Complications of human immunodeficiency virus

I. Problem/Condition.

Complications of human immunodeficiency virus (HIV) infection include a wide array of clinical problems that can affect virtually every organ system. Prior to the advent of highly active antiretroviral therapy (HAART), the bulk of the complications were comprised of opportunistic illnesses (OIs), which included infections and malignancies. In current times, the spectrum of disease encompasses more non-acquired immune deficiency syndrome (AIDS) defining cancers, complications of concomitant illnesses and side effects of HAART.

Side effects of HAART are discussed in another chapter. This chapter will focus on the approach to non-pharmacologic complications of HIV/AIDS by organ system. Please note that this chapter summarizes the approach to the hospitalized patient in the United States (US); should the patient be a recent immigrant, the differential diagnosis may need to broadened based on the area of origin.

HIV-infected individuals commonly present to the hospital setting with shortness of breath, lymphadenopathy, diarrhea, rashes, or general systemic symptoms such as weight loss and fever. The list of differential diagnoses broadens in direct proportion to the degree of immunocompromise as measured by the cluster of differentiation (CD4) count.

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While patients with CD4 counts above 200 often present with infections common to immunocompetent hosts, they also have higher rates of certain HIV-associated illnesses, such as tuberculosis (TB), candidal infections, lymphomas, and Kaposi’s sarcoma. As CD4 counts fall, hosts are susceptible to more and more infections and cancers.

This group of patients often presents a challenge to the clinician because they may not fit Occam’s razor; they may have multiple infectious or oncologic complications at one time. Additionally, many symptoms such as wasting, lymphadenopathy and diarrhea may be a manifestation of AIDS itself. Furthermore, patients can suffer systemic symptoms with immune reconstitution inflammatory syndrome (IRIS, discussed elsewhere). This can closely mimic disseminated infection.

Important points to remember are: 1) the level of immunocompromise dictates the differential diagnosis and what testing need to be ordered and 2) regardless of degree of immunocompromise, individuals with HIV often suffer from common illnesses unrelated to their immunodeficiency.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Pulmonary complications

In the pre-HAART era, infectious pulmonary complications were the predominant cause of morbidity and mortality in the HIV-infected population. Bacterial pneumonias, bronchitis and pneumocystis pneumonia were common causes of illness in this patient population. In the post-HAART era and with the advent of antimicrobial prophylaxis, the epidemiology of lung disease in HIV-infected individuals has changed. Bacterial pneumonia and pneumocystis pneumonia rates have decreased, and more non-infectious complications have emerged.

While HIV often conjures up thoughts of opportunistic infections, HIV-infected patients often fall prey to infections we see in immunocompetent individuals. Bacterial pneumonias are common in HIV-infected individuals, the most common isolated causative agent being Streptococcus pneumoniae, and occur more frequently as CD4 counts fall. The rates of bacterial pneumonia in patients with CD4 greater than 500 are similar to those of the general population, whereas patients with CD4 less than 200 are six times more likely to present with bacterial pneumonia. The highest risk individuals are injection drug users.

Pneumocystis pneumonia is one of the better known opportunistic infections in HIV-infected persons and typically occurs when the CD4 counts fall below 200. CMV pneumonia can contribute to pulmonary illness in patients with CD4 less than 100, though it is often thought to be a result of reactivation of virus, and more as a poor prognostic marker than as a sole cause of pulmonary symptoms.

TB is the most common pulmonary complication of HIV in the developing world. In the US, TB can occur in HIV-infected individuals at any CD4 count, but prevalence increases as immune function decreases. Untreated advanced HIV infection increases the chance of reactivation TB tenfold.

Endemic fungi such as Coccidioides immitis and Histoplasma can cause serious lung infections in patients infected with HIV. Aspergillus is a rare cause of tracheitis at CD4 counts below 50.

Interestingly, as more people gain access to HAART, pulmonary infectious complications of HIV are decreasing, giving way to a whole new class of non-infectious complications, including non AIDS-defining cancers (non-small cell lung cancer [NSCLC)], Hodgkin’s lymphoma) and pulmonary hypertension. The rates of AIDS-defining cancers of the lung (Kaposi’s sarcoma, Non-Hodgkin’s lymphoma [NHL]) have fallen in the HAART era.

B. Describe a diagnostic approach/method to the patient with this problem

The diagnostic approach depends on a careful history and physical examination, in addition to understanding the patient’s HIV treatment history. A recent CD4 count (and preferably a recent trend) is the single most helpful element in formulating a differential diagnosis.

All HIV-infected individuals, regardless of CD4 count, are at increased risk of the following pulmonary complications:

  • TB (those with CD4 <200 are more likely to have extrapulmonary disease)

  • Bacterial pneumonia

  • Histoplasmosis (pulmonary at any count, CD4 <150 for disseminated infection)

  • NHL

HIV-infected individuals with CD4 less than 200 are at risk for all of the above, and the following:

  • Pneumocystis pneumonia

  • Coccidioidomycosis (may have CD4 counts up to 250)

HIV-infected individuals with CD4 less than 50 are at risk for all of the above, and the following:

  • Aspergillosis (meningitis or pulmonary disease)

  • Mycobacterium avium complex (MAC)

1. Historical information important in the diagnosis of this problem.

Important questions to ask include the following:

  • Careful history and timing of chief complaint.

  • Associated symptoms – there may be more than one diagnosis.

  • History of HAART and adherence – presentation may be related to drug side effects.

  • Any bacterial prophylaxis and adherence – if on trimethoprim/sulfamethoxazole (TMP/SMX, also known as Bactrim) prophylaxis, less likely to have bacterial pneumonia, pneumocystis, or toxoplasmosis. If taking azithromycin, less likely to acquire MAC.

  • CD4 count and history – previous AIDS-defining illness or CD4 count less than 200 predisposes to more serious infection even if counts are currently above 200.

  • Travel history – Mississippi River valley for histoplasmosis; Southwest US for coccidioidomycosis; foreign TB endemic area.

  • Careful sexual history for epidemiology – Kaposi’s sarcoma is much more common in men that have sex with men (MSM); secondary syphilis can cause high fevers, rash, and mental status changes; Giardia is more common in MSM; anal intercourse may be linked to anal cancer.

  • Careful social history – IVDU increases risk for bacterial pneumonia, TB, and viral hepatitis; Smoking increases the risk for lung cancer and heart disease.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

In the scope of focusing on a HIV-infected individual presenting to a hospital setting, it is of utmost importance to perform a thorough physical examination, including skin, oropharynx, and abdominal exam regardless of the chief complaint. Skin findings such as Kaposi’s or bacillary lesions can suggest level of immunocompromise and point at the causative process. Organomegaly and lymphadenopathy can suggest the presence of a systemic process.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Pulmonary symptoms

The initial evaluation of the HIV-infected patient with pulmonary symptoms involves a chest radiograph, which helps differentiate between focal and diffuse pneumonias. Sputum sample can guide treatment, but often treatment is based on epidemiology. Blood cultures may be helpful in bacterial pneumonia.

If there is suspicion of TB based on presentation and risk, the patient should be isolated in a negative-pressure setting and sputum samples for acid-fast bacilli (AFB) smear should be obtained.

If there is severe hypoxia and pneumocystis pneumonia is suspected, an arterial blood gas will help guide the use of corticosteroids based on degree of arterial hypoxemia. Chest X-ray (CXR) or computed tomography (CT) scan can help establish the extent of the pulmonary process. Since pneumocystis cannot be cultured, the gold standard for diagnosis is immunofluorescence staining of the sputum (either induced or from bronchoalveolar lavage which has higher sensitivity 80-98%). If sputum cannot be obtained, serum 1,3 beta-D-glucan can be used to make a presumptive diagnosis. In one study, 1,3 beta-D-glucan had 92% sensitivity for the diagnosis of pneumocystis pneumonia (making it more sensitive than the induced sputum immunostaining).

Histoplasma antigen in serum or urine can detect disseminated histoplasmosis but is insensitive for pulmonary infection.

A transthoracic echocardiogram is useful when HIV-associated pulmonary hypertension is suspected.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Please see disease-specific chapters for exact diagnostic criteria.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

This is a population of patients, especially the ones with severe immunocompromise, in which it is worthwhile to cast a wide net for diagnostic purposes. HIV-infected patients often have extended hospital stays, and undergo multiple costly tests and procedures. This is hard to avoid because of the high morbidity and mortality associated with complications of this disease.

The utility of obtaining a CD4 count in the setting of acute illness is questionable. There is a body of literature showing that patients with acute illness in the intensive care unit (ICU) have falsely depressed CD4 counts even if they do not have HIV infection. This likely applies to HIV patients with acute illness; the CD4 count obtained will be falsely low leading to unnecessary investigations. Thus, if a patient has a recent CD4 count from an outpatient clinic, it is appropriate to assume those are accurate and forego obtaining a new confounding lab in the hospital.

That said, patients with a new diagnosis and no previous CD4 count should have one obtained on presentation.

Also, viral loads obtained in the hospital are often seen, but there are usually no therapeutic decisions that depend on them.

III. Management while the Diagnostic Process is Proceeding

A. Management of complications of human immunodeficiency virus.

The severity of presenting illness will dictate the amount of resuscitative effort. After stabilization, a focused investigation should be expedited based on presenting symptoms and likelihood of particular diseases based on level of immunocompromise. If the patient does not have a previous CD4 count, one should be obtained.

In the setting of severe hypoxia, if pneumocystis is suspected, obtain an arterial blood gas (ABG) as this will determine whether or not to initiate steroids prior to antibiotic therapy. Empiric treatment for pneumocystis is not generally recommended, unless the patient is critically ill. Mortality from pneumocystis has decreased 21% to less than 10% in the HAART era, but there is data to suggest this may not be true in areas with a more underserved population who receive less HAART therapy.

Do not forget to consider TB in patients who have risk factors. HIV infection greatly increases the risk of reactivation of TB. Isolate these patients in negative pressure if pulmonary TB is suspected.

For management of specific complications once diagnosed, please see disease-specific chapters.

It is ideal in these cases to have the help of a specialist who has experience in HIV, not only to aid with the diagnosis, but also to make decisions about whether to stop or continue HAART as it relates to the acute illness, and when to start HAART if the patient is not currently on antiretrovirals. The guidelines for these decisions are changing and the decision process is complex and disease-dependent.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Generally, both HAART and specific treatments for the conditions above have significant toxicities. Please see disease-specific chapters for a discussion on those and specific treatment regimens.

IV. What's the evidence?

Boyton, RJ. “Infectious lung complications in patients with HIV/AIDS”. Curr Opin Pulm Med. vol. 11. 2005. pp. 203-7.

Hirschtick, RE, Glassroth, J, Jordan, MC, Wilcosky, TC. “Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV infection Study group”. N Engl J Med. vol. 333. 1995. Sep. pp. 845-51.

Horsburgh, CR, Rubin, EJ. “Latent Tuberculosis in the United States”. N Engl J Med. vol. 365. 2011. pp. 1441-1448.

“Infectious Diseases Society of America: IDSA guidelines”.

Kanmogne, GD. “Noninfectious complications of HIV/AIDS”. Curr Opin Pulm Med. vol. 11. 2005. pp. 208-12.

Kelley, CF. “Trends in hospitalizations for AIDS-associated Pneumocystis jirovecii pneumonia in the United States (1986-2005)”. Chest. vol. 136. 2009. pp. 190-7.

Sax, PE, Komarow, L, Finkelman, MA, Grant, PM. “Blood (1→3)-beta-D-glucan as a diagnostic test for HIV-related Pneumocystis jirovecii pneumonia”. Clin Infect Dis. vol. 53. 2011. pp. 197-202. (Discussion about the newer serum test with higher sensitivity than induced sputum for diagnosis of pneumocystis pneumonia.)