1. 
   

   What conditions cause symptoms in HIV patients?

   
   
2. 
   

   How are opportunistic infections diagnosed and treated?

   
   
3. 
   

   What noninfectious problems are common in HIV patients?

   
   
4. 
   

   When should antiretroviral therapy be started?

More than 1 million people are HIV seropositive in the United States. As survival with HIV has increased because of antiretroviral therapy (ART), the spectrum of illness affecting this population has expanded. Opportunistic infections still occur in untreated patients and patients who do not adhere to therapy. However, in patients whose HIV infection is controlled by ART, noninfectious problems such as coronary artery disease, pulmonary hypertension, and malignancy are increasing in prevalence. This chapter uses a symptom-based approach to guide differential diagnosis in HIV, and outlines the presentation, diagnosis, and treatment of common opportunistic infections. Other aspects of HIV therapy important to the hospitalist are discussed, including medication interactions and side effects.

Most patients with acute HIV infection develop symptoms from two to four weeks after exposure. Some patients are asymptomatic, but many report an acute febrile illness resembling mononucleosis. Features may include rash, anorexia, mucocutaneous ulcerations, pharyngitis, lymphadenopathy, diarrhea, myalgias, and rarely meningoencephalitis. As HIV antibody does not appear until three to four weeks after the symptoms of acute HIV syndrome develop, both HIV RNA (viral load) testing and HIV antibody should be obtained. Clinicians should bear in mind that patients with acute HIV infection may also have acquired other infections, such as viral hepatitis, syphilis, or cytomegalovirus (CMV), at the time of their HIV exposure.

HIV depletes CD4+ lymphocytes, also known as T-helper cells, leading to opportunistic infections (OIs). In acute HIV infection, CD4+ cells decline sharply, generally followed by a modest rebound, as HIV replication is brought under partial control. Over time, viremia rises, CD4+ cells are gradually depleted, and AIDS develops.

The tempo for progression to AIDS has great individual variability. Illnesses such as seborrheic dermatitis, cutaneous zoster, bacterial pneumonia, and cytopenias, while not specific to HIV, occur with increased frequency in patients with waning CD4+ cells and may be a clue to undiagnosed HIV.

Admission of the patient with CD4+ count > 500 cells/mm3, suppressed viral load, and admission for a non–HIV-related reason does not necessarily require infectious diseases consultation. By contrast, newly diagnosed HIV, acute opportunistic infections, undifferentiated illness in patients with more advanced HIV, or possible modification of ART warrant review with a specialist familiar with HIV disease and its management.

The most recent CD4+ cell count is critical in determining the likelihood of an HIV-related complication (Table 195-1). If recent CD4+ counts are unavailable, there is controversy about the usefulness of CD4+ testing in the context of acute illness, which depresses the CD4+ below the patient’s true baseline. Despite this caveat, we recommend measuring CD4+ cell count during hospital admissions, as markedly low values (eg, < 100 cells/mm3) almost invariably indicate severe HIV-related immunosuppression. Conversely, OIs are unusual in patients with completely normal CD4+ cell counts. Although HIV RNA values do not give as much information about a patient’s immune status as CD4+ counts, they are excellent markers of ART medication adherence, as most patients faithfully taking appropriate ART will have HIV RNA levels below the limits of detection of available assays. One potential confounder to this rule is that acute infections transiently raise HIV RNA levels.

In general, admission of the HIV-positive patient on ART merits a baseline check of renal and hepatic function as well as a CBC. HIV therapy may result in signature laboratory abnormalities in some patients, such as the indirect hyperbilirubinemia seen in patients on atazanavir and the increased MCV due to zidovudine (Table 195-2).

For patients with excellent medication adherence, suppressed HIV RNA, and immunologic recovery with CD4+ cell counts > 200 cells/mm3, traditional AIDS-related illnesses are vanishingly rare. Individuals with these characteristics are generally admitted for similar reasons as HIV-negative patients. However, long-term follow-up of treated HIV patients shows that they do have a higher risk of certain noninfectious complications than age-matched, HIV-negative controls. Cardiovascular, hepatic, and renal disease occurs more frequently in patients with HIV, probably due to a combination of ART-induced side effects and chronic inflammation. Malignancies also seem to be increased, perhaps as a consequence of reduced immune tumor surveillance.

Respiratory Illness

Causes of respiratory symptoms in HIV include bacterial, mycobacterial, viral, and fungal pathogens, as well as malignancy and cardiovascular disease (Table 195-3). Clues to the etiology of the illness include the symptoms, time course, and imaging. A careful history can narrow the differential diagnosis significantly. For example, a relatively acute illness with fevers, chills, sputum production, and pleuritic chest pain is consistent with bacterial pneumonia. A subacute illness with progressive dyspnea, dry cough, low-grade fevers, and weight loss suggests Pneumocystis jirovecii pneumonia (PCP). The social history may elicit risk factors for endemic fungal infections and tuberculosis. Physical examination findings of cachexia or oral candidiasis should raise suspicion for more advanced HIV, as should a history of weight loss.

Initial studies in the HIV-positive patient with respiratory illness should include measurement of oxygen saturation or an arterial blood gas measurement, complete blood count with differential, two sets of blood cultures, sputum culture, chest radiograph, and serum lactate dehydrogenase (LDH), which is nonspecific, but often elevated in patients with PCP. Nasopharyngeal swab for respiratory viruses, such as influenza A and B as well as H1N1, should be sent if local epidemiology and seasonality are appropriate (Table 195-4). Induced sputum should be ordered and sent for PCP and AFB staining, as well as bacterial culture. Serum testing for 1,3 beta-D-glucan—a component of many fungi, including P jirovecii—can be quite useful, as most patients with HIV-related PCP have markedly elevated levels. A strongly positive test in a patient with a compatible clinical syndrome for PCP, therefore, can obviate the need for invasive testing such as bronchoscopy.

If the initial round of diagnostic tests is unrevealing and the patient is not improved on empiric therapy, serum cryptococcal antigen and urine histoplasmosis antigen should be considered. Other evaluation at this time may include bronchoscopy with bronchoalveolar lavage and possible transbronchial biopsy, cardiac evaluation including echocardiography, or potentially nodule or mass resection via video-assisted thoracoscopy.

Central Nervous System Illness

Causes of the central nervous system disease in HIV include cryptococcal meningitis, cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), and many others (Table 195-5). Advanced AIDS may be complicated by HIV-related dementia. Another important HIV-related CNS process is non-Hodgkin lymphoma, which may present as a primary mass lesion in the brain, or as metastatic disease to the meninges in patients with high-grade lymphoma elsewhere.

Initial evaluation of the HIV-positive patient with neurologic or neuropsychiatric symptoms should include an assessment of medication adherence, possible use of illicit drugs, immunologic status, and complete physical examination with special attention to sensory-motor and mental status assessments. Brain MRI should be performed (or head CT, if MRI is not available).

Lumbar puncture is usually indicated, even in the absence of nuchal rigidity, as many of the above processes induce a relatively indolent inflammatory response. Opening pressure should be obtained in all cases. Cerebrospinal fluid (CSF) should be sent for cell count and differential, glucose, protein, Gram stain and routine culture, as well as India ink stain (for Cryptococcus), fungal culture, CSF cryptococcal antigen. If indicated, AFB stain and culture, and VDRL may be sent as well. Leftover CSF (at least 5 cc) should be held for other potential studies including cytology, polymerase chain reaction (PCR) testing for other pathogens such as Epstein-Barr virus (EBV), varicella zoster and herpes simplex viruses, JC virus, and HIV viral load.

Mass Lesions that Enhance with Contrast

Mass lesions with enhancement occur more commonly in the setting of lower CD4+ counts (< 200 cells/mm3), and are most often due to toxoplasmosis (discussed below), primary CNS lymphoma or other malignancies, or rarely other infections, such as brain abscess or tuberculoma. If the patient has a history of positive Toxoplasma IgG serology and has multiple enhancing CNS lesions, empiric treatment for toxoplasmosis is appropriate. If the patient has a documented negative Toxoplasma serology and other etiologies such as tuberculoma or brain abscess are not suspected, neurosurgical consultation for brain biopsy is usually appropriate. Serum Toxoplasma IgM or Toxoplasma antibody studies of the cerebrospinal fluid are not useful in this clinical setting.

Patients with mass lesions and midline shift on imaging or evidence of increased intracranial pressure should receive adjunctive corticosteroids, usually dexamethasone. Symptoms and radiographic appearance of the lesion may improve on steroids, but this improvement should not shorten anticipated course of antibiotic treatment.

Since combination ART became the standard of care, the incidence of all AIDS-defining malignancies in the United States has decreased significantly. However, primary CNS lymphoma (PCNSL) is still over 1000 times more common in patients with HIV than uninfected controls. PCNSL may present with symptoms ranging from mental status changes to seizures, and with a single lesion or multiple lesions. PCNSL is most common in patients with more advanced disease, especially with CD4+ cell counts < 50 cells/mm3. Diagnostic workup includes MRI, CSF cytology, and, in most cases, stereotactic brain biopsy to confirm the diagnosis. CNS lymphoma in HIV usually involves B lymphocytes infected with EBV; PCR testing of CSF for EBV is sensitive, but not specific for this diagnosis.

The incidence of non–AIDS defining primary CNS malignancies is not higher in the HIV-positive patient population. However, lung cancer, which sometimes presents with brain metastases, is increased in HIV patients.

Nonenhancing Mass Lesions

HIV encephalopathy: HIV-related dementia, or HIV encephalopathy, is a disease of advanced immunosuppression. Characteristic findings include loss of memory, apathy, gait disturbance, and incontinence. Symptoms may be exacerbated by underlying psychiatric illness or substance abuse. There is often atrophy and nonenhancing white matter disease on MRI imaging. CSF examination may show mild lymphocytic pleocytosis, elevated protein, and detectable HIV RNA by viral load testing. Treatment with ART may lead to dramatic improvement, especially if the symptoms are of recent onset. However, the prognosis is highly variable, improvement may be delayed for months, and full recovery from severe cases is unusual. HIV encephalopathy, even when mild, may increase susceptibility of patients to the CNS side effects of antiretrovirals and other medications.

Progressive multifocal leukoencephalopathy (PML): As with HIV encephalopathy, the incidence of PML has greatly declined with the advent of ART. PML is a demyelinating disorder caused by JC virus, a common polyomavirus that is usually asymptomatic in the immunocompetent. Symptoms of PML are gradual in onset, and may culminate in hemiparesis, mental status changes, and visual field deficits, depending on the areas of involvement, which may be single or multiple. These lesions are less symmetrical than in HIV encephalopathy and are usually nonenhancing on imaging studies. The diagnosis is made on the basis of PCR testing of the CSF for JC virus. While PML is most common in patients with CD4+ counts < 200 cells/mm3, it may also be seen in patients initiating ART as an immune reconstitution inflammatory response to subclinical JC virus infection. There is currently no therapy that directly targets JC virus. One-third of patients with PML improve with effective ART; unfortunately, the remaining two-thirds have either long-term residual deficits or disease progression despite effective ART.

Gastrointestinal Illness

Gastrointestinal symptoms in HIV may result from infection or, more commonly, from side effects of antibiotics and antiretrovirals, especially the protease inhibitors. Chronic diarrhea with weight loss may be due to untreated HIV itself; this HIV enteropathy is a diagnosis of exclusion, and typically responds promptly to effective ART.

Diarrhea: Causes of diarrhea in HIV are summarized in Table 195-6. The evaluation of the HIV-positive patient with diarrhea should consist of a careful exposure history, including travel, food, drink, and sexual activity. The medication history should include both antiretrovirals as well as antibiotics. The quality, frequency, volume, and time course of the diarrhea are important, as is the presence or absence of fevers and weight loss.