査よりも優れている63。表7は、胸部CTの所見と相関する肺超音波所見の詳細であり、COVID-19は一般的に背側部に肺病変を引き起こす64。 イタリアでは、これは有用なスクリーニングツールであることが証明されている。（表1参照）
疾患の重症化に伴い、肺超音波の所見の進展がみられる場合がある64。(図７参照)
これは、COVID-19肺炎の患者の超音波スキャンのYouTubeビデオである（Giovanni Volpicelli 医師より提供）
COVID-19患者の肺実質の特徴的な変化を見つけるトレーニングに関心のある医療従事者は、最近公開された高解像度胸部CT所見に相関する超音波画像の実例を含むHuangらの記事を参照できる65。記事と画像はResearch Squareで見ることができる。
Military Medical Research誌に掲載された記事“A Rapid Advice Guideline for the Diagnosis and Treatment of 2019 Novel Coronavirus (2019-nCoV)-Infected Pneumonia (standard version),”は、いくつかの症例の迅速なアドバイスガイドラインと画像診断を提供している39。図8はCOVID-19患者の典型的なX線およびCT画像を示している。
Radiology誌に掲載された記事“Evolution of CT Manifestations in a Patient Recovered from 2019 Novel Coronavirus (2019-nCoV) Pneumonia in Wuhan, China,”では31日間で回復した42歳のCOVID-19男性患者の胸部画像の進展が6点、公開されている66。
コロナウイルス株のいずれかに感染した場合、ウイルスに対して承認された特異的な治療法はない。最近のJAMAの研究でCOVID-19肺炎を呈す患者の多くは、広域なスペクトラムを有する抗菌薬での治療（モキシフロキサシン 89 [64.4％]、セフトリアキソン 34 [24.6％]、アジスロマイシン 25 [18.1％]）を受けており、ほとんどの患者が抗インフルエンザ療法（オセルタミビル 124 [89.9％]）を受けている、さらに一部の患者はステロイド剤（グルココルチコイド療法 62 [44.9％]）を追加投与されている2。このパンデミックの発展的な性質を考えると、臨床医には実績ある治療と管理プロトコルを実施している国や医療システムの指導を求めることが有益であると考えらる。そのようなガイダンスの一つがベルギーから、「ベルギーにおけるCOVID-19感染が疑われる/確認された患者のための臨床ガイダンス（Interim Clinical Guidance For Patients Suspected Of/Confirmed With Covid-19 In Belgium）」と題されて出ている。The Italian Society of Infectious and Tropical Diseasesからの勧告はこちらから閲覧できる（イタリア語版）。
追加として、ボストン医療センターのCOVID-19治療プロトコルについては、図９を参照されたい。
COVID-19の治療に関する直接的なエビデンスがないことを考慮し、最近提案されたガイドラインは、主にSARS-CoV、MERS-CoV、インフルエンザ感染症の治療ガイドラインに基づいて作成されている。現在のところ、インターフェロンα噴霧吸入(1日2回の吸入)、ロピナビル/リトナビル経口(1日2回)の弱い推奨があります;しかし、SARS-CoV-1およびMERS-CoV感染者におけるARDS発症率および死亡率を減少させるためのエビデンスは、症例報告に限られている39。最近のシステマティックレビューでは、ロピナビル/リトナビルの抗コロナウイルス効果は主に早期の使用で認められ、時間が経ってからの使用は有意な効果は認められなかったことが示されている67。The New England Journal of Medicine誌で最近公開されたCOVID-19の入院患者199人を対象としたランダム化比較試験では、ロピナビル-リトナビル治療による死亡率や臨床的改善までの時間の改善は認められなかった。 急性腎障害の合併、重症感染症、非侵襲的または侵襲的な機械的換気療法の割合などの転帰では改善が認められた; しかし、レムデシビルを使用した別研究ができるようになったため、この研究は登録を終了された68。現時点では、COVID-19治療における抗ウイルス薬の併用については、その使用を支持するヒトを対象としたランダム化比較試験が現在のところ行われていないため、議論の余地がある69,70 。
現在、レムデシビルは in vitroおよび非ヒト霊長類モデルにおけるSARS-CoV-1およびMERS-CoV感染を含む幅広いRNAウイルスに対する有望な抗ウイルス薬として認識されている71。COVID-19を対象としたin vitro試験では、レムデシビルとクロロキンが高い選択性をもって低マイクロモル濃度で細胞のウイルス感染を阻害することが明らかになっている72。複数の国でレムデシビルの有効性を試験する臨床試験が進行中であるが、現段階で本剤は重症COVID-19症例でのコンパッショネート・ユース(人道的使用)のみであり、市販されていない。
ファビピラビルとインターフェロンα（治療群）とロピナビル/リトナビルとインターフェロンα（対照群）との間の最近の非盲検非無作為化対照研究ではウイルス除去までの時間の有意な減少（中央値4対11日、 P <0.001）と14日目の胸部CTスキャンの改善率上昇(91.4% vs 62.2%,
SARS-CoV-1 の治療に関する中国の文献のシステマティックレビューでは、ステロイドが使用された 14 研究が確認された。うち12研究では結論が出ず、2つの研究では潜在的な有害性が示された。1つの研究ではメチルプレドニゾロン療法に関連する糖尿病の発症が報告され74、40人のSARS患者を対象とした別の非対照後ろ向き研究ではコルチコステロイド治療を受けたSARS患者で無血管性骨壊死と骨粗しょう症が報告された59。ある無作為化二重盲検プラセボ対照試験では、発熱後のSARS-CoV-1の血漿中ウイルス量を経時的に測定し、発病後1週間以内のコルチコステロイドの使用がウイルス除去の遅延と関連していることが明らかにした75。
しかし、中国で行われた最近の研究では、COVID-19患者のARDS発症に関連する危険因子を検討した結果、メチルプレドニゾロンによる治療はARDS患者の死亡リスクを減少させることが明らかになった（ハザード比、0.38；95％信頼区間、0.20-0.72）45。これらのデータは、COVID-19患者の悪化が、重症ARDS患者にグルココルチコイドを投与することで緩和されるであろう免疫原性の病因、サイトカインストーム発生のため、二次的に起こるという理論を支持するものである。
SARS-CoV-2感染後、数日から数週間でCOVID-19患者の状態が悪化する原因はサイトカインストームではないかと次第に考えられてきており、炎症性細胞受容体拮抗薬や幹細胞治療が治療薬として使用される可能性を示唆している。現在、COVID-19肺炎の治療におけるトシリズマブ（IL-6受容体拮抗薬）について多施設臨床試験が進行中である20。 SARS-CoV-2への新規治療法に関する進行中の研究および臨床試験の総覧は、「Monthly Prescribing Reference」で確認できる。
多くの文献によると、COVID-19患者が重篤なARDSへ悪化するのに重要な役割を果たすと考えられているサイトカインの一種であるIL-6の抑制など、クロロキンには多様な抗ウイルス作用や免疫調節作用があるとされている20,76。また、クロロキンは、鳥インフルエンザや SARS-CoV-1に感染した動物モデルにおいても有効な抗ウイルス薬として作用することが示されている77,78。中国からの未発表データによると、クロロキンは COVID-19 の治療薬として研究され、良好な結果が得られたことが示されている79。広東省科学技術部と広東省衛生委員会は、新規コロナウイルス肺炎に対するクロロキンの治療法として1回500mgを1日2回経口投与することを禁忌がなければ推奨するという専門家によるコンセンサスを先日報告した80。Clinical Infectious Diseases誌に発表された最近の研究では、生理学的に基づいた薬物動態モデルを用いて、肺組織においてクロロキンよりもヒドロキシクロロキンの力価が高いことが示された（EC50 = 0.72μM[ヒドロキシクロロキン] vs 5.47μM[クロロキン]）。この研究では、負荷投与として1回400mg・1日2回を1日間投与し、その後1回200mg・1日2回を4日間維持投与することが推奨されている81。これらの薬剤のヒトにおけるCOVID-19に対する治療薬および予防薬としての使用を正式に調査するための臨床試験が進行中である82。20人の患者を対象とした最近の非ランダム化臨床試験では、COVID-19患者において、ヒドロキシクロロキンでの治療がウイルス量の減少と消失に有意に関連しており、この効果はアジスロマイシンの併用により増大したことが明らかになった。ヒドロキシクロロキンの投与量は1日600mg、アジスロマイシンの投与量は初日に500mg、以後の4日間は1日250mgを投与した83。（「この論文はプレプリントであり、査読を受けていない。この論文はまだ評価されていない医学研究を報告しているため、臨床診療の指針とすべきではない」と出版社が表明していることに注意すること。）
COVID-19患者における最適な輸液管理については、現在のところ重要な文献はなく、また、ウイルス感染に続発する新規発症のうっ血性心不全についての文献もない。前述のように、急速に悪化するCOVID-19患者の病態生理学における主な機序は、ARDS（非心原性肺水腫）が過剰な炎症状態によって引き起こされるというものである。これは細菌感染での敗血症に見られるような血液分布異常性ショックや循環血液量減少性ショックではなく、結果として生じる肺水腫が重症COVID-19患者にとって、命に関わる最大の危機であることを考えると、著者らはケースバイケースでの輸液に対する賢明なアプローチを推奨している。
悪化してICUレベルの治療を必要とする患者では、臨床医は必要に応じて非侵襲的換気療法（NIV）や人工呼吸器管理、体外循環による長期間の生命補助を検討すべきである39。ARDSへの進行と呼吸の代償不全は、COVID-19の病態に中心的な役割を果たしている。この意味で、COVID-19患者の管理においては、以下の治療原則が重要である。
イタリア・ベルガモのある救急外来におけるAndrea Duca医師による未発表の予備データによると、2020年2月29日から3月10日までの間にCOVID-19が疑われる患者が救急外来を受診し、酸素療法のために入院を必要とした患者の割合が138％増加したことが示されている。入院した患者のうち、31％は最大量の酸素投与でも低酸素状態が続いたため、救急外来で人工呼吸器による治療を開始しており（CPAP：81％、NIV：7％、侵襲的換気療法：12％）、82％は中等度から重度のARDSの基準を示した。
中国とイタリアのデータによれば、低酸素血症のCOVID-19患者はPEEPによく反応することが示されており、このことは気管挿管を防ぐための治療的および一時的な措置としてのNIVが重要な役割を果たすことを示している45。中国での後ろ向きの分析による統計データでは、入院患者の最大30％がNIVを必要としていることが示され84、イタリアの初期報告では31%に達することが示された。現在の疫学的傾向を踏まえると、積極的な準備を講じなければ、すべての病院ではないにせよほとんどの病院で、これらの必要性が現在のキャパシティを上回る可能性は高い。中国とイタリアの最新のデータに基づき、我々は以下の事項を推奨する。
1本蛇管のNIV機器、装着のデモンストレーション、PEEPバルブの前にウイルスフィルターが付いたヘルメット型CPAP機器の画像については、図10、11、12を参照。
患者が重度の呼吸窮迫を呈した場合、またはNIVを事前に使用できない場合、臨床医は侵襲的換気療法と気管挿管の準備をしなければならない。Rapid Sequence Intubation(RSI)の手順については、表8を参照のこと。
従来の方法を用いることでの、前酸素化の役割とウイルス粒子拡散の可能性については、現在も議論されているところである。このテーマに関するレビューはEMCritに掲載されている。差し当たって、一般的に用いられている選択肢は以下の通り。
適応、原理、及び様々なタイプの機械的換気についての簡単な概要については、Hickey et alを参照のこと。COVID-19の患者において、低容量換気でARDSの死亡率の改善が示されたARDSnet試験に基づいた「肺保護戦略」のセクションに特に重点を置くべきである85。
簡潔に説明すると、1回換気量（TV）は理想体重に基づいて、最初は6mL/kgに設定すべきである。患者が急性肺障害を発症し、ARDSへと進行すると、肺が徐々に虚脱しシャントが形成され、機能的な肺容量が減少する。低容量換気戦略は、機能的な肺の容積の減少を打ち消してくれる。1回換気量は、分時換気量の目標に基づいて調整すべきではない。呼吸回数が、分時換気量の目標および患者の酸塩基平衡に基づいて調整される。ほとんどの患者で正常二酸化炭素状態を達成するためには、16回/分の初期換気回数が適切である86。
機械的換気療法を必要とする患者の数が利用可能な人工呼吸器の数を上回るような災害レベル時には、人工呼吸器を操作して複数の患者に空気の流れを分割することができる。その方法についてのビデオチュートリアルはこちらをクリックすること。
この方法の主なポイントは以下の通り。
CDCに記載されている年齢別入院率からわかる通り、小児は重篤な合併症や死亡を比較的免れているように思われる。（表6参照）。現段階においては、米国及び北イタリアの共著者の経験の範囲で小児死亡例の報告はない。しかし、2020年3月16日にPediatrics
中国での小規模な後ろ向き研究では、SARS-CoV-2陽性が確定した20名の小児患者の胸部CT、プロカルシトニンを含む検査マーカーについて解析を行っている。プロカルシトニンは16/20例で上昇、10/20例でhaloを伴うコンソリデーション、12/20例でGround-glass opacitiesを認めた。この結果から、小児（8/20）では合併感染が多い可能性が示唆される58。小児では成人と比して合併症や死亡を免れているかもしれないとは言え、臨床医は彼等がより脆弱な群に感染を生じうることを認識し、社会的距離戦略を奨励すべきである。アメリカの小児人口におけるさらなる調査が、小児における重症例への理解とマネージメントの助けとなるだろう。
COVID-19の妊婦についてのデータは依然として不足している89。一般的に、SARS-CoV-2感染の妊婦は、非妊婦と同様の特徴を有している。9名の後顧的レビューで、Chen等はSARS-CoV-2の母体ー胎児感染のリスクを解析し、SARS-CoV-2陽性母体から子宮内感染を生じる可能性は低いと示された90。加えて、SARS感染妊婦と違い、それらの症例では妊娠に関係した合併症が極めて少ないことも判明した91,92。明らかなことではあるが、SARS-CoV-2感染が母親から胎児へ垂直感染するリスクについてより評価するためにより規模の大きい研究が必要である。
Shared decision-makingというのは、科学的根拠、臨床医の経験、患者の価値観や嗜好を考慮したうえで、患者と医療提供者が医療上の決断を一緒に行う協調的なプロセスのことである。SARS-CoV-2感染症の検査と治療の基礎となる科学的根拠はまだ浅く、急速に進歩しているところであるが、一定の知識は知られており、他の重篤な感染症からの外挿が妥当とされている。COVID-19に関連してSDMに適した臨床シナリオは少なくとも2つある：(1)症状の軽い患者におけるSARS-CoV-2の検査、(2)重症患者におけるケア目標の検討である。
本稿執筆時点では、COVID-19に有効であることが証明された治療法がないことを考えると、症状の軽い患者で本疾患の診断を行っても、臨床行動を変えないかもしれない。SARS-CoV-2の検査を行わず、典型的なウイルス性上気道感染症に用いられるような標準的な支持療法を患者に推奨して良い。これには、市販の解熱剤、鎮咳剤、鼻炎薬、鎮痛剤、経口補水液、安静が含まれる。また、COVID19が他の人に広がるのを防ぐために、患者は自己隔離を行うように指示される。RT-PCRを用いたSARS-CoV-2の現在の検査では、感度は60％から90％の間であり、偽陽性または偽陰性の結果が得られる可能性がある。検査資源に限界があるという現実的な可能性を考えると、COVID-19の可能性がある患者の検査を見送り、ウイルスを持っているものと仮定して、社会的に適切な予防措置をとるのが妥当かもしれない。協会や政府の保険機関からの検査に関するガイダンスが急速に変化していることを考えると、自らの病院、州、または地域の方針に従うべきであり、患者にもそれを説明すべきである。
また、shared decision-makingに適したもう一つの臨床シナリオは、高齢または重度の併存疾患のために予後不良の呼吸不全患者に対する気管挿管である。ARDSはCOVID-19を有する多くの患者にとってありふれた最終経過であるため、この判断には頻繁に遭遇すると思われる。初期の研究では、高齢者、特に80歳以上の患者の死亡率が高いことが示されている。このシナリオでは、医療提供者は、患者またはその代理人と共同で気管挿管が妥当であるかどうかを決断するプロセスに潜在的に取り組むことができる。これは、進行した高齢者や末期疾患を持つ患者で、コードに関して行われる、他のケアのゴールの話し合いと同様である。
当初は、私たちはまだパンデミックではない未来について予測した。残念ながら、未来はここにあり、私たちは都市、国、大陸を閉鎖したパンデミック拡大の真っ只中にいるのである。私たちは、過去の出来事を見て、他の人の失敗から学び、COVID-19がまだ氾濫していない世界の地域のために、改善の機会を模索することが最善手なのかもしれない。
COVID-19を理解し、コントロールしようとする公衆や医学界の試みとして、"コミュニティにおける伝播（Community spread）"、"ステルス感染（stealth transmission）"、"社会的距離戦略（Social distancing）"、そして "流行曲線を緩やかにする（Flattening the curve）"は、一般的な言い回しになっている。パンデミックインフルエンザに模するR0値を持つSARS-CoV-2の拡散と封じ込めは、これまでにない課題に直面している93。私たちは日々変わっていく情報（そして誤情報）が医療界を含む一般社会に更なる試練を課していることを認識し続けているのである。Lancetはオンライン論説を発表し、CDCやWHOを通じて検証された情報を求め、ソーシャルメディアやその他の未検証の情報源を避けることを医療界と一般市民に訴えている。多くの人が心配しているのは、健康な患者が救急外来に現れ、すでに過剰な負担を強いられているシステムに負担をかけてしまうことである。これは、病院の指導者が遠隔医療のオプションを開発および/または拡大する機会であり、軽度の症状を持つ心配した健康な患者やリスクの低い患者が地域の救急外来を圧倒するのを最小限に抑えるためである。
現在、SARS-CoV-2のワクチンを求めて複数のバイオテクノロジー企業や製薬企業が競争しており、研究は有望ではあるが、普及と使用には少なくとも18ヶ月（2021年夏）の時間を要する。SARS-CoV-2のDNAワクチンはヒト臨床試験を開始し、ベクターベースの2種はヒト臨床試験を開始している。タンパクベースのワクチンはまだ臨床前の段階である72。ワクチン開発の成功には、ウイルスの伝達、病原性、免疫応答の不完全な理解、最適な動物チャレンジモデルや標準化された免疫学的アッセイの欠如などの課題が残されている。
私たちは、中国、ワシントン州、イタリア、そして現在のニューヨーク都市圏が、まだSARS-CoV-2が氾濫していない世界の残りの地域のための手本となるべきだと考えている。症例の猛攻に備えることは、すべての医療システムが受け入れなければならない最初のステップである。中国、韓国、その他の地域では、感染者やその疑いのある人を早期に検査して隔離することが有効であることが示されているが、ニューヨーク市のように、大量の検査や迅速な感染拡大の封じ込めのための準備ができていない地域では、悪影響を及ぼしていることが示されている。
SARS-CoV-2に曝露された患者やCOVID-19に関連する症状を持つ患者が大量に流入した場合には、直ちに隔離が必要である。1人の感染者が混雑した救急外来のトリアージエリアに現れた場合、ウイルスが拡散し、他の患者を汚染する可能性が高くなる。CDCは、救急外来と病院の入り口に、十分な量のタッチレス手指消毒器と、配布しやすいフェイスマスクの箱を置くことを推奨している。また、施設に入る人には、「直ちにマスクを着用し、評価中は着用したままにすること、咳やくしゃみをするときは口や鼻を覆うこと、ティッシュを慎重に使用して廃棄すること、呼吸器分泌物に接触した後は手指の衛生を行うこと」を助言する標識を設置することも推奨している94。筆者等は病院および部門指導者が以下の指針に従うことを推奨する。
多くの人々を救い、罹患率を減らすための唯一の最善の方法は、受動的ではなく、積極的に行動することである。 この危機の真っ只中にいる私たちは、患者がゼロであった瞬間から、今までとは異なることをして、上記の推奨事項を実行できていればよかったと思っている。 私たちが早期検査と厳格な隔離をできていなかったことは、疫学者が感染症の発生を制御するために推奨していることに反している。私たちの失敗から学んでほしい。
あなたはすぐに個人防護具(PPE)を適切に着用するべきだと認識した。あなたと看護師は完璧なPPEを着用し、患者のバイタルサインを計測し、体温39.6℃ [103.3°F]、脈拍106回/分、呼吸数22回/分、血圧102/68mmHg、室内気でのSPO2 89%と確認した。できるかぎり多くの肺を可視化するためベットサイドで肺超音波検査のテクニックである「lawnmower法(肺の領域を分割して観察する方法)」を行った。すると、Bラインの合流が特徴的な「waterfallサイン」が背側の肺に確認された。あなたは患者を陰圧隔離室に入れ、すぐに酸素吸入を開始、彼の旅行歴、COVID-19の暴露歴(人との接触)を確認した。慎重かつ適切にPPEを脱ぎ、病院の感染症チームに連絡をとったところ、感染症チームより、患者と接触した可能性ある者の特定をお願いするために地元保健所にも連絡するように指示された。撮影しても患者マネジメントは変わらないのでCTの撮影は見送った。Dダイマー、プロカルシトニン、LDHを含む一連の検査を送り、細菌性肺炎の経験的治療を開始、追加治療の推奨に関するCDCとWHOの最新ガイダンスを参照し、患者状態が悪化してARDSを発症した場合にのみステロイドを考慮することを忘れないようにした。残った「心配性の患者さん」と臨床的に安定している患者には、CDCの最新の推奨事項を適用し、各々のリスクに準じて、対症療法またはCOVID-19の外来検査が行われ、14日間の隔離と症状のモニタリングを徹底した。当座の検査、治療法について自地域の保健所に相談すれば、自宅隔離での十分な管理を行うことが出来る。
| 組織 | リンク |
|---|---|
| United States Centers for Disease Control and Prevention | Coronavirus Disease 2019 (COVID-19) |
| World Health Organization | Coronavirus disease (COVID-19) outbreak |
| Johns Hopkins University | COVID-19 Global Case Tracker |
| United States Department of Labor, Occupational Safety and Health Administration | COVID-19 Additional Resources |
| American College of Emergency Physicians | COVID-19 Clinical Alert |
| The Lancet | COVID-19 Resource Centre |
Evidence-Based Medicineでは、研究方法と被験者数に基づいて文献を批判的に吟味する必要がある。すべての文献が同じように強固なエビデンスで支持されるとは限らない。大規模で前向き、無作為化、盲検化された試験の結果は、症例報告よりも重みを持つべきである。
読者が各参考文献の強さを判断できるように、研究の種類や研究に参加した患者数など、研究に関する関連情報は、入手可能な場合には参考文献の後に太字で記載している。
I coronavirus ricevono il loro nome dalle caratteristiche particelle virali (virioni) simili ad una corona che punteggiano la loro superficie. Questa famiglia di virus infetta un ampio spettro di vertebrati, in particolare mammiferi ed uccelli, ed è considerata una delle maggiori cause di infezioni respiratorie virali in tutto il mondo.3,4 Con la recente identificazione del nuovo coronavirus 2019 (SARS-CoV-2) e la derivante malattia a cui ha dato il nome, la malattia da coronavirus (COVID-19), sono ad oggi noti un totale di 7 coronavirus capaci di infettare l’uomo:
Prima dell’epidemia globale di SARS-CoV-1 nel 2003, HCoV-229E e HCoV-OC43 erano gli unici coronavirus noti per essere in grado di infettare l’uomo. In seguito all’epidemia di SARS-CoV-1, altri 5 coronavirus sono stati scoperti nell’uomo, piu’ recentemente il nuovo SARS-CoV-2, che si crede essere originato a Wuhan, nella provincia di Hubei, in Cina. SARS-CoV-1 e MERS-CoV sono particolarmente virulenti per gli esseri umani e sono associati ad alta mortalità. In questo articolo verrà analizzata l’epidemiologia, la fisiopatologia e la gestione clinica dell’infezione da COVID-19, con particolare attenzione alle migliori pratiche cliniche e ai risvolti per la salute pubblica.
Le pubblicazioni dal 2012 al 2020 disponibili negli archivi di Pubmed, ISI web of knowledgeweb of knowledge e Cochrane sono state consultate attraverso l’utilizzo di parole chiave come: pronto soccorsopronto soccorso, epidemiaepidemia, pandemiapandemia, coronaviruscoronavirus, SARS-CoV-2 SARS-CoV-2 e COVID-19.COVID-19. Sono stati anche consultati i siti web del Centro Statunitense per il Controllo e la Prevenzione delle Malattie (CDC), dell’Organizzazione Mondiale della Sanità (WHO), del Ministero della Salute, del Lavoro e dell’Economia Giapponese e l’EMCrit.
Fino alla data del 22 marzo 2020, i casi confermati di COVID-19 in tutto il mondo sono circa 328,275, con la maggior parte dei nuovi casi attualmente rilevati al di fuori del territorio Cinese. Le morti confermate sono circa 14,366.1 Per un numero aggiornato dei casi confermati e dei morti da COVID-19, visitare Johns Hopkins University online tracker. Al momento di questa pubblicazione, i casi confermati riguardano 169 paesi di tutti i continenti eccetto l’Antartide, evento che ha spinto la WHO a dichiarare lo stato di pandemia di SARS-CoV-2. Per quanto riguarda le morti registrate, più di metà sono attualmente avvenute al di fuori della Cina, con a capo Italia (5,476 morti) ed Iran (1,685 morti). Il tasso di mortalità globale attuale è del 4.38%. In virtù della coincidenza dell’epidemia di COVID-19 con la celebrazione del Capodanno lunare cinese a fine gennaio 2020 associata ad un’affluenza di circa 15 milioni di visitatori nella città di Wuhan, gli sforzi per contenere l’epidemia nei confini cinesi alla fine non hanno avuto successo. I report iniziali sulle popolazioni di pazienti affetti negli ospedali in Cina indicano che la maggior parte di coloro che presentavano malattia grave ed esiti peggiori (definiti come cure di livello intensivo e mortalità) tendevano a essere pazienti con comorbidità quali ipertensione, diabete, obesità, asma, broncopneumopatia cronica ostruttiva o età avanzata. 2,6
In epidemiologia, il valore R0 (pronunciato "R-zero") è noto come numero di riproduzione di base e può essere considerato come il numero atteso di casi generati direttamente da 1 caso in una popolazione in cui tutti gli individui sono suscettibili all’infezione. I primi studi epidemiologici nel caso di COVID-19 hanno stimato un valore di R0 di 2.2 (90% high density interval: 1.4-3.8), un valore simile a SARS-CoV-1 e all’influenza pandemica, suggerendo la possibilità di una trasmissione prolungata da uomo a uomo e il rischio di una pandemia globale. Come verrà discusso più dettagliatamente nella sezione "Prevenzione", il fattore R0 è lo specchio sia del comportamento del virus sia di quello umano, quindi con i corretti interventi sociali e comportamentali, tale valore di R0 può essere ridotto.
Dopo solo pochi mesi dal primo caso, il bilancio delle vittime da SARS-CoV-2 ha superato notevolmente quello di MERS-CoV e SARS-CoV messi insieme.1 Si ritiene che il vero tasso di mortalità sia inferiore al tasso di mortalità riportato per numero di casi, a causa di un bias di selezione, in quanto solo quelli con sintomatologia sufficientemente grave da richiedere una valutazione in emergenza e/o il ricovero in ospedale sono stati testati per COVID-19. 8 I dati provenienti dal focolaio della nave da crociera Diamond Princess forniscono una fotografia unica della vera mortalità e della sintomatologia della malattia, dato che tutti i passeggeri sono stati testati, indipendentemente dai sintomi. Sulla base di questi dati, analisi realizzate presso la London School of Hygiene and Tropical Medicine, non ancora pubblicate, hanno stimato che il tasso di mortalità riportato per numero di casi aggiustato per età sia pari allo 0.5%. Ad ogni modo, ciò classificherebbe la mortalita’ da COVID-19 come superiore a quella dell'influenza pandemica, mantenendo allo stesso tempo un profilo infettivo simile.9 Inoltre, secondo il Ministero Nazionale Giapponese per la Salute, il Lavoro e il Benessere, 327 delle 697 persone a bordo della nave che sono risultate positive per COVID- 19 non hanno mai mostrato sintomi, anche fino a un mese dopo il test positivo iniziale.10
Siamo fortunati a fornire una prospettiva diretta della crisi di COVID-19 in Italia, avvenuta poche settimane dopo il primo caso riportato dallo stato di Washington (21 gennaio), e di cio’ che gli epidemiologi hanno stimato essere circa 2-3 settimane in anticipo rispetto all’epidemia nell'area metropolitana di New York. Il Dr. Andrea Duca è un medico d’emergenza e membro del comitato editoriale del Emergency Medicine PracticeEmergency Medicine Practice con sede nel Nord Italia, un’area che ha subito l’iniziale onda d’urto del COVID-19. Il Dr. Duca riferisce che la rapida diffusione di SARS-CoV-2 ha portato al sovraccarico della maggior parte degli ospedali, impreparati a fronteggiare l'improvviso afflusso di pazienti che richiedevano supporto ventilatorio. Ad oggi (18 marzo 2020), l'Italia ha un tasso di mortalità riportato per numero di casi dell'8.37%, che deve servire come monito per gli altri sistemi sanitari nel mondo che si stanno preparando a trattare pazienti con infezione grave da COVID-19 nelle prossime settimane. Vedere la Tabella 1 per una sintesi delle lezioni imparate dal Dr. Andrea Duca durante la gestione dell'epidemia di SARS-CoV-2 nel suo Pronto Soccorso a Bergamo. Ulteriori dati provenienti da quell'ospedale sono inclusi nelle Figure 1, 2, 3 e 4. La Figura 1 mostra la cronologia dei casi di COVID-19 nella regione Lombardia, dal 20 febbraio al 17 marzo 2020; la Figura 2 mostra le percentuali giornaliere di ricoveri e dimissioni di pazienti affetti da COVID-19, dal 29 febbraio al 10 marzo 2020; la Figura 3 mostra il numero totale giornaliero di ricoveri e dimissioni di pazienti affetti da COVID-19; la figura 4 mostra una rappresentazione grafica della condizione dei pazienti affetti da COVID-19, dal 29 febbraio al 10 marzo 2020.
I coronavirus appartengono all’ordine dei Nidovirales, alla famiglia dei Coronaviridae e alla sottofamiglia degli Orthocoronavirinae. I coronavirus sono avvolti da RNA a singolo filamento a senso positivo e possiedono il più grande genoma di tutti i virus RNA. Due terzi del genoma dei coronavirus al capo 5’ codifica per le proteine virali coinvolte nella trascrizione dell'RNA virale e della replicazione, mentre il terzo all’estremita’ 3' codifica per le proteine virali strutturali e accessorie specifiche del gruppo.4 Allo stato attuale sono note 4 proteine principali nei coronavirus: proteine S (spike), E (pericapside), M (membrana) e N (nucleocapside). Tali biomarcatori svolgono un ruolo centrale non solo nel modo in cui facciamo diagnosi di malattia, ma anche per la futura comprensione del profilo di patogenicità e, in definitiva, per qualsiasi possibilita’ di disporre di un vaccino e/o un trattamento antivirale diretto, mirato a disinnescare il ciclo di vita virale. (Vedi Figura 5).
Si ritiene che i virus SARS-CoV-1 e MERS-CoV siano derivati dalla diffusione zoonotica di una popolazione di pipistrelli.11 La denominazione del virus che causa l'attuale pandemia di "SARS-CoV-2" è il risultato della sua somiglianza genetica con il virus che ha causato l’epidemia nel 2003, che ora si chiama "SARS-CoV-1". Mentre i coronavirus si sono probabilmente evoluti nel corso di migliaia di anni rimanendo confinati nelle popolazioni di pipistrelli, i mammiferi (come i gatti civet nel caso di SARS-CoV-1 e i cammelli dromedari nel caso di MERS-CoV) sono stati implicati come ospiti intermedi e probabilmente hanno avuto un ruolo nella trasmissione definitiva di questi nuovi coronavirus all'uomo.12,13 Si sospetta che l’epidemia di COVID-19 abbia avuto origine nei mercati di frutti di mare di Hunan nella città di Wuhan, tuttavia, altri ricercatori hanno suggerito che questo mercato potrebbe non essere la fonte originale di trasmissione virale all'uomo.2,14 I pipistrelli sono rari nei mercati in Cina, ma sono cacciati e poi venduti direttamente ai ristoranti come prodotto alimentare.15
I coronavirus infettano principalmente le vie respiratorie e gastrointestinali superiori di uccelli e mammiferi. La glicoproteina spike di superficie (proteina S) è un fattore chiave nella virulenza dei coronavirus, poiché consente di legarsi alle cellule ospiti. È stato dimostrato che MERS-CoV si lega alla dipeptidil-peptidasi 4 (DPP4), una proteina che è stata conservata fra specie note per ospitare questo ceppo di coronavirus. Mentre la maggior parte dei virus respiratori infetta le cellule ciliate, il DPP4 è espresso in cellule non ciliate delle vie respiratorie umane, e quest’ultimo si ritiene possa essere un fattore importante nella sua trasmissione zoonotica e nell'elevato tasso di mortalità riportato per numero di casi.16 In SARS-CoV-1, l'enzima umano convertente l'angiotensina 2 (ACE2) era il recettore cellulare primario a cui si legava il virus e si ritiene abbia avuto un ruolo nella capacità di SARS-CoV-1 di produrre infezioni delle vie respiratorie sia superiori che inferiori, contribuendo alla sua infettività e letalità.17
Precedenti studi hanno suggerito che l'immuno-patogenesi, nota anche come "tempesta di citochine", porti al deterioramento dei pazienti affetti da vari virus respiratori, tra cui SARS-CoV-1 e influenza aviaria.18,19 Numerosi studi supportano la teoria secondo cui il rapido peggioramento dei pazienti COVID-19 è mediato da immuno-patogenesi, per cui il rilascio di marker infiammatori induce un ciclo a feedback positivo che porta ad ARDS, insufficienza multiorgano e morte 20 In Cina, in una coorte di 41 pazienti con positivita’ per COVID-19 confermata in laboratorio , sono stati trovati livelli significativamente più alti di marker infiammatori (IL-2, IL-7, IL-10, GSCF, IP-10, MCP1, MIP1 e TNF-alfa) in pazienti in UTI rispetto ai pazienti non in UTI.21 Uno studio recente condotto in Cina fornisce un report immunopatologico dettagliato su SARS-CoV -2, suggerendo che i pazienti affetti da COVID-19 grave esprimono una "...eccessiva attivazione della risposta immunitaria...da parte di cellule Th1 patogene e monociti infiammatori", scoperte che sono state inoltre supportate da analisi immunoistochimiche di biopsie polmonari post-mortem su pazienti affetti da COVID-19. 22,23 Un corpus crescente di letteratura suggerisce che la linfoistiocitosi emofagocitica secondaria o indotta dal virus (HLH), una sindrome iperinfiammatoria, sia la causa sottostante del peggioramento di tali pazienti. Questo processo patologico ha un profilo citochinico simile ai pazienti con COVID-19 e include caratteristiche cliniche cardinali quali febbre prolungata, citopenie, iperferritinemia e coinvolgimento polmonare.24,25 Le terapie immuno-modulanti attualmente sotto valutazione nel trattamento di COVID-19 saranno discusse nella sezione "Gestione Clinica”.
SARS-CoV-2 penetra nei pneumociti di tipo 2 nell'uomo attraverso lo stesso recettore ACE2 del SARS-CoV-1.26 Uno studio di coorte retrospettivo multicentrico che esamina i fattori di rischio associati alla mortalita’ ospedaliera ha riscontrato che l'ipertensione è la comorbidità più comune nei pazienti con diagnosi di COVID-19 che necessitano ricovero (30%), seguita dal diabete (19%).27
E’ stato studiato molto nelle ultime settimane circa il potenziale legame tra gli anti-ipertensivi comunemente usati, ACE-inibitori (ACEi) e antagonisti dei recettori dell'angiotensina (ARB), e il rischio elevato di infezione severa da COVID-19 basato sul legame di SARS-CoV-2 ai recettori ACE2. Al momento, le raccomandazioni ufficiali della European Society of Cardiology, dell'American College of Cardiology, dell'American Heart Failure Society e della Heart Failure Society of America affermano collettivamente che i pazienti trattati con ACEi e ARB dovrebbero continuarne l’assunzione. La European Society of Cardiology ha affermato che "non esistono prove cliniche o scientifiche che suggeriscano che il trattamento con ACEi e ARB debba essere interrotto a causa dell'infezione da COVID-19"28 e la nota congiunta di HFSA / ACC / AHA ha osservato che "non esiste alcun dato sperimentale o clinico che dimostri esiti positivi o negativi in pazienti affetti da COVID-19 che usano ACEi o ARB." 29
Simili preoccupazioni sono state sollevate sull'uso di farmaci anti-infiammatori non steroidei (FANS), come ibuprofene, sulla base delle interazioni ipotizzate tra SARS-CoV-2 e i recettori ACE2. Tuttavia, non ci sono attualmente evidenze scientifiche che suggeriscano che l'assunzione di FANS peggiori l’infezione da COVID-19. Chiaramente, dovrebbero essere condotti studi multicentrici prospettici per indagare ulteriormente su questo aspetto. Una discussione completa sui benefici e rischi teorici per i pazienti che assumono questi farmaci si puo’ trovare su "NephJC"
Molto può essere appreso dal cambiamento delle dinamiche della trasmissione a seguito dell'attuazione di severe restrizioni di viaggio e misure di quarantena nel territorio cinese. Uno studio di modelli matematici pubblicato su The LancetThe Lancet ha stimato che il numero mediano di riproduzione giornaliera (RRt) a Wuhan è diminuito da 2.35 (intervallo di confidenza al 95% [CI], 1.15–4.77) una settimana prima dell'introduzione delle restrizioni di viaggio introdotte il il 23 gennaio 2020, a 1.05 (0.41–2.39) 1 settimana dopo.30 L'efficacia di ampi interventi governativi e sociali è stata documentata da molteplici analisi basate su dati e dovrebbe indurre tutti i governi ad agire di conseguenza per dare la priorità a individuazione precoce, isolamento e trattamento; per mettere a disposizione adeguate forniture mediche; e per stabilire un sistema in cui i pazienti siano ricoverati negli ospedali designati con una strategia terapeutica completa.30,31 Utilizzando un modello di trasmissione stocastica parametrizzato all'epidemia di COVID-19, Hellewell e colleghi hanno concluso che "è sufficiente un'efficace tracciabilità dei contatti e l'isolamento dei casi per controllare un nuovo focolaio di COVID-19 entro 3 mesi.”32
Uno studio pubblicato il 16 marzo 2020 dall'Imperial College di Londra e dall'OMS ha confrontato 2 strategie fondamentali per ridurre il tasso di diffusione di SARS-CoV-2: “(a) mitigazione, che si concentra sul rallentamento ma non necessariamente sull'arresto della diffusione dell'epidemia - riducendo il picco della domanda di assistenza sanitaria e proteggendo nel contempo le persone maggiormente a rischio di malattia grave in caso di infezione e (b) soppressione, che mira a invertire la crescita dell'epidemia, riducendo il numero dei casi a bassi livelli e mantenendo tale situazione indefinitamente. " Lo studio ha scoperto che "... politiche di mitigazione ottimali (che combinano l'isolamento domestico di casi sospetti, la quarantena domestica di familiari di casi sospetti e il distanziamento sociale di anziani e altri a maggior rischio di malattia grave) potrebbero ridurre il picco della domanda di assistenza sanitaria di due terzi e dimezzare le morti. Tuttavia, la conseguente epidemia attenuata risulterebbe comunque in centinaia di migliaia di decessi e al collasso dei sistemi sanitari (in particolare le unità di terapia intensiva)".33 Ciò fornisce una chiara spiegazione ed offre sostegno alle misure aggressive adottate dai paesi negli ultimi giorni per combattere la diffusione della pandemia di SARS-CoV-2.
Report dall'Italia suggeriscono che fino al 20% degli operatori sanitari che si occupano di pazienti COVID-19 sono stati infettati dal virus, con alcuni decessi segnalati.34 Perdere operatori sanitari a causa della malattia in un momento in cui sono necessari mai come prima e’ il punto di non ritorno per sistemi sanitari gia’ sotto stress fino al rischio di collasso per via degli elevati flussi di pazienti. Il riconoscimento della crisi in Italia sottolinea l'importanza di applicare rigorosamente misure preventive da parte di tutti gli operatori sanitari. Ciò è stato realizzato in alcuni sistemi, assegnando ad una persona il compito di monitorarne l’aderenza in PS in ogni momento.
In base alle specifiche modalita’ di trasmissione dei coronavirus come classe e ai modelli di trasmissione documentati dalle epidemie di SARS-CoV-1 e MERS-CoV, si presume che la trasmissione di SARS-CoV-2 avvenga principalmente attraverso goccioline e fomiti, sebbene le particelle virali siano state anche trovate nelle feci di pazienti sieropositivi. Un articolo in pre-stampa pubblicato sul New England Journal of MedicineNew England Journal of Medicine da ricercatori del National Institute of Health degli Stati Uniti, della Princeton University e dell'Università della California di Los Angeles, ha stimato le emivite per il virus SARS-CoV-2 su varie superfici nel modo seguente: 1.1 ore in aerosol, 0.77 ore su rame, 3.46 ore su cartone, 5.46 ore su acciaio e 6.81 ore su plastica. Questi risultati hanno indicato una verosimile modalita’ di trasmissione via aerosol e fomiti da parte di SARS-CoV-2 e danno credito al suo alto tasso di diffusione riportato in letteratura.35
Sia le linee guida dell'OMS che quelle del CDC per il controllo delle infezioni, sottolineano l'importanza di una rigorosa igiene delle mani nella riduzione della trasmissione di SARS-CoV-2. Ciò deriva dall'incertezza intorno ai vettori di trasmissione a bordo della nave da crociera Diamond PrincessDiamond Princess in quarantena al largo delle acque costiere del Giappone, nonché dai crescenti report da tutto il mondo sulla comparsa di COVID-19 in persone che non avevano avuto contatti diretti con portatori noti o sospetti o viaggiatori in una zona endemica.36,37 Dati i report del CDC cinese sul ritrovamento del virus SARS-CoV-2 nelle feci di pazienti sieropositivi, la probabilità di trasmissione oro-fecale e, quindi, tramite le mani è molto alta.38 Gli operatori sanitari e i pazienti dovrebbero seguire le tecniche standard di lavaggio delle mani: lavarsi le mani con acqua e sapone per almeno 20 secondi, soprattutto dopo essere andati in bagno; prima e dopo aver mangiato; e dopo aver soffiato il naso, tossito o starnutito. Se il sapone e l'acqua non sono disponibili, si dovrebbe usare un disinfettante a base alcolica con almeno il 60% di alcol.5
Linee guida aggiuntive per coloro che hanno contatti stretti ed esposizioni sospette includono: “forte raccomandazione" a cure mediche immediate, a un periodo di osservazione di 14 giorni, a indossare una maschera in caso di tosse o sintomi da infezione delle vie respiratorie alte, a prediligere mezzi di trasporto privato rispetto a mezzi pubblici, a preavvisare l'ospedale (o la clinica) prima dell'arrivo del paziente e alla pulizia del veicolo di trasporto con disinfettante a base di 500 mg/L di cloro, facendo circolare l’aria. 39 Va notato che il periodo di osservazione raccomandato potrebbe essere presto modificato, visto che recenti case report e studi clinici suggeriscono periodi di incubazione da 0 a 24 giorni. 40,41
Date le recenti carenze di maschere respiratorie FFP2 /FFP3 e altri DPI, vi è una crescente necessità di seguire le attuali raccomandazioni per tenere conto della disponibilità variabile di questi forniture. Queste raccomandazioni possono e dovrebbero essere seguite in tempo reale utilizzando i riferimenti forniti nella Tabella 9. Inoltre, recenti valutazioni includono la raccomandazione di dedicare intere unità ospedaliere alla gestione esclusiva di pazienti sospetti o affetti da COVID-19 mediante personale sanitario ad hoc, insieme alla necessità di disporre di stanze di isolamento a pressione negativa per infezioni a trasmissione aerea (AIIR).2
La svestizione dei dispositivi di protezione individuale (DPI) è spesso la procedura più a rischio durante l'interazione medico-paziente, in termini di diffusione del SARS-CoV-2. Di seguito è riportato un semplice approccio passo dopo passo elaborato dai medici d’emergenza su EMCrit sulla corretta svestizione dei DPI dopo la valutazione di un paziente sospetto o confermato di positivita’ al COVID-19.42 (Vedi Tabella 2.)
Un video sulle corrette procedure di vestizione e svestizione dei DPI è disponibile su YouTube
L'esperienza di Bergamo, nella regione Lombardia del Nord Italia, fornisce un modello di risposta che può aiutare altri sistemi ad essere preparati. I PS di quella regione hanno affrontato un volume straordinario di pazienti in gravi difficoltà respiratorie in un breve periodo di tempo che ha richiesto immediate modifiche al controllo del flusso e delle attività. Un riepilogo di queste modifiche e raccomandazioni è elencato nella Tabella 1. E’ necessario sottolineare che molti dei dati sono basati su stime derivanti da raccolte di dati preliminari.
Il personale del PS deve mantenere un alto livello di sospetto nella valutazione di tutti i pazienti, in particolare quelli con febbre, tosse, dispnea o segni di malattia respiratoria. Il CDC aveva inizialmente concentrato le proprie raccomandazioni di viaggio e di rischio epidemiologico su coloro che avevano effettuato di recente viaggi nella città di Wuhan, in provincia di Hubei, Cina o avuto contatti con viaggiatori provenienti dalle medesime zone; tuttavia, avendo raggiunto lo stato di pandemia con una significativa trasmissione in comunità, la connessione con la Cina non è più un criterio rilevante per l’esclusione dell'infezione da SARS-CoV-2.
Alla fine di gennaio 2020, sono stati pubblicati su The LancetThe Lancet i primi dati che descrivevano le caratteristiche cliniche, il decorso e la prognosi dell'infezione da SARS-CoV-2 rispetto alle 2 precedenti epidemie mortali di coronavirus (MERS-CoV e SARS-CoV-1). 21,43 Da allora, un'analisi di coorte retrospettiva multicentrica di 1099 pazienti è stata pubblicata sul The New England Journal of Medicine, che fornisce uno sguardo aggiornato sulle caratteristiche demografiche e cliniche del COVID-19. 41 La Tabella 3 distingue la sintomatologia dei pazienti con malattia grave da quelli con malattia non grave, come definito dalle linee guida dell'American Thoracic Society per la polmonite acquisita in comunità.44 I pazienti con malattia grave avevano un’eta’ mediana di 7 anni superiore a quelli con malattia non grave e avevano tassi di comorbidità molto più alti, come ipertensione (23.7% vs 13.4%, rispettivamente) e diabete (16.2% vs 5.7%, rispettivamente). Questa tabella e questo articolo possono essere visualizzati sul The New England Journal of Medicine. La Tabella 3 riassume le caratteristiche iniziali di SARS-CoV-2 rispetto a MERS-CoV e SARS-CoV-1.
Il 18 marzo 2020 l'American Journal of Gastroenterology ha pubblicato un nuovo studio del gruppo di esperti di Wuhan sul trattamento medico dell’infezione da COVID-19 in Cina che rivelava come i sintomi gastrointestinali, ad esempio la diarrea, fossero comuni nell'infezione da SARS-CoV-2.46 In 204 pazienti con confermata infezione da SARS-CoV-2, 99 (48.5%) presentavano sintomi gastrointestinali e 7 dei pazienti con sintomi gastrointestinali non presentavano alcun tipo di sintomo respiratorio. Questa è chiaramente una deviazione dall’orientamento vigente che inquadrava la malattia come puramente respiratoria, ma coerente con i modelli di trasmissione oro-fecale osservati nei primi studi cinesi che abbiamo citato. Inoltre, la prognosi dei pazienti con sintomi gastrointestinali era peggiore rispetto a quelli con sintomi puramente respiratori. Hanno scoperto che i pazienti senza sintomi digestivi avevano maggiori probabilità di guarire e di essere dimessi rispetto ai pazienti con sintomi digestivi (60% vs 34.3%). Gli autori non sono riusciti ad accertare la causa della differenza in termini mortalità e morbidità tra COVID-19, e si raccomandano ulteriori studi.46
Bisogna notare che nei dati preliminari di Bergamo, descritti dal Dr. Andrea Duca, si registra un’associazione dell’obesità con la gravità della malattia e la necessità di intubazione/terapia intensiva. Dagli stessi dati emerge che il tasso di pazienti che necessita di NIV o intubazione in PS sono simili ai dati di Wu e colleghi45, ovvero fino al 31% dei pazienti ricoverati in ospedale per sospetta infezione da COVID-19. È ancora troppo presto per sapere quanti dei pazienti che hanno iniziato la NIV in PS finiscono in ventilazione invasiva durante il ricovero in ospedale e quanti di coloro in ossigenoterapia si aggraveranno e dovranno essere ventilati. Questi dati sono ancora in fase di raccolta e analisi e saranno presto disponibili per una pubblicazione.
Entro 1 mese dagli iniziali report che descrivono in dettaglio l'epidemia di SARS-CoV-2, il CDC ha sviluppato un test di trascrizione inversa della PCR di tipo quantitativo (rRT-PCR) per rilevare SARS-CoV-2. Mentre i test diagnostici negli Stati Uniti erano inizialmente disponibili solo attraverso il CDC, questo test è stato reso disponibile a livello statale con l'uso dell'International Reagent Resource (IRR). L'IRR era stato inizialmente istituito dal CDC per lo studio e il rilevamento dell'influenza, ma è stato ampliato per includere l'influenza e i coronavirus di recente scoperta.47,48 Bisogna sottolienare che i pannelli virali respiratori ampiamente disponibili testano solo per le precedenti forme di coronavirus umani, ovvero i coronavirus umani 229E, NL63, OC43 e HKU1.49 I ceppi di SARS-CoV-1, MERS-CoV e SARS-CoV-2 richiedono test specialistici che stanno diventando sempre più disponibili. Sfortunatamente, gli iniziali forzi degli Stati Uniti nell’eseguire i test sono stati ostacolati da kit inizialmente difettosi (a causa di problemi con il reagente), risultando in una carenza di test disponibili per la maggior parte del paese. La Tabella 4 riassume le attuali raccomandazioni sui test per SARS-CoV-2.
Nonostante l’epidemia negli Stati Uniti sia in continuo peggioramento, c’è stata una significativa deviazione dalle precedenti indicazioni di testare a tappeto tutte le persone, incluso il personale sanitario a stretto contatto con casi sospetti o confermati di COVID-19,o con pazienti con storia di viaggio in aree endemiche entro 14 giorni dall'esordio dei sintomi. Al momento di questa pubblicazione infatti, l'attuale raccomandazione è di non testare gli operatori sanitari asintomatici che hanno contatti noti o altre persone asintomatiche con esposizioni a rischio e / o storia di viaggio in zone a rischio. C'è stata anche un retromarcia circa le raccomandazioni di testare tutte le persone che non hanno bisogno di essere ricoverate in ospedale. Non è chiaro a questo punto se tali raccomandazioni cambieranno nuovamente.
Ci sono ulteriori fattori epidemiologici che possono aiutare a influenzare le decisioni in materia di test per SARS-CoV-2. Documentare la presenza e la trasmissione dell’ infezione da COVID-19 all’interno di una comunità potrebbe forse aiutare nella stratificazione del rischio epidemiologico per guidare le decisioni sui test. Tuttavia, l'incapacità di molte localita’ e ospedali di testare tutte le persone ha portato alla revoca di questa raccomandazione. Data la crescente preoccupazione per la disponibilità e l'affidabilità dei test per SARS-CoV-2, esistono diversi orientamenti a livello federale, statale e locale. Nonostante cio’, quando i medici decidono di eseguire il test, dovrebbero ricordare che in casi ad alto sospetto, in base alle prime ricerche in Cina (oltre a quanto riportato dal Dr. Duca in Italia) sono necessari due test negativi ripetuti ad almeno 24 ore di distanza (3 giorni in Italia) per escludere la diagnosi di COVID-19.51
Durante gli esordi dell'epidemia di SARS-CoV-2 negli Stati Uniti, molti medici sono stati incoraggiati a testare altre cause di malattie respiratorie (ad es. influenza), sulla base delle raccomandazioni dei loro servizi di medicina preventiva e malattie infettive. Tuttavia, è in corso un dibattito in merito ai test e alla valutazione dell’infezione da COVID-19 in relazione alle coinfezioni con altri virus.
Dopo un'approfondita ricerca della letteratura, colloqui con diversi specialisti di malattie infettive, consultazioni in sedi nazionali e internazionali dedicate sia alla medicina d’urgenza sia al COVID-19, siamo stati in grado di trovare solo uno studio cinese non ancora revisionato su 8274 campioni raccolti e analizzati per SARS-CoV-2 e altre specie virali. (Si noti che l'editore afferma: "Questo articolo è in pre-stampa e non è stato sottoposto a revisione. Viene riportata una ricerca che deve ancora essere valutata e quindi non dovrebbe essere utilizzata per guidare la pratica clinica.") In questo studio, hanno scoperto che Il 5.8% dei pazienti con COVID-19 aveva coinfezioni con altri virus e che il 18.4% di altre infezioni (non SARS-CoV-2) ha avuto altri agenti coinfettivi. 52 Gli autori hanno riconosciuto l'inattendibilità dei loro test sia per SARS- CoV-2 che altri virus, con un rischio di sottostima del tasso effettivo di coinfezione. Inoltre, in alcuni dati preliminari riportati dagli scienziati di Stanford Medicine e immediatamente disponibili per il pubblico in rete per volontà del Dipartimento della Sanità Pubblica della California, i ricercatori hanno trovato che nei 49 pazienti risultati positivi a SARS-CoV-2, 11 (22.4%) avevano anche una coinfezione con un altro virus. 53 Prevediamo quindi che uno studio ampio e validato aiuterà a fare ulteriore luce sul tasso di coinfezione di SARS-CoV-2. Nel frattempo, dobbiamo raccomandare ai medici di mantenere un alto indice di sospetto per SARS-CoV-2, indipendentemente dalla presenza di altri virus.
Alla luce di queste informazioni, i medici d’urgenza dovrebbero ribadire al pubblico laico ciò che già sappiamo delle infezioni respiratorie virali note: ossia, cercare trattamento in ospedale per sintomi lievi come febbre, diarrea moderata o tosse isolata comporta probabilmente più rischi che benefici, sia verso se stessi che verso i pazienti vulnerabili intorno a loro. I pazienti con sintomi gravi come difficoltà respiratoria, febbre alta (> 39°C) e difficoltà all’idratazione per via orale devono richiedere una valutazione in urgenza. Per coloro che sono preoccupati per i loro sintomi o per la diffusione dell'infezione a familiari vulnerabili, è necessario osservare con cura il distanziamento sociale, l'auto-quarantena, l'utilizzo della tele-medicina e delle cliniche di screening “drive-through” per ricevere valutazione medica e test (se opportuno) riducendo al minimo il rischio di contagio. Sebbene vada oltre gli scopi di questa revisione, dovranno proseguire ulteriori discussioni sulle politiche istituzionali e dipartimentali per valutare la necessità di proteggere la salute del personale medico e l'assistenza ai pazienti rispetto alla necessità di ridurre al minimo la diffusione nosocomiale da parte di operatori sanitari asintomatici che possono infettare i pazienti.
Come illustrato nella Tabella 1 di un recente studio pubblicato su The LancetThe Lancet, le analisi univariate delle seguenti caratteristiche dei pazienti e dei marcatori di laboratorio sono state associate ad un’aumentata mortalità: età avanzata, linfopenia, leucocitosi e aumentati livelli di ALT, lattato deidrogenasi, troponina I ad elevata sensibilità, fosfocreatinchinasi, D-dimero, ferritina sierica, IL-6, tempo di protrombina, creatinina e procalcitonina.27 I modelli di regressione multivariata hanno mostrato un aumentato rischio di mortalità ospedaliera associato ad età avanzata (odds ratio [OR], 1.10; 95 % CI, aumento di 1.03-1.17 per aumento unitario di eta’, PP = .0043), a score maggiori di valutazione della disfunzione d'organo sequenziale (SOFA) (5.65, 2.61-12.23; PP <0.0001) e D-dimero > 1 mcg / mL (18.42, 2.64-128.55; PP = .0033) al momento del ricovero.27 Questa tabella può essere trovata su The Lancet.
Una meta-analisi recentemente pubblicata sulla procalcitonina nei pazienti affetti da COVID-19 suggerisce che i livelli di procalcitonina nei pazienti con infezione da COVID-19 non complicata dovrebbero rimanere nei range di normalita’, e che un aumento della procalcitonina può riflettere una coinfezione batterica nei pazienti che sviluppano una forma grave di COVID-19.54 Una meta-analisi della conta piastrinica nei pazienti affetti da COVID-19 ha mostrato che la trombocitopenia è associata ad un aumentato rischio di malattia grave e che una sostanziale riduzione della conta piastrinica dovrebbe servire da indicatore clinico di peggioramento della malattia in pazienti ricoverati con COVID- 19.55 Vedere la Tabella 5 per i marcatori di laboratorio correlati alla gravità della malattia e alla gestione clinica per i pazienti con polmonite da COVID-19.
I dati del CDC pubblicati il 17 marzo 2020 mostrano una tendenza scoraggiante nei tassi di ricovero in ospedale nelle fasce demografiche dei piu’ giovani. La Tabella 6 mostra gli ultimi tassi, con un allarmante tasso di ospedalizzazione fino al 20% nei soggetti di età compresa tra 20 e 44 anni. La buona notizia per la popolazione pediatrica è che non sono stati segnalati decessi negli Stati Uniti al momento di questo pubblicazione. (Vedi la sezione "Popolazione Pediatrica".)
I segni all’imaging del torace in pazienti affetti da COVID-19 sono simili a quelli osservati negli anni precedenti nelle epidemie di SARS-CoV-1 e MERS-CoV. Un'analisi di coorte su 41 pazienti affetti da COVID-19 ha rilevato che tutti avevano un coinvolgimento polmonare bilaterale tranne un singolo paziente.21,59 Uno studio di immagini TC su 21 pazienti affetti da COVID-19 ha mostrato 3 pazienti (21%) con TC normale; 12 (57%) con sola opacità a vetro smerigliato; 6 (29%) con opacità a vetro smerigliato e segni di addensamento alla presentazione; e, degno di nota, 3 (14%) del tutto normali al momento della diagnosi. Quindici pazienti (71%) avevano 2 o più lobi coinvolti e 16 (76%) avevano una malattia bilaterale.60 Dei 18 pazienti risultati positivi alla TC toracica, tutti presentavano opacità a vetro smerigliato, con 12 su 18 che presentavano concomitanti consolidazioni lobari.60
I dati su 101 casi di polmonite da COVID-19 analizzati retrospettivamente da 4 istituti di Hunan, Cina, hanno riscontrato che le lesioni presenti alla TC avevano maggiori probabilità di distribuzione periferica (87.1%), coinvolgimento bilaterale (82.2%), predominanza polmonare inferiore (54.5%) e multifocalita’ (54.5%).61 Questi segni, in particolare la distribuzione periferica delle lesioni, incidono positivamente sulla capacità dell’ecografia polmonare di individuare la polmonite da COVID-19.
Dato il tasso di diffusione nosocomiale del virus, l’elevato dispendio di risorse per ottenere scansioni TC in questi pazienti e il rischio di trasportare pazienti ipossiemici instabili, le scansioni TC non sono raccomandate routinariamente nei pazienti affetti da COVID-19, poiché raramente contribuiscono a un cambiamento nella gestione clinica. L'American College of Radiology supporta l'uso parsimonioso della TC, principalmente in pazienti sintomatici ospedalizzati che possono avere altre patologie che richiedono valutazione. La Figura 6 presenta un algoritmo per l’imaging in pazienti con sospetta polmonite da COVID-19.
La letteratura recente e i report aneddotici dall'Italia offrono supporto per l'uso dell'ecografia polmonare come mezzo di screening per pazienti con sospetta polmonite da COVID-19. Per la valutazione della polmonite e/o della sindrome da distress respiratorio dell'adulto (ARDS), l'ecografia polmonare fornisce risultati simili alla TC torace e superiori alla Rx torace standard, con l'ulteriore vantaggio della facilità d'uso al letto del paziente, della ripetibilità, dell’assenza di esposizione alle radiazioni e del basso costo.63 La Tabella 7 illustra in dettaglio i segni dell'ecografia polmonare e la correlazione coi segni alla TC toracica, considerando che l’infezione da COVID-19 risulta comunemente affliggere i lobi posteriori in corso di patologia polmonare.64 In Italia, l’ecografia si è dimostrata essere un utile strumento di screening. (Vedi Tabella 1)
Con l'aumentare della gravità della malattia, si può osservare un'evoluzione dei segni all'ecografia polmonare.64 (Vedi Figura 7.)
Qui si trova un video YouTube di un'ecografia di un paziente con polmonite da COVID-19 [Per gentile concessione di Giovanni Volpicelli, MD]
Gli operatori sanitari interessati a ricevere formazione per individuare i cambiamenti caratteristici del parenchima polmonare nei pazienti affetti da COVID-19 possono fare riferimento a un articolo recentemente pubblicato da Huang e colleghi, che contiene diversi esempi di immagini ecografiche correlate ai segni presenti alla TC torace ad alta risoluzione.65 L'articolo e le immagini sono visibili su Research Square.
L'articolo, “A Rapid Advice Guideline for the Diagnosis and Treatment of 2019 Novel Coronavirus (2019-nCoV)-Infected Pneumonia (standard version),” pubblicato sulla rivista, Military Medical Research, fornisce una guida rapida corredata da imaging di numerosi casi.39 La Figura 8 rappresenta tipiche immagini al Rx e alla TC di un paziente affetto da COVID-19.
L'articolo, "Evolution of CT Manifestations in a Patient Recovered from 2019 Novel Coronavirus (2019-nCoV) Pneumonia in Wuhan, China,", pubblicato sulla rivista Radiology, include 6 immagini dell'evoluzione dell'imaging toracico di un paziente di 42 anni maschio infetto da COVID-19, guarito nell’arco di 31 giorni. 66
In caso di infezione con un qualsiasi ceppo di coronavirus, non vi è nessun trattamento approvato specificatamente per il virus. In un recente studio pubblicato su JAMA, molti pazienti con polmonite accertata da COVID-19 hanno ricevuto terapia antibiotica ad ampio spettro (moxifloxacina, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azitromicina, 25 [18.1%]) e la maggior parte di questi ha ricevuto terapia anti-influenzale (oseltamivir, 124 [89.9%]) con l’aggiunta di steroidi per alcuni di loro (terapia glucocorticoidea, 62 [44.9%]).2 Considerando che la pandemia e’ ancora in evoluzione, i medici potrebbero trovare giovamento dall’esempio di nazioni o sistemi sanitari che hanno implementato protocolli di gestione e trattamento scientificamente comprovati. Uno di questi esempi proviene dal Belgio, intitolato “Interim Clinical Guidance For Patients Suspected Of/Confirmed With Covid-19 In Belgium”. Recommendations from the Italian Society of Infectious and Tropical Diseases can be found here (published in Italian)
Per un ulteriore esempio, si veda la Figura 9 relativa al protocollo di trattamento di COVID-19 del Boston Medical Center.
Data la carenza di evidenze dirette a proposito del trattamento di COVID-19, le linee guida piu’ recenti sono basate in larga parte sulle linee guida del trattamento delle infezioni da SARS-CoV, MERS-CoV e influenza. Attualmente, ci sono deboli indicazioni per l’inalazione di interferone alpha nebulizzato due volte al giorno; tuttavia, le evidenze a riguardo della riduzione dell’incidenza e della mortalita’ di ARDS in pazienti infetti da SARS-CoV-1 e MERS-CoV sono limitate a studi osservazionali di pochi casi come case report e case series.39 Una recente revisione sistematica della letteratura ha dimostrato l’effetto anti-coronavirus di lopinavir/ritonavir sopratutto in caso di terapia precoce, mentre nessun effetto significativo e’ stato osservato in caso di applicazione tardiva.67 Un trial clinico randomizzato recentemente pubblicato sul The New England Journal of Medicine non ha dimostrato nessun vantaggio in termini di mortalità o tempi di guarigione in 199 pazienti affetti da COVID-19 ospedalizzati e trattati con lopinavir/ritonavir. Sono stati osservati dei trend positivi negli outcome secondari, come complicanze da insufficienza renale acuta, infezioni gravi e tasso di ventilazione meccanica invasiva o non-invasiva; tuttavia, lo studio ha terminato il reclutamento di pazienti dopo la pubblicazione di uno studio su remdesivir.68 Al momento, l’uso di antivirali in combinazione nel trattamento di COVID-19 rimane controverso, in quanto non vi sono attualmente trial clinici randomizzati che ne supportino l’uso nell’uomo.69,70
Remdesivir e’ stato recentemente riconosciuto come un farmaco antivirale promettente contro un ampio spettro di virus a RNA, comprese infezioni da SARS-CoV-1 e MERS-CoV in vitro e in primati non umani.71 Recenti studi in vitro condotti su COVID-19 hanno trovato che remdesivir e clorochina inibiscono a basse concentrazioni micromolari l’infezione cellulare con un alto indice di selettivita’.72 Ci sono trial clinici in corso in diversi paesi per testare l’efficacia di Remdesivir, anche se attualmente questo farmaco e’ disponibile solo per uso compassionevole in casi severi di COVID-19 e non e’ disponibile commercialmente.
Un recente trial clinico open-label non randomizzato ha dimostrato una riduzione significativa del tempo di clearance virale (4 vs 11 giorni, P < .001) e del tasso di miglioramento della TC a 14 giorni (91.4% vs 62.2%, P = 0.004) in pazienti trattati con favipiravir e interferone alpha (Gruppo trattato) rispetto a lopinavir/ritonavir e interferone alpha (Gruppo di controllo); tuttavia, va sottolineato che i pazienti critici erano stati esclusi da questo studio.73
A seguito di una revisione sistematica della letteratura cinese sui trattamenti del SARS-CoV-1, sono stati identificati 14 studi in cui sono stati usati steroidi. Dodici studi sono risultati inconclusivi e 2 studi hanno dimostrato potenziali effetti collaterali. Uno studio ha riportato anche l’esordio di diabete a seguito di terapia con metilprednisolone.74 Un altro studio retrospettivo non controllato su 40 pazienti affetti da SARS ha riportato necrosi avascolare ed osteoporosi fra quelli trattati con corticosteroidi.59 Un trial clinico randomizzato in doppio cieco ha misurato la variazione della carica virale plasmatica di SARS-CoV-1 nel tempo dopo l’esordio della febbre, trovando un’associazione tra l’utilizzo di corticosteroidi entro la prima settimana della malattia e una ritardata clearance virale.75
Tuttavia, un recente studio cinese sui fattori di rischio associati allo sviluppo di ARDS in pazienti affetti da COVID-19 ha dimostrato che il trattamento con metilprednisolone riduce il rischio di morte tra pazienti con ARDS (hazard ratio, 0.38; 95% CI, 0.20-0.72).45 Questi dati forniscono supporto alla teoria che il peggioramento in pazienti affetti da COVID-19 avviene a causa dell’immuno-patogenesi in seguito allo sviluppo di una “tempesta citochinica” mitigata grazie alla somministrazione di glucocorticoidi in pazienti con ARDS severa.
La sindrome da rilascio di citochine è stata sempre piu’ individuata come la causa del rapido deterioramento di pazienti affetti da COVID-19 diversi giorni o settimane dopo l’iniziale infezione da SARS-CoV-2, facendo quindi ipotizzare la possibilità di utilizzare una terapia anti-infiammatoria (antagonisti dei recettori delle cellule infiammatorie) e una terapia con cellule staminali come potenziali agenti terapeutici. Alcuni trial clinici multicentrici sull’utilizzo di tocilizumab (antagonista del recettore di IL-6) nel trattamento della polmonite da COVID-19 sono in corso.20 Una lista più completa degli studi e dei trial sulle terapie innovative contro SARS-CoV-2 può essere consultata su Monthly Prescribing Reference.
Una considerevole quantità di letteratura ha attribuito una varietà di effetti antivirali e immunomodulanti alla clorochina, tra cui la soppressione di IL-6, che si ritiene essere la citochina che gioca un ruolo significativo nel promuovere l’ARDS severa in pazienti affetti da COVID-19.20,76 E’ stato anche dimostrato che la clorochina agisce come un efficace farmaco antivirale in modelli animali infetti da influenza aviaria e SARS-CoV-1.77,78 Dati emergenti dalla Cina ancora non pubblicati suggeriscono che la clorochina e’ stata studiata come trattamento per COVID-19 con risultati positivi.79 Il Dipartimento di Scienza e Tecnologia della Provincia di Guangdong e la Commissione Sanitaria della Provincia di Guangdong hanno recentemente presentato un rapporto di esperti che raccomanda la clorochina nel trattamento della polmonite da coronavirus con un regime di 500 mg per os due volte al giorno in pazienti privi controindicazioni.80 Un recente studio pubblicato su Clinical Infectious Diseases, mediante modelli farmacocinetici su base fisiologica, ha individuato una maggiore potenza dell’idrossiclorochina rispetto alla clorochina (EC50 = 0.72 μM vs 5.47 μM, rispettivamente) a livello del tessuto polmonare. Questo studio raccomanda una dose di carico di 400 mg due volte al die il primo giorno, seguita da una dose di mantenimento di 200 mg due volte al die per 4 giorni.81 Alcuni trial clinici sono in corso per indagare formalmente l’uso di questi farmaci sia come terapia che come profilassi contro COVID-19 in esseri umani.82 Un recente trial clinico non randomizzato su 20 pazienti ha scoperto che il trattamento con idrossiclorochina e’ associato significativamente a riduzione e scomparsa della carica virale in pazienti affetti da COVID-19, con un effetto aumentato dall’aggiunta di azitromicina. Il dosaggio di idrossiclorochina era di 600 mg per die, mentre quello di azitromicina era di 500 mg die il primo giorno e 250 mg die per i restanti quattro giorni.83 (Nota dell’autore, “Questo articolo è in pre-stampa e non è stato sottoposto a revisione. Riporta uno studio di ricerca che deve ancora essere valutato e, quindi, non dovrebbe essere usato come guida per la pratica clinica”).
Al momento, non ci sono evidenze significative né sulla gestione ottimale dei fluidi in pazienti affetti da COVID-19 né sull’insorgenza di scompenso cardiaco congestizio secondario al virus. Come descritto precedentemente, la teoria principale sulla fisiopatologia dello sviluppo di ARDS (edema polmonare non cardiogeno) dei pazienti in rapido deterioramento affetti da COVID-19 è basata sullo sviluppo di uno stato iper-infiammatorio. Dato che questa non è una forma di shock distributivo o ipovolemico, come si osserva nella sepsi batterica, e che il risultante edema polmonare è la prima minaccia di morte per pazienti affetti da COVID-19, gli autori raccomandano un approccio prudente all’infusione di fluidi su base individuale.
In pazienti che si aggravano e richiedono un livello intensivo di cure, i medici dovrebbero considerare, se necessario, la ventilazione non invasiva (NIV), la ventilazione meccanica o il supporto vitale extracorporeo.39 Lo sviluppo di ARDS e il successivo scompenso respiratorio giocano un ruolo centrale nella patogenesi del COVID-19. A questo riguardo, i seguenti principi terapeutici sono la chiave nella gestione dei pazienti affetti da COVID-19:
Dati preliminari non ancora pubblicati dal Dr. Andrea Duca, Medico d’emergenza a Bergamo, mostrano che, dal 29 Febbraio al 10 Marzo 2020, il tasso di pazienti giunti al PS per sospetto COVID-19 che hanno avuto bisogno di essere ammessi per ossigenoterapia è aumentato del 138%. Tra i pazienti ammessi, il 31% era ancora in ipossia nonostante terapia massimale con O2 e veniva sottoposto a supporto ventilatorio nel PS (81% CPAP, 7% NIV, 12% ventilazione invasiva), con l’82% dei pazienti che dimostrava positività ai criteri per ARDS moderata-severa.
I dati provenienti dalla Cina e dall’Italia suggeriscono che i pazienti ipossiemici affetti da COVID-19 rispondono bene alla PEEP, indicando un ruolo cruciale per la NIV sia come misura terapeutica che come soluzione provvisoria per evitare l’intubazione.45 Le analisi statistiche di studi cinesi retrospettivi indicano che fino al 30% dei pazienti ammessi richiede NIV,84 mentre i primi rapporti dall’Italia indicano dei numeri che si avvicinano al 31%. Dati gli attuali trend epidemiologici, tali richieste verosimilmente supereranno le capacità della maggior parte degli ospedali, se non di tutti, qualora non verranno intraprese misure drastiche. Sulla base dei dati attuali dalla Cina e dall’Italia, raccomandiamo:
Vedi Figure 10, 11, e 12 per immagini di un device di NIV a singolo tubo, dimostrazione del corretto utilizzo della maschera, e un casco per CPAP con filtro virale prossimale alla valvola PEEP.
Nel caso in cui il paziente si presenti in distress respiratorio severo o insufficienza respiratoria prima dell’uso di NIV, il medico deve essere pronto allaa ventilazione invasiva e all’intubazione con tubo endotracheale. Vedi Tabella 8 per i passaggi per la Intubazione In Sequenza Rapida (RSI).
Il ruolo della preossigenazione e della possible diffusione di particelle virali durante l’utilizzo delle tecniche tipiche e’ ancora un argomento fortemente discusso. Una revisione sull’argomento si puo’ trovare su EMcrit. Nel frattempo, le scelte comunemente utilizzate sono:
Per un breve riassunto su indicazioni, principi e vari tipi di ventilazione meccanica, consultare Hickey et al. Per i pazienti affetti da COVID-19, particolare enfasi dovrebbe essere posta sulla sezione “Strategia di Protezione Polmonare”, basata sul trial ARDSnet, che ha mostrato che una ventilazione a basso volume corrente in pazienti con ARDS migliora la mortalita’.85 In breve:
Il volume corrente (TV) dovrebbe essere impostato inizialmente a 6 mL/kg in base al peso corporeo ideale. Se i pazienti sviluppano insufficienza polmonare acuta e progrediscono ad ARDS, i loro polmoni vengono progressivamente reclutati e sviluppano shunt, che porta a una riduzione del volume polmonare funzionale. Una strategia a basso volume corrente compensa il ridotto volume polmonare funzionale. Il volume corrente non dovrebbe essere aggiustato in base agli obiettivi di ventilazione al minuto. La frequenza respiratoria e’ calibrata in base agli obiettivi di ventilazione al minuto e all’equilibrio acido-base del paziente. Una iniziale frequenza di 16 respiri/min e’ appropriata per raggiungere la normocapnia nella maggior parte dei pazienti.86
In contesti di catastrofe, quando il numero di pazienti che richiedono ventilazione meccanica supera il numero dei ventilatori a disposizione, si possono modificare i ventilatori in modo da dividere il flusso aereo su piu’ pazienti. Cliccare qui per un video tutorial su come modificare i ventilatori.
I punti chiave per questa manovra sono i seguenti:
I bambini sembrano essere relativamente immuni alle complicanze e alla mortalita’ della malattia, come e’ evidenziato dai tassi di ospedalizzazione per gruppi di eta’ secondo il CDC. (Vedi Tabella 6.) Ad oggi, negli Stati Uniti e in base alla esperienza del nostro co-autore in Nord Italia, non ci sono stati casi di morte riportati nei bambini. Tuttavia, in un articolo in pre-stampa del 16 Marzo 2020 sul Journal of Pediatrics, Dong e colleghi hanno analizzato 2143 bambini in Cina con infezione da SARS-CoV-2 (sospetta o confermata) e hanno trovato che quasi “il 4% dei bambini era asintomatico, il 51% aveva un fenotipo lieve e il 39% aveva un fenotipo moderato. All’incirca il 6% aveva malattia severa o critica, contro un 18.5% negli adulti. Un ragazzo di 14 anni e’ morto.”87 Lo studio ha anche evidenziato che gli infanti avevano un tasso maggiore di malattia severa rispetto ai bambini piu’ grandi. Circa l’11% degli infanti ha avuto una malattia severa o critica rispetto al 7% dei bambini di eta’ compresa fra 1 e 5 anni; 4% di quelli di eta’ fra i 6 e i 10 anni; 4% di quelli fra 11 e 15 anni; e 3% di quelli di eta’ uguale o superiore a 16 anni. Ci sono diverse teorie sulle grandi differenze tra adulti e bambini, come “i piu’ alti livelli di anticorpi contro i virus o risposte differenti dei loro sistemi immunitari ancora immaturi.”87 Un’altra teoria riguarda la relativa mancanza o lo scarso sviluppo dei recettori ACE2 nei bambini, che impedisce al virus di legarsi altrettanto bene alle cellule dei bambini. In un report di 72,314 casi del Centro di Controllo delle Malattie Cinese, Wu e colleghi hanno registrato all’incirca 1000 bambini sotto i 19 anni e nessuna morte in bambini sotto i 9 anni di eta’.84 In una recente corrispondenza al New England Journal of Medicine, ricercatori dalla Cina hanno trovato, su 171 casi confermati di SARS-CoV-2, un solo decesso di un bambino di 10 mesi con diverse comorbidita’.88
In un piccolo studio retrospettivo in Cina, sono state analizzate le TC toraciche e i marcatori di laboratorio, inclusa la procalcitonina, di 20 pazienti pediatrici positivi a SARS-CoV-2. Gli autori hanno riscontrato che la procalcitonina era elevata in 16 pazienti su 20, le TC toraciche mostravano consolidamento con circostanti segni di alone in 10 patienti su 20, e opacita’ a vetro smerigliato in 12 pazienti su 20. E’ stato inoltre suggerito che la sottostante coinfezione potrebbe essere piu’ comune nei bambini (8/20), e un consolidamento con circostante segno dell’alone e’ considerato un segno tipico per questa popolazione.58 Anche se la popolazione pediatrica potrebbe essere risparmiata dalla morbidita’ e dalla mortalita’ osservate negli adulti, e’ essenziale che i medici tengano a mente che i bambini potrebbero infettare popolazioni piu’ vulnerabili e che, quindi, ne incoraggino il distanziamento sociale. Ulteriori ricerche sulla popolazione pediatrica americana permetteranno di migliorare ulteriormente la comprensione e la gestione dei casi pediatrici severi negli Stati Uniti.
I dati sui pazienti in gravidanza affetti da COVID-19 rimangono ancora limitati.89 In generale, donne in gravidanza affette da SARS-CoV-2 condividono le stesse caratteristiche di donne non in gravidanza affette dal virus. In uno studio retrospettivo su 9 pazienti, Chen e colleghi hanno analizzato il rischio di trasmissione materno-fetale di SARS-CoV-2 e hanno trovato che la trasmissione intrauterina in madri positive per SARS-CoV-2 e’ considerata improbabile.90 Inoltre, in quegli stessi pazienti, hanno registrato davvero poche complicanze in gravidanza, contrariamente alle note complicanze di donne in gravidanza con SARS.91,92 Chiaramente, dovranno essere condotti studi piu’ grandi per valutare meglio il rischio di trasmissione verticale tra madre e feto nell’infezione da SARS-CoV-2.
--Marc Probst, MD
Il processo decisionale condiviso (SDM) e’ un processo collaborativo in cui pazienti e medici prendono decisioni di assistenza sanitaria insieme, tenendo conto dell’evidenza scientifica, dell’esperienza del medico, e anche delle preferenze e delle credenze del paziente. Anche se l’evidenza scientifica alla base dei test e dei trattamenti dell’infezione da SARS-CoV-2 e’ agli albori e in rapida evoluzione, alcune evidenze scientifiche sono note, perciò l’estrapolazione da altre gravi malattie infettive e’ giustificata. Ci sono almeno due scenari clinici a proposito del COVID-19 che potrebbero essere appropriate per il SDM: (1) eseguire test per SARS-CoV-2 in pazienti paucisintomatici e (2) obiettivi di cura in pazienti critici.
Dato che non ci sono trattamenti ad oggi comprovati per COVID-19, fare diagnosi in casi paucisintomatici potrebbe non modificare la gestione clinica. La terapia di supporto standard, come per le tipiche infezioni delle alte vie respiratorie, puo’ essere raccomandata ai pazienti senza eseguire test per SARS-CoV-2. Tale terapia includerebbe farmaci da banco come antipiretici, antitussigeni, decongestionanti e analgesici, oltre a reidratazione orale e riposo. I pazienti dovrebbero essere istruiti a praticare l’auto-isolamento per prevenire la diffusione del COVID19 ad altri individui. Gli attuali test per SARS-CoV-2, mediante RT-PCR, hanno una sensibilita’ tra il 60% e il 90% e possono generare risultatati falsamente positivi o falsamente negativi. Data la reale possibilita’ di una scarsita’ di risorse per eseguire i test, potrebbe essere ragionevole per i pazienti con possible infezione da COVID-19 rinunciare ai test, presumendo che abbiano il virus, e seguire le precauzioni socialmente responsabili. Date le raccomandazioni in continua evoluzione in tema di test da parte di istituzioni e agenzie sanitarie governative, si consiglia l’aderenza alle direttive ospedaliere, statali o locali, che dovrebbero essere spiegate al paziente.
Un altro scenario clinico che sarebbe appropriato per un processo decisionale condiviso sarebbe l’intubazione endotracheale di un paziente con insufficienza respiratoria a prognosi grave, sia per eta’ avanzata sia per la presenza di comorbidita’ gravi. Questa decisione verra’ affrontata spesso in quanto l’ARDS e’ una sequela comune per molti pazienti con COVID-19. I primi studi hanno dimostrato alti tassi di mortalita’ per i pazienti anziani, in particolare per gli ultraottantenni. In questo scenario, i medici potrebbero intraprendere un processo decisionale condiviso con i pazienti o con il loro delegato per le cure sanitarie (proxy) in modo da stabilire insieme se l’intubazione sia giustificata o meno. Queste speculazioni sono simili ad altre discussioni sugli obiettivi di cura riguardo alle disposizioni anticipate di trattamento in pazienti di eta’ avanzata o con malattie in fase terminale.
Nella nostra prima versione, abbiamo speculato sul futuro di ciò che non era ancora una pandemia. Sfortunatamente, il futuro è adesso e siamo nel mezzo di una pandemia in crescita che ha obbligato a chiudere città, nazioni e continenti. Forse faremmo meglio a osservare gli eventi passati per imparare dai passi falsi altrui e cercare opportunita’ di miglioramento per quelle regioni del mondo non ancora invase dal COVID-19.
"Trasmissione comunitaria", "trasmissione silenziosa", "distanziamento sociale" e "appiattimento della curva" sono termini entrati nel linguaggio comune mentre le organizzazioni pubbliche e le strutture mediche tentano di comprendere e controllare il COVID-19. Con un valore R0 simile all'influenza pandemica, la diffusione e il contenimento di SARS-CoV-2 rappresenta una sfida senza precedenti. 93 Continuiamo sempre più a notare che l’informazione in costante cambiamento quotidiano (e la disinformazione) si e’ aggiunta alle criticita’ sia per la popolazione generale che per la comunita’ medica.The Lancet ha pubblicato un editoriale online, che raccomanda sia alla comunità medica che al pubblico di raccogliere informazioni verificate attraverso il CDC o l'OMS e di evitare i social media e altre fonti di informazioni non controllate. Molti pazienti in buona salute preoccupati si presenteranno al PS, affaticando sistemi gia’ sovraccarichi. Questa è un'opportunità per la classe dirigente ospedaliera di sviluppare e/o espandere le loro opzioni di tele-medicina, riducendo al minimo il numero di pazienti preoccupati sia in buona salute sia a basso rischio con sintomi lievi che possono far collassare i PS locali.
Attualmente ci sono diverse aziende biotecnologiche e farmaceutiche in corsa per un vaccino per SARS-CoV-2, e, sebbene gli studi siano promettenti, prima della loro ampia disponibilità e utilizzo mancano almeno 18 mesi (estate 2021). Un possibile vaccino a DNA per SARS-CoV-2 è entrato in un trial clinico su esseri umani, mentre sono stati iniziati trial su esseri umani per altri 2 possibili vaccini a vettore; i vaccini a base di proteine sono ancora in fase di studio preclinica 72 Vi sono ancora numerose sfide per la riuscita dello sviluppo di un vaccino a causa dell’incompleta comprensione dei meccanismi di trasmissione virale e della patogenesi, e della carenza di modelli animali ideali e test immunologici standardizzati.
Riteniamo che la Cina, lo stato di Washington, l'Italia e ora l’area metropolitana di New York dovrebbero fungere da esempio al resto del mondo non ancora invaso da SARS-CoV-2. Essere preparati a un’impennata dei casi e’ il primo passo che tutti i sistemi sanitari devono accettare. In Cina, Corea del Sud, e altrove, e in localita’ come la citta’ di New York, eseguire test ed isolare precocemente gli infetti o le persone sospettate di esserlo ha mostrato indubbi vantaggi.
In caso di afflusso massiccio di pazienti con esposizione a SARS-CoV-2 o sintomi tipici di infezione da COVID-19 è necessario un isolamento immediato. Se 1 persona infetta si presenta al triage di un PS affollato, c'è un'alta probabilità di diffusione del virus e potenziale contaminazione altrui. Il CDC suggerisce di posizionare diverse postazioni di disinfettanti per le mani con sensori di movimento (touchless) e contenitori facilmente smaltibili di mascherine per il viso agli ingressi del PS e dell'ospedale. Essi raccomandano, inoltre, di anteporre segnaletica che suggerisca a chiunque entri nella struttura di “indossare immediatamente una mascherina e mantenerla durante la valutazione; utilizzare e smaltire con cura i fazzoletti; lavarsi le mani dopo essere venuti a contatto con secrezioni respiratorie.”94 Gli autori raccomandano ai dirigenti dell'ospedale e dei dipartimenti di seguire le seguenti direttive:
Il modo migliore per salvare la maggior parte delle persone e ridurre la morbidità è quello di essere proattivi invece che reattivi. Noi che siamo in mezzo a questa crisi avremmo voluto poter gestire le cose diversamente e implementare le raccomandazioni di cui sopra nel momento in cui abbiamo incontrato il paziente zero. La mancanza di test precoci e di rigoroso isolamento contrastano con ciò che gli epidemiologi raccomandano per controllare i focolai infettivi. Per favore, vi esorto ad imparare dai nostri errori.
| Tabella 9. Risorse Utili COVID-19 | ||
|---|---|---|
| Organizzazione | Collegamento al sito web | |
| United States Centers for Disease Control and Prevention | Coronavirus Disease 2019 (COVID-19) | |
| World Health Organization | Coronavirus disease (COVID-19) outbreak | |
| Johns Hopkins University | COVID-19 Global Case Tracker | |
| United States Department of Labor, Occupational Safety and Health Administration | COVID-19 Additional Resources | |
| American College of Emergency Physicians | COVID-19 Clinical Alert | |
| The Lancet | COVID-19 Resource Centre | |
La medicina basata sulle evidenze richiede una valutazione critica della letteratura basata sulla metodologia di studio e sul numero di soggetti. Non tutti i riferimenti bibliografici sono solidi. I risultati di un grande trial prospettico, randomizzato e in cieco, dovrebbero avere più peso di un caso clinico.
Per aiutare il lettore a valutare la solidita’ di ogni riferimento bibliografico, le informazioni pertinenti degli studi, come la tipologia dello studio e il numero di pazienti inclusi, saranno inclusi in grassetto dopo ciascun articolo, quando disponibili.
Coronavirus disease (COVID-19), caused by the SARS-CoV-2 virus, originated in Wuhan, Hubei Province, China in late 2019 and grew rapidly into a pandemic. As of the writing of this monograph, there are over 2 million confirmed cases worldwide and 147,000 deaths.1 New York City, with over 120,000 COVID-19-positive patients and over 11,000 deaths, has become the infection epicenter in the United States. The Mount Sinai Health System, with 8 hospitals spread across New York City and Long Island, has been on the forefront of the pandemic. This compendium summarizes the lessons learned through interdisciplinary collaborations to meet the varied challenges created by the explosive appearance of the infection in our community, and will be updated continuously as new research and best practices emerge. It is our hope is that the collaborations and lessons learned that went into creating these guidelines and protocols can serve as a useful template for other systems to adapt to their fight against COVID-19.
The authors would like to dedicate this issue to Dr. Lorna Breen and to recognize her contributions to our specialty and unwavering dedication to her patients.
This monograph summarizes the evaluation, treatment, and disposition tactics the Mount Sinai Health System created and implemented to help manage a new disease that posed an unprecedented volume of critical patients and had no known treatment. While by no means all-encompassing, the methods outlined here are focused on the front-line emergency clinician. We provide a rubric of how to think about major decisions regarding workup, treatment, and disposition. There is a focus on providing fundamental care in a way that maximizes safety for both patients and clinicians. Discussions regarding personal protective equipment (PPE), operational flow, and nonmedical resources are beyond the scope of this monograph. Although not discussed in detail, many of the nodal points in clinical decision-making can likely be performed by both telemedicine and advanced practice providers.
Most of the protocols presented here were developed by an interdisciplinary team of emergency physicians, infectious disease specialists, and intensivists. Incorporated into the tables is a combination of information coming out of Italy and China, local information obtained within an 8-hospital system in New York City with both community and academic sites, extensive discussion with emergency medicine experts around the country, and literature searches focused primarily on acute respiratory distress syndrome (ARDS) and analyses from prior viral outbreaks, including SARS, MERS, and H1N1.
Disclaimer: While the recommendations presented in this monograph are based on the best evidence available at the time of their creation, we acknowledge that our understanding of COVID-19 is changing daily. The protocols presented were developed by individuals, and though adopted by our Health System, the protocols are not necessarily endorsed by the Mount Sinai Health System, but are the independent product of the authors. We note that there is controversy, and that some of the recommendations may be controversial. We thank our many colleagues for their input, and we have tried, to the best of our ability, to note the sources from which protocols were adapted.
While laboratory testing and imaging may assist with management and prognosis, they are generally adjuncts to the history and physical examination and rarely change initial management, especially in the well-appearing patient.
While clinical management for patients with COVID-19 continues to evolve and change on a nearly a daily basis, we have come to some clinical equipoise regarding laboratory studies and imaging. Laboratory studies are generally not required for the well-appearing patient under investigation with few or no risk factors. When drawn for concerning presentation in the emergency department (ED), labs are fairly standard, with the addition of inflammatory markers if the patient is expected to be admitted to the hospital. Although many are nonspecific, some may offer assistance in diagnosis, pending confirmatory testing.
Troponins may be elevated due to myocarditis or ischemia (demand or thrombosis). The basic metabolic panel may show electrolyte abnormalities due to dehydration or medication noncompliance; renal injury due to inflammation, vasculitis, and thrombosis has also been reported. The inflammatory markers will allow the inpatient team to trend them and potentially aid in directing therapy. Because knowledge is continuously evolving and there are often local protocols, a discussion with inpatient leadership may help guide which markers may be useful.
We use imaging less as a primary diagnostic tool than to rule out other diagnoses and to measure extent and progression of disease. Similar to lab testing, low-acuity patients without tachypnea, hypoxia, or more than minimal shortness of breath do not necessarily require imaging. In the early days of the pandemic, when the availability of PCR testing was limited, the use of CT scans was often substituted as a diagnostic modality.2 With PCR testing becoming more readily available, CT scanning is less useful for diagnosis, although it may be more sensitive than some current PCR testing.3 Despite its impressive sensitivity, the resources required for multiple diagnostic CTs, especially in the time of pandemic, makes this an implausible diagnostic modality.
The variation in clinical presentation and course of COVID-19 poses a unique challenge in safely dispositioning patients from the ED. Given that respiratory distress may present as a late finding in the second week after initial onset of symptoms, decisions as to whether to admit or discharge patients must include a thorough evaluation of all relevant risk factors as well as the patient’s capacity to self-monitor and isolate at home. Discharge must also assess whether appropriate outpatient follow-up is available as well as the ability to return if the patient worsens.4 It is a given that some patients will worsen and require hospitalization; however, resources and safety considerations often preclude routine admission. While the absolute criteria for admission include signs and symptoms of respiratory distress or developing sepsis, the patient’s medical history and overall conditioning should also be taken into account on a case-by-case basis. While mortality is known to be higher among certain groups of hospitalized patients, eg, age > 65 years and patients with chronic cardiovascular, pulmonary, liver, renal diseases, etc, it is not yet fully clear which patients will decompensate as outpatients.5,6
Patients with suspected or confirmed COVID-19 who are not exhibiting increased work of breathing, tachypnea, or evidence of hypoxia may be managed in the outpatient setting with follow-up as needed for any new or worsening symptoms. One useful strategy is to ambulate patients prior to discharge to confirm that their oxygen saturation remains stable. Although this is not a proven strategy at this point, anecdotally it has been very helpful in finding unexpected hypoxia. Patients who are admitted for respiratory distress may be considered for discharge after 48 hours if they remain clinically stable. Persistently hypoxic patients without increasing supplemental oxygen requirements who do not have other significant risk factors may also be considered for discharge on home oxygen or with an oxygen concentrator. While higher mortality was associated with oxygen saturations < 92% on ambient air or respiratory rates > 24 breaths/min, borderline objective findings in COVID-19 patients have less predictable clinical outcomes.6 Traditional approaches, such as observation units, may not be available or may increase the risk of cross-contamination with other patients. If available, scheduling patients for 24-hour telemedicine follow-up appointments may provide an expedient strategy for safely discharging patients with mild dyspnea or hypoxia, in order to closely monitor them for any signs of decline while reducing overcrowding and nosocomial transmission in the ED.
Table 3 provides a list of the risk factors associated with the potential for clinical deterioration and thus need for hospitalization. Table 4 provides the context for which patients might be safe for discharge with close outpatient monitoring. We are currently assessing our experience with this pathway to find whether it has been successful in both decreasing admissions and providing safe discharges.
With the ongoing pandemic, there are inevitably cardiac arrests associated with caring for the COVID-positive patient. Cardiopulmonary resuscitation (CPR), by its very nature, is an aerosolizing procedure. Whether this is from intubation, compressions, or bagging the airway, they all pose a real risk to staff. Also, given that a resuscitation can often be labor-intensive, it becomes even more important to minimize exposure. Therefore, a protocol to ensure the best care of the patients while protecting front-line staff must be followed. Risks and benefits for each case must be assessed, as overall favorable neurological outcome following CPR in many cases has been found been found to be < 1%.7 In Wuhan, a case series of in-hospital cardiac arrest found that, while most arrests were respiratory in nature, only 1 person out of 136 survived neurologically intact to discharge. We do not have enough local or critical US data to make any clear recommendations regarding in-hospital arrest.7
We have recommended the use of a mechanical CPR device (mCPR) to minimize the number of staff in the room. Again, while the studies for mCPR have been mixed, at best, the balance between safety and treatment must be maintained.8,9 Likewise, the protocol limits the amount of equipment contaminated during resuscitation. Equipment shortages are inevitable when dealing with a pandemic, and resources must be guarded.
Although many pharmacologic agents are undergoing urgent investigation for use in patients with COVID-19, no curative or preventative treatments have been confirmed. At this time, medications targeted against SARS-CoV-2 and COVID-19 should generally be applied in the context of a clinical trial.11 While discussions of inpatient medications and current trials are beyond the scope of this monograph, recommended information sources include the CDC and the NIH.
ED treatments are typically focused on symptom control and treatment of the manifestations of the disease (eg, shortness of breath, fever, pain). An electrocardiogram (ECG), basic coagulopathy biomarkers, and an assessment of kidney and liver function are generally performed in the ED, as some of the inpatient treatment may affect or be affected by other organs.
Advanced treatments are not usually started in the ED. Patients admitted should be screened for additional or research studies. For severe cases of COVID-19, convalescent plasma, immunomodulators (tocilizumab and sarilumab), and antivirals such as remdesivir should be considered in the setting of clinical trials.12 The effectiveness of these and other antimicrobial agents has yet to be determined, and they remain under active investigation. Recommendations for the use of alternate or adjuvant therapies may change, as the literature on COVID-19 continues to evolve rapidly.13
Please note that in this document, The Mount Sinai Health System is currently recommending steroids and full anticoagulation in the most critical patients who do not have contraindications. These both remain highly debated and controversial and are based on expert opinion, early evidence, and theoretical considerations. The evidence is constantly changing, and we recommend regular review of practice.
The exact mechanisms and pathophysiology of how COVID-19 attacks the human body are incompletely understood. However, there is an increasing amount of evidence that COVID patients are in a hypercoagulable state, with autopsy evidence of microthrombi seen throughout the body, including the lungs, brain, heart, kidneys, and other organs.1 Anecdotally, we are seeing significant numbers of pulmonary emboli, although it is unclear whether this is related to the disease or critical illness. These patients may show abnormalities including elevated D-dimer, fibrinogen, and abnormal thromboelastography. One recent Dutch study of COVID-positive ICU patients found a 31% incidence of thrombotic complications.14
The Mount Sinai Health System developed an anticoagulation protocol for patients being admitted with COVID-19 based on the acuity of the patient’s respiratory status, admission destination, and renal function (though efficacy is unproven). It is believed that heparins bind tightly to COVID-19 spike proteins 3,4, and that heparins also downregulate IL-6 and directly dampen immune activation.5 It is hoped that early anticoagulation may prevent propagation of microthrombi at disease presentation and result in decreased mortality.15-19
COVID-19 is a disease with multiple manifestations; however, the common manifestation of acute respiratory disease is what leads to most concerning ED presentations. A minority—but concerning number—of patients will have profound acute hypoxic respiratory failure and ARDS.20-23 In additions to concerns about aerosolization of the virus during noninvasive ventilation and high-flow oxygenation, the timing and early need for intubation of hypoxic patients remains controversial.24 However, initial early intubation strategies have evolved to include expanded use of noninvasive ventilation and proning to try to delay or prevent intubation. When intubation is being contemplated, it is also very important to address goals of care with the patient and family, as current data show high mortality for intubated patients, especially with increased age and medical comorbidities.
Currently, we are using a stepwise approach to respiratory management for the COVID-19 patient. Patients with pure hypoxemia will be up-titrated from room air, to nasal canula, to non-rebreather, and HFNC. Patients with increased work of breathing and tachypnea despite supplemental oxygen are candidates for a trial of CPAP/BiPAP with close monitoring. If possible, CPAP/BiPAP and HFNC should be used in negative-pressure, closed rooms. A room with a closed door (or within a full COVID-19 unit) with all providers using N95 masks, is an option if negative pressure is not available. Additionally, a surgical mask can be placed over the HFNC to help decrease the amount of aerosolization. If intubation is necessary, the Mount Sinai Health System has developed a systemwide protocol for airway management as a collaboration between the Department of Emergency Medicine, the Institute for Critical Care Medicine, and the Department of Anesthesiology.3 This protocol was based on recommendations from both the Society of Critical Care Medicine and the American Society of Anesthesia. They have been updated regularly, with both new data and experience gained taking care of COVID patients.13,25-27
EDs in the United States see over 1.5 million visits per year for obstructive lung disease.28 We are now aware that some of those most affected by COVID-19 have been patients with intrinsic lung disease.20,29 Because aerosolizing procedures such as nebulization of albuterol or ipratropium, used for treatment of lung disease, cause dissemination and spread of viral particles, we have created a COPD/asthma protocol that minimizes these therapies.20 The protocol is designed to maximize treatment efficacy while ensuring safety of staff and providers. Within this protocol, breath-actuated nebulizers (eg, AeroEclipse*) can be used interchangeably with an albuterol (+/- ipratropium) MDI and spacer. Should a patient require respiratory support with noninvasive ventilation, this should ideally be done within the confines of a negative pressure room.
Special thanks to Sean Hickey, MD from the Icahn School of Medicine at Mount Sinai, whose work was critical in developing the guidelines in Tables 9 and 10.
While palliative care should not be equated with hospice or immediate end-of-life care, providing palliation to ill patients with COVID-19 implies a low chance of survivability.4,30 In these cases, palliation is often focused upon providing appropriate, proportional pharmacological management of pain, dyspnea, agitation, and other common symptoms to maximize patient comfort at the end of life. Interventions should be titrated to observed or reported symptoms and not based on specific physiologic parameters. The flow sheet in Figure 1 represents a simple approach to dyspnea and agitation.
Given the high mortality with COVID-19 in the critically ill, an early discussion with patients and their families is highly recommended. Although increasing mortality is associated with underlying chronic medical conditions such as pulmonary, renal, and cardiac conditions, the absolute mortality is still unclear and studies may have incomplete data, given the relative newness of the disease. Scales such as the Sequential Organ Failure Assessment (SOFA) score may assist with offering some sense of prognosis. Overall, critically ill patients older than 70 years of age who require intubation have a reported mortality > 60%.31,32
Special thanks to Dr. Claire Akuna and Dr. Christopher Richardson and the Brookdale Department of Palliative Care at the Icahn School of Medicine at Mount Sinai who provided invaluable help with this guideline and review of palliative care assistance.
The COVID-19 pandemic has caused a radical shift in the practice of emergency medicine, and operational and communication issues have emerged that had not been encountered previously. Emergency physicians have quickly had to have many goals-of-care discussions as well as breaking bad news to family members. While emergency clinicians are familiar with these types of discussions, the large numbers in a short period of time can become overwhelming. In addition, New York and other hard-hit areas have also had the number of deaths exceed morgue and funeral home capacity. Families are understandably upset by these occurrences. We have included scripting that is designed to help with these difficult conversations.33
In order to rapidly chart and provide an overview with common ED patient presentations, smart phrases based on common presentations were developed. These were developed for use in the Epic electronic health records system, but can be adapted for any system. Included below are modified phrases for discharged COVID patients, tent/telehealth evaluation, and consultation template.
Please see the resources below for more information:
Local DOH Office Phone Numbers
For hypoxemic patients, there are many physiologic benefits to the prone position. These include better matching of pulmonary perfusion to ventilation, better recruitment of dependent areas of the lung, and improved arterial oxygenation. In addition, there is evidence that the prone position results in a more homogenous distribution of stresses in the lung and thus may prevent patients with hypoxemia from developing frank respiratory failure. Prone positioning is used extensively in the ICU to treat intubated patients with hypoxemic respiratory failure,34,35 but the benefits cited above may also apply to nonintubated patients as well. For this reason, patients presenting with hypoxemia should be encouraged to adopt the prone position, where practical. Prone positioning may be tried as a rescue therapy in patients with escalating oxygen needs, although this will require close monitoring.36
Special thanks to Dr. Susan Wilcox and Dr. David Brown, and the Department of Emergency Medicine at Massachusetts General Hospital in Boston, MA, from which this guideline was largely adapted.
Despite being confronted with a novel virus where evidence-based treatments are still lacking, it must be emphasized that proper critical care remains the cornerstone of current management. COVID-19 has an observed case-fatality ratio of 4.9% in the United States. Although this is based on sicker patients who are tested, at a minimum it should emphasize that the provision of high-quality critical care is imperative.37 Management of shock and hypoxia are the focus of COVID-19 critical care.
Norepinephrine and vasopressin are the vasopressors of choice as per standard of care.38-40 We recommend the prioritization of early vasopressors use in the management of these patients’ hypotension and only judicious use of volume, given their tenuous respiratory status.41,42 If available, point-of-care bedside ultrasound is extremely useful to assess cardiac function and volume status and to guide resuscitation.
Ventilator management is largely grounded in a lung-protective strategy. While debates rage regarding the nature of the disease and best practices for ventilatory management, we recommend the ARDS Clinical Network Ventilation protocol.43 Rescue strategies have been included in our guidelines for difficult-to-oxygenate patients. Patients must be synchronized with the ventilator to maximize our ability to oxygenate them; a RASS score of -2 to -3 is to be targeted. Should the patient remain hypoxic, a trial of paralysis can be attempted to improve oxygenation.40 Prone positioning of intubated patients to improve oxygenation is safest in the ICU with clinicians and teams that are experienced with the practice.35 Repositioning the patients into a lateral decubitus positioning may be a safer halfway mark to attempt in the ED while patients are waiting for an ICU bed. If rescue maneuvers fail, ECMO should be considered, if available.
In this episode of EMplify, Dr. Sam Ashoo interviews Dr. Ilene Claudius and Dr. Mohsen Saidinejad about Multi-system Inflammatory Syndrome in Children (MIS-C) with COVID-19.
Multi-system Inflammatory Syndrome in Children (MIS-C) with COVID-19: An Interview with Dr. Ilene Claudius and Dr. Mohsen Saidinejad.
Have questions or comments on the podcast? Leave us a voicemail at 678-336-8466, ext 128 or write us at emplify@ebmedicine.net.
Children’s Hospital of Philadelphia Clinical Pathway for MIS-C.
In this episode of EMplify, Dr. Sam Ashoo interviews Dr. Harry Wingate and Dr. Ken Gramyk about Rural Emergency Medicine during the COVID-19 pandemic.
Rural Emergency Medicine and COVID-19: An Interview with Dr. Harry Wingate and Dr. Ken Gramyk.
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In this episode of EMplify, Dr. Sam Ashoo interviews Dr. Ashley Shreves about her experience as an emergency clinician and palliative medicine clinician in New Orleans during the COVID-19 pandemic.
EBMedicine Live Webinars:
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In this episode of EMplify, Dr. Sam Ashoo interviews Dr. Eric Legome about "Emergency Department COVID Management Protocols: One Institution’s Experience and Lessons Learned."
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Emergency Department COVID Management Protocols: One Institution’s Experience and Lessons Learned
In this episode of EMplify, Dr. Sam Ashoo interviews Dr. Colby Redfield, about triage, tent Implementation, telemedicine, PPE, and EMS.
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COVID-19 Topics:
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In this episode of EMplify, Dr. Sam Ashoo interviews Dr. Joe Habboush, MD, CEO of MDCalc about new COVID-19 tools and his New York City experience.
In this episode of EMplify, Dr. Sam Ashoo interviews Dr. Andrea Duca, an attending physician in the Emergency Department of Papa Giovanni XXIII Hospital in Bergamo, Italy.
01:29 Dr. Andrea Duca introduction.
ER physician working in Milan.
02:05 What were your shifts like at the start of the epidemic?
Initially started seeing a few patients who had recently returned from China. They were screened in triage and isolated based on travel to china or contact with someone who had traveled to China and fever. Over the next few days the number of patients increased with mild upper airway and fever symptoms.
04:50 Were you testing patients for COVID-19 initially?
Only the patients coming from China or Caulonia Italy (First confirmed case in Italy).
05:08 Were the COVID-19 tests completed in-house or sent out to a government lab?
Test had to be sent out for confirmation.
05:35 The arrival of the first cases. Then… and now.
Initially only a few patients required admission. Around the 27th or 28th of February a lot of patients presented with lower respiratory symptoms and fever requiring increased admission rates. Around the first week of March the admission rate increased.
07:03 What percent of your daily volume is due to COVID-19 patients?
80% of patients presenting to the ED were hypoxic. 80% of those patients required oxygen and 30% of the patients required ventilatory support.
08:17 Are COVID-19 patients diverted to a regional facility?
No. 90% of our patients are COVID-19
09:13 Are you still testing patients for COVID-19 today?
We test only the patients we are admitting to the hospital
09:57 What is your current medication protocol?
We start antibiotics on almost all of COVID-19 patients. If the patient has severe respiratory failure, we start hydroxychloroquine. We have started using an antiviral also.
10:54 Hydroxychloroquine
Only if in severe respiratory failure
11:14 Do you use non-invasive ventilation?
We do not have the resources to intubate all of these patients. We start most patients on non-invasive ventilation, mostly helmet ventilation which works very well for most of the patients. This helps us buy some time to get an ICU bed
13:35 What kind of isolation do you use, airborne or droplet?
We only have one isolation room in the ED and usually about 100 patients needing it.
14:46 Do you put on new PPE as you go room to room?
We do not have enough supplies to change for every patient, so we just change the gloves.
15:21 What PPE do you currently use?
Gown, gloves, shoe covers, head cover and glasses
15:38 When did you create dirty and clean zones in the emergency department?
We created a dirty zone very early
16:45 Do you have a dirty and clean side in the waiting room?
Yes. They are screened and separated upon arrival
17:03 What is your annual emergency department volume? Daily volume?
100,000/year
18:04 How many treatment rooms are in your emergency department?
We have a lot of space
18:38 What percent of patients are admitted? Do you have boarders?
80%- 90% right now. Yes, we have boarders
19:54 Where do discharged patients go?
They go to a convalescent home
20:14 Have you personally been infected?
I got tested and I was negative and went back to work
20:58 Do you test your staff who are ill? What is your protocol for infected staff?
We do not test staff anymore. We cannot afford to stay home for 14 days and we all have some mild symptoms. If we have fever, we wait 7 days and then go back to work.
22:46 What percent of the ED staff were sick at any given time? And inpatient nurses?
Rates are low in the ED (10%) and much higher in the inpatient units (40%-50%)
24:00 How did you deal with so many inpatient nurses being sick?
Cancel elective procedures so everyone can treat COVID patients 24:36 What are your surgeons, who cannot operate, currently doing?
Surgeons are treating COVID patients in the inpatient wards not the ED. They started courses on how to use helmet CPAP and they follow these patients.
25:35 Are you running out of non-invasive ventilation equipment?
Not really. We have a lot of helmets.
26:20 Summary of current workflow for infected staff.
If staff get sick with a fever, they go home and after the fever is gone, they wait 7 days and then return to work.
26:36 How do you use ultrasound for COVID-19 patients in the ED?
We use ultrasound because we cannot CT scan everyone.
29:50 What criteria must a patient meet to be discharged?
Normal vitals, unremarkable labs, normal CXR, normal pulmonary chest US, O2 sat does not Drop by more than 3 points with ambulation
31:00 EMS and their role in community screening
EMS is field screening all patients. If the patient is not in distress and the oxygen saturation is Above 90%, they are not transported to the ED.
32:20 What are you looking for on ultrasound examination?
Minor abnormalities and lung consolidation
34.42 What size chest tube are you utilizing for a pneumothorax in a patient with positive pressure ventilation?
24 Fr
26:33 What inpatient location are patients sent to? By what criteria?
ICU is reserved for intubated patients. Chest tubes and CPAP are sent to regular floors
37:05 Have you seen any infected pregnant patients or staff?
Have not seen pregnant patient or staff infected with COVID 19 in the ED
38:02 Have you seen any infected children?
No. The ED sees only critically ill otherwise they would be seen by pediatricians
38:43 Are you still testing patients? How many times are you testing them?
Now the testing in completed in house. It takes about 8-10 hours. We test them on admission and 2-3 days later
39:21 What psychological support do you have for staff?
Staff have a number that they can call to organize a meeting and they are in the department every day. The stress is very high due to isolation at the hospital and at home
42:25 What would you have liked to know early on?
The rates of patients needing ventilation was going to be so high. Preparation is the key to managing this.
In this episode of EMplify, Dr. Sam Ashoo interviews Drs. Al Giwa and Akash Desai, the authors of Emergency Medicine Practice’s recent article: Novel Coronavirus COVID-19: An Overview for Emergency Clinicians
This episode, designed specifically for emergency clinicians, discusses Coronavirus COVID-19, including:
Get quick-hit summaries of hot topics in emergency medicine. EMplify summarizes evidence-based reviews in a monthly podcast. Highlights of the latest research published in EB Medicine's peer-reviewed journals educate and arm you for life in the ED.
Why to Use
The BCRSS/algorithm uses patient examination features along with the need for escalating levels of respiratory support (noninvasive ventilation, intubation, proning) to suggest treatment recommendations. The scale drastically simplifies the clinical summary of a patient’s status, and allows clinicians to compare patients to one another and to track the trend of a patient’s level of respiratory severity over time. It also allows clinicians to more closely monitor patients nearing a critical action point (eg, Level 3–possibly nearing the need for intubation).
When to Use
Next Steps
Abbreviations: BCRSS, Brescia-COVID repiratory severity scale; ED, emergency department; PCR, polymerase chain reaction.
Patients with tachypnea and patients who require significant levels of oxygen or ventilatory support are at very high risk for clinical decompensation and death.
This scale has not been externally validated and has been published by MDCalc as a possible method to easily assess and compare patients in a time of crisis.
Original/Primary Reference
Information about COVID-19 is changing rapidly. This review is based on incomplete data and reviews some newer calculators that have not yet been externally validated. As we learn more, this review may quickly become outdated. It is being published in order to provide potentially helpful information, even if incomplete, to clini-cians at the frontlines of the pandemic.
Even well-validated calculators should never be used alone to guide patient care, nor should they substitute for clinical judgment.
SARS-CoV-2, also known as the 2019 novel coronavirus, was first reported in China in December 2019 as the pathogen behind the pattern of severe infectious pneumonias that were particularly fatal in the elderly. By January 2020, it was declared a global public health emergency.
In the near future, clinicians may face scenarios in which there are not have enough resources (ventilators, extracorporeal membrane oxygenation [ECMO] machines, etc) available for the number of critically sick COVID-19 patients. There may not be enough healthcare workers, as those who are positive for COVID-19 or those who have been exposed to the virus and need to be quarantined. During these worst-case scenarios, new crisis standards of care and thresholds for intensive care unit (ICU) admissions will be needed. Clinical decision scores may support the clinician’s decision-making, especially if properly adapted for this unique pandemic and for the patient being treated.1
This review will discuss the use of clinical prediction scores for pneumonia severity at 3 main decision points to examine which scores may provide value in this unique situation. Initial data from a cohort of over 44,000 COVID-19 patients in China, including risk factors for mortality, were compared with data from cohorts used to study the clinical scores, in order to estimate the potential appropriateness of each score and determine how to best adjust results at the bedside. For example, age ≥ 60 years is a risk factor for mortality in bacterial pneumonia (odds ratio [OR] 5.2), but it is a considerably stronger risk factor for mortality in COVID-19 patients (OR 9.9-32). Other risk factors seem to confer even higher risk in COVID-19 patients than in typical bacterial pneumonia patients, including cardiovascular disease, diabetes, and lung disease. There is also a surprisingly large correlation between low lymphocyte counts and higher mortality in COVID-19 patients.1-3 (See Table 1.)
There is evidence, based on a much smaller cohort of 191 patients, that a SOFA score > 5 (OR 5.5; 95% confidence interval [CI], 2.6-12.2; P < 0.0001) and D-dimer concentration > 1000 ng/mL on admission (OR 18; 95% CI, 2.6-128.6; P < 0.0001) confer significant mortality risk in COVID-19 patients.1 In addition, prolactin levels have been found to be normal or even low; if levels are found to be high, this may suggest a bacterial coinfection necessitating administration of antibiotics. C-reactive protein levels have been found to be higher in worsening disease and may provide prognostic value.4-5
PSI/PORT may add value; consider the new MuLBSTA score; adjust for elderly patients.
Each of these scores was designed to predict mortality and is used to determine which patients can safely be sent home. A low-risk CURB-65 score (0 or 1) confers a 0.6% to 2.7% risk of mortality.6 A low-risk PSI/PORT score (< 90) confers a 0.1% to 2.8% risk of mortality.7 Comparing the utility of the 2 scores, CURB-65 may not identify patients requiring ICU admission as well as PSI/PORT. In addition, CURB- 65 does not take into account patients’ comorbidities (eg, COPD), which may have a major impact on outcomes in COVID-19 patients. While CURB-65 is considerably faster to compute, with fewer inputs, this advantage matters less in the age of electronic records and resources. PSI/PORT places a larger emphasis on age than CURB-65, assigning points by absolute age (ie, a 70-year-old gets 70 points), which seems more consistent with what we know about the high mortality of COVID-19 in elderly patients.
In both of these cohorts, community acquired pneumonia (CAP) was generally defined as a combination of clinical (eg, fever, cough, dyspnea, rales) and radiographic (eg, infiltrate on chest x-ray) findings in the absence of risk factors for healthcare-associated pneumonia. Neither the CURB-65 or PSI/PORT studies differentiated between viral and bacterial pathogens as a cause for the pneumonia, although the incidence of viral-associated CAP may be up to 29%, with rhinoviruses and influenza being the most common.8-9
Recently, the MuLBSTA score was developed as a clinical prediction tool to risk stratify patients specifically diagnosed with viral pneumonia.9 The aim of this tool was to predict clinical characteristics that affect mortality in patients with viral pneumonia. Interestingly, the score uses predictors of adverse outcomes that correlate with the clinical characteristics that are reported in COVID-19 patients. The presence of a multilobar infiltrate, low lymphocyte count, smoking history, and advanced age all were independent risk factors for mortality in this population, and are all relatively consistent with risk factors from the Chinese COVID-19 cohort. However, this score was derived from a single-center, retrospective, not-externally-validated study design, which may lead to bias and has unknown applicability and generalizability.
SMART-COP for decision to start respiratory or vasopressors; LIPS to predict acute respiratory distress syndrome (ARDS); CAP-PIRO for mortality after ICU admission. None are designed specifically for viral pneumonia.
For patients presenting to the emergency department with CAP, it has been established that delayed admission to the ICU is associated with higher mortality.11 The SMART-COP score was designed to predict which patients with CAP require intensive respiratory or vasopressor support.12 It uses readily available information, and is 92.3% sensitive in identifying which patients need ICU-level care. In contrast to other scores, SMART-COP does not explicitly consider age as a variable, although it does include age-adjusted cutoffs for respiratory rate and oxygen level.
The SCAP score uses 8 variables that identify patients at risk for “severe CAP,” defined by adverse outcomes such as need for ICU admission, development of sepsis, or requirement of mechanical ventilation.13 SMART-COP and SCAP share several common predictors of adverse patient-oriented outcomes potentially necessitating a higher level of care: age (SMART-COP, aged > 50 years; SCAP aged > 80 years), multilobar involvement on radiography, respiratory rate > 30 breaths/min, confusion (new onset), PaO2/FiO2 < 250 mm Hg, decreased pH (SMART-COP, < 7.35; SCAP, < 7.30), and systolic blood pressure < 90 mm Hg.
If the pandemic stretches resources beyond the ability to care for all patients, some states have developed plans to use a SOFA score > 11 as a cutoff to help with decision-making in these dire situations.14 However, recent studies have shown that SOFA should be used cautiously as part of a decision-making framework and does not meet the ethical cutoffs for prediction across different patient populations.14-15
The LIPS score is differentiated in that it was designed to estimate risk of ARDS, and it has utility at the time of critical care contact.16 The CAP-PIRO score was designed to predict mortality of CAP patients who are already admitted to the ICU, therefore limiting its utility in the disposition decision-making process.17 Like most scores, these scores do not differentiate between causes of pneumonia, nor were they designed to specifically risk stratify patients with viral pneumonia.
Very little specific experience for COVID-19 patients, but tools exist to guide resource use.
Many of the COVID-19 fatalities are due to ARDS. The Murray score was developed to determine which patients are sick enough for veno-venous ECMO, a critical decision point during this crisis.18 The RESP and PRESET scores attempt to predict mortality of patients on ECMO, which may be helpful during the difficult potential situation when rationing of ECMO may become necessary.19-20 At this point, there is very limited guidance specific to the use of ECMO in COVID-19 patients, though it has been utilized in China.
For patients with worsening respiratory failure, a Murray score ≥ 3 suggests a condition severe enough to consider initiating ECMO. The score was initially developed to assess the severity of ARDS but was then utilized in the CESAR trial (the first modern randomized controlled trial to compare traditional vent management to ECMO) to determine appropriateness for ECMO.21 The initial and validation trials did not specifically address ARDS due to viral causes, but they also did not exclude these patients, so it is likely that the score is applicable to COVID-19 patients.
If the pandemic stretches beyond available healthcare resources, these tools may assist in a framework to develop new crisis standards of care for patients requiring ECMO. The RESP score had a lower predictive ability within its derivation cohort (internal area under receiver operating curve) than PRESET, but PRESET’s patient population had a higher critical illness severity than has been noted in other ECMO cohorts and thus had a lower predictive ability when validated in subsequent cohorts. RESP requires 12 input variables, whereas PRESET requires 5. While this makes RESP more complicated to use, it has been validated in more subsequent cohorts than PRESET, so it may be preferable. RESP also specifically takes into account whether a viral pneumonia is underlying respiratory failure, which may increase its applicability to COVID-19 patients.
Authors
Peer Reviewers
The novel coronavirus, SARS-CoV-2, and its infection, COVID-19, has quickly become a worldwide threat to health, travel, and commerce. It is essential for emergency clinicians to learn as much as possible about this pandemic to manage the unprecedented burdens on healthcare providers and hospital systems. This review analyzes information from worldwide research and experience on the epidemiology, prevention, and treatment of COVID-19, and offers links to the most reliable and trustworthy resources to help equip healthcare professionals in managing this public health challenge. As the pandemic sweeps the United States, lessons learned from early centers of infection, notably New York and Northern Italy, can help localities to prepare.
A 42-year-old man presents to your ED triage area with a high-grade fever (39.6°C [103.3°F]), cough, and fatigue for 1 week. He said that the week prior, he was at an emergency medicine conference in New York City, and took the subway with some people who were coughing excessively. The triage nurses immediately recognize the infectious risk, place a mask on the patient, place him in a negative pressure room, and inform you that the patient is ready to be seen. You wonder what to do with the other 10 individuals who were sitting near the patient while he was waiting to be triaged, and what you should do next... Later in your shift, a steady flow of patients with varying degrees of upper and lower respiratory symptoms arrive. Additionally, there are several “worried well” patients without symptoms, who are requesting testing for COVID-19, based on varying degrees of perceived exposures. What do you tell them? How do you handle the throngs of patients now potentially contaminating higherrisk patients?
Coronaviruses earn their name from the characteristic crown-like viral particles (virions) that dot their surface. This family of viruses infects a wide range of vertebrates, most notably mammals and birds, and are considered to be a major cause of viral respiratory infections worldwide.3,4 With the recent detection of the 2019 novel coronavirus (SARS-CoV-2), and the resultant disease that has been given the name, coronavirus disease 2019 (COVID-19), there are now a total of 7 coronaviruses known to infect humans:
Prior to the global outbreak of SARS-CoV-1 in 2003, HCoV-229E and HCoV-OC43 were the only coronaviruses known to infect humans. Following the SARS-CoV-1 outbreak, 5 additional coronaviruses have been discovered in humans, most recently the novel coronavirus SARS-CoV-2, believed to have originated in Wuhan, Hubei Province, China. SARS-CoV-1 and MERS-CoV are particularly pathogenic in humans and are associated with high mortality. In this article, the epidemiology, pathophysiology, and management of COVID-19 are reviewed, with a focus on best practices and public health implications.
PubMed, ISI Web of Knowledge, and the Cochrane Database of Systematic Reviews resources from 2012 to 2020 were accessed using the keywords emergency department, epidemic, pandemic, coronavirus, SARS-CoV-2, and COVID-19. The websites of the United States Centers for Disease Control and Prevention (CDC); the World Health Organization (WHO); Japan’s National Ministry of Health, Labor, and Welfare; and EMCrit were also accessed.
As of March 27, 2020, there have been 566,269 confirmed cases of COVID-19 globally, with the majority of new cases now occurring outside of mainland China. There have been 25,423 confirmed deaths.1 For up-to-date numbers on global confirmed cases/deaths from COVID-19, go to the Johns Hopkins University online tracker. At the time of this printing, confirmed cases span 176 countries across all continents except Antarctica, prompting the WHO to declare the SARS-CoV-2 infection a pandemic. Of the deaths, over half have now occurred outside of China, led by Italy (8215 deaths), and Iran (2378 deaths). The current global case fatality rate is 4.38%. With the outbreak of COVID-19 coinciding with the celebration of the Chinese Lunar New Year in late January 2020 and an associated approximately 15 million visits to Wuhan City, the efforts to contain the outbreak to mainland China were ultimately unsuccessful. Initial reports from affected patient populations in hospitals in China indicated that the majority of those infected with severe disease and poor outcomes (as measured by intensive care unit [ICU]-level care and mortality) tended to be patients with comorbid conditions such as hypertension, diabetes, obesity, asthma, chronic obstructive pulmonary disease, or advanced age.2,6
In epidemiology, the R0 value (pronounced “R-naught”) is known as the basic reproduction number and can be thought of as the expected number of cases generated directly by 1 case in a population, where all individuals are susceptible to infection. Early epidemiologic studies in the case of COVID-19 estimated an R0 value of 2.2 (90% high density interval: 1.4-3.8), a value similar to SARS-CoV-1 and pandemic influenza, suggesting the potential for sustained human-to-human transmission and a global pandemic.7 As will be discussed in more detail in the “Prevention” section, R0 is a reflection of both virus behavior and human behavior, so with the correct societal and behavioral interventions, this R0 value can be reduced.
With just mere months since the first case, the death toll from SARS-CoV-2 has far exceeded that of both MERS-CoV and SARS-CoV combined.1 The true mortality rate is believed to be lower than the case fatality rate, due to selection bias, as only those with symptomatology severe enough to prompt emergency evaluation and/or hospitalization are being tested for COVID-19.8 Data from the Diamond Princess cruise ship outbreak provides a unique snapshot of the true mortality and symptomatology of the disease, given that everyone on board was tested, regardless of symptoms. Based on this data, unpublished analyses at the London School of Hygiene and Tropical Medicine have estimated an age-adjusted case fatality rate of 0.5%. This would still rank COVID-19 as deadlier than pandemic influenza, while maintaining a similar infectious profile.9 Additionally, according to Japan’s National Ministry of Health, Labor, and Welfare, 327 of the 697 people aboard the ship who tested positive for COVID-19 never showed symptoms, even up to a month after the initial positive test.10
We are fortunate to provide a first-hand perspective to the COVID-19 crisis in Italy, which occurred a few weeks after Washington state’s first reported case (January 21), and what epidemiologists have estimated is about 2 to 3 weeks ahead of the New York metropolitan area outbreak. Andrea Duca, MD is an emergency medicine physician and member of the Editorial Board of Emergency Medicine Practice based in Northern Italy, an area which bore the initial brunt of COVID-19. He reports that the rapid spread of SARS-CoV-2 overwhelmed most hospitals, which were unprepared to deal with the sudden influx of patients requiring ventilatory support. To date (as of March 18, 2020), Italy has a case fatality rate of 8.37%, which should serve as a warning to other healthcare systems around the world preparing to deal with patients with severe COVID-19 in the upcoming weeks. See Table 1 for Dr. Andrea Duca’s summary of lessons learned managing the SARS-CoV-2 outbreak in his ED in Bergamo, Italy. Additional data from that hospital are included in Figures 1, 2, 3, and 4. Figure 1 presents a timeline of COVID-19 cases in the Lombardy region, February 20 to March 17, 2020; Figure 2 lists the percentage of daily census admissions and discharges of COVID-19 patients, February 29 to March 10, 2020; Figure 3 presents the total daily census admissions and discharges of COVID-19 patients; Figure 4 presents a graphic display of the disposition of COVID-19 patients, February 29 to March 10, 2020.
Coronaviruses are in the order Nidovirales, in the family Coronaviridae, and subfamily Orthocoronavirinae. Coronaviruses are enveloped with positive-sense single-stranded RNA, and possess the largest genome of all RNA viruses. Two-thirds of the coronavirus genome at the 5’ terminus encodes viral proteins involved in transcribing viral RNA and replication, while one-third at the 3’ terminus encodes viral structural and group-specific accessory proteins.4 Our current understanding highlights 4 major proteins in coronaviruses: S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins. These biomarkers play a central role not just in how we diagnose the disease, but how we will come to understand its pathogenicity profile, and ultimately any options for a vaccine and/or direct antiviral treatment targeted to dismantle the viral life cycle. (See Figure 5.)
The SARS-CoV-1 and MERS-CoV viruses were both believed to have resulted from zoonotic spread from the bat population.11 Naming the virus causing the current pandemic “SARS-CoV-2” is a result of its genetic similarity to the virus that caused the outbreak in 2003, which is now called “SARS-CoV-1.” While coronaviruses likely evolved over thousands of years remaining confined to bat populations, intermediate mammalian hosts (such as civet cats in the case of SARS-CoV-1 and dromedary camels in the case of MERS-CoV) have been implicated and likely played a role in the ultimate transmission of these novel coronaviruses to humans.12,13 The outbreak of COVID-19 is suspected to have originated in the Huanan Seafood Wholesale Market in Wuhan City; however, other researchers have suggested that this market may not be the original source of viral transmission to humans.2,14 Bats are rare in markets in China, but they are hunted and sold directly to restaurants for food.15
Coronaviruses primarily infect the upper respiratory and gastrointestinal tracts of birds and mammals. The surface spike glycoprotein (S-protein) is a key factor in the virulence of coronaviruses, as it enables it to attach to host cells. MERS-CoV has been shown to bind to dipeptidyl-peptidase 4 (DPP4), a protein that has been conserved across species known to harbor this strain of coronavirus. While most respiratory viruses infect ciliated cells, DPP4 is expressed in nonciliated cells in human airways, which is believed to be an important factor in its zoonotic transmission and high case fatality rate.16 In SARS-CoV-1, human angiotensin-converting enzyme 2 (ACE2) was the primary cellular receptor to which the virus attached, and is believed to have played a role in the ability of SARS-CoV-1 to produce infections of both the upper and lower respiratory tracts, contributing to its infectivity and .lethality.17
Previous studies have suggested that immunopathogenesis, also referred to as “cytokine storm,” leads to the deterioration of patients dealing with various respiratory viruses, including SARS-CoV-1 and avian influenza.18,19 A number of studies support the theory that the rapid deterioration of COVID-19 patients is driven by immunopathogenesis, whereby release of inflammatory markers initiates a positive feedback loop that leads to ARDS, multiorgan failure, and death.20 A cohort of 41 laboratory-confirmed COVID-19 patients in China found that ICU patients had significantly higher levels of inflammatory markers (IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1, and TNF-alpha) than non-ICU patients.21 A recent study conducted in China provides a detailed immunopathology report on SARS-CoV-2, suggesting patients with severe COVID-19 express an “…excessive activated immune response…by pathogenic Th1 cells and inflammatory monocytes,” findings that are additionally supported by immunohistochemical analysis of postmortem lung biopsies of COVID-19 patients.22,23 A growing body of literature suggests secondary or virus-induced hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome, to be the underlying cause of deterioration in these patients. This disease process carries a similar cytokine profile to patients with COVID-19, and includes cardinal clinical features of unremitting fever, cytopenias, hyperferritinemia, and pulmonary involvement.24,25 Immunomodulatory therapies that are being considered in the treatment of COVID-19 will be discussed in the “Management” section.
SARS-CoV-2 enters type 2 pneumocytes in humans via the same ACE2 receptor as SARS-CoV-1.26 A multicenter retrospective cohort study examining risk factors associated with inhospital death found hypertension to be the most common comorbidity in COVID-19-diagnosed patients requiring admission (30%), followed by diabetes (19%).27
Much has been made in recent weeks of the potential link between the commonly used antihypertensives, ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), and elevated risk for severe COVID-19 infection based on the binding of SARS-CoV-2 on ACE2 receptors. At this time, the official recommendations by the European Society of Cardiology, the American College of Cardiology, American Heart Failure Society, and the Heart Failure Society of America collectively state that patients on ACEIs and ARBs should continue their medications. The European Society of Cardiology stated, “there is no clinical or scientific evidence to suggest that treatment with ACEIs and ARBs should be discontinued because of the COVID-19 infection,”28 and the joint HFSA/ACC/AHA statement noted, "there are no experimental or clinical data demonstrating beneficial or adverse outcomes among COVID-19 patients using ACEI or ARB medications.”29
Similar concerns over the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, have been raised based on postulated interactions with SARS-CoV-2 binding to ACE2 receptors. There is currently no scientific evidence to suggest that taking NSAIDs worsens COVID-19. Clearly, prospective multicenter trials should be conducted to investigate this issue further. A full discussion of the theoretical benefits and harms to patients on these medications can be found in the "Nephrology Journal Club"
Much can be learned from the change in the dynamics of transmission following implementation of strict travel restrictions and quarantining measures in mainland China. A mathematical modeling study published in The Lancet estimated that the median daily reproduction number (Rt) in Wuhan declined from 2.35 (95% confidence interval [CI], 1.15–4.77) 1 week before travel restrictions were introduced on January 23, 2020, to 1.05 (0.41–2.39) 1 week after.30 The effectiveness of broad governmental and societal interventions has been documented by multiple data-driven analyses, and should prompt all governments to act accordingly to prioritize early detection, isolation, and treatment; to supply adequate medical supplies; and to establish a system in which patients are admitted to designated hospitals with a comprehensive therapeutic strategy.30,31 Utilizing a stochastic transmission model parameterized to the COVID-19 outbreak, Hellewell et al concluded that “highly effective contact tracing and case isolation is enough to control a new outbreak of COVID-19 within 3 months.”32
A study published on March 16, 2020 by the Imperial College of London and WHO compared 2 fundamental policy strategies to reduce the rate of spread of SARS-CoV-2: “(a) mitigation, which focuses on slowing but not necessarily stopping epidemic spread – reducing peak healthcare demand while protecting those most at risk of severe disease from infection, and (b) suppression, which aims to reverse epidemic growth, reducing case numbers to low levels and maintaining that situation indefinitely.” The study found that “…optimal mitigation policies (combining home isolation of suspect cases, home quarantine of those living in the same household as suspect cases, and social distancing of the elderly and others at most risk of severe disease) might reduce peak healthcare demand by two-thirds, and deaths by half. However, the resulting mitigated epidemic would still result in hundreds of thousands of deaths and health systems (most notably intensive care units) being overwhelmed.”33 This explains and lends support to the aggressive measures taken by countries in recent days to battle the spread of the SARS-CoV-2 pandemic.
Reports from Italy suggest that up to 20% of healthcare professionals dealing with COVID-19 patients became infected with the virus, with some reported deaths.34 Losing healthcare workers to illness at a time when they are needed the most can be the tipping point for healthcare systems that are already stretched to the breaking point by high volumes of sick patients. Recognition of the crisis in Italy underscores the importance of strictly enforcing preventive measures to all healthcare professionals. This has been accomplished in some systems by assigning one person to monitor compliance in the ED at all times.
Based on the transmission specifications of coronaviruses as a class, and documented transmission patterns of the SARS-CoV-1 and MERS-CoV outbreaks, the transmission of SARS-CoV-2 is presumed to be primarily through droplets and fomites, although viral particles have also been found in feces of seropositive patients. A preprint article published in The New England Journal of Medicine by researchers at the United States National Institutes of Health, Princeton University, and the University of California Los Angeles, found estimated half-lives for SARS-CoV-2 virus on various surfaces as follows: 1.1 hours in aerosols, 0.77 hours on copper, 3.46 hours on cardboard, 5.46 hours on steel, and 6.81 hours on plastic. These results indicated a plausible likelihood of aerosol and fomite transmission of SARS-CoV-2, and lend credence to its reported high rate of spread.35
Both the WHO and CDC guidelines for infection control emphasize the importance of strict hand hygiene in curtailing SARS-CoV-2 transmission. This stems from the uncertainty surrounding the transmission vectors aboard the quarantined Diamond Princess cruise ship off the coastal waters of Japan, as well as increasing reports from around the world of COVID-19 appearing in people who had not had direct contact with known or suspected carrier(s) or traveler(s) to an endemic area.36,37 Given the reports from the Chinese CDC of SARS-CoV-2 virus being found in the feces of seropositive patients, the likelihood of fecal-oral and, hence, hand transmission is very high.38 Healthcare professionals and patients should follow standard hand-washing techniques: wash hands with soap and water for at least 20 seconds, especially after going to the bathroom; before and after eating; and after blowing the nose, coughing, or sneezing. If soap and water are not available, one should use an alcohol-based sanitizer with at least 60% alcohol.5
Additional guidelines for those with close contacts and suspicious exposures include “strong recommendations” for immediate medical attention, an observation period of 14 days, wearing of a facemask if coughing or with URI symptoms, prioritizing private transportation over public, prenotification of the hospital (or clinic) prior to patient arrival, and cleansing of the transport vehicle with 500 mg/L chlorine-containing disinfectant, with open ventilation.39 Note that the recommended observation period may soon be modified, given recent case reports and studies suggesting incubation periods from 0 to 24 days.40,41
Given the recent shortages of N95 respirator masks and other PPE, there is an increased need to follow current recommendations to account for changing availability of these necessary supplies. These can and should be followed in real time using the links supplied in Table 3. Additionally, recent considerations include recommendations to designate entire units within the facility with dedicated healthcare personnel to care for known or suspected COVID-19 patients, along with need for airborne infection isolation rooms (AIIRs).2
Doffing of personal protective equipment (PPE) is often the highest-risk procedure during the patient-physician interaction, in terms of spread of SARS-CoV-2. Below is a simple step-by-step approach put together by emergency clinicians at EMCrit on the proper doffing of PPE after evaluation of a suspected or confirmed COVID-19 patient.42 (See Table 2.)
A video of the correct procedures for donning and doffing PPE is available in youtube
Experience from Bergamo, in the region of Lombardia in Northern Italy, provides a model of response that may help other systems prepare. That region’s EDs encountered an overwhelming volume of patients in severe respiratory distress over short periods of time which required immediate adjustments to flow and throughput. A summary of these changes and recommendations are listed in Table 1. Of note, much of the data are estimates based on preliminary data collection.
ED staff must maintain a high index of suspicion when evaluating all patients, but especially those with fever, cough, dyspnea, or signs of a respiratory illness. The CDC had initially focused their travel warnings and epidemiological risks on those with recent travel or contact with a traveler to Wuhan City, Hubei province, China; however, having reached pandemic status with significant community spread, the connection to China is no longer relevant as a criterion to rule out SARS-CoV-2 infection.
In late January 2020, the first data detailing the clinical features, course, and prognosis from infection with SARS-CoV-2 relative to the previous 2 deadly coronavirus outbreaks (MERS-CoV and SARS-CoV-1) were published in The Lancet.21,43 Since then, a multicenter retrospective cohort analysis of 1099 patients was published in The New England Journal of Medicine, which provides an updated glimpse of demographic and clinical characteristics of COVID-19.41 Table 3 differentiates symptomatology in patients with severe versus nonsevere disease, as defined by the American Thoracic Society guidelines for community-acquired pneumonia.44 Patients with severe disease were older than those with nonsevere disease by a median of 7 years, and had much higher rates of comorbidity, namely hypertension (23.7% vs 13.4%, respectively) and diabetes (16.2% vs 5.7%, respectively). This table and article can be viewed in The New England Journal of Medicine. Table 3 summarizes the early characteristics of SARS-CoV-2 compared to MERS-CoV and SARS-CoV-1.
On March 18, 2020 the American Journal of Gastroenterology published a new study from the Wuhan Medical Treatment Expert Group for COVID-19 in China revealing that GI symptoms, such as diarrhea, are common in SARS-CoV-2 infection.46 In 204 patients confirmed to have SARS-CoV-2, 99 (48.5%) had GI symptoms, and 7 of the patients with GI symptoms had no respiratory symptoms whatsoever. This is clearly a departure from the purely respiratory disease current guidance has provided, but consistent with the observed fecal-oral transmission patterns noted in earlier cited Chinese studies. Furthermore, the prognosis of patients with GI symptoms was worse than for those with purely respiratory symptoms. They found that patients without digestive symptoms were more likely to be cured and discharged than patients with digestive symptoms (60% vs 34.3%). The authors failed to ascertain the etiology of the mortality and morbidity difference between COVID-19, and recommend further studies.46
It should be noted that in the initial data from Bergamo, Italy described by Dr. Andrea Duca, there is a reported association of obesity with disease severity and need for intubation/critical care. From the same data, the rates of patients needing NIV or intubation in the ED are similar to data from Wu et al,45 accounting for up to 31% of suspected COVID-19 patients admitted to the hospital. It is still too early to know how many patients who were started on NIV in the ED will be converted to invasive ventilation during the hospital stay and how many on oxygen will deteriorate and need to be ventilated. These data are still being collected and analyzed, and will soon be available for analysis and publication.
Within 1 month of initial reports detailing the SARS-CoV-2 outbreak, the CDC developed a real-time reverse transcription-polymerase chain reaction (rRT-PCR) test to detect SARS-CoV-2. While diagnostic testing in the United States was available initially only through the CDC, this assay is now being made available at the state level with the use of the International Reagent Resource (IRR). The IRR was initially established by the CDC for the study and detection of influenza, but it has been expanded to include newly discovered influenza and coronaviruses.47,48 It should be noted that widely available respiratory viral panels test only for the earlier forms of human coronavirus, namely human coronaviruses 229E, NL63, OC43, and HKU1.49 The SARS-CoV-1, MERS-CoV, and SARS-CoV-2 strains require specialized assays that are becoming increasingly available. Unfortunately, the initial United States testing efforts were hampered by faulty initial test kits (due to problems with the reagent), and as a result, there was a lack of testing available for the majority of the country. Table 4 summarizes the current recommendations for SARS-CoV-2 testing.
In what has become a controversial policy reversal as the outbreak increases in the United States, there is a significant departure from previous guidance of testing any persons, including healthcare personnel who have had close contact with a suspected or laboratory-confirmed COVID-19 patient, or who have a history of travel from endemic areas within 14 days of their symptom onset. At the time of this publication, the current recommendation is to not test the asymptomatic healthcare workers who have known exposures, or other asymptomatic individuals with concerning exposures and/or travel history. There is also a pedaling back of recommendations to test any persons who do not need to be admitted to the hospital. It is unclear at this point whether these recommendations will change again.
There are additional epidemiologic factors that may also help guide decisions about SARS-CoV-2 testing. Documentation of COVID-19 in a locality with known community transmission may assist with the epidemiologic risk assessment to guide testing decisions. However, the inability of many locales and hospitals to test all persons has led to a rescinding of this recommendation. Given the increasing concern about the availability and reliability of SARS-CoV-2 testing, there is varying guidance provided at the federal, state, and local levels. Nonetheless, when clinicians decide to test, they should recall that in cases of high suspicion and based on early research in China (as well as reported by Duca in Italy, two negative tests repeated at least 24 hours apart (3 days in Italy), are needed to exclude COVID-19 as a diagnosis.51
Given this information, emergency clinicians should re-emphasize to the lay public what we already know of viral respiratory infections: that seeking treatment in a hospital setting for mild symptoms, fever, mild diarrhea, or cough alone likely carries with it more risk than benefit, both to themselves and to vulnerable patients around them. Patients experiencing severe symptoms such as difficulty breathing, high fever (>39°C), and an inability to tolerate oral hydration should seek emergency evaluation. For those who are concerned about their symptoms or concerned about spreading the infection to vulnerable family members, care should be taken to practice social distancing, self-quarantining, and utilization of telehealth and drive-through screening clinics to receive medical evaluation and testing (if warranted) while minimizing risk of infectious spread. Though beyond the scope of this review, further discussions regarding institutional and departmental policies that weigh the need to protect the health of medical staff and care for patients versus the need to minimize nosocomial spread from asymptomatic healthcare workers who may infect patients, will need to continue.
In the initial onset of SARS-CoV-2 outbreak in the United States, many clinicians were encouraged to test for other causes of respiratory illness (eg, influenza), based on recommendations from their infectious disease and infection prevention services. However, there has been ongoing debate regarding the testing and evaluation for COVID-19 in relation to co-infections with other viruses.
After an exhaustive search of the literature, interviews with several infectious disease physicians, consultation of several national and international forums dedicated to both emergency medicine and COVID-19, we were able to find only a single non-peer reviewed Chinese study of 8274 specimens collected and analyzed for SARS-CoV-2 and other viral species. (Note that the publisher states, “This article is a preprint and has not been peer reviewed. It reports medical research that has yet to be evaluated and so should not be used to guide clinical practice.”) In this study, they found that 5.8% of COVID-19 patients had co-infections with other viruses, and that 18.4% of other (non-SARS-CoV-2) infections had other co-infectants.52 The authors acknowledged the unreliability of their tests for both SARS-CoV-2 and other viruses, which may underreport the actual co-infection rate. Furthermore, in some preliminary data reported by Stanford Medicine Data scientists, and immediately available to the public online at the behest of the California Department of Public Health, researchers found that in the 49 positive SARS-CoV-2 results, 11 (22.4%) also had co-infection with another virus.53 We anticipate that a large, validated study will help to shed further light on the rate of co-infection with SARS-CoV-2. In the meantime, we must recommend that clinicians maintain a high index of suspicion for SARS-CoV-2, regardless of the presence of other viruses.
As illustrated in Table 1 of a recent study published in The Lancet, univariate analyses of the following patient characteristics and laboratory markers were associated with increased mortality: increased age, lymphopenia, leukocytosis, and elevations in ALT, lactate dehydrogenase, high-sensitivity cardiac troponin I, creatine kinase, D-dimer, serum ferritin, IL-6, prothrombin time, creatinine, and procalcitonin.27 Multivariate regression models showed increasing odds of in-hospital death associated with older age (odds ratio [OR], 1.10; 95% CI,1.03-1.17 per year increase, P = .0043), higher sequential organ failure assessment (SOFA) score (5.65, 2.61-12.23; P < .0001), and D-dimer > 1 mcg/mL (18.42, 2.64–128.55; P = .0033) on admission.27 This table can be found at The Lancet
A recently published meta-analysis on procalcitonin in COVID-19 patients suggests that procalcitonin levels should remain in the reference range in patients with noncomplicated COVID-19, and that an elevation in procalcitonin may reflect bacterial co-infection in patients developing a severe form of COVID-19.54 A meta-analysis of platelet counts in COVID-19 patients found that thrombocytopenia is associated with increased risk of severe disease, and that a substantial decrease in platelet count should serve as a clinical indicator of worsening illness in patients hospitalized with COVID-19.55 See Table 5 for laboratory markers correlating with disease severity and clinical management for patients with COVID-19 pneumonia.
Data from the CDC released on March 17, 2020 shows a disconcerting trend in hospitalization rates in the younger-age demographic. Table 6 shows the latest rates, with an alarming rate of hospitalization of up to 20% in individuals aged 20 to 44 years. The good news for the pediatric population is that there have been no deaths reported in the United States at the time of publication. (See the “Pediatric Population” section.)
Findings on chest imaging in COVID-19 have been similar to findings seen in previous years from the SARS-CoV-1 and MERS-CoV outbreaks. A cohort analysis of 41 COVID-19 patients found all but 1 with bilateral lung involvement.21,59 A study of computed tomography (CT) scans of 21 COVID-19 patients showed 3 (21%) with normal CT scans; 12 (57%) with ground-glass opacity only; 6 (29%) with ground-glass opacity and consolidation at presentation; and interestingly, 3 (14%) with normal scans at diagnosis. Fifteen patients (71%) had 2 or more lobes involved, and 16 (76%) had bilateral disease.60 Of the 18 patients with positive findings on chest CT, all had the presence of ground-glass opacities, with 12 of the 18 having concomitant lobar consolidations.60
Data on 101 cases of COVID-19 pneumonia analyzed retrospectively from 4 institutions in Hunan, China found lesions present on CT were more likely to show a peripheral distribution (87.1%), bilateral involvement (82.2%), lower lung predominant (54.5%), and multifocal (54.5%).61 These findings, specifically the peripheral distribution of lesions, reflect positively on the ability of lung ultrasound to detect COVID-19 pneumonia.
Given the rate of nosocomial spread of the virus, the resource-intensive nature of obtaining CT scans in these patients, and the risk of transporting unstable hypoxemic patients, routine CT scans are not recommended in COVID-19 patients, as it rarely leads to a change in management. The American College of Radiology supports the use of CT sparingly, mainly in hospitalized symptomatic patients who may have other pathologies that need to be considered.62 Figure 6 presents a schema for imaging in patients with suspected COVID-19 pneumonia.
Recent literature as well as anecdotal reports from Italy offer support for using lung ultrasound as a way to screen patients with suspected COVID-19 pneumonia. For evaluation of pneumonia and/or adult respiratory distress syndrome (ARDS), lung ultrasound gives results that are similar to chest CT and are superior to standard chest radiography, with the added advantage of ease of use at point of care, repeatability, absence of radiation exposure, and low cost.63 Table 7 details findings on lung ultrasound as they correlate to findings on chest CT, with COVID-19 commonly resulting in lung pathology in the posterior lobes.64 In Italy, this has proven to be a useful screening tool. (See Table 1.)
With increasing disease severity, an evolution of findings on lung ultrasound may be seen.64 (See Figure 7.)
A YouTube video of an ultrasound scan of a patient with COVID-19 pneumonia [Courtesy Giovanni Volpicelli, MD]
Healthcare providers interested in receiving training to spot characteristic changes in the lung parenchyma in patients with COVID-19 can reference a recently published article by Huang et al, which has multiple examples of ultrasound images correlated to findings on high-resolution chest CT.65 This article and the images can be seen in Research Square
The article, “A Rapid Advice Guideline for the Diagnosis and Treatment of 2019 Novel Coronavirus (2019-nCoV)-Infected Pneumonia (standard version),” published in the journal, Military Medical Research, provides rapid advice guidelines and diagnostic imaging of several cases.39 Figure 8 presents a typical x-ray and CT images of a patient with COVID-19.
The article, “Evolution of CT Manifestations in a Patient Recovered from 2019 Novel Coronavirus (2019-nCoV) Pneumonia in Wuhan, China,” published in the journal Radiology, published 6 images of the evolution of chest imaging of a 42-year-old male patient infected with COVID-19 who recovered over 31 days.66
In the case of infection with any of the coronavirus strains, there is no approved treatment specific to the virus. Many patients with confirmed COVID-19 pneumonia in a recent JAMA study received broad-spectrum antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) with most receiving anti-influenza therapy (oseltamivir, 124 [89.9%]), and some additionally receiving steroids (glucocorticoid therapy, 62 [44.9%]).2 Given the evolving nature of this pandemic, clinicians may be well served by seeking the guidance of nations or health systems that have implemented proven treatment and management protocols. One such guidance from Belgium, entitled “Interim Clinical Guidance For Patients Suspected Of/Confirmed With Covid-19 In Belgium”. Recommendations from the Italian Society of Infectious and Tropical Diseases can be found here (published in Italian)
For an additional example, see Figure 9 for the Boston Medical Center’s COVID-19 treatment protocol.
Considering the lack of direct evidence with regard to treatment of COVID-19, recently proposed guidelines have been built largely on treatment guidelines for SARS-CoV, MERS-CoV, and influenza infections. Currently, there are weak recommendations for alpha-interferon atomization inhalation twice/day, and lopinavir/ritonavir orally twice/day; however, evidence supporting these in reducing the incidence and mortality of ARDS in patients infected with SARS-CoV-1 and MERS-CoV are limited to case series and case reports.39 A recent systematic review showed that lopinavir/ritonavir’s anticoronavirus effect was seen mainly in its early application, and no significant effect was seen in late application of therapy.67 A recently published randomized controlled trial in The New England Journal of Medicine on 199 hospitalized COVID-19 patients found no benefit to mortality or time to clinical improvement with lopinavir-ritonavir treatment. Positive trends in nonprimary outcomes, such as complications of acute kidney injury, serious infections, and rate of noninvasive or invasive mechanical ventilation were noted; however, the study ended enrollment as another study using remdesivir became available.68 At this time, the use of combination antivirals in the treatment of COVID-19 is controversial, as there are currently no randomized controlled trials in humans to support their use.69,70
Remdesivir has recently been recognized as a promising antiviral drug against a wide array of RNA viruses, including SARS-CoV-1 and MERS-CoV infection in vitro and in nonhuman primate models.71 Recent in vitro studies conducted on COVID-19 have found that remdesivir and chloroquine inhibit viral infection of cells with low micromolar concentration with a high selectivity index.72 There are ongoing clinical trials in multiple countries testing the efficacy of remdesivir, though at this time this drug is available only for compassionate use in severe COVID-19 cases, and is not available commercially.
A recent open-label non-randomized control study between treatment with favipiravir and interferon-alpha (treatment group) and lopinavir/ritonavir and interferon-alpha (control group) found significant reduction in the time to viral clearance (median 4 versus 11 days, P < .001) and improvement rate on chest CT scan at day 14 (91.4% to 62.2%, P = 0.004); it should be noted, severely ill patients were excluded from this study.73
In a systematic review in the Chinese literature of treatments for SARS-CoV-1, 14 studies were identified in which steroids were used. Twelve studies were inconclusive and 2 showed potential harm. One study reported diabetes onset associated with methylprednisolone treatment.74 Another uncontrolled, retrospective study of 40 SARS patients reported avascular necrosis and osteoporosis among corticosteroid-treated SARS patients.59 A randomized, double-blind, placebo-controlled trial measured SARS-CoV-1 plasma viral load across time after fever onset and found corticosteroid use within the first week of illness was associated with delayed viral clearance.75
However, a recent study performed in China examining risk factors associated with the development of ARDS in COVID-19 patients found that treatment with methylprednisolone decreased the risk of death among patients with ARDS (hazard ratio, 0.38; 95% CI, 0.20-0.72).45 These data lend support to the theory that deterioration in COVID-19 patients occurs secondary to an immunopathogenesis and development of a “cytokine storm,” which can be mitigated by administration of glucocorticoids in patients with severe ARDS.
Cytokine storm is being increasingly examined as a culprit behind the rapid deterioration of COVID-19 patients several days to weeks after initial infection by SARS-CoV-2, which raises the possibility of utilizing inflammatory cell receptor blockers and stem cell therapy as potential therapeutic agents. Multicenter clinical trials are underway investigating tocilizumab (IL-6 receptor blocker) in the treatment of COVID-19 pneumonia.20 A more comprehensive list of ongoing investigations and trials into novel therapies against SARS-CoV-2 can be found in Monthly Prescribing Reference.
A considerable amount of literature has attributed a variety of antiviral and immunomodulatory effects to chloroquine, including the suppression of IL-6, a cytokine believed to play a significant role in the deterioration of COVID-19 patients into severe ARDS.20,76 Chloroquine has also been shown to act as an effective antiviral medication in animal models infected with avian influenza and SARS-CoV-1.77,78 Unpublished data emerging from China suggest that chloroquine has been studied as a treatment for COVID-19, with favorable results.79 The Guangdong Provincial Department of Science and Technology and the Guangdong Provincial Health Commission recently submitted an expert consensus report that recommended chloroquine treatment of new coronavirus pneumonia with a treatment regimen of 500 mg orally twice daily for patients without contraindications.80 A recent study published in Clinical Infectious Diseases, using physiologically based pharmacokinetic models, found increased potency of hydroxychloroquine over chloroquine (EC50 = 0.72 μM vs 5.47 μM, respectively) in lung tissue. This study recommends a 400 mg loading dose twice daily for 1 day, followed by a 200 mg maintenance dose twice daily for 4 days.81 Clinical trials are underway to formally investigate the use of these medications both as a therapeutic and prophylactic agent against COVID-19 in humans.82 A recent nonrandomized clinical trial of 20 patients found hydroxychloroquine treatment to be significantly associated with viral load reduction and disappearance in COVID-19 patients, with this effect increased by the addition of azithromycin. Hydroxychloroquine dosing was 600 mg daily, and azithromycin was 500 mg on the first day followed by 250 mg daily for 4 days.83 (Note that the publisher states, “This article is a preprint and has not been peer reviewed. It reports medical research that has yet to be evaluated and so should not be used to guide clinical practice.”) Clinical trials are underway to formally investigate the use of these medications both as a therapeutic and prophylactic agent against COVID-19 in humans
There is no significant literature at present on optimal fluid management in patients with COVID-19, nor is there literature that describes new-onset congestive heart failure secondary to the virus. As previously described, a leading theory in the pathophysiology of rapidly deteriorating COVID-19 patients is that ARDS (noncardiogenic pulmonary edema) is brought on by a hyperinflammatory state. Given that this is not a form of distributive or hypovolemic shock that is seen in bacterial sepsis and the resulting pulmonary edema is the primary life-threat to those with severe COVID-19, the authors recommend a judicious approach to fluid resuscitation on a case-by-case basis.
In patients who deteriorate and require ICU-level care, clinicians should consider noninvasive ventilation (NIV), mechanical ventilation, or extracorporeal life support, if necessary.39 The development of ARDS and respiratory decompensation plays a central role in the pathogenesis of COVID-19. In this sense, the following treatment principles are key in managing COVID-19 patients:
Preliminary unpublished data from Andrea Duca, MD in an ED in Bergamo, Italy shows that from February 29 to March 10, 2020, the rate of patients presenting to the ED with suspected COVID-19 who needed admission for oxygen therapy increased by 138%. Among those admitted patients, 31% were still hypoxic on maximal oxygen therapy and started on ventilatory support in the ED (81% CPAP, 7% NIV, 12% invasive ventilation), with 82% showing criteria for moderate to severe ARDS.
Data from China and Italy suggest that COVID-19 patients who are hypoxemic respond well to PEEP, indicating a crucial role for NIV as a therapeutic and stopgap measure to prevent intubation.45 The statistics from retrospective analyses in China indicate that up to 30% of admitted patients required NIV,84 while early reports from Italy indicate figures approaching 31%. Given current epidemiological trends, these requirements are likely to outpace the current capacity of most, if not all, hospitals if aggressive preparatory measures are not taken. Based on the current data from China and Italy, we recommend the following:
See Figures 10, 11, and 12 for image of single-limb NIV device, demonstration of wear, and a helmet CPAP with viral filter before PEEP valve .
In the event a patient presents in severe respiratory distress or fails prior use of NIV, the clinician must prepare for invasive ventilation and endotracheal tube intubation. See Table 8 for rapid sequence intubation (RSI) steps.
There is ongoing controversy as to the role of preoxygenation and the possible spread of viral particles while utilizing the typical techniques. A review on this subject can be found in EMcrit. In the meantime, the commonly utilized choices are:
For a brief synopsis on the indications, principles, and various types of mechanical ventilation, please see Hickey et al. For COVID-19 patients, special emphasis should be placed on the “Lung Protective Strategy” section, based on the ARDSnet trials, which showed that low tidal volume ventilation in patients with ARDS improved mortality.85 Briefly:
Tidal volume (TV) should be initially set at 6 mL/kg based upon ideal body weight. As patients develop acute lung injury and progress into ARDS, their lungs become progressively recruited and develop shunts, which leads to decreased functional lung volume. A low tidal volume strategy offsets the decreased functional lung volume. Tidal volume should not be adjusted based on minute ventilation goals. Respiratory rate is adjusted based upon minute ventilation goals and the acid-base status of the patient. An initial rate of 16 breaths/min is appropriate for most patients to achieve normocapnia.86
In disaster situations when the number of patients requiring mechanical ventilation outpaces the number of available ventilators, ventilators can be rigged to split airflow to multiple patients. Click here for a video tutorial on how to accomplish.
The key take-aways for this maneuver include the following:
Children seem to have been relatively spared from the worst complications and mortality of this disease, as noted in the CDC rates of hospitalization per age group. (See Table 6.) To date in the United States, and from our co-author’s experience in Northern Italy, there have been no reported deaths in children. However, in a prepublication paper released on March 16, 2020 in the Journal of Pediatrics, Dong et al analyzed 2143 children in China with suspected and confirmed SARS-CoV-2 infection and found that almost “4% of children were asymptomatic, 51% had mild illness and 39% had moderate illness. About 6% had severe or critical illness, compared to 18.5% of adults. One child, a 14-year-old boy, died.”87 The study also found that infants had higher rates of serious illness when compared with older children. Approximately 11% of infants had severe or critical cases compared to 7% of children ages 1 to 5 years; 4% of those 6 to 10 years; 4% of those 11 to 15 years; and 3% of those aged 16 years and older. There are several theories speculating on the vast differences between adults and children, such as “higher levels of antibodies against viruses or different responses from their developing immune systems.”87 Another theory is related to the relative lack of or poorly developed ACE2 receptors in children, which prevents the virus from being able to bind as well to children’s cells. Wu et al reported in their Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention of approximately 1000 children under the age of 19, no reported deaths in children younger than 9 years of age.84 In a recent correspondence to the New England Journal of Medicine, researchers from China found that of the 171 cases confirmed to have SARS-CoV-2, there was only 1 death in a 10-month old child, who had multiple co-morbidities.88
In a small retrospective study in China, 20 confirmed SARS-CoV-2-positive pediatric patients were analyzed with CT scans of their chests as well as laboratory markers, including procalcitonin. The authors found that procalcitonin was elevated in 16/20 patients, chest CTs showed consolidation with surrounding halo signs in 10/20 patients, and 12/20 showed ground-glass opacities. It was also suggested that underlying co-infection may be more common in children (8/20), and a consolidation with surrounding halo sign is considered a typical sign for this population.58 Even though the pediatric population may be spared the morbidity and mortality seen in adults, clinicians should be aware that they may infect more vulnerable populations and should encourage social distancing. Further research in the American pediatric population will better help the understanding and management of severe disease presentations in children in the United States.
The data on pregnant patients with COVID-19 still remains sparse.89 Generally, pregnant women with SARS-CoV-2 infection share the same characteristics of nonpregnant women with the virus. In a retrospective review of 9 patients, Chen et al analyzed the risk of maternal-fetal transmission of SARS-CoV-2 and found that intrauterine transmission from SARS-CoV-2-positive mothers was shown to be unlikely.90 Additionally, in those patients, they found very few complications related to pregnancy, unlike the complications that were characteristic of pregnant women with SARS.91,92 . Clearly, larger studies will need to be conducted to better evaluate the risk of vertical transmission between mother and fetus with SARS-CoV-2 infection.
Shared decision-making is a collaborative process in which patients and providers make healthcare decisions together, taking into account scientific evidence, the clinician’s experience, as well as the patient's values and preferences. Although the scientific evidence underlying the testing and treatment of SARS-CoV-2 infection is nascent and evolving rapidly, certain knowledge is known and extrapolation from other serious infectious diseases is justified. There are at least 2 clinical scenarios related to COVID-19 that may be appropriate for SDM: (1) testing for SARS-CoV-2 in mildly symptomatic patients and (2) goals-of-care discussion in critically ill patients.
Given that there are no treatments proven to be beneficial for COVID-19 at the time of this writing, making the diagnosis of this disease in mildly symptomatic patients may not change clinical management. Standard supportive care, as is used for typical viral upper respiratory infections, can be recommended for patients, without testing for SARS-CoV-2. These would include over-the-counter antipyretics, antitussives, decongestants, analgesics, oral fluids, and rest. Patients would also be instructed to practice self-isolation to prevent spread of COVID19 to other individuals. The current tests for SARS-CoV-2, using RT-PCR, has a sensitivity between 60% and 90% and can generate false-positive or false-negative results. Given the real possibility of a limitation in testing resources, it may be reasonable for patients with possible COVID-19 to forgo testing, assume that they have the virus, and take the socially responsible precautions. Given the rapidly changing guidance around testing from institutions and government health agencies, adherence to your hospital, state, or local policies should be followed and explained to the patient.
Another clinical scenario that would be appropriate for shared decision-making would be endotracheal intubation for a patient in respiratory failure with a poor prognosis, either due to advanced age or severe comorbidities. This decision will be frequently encountered since ARDS is a common final pathway for many patients with COVID-19. Early studies have demonstrated high mortality rates for older patients, particularly those over age 80. In this scenario, providers could potentially engage in shared decision-making with patients or their surrogates to collaboratively decide whether or not intubation is justified. This is similar to other goals-of-care discussion around code status for patients with advanced age and/or end-stage diseases.
In our first iteration, we speculated on the future of what was not yet a pandemic. Unfortunately, the future is here, and we are in the midst of a growing pandemic that has shut down cities, nations, and continents. We may be best served to look at past events to learn from others’ missteps and seek opportunities to improve for the regions of the world not yet inundated with COVID-19.
“Community spread,” “stealth transmission,” “social distancing,” and “flattening the curve” have become common parlance as the public and medical societies attempt to understand and control COVID-19. With an R0 value mimicking pandemic influenza, the spread and containment of SARS-CoV-2 faces unprecedented challenges.93 We continue to find that constantly changing daily information (and misinformation) have added to the challenges to the general public as well as the medical community. The Lancet published an online editorial, which appeals to the medical community and the public alike to seek verified information through the CDC or WHO and avoid social media and other unverified sources for information. Many worried well patients will show up in the ED, taxing already overburdened systems. This is an opportunity for hospital leadership to develop and/or expand their telehealth options, to minimize the numbers of worried well or low-risk patients with mild symptoms overwhelming local EDs.
There are now several biotech and pharmaceutical companies racing for a vaccine for SARS-CoV-2, and although studies are promising, widespread availability and use are at least 18 months away (summer of 2021). A DNA vaccine candidate for SARS-CoV-2 has entered into human clinical trials, while 2 vector-based candidates have begun human trials; protein-based vaccines are still at the preclinical stage.72 There are still challenges to the successful development of a vaccine due to incomplete understanding of viral transmission, pathogenesis, and immune response; and lack of optimal animal challenge models and standardized immunological assays.
We believe China, Washington state, Italy, and now the New York metropolitan area should serve as examples for the rest of the world not yet inundated with SARS-CoV-2. Being prepared for an onslaught of cases is the first step all healthcare systems need to accept. Testing and isolating infected or suspected persons early has shown benefit in China, South Korea, and elsewhere, and locales such as New York City can attest to the negative effect of being unprepared for mass testing and expeditious containment of spread on its populations.
In the event of a mass influx of patients with exposure to SARS-CoV-2 or symptoms concerning for COVID-19, immediate isolation is required. If 1 infected person presents to a busy ED triage area, there is a high likelihood of spreading the virus and potentially contaminating others. The CDC recommends placing ample touchless hand sanitizer stations and easy-to-dispense boxes of face masks at entrances to the ED and hospital. They also recommend placing signs that advise anyone entering the facility to “immediately put on a mask and keep it on during their assessment; cover their mouth/nose when coughing or sneezing; use and dispose of tissues carefully; and perform hand hygiene after contact with respiratory secretions.”94 The authors recommend hospital and departmental leadership pursue the following directives:
The single best way to save the most people and reduce morbidity is to be proactive and not reactive. Those of us in the midst of this crisis wish we could have done things differently and implemented the above recommendations from the moment we encountered patient zero. Our lack of early testing and strict isolation run counter to what epidemiologists recommend to control infectious outbreaks. Please learn from our mistakes.
You recognized the need for immediate and proper donning of personal protective equipment. You and a nurse put on your complete PPE and obtained the patient’s vital signs, which confirmed a temperature of 39.6°C [103.3°F], pulse of 106 beats/min, respirations of 22 breaths/min, blood pressure 102/68 mm Hg, and pulse oximetry 89% on room air. You performed bedside lung ultrasound using the “lawnmower” technique to visualize as much lung as possible, which confirmed bilateral B-lines in the posterior lungs with confluence producing a characteristic “waterfall sign.” You placed him in a negative pressure isolation room, starting him immediately on supplemental oxygen, and confirmed his travel history and possible contacts with people who may have been exposed to COVID-19. After careful, proper doffing of your PPE, you contacted your hospital infectious disease and infection prevention team, who directed you to also contact your local department of public health, who then sent a representative to find out his possible contacts. You deferred obtaining a CT, as it would not have changed this patient’s management. You sent a battery of lab tests, including a D-dimer, procalcitonin, and LDH, started empirical coverage for bacterial pneumonia, consulted the CDC and WHO for up-to-date guidance on additional treatment recommendations, and remembered to consider steroids only if the patient’s condition deteriorated and he developed ARDS.
The remaining “worried well” and otherwise clinically stable patients were given the current recommendations of the CDC and, based on their respective risk profiles, offered symptomatic treatment or outpatient testing of COVID-19 with mandatory isolation for 14 days and symptom monitoring. Consultation with your local Department of Health and Infection Prevention department for the current testing and treatment protocols will help guide the management for those well enough to self-isolate at home.
| Table 9. Helpful Resources for COVID-19 | ||
|---|---|---|
| Organization | Link | |
| United States Centers for Disease Control and Prevention | Coronavirus Disease 2019 (COVID-19) | |
| World Health Organization | Coronavirus disease (COVID-19) outbreak | |
| Johns Hopkins University | COVID-19 Global Case Tracker | |
| United States Department of Labor, Occupational Safety and Health Administration | COVID-19 Additional Resources | |
| American College of Emergency Physicians | COVID-19 Clinical Alert | |
| The Lancet | COVID-19 Resource Centre | |
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study will be included in bold type following the references, where available.
Updated: 6/18/20
Al Giwa, LLB, MD, MBA, FACEP, FAAEM; Akash Desai, MD; Andrea Duca, MD
Andy Jagoda, MD, FACEP; Trevor Pour, MD, FACEP; Marc A. Probst, MD, MS, FACEP
May 1, 2020
June 1, 2023
4 AMA PRA Category 1 Credits™, 4 ACEP Category I Credits, 4 AAFP Prescribed Credits, 4 AOA Category 2-A or 2-B Credits
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