The Febrile HIV Patient

Author: Levi Kitchen, MD (EM Chief Resident, Naval Medical Center — Portsmouth) // Editors: Alex Koyfman, MD & Justin Bright, MD

In the febrile HIV patient, there are many diagnostic dilemmas and potential life-threatening disease processes which make the diagnosis and treatment difficult.  When approaching these patients, it is useful to separate complications into organ systems and then try to estimate the patient’s immune status if it is not known.  CD4 counts > 500 cells/uL indicate early infection where the most common infections are similar to non-HIV infected people.  The risk for opportunistic infections (OI) changes as the disease progresses and CD4 count drops, decreasing the body’s cell-mediated and humoral immunity capabilities.

In general, CD4 values < 500 cells/uL, < 200 cells/uL and < 50 cells/uL correspond with mild, moderate and severe immune impairment respectively.  While these classifications are important for risk stratification, they are less important in the ED setting where real-time CD4 counts are almost never available.

What if the patient/provider cannot find the CD4 count? 

Absolute lymphocyte count < 1,200 is suggestive of CD4 < 200 cells/uL; although this is flawed as certain infections can cause a transient decrease in lymphocyte count.

-Presence of conditions suggestive of AIDS/immune suppression in the right clinical setting such as oral candidiasis, oral hairy leukoplakia, Kaposi Sarcoma, persistent HSV infection, lymphoma, PCP pneumonia, encephalopathy, etc.

Some cases to facilitate discussion of some of the more common febrile presentations in HIV:

36 yo male with known HIV but poorly compliant with ART (anti-retroviral therapy) presents with 2 weeks of dry cough, fever, weight loss, and worsening dyspnea on exertion.

Pulmonary disease is the leading cause of morbidity and mortality amongst the HIV population.  Common things being common, the most common infections are the same ones that people with normal immune systems get such as pneumonia, bronchitis, URI, etc.  Once the CD4 count drops below 500, patients are at higher risk for common infections as well as OI.  Of these, the most common is PCP (pneumocystis jiroveci pneumonia).

PCP is characterized by an indolent course over days to weeks of fevers, dry cough, and increasing dyspnea on exertion in a patient who has known or suspected HIV infection.  Factors supportive of this diagnosis include a serum LDH 2-3x upper limit of lab reference normal values, CXR with bilateral symmetric interstitial infiltrates, or ground glass appearance especially on CT chest.  Treatment is with TMP-SMX (trimethoprim- sulfamethoxazole) oral vs. intravenous depending on severity of disease.  A prolonged steroid taper over three weeks should be considered in patients who are hypoxic (O2 sats < 90% or PaO2 < 70mmHg on ABG).

Mycobacterium tuberculosis (TB) is another concern.  In the right patient population, i.e. homeless, incarcerated, immigrant, or high-risk travel + immune compromise, this must be high on the differential.  The typical upper lobe cavitary lesions on CXR may be absent and instead replaced with atypical findings such as pleural effusion; pulmonary infiltrate may be more common.  Any patient with moderate to severe symptoms suspected of TB will require respiratory isolation and admission for confirmatory testing.

44 yo homeless man well known to ED arrives by EMS found unresponsive after a seizure in his bed at the homeless shelter.  Hypoxic and febrile although otherwise hemodynamically stable, respiratory depression and disordered breathing lead to intubation.

It’s highly likely this patient has a CNS infection related to his HIV.  It is unknown whether he has been taking his prophylactic medicines and his latest CD4 count is unknown as well. No reliable history is available from EMS or the prior visits.

The most common CNS infection in HIV is Cryptococcus neoformans.  It presents as insidious onset over weeks of recurrent headache and fevers, in the later stages can cause increased ICP leading to seizures and AMS.  The diagnosis is made by CNS cryptococcal antigen testing which will require a lumbar puncture to obtain CSF.  Treatment is as inpatient with IV amphotericin B and flucytosine, followed by prolonged oral therapy with fluconazole.

Complicating matters are the other typical CNS processes in HIV – toxoplasmosis, EBV-related lymphoma, tuberculosis, and progressive multifocal leukoencephalopathy caused by the JC virus.  The former two disorders will cause ring enhancing/mass lesions best visualized by CT with contrast.  These lesions and masses can cause CSF flow obstruction, hydrocephalus, etc and so the CT should be obtained prior to LP in all HIV patients with suspected CNS infection.

As an aside, CNS infections typically present in the later stages of AIDS with a CD4 count < 100.  With proper follow-up, these patients should already be on TMP-SMX prophylaxis for PCP which also covers for toxoplasmosis, so this diagnosis would be much less likely in someone who is compliant.

54 yo female recently diagnosed with severe HIV (CD4 < 50 on diagnosis), started on ART two weeks prior to presentation, now with severe dyspnea, fever, tachycardia, and multiple pulmonary infiltrates, lymphadenopathy consistent with disseminated Mycobacterium Avium Complex (MAC) .

Immune reconstitution inflammatory syndrome (IRIS) is a phenomena being encountered more frequently as ART improves.  As the patient’s CD4 counts rise, the body’s immune system which was previously suppressed now has a vigorous response to latent infections such as TB, MAC, CMV retinitis, or a previously unidentified OI like MAC is “unmasked” by the body’s new ability to fight infection.  This immune response may cause scarring; in the case of CMV retinitis, blindness can result.  The result is a systemic inflammatory response consistent with what would be expected for fulminant disease in an untreated patient.

Patients with IRIS require admission and treatment, and will need to remain on ART medications after discharge as the symptoms will resolve over 4-6 weeks.

62 yo female with history of HIV, poorly compliant with medications and follow-up, arrives with complaints of malaise, fever, dry cough, night sweats, weight loss, abdominal pain, and diarrhea.  CXR shows lymphadenopathy, physical exam with hepatosplenomegaly.  Labs show anemia and elevated alkaline phosphatase.

Mycobacterium Avium Complex (MAC) is a disseminated multi-organ infection characterized by constitutional symptoms, diffuse lymphadenopathy, diarrhea, and abdominal pain.  MAC typically infects only the most severely immune compromised, CD4 < 50.  Localized infection is possible as well.  Diagnosis is confirmed by blood or other sterile body fluid/substance culture-positive for MAC; AFB smear for stool and other tissues can be helpful as well.  Treatment is with IV clarithromycin, or azithromycin if intolerable to the side effects of clarithromycin.

Diarrhea and abdominal pain

Multiple causes including the typical bacterial salmonella, shigella, campylobacter, Yersinia and Clostridium difficile remain the most common causes of febrile diarrheal illness in HIV.  Due to immune suppression, the body is also susceptible to more exotic organisms such as Cryptosporidium and IsosporaFluid losses from Cryptosporidium-induced diarrhea can cause fulminant dehydration and even death. In the severely immune compromised (CD4 < 50), CMV can cause severe enteritis.  Mycobacterium tuberculosis can also cause severe diarrhea especially in high-risk individuals and those from developing countries.

Diagnosis relies on stool studies for ova and parasites, specific toxin assays, culture, AFB staining.  Treatment is generally supportive.

Remember that oral thrush and esophagitis can be the presenting symptoms of HIV infection as well, this is most commonly caused by candidiasis but can be related to viral etiology such as HSV, EBV, or CMV.

Extra credit

Cutaneous manifestations of HIV are numerous.  Initial infection is typically associated with a morbilliform maculopapular rash with oral / mucosal lesions and rash that includes the palms and soles.  Other infectious agents such as HSV and VZV can be recurrent and more severe than expected in the undiagnosed.  Kaposi sarcoma is a vascular neoplasm which is very common and presents as violaceous patches, nodules and patches.

References / Further Reading:

– Rosen’s Emergency Medicine – Concepts and Clinical Practice.  8th Edition.

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