Fever in HIV Patients

Chinese Version

Lynne Strasfeld, M.D., Kent A. Sepkowitz, M.D.

INTRODUCTION

               Fever is a common complaint among patients with HIV infection and may occur at any point during viral infection (144). Patients with primary HIV infection, the "acute retroviral syndrome," can present clinically with a febrile illness resembling mononucleosis. Symptoms may include headache, myalgia, pharyngitis, lymphadenopathy, maculopapular rash, aphthous ulcers, weight loss, retroorbital pain, nausea, diarrhea or meningeal signs (115). Symptomatic infection typically occurs two to six weeks after exposure to HIV-1 and usually resolves within one to two weeks. Establishment of the diagnosis typically requires demonstration of p24 antigenemia or evidence of HIV viral RNA in blood.

               Following primary HIV infection, most patients enter a prolonged, asymptomatic phase characterized immunologically by a progressive decline in the CD4 count. As the CD4 count continues to fall, opportunistic infections and malignancies that define clinical AIDS and characterize the later stages of immune dysfunction become increasingly common. In studies done prior to the availability of active antiretroviral therapy, the median time from seroconversion to AIDS was roughly seven to twelve years (4).

DIFFERENTIAL DIAGNOSIS

               At each stage in the course of HIV infection, there are numerous potential causes of fever to consider. Studies have documented that with thorough investigation, the etiology of fever can be identified in over 80% of cases (13, 144).

               Numerous observational studies have confirmed the predictive value of the CD4 count as a rough guide to the temporal sequence of opportunistic infections and malignancies that occur throughout the lifetime of the AIDS patient (50, 157, 167). The Centers for Disease Control and Prevention (CDC) classification scheme for HIV infection stratifies patients according to CD4 count: patients with counts greater than 500/mm³, those with counts between 200 and 500/mm³, and those with counts less than 200/mm³ (35). This breakdown provides a useful, though imperfect, framework to discuss the evaluation of fever in the HIV-infected patient in each of these categories. Preliminary studies have found little association between viral load and risk for opportunistic infections (48).

Patients with CD4 cell counts greater than 500/mm³

               Patients with HIV and a CD4 cell count greater than 500/mm³ should generally be evaluated for fever as if they were relatively immunocompetent hosts (158). Infections that are more common in this group relative to their HIV-negative counterparts, however, include Mycobacterium tuberculosis (164) and bacterial sinopulmonary infections (75, 107).

Patients with CD4 cell counts between 200 and 500/mm³

               Patients with CD4 counts of 200 to 500/mm³ develop upper and lower bacterial respiratory tract infections more commonly than their HIV-negative counterparts, with a well-documented increased risk for bacterial pneumonia (75, 125, 168, 175). Opportunistic infections such as Pneumocystis pneumonia are seldom seen at CD4 counts greater than 250/mm³  (88). M. tuberculosis, however, remains of particular concern. Patients with tuberculosis and CD4 counts greater than 200/mm³  often present with typical reactivation disease affecting the lung apices, whereas patients with lower CD4 counts often have atypical radiographic presentations such as atypical infiltration and mediastinal lymphadenopathy (72, 92).

Patients with CD4 cell counts less than 200/mm³

               In the setting of advanced immunosuppression, which is the sin que non of advanced HIV-infection, fever is ever more common. With progressive decline in the CD4 count, both the frequency and variety of infectious complications increases. It is in this range that opportunistic infections such as Pneumocystis pneumonia, CMV, toxoplasmosis, disseminated MAC, disseminated histoplasmosis and coccidioidomycosis, and cryptococcal meningitis must be considered in the differential diagnosis of fever.

INFECTIOUS ETIOLOGIES

Pulmonary

               The three most common infectious pulmonary etiologies of fever are Pneumocystis  pneumonia, bacterial pneumonia, and tuberculosis (68, 143). During the early years of the HIV epidemic, Pneumocystis pneumonia was the most frequent pulmonary complication, accounting for nearly two-thirds of AIDS index diagnoses (169). However, increasing use of Pneumocystis pneumonia prophylaxis in the late 1980s led to a decline in the frequency of this disease. Coincident with this, changes in the demographic composition of the AIDS epidemic led to an increasing number of persons at risk for bacterial pneumonia. Specifically, the increasing proportion of patients with intravenous drug use as their HIV risk factor led to additional risk for bacterial pneumonia (168). Intravenous drug users have been found to be at higher risk for bacterial pneumonia and tuberculosis than other HIV-infected groups (68, 75, 168).

               The incidence of tuberculosis in patients with AIDS is 100 to 500 times the incidence in the general population (124) due to both increased risk of reactivation of latent tuberculosis infection (142) and an increased risk of progressive disease from primary infection (53). Whereas the lifetime risk for active tuberculosis among latently infected persons is approximately 10% in the general population, the risk of active tuberculosis among HIV-infected patients with positive tuberculin tests is estimated to be 8% per year (142). Furthermore, active disease after exposure, which occurs in approximately 3 to 5% of normal hosts, may be seen in 30 to 40% of newly exposed HIV-positive persons (51).

               Tuberculosis in cases of advanced immunosuppression can present with dissemination, extrapulmonary disease and unusual radiographic manifestations (77. Patients with tuberculosis and CD4 counts greater than 200/mm³ often present with typical reactivation diseases affecting the apices. Tuberculosis in cases of advanced immunosuppression can present with dissemination, extrapulmonary disease,, and unusual radiographic manifestations such as hilar adenopathy and pleural effusions (14, 65, 77, 92). Extrapulmonary tuberculosis is observed to be more common in patients with more severe HIV-induced immunosuppression (122, 159, 164).

               Both atypical mycobacteria and CMV should also be considered in the evaluation of AIDS patients with advanced disease who present with respiratory signs or symptoms. As opposed to Mycobacterium tuberculosis, serious infection with nontuberculous mycobacteria occurs only in patients with advanced immunodeficiency. Localized and clinically significant pulmonary disease due to Mycobacterium avium intracellularae (MAC) occurs in HIV-infected patients, but is uncommon (76, 87, 136). One study found pulmonary MAC disease to be present in only 2.5% of patients with disseminated MAC infection (87). Respiratory tract colonization is much more common than true pulmonary disease (80).

Gastrointestinal

               The gastrointestinal tract is a frequent site for opportunistic infections. Diarrhea is a common gastrointestinal manifestation, affecting 30 to 60% of North American patients with HIV (15, 69, 100, 152, 153). While frequent causes of HIV-associated diarrhea, the protozoans Cryptosporidium parvum and microsporidia species are rarely associated with significant fever (153). Salmonella species, Shigella species, and Campylobacter jejuni may present with high fever. AIDS patients either acquire or are symptomatic with these pathogens more often than their HIV-negative counterparts (42). While Shigella is commonly diagnosed in the early stages of HIV infection, Campylobacter and Salmonella are associated with more severe immunodeficiency (112). The association between AIDS and infection with both typhi and non-typhi Salmonella species is well recognized (66), with a 20-fold increase in risk for infection seen among US patients with HIV (33, 81, 155). Septicemia with Salmonella is more likely to occur in individuals with more advanced immunosuppression. Relapse of bacteremia after appropriate antibiotic therapy is well described in AIDS patients (33). Thus, HIV-positive patients with Salmonella who have low CD4 counts and/or prior septicemia should receive life-long secondary prophylaxis (112).

               Clostridium difficile colitis, commonly presenting as diarrhea and abdominal pain with associated fever, is also more common among patients with AIDS (29).

               The most common and serious viral infection affecting the gastrointestinal tract is cytomegalovirus. Approximately one third of all AIDS patients develop gastrointestinal cytomegalovirus infections (133). Although the colon is the site most often affected, involvement of any part from mouth to anus has been reported (63, 98). Manifestations range from esophageal ulcers to colitis to toxic megacolon with perforation. Most patients with colitis have fever, reflecting the invasive nature of cytomegalovirus, along with diarrhea which is sometimes bloody, crampy lower abdominal pain, tenesmus, weight loss, malaise, and anorexia. Clinical cytomegalovirus disease usually occurs after the CD4 count has fallen below 100 (63).

               Esophageal infection with Candida, HSV and CMV, as well as aphthous stomatitis, is not uncommon in the course of HIV infection. Dysphagia and odynophagia are the most frequent presenting symptoms of esophagitis. Fever accompanying esophageal symptoms is rare in Candidal or HSV esophagitis, but is more common in CMV. A review of presenting signs and symptoms of HIV-positive patients with esophageal infection revealed that 20% of patients with either CMV or mycobacterial esophagitis had fever (12). Likely this is because esophagitis in these instances is more often a representation of a systemic illness involving multiple organs in addition to the esophagus.

               In the evaluation of fever and abdominal pain in HIV-positive patients, pancreatitis always must be on the differential. As well as the usual etiologies such as alcohol use and gallstones, medications also must be considered, especially ddI, ddC, Trimethoprim-sulfamethoxazole, and intravenous or inhaled pentamidine (1, 120, 141,165). Certain opportunistic infections including CMV, Toxoplasma gondii, Cryptococcus neoformans, and MAC are also reported to be potential etiologic agents of pancreatitis in AIDS patients (2, 42, 52, 58).

Biliary

               Signs of biliary tract disease in HIV-infected patients are similar to those of HIV-negative patients – right upper quadrant pain, fever, and elevated serum alkaline phosphatase. Causes include gallstone disease as well as AIDS-related cholangitis. Although the pathogenesis of AIDS-related cholangitis remains unknown, it is suggested that several different opportunistic pathogens damage the biliary sphincter segment resulting in papillary stenosis (11). The pathogens most often identified include Cryptosporidium, cytomegalovirus, microsporidia, and Mycobacterium avium intracellulare ; the clinical pattern is similar regardless of the organism involved (111). Patients typically have advanced AIDS and a CD4 count <100 (32). Diagnosis is based on typical cholangiographic findings (papillary stenosis, sclerosing cholangitis, combined papillary stenosis and sclerosing cholangitis, and long extrahepatic bile duct strictures) in patients with advanced HIV disease (32). Abdominal ultrasound is a reasonable first step in diagnosis, as it is abnormal in approximately 75% of patients, with the gold standard defined as an abnormal cholangiogram (19, 24, 32). If ultrasound reveals dilated ducts, an ERCP should be performed as it allows both diagnostic biopsy specimens to be obtained while at the same time allowing for a therapeutic sphincterotomy. Infection of the gallbladder itself with CMV and/or Cryptosporidium may occur, with a clinical presentation that mirrors typical cholecystitis (79).

Neurologic

               Cerebral toxoplasmosis is the most common CNS opportunistic infection in AIDS (103). Caused by reactivation of infection by Toxoplasma gondii, cerebral toxoplasmosis typically manifests as a subacute focal syndrome characterized by single or, more frequently, multiple brain abscesses. One large retrospective study found the most common presenting symptoms to be headache (55%), confusion (52%), and fever (47%) (126). Fever is seldom high. Diagnosis is suggested by the finding of characteristic ring-enhancing lesions on neuroimaging.

               Cryptococcal disease, the most common life-threatening fungal infection associated with AIDS, disseminates widely in the immunocompromised, especially to the CNS. Most patients who are infected with Cryptococcus neoformans develop meningitis, though infection of nearly every organ has been described. Approximately 6 to 10% of patients with AIDS will develop cryptococcal meningitis, usually in the setting of severe immunodeficiency with CD4 counts nearly always less than 100/mm³ (50, 127). Most often patients have features of subacute meningitis or meningoencephalitis characterized by fever, malaise, and headache generally for two to four weeks prior to presentation. Overt meningeal signs are unsual, and focal neurologic signs or seizures occur infrequently. One large retrospective analysis of 89 cases of culture-confirmed cryptococcal meningitis found that approximately two thirds reported fever, headache, and malaise, but only 15% had focal deficits and 27% had meningeal signs on examination (41). Presentation may be subtle, and it is thus important to include cryptococcaal disease in the differential diagnosis of all AIDS patients with fever.

               While HIV-infected patients with tuberculosis are at increased risk for meningeal involvement, comparison of the presentation of tuberculous meningitis in patients with and without HIV infection has revealed similar clinical manifestations, cerebrospinal fluid findings, and mortality (22, 55).

               CNS lymphoma, the second most common CNS mass lesion after toxoplasmosis may be associated with fever (116). Progressive multifocal leukocencephalopathy (PML), caused by reactivation of JC papovavirus, affects between 4-8% of HIV patients in the later stages of disease. Focal neurologic deficit is the clinical hallmark of PML, and fever is unusual (139).

Multisystem Disease

               Endemic in the Midwestern and southeastern United States, Histoplasma capsulatum can cause acute pulmonary infection characterized by fever, hypoxia, and pulmonary infiltrates in immunocompetent hosts. In patients with HIV and defects in cell-mediated immunity, however, the picture is that of progressive disseminated disease (6, 25). Clinical presentation is often nonspecific; fever, weight loss, hepatosplenomegaly, lymphadenopathy, and anemia are common (83). Wheat and colleagues found that most patients presented with symptoms of fever and weight loss of at least one month's duration, which, if untreated, can progress to a fulminant picture resembling septicemia (173).

               Coccidioidomycosis, a disease caused by the soil fungus Coccidioides immitis, is edemic in the southwestern United States, northern Mexico, and portions of Central and South America (119). Acquisition via inhalation of fungal arthrospores, and activities that involve repeated direct exposure to soil and dust have been shown to be associated with coccidioidomycosis (170). Among otherwise healthy persons, C. immitis may be asymptomatic or may manifest as a subacute and self-limited febrile illness (valley fever), pulmonary disease, or disseminated disease. While rare in immunocompetent hosts, disseminated disease is common in HIV-positive patients, particularly those with depressed CD4 counts, living in endemic regions (7, 85). Disseminated coccidioidomycosis, defined as the identification of C. immitis by histopathology, culture, or antigen detection at a site other than or in addition to the lungs or cervical or hilar lymph nodes, was added to the surveillance case definition for AIDS in 1987 (34). A retrospective review of clinical manifestations of patients with HIV and coccidioidomycosis at a single institution in Maricopa county Arizona found the most frequent symptoms to be fever and chills (68%), cough (64%), and weight loss (50%) (149). In this series, the lung was the most frequently involved organ (80%), followed by the meninges (15%). Chest radiographs revealed diffuse reticulonodular infiltrates in 65% of those with pulmonary involvement and focal pulmonary disease in 14%. Approximately two-thirds of respiratory secretions (either expectorated sputum or bronchoscopy with bronchoalveolar lavage) were positive either by culture or histopathology, with transbronchial biopsy even more sensitive. HIV-positive patients with diffuse pulmonary involvement have been shown to have a high mortality (7,149).

               Penicillium marneffei, another systemic mycosis, should be considered in patients with history of travel to or residence in areas of endemicity that include Southeast Asia, the Guangxi Provence of China and in some areas of Hong Kong. Disseminated P. marneffei is an emerging pathogen, reported in 1994 to be the third most common opportunistic infection in HIV-infected patients in certain parts of Southeast Asia, following extrapulmonary tuberculosis and cryptococcosis (161). Although no definitive route of transmission has been determined, it is suggested that the organism is most often acquired via ingestion and inhalation. Clinical manifestations typically resemble those of other systemic fungal infections. The most common clinical features include fever, weight loss, anemia, and skin lesions; cough and pulmonary involvement has been reported as well (39, 56, 160).

               Disseminated MAC is the most common opportunistic infection of bacterial origin among patients with AIDS in the United States (21). A prospective study at one urban institution revealed that 43% of patients who survived one year after their CD4 count fell below 200 developed MAC bacteremia (114). The most important risk factor for disseminated MAC is a low CD4 count, with infection rarely observed in patients with CD4 counts greater than 100 ( 37, 50, 74, 78,163). Whereas disease due to M. tuberculosis commonly precedes the diagnosis of AIDS, MAC usually causes disease only in the late stages of HIV infection, when cellular immunity is severely impaired (108). MAC is ubiquitous, with the gastrointestinal tract the main portal for entry, and asymptomatic colonization often precedes disseminated MAC. When dissemination occurs, the most commonly affected sites are blood, bone marrow, liver, spleen, and lymph nodes. The most frequently described symptoms at presentation include fever, night sweats, diarrhea, and abdominal pain (21), and the laboratory abnormalities most often identified among patients with disseminated MAC are anemia and an elevated serum alkaline phosphatase level (74).

               Most commonly, Toxoplasma gondii infection presents with central nervous system manifestations including fever, headache, change in mental status, seizure, and focal neurological deficits. Extracerebral manifestations are much less common, with fulminant sepsis described in case reports (27, 67). The small number of such cases described in the literature do not provide for a recognizable pattern of disease. Additionally, case reports have described attenuated, but probably disseminated, toxoplasmosis manifested by prolonged fever in patients receiving trimethoprim-sulfamethoxazole as Pneumocystis pneumonia prophylaxis (178). In patients with HIV-related fever and sepsis of unknown origin, disseminated T. gondii infection should be considered.

               Visceral leishmaniasis must be considered in patients with an appropriate travel history presenting with fever, hepatosplenomegaly, and/or pancytopenia (3). Leishmania species, typically transmitted through the bite of infected female sandflies, are endemic in the Mediterranean area, the Middle East, India, Central and South America, northern and eastern China, some of the former Soviet republics, and northern Africa. A large series of HIV-positive patients with visceral leishmaniasis in Spain revealed the presence of fever in 95% of patients, enlargement of the liver and/or spleen in 92.5%, and pancytopenia in 82.5% (110). Characteristic features of visceral leishmaniasis in HIV-infected patients include a lack of leishmania antibodies and a frequent chronic-relapsing course. While reliable in immunocompetent patients, the value of antibody testing is extremely limited in HIV-infected individuals. Thus, diagnosis in this population must rely upon direct detection of amastigotes in tissue samples or promastigotes in culture.

               Bacillary angiomatosis (typified by vascular-proliferative lesions that are classically cutaneous) and bacillary peliosis (characterized by vascular-proliferative disease affecting the liver and spleen) are different manifestations of the same infection caused by either Bartonella henselae or Bartonella quintana, with a broad spectrum of presentation in immunocompromised hosts. One case-control study revealed fever to be present in 93% of patients with HIV and histologically confirmed bacillary angiomatosis-bacillary peliosis; other common signs and symptoms included cutaneous or subcutaneous vascular lesions (55%), lymphadenopathy (21%), and abdominal symptoms (24%) (109).

               Cytomegalovirus (CMV) is the most common viral cause of serious opportunistic infection in HIV. A wide range of clinical syndromes are seen, most commonly retinitis, esophagitis, colitis, and gastirits as described above (63, 82). Positive blood or urine cultures of CMV provide supporting evidence for infection but do not establish end-organ involvement. Except in the case of retinitis, diagnosis of end organ disease should be based on histologic evidence of CMV (40, 54). There is, however, recent data suggesting that the detection of CMV antigenemia and/or CMV DNA by PCR in the blood of AIDS patients predicts the subsequent development of CMV disease (40,148). This may lead to the use of preemptive antiviral therapy to prevent the development of end-organ disease.

Fever of Unknown Origin

               Since its first definition by Petersdorf and Beeson in 1961 as "fever higher than 38.3 C (101 F) on several occasions, persisting without diagnosis for at least 3 weeks in spite of at least 1 week's investigation in hospital" (121), fever of unknown origin remains a vexing clinical dilemma, particularly so in the HIV-positive population where the range of disease possibilities looms large. The criteria of Durack and Street (57) proposed in 1991 are used to define HIV-associated FUO: temperature of 38.3 C (101 F) or higher on several occasions; confirmed positive serology for HIV infection; fever of more than 4 weeks' duration for outpatients, or more than 3 days' duration in hospital; diagnosis uncertain after 3 days despite appropriate investigation, including at least 2 day's incubation of microbiologic cultures. The pursuit of a thorough investigation is warranted since diagnosis can be made in over 80% of patients with HIV and fever. HIV infection itself is rarely the cause of fever in patients with advanced immunosuppression (147). Several series have examined FUO in AIDS (10, 23, 64, 93, 102, 105, 106, 144) (Table 4). Although great variability with respect to the criteria used to define FUO, the demographics of the population studied and the diagnostic approach is evident among these studies, their conclusions bear similarity. The predominant etiologies of fever identified include mycobacterial diseases, leishmaniasis (in series from endemic regions), Pneumocystis pneumonia and lymphoma.

Highly Active Antiretroviral Therapy and Immune Restoration Disease

               The combination of antiretroviral agents containing protease inhibitors, referred to as highly active antiretroviral therapy (HAART), has significantly changed the pace of HIV-related disease and has reduced AIDS-related complications thereby decreasing morbidity and mortality (118). One recently described unexpected side effect of HAART, though, is "immune restoration disease." Thought to represent an exuberant inflammatory response around established infection in the setting of immune restoration, the clinical syndrome is characterized by lymphadenopathy, fever, leukocytosis, and malaise occurring soon after the initiation of HAART and predominantly in patients whose nadir CD4 count was less than 100 (62, 146). This immunologic phenomenon has been associated with infection with MAC and M. tuberculosis manifesting as localized lymphadenitis (132), CMV manifesting as acute intraocular inflammation (174), hepatitis B and C virus infection manifesting as acute hepatitis flare (104, 166), and herpes simplex virus manifesting as extensive herpetic lesions that may be hemorrhagic (5).

NON-INFECTIOUS ETIOLOGIES

               a) Drug reactions are significantly more common in the HIV-infected population, occurring with an increasing incidence with advancing immunodeficiency (46, 151), commonly manifesting as maculopapular or morbilliform eruptions, and at times accompanied by fever, arthralgias, eosinophilia, and/or serum transaminase elevation (17). Possible explanations for the mechanism of increased drug reactivity seen in the HIV-positive population include an increased use of provocative drugs, an increased incidence of viral infections, and immune dysregulation (43, 150).

               b) Several rheumatologic conditions have been associated with HIV-1 infection, notably Reiter's syndrome, psoriatic arthritis, Sjogren's syndrome, polymyositis, rheumatoid arthritis, Still's disease and vasculitis (8, 91). The reason for this association is not known.

               c) The most common malignancies associated with fever in HIV infection are non-Hodgkin's lymphoma, primary CNS lymphoma, and rarely Kaposi's sarcoma. While non-Hodgkin's lymphomas (usually aggressive high-grade B-cell lymphomas) can be found in early HIV infection and commonly cause fever, primary CNS lympomas are found almost exclusively in late-stage HIV and are less often associated with fever (116). It appears also that Hodgkin's disease with extranodal involvement occurs with increased frequency in the setting of HIV infection (45, 89. Fever is a common presenting and enduring symptom of HIV-related lymphoma.

               d) Thrombophlebitis is seen more commonly in the HIV-infected population (99), thought to be due to hypercoagulable states and predisposing factors such as immobility (18, 156).

DIAGNOSTIC STUDIES

               As with fever in any other setting, the diagnostic evaluation should be guided by the history, findings on physical examination, and underlying patient characteristics. The diagnostic evaluation of fever in the relatively immunocompetent group, i.e. patients with CD4 cell counts above 200/mm³, should be performed in a symptom-directed manner (Table 1), as guided by a comprehensive history and physical examination. Factors of particular relevance include travel and exposure history, associated conditions such as intravenous drug use, and medication history. Tests to consider early in the evaluation of fever include a complete blood count, bacterial blood cultures, chest radiography, urinalysis and urine culture, with more invasive studies pursued on a symptom-directed basis.

               In the severely immunosuppressed patients, i.e. those with CD4 cell count less than 200/mm³ with a myriad of infectious complications, can present in a similar and non-specific fashion with fever, malaise, anemia, and weight loss. Diagnostic acuity based on history and physical examination is diminished, and therefore the scope of diagnostic evaluation must be broadened (Table 1).

               In pursuing the possibility of tuberculosis, demographic characteristics and previous tuberculosis exposure are of particular importance. A PPD should be placed in patients with CD4 cell counts at above 200/mm³ since anergy is unlikely (84). Normal chest radiographs are reported to occur in 5 to 10% of patients with HIV and tuberculosis (96, 101, 123, 135). Thus, chest radiography should play a complementary role with sputum AFB smear and culture, skin testing, and clinical examination in screening HIV-positive patients for tuberculosis. Sputum smears in patients with HIV and tuberculosis appear to be positive with the same frequency as in patients without HIV (154). A retrospective chart review of 52 of 54 HIV-infected patients with culture-proven tuberculosis evaluated at the Los Angeles County-University of Southern California Medical Center over a seven month period in the late eighties found that the most common error leading to delay in diagnosis and thus treatment was not due to atypical manifestations of tuberculosis, but rather due to failure to obtain at least three sputum samples for acid-fast smear and mycobacterial culture in patients with clinical and chest radiographic findings consistent with tuberculosis (96).

               The typical radiographic presentation of Pneumocystis pneumonia is a bilateral interstitial pattern which may be characterized as finely granular, reticular or ground-glass opacities (49). In immunodeficient HIV-infected patients, however, a normal chest radiograph does not exclude the diagnosis of Pneumocystis pneumonia. In a study conducted in a university hospital in Zurich, Switzerland over a 12 month period in 1989, 93 consecutive chest radiographs of HIV-infected patients (median CD4 count of 50) with their first documented Pneumocystis  pneumonia episode were retrospectively reviewed by radiologists blinded to the diagnosis of the subjects. Findings on chest radiograph were judged as normal in 39%, interstitial in 36%, and acinar in 25%. Normal chest radiographs were predicted by low LDH and low peripheral blood granulocytes. Of note, no statistical correlation was found between the severity of lung infiltrates and the CD4 count or severity of clinical symptoms (117). Consistent with standard practice in 1989, no primary Pneumocystis  pneumonia prophylaxis had been given to the patients. Prophylaxis with aerosolized pentamidine, however, can impose additional diagnostic difficulties by altering the typical radiographic appearance of Pneumocystis pneumonia (36, 59, 86). Patients receiving aerosolized pentamidine may develop upper lobe infiltrates (16). When findings on chest radiograph suggest Pneumocystis pneumonia, empiric therapy should be initiated and definitive diagnosis pursued with examination of induced sputum and, if necessary, bronchoalveolar lavage (BAL). Treatment should also be offered to patients for whom there is a strong clinical suspicion of Pneumocystis pneumonia (including fever, cough, dyspnea, and oxygen desaturation with exercise) but in whom the chest radiograph is normal. Recent literature suggests that high resolution computed tomography (HRCT) is useful in the evaluation of such patients. The classic CT finding of Pneumocystis pneumonia is extensive ground-glass appearance. In one series of AIDS patients with active pulmonary disease, accurate diagnosis of Pneumocystis pneumonia was made by HRCT in 94% of cases (73). In several small series (70, 134), HRCT has been shown to have a 100% negative predictive value in HIV positive patients undergoing evaluation for possible Pneumocystis pneumonia. HRCT may allow the exclusion of Pneumocystis pneumonia in patients with normal or equivocal findings on chest radiography and may obviate the need for bronchoscopy or empiric therapy in patients with a low likelihood of Pneumocystis pneumonia. Given that the "gold standard" remains direct microscopic confirmation, BAL is still indicated for definitive diagnosis in patients with suggestive radiographic studies if induced sputum is unrevealing. Although sensitive, elevated serum LDH is not specific for the diagnosis of Pneumocystis   pneumonia, as elevations are also found in patients with disseminated and pulmonary tuberculosis, bacterial pneumonias (131), and in disseminated histoplasmosis (47).

               In evaluation of diarrhea in the febrile patient with advanced HIV, it is particularly important to elicit clues such as diet, travel history, medication profile, and sexual practices. Suggested diagnostic studies are outlined in Table 2. Initial work-up should include microscopic examination and culture for bacterial pathogens, standard acid-fast and ova and parasite preparations, Clostridium difficile toxin assay, and blood cultures in the setting of high fevers. Diagnosis of these bacterial enteropathogens is usually made by stool culture, with stool examination often revealing suggestive fecal leukocytes. Blood cultures, especially in the case of Salmonella, can reveal associated bacteremia.

               Colonoscopy with biopsy should be considered in patients with persistent diarrhea and unrevealing stool studies. As mucosa can appear normal on endoscopy and infection frequently occurs in the right colon, full colonoscopy with multiple biopsies is often required (98). Diagnosis is established by the demonstration of characteristic histology and staining of biopsy samples.

               With regard to pancreatitis, diagnosis is suggested by elevated pancreatic enzymes and a compatible exam. Confirmation of opportunistic infection-related pancreatitis can be made either by CT-guided needle aspiration of the pancreas or via ERCP and culture of fluid obtained by pancreatic duct washing.

               In the evaluation of suspected abdominal tuberculosis, CT is the imaging study of choice, revealing radiographic evidence of disease and allowing for biopsy of involved lymph nodes in order to make a definitive microbiologic diagnosis with acid fast smear and culture (71, 162).

               Patients with fever and headache or other neurologic symptoms should undergo contrast-enhanced head CT or MRI. If there are no contraindications, lumbar puncture should be performed for CSF evaluation (Table 3). Opening pressure should be recorded and cell count, protein, and glucose levels measured. Microbiologic studies should include Gram's stain, bacterial culture, India ink stain, cryptococcal antigen titer determination, fungal culture, AFB stain, and mycobacterial culture. Pursuit of a viral cause, such as HSV, CMV, VZV, should be reserved for specific cases in which suspicion for the diagnosis has been raised. Diagnosis of cryptococcal meningitis is made by demonstrating cryptococcal antigen titers in blood and CSF. Although less sensitive than either cryptococcal antigen or culture determination, India ink staining can provide an early diagnosis. CSF is typically characterized by a minimal lymphocytic inflammatory response with mild elevation of protein and a normal glucose.

               In the evaluation of patients with suspected CNS space-occupying lesions, contrast-enhanced CT is an appropriate first screening test, with MRI reserved for patients with negative scans in whom clinical suspicion remains high. Serum toxoplasmosis antibodies can be helpful to establish previous infection, but negative serology does not with certainty rule out infection (126). Standard practice is to treat CNS lesions in AIDS patients that are suspicious for toxoplasmosis with empiric therapy for 2 weeks and then reevaluate with CT (44).

               Given the nonspecific nature of presentation, clinical suspicion is essential in the diagnosis of the systemic mycotic infections. A careful history with attention to region of residence and travel as well as occupation and hobbies is important. Laboratory evaluation often reveals cytopenias and elevated liver function tests, but is nonspecific. Pulmonary manifestations of Histoplasma capsulatum infection with prominent chest radiograph findings are significantly less common in the setting of disseminated disease in the AIDS population than in localized disease seen in the immunocompetent population (25). Coccidioidomycosis, however, frequently involves the lung and can mimic Pneumocystis  pneumonia radiographically (149). Thus, given the lack of specificity of clinical presentation as well as laboratory and radiographic evaluation, fungal culture is recommended to confirm diagnosis. Yield for culture diagnosis of histoplasmosis is greatest from bone marrow biopsy, and for diagnosis of coccidioidomycosis in patients with pulmonary manifestations evaluation of respiratory secretions (obtained either as expectorated sputum or via bronchoscopy with bronchoalveolar lavage) is a reasonable first step with transbronchial biopsy reserved for those with negative washings. Fungal blood cultures have been shown to have limited diagnostic value in the evaluation of the febrile AIDS patient in the absence of other evidence of fungal infection, yielding unique diagnoses only in patients near death (38, 90).

               Though nonspecific, one clue to diagnosis of histoplasmosis may be a markedly elevated serum LDH level (47). Infection of the reticuloendothelial system accounts for the majority of signs of disseminated histoplasmosis, with bone marrow involvement and resultant cytopenias common manifestations (97). Although the histoplasma urine antigen test is a very sensitive test, patients with a negative urine antigen and compatible syndrome may require bone marrow biopsy (172). Serology and skin testing are inconsistently positive in AIDS patients and are not specific for active disease (171). Reactive hemophagocytic syndrome, a disorder due to inappropriate monocyte activation and characterized by fever, unexplained cytopenias and bone marrow findings of hemophagocytic histiocytosis, has been described in patients with AIDS and disseminated histoplasmosis (94).

               Diagnosis of C. immitis is established by culture from respiratory secretions or other pathology specimens or by recognition of the organism histopathologically. Serologic testing for complement-fixing antibodies to C. immitis is helpful, but negative serology does not exclude coccidioidomycosis in the HIV population (9, 7, 149). Intradermal skin testing is of little value in establishing the diagnosis of active coccidioidomycosis in this population (7, 149).

               With regard to Penicillium marneffei, diagnosis is established by culture from blood, bone marrow or other pathologic specimen, with a potential role for serodiagnosis (177).

               Systemic MAC diagnosis is established by culture of the organism from any normally sterile site such as bone marrow, liver, lymph nodes and blood. Blood culture is the preferred method for diagnosis, with two blood cultures sufficient for the detection of the overwhelming majority of cases of MAC bacteremia (176).

               When considering disseminated Toxoplasmosis, markedly elevated lactate dehydrogenase level may suggest the diagnosis, which can be further investigated by means of polymerase chain reaction and serology for T. gondii DNA (27,178). Polymerase chain reaction testing of blood, which is available through commercial labs, may help establish the diagnosis.

               In the initial approach to the evaluation of FUO, a careful history and examination, with particular attention to medication history as well as the local prevalence of certain diseases, is imperative. Patients on primary or secondary opportunistic infection prophylaxis may have attenuated and atypical presentations of disease (86, 145, 178). As in the HIV-negative population, the diagnostic evaluation of FUO in the HIV population is fraught with controversy. Routine laboratory tests tend to be nonspecific. A high serum LDH may suggest the diagnosis of Pneumocystis  pneumonia, tuberculosis, extracerebral toxoplasmosis, histoplasmosis or lymphoma; anemia and an elevated serum alkaline phosphatase may suggest disseminated MAC or tuberculosis. Bone marrow examination has been shown to be a valuable method for detecting opportunistic mycobacterial and fungal infections (particularly MAC and histoplasmosis), as well as leishmaniasis in endemic regions, and non-Hodgkin's lymphoma. Several studies have examined the diagnostic utility of bone marrow biopsy and culture (20, 26, 60, 113, 137). While bone marrow biopsy and culture is indicated in the evaluation of pancytopenia, its role in the evaluation of fever alone is less clear cut. Bone marrow examination has been shown to be a valuable method for detecting opportunistic mycobacterial and fungal infections (particularly MAC and histoplasmosis), as well as leishmaniasis in endemic regions, and non-Hodgkin's lymphoma. Although bone marrow biopsy may offer an earlier diagnosis of disseminated MAC through microscopic examination, blood culture is more sensitive (128). Bone marrow sampling has been shown to reveal the cause of fever in approximately 30% of HIV-infected patients with FUO (26); however, the same diagnosis can often be arrived at by less invasive means. Thus, a reasonable approach in the febrile, stable outpatient is to perform bone marrow sampling after three to four weeks have elapsed (to allow time for mycobacteria to grow in culture) following initial evaluation, with three blood cultures for bacteria and mycobacteria and appropriate imaging and tissue sampling based on presentation. The role of liver biopsy in the evaluation of FUO in this population is even less clear, with the reported yield ranging from 20 to 54% (30,138).

               Of various radiographic techniques used to study FUO in HIV-infected patients, there is no one test that is uniformly revealing. Abdominal CT scanning has been shown to have a relatively low yield in this scenario, contributing to management in the minority. Sansom et al retrospectively evaluated the role of abdominal CT imaging in FUO, finding that in the majority of cases the diagnosis would have been made without resorting to CT if the results of culture from blood, bone marrow, or other tissues had been awaited (140). While useful in identifying extrathoracic infection, the insensitivity of technetium-99m-labeled antigranulocyte monoclonal antibody to pulmonary infection and lymphoma limits its role in FUO diagnosis (130). In contrast, gallium-67 citrate and indium-111-labeled polyclonal human immunoglobulin (¹¹¹In HIG) scanning more effectively image intrathoracic complications of AIDS but fail to identify gastrointestinal pathology given their lack of colonic activity (129). As a general rule of thumb, radiolabeled leukocytes are used in cases of fever of less that one week's duration and Ga-67 or ¹¹¹In HIG are used in fever of more than two week's duration. Given that most cases of FUO have a predominantly monocytic and/or lymphocytic infiltrate, gallium-67 or ¹¹¹In HIG imaging is preferable to the use of labeled leukocytes. Additionally, the use of radiolabeled leukocytes is less desirable in the HIV-positive population given the risk of needlestick injury with venipuncture and the theoretical risk of cross contamination of patients with HIV-infected blood products. Ga-67 is quite sensitive for occult pulmonary, soft tissue, and bony infection but only moderately specific; ¹¹¹In HIG is just as sensitive as Ga-67 imaging, though significantly more accurate (28). The purpose of Ga-67 imaging is to localize a potential cause for fever which can then be further investigated with other modalities such as ultrasound, CT or MRI.

               The development of fever and evidence of systemic inflammation in a patient with HIV who has a virologic and immunologic response to antiretroviral therapy represents a diagnostic dilemma - possibilities include infection with an opportunistic pathogen, immune restoration disease, or drug reaction. Measurement of pathogen-specific immune responses may be a useful strategy in some circumstances (61, 95), though at this time there are no prospective trials demonstrating the clinical utility of such assays. Thus, in the case where immune restoration disease is the most likely cause of fever and inflammation, an advisable initial approach is the continuation of antiretroviral therapy, addition of antimicrobial therapy to suppress the replication of opportunistic pathogens, and anti-inflammatory therapy as necessary.

EMPIRIC THERAPY

               The role of empiric therapy for various opportunistic infections is not well established. After a thorough work-up, an empiric trial may be considered in cases where there is a high degree of clinical suspicion despite negative test results. Once appropriate cultures have been obtained, it is reasonable in some cases of suspected MAC to consider an empiric trial. Given the fact the many of the antimycobacterial agents have activity against both tuberculosis and MAC, one must be particularly cautious with the choice of antimicrobial agents. A practical approach is the combination of a macrolide (which has no activity against tuberculosis) with ethambutol (a relatively weak antituberculosis agent). Following initiation of this regimen, most patients with disseminated MAC will defervesce while few with tuberculosis would be expected to respond.

SUMMARY

               Fever continues to be a common symptom among HIV-infected patients at all stages of disease progression. While antiretroviral regimens and OI prophylaxis have had a significant impact on overall survival, they have also added a layer of complexity to the approach to fever in this population. The CD4+ T-cell count can be used as a rough, though imperfect, guide to the evaluation of fever. Patients with CD4+ T-cell counts greater than 500/mm³ and between 200 & 500/ mm³ are more prone to M. tuberculosis and bacterial sinopulmonary infections. The evaluation of fever in patients with CD4+ T-cell counts less than 200/mm³ is more challenging because the differential diagnosis is larger and the specificity of many presentations is lost. The most common causes of fever are atypical mycobacteria, M. tuberculosis, Pneumocystis pneumonia, lymphoma and, in areas of endemicity, leishmaniasis. Despite the multitude of possible etiologies, studies have shown that the source of fever can be identified in the majority of patients. A thorough diagnostic evaluation should be pursued in all cases.

Tables and Figures

Table 1. Suggested Diagnostic Evaluation of the Febrile HIV-Infected Patient Based on CD4+ T-Cell Count

Table 2. Recommended Stool Sample Evaluation in the HIV-Infected Patient with Diarrhea

Table 3. Recommended CSF Evaluation in the HIV-Infected Patient

Table 4. Summary of Series Examining Fever of Unknown Origin in HIV-Infected Patients

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