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.

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.

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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?

Gastrointestinal complications

Gastrointestinal complications are common in HIV-infected individuals, and diarrhea is reported in up to 90% of patient with HIV. Infectious causes of diarrhea most often found on endoscopic biopsy are: Clostridium difficile, Salmonella, Shigella, Campylobacter, Giardia, Cryptosporidium, Isospora, Microspora, Strongyloides stercoralis, cytomegalovirus (CMV), and Mycobacterium avium complex (MAC).

Kaposi’s sarcoma and lymphoma can also affect the gastrointestinal (GI) tract, causing malabsorption and diarrhea. Lymphoma of the stomach is often diagnosed in late stage and presents with obstruction.

HIV enteropathy (direct HIV infection of the gut cells) causes altered bowel motility, bacterial overgrowth, and chronic diarrhea.

Odynophagia is another common symptom in advanced HIV infection and can be caused by esophageal candida, CMV, herpes simplex virus (HSV), Kaposi’s sarcoma, or aphthous ulcers.

Hepatobiliary disease in HIV-infected individuals can have a variety of etiologies. Rates of chronic hepatitis B virus (HBV) infection are higher and rates of progression to cirrhosis and decompensated liver failure are faster in HIV infection. Hepatitis C virus (HCV) prevalence is markedly elevated in HIV-infected individuals compared to age-matched controls. AIDS cholangiopathy, a syndrome of biliary obstruction, can occur with CD4 counts less than 100. Cryptosporidiosis, CMV and Giardia, MAC, disseminated TB, and histoplasmosis all have a propensity for the liver.

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

The diagnostic approach will depend 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 gastrointestinal complications:

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

  • Bacterial enteric disease

  • Human herpes virus 8 (HHV-8) (Kaposi’s sarcoma)

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

  • Oral candidiasis

  • NHL

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

  • Candidal esophagitis

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

  • CMV (retinitis, esophagitis, colitis, CNS disease)

  • Bartonella infection

  • 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 – intravenous drug use (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.

Gastrointestinal symptoms

The evaluation of patients with HIV and diarrhea pivots around stool culture data, including careful examination for ova (with acid fast [AF] technique) and parasites. Up to 50% stool samples obtained fail to identify a causative organism. The most appropriate endoscopic approach to HIV-infected patients with unrelenting diarrhea is unclear, but colonoscopy with ileal intubation appears to have the highest yield for new diagnoses, especially for microsporidium and CMV. If the ileum cannot be intubated, upper endoscopy may be needed for small bowel biopsy.

Yields are usually highest with endoscopy for patients with CD4 less than 100 and with systemic symptoms.

The approach to the HIV-infected patient who presents with hepatobiliary complaints is similar to the approach in an immunocompetent patient and includes hepatic panel, imaging and endoscopic retrograde cholangiopancreatography (ERCP) if necessary, and broad-spectrum antibiotic therapy if there is evidence of cholangitis.

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 general, it is not appropriate to initiate an antibiotic regimen for diarrhea for which a causative agent has not been identified.

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?

Bhaijee, F, Subramony, C, Tang, SJ, Pepper, DJ. “Human immunodeficiency virus-associated gastrointestinal disease: common endoscopic biopsy diagnoses”. Patholog Res Int.

“Infectious Diseases Society of America. IDSA Guidelines”.

Oldfield, EC. “Evaluation of chronic diarrhea in patients with human immunodeficiency virus infection”. Rev Gastroenterol Disord. vol. 2. 2002. pp. 176-88.

Poles, MA, Dieterich, DT. “Infections of the liver in HIV-infected patients”. Infect Dis Clin North Am. vol. 14. 2000. pp. 741-59.