System-Based Disease And Medication Effects
System-Based Disease And Medication Effects
As the life expectancy of HIV-infected patients has increased, so have observed rates of traditional age-related conditions (such as cardiovascular disease) increased among this population. A recent study estimated the increased relative risk of myocardial infarction among HIV-infected persons to be 1.75 (95% CI, 1.51-2.02) compared to patients not HIV-infected.24 The pathophysiology of this increase involves not only traditional risk factors such as age and smoking, but also HAART. As mentioned previously, HAART causes metabolic side effects that also likely contribute the increased risk of cardiovascular disease.17,25-27
Prior to HAART, Pneumocystis pneumonia used to be one of the most common opportunistic pulmonary infections. Patients with Pneumocystis pneumonia classically present with an indolent, nonproductive cough and exertional dyspnea. On x-ray, a perihilar or “batwing” infiltrate is seen. (See Figure 1.) Lactate dehydrogenase (LDH) is typically elevated in patients with Pneumocystis pneumonia, and a normal value is helpful in ruling out the disease.28 Patients infected with HIV are at increased risk of tuberculosis (TB), (both novel infection and reactivation) after diagnosis with HIV because of the depletion of TB-specific T-cells. With poorly controlled HIV infection, the risk of TB increases. In the developed world (where there are lower rates of TB in general), the disease is not seen as frequently, but it must remain on the differential in HIV-infected patients with possible exposures.
Today, patients with well-controlled HIV on HAART more commonly develop the traditional pulmonary infections of immunocompetent patients, of which, Streptococcus pneumonia is most common.29 Treatment for common pneumonias is the same as for non–HIV-infected patients, using antibiotics and fluid resuscitation or other supportive measures. Patients with immunosuppressive disease are at risk for drug-resistant organisms, and the emergency clinician should consider expanding therapy in those patients whose disease is not well-controlled.
Guidance on the disposition of HIV-infected patients with pneumonia from the ED likely can mirror practice for patients without an HIV infection, although there are no evidence-based guidelines on this topic. However, patients with good social support who are followed closely by a primary care provider and known to be compliant with treatment are likely to be good candidates for outpatient treatment.30
Chronic obstructive pulmonary disease (COPD) is an increasing concern in HIV patients. Higher rates of smoking in HIV-infected patients, lung injury from previous OIs, and drug effects are all risk factors for the development of COPD.31 Treatment for COPD is the same as for noninfected patients. Some data suggest that chronic HIV infection itself may also be an independent risk factor for the disease.32 The higher risk could be related to the chronic systemic inflammatory response present in longstanding infection. This inflammatory state is also associated with hypercoagulability, leading to higher rates of venous thromboembolism and pulmonary embolism in this population.33 The Pulmonary Embolism Rule-out Criteria (PERC) did not report HIV status on the participants of the study, so it is difficult to conclude whether these criteria can be applied to HIV-infected individuals.
Emergency clinicians should have a high index of suspicion for concomitant conditions in the context of a patient’s CD4 count and be prepared to evaluate patients with laboratory and radiologic studies, as appropriate. Imaging with chest x-ray should be considered in all patients with HIV and pulmonary complaints.
Renal disease in HIV patients can be caused both by the HIV infection itself as well as the nephrotoxicity of HAART. Patients present with acute kidney injury similar to non–HIV-infected patients, and their treatment is the same. Nephrotoxic medications should be withheld temporarily while the patient is resuscitated. Nephrolithiasis and urolithiasis are common side effects of PIs, particularly indinavir (although few HIV-infected patients take this medication and, instead, take one of the newer PIs). PIs have poor solubility and significant urinary excretion that leads to stone formation. Urinalysis will most likely demonstrate hematuria; however, stones comprised of indinavir deposits are typically radiolucent and may be missed by standard radiologic imaging. Therefore, secondary signs of obstruction, such as hydroureter and perinephric stranding, may be the only findings on imaging. Discussion with the patient’s HIV provider regarding the continuation or cessation of indinavir is advised. Treatment of nephrolithiasis and urolithiasis are the same as for the non–HIV-infected patient.
Evaluation of the HIV-infected patient with a neurologic complaint should be guided by the CD4 count. Patients with HIV infection, even if it is well-controlled, have a slightly higher risk of cerebrovascular disease due to the chronic inflammatory state, accelerated atherosclerosis, and metabolic effects of medications. The evaluation of patients with focal neurologic deficits should follow typical stroke algorithms.
Rates of central nervous system OIs, such as cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, and Cytomegalovirus have decreased significantly with treatment adherence. However, if a patient with a low CD4 count is identified, imaging and, possibly, lumbar puncture aimed at the identification of OI is indicated. CT of the head may require contrast in order to better identify infectious processes or central nervous system malignancy, such as lymphoma. MRI provides identification of smaller lesions and evaluates leptomeningeal enhancement better than CT.
HIV myelopathy may develop at the end stages of untreated disease. Patients develop lower extremity weakness associated with sensory abnormalities, imbalance, and incontinence. Patients are hyperreflexic, with normal imaging studies and abnormalities on electrophysiologic testing.
The prevalence of HIV-associated dementia has also decreased since the introduction of HAART.34 Rates of milder neurocognitive disorders also appear to decrease with longer periods of undetectable virus.35,36
Gastrointestinal And Hepatobiliary Disease
Gastrointestinal symptoms, especially diarrhea, are some of the most common presentations of HIV-infected patients in the ED. In a large cohort study, 40% of HIV infected adults on HAART reported at least 1 episode of diarrhea in the past month, with 3% reporting severe diarrhea (defined as > 6 stools per day).37 Etiologies include infectious diseases, malignancies, and medication-induced diarrhea.
The pathogenesis of gastrointestinal symptoms depends on the degree of immunocompromise. Common pathogens that cause diarrhea in healthy individuals will also do so in HIV-infected patients on HAART. In the pre-HAART era, Clostridium difficile was the most common pathogen isolated in HIV-infected patients with diarrhea; however, with successful treatment with HAART, the frequency of hospitalizations and diagnosis of AIDS are both decreased. Therefore, C difficile may not be the most frequent infection, though it is more common in HIV-infected individuals than in non–HIV-infected individuals.38
As the CD4 count drops, the patient is at risk for OIs such as Cryptococcus, Cytomegalovirus, microsporidiosis, and Mycobacterium avium complex. In many cases, initiation of HAART to restore the gastrointestinal immune system will help eradicate these infections. Stool laboratory studies are guided based on the patient’s stage of disease.
Hepatobiliary complaints are also common in HIV-infected patients and may be caused by a variety of etiologies from infectious to infiltrative to medication-related problems. Co-infection with hepatitis C virus affects 30% to 80% of HIV patients and chronic hepatitis B virus affects 5% to 10% of patients.39,40 Co-infection with either virus increases a patient's risk of developing chronic hepatitis 2 to 3 times compared to non–HIV-infected patients with hepatitis B virus or hepatitis C virus. Nearly all of the HAART medications have potential hepatotoxicity that can be worsened by co-infection with hepatitis B virus or hepatitis C virus.41
Patients with hepatobiliary complaints should be asked about their medication regimens and any co-infections with hepatitis B virus or hepatitis C virus. Laboratory evaluations should include transaminases, bilirubin, and lipase.
Cytopenias of all cell lines are common in HIV-infected patients. Patients with an uncontrolled HIV infection may develop pancytopenia, as bone marrow production is suppressed. Anemia may be caused by a primary HIV infection or as a result of medication use. Medication-induced anemia is often macrocytic, although in the ED evaluation, this is a diagnosis of exclusion.
The rate of HIV-associated thrombocytopenia increases with decreasing CD4 count. Initiation of HAART, particularly AZT/ZDV, is the mainstay of treatment. These medications are rarely initiated in the ED, and patients with severe or symptomatic thrombocytopenia should be evaluated in consultation with the appropriate specialists.
HIV-infected patients also have higher rates of thromboembolic disease, with a large prospective study estimating the rate to be 2.6 per 1000 patient-years.42 The chronic inflammatory state of HIV infection appears to be a risk factor for thromboembolic disease. In HIV-infected patients without well-controlled disease, factors associated with thrombotic complications include lower CD4 count, higher viral load, presence of OI, malignancy, and indwelling central venous catheters.43 Thrombotic thrombocytopenic purpura occurs in HIV-infected patients, although its prevalence has decreased in the HAART era. Patients with hemolytic anemia and thrombocytopenia should be evaluated for thrombotic thrombocytopenic purpura.44
HAART is associated with dyslipidemia and truncal obesity. This pattern of central fat accumulation and peripheral fat loss has been termed HIV-associated lipodystrophy syndrome. Prevalence of lipodystrophy of ranges from 10% to 80%, depending on the definition of lipodystrophy.45 The most important risk factor for development of this condition appears to be NRTI use.46
Prior to widespread use of HAART, endocrine complications of OIs were much more prevalent. These complications included glandular infection and infiltration of the pituitary, adrenal, and, rarely, thyroid glands. Although these conditions are much less common now because of HAART, they should still be considered, especially in patients not on HAART or patients with AIDS. Glucocorticoid deficiency can result from adrenal involvement, and while it is usually subclinical, it should be considered in patients with AIDS and hypotension or critical illness. Treatment for these patients is the same as for non–HIV-infected patients.
Patients on HAART are at risk for developing thyrotoxicosis in association with immune reconstitution inflammatory syndrome due to autoimmune activation against the thyroid. Patients generally present months to years after starting HAART with symptoms of Grave disease, weight loss, and tachycardia.47
Disorders of glucose metabolism are associated with the use of HAART, particularly PIs. Additionally, the disease itself is associated with an increased incidence of diabetes as a result of chronic inflammation leading to insulin resistance.48
Patients with longstanding HIV infection who are on treatment have lower bone mineral density when compared with noninfected individuals of similar age.49 Therefore, HIV-infected patients are at increased risk of fracture. HIV itself, as well as antiretroviral medications, are implicated in higher rates of avascular necrosis. Benign musculoskeletal and joint complaints of pain are common in the HIV-infected patient, and the emergency clinician must differentiate between these and more significant pathology. Infectious complications (such as septic arthritis) are less common with improved control of the disease. As the CD4 count drops, septic arthritis, osteomyelitis, and discitis must be considered with appropriate evaluation, including laboratory testing and imaging studies.50
Neuropsychiatric illness is prevalent and multifactorial in HIV-infected individuals. Direct effects of the virus, underlying mental illness, and the social implications of an HIV diagnosis all contribute to psychiatric illness. Medication effects, notably efavirenz, also contribute. Depression is one of the most common diagnoses in HIV-infected patients and is associated with decreased medication compliance.23
Demoralization syndrome is similar to depression in that patients experience a sense of hopelessness or sadness. However, it is different from depression because it is not associated with anhedonia. Demoralization is common in patients with HIV and may be related to the social implications of being diagnosed with HIV. Unlike depression, demoralization does not respond to antidepressants and requires further evaluation and treatment by a psychiatrist.
Mania is also a recognized complication of HIV disease. Patients presenting to the ED with symptoms consistent with this should be evaluated for organic etiologies of their symptoms and then referred to psychiatric services. Patients presenting to the ED with symptoms concerning for any mental illness should be questioned about suicidal and homicidal ideation and admitted if either are present; otherwise, they should receive prompt outpatient follow-up.
Dermatologic complaints are common in HIV-infected patients. HAART is associated with a high rate of drug-related skin reactions, which can lead to medication noncompliance.51 Dermatologic hypersensitivity and photosensitivity are both common with HAART.
Although treatment with HAART seems to be associated with a lower risk of infectious dermatologic conditions, rates of these infections remain high.52 Folliculitis is likely the most common of these, with Staphylococcus aureus being the most common pathogen, particularly the methicillin-resistant strain. Other common infectious dermatologic complaints, including herpes zoster, human papillomavirus-associated warts, seborrheic dermatitis, and molluscum contagiosum, are more common in HIV-infected patients, with treatment considerations being the same as in non–HIV-infected patients.
David L. Gutteridge, MD, MPH; Daniel J. Egan, MD
February 1, 2016
March 1, 2019