Symptoms of HIV disease can appear at any time during the course of HIV infection. Generally speaking, the spectrum of illnesses that one observes changes as the CD4+ T cell count declines. The more severe and life-threatening complications of HIV infection occur in patients with CD4+ T cell counts <200/μL. A diagnosis of AIDS is made in anyone with HIV infection and a CD4+ T cell count <200/μL and in anyone with HIV infection who develops one of the HIV-associated diseases considered to be indicative of a severe defect in cell-mediated immunity (category C, Table 189-2). While the causative agents of the secondary infections are characteristically opportunistic organisms such as P. jiroveci, atypical mycobacteria, CMV, and other organisms that do not ordinarily cause disease in the absence of a compromised immune system, they also include common bacterial and mycobacterial pathogens. Following the widespread use of cART and implementation of guidelines for the prevention of opportunistic infections (Table 189-10), the incidence of these secondary infections has decreased dramatically (Fig. 189-34). Overall, the clinical spectrum of HIV disease is constantly changing as patients live longer and new and better approaches to treatment and prophylaxis are developed. In addition to the classic AIDS-defining illnesses, patients with HIV infection also have an increase in serious non-AIDS illnesses, including non-AIDS related cancers and, cardiovascular, renal and hepatic disease. Non-AIDS events dominate the disease burden for patients with HIV infection receiving cART (Table 189-3). Fewer than 50% of deaths among AIDS patients are as a direct result of an AIDS-defining illness. The physician providing care to a patient with HIV infection must be well versed in general internal medicine as well as HIV-related opportunistic diseases. In general, it should be stressed that a key element of treatment of symptomatic complications of HIV disease, whether they are primary or secondary, is achieving good control of HIV replication through the use of cART and instituting primary and secondary prophylaxis for opportunistic infections as indicated.
Table 189-10 NIH/CDC/IDSA 2009 Guidelines for the Prevention of Opportunistic Infections in Persons Infected With HIV |Favorite Table|Download (.pdf)
Table 189-10 NIH/CDC/IDSA 2009 Guidelines for the Prevention of Opportunistic Infections in Persons Infected With HIV
|Recommended as Standard of Care for Primary and Secondary Prophylaxis|
CD4+ T cell count <200/μL
Prior bout of PCP
Trimethoprim/sulfamethoxazole (TMP/SMX), 1 DS tablet qd PO
Dapsone 50 mg bid PO or 100 mg/d PO
Dapsone 50 mg/d PO +
Pyrimethamine 50 mg/week PO +
Leucovorin 25 mg/week PO
|May stop prophylaxis if CD4+ T cell count >200/μL for ≥3 months||TMP/SMX, 1 SS tablet qd PO|
(Dapsone 200 mg PO +
Pyrimethamine 75 mg PO +
Leucovorin 25 mg) weekly PO
Aerosolized pentamidine, 300 mg via
Respirgard II nebulizer every month
Atovaquone 1500 mg/d PO
TMP/SMX 1 DS tablet 3×/week PO
Skin test >5 mm
Prior positive test without treatment
Close contact with case of active pulmonary TB
(Isoniazid 300 mg PO +
Pyridoxine 50 mg PO) qd × 9 months
Isoniazid 900 mg PO twice weekly
+ Pyridoxine 50 mg PO daily × 9 months
Rifabutin 300 mg or rifampin 600 mg PO qd × 4 months
Same with high probability of exposure to isoniazid-resistant TB
|(Rifabutin 300 mg or Rifampin 600 mg) PO qd ×4 months|
|Same with high probability of exposure to multidrug-resistant TB||Consult local public health authorities|
|Mycobacterium-avium complex||CD4+ T cell count <50/μL|
Azithromycin 1200 mg weekly PO or
Clarithromycin 500 mg bid PO
Rifabutin 300 mg/d PO
Azithromycin 600 mg twice weekly PO
Prior documented disseminated disease
May stop prophylaxis if CD4+ T cell count >100/μL for ≥3 months
Clarithromycin 500 mg bid PO +
Ethambutol 15 (mg/kg)/d PO ±
Rifabutin 300 mg/d PO
Azithromycin 500 mg/d PO +
Ethambutol 15 (mg/kg)/d PO ±
Rifabutin 300 mg/d PO
TOXO IgG antibody positive and
CD4+ T cell count <100/μL
|TMP/SMX 1 DS tablet PO qd|
TMP/SMX 1 DS 3× weekly PO
TMP/SMX, 1 SS PO daily
Dapsone 50 mg/d PO +
Pyrimethamine 50 mg weekly PO +
Leucovorin 25 mg weekly PO
(Dapsone 200 mg PO +
Pyrimethamine 75 mg PO +
Leucovorin 25 mg PO) weekly
(Atovaquone 1500 mg PO ±
Pyrimethamine 25 mg PO +
Leucovorin 10 mg PO) daily
Prior toxoplasmic encephalitis and CD4+
T cell count <200/μL
Sulfadiazine 500–1000 mg qid PO +
Pyrimethamine 25–50 mg/d PO + Leucovorin 10–25 mg/d PO
Clindamycin 600 mg q8h PO +
Pyrimethamine 25–50 mg/d PO +
Leucovorin 10–25 mg/d PO
|May stop prophylaxis if CD4+ T cell count >200/μL for ≥3 months|
Atovaquone 750 mg PO q6–12 h ±
Pyrimethamine 25 mg/d PO +
Leucovorin 10 mg/d PO
|Varicella zoster virus||Significant exposure to chickenpox or shingles in a patient with no history of immunization or prior exposure to either||Varicella zoster immune globulin, IM, within 96 h of exposure (1-800-843-74+77)||Acyclovir 800 mg PO 5 × 1 day for 5 days|
Prior documented disease
May stop prophylaxis if CD4+ T cell count >200/μL for 6 months and no evidence of active infection
|Fluconazole 200 mg/d PO||Itraconazole 200 mg/d PO|
Prior documented disease or CD4+ T cell count <150μL and high risk (endemic area or occupational exposure)
May stop prophylaxis after 1 year if CD4+ T cell count >150/μL and patient on ARV therapy for ≥6 months
|Itraconazole 200 mg bid PO||Fluconazole 800 mg/d PO|
Prior documented disease or positive
serology and CD4+ T cell count <250/μL
if from a disease endemic area. (For this indication prophylaxis can be stopped if CD4+ T cell count ≥250 for 6 months.)
|Fluconazole 400 mg/d PO||Itraconazole 200 mg bid PO|
Prior documented disease
May stop secondary prophylaxis in patients on ARV therapy with CD4+ T cell count >100/μL for ≥6 months
|Itraconazole 200 mg/d PO|
|Salmonella species||Prior reament bacteremia||Ciprofloxacin 500 mg bid PO for ≥6 months|
May stop if CD4+ T cell count >200/μL for
Doxycycline 200 mg/d
Azithromycin 1200 mg weekly PO
Clarithromycin 500 mg bid PO
Prior end-organ disease
May stop prophylaxis if CD4+ T cell count >100/μL for 6 months and no evidence of active CMV disease
Restart if prior retinitis and CD4+ T cells <100/μL
Valganciclovir 900 mg bid PO
Ganciclovir sustained-release implant q6–9 months +
Valganciclovir 900 mg bid PO
Cidofovir 5 mg/kg every other week IV +
Fomivirsen 330 μg intravitreal q2–4 week
Foscarnet 90–120 (mg/kg)/d IV
|Immunizations Generally Recommended|
|Hepatitis B virus||All susceptible (anti-HBc-and anti-HBs-negative) patients||Hepatitis B vaccine: 3 doses|
|Hepatitis A virus||All susceptible (anti-HAV-negative) patients||Hepatitis A vaccine: 2 doses|
|Influenza virus||All patients annually||Inactivated trivalent influenza virus vaccine 1 dose yearly|
Oseltamivir 75 mg PO qd
Rimantadine or amantadine 100 mg PO bid (influenza A only)
|Streptococcus pneumoniae||All patients, preferably before CD4+ T cell count ≤200/μL|
Pneumococcal vaccine 0.5 mL IM ×1 if CD4+ T cell count >200/μL
Reimmunize patients initially
immunized at a CD4+ T cell count <100/μL whose CD4+ T cell count then increases to >200/μL
|Human papillomavirus||All patients 9–26 years of age||HPV vaccine; 3 doses|
|Recommended for Prevention of Severe or Frequent Recurrences|
|Herpes simplex||Frequent/severe recurrences|
Valacyclovir 500 mg bid PO
Acyclovir 400 mg bid PO
Famciclovir 500 mg bid PO
|Candida||Frequent/severe recurrences||Fluconazole 100–200 mg/d PO||Itraconazole solution 200 mg/d PO posacomagole 400 mg bid PO|
A. Decrease in the incidence of opportunistic infections and Kaposi's sarcoma in HIV-infected individuals with CD4+ T cell counts <100/μL from 1992 through 1998. [Adapted and updated from FJ Palella et al: N Engl J Med 338:853, 1998, and JE Kaplan et al: Clin Infect Dis 30(S1):S5, 2000, with permission.] B. Quarterly incidence rates of cytomegalovirus (CMV), Pneumocystis jiroveci pneumonia (PCP), and Mycobacterium avium complex (MAC) from 1995 to 2001. (From FJ Palella et al: AIDS 16:1617, 2002.)
Diseases of the Respiratory System
Acute bronchitis and sinusitis are prevalent during all stages of HIV infection. The most severe cases tend to occur in patients with lower CD4+ T cell counts. Sinusitis presents as fever, nasal congestion, and headache. The diagnosis is made by CT or MRI. The maxillary sinuses are most commonly involved; however, disease is also frequently seen in the ethmoid, sphenoid, and frontal sinuses. While some patients may improve without antibiotic therapy, radiographic improvement is quicker and more pronounced in patients who have received antimicrobial therapy. It is postulated that this high incidence of sinusitis results from an increased frequency of infection with encapsulated organisms such as H. influenzae and Streptococcus pneumoniae. In patients with low CD4+ T cell counts one may see mucormycosis infections of the sinuses. In contrast to the course of this infection in other patient populations, mucormycosis of the sinuses in patients with HIV infection may progress more slowly. In this setting aggressive, frequent local debridement in addition to local and systemic amphotericin B may result in effective treatment.
Pulmonary disease is one of the most frequent complications of HIV infection. The most common manifestation of pulmonary disease is pneumonia. Three of the 10 most common AIDS-defining illnesses are recurrent bacterial pneumonia, tuberculosis, and pneumonia due to the unicellular fungus P. jiroveci. Other major causes of pulmonary infiltrates include other mycobacterial infections, other fungal infections, nonspecific interstitial pneumonitis, KS, and lymphoma.
Bacterial pneumonia is seen with an increased frequency in patients with HIV infection, with 0.8–2.0 cases per 100 person-years. Patients with HIV infection are particularly prone to infections with encapsulated organisms. S. pneumoniae (Chap. 134) and H. influenzae (Chap. 145) are responsible for most cases of bacterial pneumonia in patients with AIDS. This may be a consequence of altered B cell function and/or defects in neutrophil function that may be secondary to HIV disease (see above). Pneumonias due to S. aureus (Chap. 135) and P. aeruginosa (Chap. 152) are also reported to occur with an increased frequency in patients with HIV infection. S. pneumoniae (pneumococcal) infection may be the earliest serious infection to occur in patients with HIV disease. This can present as pneumonia, sinusitis, and/or bacteremia. Patients with untreated HIV infection have a sixfold increase in the incidence of pneumococcal pneumonia and a 100-fold increase in the incidence of pneumococcal bacteremia. Pneumococcal disease may be seen in patients with relatively intact immune systems. In one study, the baseline CD4+ T cell count at the time of a first episode of pneumococcal pneumonia was ∼300/μL. Of interest is the fact that the inflammatory response to pneumococcal infection appears proportional to the CD4+ T cell count. Due to this high risk of pneumococcal disease, immunization with pneumococcal polysaccharide is one of the generally recommended prophylactic measures for patients with HIV infection. This is likely most effective if given while the CD4+ T cell count is >200/μL and, if given to patients with lower CD4+ T cell counts, should be repeated once the count has been above 200 for 6 months. Although clear guidelines do not exist, it also makes sense to repeat immunization every 5 years. The incidence of bacterial pneumonia is cut in half when patients quit smoking.
Pneumocystis pneumonia (PCP), once the hallmark of AIDS, has dramatically declined in incidence following the development of effective prophylactic regimens and the widespread use of cART. It is, however, still the single most common cause of pneumonia in patients with HIV infection in the United States and can be identified as a likely etiologic agent in 25% of cases of pneumonia in patients with HIV infection, with an incidence in the range of 2–3 cases per 100 person-years. Approximately 50% of cases of HIV-associated PCP occur in patients who are unaware of their HIV status. The risk of PCP is greatest among those who have experienced a previous bout of PCP and those who have CD4+ T cell counts of <200/μL. Overall, 79% of patients with PCP have CD4+ T cell counts <100/μL and 95% of patients have CD4+ T cell counts <200/μL. Recurrent fever, night sweats, thrush, and unexplained weight loss are also associated with an increased incidence of PCP. For these reasons, it is strongly recommended that all patients with CD4+ T cell counts <200/μL (or a CD4 percentage <15) receive some form of PCP prophylaxis. The incidence of PCP is approaching zero in patients with known HIV infection receiving appropriate cART and prophylaxis. In the United States, primary PCP is now occurring at a median CD4+ T cell count of 36/μL, while secondary PCP is occurring at a median CD4+ T cell count of 10/μL. Patients with PCP generally present with fever and a cough that is usually nonproductive or productive of only scant amounts of white sputum. They may complain of a characteristic retrosternal chest pain that is worse on inspiration and is described as sharp or burning. HIV-associated PCP may have an indolent course characterized by weeks of vague symptoms and should be included in the differential diagnosis of fever, pulmonary complaints, or unexplained weight loss in any patient with HIV infection and <200 CD4+ T cells/μL. The most common finding on chest x-ray is either a normal film, if the disease is suspected early, or a faint bilateral interstitial infiltrate. The classic finding of a dense perihilar infiltrate is unusual in patients with AIDS. In patients with PCP who have been receiving aerosolized pentamidine for prophylaxis, one may see an x-ray picture of upper lobe cavitary disease, reminiscent of TB. Other less common findings on chest x-ray include lobar infiltrates and pleural effusions. Thin-section CT may demonstrate a patchy ground-glass appearance. Routine laboratory evaluation is usually of little help in the differential diagnosis of PCP. A mild leukocytosis is common, although this may not be obvious in patients with prior neutropenia. Elevation of lactate dehydrogenase is common. Arterial blood-gases may indicate hypoxemia with a decline in PaO2 and an increase in the arterial-alveolar (a–A) gradient. Arterial blood-gas measurements not only aid in making the diagnosis of PCP but also provide important information for staging the severity of the disease and directing treatment (see below). A definitive diagnosis of PCP requires demonstration of the organism in samples obtained from induced sputum, bronchoalveolar lavage, transbronchial biopsy, or open-lung biopsy. PCR has been used to detect specific DNA sequences for P. jiroveci in clinical specimens where histologic examinations have failed to make a diagnosis.
In addition to pneumonia, a number of other clinical problems have been reported in HIV-infected patients as a result of infection with P. jiroveci. Otic involvement may be seen as a primary infection, presenting as a polypoid mass involving the external auditory canal. In patients receiving aerosolized pentamidine for prophylaxis against PCP, one may see a variety of extrapulmonary manifestations of P. jiroveci. These include ophthalmic lesions of the choroid, a necrotizing vasculitis that resembles Burger's disease, bone marrow hypoplasia, and intestinal obstruction. Other organs that have been involved include lymph nodes, spleen, liver, kidney, pancreas, pericardium, heart, thyroid, and adrenals. Organ infection may be associated with cystic lesions that may appear calcified on CT or ultrasound.
The standard treatment for PCP or disseminated pneumocystosis is trimethoprim/sulfamethoxazole (TMP/SMX). A high (20–85%) incidence of side effects, particularly skin rash and bone marrow suppression, is seen with TMP/SMX in patients with HIV infection. Alternative treatments for mild to moderate PCP include dapsone/trimethoprim, clindamycin/primaquine, and atovaquone. IV pentamidine is the treatment of choice for severe disease in the patient unable to tolerate TMP/SMX. For patients with a PaO2 <70 mmHg or with an a–a gradient >35 mmHg, adjunct glucocorticoid therapy should be used in addition to specific antimicrobials. Overall, treatment should be continued for 21 days and followed by secondary prophylaxis. Prophylaxis for PCP is indicated for any HIV-infected individual who has experienced a prior bout of PCP, any patient with a CD4+ T cell count of <200/μL or a CD4 percentage <15, any patient with unexplained fever for >2 weeks, and any patient with a history of oropharyngeal candidiasis. The preferred regimen for prophylaxis is TMP/SMX, one double-strength tablet daily. This regimen also provides protection against toxoplasmosis and some bacterial respiratory pathogens. For patients who cannot tolerate TMP/SMX, alternatives for prophylaxis include dapsone plus pyrimethamine plus leucovorin, aerosolized pentamidine administered by the Respirgard II nebulizer, and atovaquone. Primary or secondary prophylaxis for PCP can be discontinued in those patients treated with cART who maintain good suppression of HIV (<50 copies per milliliter) and CD4+ T cell counts >200/μL for 3–6 months.
M. tuberculosis, once thought to be on its way to extinction in the United States, experienced a resurgence associated with the HIV epidemic (Chap. 165). Worldwide, approximately one-third of all AIDS-related deaths are associated with TB, and TB is the primary cause of death for 10–15% of patients with HIV infection. In the United States ∼5% of AIDS patients have active TB. Patients with HIV infection are more likely to have active TB by a factor of 100 when compared with an HIV-negative population. For an asymptomatic HIV-negative person with a positive purified protein derivative (PPD) skin test, the risk of reactivation TB is around 1% per year. For the patient with untreated HIV infection, a positive PPD skin test, and no signs or symptoms of TB, the rate of reactivation TB is 7–10% per year. Untreated TB can accelerate the course of HIV infection. Levels of plasma HIV RNA increase in the setting of active TB and decline in the setting of successful TB treatment. Active TB is most common in patients 25–44 years of age, in African Americans and Hispanics, in patients in New York City and Miami, and in patients in developing countries. In these demographic groups, 20–70% of the new cases of active TB are in patients with HIV infection. The epidemic of TB embedded in the epidemic of HIV infection probably represents the greatest health risk to the general public and the health care profession associated with the HIV epidemic. In contrast to infection with atypical mycobacteria such as MAC, active TB often develops relatively early in the course of HIV infection and may be an early clinical sign of HIV disease. In one study, the median CD4+ T cell count at presentation of TB was 326/μL. The clinical manifestations of TB in HIV-infected patients are quite varied and generally show different patterns as a function of the CD4+ T cell count. In patients with relatively high CD4+ T cell counts, the typical pattern of pulmonary reactivation occurs: patients present with fever, cough, dyspnea on exertion, weight loss, night sweats, and a chest x-ray revealing cavitary apical disease of the upper lobes. In patients with lower CD4+ T cell counts, disseminated disease is more common. In these patients the chest x-ray may reveal diffuse or lower lobe bilateral reticulonodular infiltrates consistent with miliary spread, pleural effusions, and hilar and/or mediastinal adenopathy. Infection may be present in bone, brain, meninges, GI tract, lymph nodes (particularly cervical lymph nodes), and viscera. Some patients with advanced HIV infection and active TB may have no symptoms of illness, and thus screening for TB should be part of the initial evaluation of every patient with HIV infection. Approximately 60–80% of HIV-infected patients with TB have pulmonary disease, and 30–40% have extrapulmonary disease. Respiratory isolation and a negative-pressure room should be used for patients in whom a diagnosis of pulmonary TB is being considered. This approach is critical to limit nosocomial and community spread of infection. Culture of the organism from an involved site provides a definitive diagnosis. Blood cultures are positive in 15% of patients. This figure is higher in patients with lower CD4 +T cell counts. In the setting of fulminant disease one cannot rely on the accuracy of a negative PPD skin test to rule out a diagnosis of TB. TB is one of the conditions associated with HIV infection for which cure is possible with appropriate therapy. Therapy for TB is generally the same in the HIV-infected patient as in the HIV-negative patient (Chap. 165). Due to the possibility of multidrug-resistant or extensively drug-resistant TB, drug susceptibility testing should be performed to guide therapy. Due to pharmacokinetic interactions, adjusted doses of rifabutin should be substituted for rifampin in patients receiving the HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Treatment is most effective in programs that involve directly observed therapy. Initiation of cART and/or anti-TB therapy may be associated with clinical deterioration due to immune reconstitution inflammatory syndrome (IRIS) reactions. These are most common in patients initiating both treatments at the same time, may occur as early as 1 week after initiation of therapy, and are seen more frequently in patients with advanced HIV disease. For these reasons it is often recommended that initiation of cART be delayed in antiretroviral-naïve patients until 2–8 weeks following the initiation of treatment for TB. Effective prevention of active TB can be a reality if the health care professional is aggressive in looking for evidence of latent or active TB by making sure that all patients with HIV infection receive a PPD skin test or evaluation with an IFN-γ release assay. Anergy testing is not of value in this setting. Since these tests rely on the host mounting an immune response to M. tuberculosis, patients with CD4+ T cell counts <200 cells/μL should be retested if their CD4+ T cell counts rise to persistently above 200. Patients at risk of continued exposure to TB should be tested annually. HIV-infected individuals with a skin-test reaction of >5 mm, those with a positive IFN-γ release assay, or those who are close household contacts of persons with active TB should receive treatment with 9 months of isoniazid and pyridoxine.
Atypical mycobacterial infections are also seen with an increased frequency in patients with HIV infection. Infections with at least 12 different mycobacteria have been reported, including M. bovis and representatives of all four Runyon groups. The most common atypical mycobacterial infection is with M. avium or M. intracellulare species—the Mycobacterium avium complex (MAC). Infections with MAC are seen mainly in patients in the United States and are rare in Africa. It has been suggested that prior infection with M. tuberculosis decreases the risk of MAC infection. MAC infections probably arise from organisms that are ubiquitous in the environment, including both soil and water. There is little evidence for person-to-person transmission of MAC infection. The presumed portals of entry are the respiratory and GI tract. MAC infection is a late complication of HIV infection, occurring predominantly in patients with CD4+ T cell counts of <50/μL. The average CD4+ T cell count at the time of diagnosis is 10/μL. The most common presentation is disseminated disease with fever, weight loss, and night sweats. At least 85% of patients with MAC infection are mycobacteremic, and large numbers of organisms can often be demonstrated on bone marrow biopsy. The chest x-ray is abnormal in ∼25% of patients, with the most common pattern being that of a bilateral, lower lobe infiltrate suggestive of miliary spread. Alveolar or nodular infiltrates and hilar and/or mediastinal adenopathy can also occur. Other clinical findings include endobronchial lesions, abdominal pain, diarrhea, and lymphadenopathy. Anemia and elevated liver alkaline phosphatase are common. The diagnosis is made by the culture of blood or involved tissue. The finding of two consecutive sputum samples positive for MAC is highly suggestive of pulmonary infection. Cultures may take 2 weeks to turn positive. Therapy consists of a macrolide, usually clarithromycin, with ethambutol. Some physicians elect to add a third drug from among rifabutin, ciprofloxacin, or amikacin in patients with extensive disease. Therapy was generally for life; however, with the use of cART it is possible to discontinue therapy in patients with sustained suppression of HIV replication and CD4+ T cell counts >100/μL for 3–6 months. Primary prophylaxis for MAC is indicated in patients with HIV infection and CD4+ T cell counts <50/μL (Table 189-10). This may be discontinued in patients in whom cART induces a sustained suppression of viral replication and increases in CD4+ T cell counts to >100/μL for ≥3 months.
Rhodococcus equi is a gram-positive, pleomorphic, acid-fast, non-spore-forming bacillus that can cause pulmonary and/or disseminated infection in patients with advanced HIV infection. Fever and cough are the most common presenting signs. Radiographically one may see cavitary lesions and consolidation. Blood cultures are often positive. Treatment is based on antimicrobial sensitivity testing.
Fungal infections of the lung, in addition to PCP, can be seen in patients with AIDS. Patients with pulmonary cryptococcal disease present with fever, cough, dyspnea, and, in some cases, hemoptysis. A focal or diffuse interstitial infiltrate is seen on chest x-ray in >90% of patients. In addition, one may see lobar disease, cavitary disease, pleural effusions, and hilar or mediastinal adenopathy. More than half of patients are fungemic, and 90% of patients have concomitant CNS infection. Coccidioides immitis is a mold that is endemic in the southwest United States. It can cause a reactivation pulmonary syndrome in patients with HIV infection. Most patients with this condition will have CD4+ T cell counts <250/μL. Patients present with fever, weight loss, cough, and extensive, diffuse reticulonodular infiltrates on chest x-ray. One may also see nodules, cavities, pleural effusions, and hilar adenopathy. While serologic testing is of value in the immunocompetent host, serologies are negative in 25% of HIV-infected patients with coccidioidal infection. Invasive aspergillosis is not an AIDS-defining illness and is generally not seen in patients with AIDS in the absence of neutropenia or administration of glucocorticoids. When it does occur, Aspergillus infection may have an unusual presentation in the respiratory tract of patients with AIDS, where it gives the appearance of a pseudomembranous tracheobronchitis. Primary pulmonary infection of the lung may be seen with histoplasmosis. The most common pulmonary manifestation of histoplasmosis, however, is in the setting of disseminated disease, presumably due to reactivation. In this setting respiratory symptoms are usually minimal, with cough and dyspnea occurring in 10–30% of patients. The chest x-ray is abnormal in ∼50% of patients, showing either a diffuse interstitial infiltrate or diffuse small nodules.
Two forms of idiopathic interstitial pneumonia have been identified in patients with HIV infection: lymphoid interstitial pneumonitis (LIP) and nonspecific interstitial pneumonitis (NIP). LIP, a common finding in children, is seen in about 1% of adult patients with untreated HIV infection. This disorder is characterized by a benign infiltrate of the lung and is thought to be part of the polyclonal activation of lymphocytes seen in the context of HIV and EBV infections. Transbronchial biopsy is diagnostic in 50% of the cases, with an open-lung biopsy required for diagnosis in the remainder of cases. This condition is generally self-limited and no specific treatment is necessary. Severe cases have been managed with brief courses of glucocorticoids. Although rarely a clinical problem since the use of cART, evidence of NIP may be seen in up to half of all patients with untreated HIV infection. Histologically, interstitial infiltrates of lymphocytes and plasma cells in a perivascular and peribronchial distribution are present. When symptomatic, patients present with fever and nonproductive cough occasionally accompanied by mild chest discomfort. Chest x-ray is usually normal or may reveal a faint interstitial pattern. Similar to LIP, NIP is a self-limited process for which no therapy is indicated other than appropriate management of the underlying HIV infection. HIV-related pulmonary arterial hypertension (HIV-PAH) is seen in ∼0.5% of HIV-infected individuals. Patients may present with an array of symptoms including shortness of breath, fatigue, syncope, chest pain, and signs of right-sided heart failure. Chest x-ray reveals dilated pulmonary vessels and right-sided cardiomegaly with right ventricular hypertrophy seen on electrocardiogram. cART does not appear to be of clear benefit, and the prognosis is quite poor with a median survival in the range of 2 years.
Neoplastic diseases of the lung including KS and lymphoma are discussed below in the section on neoplastic diseases.
Diseases of the Cardiovascular System
Heart disease is a relatively common postmortem finding in HIV-infected patients (25–75% in autopsy series). The most common form of heart disease is coronary heart disease. In one large series the overall rate of myocardial infarction (MI) was 3.5/1000 patient-years, 28% of these events were fatal, and MI was responsible for 7% of all deaths in the cohort. In patients with HIV infection, cardiovascular disease may be associated with classic risk factors such as smoking, a direct consequence of HIV infection, or a complication of cART. Patients with HIV infection have higher levels of triglycerides, lower levels of high-density lipoprotein cholesterol, and a higher prevalence of smoking than cohorts of individuals without HIV infection. The finding that the rate of cardiovascular disease events was lower in patients on antiretroviral therapy than in those randomized to undergo a treatment interruption identified a clear association between HIV replication and risk of cardiovascular disease. In one study, a baseline CD4+ T cell count of <500/μL was found to be an independent risk factor for cardiovascular disease comparable in magnitude to that attributable to smoking. While the precise pathogenesis of this association remains unclear, it is likely related to the immune activation and increased propensity for coagulation seen as a consequence of HIV replication. Exposure to HIV protease inhibitors and certain reverse transcriptase inhibitors has been associated with increases in total cholesterol and/or risk of MI. Any increases in the risk of death from MI resulting from the use of certain antiretrovirals must be balanced against the marked increases in overall survival brought about by these drugs.
Another form of heart disease associated with HIV infection is a dilated cardiomyopathy associated with congestive heart failure (CHF) referred to as HIV-associated cardiomyopathy. This generally occurs as a late complication of HIV infection and, histologically, displays elements of myocarditis. For this reason some have advocated treatment with IV immunoglobulin (IVIg). HIV can be directly demonstrated in cardiac tissue in this setting, and there is debate over whether it plays a direct role in this condition. Patients present with typical findings of CHF including edema and shortness of breath. Patients with HIV infection may also develop cardiomyopathy as side effects of IFN-α or nucleoside analogue therapy. These are reversible once therapy is stopped. KS, cryptococcosis, Chagas′ disease, and toxoplasmosis can involve the myocardium, leading to cardiomyopathy. In one series, most patients with HIV infection and a treatable myocarditis were found to have myocarditis associated with toxoplasmosis. Most of these patients also had evidence of CNS toxoplasmosis. Thus, MRI or double-dose contrast CT scan of the brain should be included in the workup of any patient with advanced HIV infection and cardiomyopathy.
A variety of other cardiovascular problems are found in patients with HIV infection. Pericardial effusions may be seen in the setting of advanced HIV infection. Predisposing factors include TB, CHF, mycobacterial infection, cryptococcal infection, pulmonary infection, lymphoma, and KS. While pericarditis is quite rare, in one series 5% of patients with HIV disease had pericardial effusions that were considered to be moderate or severe. Tamponade and death have occurred in association with pericardial KS, presumably owing to acute hemorrhage. Nonbacterial thrombotic endocarditis has been reported and should be considered in patients with unexplained embolic phenomena. Intravenous pentamidine, when given rapidly, can result in hypotension as a consequence of cardiovascular collapse.
Diseases of the Oropharynx and Gastrointestinal System
Oropharyngeal and GI diseases are common features of HIV infection. They are most frequently due to secondary infections. In addition, oral and GI lesions may occur with KS and lymphoma.
Oral lesions, including thrush, hairy leukoplakia, and aphthous ulcers (Fig. 189-35), are particularly common in patients with untreated HIV infection. Thrush, due to Candida infection, and oral hairy leukoplakia, presumed due to EBV, are usually indicative of fairly advanced immunologic decline; they generally occur in patients with CD4+ T cell counts of <300/μL. In one study, 59% of patients with oral candidiasis went on to develop AIDS in the next year. Thrush appears as a white, cheesy exudate, often on an erythematous mucosa in the posterior oropharynx. While most commonly seen on the soft palate, early lesions are often found along the gingival border. The diagnosis is made by direct examination of a scraping for pseudohyphal elements. Culturing is of no diagnostic value, as patients with HIV infection may have a positive throat culture for Candida in the absence of thrush. Oral hairy leukoplakia presents as white, frondlike lesions, generally along the lateral borders of the tongue and sometimes on the adjacent buccal mucosa (Fig. 189-35). Despite its name, oral hairy leukoplakia is not considered a premalignant condition. Lesions are associated with florid replication of EBV. While usually more disconcerting as a sign of HIV-associated immunodeficiency than a clinical problem in need of treatment, severe cases have been reported to respond to topical podophyllin or systemic therapy with anti-herpesvirus agents. Aphthous ulcers of the posterior oropharynx are also seen with regularity in patients with HIV infection (Fig. 189-35). These lesions are of unknown etiology and can be quite painful and interfere with swallowing. Topical anesthetics provide immediate symptomatic relief of short duration. The fact that thalidomide is an effective treatment for this condition suggests that the pathogenesis may involve the action of tissue-destructive cytokines. Palatal, glossal, or gingival ulcers may also result from cryptococcal disease or histoplasmosis.
Various oral lesions in HIV-infected individuals. A. Thrush. B. Hairy leukoplakia. C. Aphthous ulcer. D. Kaposi's sarcoma.
Esophagitis (Fig. 189-36) may present with odynophagia and retrosternal pain. Upper endoscopy is generally required to make an accurate diagnosis. Esophagitis may be due to Candida, CMV, or HSV. While CMV tends to be associated with a single large ulcer, HSV infection is more often associated with multiple small ulcers. The esophagus may also be the site of KS and lymphoma. Like the oral mucosa, the esophageal mucosa may have large, painful ulcers of unclear etiology that may respond to thalidomide. While achlorhydria is a common problem in patients with HIV infection, other gastric problems are generally rare. Among the neoplastic conditions involving the stomach are KS and lymphoma.
Barium swallow of a patient with Candida esophagitis. The flow of barium along the mucosal surface is grossly irregular.
Infections of the small and large intestine leading to diarrhea, abdominal pain, and occasionally fever are among the most significant GI problems in HIV-infected patients. They include infections with bacteria, protozoa, and viruses.
Bacteria may be responsible for secondary infections of the GI tract. Infections with enteric pathogens such as Salmonella, Shigella, and Campylobacter are more common in homosexual men and are often more severe and more apt to relapse in patients with HIV infection. Patients with untreated HIV have approximately a 20-fold increased risk of infection with S. typhimurium. They may present with a variety of nonspecific symptoms including fever, anorexia, fatigue, and malaise of several weeks′ duration. Diarrhea is common but may be absent. Diagnosis is made by culture of blood and stool. Long-term therapy with ciprofloxacin is the recommended treatment. HIV-infected patients also have an increased incidence of S. typhi infection in areas of the world where typhoid is a problem. Shigella spp., particularly S. flexneri, can cause severe intestinal disease in HIV-infected individuals. Up to 50% of patients will develop bacteremia. Campylobacter infections occur with an increased frequency in patients with HIV infection. While C. jejuni is the strain most frequently isolated, infections with many other strains have been reported. Patients usually present with crampy abdominal pain, fever, and bloody diarrhea. Infection may also present as proctitis. Stool examination reveals the presence of fecal leukocytes. Systemic infection can occur, with up to 10% of infected patients exhibiting bacteremia. Most strains are sensitive to erythromycin. Abdominal pain and diarrhea may be seen with MAC infection.
Fungal infections may also be a cause of diarrhea in patients with HIV infection. Histoplasmosis, coccidioidomycosis, and penicilliosis have all been identified as a cause of fever and diarrhea in patients with HIV infection. Peritonitis has been seen with C. immitis.
Cryptosporidia, microsporidia, and Isospora belli (Chap. 215) are the most common opportunistic protozoa that infect the GI tract and cause diarrhea in HIV-infected patients. Cryptosporidial infection may present in a variety of ways, ranging from a self-limited or intermittent diarrheal illness in patients in the early stages of HIV infection to a severe, life-threatening diarrhea in severely immunodeficient individuals. In patients with untreated HIV infection and CD4+ T cell counts of <300/μL, the incidence of cryptosporidiosis is ∼1% per year. In 75% of cases the diarrhea is accompanied by crampy abdominal pain, and 25% of patients have nausea and/or vomiting. Cryptosporidia may also cause biliary tract disease in the HIV-infected patient, leading to cholecystitis with or without accompanying cholangitis and pancreatitis secondary to papillary stenosis. The diagnosis of cryptosporidial diarrhea is made by stool examination or biopsy of the small intestine. The diarrhea is noninflammatory, and the characteristic finding is the presence of oocysts that stain with acid-fast dyes. Therapy is predominantly supportive, and marked improvements have been reported in the setting of effective cART. Treatment with up to 2000 mg/d of nitazoxanide (NTZ) is associated with improvement in symptoms or a decrease in shedding of organisms in about half of patients. Its overall role in the management of this condition remains unclear. Patients can minimize their risk of developing cryptosporidiosis by avoiding contact with human and animal feces, by not drinking untreated water from lakes or rivers, and by not eating raw shellfish.
Microsporidia are small, unicellular, obligate intracellular parasites that reside in the cytoplasm of enteric cells (Chap. 215). The main species causing disease in humans is Enterocytozoon bieneusi. The clinical manifestations are similar to those described for cryptosporidia and include abdominal pain, malabsorption, diarrhea, and cholangitis. The small size of the organism may make it difficult to detect; however, with the use of chromotrope-based stains, organisms can be identified in stool samples by light microscopy. Definitive diagnosis generally depends on electron-microscopic examination of a stool specimen, intestinal aspirate, or intestinal biopsy specimen. In contrast to cryptosporidia, microsporidia have been noted in a variety of extraintestinal locations, including the eye, brain, sinuses, muscle, and liver, and they have been associated with conjunctivitis and hepatitis. The most effective way to deal with microsporia in a patient with HIV infection is to restore the immune system by treating the HIV infection with cART. Albendazole, 400 mg bid, has been reported to be of benefit in some patients.
I. belli is a coccidian parasite (Chap. 215) most commonly found as a cause of diarrhea in patients from tropical and subtropical regions. Its cysts appear in the stool as large, acid-fast structures that can be differentiated from those of cryptosporidia on the basis of size, shape, and number of sporocysts. The clinical syndromes of Isospora infection are identical to those caused by cryptosporidia. The important distinction is that infection with Isospora is generally relatively easy to treat with TMP/SMX. While relapses are common, a thrice-weekly regimen of TMP/SMX appears adequate to prevent recurrence.
CMV colitis was once seen as a consequence of advanced immunodeficiency in 5–10% of patients with AIDS. It is much less common with the advent of cART. CMV colitis presents as diarrhea, abdominal pain, weight loss, and anorexia. The diarrhea is usually nonbloody, and the diagnosis is achieved through endoscopy and biopsy. Multiple mucosal ulcerations are seen at endoscopy, and biopsies reveal characteristic intranuclear and cytoplasmic inclusion bodies. Secondary bacteremias may result as a consequence of thinning of the bowel wall. Treatment is with either ganciclovir or foscarnet for 3–6 weeks. Relapses are common, and maintenance therapy is typically necessary in patients whose HIV infection is poorly controlled. Patients with CMV disease of the GI tract should be carefully monitored for evidence of CMV retinitis.
In addition to disease caused by specific secondary infections, patients with HIV infection may also experience a chronic diarrheal syndrome for which no etiologic agent other than HIV can be identified. This entity is referred to as AIDS enteropathy or HIV enteropathy. It is most likely a direct result of HIV infection in the GI tract. Histologic examination of the small bowel in these patients reveals low-grade mucosal atrophy with a decrease in mitotic figures, suggesting a hyporegenerative state. Patients often have decreased or absent small-bowel lactase and malabsorption with accompanying weight loss.
The initial evaluation of a patient with HIV infection and diarrhea should include a set of stool examinations, including culture, examination for ova and parasites, and examination for Clostridium difficile toxin. Approximately 50% of the time this workup will demonstrate infection with pathogenic bacteria, mycobacteria, or protozoa. If the initial stool examinations are negative, additional evaluation, including upper and/or lower endoscopy with biopsy, will yield a diagnosis of microsporidial or mycobacterial infection of the small intestine ∼30% of the time. In patients for whom this diagnostic evaluation is nonrevealing, a presumptive diagnosis of HIV enteropathy can be made if the diarrhea has persisted for >1 month. An algorithm for the evaluation of diarrhea in patients with HIV infection is given in Fig. 189-37.
Algorithm for the evaluation of diarrhea in a patient with HIV infection. HIV-associated enteropathy is a diagnosis of exclusion and can be made only after other, generally treatable, forms of diarrheal illness have been ruled out.
Rectal lesions are common in HIV-infected patients, particularly the perirectal ulcers and erosions due to the reactivation of HSV (Fig. 189-38). These lesions may appear quite atypical, as denuded skin without vesicles, and they respond well to treatment with acyclovir, famciclovir, or foscarnet. Other rectal lesions encountered in patients with HIV infection include condylomata acuminata, KS, and intraepithelial neoplasia (see below).
Severe, erosive perirectal herpes simplex in a patient with AIDS.
Diseases of the hepatobiliary system are a major problem in patients with HIV infection. It has been estimated that approximately one-third of the deaths of patients with HIV infection are in some way related to liver disease. While this is predominantly a reflection of the problems encountered in the setting of co-infection with hepatitis B or C, it is also a reflection of the hepatic injury, ranging from hepatic steatosis to hypersensitivity reactions to immune reconstitution, that can be seen in the context of cART.
The prevalence of co-infection with HIV and hepatitis viruses varies by geographic region. In the United States, ∼90% of HIV-infected individuals have evidence of infection with HBV; 6–14% have chronic HBV infection; 5–50% of current or past patients are co-infected with HCV; and co-infection with hepatitis D, E, and/or G viruses is common. Among IV drug users with HIV infection, rates of HCV infection range from 70 to 95%. HIV infection has a significant impact on the course of hepatitis virus infection. It is associated with approximately a threefold increase in the development of persistent hepatitis B surface antigenemia. Patients infected with both HBV and HIV have decreased evidence of inflammatory liver disease. The presumption that this is due to the immunosuppressive effects of HIV infection is supported by the observations that this situation can be reversed, and one may see the development of more severe hepatitis following the initiation of effective cART. In studies of the impact of HIV on HBV infection, four- to tenfold increases in liver-related mortality rates have been noted in patients with HIV and active HBV infection compared to rates in patients with either infection alone. There is, however, only a slight increase in overall mortality rate in HIV-infected individuals who are also hepatitis B surface antigen (HBsAg)–positive. IFN-α is less successful as a treatment of HBV in patients with HIV co-infection. Lamivudine, emtricitabine, adefovir/tenofovir/entecavir, and telbivudine alone or in combination are useful in the treatment of hepatitis B in patients with HIV infection. It is important to remember that all the above-mentioned drugs also have activity against HIV and should not be used alone in patients with HIV infection, in order to avoid the emergence quasispecies of HIV resistant to these drugs. For this reason, the need to treat hepatitis B infection in a patient with HIV infection is an indication to treat HIV infection in that same patient, regardless of CD4+ T cell count. HCV infection is more severe in the patient with HIV infection; it does not appear to affect overall mortality rate in HIV-infected individuals when other variables such as age, baseline CD4+ T cell count, and use of cART are taken into account. In the setting of HIV and HCV co-infection, levels of HCV are approximately tenfold higher than in the HIV-negative patient with HCV infection and there is a tenfold increased risk of death due to liver disease in co-infected patients. Treatment for HCV infection consists of pegylated IFN-α and ribavirin with an array of experimental therapies currently in clinical trials. If a 2-log drop in levels of HCV RNA is not seen within 12 weeks, it is unlikely that therapy will be of value. Hepatitis A virus infection is not seen with an increased frequency in patients with HIV infection. It is recommended that all patients with HIV infection who have not experienced natural infection be immunized with hepatitis A and/or hepatitis B vaccines. Infection with hepatitis G virus, also known as GB virus C, is seen in ∼50% of patients with HIV infection. For reasons that are currently unclear, there are data to suggest that patients with HIV infection co-infected with this virus have a decreased rate of progression to AIDS.
A variety of other infections may also involve the liver. Granulomatous hepatitis may be seen as a consequence of mycobacterial or fungal infections, particularly MAC infection. Hepatic masses may be seen in the context of TB, peliosis hepatis, or fungal infection. Among the fungal opportunistic infections, C. immitis and Histoplasma capsulatum are those most likely to involve the liver. Biliary tract disease in the form of papillary stenosis or sclerosing cholangitis has been reported in the context of cryptosporidiosis, CMV infection, and KS.
Many of the drugs used to treat HIV infection are metabolized by the liver and can cause liver injury. Fatal hepatic reactions have been reported with a wide array of antiretrovirals including nucleoside analogues, nonnucleoside analogues, and protease inhibitors. Nucleoside analogues work by inhibiting DNA synthesis. This can result in toxicity to mitochondria, which can lead to disturbances in oxidative metabolism. This may manifest as hepatic steatosis and, in severe cases, lactic acidosis and fulminant liver failure. It is important to be aware of this condition and to watch for it in patients with HIV infection receiving nucleoside analogues. It is reversible if diagnosed early and the offending agent(s) discontinued. Nevirapine has been associated with at times fatal fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure. Indinavir may cause mild to moderate elevations in serum bilirubin in 10–15% of patients in a syndrome similar to Gilbert's syndrome. A similar pattern of hepatic injury may be seen with atazanavir. In the patient receiving cART with an unexplained increase in hepatic transaminases, strong consideration should be given to drug toxicity. Pancreatic injury is most commonly a consequence of drug toxicity, notably that secondary to pentamidine or dideoxynucleosides. While up to half of patients in some series have biochemical evidence of pancreatic injury, <5% of patients show any clinical evidence of pancreatitis that is not linked to a drug toxicity.
Diseases of the Kidney and Genitourinary Tract
Diseases of the kidney or genitourinary tract may be a direct consequence of HIV infection, due to an opportunistic infection or neoplasm, or related to drug toxicity. Overall, microalbuminuria is seen in ∼20% of untreated HIV-infected patients; significant proteinuria is seen in closer to 2%. The presence of microalbuminuria has been associated with an increase in all-cause mortality rate. HIV-associated nephropathy (HIVAN) was first described in IDUs and was initially thought to be IDU nephropathy in patients with HIV infection; it is now recognized as a true direct complication of HIV infection. Although the majority of patients have CD4+ T cell counts <200/μL, HIV-associated nephropathy can be an early manifestation of HIV infection and is also seen in children. Over 90% of reported cases have been in African-American or Hispanic individuals; the disease is not only more prevalent in these populations but also more severe and is the third leading cause of end-stage renal failure among African Americans age 20–64 in the United States. Proteinuria is the hallmark of this disorder. Edema and hypertension are rare. Ultrasound examination reveals enlarged, hyperechogenic kidneys. A definitive diagnosis is obtained through renal biopsy. Histologically, focal segmental glomerulosclerosis is present in 80%, and mesangial proliferation in 10–15% of cases. Prior to effective antiretroviral therapy, this disease was characterized by relatively rapid progression to end-stage renal disease. Patients with HIV-associated nephropathy should be treated for their HIV infection regardless of CD4+ T cell count. Treatment with angiotensin-converting enzyme (ACE) inhibitors and/or prednisone, 60 mg/d, has also been reported to be of benefit in some cases. The incidence of this disease in patients receiving adequate cART has not been well defined; however, the impression is that it has decreased in frequency and severity. It is the leading cause of end-stage renal disease in patients with HIV infection.
Among the drugs commonly associated with renal damage in patients with HIV disease are pentamidine, amphotericin, adefovir, cidofovir, tenofovir, and foscarnet. TMP/SMX may compete for tubular secretion with creatinine and cause an increase in the serum creatinine level. Sulfadiazine may crystallize in the kidney and result in an easily reversible form of renal shutdown, while indinavir may form renal calculi. Adequate hydration is the mainstay of treatment and prevention for these latter two conditions.
Genitourinary tract infections are seen with a high frequency in patients with HIV infection; they present with skin lesions, dysuria, hematuria, and/or pyuria and are managed in the same fashion as in patients without HIV infection. Infections with HSV are covered below (“Dermatologic Diseases”). Infections with T. pallidum, the etiologic agent of syphilis, play an important role in the HIV epidemic. In HIV-negative individuals, genital syphilitic ulcers as well as the ulcers of chancroid are major predisposing factors for heterosexual transmission of HIV infection. While most HIV-infected individuals with syphilis have a typical presentation, a variety of formerly rare clinical problems may be encountered in the setting of dual infection. Among them are lues maligna, an ulcerating lesion of the skin due to a necrotizing vasculitis; unexplained fever; nephrotic syndrome; and neurosyphilis. The most common presentation of syphilis in the HIV-infected patient is that of condylomata lata, a form of secondary syphilis. Neurosyphilis may be asymptomatic or may present as acute meningitis, neuroretinitis, deafness, or stroke. The rate of neurosyphilis may be as high as 1% in patients with HIV infection, and one should consider a lumbar puncture to look for neurosyphilis in all patients with HIV infection and secondary syphilis. As a consequence of the immunologic abnormalities seen in the setting of HIV infection, diagnosis of syphilis through standard serologic testing may be challenging. On the one hand, a significant number of patients have false-positive Venereal Disease Research Laboratory (VDRL) tests due to polyclonal B cell activation. On the other hand, the development of a new positive VDRL may be delayed in patients with new infections, and the anti–fluorescent treponemal antibody (anti-FTA) test may be negative due to immunodeficiency. Thus, dark-field examination of appropriate specimens should be performed in any patient in whom syphilis is suspected, even if the patient has a negative VDRL. Similarly, any patient with a positive serum VDRL test, neurologic findings, and an abnormal spinal fluid examination should be considered to have neurosyphilis and treated accordingly, regardless of the CSF VDRL result. In any setting, patients treated for syphilis need to be carefully monitored to ensure adequate therapy. Approximately one-third of patients with HIV infection will experience a Jarisch-Herxheimer reaction upon initiation of therapy for syphilis.
Vulvovaginal candidiasis is a common problem in women with HIV infection. Symptoms include pruritus, discomfort, dyspareunia, and dysuria. Vulvar infection may present as a morbilliform rash that may extend to the thighs. Vaginal infection is usually associated with a white discharge, and plaques may be seen along an erythematous vaginal wall. Diagnosis is made by microscopic examination of the discharge for pseudohyphal elements in a 10% potassium hydroxide solution. Mild disease can be treated with topical therapy. More serious disease can be treated with fluconazole. Other causes of vaginitis include Trichomonas and mixed bacteria.
Diseases of the Endocrine System and Metabolic Disorders
A variety of endocrine and metabolic disorders are seen in the context of HIV infection. These may be a direct consequence of HIV infection, secondary to opportunistic infections or neoplasms, or related to medication side effects. Between 33 and 75% of patients with HIV infection receiving cART develop a syndrome often referred to as lipodystrophy, consisting of elevations in plasma triglycerides, total cholesterol, and apolipoprotein B, as well as hyperinsulinemia and hyperglycemia. Many of the patients have been noted to have a characteristic set of body habitus changes associated with fat redistribution, consisting of truncal obesity coupled with peripheral wasting (Fig. 189-39). Truncal obesity is apparent as an increase in abdominal girth related to increases in mesenteric fat, a dorsocervical fat pad (“buffalo hump”) reminiscent of patients with Cushing's syndrome, and enlargement of the breasts. The peripheral wasting, or lipoatrophy, is particularly noticeable in the face and buttocks and by the prominence of the veins in the legs. These changes may develop at any time ranging from ∼6 weeks to several years following the initiation of cART. Approximately 20% of the patients with HIV-associated lipodystrophy meet the criteria for the metabolic syndrome as defined by The International Diabetes Federation or The U.S. National Cholesterol Education Program Adult Treatment Panel III. The lipodystrophy syndrome has been reported in association with regimens containing a variety of different drugs, and while initially reported in the setting of protease inhibitor therapy, it appears that similar changes can also be induced by potent protease-sparing regimens. It has been suggested that the lipoatrophy changes are particularly severe in patients receiving the thymidine analogues stavudine and zidovudine. National Cholesterol Education Program (NCEP) guidelines should be followed in the management of these lipid abnormalities (Chap. 241). Due to concerns regarding drug interactions, the most commonly utilized lipid-lowering agents in this setting are gemfibrozil and atorvastatin.
Characteristics of lipodystrophy. A. Truncal obesity and buffalo hump. B. Facial wasting. C. Accumulation of intraabdominal fat on CT scan.
In addition to these abnormalities, patients with HIV infection treated with cART have been found to have an increased incidence of osteonecrosis or avascular necrosis of the hip and shoulders. In a study of asymptomatic patients, 4.4% were found to have evidence of osteonecrosis on MRI. This complication has been associated with the use of lipid-lowering agents, systemic glucocorticoids, or testosterone; bodybuilding exercise; alcohol consumption; and the presence of anticardiolipin antibodies. Osteoporosis has been reported in 7% of women with HIV infection, with 41% of women demonstrating some degree of osteopenia. In addition, lactic acidosis is associated with cART. This is most commonly seen with nucleoside analogue reverse transcriptase inhibitors and can be fatal (see below).
Patients with advanced HIV disease may develop hyponatremia due to the syndrome of inappropriate antidiuretic hormone (vasopressin) secretion (SIADH) as a consequence of increased free-water intake and decreased free-water excretion. SIADH is usually seen in conjunction with pulmonary or CNS disease. Low serum sodium may also be due to adrenal insufficiency; a concomitant high serum potassium should alert one to this possibility. Hyperkalemia may be secondary to adrenal insufficiency; HIV nephropathy; or medications, particularly trimethoprim and pentamidine. Hypokalemia may be seen in the setting of tenofovir therapy. Adrenal gland disease may be due to mycobacterial infections, CMV disease, cryptococcal disease, histoplasmosis, or ketoconazole toxicity. Iatrogenic Cushing's syndrome with suppression of the hypothalamic-pituitary-adrenal axis may be seen with the use of local glucocorticoids (injected or inhaled) in patients receiving ritonavir. This is due to inhibition of the hepatic enzyme CYP3A4 by ritonavir leading to prolongation of the glucocorticoid half-life.
Thyroid function may be altered in 10–15% of patients with HIV infection. Both hypo- and hyperthyroidism may be seen. The predominant abnormality is subclinical hypothyroidism. In the setting of cART, up to 10% of patients have been noted to have elevated thyroid-stimulating hormone levels, suggesting that this may be a manifestation of immune reconstitution. Immune-reconstitution Graves′ disease may occur as a late (9–48 months) complication of cART. In advanced HIV disease, infection of the thyroid gland may occur with opportunistic pathogens, including P. jiroveci, CMV, mycobacteria, Toxoplasma gondii, and Cryptococcus neoformans. These infections are generally associated with a nontender, diffuse enlargement of the thyroid gland. Thyroid function is usually normal. Diagnosis is made by fine-needle aspirate or open biopsy.
Depending on the severity of disease, HIV infection is associated with hypogonadism in 20–50% of men. While this is generally a complication of underlying illness, testicular dysfunction may also be a side effect of ganciclovir therapy. In some surveys, up to two-thirds of patients report decreased libido and one-third complain of erectile dysfunction. Androgen-replacement therapy should be considered in patients with symptomatic hypogonadism. HIV infection does not seem to have a significant effect on the menstrual cycle outside the setting of advanced disease.
Immunologic and Rheumatologic Diseases
Immunologic and rheumatologic disorders are common in patients with HIV infection and range from excessive immediate-type hypersensitivity reactions (Chap. 317) to an increase in the incidence of reactive arthritis (Chap. 325) to conditions characterized by a diffuse infiltrative lymphocytosis. The occurrence of these phenomena is an apparent paradox in the setting of the profound immunodeficiency and immunosuppression that characterizes HIV infection and reflects the complex nature of the immune system and its regulatory mechanisms.
Drug allergies are the most significant allergic reactions occurring in HIV-infected patients and appear to become more common as the disease progresses. They occur in up to 65% of patients who receive therapy with TMP/SMX for PCP. In general, these drug reactions are characterized by erythematous, morbilliform eruptions that are pruritic, tend to coalesce, and are often associated with fever. Nonetheless, ∼33% of patients can be maintained on the offending therapy, and thus these reactions are not an immediate indication to stop the drug. Anaphylaxis is extremely rare in patients with HIV infection, and patients who have a cutaneous reaction during a single course of therapy can still be considered candidates for future treatment or prophylaxis with the same agent. The one exception to this is the nucleoside analogue abacavir, where fatal hypersensitivity reactions have been reported with rechallenge. This hypersensitivity is strongly associated with the HLA-B5701 haplotype, and a hypersensitivity reaction to abacavir is an absolute contraindication to future therapy. For other agents, including TMP/SMX, desensitization regimens are moderately successful. While the mechanisms underlying these allergic-type reactions remain unknown, patients with HIV infection have been noted to have elevated IgE levels that increase as the CD4+ T cell count declines. The numerous examples of patients with multiple drug reactions suggest that a common pathway is involved.
HIV infection shares many similarities with a variety of autoimmune diseases, including a substantial polyclonal B cell activation that is associated with a high incidence of antiphospholipid antibodies, such as anticardiolipin antibodies, VDRL antibodies, and lupus-like anticoagulants. In addition, HIV-infected individuals have an increased incidence of antinuclear antibodies. Despite these serologic findings, there is no evidence that HIV-infected individuals have an increase in two of the more common autoimmune diseases, i.e., systemic lupus erythematosus and rheumatoid arthritis. In fact, it has been observed that these diseases may be somewhat ameliorated by the concomitant presence of HIV infection, suggesting that an intact CD4+ T cell limb of the immune response plays an integral role in the pathogenesis of these conditions. Similarly, there are anecdotal reports of patients with common variable immunodeficiency (Chap. 316), characterized by hypogammaglobulinemia, who have had a normalization of Ig levels following the development of HIV infection, suggesting a possible role for overactive CD4+ T cell immunity in certain forms of that syndrome. The one autoimmune disease that may occur with an increased frequency in patients with HIV infection is a variant of primary Sjögren's syndrome (Chap. 324). Patients with HIV infection may develop a syndrome consisting of parotid gland enlargement, dry eyes, and dry mouth that is associated with lymphocytic infiltrates of the salivary gland and lung. One also can see peripheral neuropathy, polymyositis, renal tubular acidosis, and hepatitis. In contrast to Sjögren's syndrome, in which the lymphocytic infiltrates are composed predominantly of CD4+ T cells, in patients with HIV infection the infiltrates are composed predominantly of CD8+ T cells. In addition, while patients with Sjögren's syndrome are mainly women who have autoantibodies to Ro and La and who frequently have HLA-DR3 or -B8 MHC haplotypes, HIV-infected individuals with this syndrome are usually African-American men who do not have anti-Ro or anti-La and who most often are HLA-DR5. This syndrome appears to be less common with the increased use of effective cART. The term diffuse infiltrative lymphocytosis syndrome (DILS) is used to describe this entity and to distinguish it from Sjögren's syndrome.
Approximately one-third of HIV-infected individuals experience arthralgias; furthermore, 5–10% are diagnosed as having some form of reactive arthritis, such as Reiter's syndrome or psoriatic arthritis as well as undifferentiated spondyloarthropathy (Chap. 325). These syndromes occur with increasing frequency as the competency of the immune system declines. This association may be related to an increase in the number of infections with organisms that may trigger a reactive arthritis with progressive immunodeficiency or to a loss of important regulatory T cells. Reactive arthritides in HIV-infected individuals generally respond well to standard treatment; however, therapy with methotrexate has been associated with an increase in the incidence of opportunistic infections and should be used with caution and only in severe cases.
HIV-infected individuals also experience a variety of joint problems without obvious cause that are referred to generically as HIV- or AIDS-associated arthropathy. This syndrome is characterized by subacute oligoarticular arthritis developing over a period of 1–6 weeks and lasting 6 weeks to 6 months. It generally involves the large joints, predominantly the knees and ankles, and is nonerosive with only a mild inflammatory response. X-rays of the joint are nonrevealing. Nonsteroidal anti-inflammatory drugs are only marginally helpful; however, relief has been noted with the use of intraarticular glucocorticoids. A second form of arthritis also thought to be secondary to HIV infection is called painful articular syndrome. This condition, reported as occurring in as many as 10% of AIDS patients, presents as an acute, severe, sharp pain in the affected joint. It affects primarily the knees, elbows, and shoulders; lasts 2–24 h; and may be severe enough to require narcotic analgesics. The cause of this arthropathy is unclear; however, it is thought to result from a direct effect of HIV on the joint. This condition is reminiscent of the fact that other lentiviruses, in particular the caprine arthritis-encephalitis virus, are capable of directly causing arthritis.
A variety of other immunologic or rheumatologic diseases have been reported in HIV-infected individuals, either de novo or in association with opportunistic infections or drugs. Using the criteria of widespread musculoskeletal pain of at least 3 months′ duration and the presence of at least 11 of 18 possible tender points by digital palpation, 11% of an HIV-infected cohort containing 55% IDUs were diagnosed as having fibromyalgia (Chap. 335). While the incidence of frank arthritis was less in this population than in other studied populations that consisted predominantly of men who have sex with men, these data support the concept that there are musculoskeletal problems that occur as a direct result of HIV infection. In addition there have been reports of leukocytoclastic vasculitis in the setting of zidovudine therapy. CNS angiitis and polymyositis have also been reported in HIV-infected individuals. Septic arthritis is surprisingly rare, especially given the increased incidence of staphylococcal bacteremias seen in this population. When septic arthritis has been reported, it has usually been due to Staphylococcus aureus, systemic fungal infection with C. neoformans, Sporothrix schenckii, or H. capsulatum or to systemic mycobacterial infection with M. tuberculosis, M. haemophilum, M. avium, or M. kansasii.
As noted above, 4.4% of patients with HIV infection were found to have some evidence of osteonecrosis by MRI during systematic screening of asymptomatic patients. The percentage of patients with symptomatic osteonecrosis has been estimated to be as high as 1%. While this problem was first recognized in the setting of cART, it has been difficult to establish a cause-and-effect relationship. Alcohol consumption and a history of glucocorticoid use have been particularly associated with this condition in patients with HIV infection.
Immune Reconstitution Inflammatory Syndrome (Iris)
Following the initiation of effective cART, a paradoxical worsening of preexisting, untreated, or partially treated opportunistic infections may be noted. One may also see exacerbations of pre-existing or the development of new autoimmune conditions following the initiation of antiretrovirals (Table 189-11). IRIS related to a pre-existing infection is often referred to as immune reconstitution disease (IRD) to distinguish it from the autoimmune manifestations of IRIS. IRD is particularly common in patients with underlying untreated mycobacterial or fungal infections. IRIS is seen in anywhere from 10 to 30% of patients, depending on the clinical setting, and is most common in patients starting therapy with CD4+ T cell counts <50 cells/μL who have a precipitous drop in HIV RNA levels following the initiation of cART. Signs and symptoms may appear anywhere from 2 weeks to 2 years after the initiation of cART and can include localized lymphadenitis, prolonged fever, pulmonary infiltrates, increased intracranial pressure, uveitis, sarcoidosis, and Graves′ disease. The clinical course can be protracted and severe cases can be fatal. The underlying mechanism appears to be related to a phenomenon similar to type IV hypersensitivity reactions and reflects the immediate improvements in immune function that occur as levels of HIV RNA drop and the immunosuppressive effects of HIV infection are controlled. In severe cases, the use of immunosuppressive drugs such as glucocorticoids may be required to blunt the inflammatory component of these reactions while specific antimicrobial therapy takes effect.
Table 189-11 Characteristics of Immune Reconstitution Inflammatory Syndrome (IRIS) |Favorite Table|Download (.pdf)
Table 189-11 Characteristics of Immune Reconstitution Inflammatory Syndrome (IRIS)
|• Paradoxical worsening of clinical condition is seen following the initiation of antiretroviral therapy|
|• Occurs weeks to months following the initiation of antiretroviral therapy|
|• Is most common in patients starting therapy with a CD4+ T cell count under 50/μL who experience a precipitous drop in viral load|
|• Is frequently seen in the setting of tuberculosis|
|• Can be fatal|
Diseases of the Hematopoietic System
Disorders of the hematopoietic system including lymphadenopathy, anemia, leukopenia, and/or thrombocytopenia are common throughout the course of HIV infection and may be the direct result of HIV, manifestations of secondary infections and neoplasms, or side effects of therapy (Table 189-12). Direct histologic examination and culture of lymph node or bone marrow tissue are often diagnostic. A significant percentage of bone marrow aspirates from patients with HIV infection have been reported to contain lymphoid aggregates, the precise significance of which is unknown. Initiation of cART will lead to reversal of most hematologic complications that are the direct result of HIV infection.
Table 189-12 Causes of Bone Marrow Suppression in Patients With HIV Infection |Favorite Table|Download (.pdf)
Table 189-12 Causes of Bone Marrow Suppression in Patients With HIV Infection
B19 parvovirus infection
Some patients, otherwise asymptomatic, may develop persistent generalized lymphadenopathy as an early clinical manifestation of HIV infection. This condition is defined as the presence of enlarged lymph nodes (>1 cm) in two or more extrainguinal sites for >3 months without an obvious cause. The lymphadenopathy is due to marked follicular hyperplasia in the node in response to HIV infection. The nodes are generally discrete and freely movable. This feature of HIV disease may be seen at any point in the spectrum of immune dysfunction and is not associated with an increased likelihood of developing AIDS. Paradoxically, a loss in lymphadenopathy or a decrease in lymph node size outside the setting of cART may be a prognostic marker of disease progression. In patients with CD4+ T cell counts >200/μL, the differential diagnosis of lymphadenopathy includes KS, TB, Castleman's disease, and lymphoma. In patients with more advanced disease, lymphadenopathy may also be due to atypical mycobacterial infection, toxoplasmosis, systemic fungal infection, or bacillary angiomatosis. While indicated in patients with CD4+ T cell counts <200/μL, lymph node biopsy is not indicated in patients with early-stage disease unless there are signs and symptoms of systemic illness, such as fever and weight loss, or unless the nodes begin to enlarge, become fixed, or coalesce. Monoclonal gammopathy of unknown significance (MGUS) (Chap. 111), defined as the presence of a serum monoclonal IgG, IgA, or IgM in the absence of a clear cause, has been reported in 3% of patients with HIV infection. The overall clinical significance of this finding in patients with HIV infection is unclear, although it has been associated with other viral infections, non-Hodgkin's lymphoma, and plasma cell malignancy.
Anemia is the most common hematologic abnormality in HIV-infected patients and, in the absence of a specific treatable cause, is independently associated with a poor prognosis. While generally mild, anemia can be quite severe and require chronic blood transfusions. Among the specific reversible causes of anemia in the setting of HIV infection are drug toxicity, systemic fungal and mycobacterial infections, nutritional deficiencies, and parvovirus B19 infections. Zidovudine may block erythroid maturation prior to its effects on other marrow elements. A characteristic feature of zidovudine therapy is an elevated mean corpuscular volume (MCV). Another drug used in patients with HIV infection that has a selective effect on the erythroid series is dapsone. This drug can cause a serious hemolytic anemia in patients who are deficient in glucose-6-phosphate dehydrogenase and can create a functional anemia in others through induction of methemoglobinemia. Folate levels are usually normal in HIV-infected individuals; however, vitamin B12 levels may be depressed as a consequence of achlorhydria or malabsorption. True autoimmune hemolytic anemia is rare, although ∼20% of patients with HIV infection may have a positive direct antiglobulin test as a consequence of polyclonal B cell activation. Infection with parvovirus B19 may also cause anemia. It is important to recognize this possibility given the fact that it responds well to treatment with IVIg. Erythropoietin levels in patients with HIV infection and anemia are generally lower than expected given the degree of anemia. Treatment with erythropoietin may result in an increase in hemoglobin levels. An exception to this is a subset of patients with zidovudine-associated anemia in whom erythropoietin levels may be quite high.
During the course of HIV infection, neutropenia may be seen in approximately half of patients. In most instances it is mild; however, it can be severe and can put patients at risk of spontaneous bacterial infections. This is most frequently seen in patients with severely advanced HIV disease and in patients receiving any of a number of potentially myelosuppressive therapies. In the setting of neutropenia, diseases that are not commonly seen in HIV-infected patients, such as aspergillosis or mucormycosis, may occur. Both granulocyte colony-stimulating factor (G-CSF) and GM-CSF increase neutrophil counts in patients with HIV infection regardless of the cause of the neutropenia. Earlier concerns about the potential of these agents to also increase levels of HIV were not confirmed in controlled clinical trials.
Thrombocytopenia may be an early consequence of HIV infection. Approximately 3% of patients with untreated HIV infection and CD4+ T cell counts ≥400/μL have platelet counts <150,000/μL. For untreated patients with CD4+ T cell counts <400/μL, this incidence increases to 10%. In patients receiving antiretrovirals, thrombocytopenia is associated with hepatitis C, cirrhosis, and ongoing high-level HIV replication. Thrombocytopenia is rarely a serious clinical problem in patients with HIV infection and generally responds well to successful cART. Clinically, it resembles the thrombocytopenia seen in patients with idiopathic thrombocytopenic purpura (Chap. 115). Immune complexes containing anti-gp120 antibodies and anti-anti-gp120 antibodies have been noted in the circulation and on the surface of platelets in patients with HIV infection. Patients with HIV infection have also been noted to have a platelet-specific antibody directed toward a 25-kDa component of the surface of the platelet. Other data suggest that the thrombocytopenia in patients with HIV infection may be due to a direct effect of HIV on megakaryocytes. Whatever the cause, it is very clear that the most effective medical approach to this problem has been the use of cART. For patients with platelet counts <20,000/μL a more aggressive approach combining IVIg or anti-Rh Ig for an immediate response with cART for a more lasting response is appropriate. Rituximab has been used with some success in otherwise refractory cases. Splenectomy is a rarely needed option and is reserved for patients refractory to medical management. Because of the risk of serious infection with encapsulated organisms, all patients with HIV infection about to undergo splenectomy should be immunized with pneumococcal polysaccharide. It should be noted that, in addition to causing an increase in the platelet count, removal of the spleen will result in an increase in the peripheral blood lymphocyte count, making CD4+ T cell counts unreliable markers of immunocompetence. In this setting, the clinician should rely on the CD4+ T cell percent for making diagnostic decisions with respect to the likelihood of opportunistic infections. A CD4+ T cell percent of 15 is approximately equivalent to a CD4+ T cell count of 200/μL. In patients with early HIV infection, thrombocytopenia has also been reported as a consequence of classic thrombotic thrombocytopenic purpura (Chap. 115). This clinical syndrome, consisting of fever, thrombocytopenia, hemolytic anemia, and neurologic and renal dysfunction, is a rare complication of early HIV infection. As in other settings, the appropriate management is the use of salicylates and plasma exchange. Other causes of thrombocytopenia include lymphoma, mycobacterial infections, and fungal infections.
The incidence of venous thromboembolic disease such as deep-vein thrombosis or pulmonary embolus is approximately 1% per year in patients with HIV infection. This is approximately 10 times higher than that seen in an age-matched population. Among the factors associated with clinical thrombosis are age over 45, history of an opportunistic infection, lower CD4 count, and estrogen use. Abnormalities of the coagulation cascade including decreased protein S activity, increases in factor VIII, anticardiolipin antibodies, or lupus-like anticoagulant have been reported in more than 50% of patients with HIV infection. The clinical significance of this increased propensity toward thromboembolic disease is likely reflected in the observation that elevations in d-dimer are strongly associated with all-cause mortality in patients with HIV infection (Table 189-8).
Dermatologic problems occur in >90% of patients with HIV infection. From the macular, roseola-like rash seen with the acute seroconversion syndrome to extensive end-stage KS, cutaneous manifestations of HIV disease can be seen throughout the course of HIV infection. Among the more common nonneoplastic problems are seborrheic dermatitis, folliculitis, and opportunistic infections. Extrapulmonary pneumocystosis may cause a necrotizing vasculitis. Neoplastic conditions are covered below.
Seborrheic dermatitis occurs in 3% of the general population and in up to 50% of patients with HIV infection. Seborrheic dermatitis increases in prevalence and severity as the CD4+ T cell count declines. In HIV-infected patients, seborrheic dermatitis may be aggravated by concomitant infection with Pityrosporum, a yeastlike fungus; use of topical antifungal agents has been recommended in cases refractory to standard topical treatment.
Folliculitis is among the most prevalent dermatologic disorders in patients with HIV infection and is seen in ∼20% of patients. It is more common in patients with CD4+ T cell counts <200 cells/μL. Pruritic papular eruption is one of the most common pruritic rashes in patients with HIV infection. It appears as multiple papules on the face, trunk, and extensor surfaces and may improve with cART. Eosinophilic pustular folliculitis is a rare form of folliculitis that is seen with increased frequency in patients with HIV infection. It presents as multiple, urticarial perifollicular papules that may coalesce into plaquelike lesions. Skin biopsy reveals an eosinophilic infiltrate of the hair follicle, which in certain cases has been associated with the presence of a mite. Patients typically have an elevated serum IgE level and may respond to treatment with topical anthelmintics. Pruritus is a common symptom in patients with HIV infection and can lead to prurigo nodularis. Patients with HIV infection have also been reported to develop a severe form of Norwegian scabies with hyperkeratotic psoriasiform lesions.
Both psoriasis and ichthyosis, although they are not reported to be increased in frequency, may be particularly severe when they occur in patients with HIV infection. Preexisting psoriasis may become guttate in appearance and more refractory to treatment in the setting of HIV infection.
Reactivation herpes zoster (shingles) is seen in 10–20% of patients with HIV infection. This reactivation syndrome of varicella-zoster virus indicates a modest decline in immune function and may be the first indication of clinical immunodeficiency. In one series, patients who developed shingles did so an average of 5 years after HIV infection. In a cohort of patients with HIV infection and localized zoster, the subsequent rate of the development of AIDS was 1% per month. In that study, AIDS was more likely to develop if the outbreak of zoster was associated with severe pain, extensive skin involvement, or involvement of cranial or cervical dermatomes. The clinical manifestations of reactivation zoster in HIV-infected patients, although indicative of immunologic compromise, are not as severe as those seen in other immunodeficient conditions. Thus, while lesions may extend over several dermatomes, involve the spinal cord, and/or be associated with frank cutaneous dissemination, visceral involvement has not been reported. In contrast to patients without a known underlying immunodeficiency state, patients with HIV infection tend to have recurrences of zoster with a relapse rate of ∼20%. Valacyclovir, acyclovir or famciclovir is the treatment of choice. Foscarnet may be of value in patients with acyclovir-resistant virus.
Infection with herpes simplex virus in HIV-infected individuals is associated with recurrent orolabial, genital, and perianal lesions as part of recurrent reactivation syndromes (Chap. 179). As HIV disease progresses and the CD4+ T cell count declines, these infections become more frequent and severe. Lesions often appear as beefy red, are exquisitely painful, and have a tendency to occur high in the gluteal cleft (Fig. 189-38). Perirectal HSV may be associated with proctitis and anal fissures. HSV should be high in the differential diagnosis of any HIV-infected patient with a poorly healing, painful perirectal lesion. In addition to recurrent mucosal ulcers, recurrent HSV infection in the form of herpetic whitlow can be a problem in patients with HIV infection, presenting with painful vesicles or extensive cutaneous erosion. Valacyclovir, acyclovir or famciclovir is the treatment of choice in these settings. Of note is the fact that even subclinical reactivation of herpes simplex may be associated with increases in plasma HIV RNA levels.
Diffuse skin eruptions due to Molluscum contagiosum may be seen in patients with advanced HIV infection. These flesh-colored, umbilicated lesions may be treated with local therapy. They tend to regress with effective cART. Similarly, condyloma acuminatum lesions may be more severe and more widely distributed in patients with low CD4+ T cell counts. Imiquimod cream may be helpful in some cases. Atypical mycobacterial infections may present as erythematous cutaneous nodules, as may fungal infections, Bartonella, Acanthamoeba, and KS.
The skin of patients with HIV infection is often a target organ for drug reactions (Chap. 55). Although most skin reactions are mild and not necessarily an indication to discontinue therapy, patients may have particularly severe cutaneous reactions, including erythroderma, Stevens-Johnson syndrome, and toxic epidermal necrolysis, as a reaction to drugs—particularly sulfa drugs, the nonnucleoside reverse transcriptase inhibitors, abacavir, amprenavir, darunavir, fosamprenavir, and tipranavir. Similarly, patients with HIV infection are often quite photosensitive and burn easily following exposure to sunlight or as a side effect of radiation therapy (Chap. 56).
HIV infection and its treatment may be accompanied by cosmetic changes of the skin that are not of great clinical importance but may be troubling to patients. Yellowing of the nails and straightening of the hair, particularly in African-American patients, have been reported as a consequence of HIV infection. Zidovudine therapy has been associated with elongation of the eyelashes and the development of a bluish discoloration to the nails, again more common in African-American patients. Therapy with clofazimine may cause a yellow-orange discoloration of the skin and urine.
Clinical disease of the nervous system accounts for a significant degree of morbidity in a high percentage of patients with HIV infection (Table 189-13). The neurologic problems that occur in HIV-infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to opportunistic infections or neoplasms (see above). Among the more frequent opportunistic diseases that involve the CNS are toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma. Other less common problems include mycobacterial infections; syphilis; and infection with CMV, HTLV-I, Trypanosoma cruzi, or Acanthamoeba. Overall, secondary diseases of the CNS have been reported to occur in approximately one-third of patients with AIDS. These data antedate the widespread use of cART, and this frequency is considerably lower in patients receiving effective antiretroviral drugs. Primary processes related to HIV infection of the nervous system are reminiscent of those seen with other lentiviruses, such as the Visna-Maedi virus of sheep.
Table 189-13 Neurologic Diseases in Patients With HIV Infection |Favorite Table|Download (.pdf)
Table 189-13 Neurologic Diseases in Patients With HIV Infection
- Progressive multifocal leukoencephalopathy
- Mycobacterium tuberculosis
- HTLV-I infection
- Primary CNS lymphoma
- Kaposi's sarcoma
Result of HIV-1 infection
- Aseptic meningitis
- HIV-associated neurocognitive disorders, including HIV encephalopathy/AIDS dementia complex
- Vacuolar myelopathy
- Pure sensory ataxia
- Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
- Mononeuritis multiplex
- Distal symmetric polyneuropathy
Neurologic problems directly attributable to HIV occur throughout the course of infection and may be inflammatory, demyelinating, or degenerative in nature. The term HIV-associated neurocognitive disorders (HAND) is used to describe a spectrum of disorders that range from asymptomatic neurocognitive impairment (ANI) to minor neurocognitive disorder (MND) to clinically severe dementia. The most severe form, HIV-associated dementia (HAD), also referred to as the AIDS dementia complex, or HIV encephalopathy, is considered an AIDS-defining illness. Most HIV-infected patients have some neurologic problem during the course of their disease. Even in the setting of suppressive cART, approximately 50% of HIV-infected individuals can be shown to have mild to moderate neurocognitive impairment using sensitive neuropsychiatric testing. As noted in the section on pathogenesis, damage to the CNS may be a direct result of viral infection of the CNS macrophages or glial cells or may be secondary to the release of neurotoxins and potentially toxic cytokines such as IL-1β, TNF-α, IL-6, and TGF-β. It has been reported that HIV-infected individuals with the E4 allele for apo E are at increased risk for AIDS encephalopathy and peripheral neuropathy. Virtually all patients with HIV infection have some degree of nervous system involvement with the virus. This is evidenced by the fact that CSF findings are abnormal in ∼90% of patients, even during the asymptomatic phase of HIV infection. CSF abnormalities include pleocytosis (50–65% of patients), detection of viral RNA (∼75%), elevated CSF protein (35%), and evidence of intrathecal synthesis of anti-HIV antibodies (90%). It is important to point out that evidence of infection of the CNS with HIV does not imply impairment of cognitive function. The neurologic function of an HIV-infected individual should be considered normal unless clinical signs and symptoms suggest otherwise.
Aseptic meningitis may be seen in any but the very late stages of HIV infection. In the setting of acute primary infection, patients may experience a syndrome of headache, photophobia, and meningismus. Rarely, an acute encephalopathy due to encephalitis may occur. Cranial nerve involvement may be seen, predominantly cranial nerve VII but occasionally V and/or VIII. CSF findings include a lymphocytic pleocytosis, elevated protein level, and normal glucose level. This syndrome, which cannot be clinically differentiated from other viral meningitides (Chap. 382), usually resolves spontaneously within 2–4 weeks; however, in some patients, signs and symptoms may become chronic. Aseptic meningitis may occur any time in the course of HIV infection; however, it is rare following the development of AIDS. This fact suggests that clinical aseptic meningitis in the context of HIV infection is an immune-mediated disease.
C. neoformans is the leading infectious cause of meningitis in patients with AIDS (Chap. 202). It is the initial AIDS-defining illness in ∼2% of patients and generally occurs in patients with CD4+ T cell counts <100/μL. Cryptococcal meningitis is particularly common in untreated patients with AIDS in Africa, occurring in ∼5% of patients. Most patients present with a picture of subacute meningoencephalitis with fever, nausea, vomiting, altered mental status, headache, and meningeal signs. The incidence of seizures and focal neurologic deficits is low. The CSF profile may be normal or may show only modest elevations in WBC or protein levels and decreases in glucose. The opening pressure in the CSF is usually elevated. In addition to meningitis, patients may develop cryptococcomas and cranial nerve involvement. Approximately one-third of patients also have pulmonary disease. Uncommon manifestations of cryptococcal infection include skin lesions that resemble molluscum contagiosum, lymphadenopathy, palatal and glossal ulcers, arthritis, gastroenteritis, myocarditis, and prostatitis. The prostate gland may serve as a reservoir for smoldering cryptococcal infection. The diagnosis of cryptococcal meningitis is made by identification of organisms in spinal fluid with india ink examination or by the detection of cryptococcal antigen. Blood cultures for fungus are often positive. A biopsy may be needed to make a diagnosis of CNS cryptococcoma. Treatment is with IV amphotericin B 0.7 mg/kg daily, or liposomal amphotericin 4–6 mg/kg daily, with flucytosine 25 mg/kg qid for at least 2 weeks and, if possible, until the CSF culture turns negative. This is followed by fluconazole 400 mg/d PO for 8 weeks, and then fluconazole 200 mg/d until the CD4+ T cell count has increased to >200 cells/μL for 6 months in response to cART. Repeated lumbar puncture may be required to manage increased intracranial pressure. Symptoms may recur with initiation of cART as an immune reconstitution syndrome (see above). Other fungi that may cause meningitis in patients with HIV infection are C. immitis and H. capsulatum. Meningoencephalitis has also been reported due to Acanthamoeba or Naegleria.
HIV-associated dementia consists of a constellation of signs and symptoms of CNS disease. While this is generally a late complication of HIV infection that progresses slowly over months, it can be seen in patients with CD4+ T cell counts >350 cells/μL. A major feature of this entity is the development of dementia, defined as a decline in cognitive ability from a previous level. It may present as impaired ability to concentrate, increased forgetfulness, difficulty reading, or increased difficulty performing complex tasks. Initially these symptoms may be indistinguishable from findings of situational depression or fatigue. In contrast to “cortical” dementia (such as Alzheimer's disease), aphasia, apraxia, and agnosia are uncommon, leading some investigators to classify HIV encephalopathy as a “subcortical dementia” characterized by defects in short-term memory and executive function (see below). In addition to dementia, patients with HIV encephalopathy may also have motor and behavioral abnormalities. Among the motor problems are unsteady gait, poor balance, tremor, and difficulty with rapid alternating movements. Increased tone and deep tendon reflexes may be found in patients with spinal cord involvement. Late stages may be complicated by bowel and/or bladder incontinence. Behavioral problems include apathy, irritability, and lack of initiative, with progression to a vegetative state in some instances. Some patients develop a state of agitation or mild mania. These changes usually occur without significant changes in level of alertness. This is in contrast to the finding of somnolence in patients with dementia due to toxic/metabolic encephalopathies.
HIV-associated dementia is the initial AIDS-defining illness in ∼3% of patients with HIV infection and thus only rarely precedes clinical evidence of immunodeficiency. Clinically significant encephalopathy eventually develops in ∼25% of untreated patients with AIDS. As immunologic function declines, the risk and severity of HIV-associated dementia increases. Autopsy series suggest that 80–90% of patients with HIV infection have histologic evidence of CNS involvement. Several classification schemes have been developed for grading HIV encephalopathy; a commonly used clinical staging system is outlined in Table 189-14.
Table 189-14 Clinical Staging of HIV Encephalopathy (AIDS Dementia Complex) |Favorite Table|Download (.pdf)
Table 189-14 Clinical Staging of HIV Encephalopathy (AIDS Dementia Complex)
|0 (Normal)||Normal mental and motor function.|
|0.5 (Equivocal/subclinical)||Absent, minimal, or equivocal symptoms without impairment of work or capacity to perform activities of daily living. Mild signs (snout response, slowed ocular or extremity movements) may be present. Gait and strength are normal.|
|1 (Mild)||Able to perform all but the more demanding aspects of work or activities of daily living but with unequivocal evidence (signs or symptoms that may include performance on neuropsychological testing) of functional, intellectual, or motor impairment. Can walk without assistance.|
|2 (Moderate)||Able to perform basic activities of self-care but cannot work or maintain the more demanding aspects of daily life. Ambulatory, but may require a single prop.|
|3 (Severe)||Major intellectual incapacity (cannot follow news or personal events, cannot sustain complex conversation, considerable slowing of all output) or motor disability (cannot walk unassisted, usually with slowing and clumsiness of arms as well).|
|4 (End-stage)||Nearly vegetative. Intellectual and social comprehension and output are at a rudimentary level. Nearly or absolutely mute. Paraparetic or paraplegic with urinary and fecal incontinence.|
The precise cause of HIV-associated dementia remains unclear, although the condition is thought to be a result of a combination of direct effects of HIV on the CNS and associated immune activation. HIV has been found in the brains of patients with HIV encephalopathy by Southern blot, in situ hybridization, PCR, and electron microscopy. Multinucleated giant cells, macrophages, and microglial cells appear to be the main cell types harboring virus in the CNS. Histologically, the major changes are seen in the subcortical areas of the brain and include pallor and gliosis, multinucleated giant cell encephalitis, and vacuolar myelopathy. Less commonly, diffuse or focal spongiform changes occur in the white matter. Areas of the brain involved in motor, language, and judgment are most severely affected.
There are no specific criteria for a diagnosis of HIV-associated dementia, and this syndrome must be differentiated from a number of other diseases that affect the CNS of HIV-infected patients (Table 189-13). The diagnosis of dementia depends on demonstrating a decline in cognitive function. This can be accomplished objectively with the use of a Mini-Mental Status Examination (MMSE) in patients for whom prior scores are available. For this reason, it is advisable for all patients with a diagnosis of HIV infection to have a baseline MMSE. However, changes in MMSE scores may be absent in patients with mild HIV encephalopathy. Imaging studies of the CNS, by either MRI or CT, often demonstrate evidence of cerebral atrophy (Fig. 189-40). MRI may also reveal small areas of increased density on T2-weighted images. Lumbar puncture is an important element of the evaluation of patients with HIV infection and neurologic abnormalities. It is generally most helpful in ruling out or making a diagnosis of opportunistic infections. In HIV encephalopathy, patients may have the nonspecific findings of an increase in CSF cells and protein level. While HIV RNA can often be detected in the spinal fluid and HIV can be cultured from the CSF, this finding is not specific for HIV encephalopathy. There appears to be no correlation between the presence of HIV in the CSF and the presence of HIV encephalopathy. Elevated levels of macrophage chemoattractant protein (MCP-1), β2-microglobulin, neopterin, and quinolinic acid (a metabolite of tryptophan reported to cause CNS injury) have been noted in the CSF of patients with HIV encephalopathy. These findings suggest that these factors as well as inflammatory cytokines may be involved in the pathogenesis of this syndrome.
AIDS dementia complex. Postcontrast CT scan through the lateral ventricles of a 47-year-old man with AIDS, altered mental status, and dementia. The lateral and third ventricles and the cerebral sulci are abnormally prominent. Mild white matter hypodensity is also seen adjacent to the frontal horns of the lateral ventricles.
Combination antiretroviral therapy is of benefit in patients with HIV-associated dementia. Improvement in neuropsychiatric test scores has been noted for both adult and pediatric patients treated with antiretrovirals. The rapid improvement in cognitive function noted with the initiation of cART suggests that at least some component of this problem is quickly reversible, again supporting at least a partial role of soluble mediators in the pathogenesis. It should also be noted that these patients have an increased sensitivity to the side effects of neuroleptic drugs. The use of these drugs for symptomatic treatment is associated with an increased risk of extrapyramidal side effects; therefore, patients with HIV encephalopathy who receive these agents must be monitored carefully. It is felt by many physicians that the decrease in the prevalence of severe cases of HAND brought about by cART has resulted in an increase in the prevalence of milder forms of this disorder.
Seizures may be a consequence of opportunistic infections, neoplasms, or HIV encephalopathy (Table 189-15). The seizure threshold is often lower than normal in patients with advanced HIV infection due to the frequent presence of electrolyte abnormalities. Seizures are seen in 15–40% of patients with cerebral toxoplasmosis, 15–35% of patients with primary CNS lymphoma, 8% of patients with cryptococcal meningitis, and 7–50% of patients with HIV encephalopathy. Seizures may also be seen in patients with CNS tuberculosis, aseptic meningitis, and progressive multifocal leukoencephalopathy. Seizures may be the presenting clinical symptom of HIV disease. In one study of 100 patients with HIV infection presenting with a first seizure, cerebral mass lesions were the most common cause, responsible for 32 of the 100 new-onset seizures. Of these 32 cases, 28 were due to toxoplasmosis and 4 to lymphoma. HIV encephalopathy accounted for an additional 24 new-onset seizures. Cryptococcal meningitis was the third most common diagnosis, responsible for 13 of the 100 seizures. In 23 cases, no cause could be found, and it is possible that these cases represent a subcategory of HIV encephalopathy. Of these 23 cases, 16 (70%) had two or more seizures, suggesting that anticonvulsant therapy is indicated in all patients with HIV infection and seizures unless a rapidly correctable cause is found. While phenytoin remains the initial treatment of choice, hypersensitivity reactions to this drug have been reported in >10% of patients with AIDS, and therefore the use of phenobarbital or valproic acid must be considered as alternatives. Due to a variety of drug-drug interactions between antiseizure medications and antiretrovirals, drug levels need to be monitored carefully.
Table 189-15 Causes of Seizures in Patients With HIV Infection |Favorite Table|Download (.pdf)
Table 189-15 Causes of Seizures in Patients With HIV Infection
|Disease||Overall Contribution to First Seizure, %||Fraction of Patients Who Have Seizures, %|
|Primary central nervous system lymphoma||4||15–30|
|Progressive multifocal leukoencephalopathy||1|
Patients with HIV infection may present with focal neurologic deficits from a variety of causes. The most common causes are toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma. Other causes include cryptococcal infections (discussed above; also Chap. 202), stroke, and reactivation of Chagas′ disease.
Toxoplasmosis has been one of the most common causes of secondary CNS infections in patients with AIDS, but its incidence is decreasing in the era of cART. It is most common in patients from the Caribbean and from France, where the seroprevalence of T. gondii is around 50%. This figure is closer to 15% in the United States. Toxoplasmosis is generally a late complication of HIV infection and usually occurs in patients with CD4+ T cell counts <200/μL. Cerebral toxoplasmosis is thought to represent a reactivation of latent tissue cysts. It is 10 times more common in patients with antibodies to the organism than in patients who are seronegative. Patients diagnosed with HIV infection should be screened for IgG antibodies to T. gondii during the time of their initial workup. Those who are seronegative should be counseled about ways to minimize the risk of primary infection including avoiding the consumption of undercooked meat and careful hand washing after contact with soil or changing the cat litter box. The most common clinical presentation of cerebral toxoplasmosis in patients with HIV infection is fever, headache, and focal neurologic deficits. Patients may present with seizure, hemiparesis, or aphasia as a manifestation of these focal deficits or with a picture more influenced by the accompanying cerebral edema and characterized by confusion, dementia, and lethargy, which can progress to coma. The diagnosis is usually suspected on the basis of MRI findings of multiple lesions in multiple locations, although in some cases only a single lesion is seen. Pathologically, these lesions generally exhibit inflammation and central necrosis and, as a result, demonstrate ring enhancement on contrast MRI (Fig. 189-41) or, if MRI is unavailable or contraindicated, on double-dose contrast CT. There is usually evidence of surrounding edema. In addition to toxoplasmosis, the differential diagnosis of single or multiple enhancing mass lesions in the HIV-infected patient includes primary CNS lymphoma and, less commonly, TB or fungal or bacterial abscesses. The definitive diagnostic procedure is brain biopsy. However, given the morbidity rate that can accompany this procedure, it is usually reserved for the patient who has failed 2–4 weeks of empiric therapy. If the patient is seronegative for T. gondii, the likelihood that a mass lesion is due to toxoplasmosis is <10%. In that setting, one may choose to be more aggressive and perform a brain biopsy sooner. Standard treatment is sulfadiazine and pyrimethamine with leucovorin as needed for a minimum of 4–6 weeks. Alternative therapeutic regimens include clindamycin in combination with pyrimethamine; atovaquone plus pyrimethamine; and azithromycin plus pyrimethamine plus rifabutin. Relapses are common, and it is recommended that patients with a history of prior toxoplasmic encephalitis receive maintenance therapy with sulfadiazine, pyrimethamine, and leucovorin as long as their CD4+ T cell counts remain <200 cells/μL. Patients with CD4+ T cell counts <100/μL and IgG antibody to Toxoplasma should receive primary prophylaxis for toxoplasmosis. Fortunately, the same daily regimen of a single double-strength tablet of TMP/SMX used for P. jiroveci prophylaxis provides adequate primary protection against toxoplasmosis. Secondary prophylaxis/maintenance therapy for toxoplasmosis may be discontinued in the setting of effective cART and increases in CD4+ T cell counts to >200/μL for 6 months.
Central nervous system toxoplasmosis. A coronal postcontrast T1-weighted MRI scan demonstrates a peripheral enhancing lesion in the left frontal lobe, associated with an eccentric nodular area of enhancement (arrow); this so-called eccentric target sign is typical of toxoplasmosis.
JC virus, a human polyomavirus that is the etiologic agent of progressive multifocal leukoencephalopathy (PML), is an important opportunistic pathogen in patients with AIDS (Chap. 381). While ∼80% of the general adult population has antibodies to JC virus, indicative of prior infection, <10% of healthy adults show any evidence of ongoing viral replication. PML is the only known clinical manifestation of JC virus infection. It is a late manifestation of AIDS and is seen in ∼4% of patients with AIDS. The lesions of PML begin as small foci of demyelination in subcortical white matter that eventually coalesce. The cerebral hemispheres, cerebellum, and brainstem may all be involved. Patients typically have a protracted course with multifocal neurologic deficits, with or without changes in mental status. Approximately 20% of patients experience seizures. Ataxia, hemiparesis, visual field defects, aphasia, and sensory defects may occur. Headache, fever, nausea, and vomiting are rarely seen. Their presence should suggest another diagnosis. MRI typically reveals multiple, nonenhancing white matter lesions that may coalesce and have a predilection for the occipital and parietal lobes. The lesions show signal hyperintensity on T2-weighted images and diminished signal on T1-weighted images. The measurement of JC virus DNA levels in CSF has a diagnostic sensitivity of 76% and a specificity of close to 100%. Prior to the availability of cART, the majority of patients with PML died within 3–6 months of the onset of symptoms. Paradoxical worsening of PML has been seen with initiation of cART as an immune reconstitution syndrome. There is no specific treatment for PML; however, a median survival of 2 years and survival of >15 years have been reported in patients with PML treated with cART for their HIV disease. Despite having a significant impact on survival, only ∼50% of patients with HIV infection and PML show neurologic improvement with cART. Studies with other antiviral agents such as cidofovir have failed to show clear benefit. Factors influencing a favorable prognosis for PML in the setting of HIV infection include a CD4+ T cell count >100/μL at baseline and the ability to maintain an HIV viral load of <500 copies per milliliter. Baseline HIV-1 viral load does not have independent predictive value of survival. PML is one of the few opportunistic infections that continues to occur with some frequency despite the widespread use of cART.
Reactivation American trypanosomiasis may present as acute meningoencephalitis with focal neurologic signs, fever, headache, vomiting, and seizures. Accompanying cardiac disease in the form of arrhythmias or heart failure should increase the index of suspicion. The presence of antibodies to T. cruzi supports the diagnosis. In South America, reactivation of Chagas′ disease is considered to be an AIDS-defining condition and may be the initial AIDS-defining condition. The majority of cases occur in patients with CD4+ T cell counts <200 cells/μL. Lesions appear radiographically as single or multiple hypodense areas, typically with ring enhancement and edema. They are found predominantly in the subcortical areas, a feature that differentiates them from the deeper lesions of toxoplasmosis. T. cruzi amastigotes, or trypanosomes, can be identified from biopsy specimens or CSF. Other CSF findings include elevated protein and a mild (<100 cells/μL) lymphocytic pleocytosis. Organisms can also be identified by direct examination of the blood. Treatment consists of benzimidazole (2.5 mg/kg bid) or nifurtimox (2 mg/kg qid) for at least 60 days, followed by maintenance therapy for the duration of immunodeficiency with either drug at a dose of 5 mg/kg three times a week. As is the case with cerebral toxoplasmosis, successful therapy with antiretrovirals may allow discontinuation of therapy for Chagas′ disease.
Stroke may occur in patients with HIV infection. In contrast to the other causes of focal neurologic deficits in patients with HIV infection, the symptoms of a stroke are sudden in onset. Patients with HIV infection have an increased prevalence of many classic risk factors associated with stroke, including smoking and diabetes. It also appears that HIV infection itself can lead to an increase in carotid artery stiffness. Among the secondary infectious diseases in patients with HIV infection that may be associated with stroke are vasculitis due to cerebral varicella zoster or neurosyphilis and septic embolism in association with fungal infection. Other elements of the differential diagnosis of stroke in the patient with HIV infection include atherosclerotic cerebral vascular disease, thrombotic thrombocytopenic purpura, and cocaine or amphetamine use.
Primary CNS lymphoma is discussed below in the section on neoplastic diseases.
Spinal cord disease, or myelopathy, is present in ∼20% of patients with AIDS, often as part of HIV-associated neurocognitive disorder. In fact, 90% of the patients with HIV-associated myelopathy have some evidence of dementia, suggesting that similar pathologic processes may be responsible for both conditions. Three main types of spinal cord disease are seen in patients with AIDS. The first of these is a vacuolar myelopathy, as mentioned above. This condition is pathologically similar to subacute combined degeneration of the cord, such as that occurring with pernicious anemia. Although vitamin B12 deficiency can be seen in patients with AIDS as a primary complication of HIV infection, it does not appear to be responsible for the myelopathy seen in the majority of patients. Vacuolar myelopathy is characterized by a subacute onset and often presents with gait disturbances, predominantly ataxia and spasticity; it may progress to include bladder and bowel dysfunction. Physical findings include evidence of increased deep tendon reflexes and extensor plantar responses. The second form of spinal cord disease involves the dorsal columns and presents as a pure sensory ataxia. The third form is also sensory in nature and presents with paresthesias and dysesthesias of the lower extremities. In contrast to the cognitive problems seen in patients with HIV encephalopathy, these spinal cord syndromes do not respond well to antiretroviral drugs, and therapy is mainly supportive.
One important disease of the spinal cord that also involves the peripheral nerves is a myelopathy and polyradiculopathy seen in association with CMV infection. This entity is generally seen late in the course of HIV infection and is fulminant in onset, with lower extremity and sacral paresthesias, difficulty in walking, areflexia, ascending sensory loss, and urinary retention. The clinical course is rapidly progressive over a period of weeks. CSF examination reveals a predominantly neutrophilic pleocytosis, and CMV DNA can be detected by CSF PCR. Therapy with ganciclovir or foscarnet can lead to rapid improvement, and prompt initiation of foscarnet or ganciclovir therapy is important in minimizing the degree of permanent neurologic damage. Combination therapy with both drugs should be considered in patients who have been previously treated for CMV disease. Other diseases involving the spinal cord in patients with HIV infection include HTLV-I-associated myelopathy (HAM) (Chap. 188), neurosyphilis (Chap. 169), infection with herpes simplex (Chap. 179) or varicella-zoster (Chap. 180), TB (Chap. 165), and lymphoma (Chap. 110).
Peripheral neuropathies are common in patients with HIV infection. They occur at all stages of illness and take a variety of forms. Early in the course of HIV infection, an acute inflammatory demyelinating polyneuropathy resembling Guillain-Barré syndrome may occur (Chap. 385). In other patients, a progressive or relapsing-remitting inflammatory neuropathy resembling chronic inflammatory demyelinating polyneuropathy (CIDP) has been noted. Patients commonly present with progressive weakness, areflexia, and minimal sensory changes. CSF examination often reveals a mononuclear pleocytosis, and peripheral nerve biopsy demonstrates a perivascular infiltrate suggesting an autoimmune etiology. Plasma exchange or IVIg has been tried with variable success. Because of the immunosuppressive effects of glucocorticoids, they should be reserved for severe cases of CIDP refractory to other measures. Another autoimmune peripheral neuropathy seen in patients with AIDS is mononeuritis multiplex (Chaps. 385 and 326) due to a necrotizing arteritis of peripheral nerves. The most common peripheral neuropathy in patients with HIV infection is a distal sensory polyneuropathy (DSPN) also referred to as painful sensory neuropathy (HIV-SN), predominantly sensory neuropathy, or distal symmetric peripheral neuropathy. This condition may be a direct consequence of HIV infection or a side effect of dideoxynucleoside therapy. It is more common in taller individuals, older individuals, and those with lower CD4 counts. Two-thirds of patients with AIDS may be shown by electrophysiologic studies to have some evidence of peripheral nerve disease. Presenting symptoms are usually painful burning sensations in the feet and lower extremities. Findings on examination include a stocking-type sensory loss to pinprick, temperature, and touch sensation and a loss of ankle reflexes. Motor changes are mild and are usually limited to weakness of the intrinsic foot muscles. Response of this condition to antiretrovirals has been variable, perhaps because antiretrovirals are responsible for the problem in some instances. When due to dideoxynucleoside therapy, patients with lower extremity peripheral neuropathy may complain of a sensation that they are walking on ice. Other entities in the differential diagnosis of peripheral neuropathy include diabetes mellitus, vitamin B12 deficiency, and side effects from metronidazole or dapsone. For distal symmetric polyneuropathy that fails to resolve following the discontinuation of dideoxynucleosides, therapy is symptomatic; gabapentin, carbamazepine, tricyclics, or analgesics may be effective for dysesthesias. Treatment-naïve patients may respond to cART.
Myopathy may complicate the course of HIV infection; causes include HIV infection itself, zidovudine, and the generalized wasting syndrome. HIV-associated myopathy may range in severity from an asymptomatic elevation in creatine kinase levels to a subacute syndrome characterized by proximal muscle weakness and myalgias. Quite pronounced elevations in creatine kinase may occur in asymptomatic patients, particularly after exercise. The clinical significance of this as an isolated laboratory finding is unclear. A variety of both inflammatory and noninflammatory pathologic processes have been noted in patients with more severe myopathy, including myofiber necrosis with inflammatory cells, nemaline rod bodies, cytoplasmic bodies, and mitochondrial abnormalities. Profound muscle wasting, often with muscle pain, may be seen after prolonged zidovudine therapy. This toxic side effect of the drug is dose-dependent and is related to its ability to interfere with the function of mitochondrial polymerases. It is reversible following discontinuation of the drug. Red ragged fibers are a histologic hallmark of zidovudine-induced myopathy.
Ophthalmologic problems occur in ∼50% of patients with advanced HIV infection. The most common abnormal findings on funduscopic examination are cotton-wool spots. These are hard white spots that appear on the surface of the retina and often have an irregular edge. They represent areas of retinal ischemia secondary to microvascular disease. At times they are associated with small areas of hemorrhage and thus can be difficult to distinguish from CMV retinitis. In contrast to CMV retinitis, however, these lesions are not associated with visual loss and tend to remain stable or improve over time.
One of the most devastating consequences of HIV infection is CMV retinitis. Patients at high risk of CMV retinitis (CD4+ T cell count <100/μL) should undergo an ophthalmologic examination every 3–6 months. The majority of cases of CMV retinitis occur in patients with a CD4+ T cell count <50/μL. Prior to the availability of cART, this CMV reactivation syndrome was seen in 25–30% of patients with AIDS. CMV retinitis usually presents as a painless, progressive loss of vision. Patients may also complain of blurred vision, “floaters,” and scintillations. The disease is usually bilateral, although typically it affects one eye more than the other. The diagnosis is made on clinical grounds by an experienced ophthalmologist. The characteristic retinal appearance is that of perivascular hemorrhage and exudate. In situations where the diagnosis is in doubt due to an atypical presentation or an unexpected lack of response to therapy, vitreous or aqueous humor sampling with molecular diagnostic techniques may be of value. CMV infection of the retina results in a necrotic inflammatory process, and the visual loss that develops is irreversible. CMV retinitis may be complicated by rhegmatogenous retinal detachment as a consequence of retinal atrophy in areas of prior inflammation. Therapy for CMV retinitis consists of oral valganciclovir, IV ganciclovir, or IV foscarnet, with cidofovir as an alternative. Combination therapy with ganciclovir and foscarnet has been shown to be slightly more effective than either ganciclovir or foscarnet alone in the patient with relapsed CMV retinitis. A 3-week induction course is followed by maintenance therapy with oral valganciclovir. If CMV disease is limited to the eye, a ganciclovir-releasing intraocular implant, periodic injections of the antisense nucleic acid preparation fomivirsen (no longer available in the United States), or intravitreal injections of ganciclovir or foscarnet may be considered; some choose to combine intraocular implants with oral valganciclovir. Intravitreal injections of cidofovir are generally avoided due to the increased risk of uveitis and hypotony. Maintenance therapy is continued until the CD4+ T cell count remains >100–150/μL for >6 months. The majority of patients with HIV infection and CMV disease develop some degree of uveitis with the initiation of cART. The etiology of this is unknown; however, it has been suggested that this may be due to the generation of an enhanced immune response to CMV as an IRIS (see above). In some instances this has required the use of topical glucocorticoids.
Both HSV and varicella zoster virus can cause a rapidly progressing, bilateral necrotizing retinitis referred to as the acute retinal necrosis syndrome, or progressive outer retinal necrosis (PORN). This syndrome, in contrast to CMV retinitis, is associated with pain, keratitis, and iritis. It is often associated with orolabial HSV or trigeminal zoster. Ophthalmologic examination reveals widespread pale gray peripheral lesions. This condition is often complicated by retinal detachment. It is important to recognize and treat this condition with IV acyclovir as quickly as possible to minimize the loss of vision.
Several other secondary infections may cause ocular problems in HIV-infected patients. P. jiroveci can cause a lesion of the choroid that may be detected as an incidental finding on ophthalmologic examination. These lesions are typically bilateral, are from half to twice the disc diameter in size, and appear as slightly elevated yellow-white plaques. They are usually asymptomatic and may be confused with cotton-wool spots. Chorioretinitis due to toxoplasmosis can be seen alone or, more commonly, in association with CNS toxoplasmosis. KS may involve the eyelid or conjunctiva, while lymphoma may involve the retina. Syphilis may lead to a uveitis that is highly associated with the presence of neurosyphilis.
Additional Disseminated Infections and Wasting Syndrome
Infections with species of the small, gram-negative, Rickettsia-like organism Bartonella (Chap. 160) are seen with increased frequency in patients with HIV infection. While it is not considered an AIDS-defining illness by the CDC, many experts view infection with Bartonella as indicative of a severe defect in cell-mediated immunity. It is usually seen in patients with CD4+ T cell counts <100/μL and is a significant cause of unexplained fever in patients with advanced HIV infection. Among the clinical manifestations of Bartonella infection are bacillary angiomatosis, cat-scratch disease, and trench fever. Bacillary angiomatosis is usually due to infection with B. henselae and is linked to exposure to flea-infested cats. It is characterized by a vascular proliferation that leads to a variety of skin lesions that have been confused with the skin lesions of KS. In contrast to the lesions of KS, the lesions of bacillary angiomatosis generally blanch, are painful, and typically occur in the setting of systemic symptoms. Infection can extend to the lymph nodes, liver (peliosis hepatis), spleen, bone, heart, CNS, respiratory tract, and GI tract. Cat-scratch disease is also due to B. henselae and generally begins with a papule at the site of inoculation. This is followed several weeks later by the development of regional adenopathy and malaise. Infection with B. quintana is transmitted by lice and has been associated with case reports of trench fever, endocarditis, adenopathy, and bacillary angiomatosis. The organism is quite difficult to culture, and diagnosis often relies on identifying the organism in biopsy specimens using the Warthin-Starry or similar stains. Treatment is with either doxycycline or erythromycin for at least 3 months.
Histoplasmosis is an opportunistic infection that is seen most frequently in patients in the Mississippi and Ohio River valleys, Puerto Rico, the Dominican Republic, and South America. These are all areas in which infection with H. capsulatum is endemic (Chap. 199). Because of this limited geographic distribution, the percentage of AIDS cases in the United States with histoplasmosis is only ∼0.5. Histoplasmosis is generally a late manifestation of HIV infection; however, it may be the initial AIDS-defining condition. In one study, the median CD4+ T cell count for patients with histoplasmosis and AIDS was 33/μL. While disease due to H. capsulatum may present as a primary infection of the lung, disseminated disease, presumably due to reactivation, is the most common presentation in HIV-infected patients. Patients usually present with a 4- to 8-week history of fever and weight loss. Hepatosplenomegaly and lymphadenopathy are each seen in about 25% of patients. CNS disease, either meningitis or a mass lesion, is seen in 15% of patients. Bone marrow involvement is common, with thrombocytopenia, neutropenia, and anemia occurring in 33% of patients. Approximately 7% of patients have mucocutaneous lesions consisting of a maculopapular rash and skin or oral ulcers. Respiratory symptoms are usually mild, with chest x-ray showing a diffuse infiltrate or diffuse small nodules in ∼50% of cases. Diagnosis is made by culturing the organisms from blood, bone marrow, or tissue or by detecting antigen in blood or urine. Treatment is typically with liposomal amphotericin B followed by maintenance therapy with oral itraconazole until the serum histoplasma antigen is <2 units, the patient has been on antiretrovirals for at least 6 months, and the CD4 count is >150 cells/μL. In the setting of mild infection, it may be appropriate to initiate therapy with itraconazole alone.
Following the spread of HIV infection to southeast Asia, disseminated infection with the fungus Penicillium marneffei was recognized as a complication of HIV infection and is considered an AIDS-defining condition in those parts of the world where it occurs. P. marneffei is the third most common AIDS-defining illness in Thailand, following TB and cryptococcosis. It is more frequently diagnosed in the rainy than the dry season. Clinical features include fever, generalized lymphadenopathy, hepatosplenomegaly, anemia, thrombocytopenia, and papular skin lesions with central umbilication. Treatment is with amphotericin B followed by itraconazole until the CD4+ T cell count is >100 cells/μL for at least 6 months.
Visceral leishmaniasis (Chap. 212) is recognized with increasing frequency in patients with HIV infection who live in or travel to areas endemic for this protozoal infection transmitted by sandflies. The clinical presentation is one of hepatosplenomegaly, fever, and hematologic abnormalities. Lymphadenopathy and other constitutional symptoms may be present. A chronic, relapsing course is seen in two-thirds of co-infected patients. Organisms can be isolated from cultures of bone marrow aspirates. Histologic stains may be negative, and antibody titers are of little help. Patients with HIV infection usually respond well initially to standard therapy with amphotericin B or pentavalent antimony compounds. Eradication of the organism is difficult, however, and relapses are common.
Patients with HIV infection are at a slightly increased risk of clinical malaria. This is particularly true for patients from nonendemic areas with presumed primary infection and in patients with lower CD4+ T cell counts. HIV-positive individuals with CD4+ T cell counts <300 cells/μL have a poorer response to malaria treatment than others. Co-infection with malaria is associated with a modest increase in HIV viral load. The risk of malaria may be decreased with TMP/SMX prophylaxis.
Generalized wasting is an AIDS-defining condition; it is defined as involuntary weight loss of >10% associated with intermittent or constant fever and chronic diarrhea or fatigue lasting >30 days in the absence of a defined cause other than HIV infection. Prior to the widespread use of cART it was the initial AIDS-defining condition in ∼10% of patients with AIDS in the United States and is an indication for initiation of cART. Generalized wasting is rarely seen today with the earlier initiation of antiretrovirals. A constant feature of this syndrome is severe muscle wasting with scattered myofiber degeneration and occasional evidence of myositis. Glucocorticoids may be of some benefit; however, this approach must be carefully weighed against the risk of compounding the immunodeficiency of HIV infection. Androgenic steroids, growth hormone, and total parenteral nutrition have been used as therapeutic interventions with variable success.
The neoplastic diseases considered to be AIDS-defining conditions are Kaposi's sarcoma, non-Hodgkin's lymphoma, and invasive cervical carcinoma. In addition, there is also an increase in the incidence of a variety of non-AIDS-defining malignancies including Hodgkin's disease; multiple myeloma; leukemia; melanoma; and cervical, brain, testicular, oral, lung, gastric, liver, renal, and anal cancers. Since the introduction of potent cART, there has been a marked reduction in the incidence of KS (Fig. 189-34) and CNS lymphoma, such that the non-AIDS-defining malignancies now account for more morbidity and mortality in patients with HIV infection than the AIDS-defining malignancies. Rates of non-Hodgkin's lymphoma have declined as well; however, this decline has not been as dramatic as the decline in rates of KS. In contrast, cART has had little effect on human papillomavirus (HPV)-associated malignancies. As patients with HIV infection live longer, a wider array of cancers is seen in this population. While some may only reflect known risk factors (e.g., smoking, alcohol consumption, co-infection with other viruses such as hepatitis B) that are increased in patients with HIV infection, some may be a direct consequence of HIV and are clearly increased in patients with lower CD4+ T cell counts.
Kaposi's sarcoma is a multicentric neoplasm consisting of multiple vascular nodules appearing in the skin, mucous membranes, and viscera. The course ranges from indolent, with only minor skin or lymph node involvement, to fulminant, with extensive cutaneous and visceral involvement. In the initial period of the AIDS epidemic, KS was a prominent clinical feature of the first cases of AIDS, occurring in 79% of the patients diagnosed in 1981. By 1989 it was seen in only 25% of cases, by 1992 the number had decreased to 9%, and by 1997 the number was <1%. HHV-8 or KSHV has been strongly implicated as a viral cofactor in the pathogenesis of KS.
Clinically, KS has varied presentations and may be seen at any stage of HIV infection, even in the presence of a normal CD4+ T cell count. The initial lesion may be a small, raised reddish-purple nodule on the skin (Fig. 189-42), a discoloration on the oral mucosa (Fig. 189-35D), or a swollen lymph node. Lesions often appear in sun-exposed areas, particularly the tip of the nose, and have a propensity to occur in areas of trauma (Koebner phenomenon). Because of the vascular nature of the tumors and the presence of extravasated red blood cells in the lesions, their colors range from reddish to purple to brown and often take the appearance of a bruise, with yellowish discoloration and tattooing. Lesions range in size from a few millimeters to several centimeters in diameter and may be either discrete or confluent. KS lesions most commonly appear as raised macules; however, they can also be papular, particularly in patients with higher CD4+ T cell counts. Confluent lesions may give rise to surrounding lymphedema and may be disfiguring when they involve the face and disabling when they involve the lower extremities or the surfaces of joints. Apart from skin, the lymph nodes, GI tract, and lung are the organ systems most commonly affected by KS. Lesions have been reported in virtually every organ, including the heart and the CNS. In contrast to most malignancies, in which lymph node involvement implies metastatic spread and a poor prognosis, lymph node involvement may be seen very early in KS and is of no special clinical significance. In fact, some patients may present with disease limited to the lymph nodes. These are generally patients with relatively intact immune function and thus the patients with the best prognosis. Pulmonary involvement with KS generally presents with shortness of breath. Some 80% of patients with pulmonary KS also have cutaneous lesions. The chest x-ray characteristically shows bilateral lower lobe infiltrates that obscure the margins of the mediastinum and diaphragm (Fig. 189-43). Pleural effusions are seen in 70% of cases of pulmonary KS, a fact that is often helpful in the differential diagnosis. GI involvement is seen in 50% of patients with KS and usually takes one of two forms: (1) mucosal involvement, which may lead to bleeding that can be severe; these patients sometimes also develop symptoms of GI obstruction if lesions become large; and (2) biliary tract involvement. KS lesions may infiltrate the gallbladder and biliary tree, leading to a clinical picture of obstructive jaundice similar to that seen with sclerosing cholangitis. Several staging systems have been proposed for KS. One in common use was developed by the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group; it distinguishes patients on the basis of tumor extent, immunologic function, and presence or absence of systemic disease (Table 189-16).
Table 189-16 National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group TIS Staging System for Kaposi's Sarcoma |Favorite Table|Download (.pdf)
Table 189-16 National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group TIS Staging System for Kaposi's Sarcoma
|Parameter||Good Risk (Stage 0): All of the Following||Poor Risk (Stage 1): Any of the Following|
|Tumor (T)||Confined to skin and/or lymph nodes and/or minimal oral disease|
Tumor-associated edema or ulceration
Extensive oral lesions
Nonnodal visceral lesions
|Immune system (I)||CD4+ T cell count ≥200/μL||CD4+ T cell count <200/μL|
|Systemic illness (S)|
No B symptomsa
No history of opportunistic infection, neurologic disease, lymphoma, or thrush
B symptomsa present
Karnofsky performance status <70
History of opportunistic infection, neurologic disease, lymphoma, or thrush
Kaposi's sarcoma in three patients with AIDS demonstrating (A) periorbital edema and bruising; (B) classic truncal distribution of lesions; and (C) upper extremity lesions.
Chest x-ray of a patient with AIDS and pulmonary Kaposi's sarcoma. The characteristic findings include dense bilateral lower lobe infiltrates obscuring the heart borders and pleural effusions.
A diagnosis of KS is based on biopsy of a suspicious lesion. Histologically one sees a proliferation of spindle cells and endothelial cells, extravasation of red blood cells, hemosiderin-laden macrophages, and, in early cases, an inflammatory cell infiltrate. Included in the differential diagnosis are lymphoma (particularly for oral lesions), bacillary angiomatosis, and cutaneous mycobacterial infections.
Management of KS (Table 189-17) should be carried out in consultation with an expert since definitive treatment guidelines do not exist. In the majority of cases, effective cART will go a long way in achieving control. Antiretroviral therapy has been associated with the spontaneous regression of KS lesions. Paradoxically, it has also been associated with the initial appearance of KS as a form of IRIS. For patients in whom tumor persists or in whom control of HIV replication is not possible, a variety of options exist. In some cases, lesions remain quite indolent, and many of these patients can be managed with no specific treatment. Fewer than 10% of AIDS patients with KS die as a consequence of their malignancy, and death from secondary infections is considerably more common. Thus, whenever possible one should avoid treatment regimens that may further suppress the immune system and increase susceptibility to opportunistic infections. Treatment is indicated under two main circumstances. The first is when a single lesion or a limited number of lesions are causing significant discomfort or cosmetic problems, such as with prominent facial lesions, lesions overlying a joint, or lesions in the oropharynx that interfere with swallowing or breathing. Under these circumstances, treatment with localized radiation, intralesional vinblastine, topical 9-cis-retinoic acid, or cryotherapy may be helpful. It should be noted that patients with HIV infection are particularly sensitive to the side effects of radiation therapy. This is especially true with respect to the development of radiation-induced mucositis; doses of radiation directed at mucosal surfaces, particularly in the head and neck region, should be adjusted accordingly. The use of systemic therapy, either IFN-α or chemotherapy, should be considered in patients with a large number of lesions or in patients with visceral involvement. The single most important determinant of response appears to be the CD4+ T cell count. This relationship between response rate and baseline CD4+ T cell count is particularly true for IFN-α. The response rate for patients with CD4+ T cell counts >600/μL is ∼80%, while the response rate for patients with counts <150/μL is <10%. In contrast to the other systemic therapies, IFN-α provides an added advantage of having antiretroviral activity; thus, it may be the appropriate first choice for single-agent systemic therapy for early patients with disseminated disease. A variety of chemotherapeutic agents have also been shown to have activity against KS. Three of them, liposomal daunorubicin, liposomal doxorubicin, and paclitaxel, have been approved by the FDA for this indication. Liposomal daunorubicin is approved as first-line therapy for patients with advanced KS. It has fewer side effects than conventional chemotherapy. In contrast, liposomal doxorubicin and paclitaxel are approved only for KS patients who have failed standard chemotherapy. Response rates vary from 23 to 88%, appear to be comparable to what had been achieved earlier with combination chemotherapy regimens, and are greatly influenced by CD4+ T cell count.
Table 189-17 Management of AIDS-Associated Kaposi's Sarcoma |Favorite Table|Download (.pdf)
Table 189-17 Management of AIDS-Associated Kaposi's Sarcoma
|Observation and optimization of antiretroviral therapy|
|Single or limited number of lesions|
|Interferon α (if CD4+ T cells >150/ L)|
|Combination chemotherapy with low-dose doxorubicin, bleomycin,|
|and vinblastine (ABV)|
Lymphomas occur with an increased frequency in patients with congenital or acquired T cell immunodeficiencies (Chap. 316). AIDS is no exception; at least 6% of all patients with AIDS develop lymphoma at some time during the course of their illness. This is a 120-fold increase in incidence compared with the general population. In comparison to the situation with KS, primary CNS lymphoma, and most opportunistic infections, the incidence of AIDS-associated systemic lymphomas has not experienced as dramatic a decrease as a consequence of the widespread use of effective cART. Lymphoma occurs in all risk groups, with the highest incidence in patients with hemophilia and the lowest incidence in patients from the Caribbean or Africa with heterosexually acquired infection. Lymphoma is a late manifestation of HIV infection, generally occurring in patients with CD4+ T cell counts <200/μL. As HIV disease progresses, the risk of lymphoma increases. The attack rate for lymphoma increases exponentially with increasing duration of HIV infection and decreasing level of immunologic function. At 3 years following a diagnosis of HIV infection, the risk of lymphoma is 0.8% per year; by 8 years after infection, it is 2.6% per year. As individuals with HIV infection live longer as a consequence of improved cART and better treatment and prophylaxis of opportunistic infections, it is anticipated that the incidence of lymphomas may increase.
Three main categories of lymphoma are seen in patients with HIV infection: grade III or IV immunoblastic lymphoma, Burkitt's lymphoma, and primary CNS lymphoma. Approximately 90% of these lymphomas are B cell in phenotype; more than half contain EBV DNA. Some are associated with KSHV. These tumors may be either monoclonal or oligoclonal in nature and are probably in some way related to the pronounced polyclonal B cell activation seen in patients with AIDS.
Immunoblastic lymphomas account for ∼60% of the cases of lymphoma in patients with AIDS. The majority of these are diffuse large B cell lymphomas (DLBCL). They are generally high grade and would have been classified as diffuse histiocytic lymphomas in earlier classification schemes. This tumor is more common in older patients, increasing in incidence from 0% in HIV-infected individuals <1 year old to >3% in those >50. Two variants of immunoblastic lymphoma that are seen primarily in HIV-infected patients are primary effusion lymphoma (PEL) and its solid variant, plasmacytic lymphoma of the oral cavity. PEL, also referred to as body cavity lymphoma, presents with lymphomatous pleural, pericardial, and/or peritoneal effusions in the absence of discrete nodal or extranodal masses. The tumor cells do not express surface markers for B cells or T cells and are felt to represent a preplasmacytic stage of differentiation. While both HHV-8 and EBV DNA sequences have been found in the genomes of the malignant cells from patients with body cavity lymphoma, KSHV is felt to be the driving force behind the oncogenesis (see above).
Small noncleaved cell lymphoma (Burkitt's lymphoma) accounts for ∼20% of the cases of lymphoma in patients with AIDS. It is most frequent in patients 10–19 years old and usually demonstrates characteristic c-myc translocations from chromosome 8 to chromosomes 14 or 22. Burkitt's lymphoma is not commonly seen in the setting of immunodeficiency other than HIV-associated immunodeficiency, and the incidence of this particular tumor is more than 1000-fold higher in the setting of HIV infection than in the general population. In contrast to African Burkitt's lymphoma, where 97% of the cases contain EBV genome, only 50% of HIV-associated Burkitt's lymphomas are EBV-positive.
Primary CNS lymphoma accounts for ∼20% of the cases of lymphoma in patients with HIV infection. In contrast to HIV-associated Burkitt's lymphoma, primary CNS lymphomas are usually positive for EBV. In one study, the incidence of Epstein-Barr positivity was 100%. This malignancy does not have a predilection for any particular age group. The median CD4+ T cell count at the time of diagnosis is ∼50/μL. Thus, CNS lymphoma generally presents at a later stage of HIV infection than does systemic lymphoma. This may explain, at least in part, the poorer prognosis for this subset of patients.
The clinical presentation of lymphoma in patients with HIV infection is quite varied, ranging from focal seizures to rapidly growing mass lesions in the oral mucosa (Fig. 189-44) to persistent unexplained fever. At least 80% of patients present with extranodal disease, and a similar percentage have B-type symptoms of fever, night sweats, or weight loss. Virtually any site in the body may be involved. The most common extranodal site is the CNS, which is involved in approximately one-third of all patients with lymphoma. Approximately 60% of these cases are primary CNS lymphoma. Primary CNS lymphoma generally presents with focal neurologic deficits, including cranial nerve findings, headaches, and/or seizures. MRI or CT generally reveals a limited number (one to three) of 3- to 5-cm lesions (Fig. 189-45). The lesions often show ring enhancement on contrast administration and may occur in any location. Contrast enhancement is usually less pronounced than that seen with toxoplasmosis. Locations that are most commonly involved with CNS lymphoma are deep in the white matter. The main diseases in the differential diagnosis are cerebral toxoplasmosis and cerebral Chagas′ disease. In addition to the 20% of lymphomas in HIV-infected individuals that are primary CNS lymphomas, CNS disease is also seen in HIV-infected patients with systemic lymphoma. Approximately 20% of patients with systemic lymphoma have CNS disease in the form of leptomeningeal involvement. This fact underscores the importance of lumbar puncture in the staging evaluation of patients with systemic lymphoma.
Immunoblastic lymphoma involving the hard palate of a patient with AIDS.
Central nervous system lymphoma. Postcontrast T1-weighted MRI scan in a patient with AIDS, an altered mental status, and hemiparesis. Multiple enhancing lesions, some ring-enhancing, are present. The left sylvian lesion shows gyral and subcortical enhancement, and the lesions in the caudate and splenium (arrowheads) show enhancement of adjacent ependymal surfaces.
Systemic lymphoma is seen at earlier stages of HIV infection than primary CNS lymphoma. In one series the mean CD4+ T cell count was 189/μL. In addition to lymph node involvement, systemic lymphoma may commonly involve the GI tract, bone marrow, liver, and lung. GI tract involvement is seen in ∼25% of patients. Any site in the GI tract may be involved, and patients may complain of difficulty swallowing or abdominal pain. The diagnosis is usually suspected on the basis of CT or MRI of the abdomen. Bone marrow involvement is seen in ∼20% of patients and may lead to pancytopenia. Liver and lung involvement are each seen in ∼10% of patients. Pulmonary disease may present as a mass lesion, multiple nodules, or an interstitial infiltrate.
Both conventional and unconventional approaches have been employed in an attempt to treat HIV-related lymphomas. Systemic lymphoma is generally treated by the oncologist with combination chemotherapy. Earlier disappointing figures are being replaced with more optimistic results for the treatment of systemic lymphoma following the availability of more effective cART and the use of rituximab in CD20+ tumors. While there is controversy regarding the use of antiretrovirals during chemotherapy, there is no question that their use overall in patients with HIV lymphoma has improved survival. As in most situations in patients with HIV disease, those with the higher CD4+ T cell counts tend to fare better. Response rates as high as 72% with a median survival of 33 months and disease-free intervals up to 9 years have been reported. Treatment of primary CNS lymphoma remains a significant challenge. Treatment is complicated by the fact that this illness usually occurs in patients with advanced HIV disease. Palliative measures such as radiation therapy provide some relief. The prognosis remains poor in this group, with a 2-year survival of 29%.
Multicentric Castleman's disease is a KSHV-associated lymphoproliferative disorder that is seen with an increased frequency in patients with HIV infection. While not a true malignancy, it shares many features with lymphoma including generalized lymphadenopathy, hepatosplenomegaly, and systemic symptoms of fever, fatigue, and weight loss. Pulmonary symptoms may be seen in ∼50% of patients. KS is present in 75–82% of cases. Lymph node biopsies reveal a predominance of interfollicular plasma cells and/or germinal centers with vascularization and an “onionskin” (hyaline vascular) appearance. Prior to the availability of cART, HIV-infected patients with multicentric Castleman's disease had a 15-fold increased risk of developing non-Hodgkin's lymphoma compared with HIV-infected patients in general. Treatment typically involves chemotherapy. Anecdotal reports of success with rituximab suggest that more specific treatment may be successful, although in one series treatment with rituximab was associated with worsening of coexisting KS. The median survival of patients with treated multicentric Castleman's disease pre-cART was 14 months. This has increased to a 2-year survival of more than 90% in the era of cART.
Evidence of infection with human papillomavirus (HPV), associated with intraepithelial dysplasia of the cervix or anus, is approximately twice as common in HIV-infected individuals as in the general population and can lead to intraepithelial neoplasia and eventually invasive cancer. In a series of studies, HIV-infected men were examined for evidence of anal dysplasia, and Papanicolaou (Pap) smears were found to be abnormal in 20–80%. These changes tend to persist and are generally not affected by cART, raising the possibility of a subsequent transition to a more malignant condition. While the incidence of an abnormal Pap smear of the cervix is ∼5% in otherwise healthy women, the incidence of abnormal cervical smears in women with HIV infection is 30–60%, and invasive cervical cancer is included as an AIDS-defining condition. Thus far, however, only small increases in the incidence of cervical or anal cancer have been seen as a consequence of HIV infection. However, given this high rate of dysplasia, a comprehensive gynecologic and rectal examination, including Pap smear, is indicated at the initial evaluation and 6 months later for all patients with HIV infection. If these examinations are negative at both time points, the patient should be followed with yearly evaluations. If an initial or repeat Pap smear shows evidence of severe inflammation with reactive squamous changes, the next Pap smear should be performed at 3 months. If, at any time, a Pap smear shows evidence of squamous intraepithelial lesions, colposcopic examination with biopsies as indicated should be performed. The 2-year survival rate for HIV-infected patients with invasive cervical cancer is 64% compared with 79% in non-HIV-infected patients. The most common HPV genotypes in the general population and the genotypes upon which current HPV vaccines are based are 16 and 18. This is not the case in the HIV-infected population, where other genotypes such as 56 and 53 predominate. This raises concerns as to the potential effectiveness of the current HPV vaccines for HIV-infected patients.