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?

Systemic complications/disseminated disease

Though now more rarely seen due to the advent of HAART, disseminated diseases are still common in the developing world and may be the initial presentation of HIV. MAC often presents with fever, weight loss, anemia, lymphadenopathy, diarrhea, and hepatitis. Histoplasmosis and coccidiomycosis present with systemic symptoms and commonly pulmonary disease. Bacillary angiomatosis (Bartonella infection) presents with fever, malaise and vascular skin lesions.

CMV is rarely the sole cause of severe systemic disease, but it can infect any organ in the body, and causes CMV retinitis at CD4 counts less than 50.

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:

  • Cardiovascular and renal complications (may depend on current therapy)

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

  • Bacterial pneumonia

  • Bacterial enteric disease

  • Syphilis

  • HSV

  • Varicella zoster virus (VZV)

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

  • HPV (cervical and rectal cancers)

  • 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:

  • Pneumocystis pneumonia

  • Toxoplasmosis

  • Coccidioidomycosis (may have CD4 counts up to 250)

  • Candidal esophagitis

HIV-infected individuals with CD4 less than 100 are at risk for all of the above, and the following:

  • Microsporidium

  • Cryptosporidium

  • PML

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

  • Cryptococcosis (meningitis)

  • Aspergillosis (meningitis or pulmonary disease)

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

  • Bartonella infection

  • MAC

  • CNS lymphoma

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 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, Southeast 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.

This chapter focuses on a variety of clinical problems that affect virtually all organ systems; please see disease-specific chapters for physical exam pearls.

In the scope of focusing on a HIV-infected individual presenting to a hospital setting, it is of utmost importance to perform athorough 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.

Disseminated disease

When disseminated disease is suspected, blood cultures are helpful for implicating MAC infection. Biopsy is the most sensitive means of arriving at the causative organism in MAC, coccidiomycosis and bacillary angiomatosis. Histoplasma urinary and serum antigen are more than 90% sensitive for disseminated infection. Cryptococcal antigen in serum is suggestive of disseminatedCryptococcus and requires LP to rule out CSF involvement.

It is important to keep in mind that a patient presenting with systemic symptoms in this population can be exhibiting IRIS, especially in the setting of recent initiation of HAART. The pathophysiology of IRIS is not completely understood, but may be the manifestation of an immune system that is “waking up” and responding to large amounts of antigen it did not recognize before. These patients usually exhibit systemic symptoms within 3 months of starting HAART (but can have symptoms years later), have more severe responses the lower their CD4 nadir and usually react against infections that they have had in the past (CMV, HCV/HBV, MAC,Cryptococcus, TB).

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, presentations of acute and subacute meningitis or meningoencephalitis can often be fatal if not treated rapidly, thus a timely investigation should be performed to isolate the causative organism. As stated previously, CNS lymphoma and TE may often be hard to distinguish from each other radiographically. If such a case arose clinically, it would be reasonable to treat for TE while undergoing further evaluation, especially if toxoplasma serum antigen is positive.

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

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, and induced sputum staining has very high specificity. 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?

Feeney, C. “T-lymphocyte subsets in acute illness”. Crit Care Med. vol. 23. 1995. pp. 1680-5.

Gardner, EM, Connick, E. “Illness of Immune Reconstitution: recognition and management”. Curr Infect Dis Rep. vol. 6. 2004. pp. 483-493.

Horsburgh CR, Jr, Rubin, EJ. “Latent Tuberculosis in the United States”. NEJM. vol. 365. 2011. pp. 1441-1448.

IDSA guidelines..