Table of Contents
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Abstract
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Case Presentations
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Critical Appraisal of the Literature
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Introduction
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Etiology And Pathophysiology
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Etiology And Pathophysiology Of Diphtheria
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Etiology And Pathophysiology Of Pertussis
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Etiology And Pathophysiology Of Tetanus
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Epidemiology And Prevalence
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Epidemiology And Prevalence Of Diphtheria
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Epidemiology And Prevalence Of Pertussis
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Epidemiology And Prevalence Of Tetanus
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Vaccines For Diphtheria, Pertussis, And Tetanus
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Clinical Features
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Clinical Features Of Diphtheria
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Clinical Features Of Pertussis
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Clinical Features Of Tetanus
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Differential Diagnosis
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Prehospital Care
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Emergency Department Evaluation
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History
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Physical Examination
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Diagnostic Studies
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Diagnostic Studies For Diphtheria
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Treatment
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Treatment For Diphtheria
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Treatment For Pertussis
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Treatment For Tetanus
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Reducing Circulating Toxin And Eradicating The Organism
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Controlling Muscle Spasms
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Benzodiazepines
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Magnesium Sulfate
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Other Drugs
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Maintaining Autonomic Stability
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Wound Care
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Treatment Of Vaccine Side Effects And Adverse Events
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Reporting Cases Of Diphtheria, Pertussis, And Tetanus
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Special Circumstances
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Managing Close Contacts Of Patients With Diphtheria
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Managing Close Contacts Of Patients With Pertussis
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Controversies And Cutting Edge
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Vaccine Refusal
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Acellular Pertussis Efficacy
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Disposition
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Summary
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Risk Management Pitfalls In Patients with Diphtheria, Pertussis, Or Tetanus
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Time- And Cost-Effective Strategies
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Case Conclusions
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Clinical Pathway For The Management Of Patients With Suspected Diphtheria, Pertussis, Or Tetanus
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Tables and Figures
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Figure 1. A Strongly Adherent Pseudomembrane Of Diphtheria
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Figure 2. The “Bull Neck” Appearance Of Diphtheria
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Figure 3. Facial Grimacing In An Infant With Neonatal Tetanus
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Table 1. Possible Causes Of Membranous Pharyngitis
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Table 2. Illnesses Causing Sporadic Prolonged Cough
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Table 3. Conditions Presenting With Muscular Contractions
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Table 4. Post–Wound Tetanus Vaccination Guidelines
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References
Abstract
Diphtheria, pertussis, and tetanus are potentially deadly bacterial infections that are largely preventable through vaccination, though they remain in the population. This issue reviews the epidemiology, pathophysiology, diagnosis, and current recommended emergency management of these conditions. Disease-specific medications, as well as treatment of the secondary complications, are examined in light of the best current evidence. Resources include obtaining diphtheria antitoxin from the United States Centers for Disease Control and Prevention and best-practice recommendations with regard to testing, involvement of government health agencies, isolation of the patient, and identification and treatment of close contacts. Most importantly, issues regarding vaccination and prevention are highlighted.
Case Presentations
A panicked mother rushes into the emergency department, screaming that her baby is not breathing. Taking the apneic infant from her, you hurry to the resuscitation bay. Within seconds, the infant begins to breathe spontaneously. You provide supplemental oxygen by face mask as the team attaches leads and obtains vital signs. The monitor shows a respiratory rate of 30 breaths/min, heart rate of 140 beats/min, and oxygen saturation of 98% on room air. As you note a rather unremarkable physical examination, apart from occasional gagging, his school-age sibling begins coughing. Does this sibling’s apparent upper respiratory illness have anything to do with your patient’s condition? You consider the infectious processes that could present with apnea and the key historical questions you should ask the mother, and you begin to plan your next step in the assessment and management of this baby.
Leaving a resident to begin appropriate investigations on the baby, you enter an examination room to find a 5-year-old boy holding a bandage to his foot. His parents report that he stepped on a nail while playing at a farm earlier that day. On examination, you note a small puncture wound that does not appear grossly soiled and is not actively bleeding. He is otherwise both engaging and well-appearing. As you review the triage notes, your eye falls to a red circle around the words, “No Imm!” You quickly realize this child is unimmunized and at risk for tetanus. You sigh, hesitant to broach the topic. It seems unlikely you alone can change the parents’ minds about vaccines. Should you bother discussing the topic? Should you call the primary care doctor and see if he can convince them? Could an antibiotic prevent tetanus infection?
As you consider your options, the ambulance bay doors open and a local EMS crew comes rushing in with a toxic-appearing young girl on the gurney in obvious respiratory distress. The child has a fever of 38ºC, respiratory rate of 35 breaths/min, heart rate of 150 beats/min, and a blood pressure of 75/45 mm Hg. On examination, there is inspiratory stridor, significant cervical lymphadenopathy, and a thick, grayish membrane that seems to be coating the posterior pharynx. Chest examination reveals bilateral rales and tachycardia with frequent ectopic beats. Having now decided that this patient is your top priority, you ask the charge nurse to notify the PICU and cardiology, and you begin to form a differential diagnosis in your mind. Could this child have a viral myocarditis associated with a simple pharyngitis? Or is there is a more sinister etiology at play? You turn to your senior resident and ask him to page the on-call pediatric infectious disease specialist. You ask the nurse to institute strict isolation precautions. As the phone rings, you grow increasingly confident of your patient’s diagnosis.
Critical Appraisal Of The Literature
A PubMed search for the terms diphtheria, pertussis, and tetanus was performed, along with terms such as diagnosis, treatment, and case report. A search of the Cochrane Database of Systematic Reviews was also performed for each of the 3 diseases. The United States Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics (AAP), the World Health Organization (WHO), and the National Guideline Clearinghouse websites were searched for related articles or web pages. The vast majority of recent literature on these illnesses focuses on the vaccines themselves rather than the management of the diseases. Pediatric-specific literature is extremely limited. Most of the relevant literature for this issue is in the form of expert consensus, review articles, and case reports.
Introduction
At the beginning of the 20th century, 10% of all babies born in the United States died before their first birth day, often from infectious diseases.1 Current estimates are that childhood vaccination will save over 700,000 American lives for those born in the United States in the last 20 years.2 The Advisory Committee on Immunization Practice (ACIP) annually reviews the recommended routine childhood (age 0-18 years) vaccination schedule.3 Despite this carefully considered schedule that is designed to be both maximally safe and effective, there has been an increase in certain vaccine-preventable diseases in the United States. This is due, in part, to geographical pockets of low vaccination coverage despite overall high vaccination coverage nationally.4 Because of this, emergency clinicians should not only advocate for vaccination, but also be able to recognize and manage these illnesses when they do occur. This issue of Pediatric Emergency Medicine Practice reviews 3 vaccine-preventable illnesses—diphtheria, pertussis, and tetanus—and describes the role of the emergency clinician in managing these illnesses, identifying and managing close contacts, and involving local health officials.
Risk Management Pitfalls In Patients with Diphtheria, Pertussis, Or Tetanus
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“The nurse marked ‘immunizations up to date,’ so there was no need to ask.”
It is essential for the emergency clinician to have an accurate vaccination history on each patient. Not only does this information have a significant effect on clinical decision making, it provides an opportunity to stress the importance of vaccines to all families.
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“That baby with an episode of apnea had a completely normal examination. There was no need for labs. I’ll just admit her for observation.”
While true for many infants presenting with apneic spells, further testing (eg, a complete blood count) to look for hyperleukocytosis should be considered based upon the clinical history and examination. A lack of maternal immunization, ill family members or close contacts, or a high local prevalence of B pertussis should lead, at least, to consideration of pertussis infection as the cause of apnea in an otherwise well-appearing baby.
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“Everyone in the waiting room is coughing! Why worry about isolation?”
While many conditions may cause cough in children, a severe spasmodic cough, posttussive emesis, and family members with similar symptoms should heighten the suspicion for pertussis infection. Respiratory isolation of patients suspected of infection with B pertussis is essential to control further spread, particularly among the more vulnerable patients in the pediatric emergency department.
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“The siblings of the patient with known pertussis all had their vaccinations, so I did not give them antibiotics.”
Current recommendations are for postexposure antibiotics for all close contacts of patients diagnosed with pertussis, regardless of their vaccination history. Because the vaccine is not 100% effective, immunity wanes rapidly with time, and given the high infectivity of B pertussis, even fully immunized siblings should be treated with azithromycin unless it is contraindicated.
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“That cough is pretty nasty. I think we should try some albuterol.”
Multiple medications have been studied for symptomatic treatment of pertussis and, based on current evidence, cannot be routinely recommended. Cough medicine in children should be avoided due to a lack of efficacy and a high risk of side effects.
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“It can’t be diphtheria, the child lives just down the street. I doubt he’s ever left the state.”
A travel history is not essential for the diagnosis of diphtheria. Both toxigenic and nontoxigenic strains exist in the United States. Toxigenicity can be induced via phage conversion, and severe illness can occur with nontoxigenic strains. Therefore, awareness of the early signs and symptoms of diphtheria is crucial to identifying patients who need early and life-saving treatment.
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“We need to wait for laboratory confirmation of diphtheria before calling the CDC.”
The expedient administration of DAT is critical to prevent progression and to lessen the severity of diphtheria. Because DAT is only available through the CDC’s Emergency Operations Center, a suspicion of toxigenic C diphtheriae infection warrants a phone call to discuss whether DAT is indicated. Information on the process for requesting DAT can be found on the CDC’s website at: http://www.cdc.gov/diphtheria/dat.html.
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“The wound is not that dirty, I think we can skip the TIG.”
Current recommendations for wound management emphasize the need for TIG for patients with tetanus-prone wounds and either an uncertain or incomplete immunization schedule. Young children who have received < 3 primary boosters meet CDC criteria for TIG administration. However, it is important to remember than seemingly clean wounds and even surgical incisions are potential entry points for C tetani.
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“Paralyze and sedate. That’s really all we can do for tetanus.”
The successful management of tetanus requires treatment of the muscle spasms and autonomic dysfunction, as well as any secondary morbidity. Therefore, a variety of medications may be necessary to maintain cardiorespiratory function while minimizing the risks associated with long-term sedation, paralysis, and mechanical ventilation. This should be done after administration of antibiotics and TIG to prevent further toxin effects.
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“That pregnant woman is afraid of shots. She probably doesn’t need one as long as the father and grandmother of the fetus have a booster shot.”
While immunizing adults who have contact with an infant provides indirect protection, this should be considered a secondary strategy. Immunizing pregnant women between 27 and 36 weeks of each pregnancy directly confers maximal antibody protection to babies too young to receive the vaccine. Thus, a key strategy to protect the most vulnerable patients is by maternal vaccination.
Tables And Figures
Source: Centers for Disease Control and Prevention. Checklist for Assessing a Patient with Suspected Diphtheria.
References
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 is included in bold type following the references, where available. The most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.
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Committee to Review Adverse Effects of Vaccines, Institute of Medicine. In: Stratton K, Ford A, Rusch E, et al, eds. Adverse Effects of Vaccines: Evidence and Causality. Washington DC, National Academies Press. 2011. (Expert review)
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Whitney CG, Zhou F, Singleton J, et al. Benefits from immunization during the vaccines for children program era - United States, 1994-2013. MMWR Morb Mortal Wkly Rep. 2014;63(16):352-355. (National database summary)
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Strikas RA. Advisory committee on immunization practices recommended immunization schedules for persons aged 0 through 18 years--United States, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(4):93-94. (Expert group opinion ACIP report)
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Seither R, Calhoun K, Knighton CL, et al. Vaccination coverage among children in kindergarten - United States, 2014-15 school year. MMWR Morb Mortal Wkly Rep. 2015;64(33):897- 904. (Expert opinion statement)
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* Centers for Disease Control and Prevention. Diphtheria. In: Hamborsky J, Kroger A, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Washington, DC: Public Health Foundation; 2015. (Textbook chapter)
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Brennan M, Vitek C, Strebel P, et al. How many doses of diphtheria toxoid are required for protection in adults? Results of a case-control study among 40- to 49-year-old adults in the Russian Federation. J Infect Dis. 2000;181 Suppl 1:S193-S196. (Case-control study; 156 patients)
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Lake JA, Ehrhardt MJ, Suchi M, et al. A case of necrotizing epiglottitis due to nontoxigenic Corynebacterium diphtheriae. Pediatrics. 2015;136(1):e242-e245. (Case report; 1 patient)
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Tiley SM, Kociuba KR, Heron LG, et al. Infective endocarditis due to nontoxigenic Corynebacterium diphtheriae: report of seven cases and review. Clin Infect Dis. 1993;16(2):271-275. (Case series; 7 patients)
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Rakhmanova AG, Lumio J, Groundstroem KW, et al. Fatal respiratory tract diphtheria apparently caused by nontoxigenic strains of Corynebacterium diphtheriae. Eur J Clin Microbiol Infect Dis. 1997;16(11):816-820. (Case report; 1 patient)
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Berger A, Huber I, Merbecks SS, et al. Toxigenic Corynebacterium ulcerans in woman and cat. Emerg Infect Dis. 2011;17(9):1767-1769. (Case report; 1 patient)
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Both L, Collins S, de Zoysa A, et al. Molecular and epidemiological review of toxigenic diphtheria infections in England between 2007 and 2013. J Clin Microbiol. 2015;53(2):567-572. (Case series; 20 patients)
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Centers for Disease Control and Prevention. Diphtheria clinicians. 2014. Available at: http://www.cdc.gov/diphtheria/clinicians.html. Accessed January 15, 2017. (Website)
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* Centers for Disease Control and Prevention. Pertussis. In: Hamborsky J, Kroger A, Wolfe S, ed. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Washington, DC: Public Health Foundation; 2015. (Textbook chapter)
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Scanlon KM, Skerry C, Carbonetti NH. Novel therapies for the treatment of pertussis disease. Pathog Dis. 2015;73(8):ftv074. (Review article)
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Grant CC, McKay EJ, Sci DM, et al. Pertussis encephalopathy with high cerebrospinal fluid antibody titers to pertussis toxin and filamentous hemagglutinin. Pediatrics. 1998;102(4):986-989. (Case report; 1 patient)
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* Committee on Infectious Diseases. Pertussis. In: Kimberlin DW, Long SS, Brady MT, et al, eds. Red Book. Elk Grove Village: American Academy of Pediatrics. 2015:608-621. (Textbook chapter)
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World Health Organization. Managing pertussis outbreaks during humanitarian emergencies. 2008. Available at: http://apps.who.int/iris/bitstream/10665/69755/1/WHO_HSE_EPR_DCE_2008.2_eng.pdf. Accessed January 15, 2017. (WHO technical note)
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Tiwari TS, Baughman AL, Clark TA. First pertussis vaccine dose and prevention of infant mortality. Pediatrics. 2015;135(6):990-999. (Retrospective cohort study; 45,404 patients)
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* Centers for Disease Control and Prevention. Tetanus. In: Hamborsky J, Kroger A, Wolfe S, ed. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Washington, DC: Public Health Foundation; 2015. (Textbook chapter)
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World Health Organization. Current recommendations for treatment of tetanus during humanitarian emergencies. WHO Technical Note 2010. Available at: http://apps.who.int/iris/bitstream/10665/70219/1/WHO_HSE_GAR_DCE_2010.2_eng.pdf. Accessed January 15, 2017. (WHO technical note)
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Centers for Disease Control and Prevention. Tetanus: causes and transmission. Available at: http://www.cdc.gov/tetanus/about/causes-transmission.html. Accessed January 15, 2017. (Website)
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Sampson CS. Tetanus after home piercing. J Emerg Med. 2013;45(1):95-96. (Case report; 1 patient)
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Hahn BJ, Erogul M, Sinert R. Case report of tetanus in an immunized, healthy adult and no point of entry. J Emerg Med. 2004;27(3):257-260. (Case report; 1 patient)
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Thwaites CL, Yen LM, Cordon SM, et al. Urinary catecholamine excretion in tetanus. Anaesthesia. 2006;61(4):355-359. (Prospective observational study; 42 patients)
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Tubiana S, Belchior E, Guillot S, et al. Monitoring the impact of vaccination on pertussis in infants using an active hospital-based pediatric surveillance network: results from 17 years’ experience, 1996-2012, France. Pediatr Infect Dis J. 2015;34(8):814-820. (Observational study; 2227 patients)
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Adeel M, Rajput SA, Awan MS, et al. A case of otogenic tetanus. BMJ Case Rep. Jul 3 2012. (Case report; 1 patient)
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* Brandon L, Nurdin NF, Byrne M, et al. Clinical tetanus in an 11 year old boy. Ir Med J. 2013;106(10):313-314. (Case report; 1 patient)
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Centers for Disease Control and Prevention. Tetanus; for clinicians. Available at: http://www.cdc.gov/tetanus/clinicians.html. Accessed January 15, 2017. (Website)
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Kaur S, Mishra D, Juneja M. Acute renal failure in tetanus. Indian J Pediatr. 2014;81(2):207. (Case report; 1 patient)
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Chatterjee S, Hemram S, Bhattacharya S, et al. A case of neonatal tetanus presented within 24 hours of life. Trop Doct. 2013;43(1):43-45. (Case report; 1 patient)
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Hassan B, Popoola A, Olokoba A, et al. A survey of neonatal tetanus at a district general hospital in north-east Nigeria. Trop Doct. 2011;41(1):18-20. (Case series; 89 patients)
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Trieu HT, Lubis IN, Qui PT, et al. Neonatal tetanus in Vietnam: comprehensive intensive care support improves mortality. J Pediatric Infect Dis Soc. 2016;5(2):227-230. (Case series; 20 patients)
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Lam PK, Trieu HT, Lubis IN, et al. Prognosis of neonatal tetanus in the modern management era: an observational study in 107 Vietnamese infants. Int J Infect Dis. 2015;33:7-11. (Case-control study; 107 patients)
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Farizo KM, Strebel PM, Chen RT, et al. Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control. Clin Infect Dis. 1993;16(1):59-68. (Case report; 1 patient)
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Bethell DB, Nguyen Minh D, Ha Thi L, et al. Prognostic value of electrocardiographic monitoring of patients with severe diphtheria. Clin Infect Dis. 1995;20(5):1259-1265. (Prospective observational study; 15 patients)
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Tiwari T. Tetanus. Manual for the Surveillance of Vaccine-Preventable Diseases: Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/vaccines/pubs/surv-manual/index.html. Accessed January 15, 2017. (Website)
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Dung NM, Kneen R, Kiem N, et al. Treatment of severe diphtheritic myocarditis by temporary insertion of a cardiac pacemaker. Clin Infect Dis. 2002;35(11):1425-1429. (Prospective study; 32 patients)
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Both L, White J, Mandal S, et al. Access to diphtheria antitoxin for therapy and diagnostics. Euro Surveill. 2014;19(24). (Review article)
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World Health Organization. WHO Model list for Essential Medicines for Children. Available at: http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed January 15, 2017. (Website)
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From the Centers for Disease Control and Prevention. Availability of diphtheria antitoxin through an investigational new drug protocol. JAMA. 1997;277(21):1665. (CDC statement on DAT)
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Tiwari T, Clark, T. Use of diphtheria antitoxin (DAT) for suspected diphtheria cases. CDC protocol available at: http://www.cdc.gov/diphtheria/downloads/protocol.pdf. Accessed January 15, 2017. (CDC protocol)
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* Ganeshalingham A, Murdoch I, Davies B, et al. Fatal laryngeal diphtheria in a UK child. Arch Dis Child. 2012;97(8):748- 749. (Case report; 1 patient)
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Committee on Infectious Diseases. Diphtheria. In: Kimberlin DW, Long SS, Brady MT, et al, eds. Red Book. Elk Grove Village: American Academy of Pediatrics. 2015:325-329. (Textbook chapter)
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FitzGerald RP, Rosser AJ, Perera DN. Non-toxigenic penicillin-resistant cutaneous C. diphtheriae infection: a case report and review of the literature. J Infect Public Health. 2015;8(1):98-100. (Case report; 1 patient)
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Winter K, Zipprich J, Harriman K, et al. Risk factors associated with infant deaths from pertussis: a case-control study. Clin Infect Dis. 2015;61(7):1099-1106. (Case-control study; 236 patients)
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Eberly MD, Eide MB, Thompson JL, et al. Azithromycin in early infancy and pyloric stenosis. Pediatrics. 2015;135(3):483- 488. (Retrospective cohort study; 1,074,236 patients)
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Altunaiji S, Kukuruzovic R, Curtis N, et al. Antibiotics for whooping cough (pertussis). Cochrane Database Syst Rev. 2007(3):CD004404. (Cochrane review; 2197 patients)
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Wang K, Bettiol S, Thompson MJ, et al. Symptomatic treatment of the cough in whooping cough. Cochrane Database Syst Rev. 2014;9:CD003257. (Cochrane review; 196 patients)
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Committee on Infectious Diseases. Tetanus. In: Kimberlin DW, Long SS, Brady MT, et al, eds. Red Book. Elk Grove Village: American Academy of Pediatrics. 2015:773-778. (Textbook chapter)
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Blake PA, Feldman RA, Buchanan TM, et al. Serologic therapy of tetanus in the United States, 1965-1971. JAMA. 1976;235(1):42-44. (Retrospective review; 545 patients)
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Kabura L, Ilibagiza D, Menten J, et al. Intrathecal vs. intramuscular administration of human antitetanus immunoglobulin or equine tetanus antitoxin in the treatment of tetanus: a meta-analysis. Trop Med Int Health. 2006;11(7):1075-1081. (Meta-analysis; 942 patients in 12 studies)
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Ahmadsyah I, Salim A. Treatment of tetanus: an open study to compare the efficacy of procaine penicillin and metronidazole. Br Med J (Clin Res Ed). 1985;291(6496):648-650. (Nonrandomized clinical trial; 173 patients)
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Ganesh Kumar AV, Kothari VM, Krishnan A, et al. Benzathine penicillin, metronidazole and benzyl penicillin in the treatment of tetanus: a randomized, controlled trial. Ann Trop Med Parasitol. 2004;98(1):59-63. (Randomized controlled trial; 105 patients)
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Campbell JI, Lam TM, Huynh TL, et al. Microbiologic characterization and antimicrobial susceptibility of Clostridium tetani isolated from wounds of patients with clinically diagnosed tetanus. Am J Trop Med Hyg. 2009;80(5):827-831. (Case review; 84 patients)
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Hassel B. Tetanus: pathophysiology, treatment, and the possibility of using botulinum toxin against tetanus-induced rigidity and spasms. Toxins (Basel). 2013;5(1):73-83. (Review article)
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Thwaites CL, Yen LM, Loan HT, et al. Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial. Lancet. 2006;368(9545):1436-1443. (Randomized double-blind placebo-controlled trial; 256 patients)
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Rodrigo C, Samarakoon L, Fernando SD, et al. A meta-analysis of magnesium for tetanus. Anaesthesia. 2012;67(12):1370- 1374. (Meta-analysis; 3 studies with 275 patients total)
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