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320 Causes of Fever in Patients Infected with Human Immunodeficiency Virus Who Were Admitted to Boston City Hospital Lawrence M. Barat, Julia E. Gunn, Kathleen A. Steger, Chris J. Perkins, and Donald E. Craven From The Maxwell Finland Laboratory for Infectious Diseases, Section of Infectious Diseases, Boston City Hospital and Boston University School of Medicine; Adult Clinical AIDS Program, Department of Medicine, Boston City Hospital; and Epidemiology and Health Services Sections, Boston University School of Public Health, Boston, Massachusetts We prospectively studied causes of fever in patients with human immunodeficiency virus (HIV) infection that required admission to a municipal hospital. A total of 168 HIV-infected persons were admitted for 220 episodes of fever: 72% were male, 80% were nonwhite, 65% reported prior injection drug use, and 74% had a baseline CD4 lymphocyte count of <2oo/mm3 • Bacterial infections, principally pneumonia, accounted for >60% of the episodes; Streptococcus pneumoniae and Staphylococcus aureuswere most commonly isolated. Pneumocystis carinii pneumonia (PCP) and disseminated infection with Mycobacterium avium complex (MAC) comprised 53% of the remaining sources of fever. In comparison with episodes of fever due to nonbacterial causes, those associated with common bacterial infections were significantly more likely to involve patients with a history of injection drug use (P = .02), higher admission leukocyte count (P < .004), shorter duration of fever (P = .003), shorter hospital stays (P = .0001), and a CD4 count of >loo/mm3 (P = .002). We conclude that bacterial infection, especially pneumonia, is a common cause of fever in HIV-infected patients admitted to our hospital. Patients with bacterial infections are more likely to report a history of injection drug use and have CD4 counts of > lOO/mm3, shorter duration of fever, decreased length of hospitalization, and lower mortality than patients with fever due to PCP, disseminated MAC infection, or other causes. Fever is a frequent symptom in people infected with HIV. Infection is a common cause of fever, especially in the symptomatic stages of HIV disease [1-16]. In the United States, fever may be associated with opportunistic infections, such as Pneumocystis carinii pneumonia (PCP) or disseminated Mycobacterium avium complex (MAC) infection [1-3], or with bacterial infections due to Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus injiuenzae [1-16]. Previous detailed studies of fever in HIV-infected persons have focused on fever of unknown origin or on outpatients [17-19]. Sepkowitz and co-workers described causes of fever in an outpatient cohort of predominantly homosexual males with advanced HIV disease [20]. Approximately one-half of the cohort had fevers during the study, most of which were caused by opportunistic infections, such as PCP or MAC infection, or by bacterial infections due to infected central venous catheters. Our study analyzes causes of fever in HIV-infected persons admitted for fever to the medical service at a municipal Received 31 October 1995; revised 3 April 1996. Presented in part at the 7th International Conference on AIDS (abstract no. MB2413), held in Florence in June 1991, and at the 8th International Conference on AIDS (abstract no. PoB3832), held in Amsterdam in July 1992. Reprints or correspondence: Dr. Donald E. Craven, Thorndike 311, Boston City Hospital, 818 Harrison Avenue, Boston, Massachusetts 02118. Clinical Infectious Diseases 1996;23:320-8 © 1996 by The Universityof Chicago. All rights reserved. 1058--4838/96/2302-0017$02.00 hospital, and it examines differences in risk factors and outcome for those with bacterial infections vs. other causes of fever. Methods Study Population This prospective study was conducted in the inpatient medical service at Boston City Hospital from November 1990 through March 1991 and again from October 1991 through March 1992. Eligibility requirements were admission to the inpatient medical service at Boston City Hospital and evidence of HIV infection, either by documentation of HIV-1 seropositivity or diagnosis of AIDS on the basis of the 1987 criteria of the Centers for Disease Control and Prevention (CDC) [21]. In order to be enrolled, a patient had to have an oral temperature of ~100.4°F on 2 successive days (or of ~101°F during any single measurement within the first 48 hours of admission) and had to undergo a diagnostic evaluation for the cause of fever. Inpatients were identified through the Clinical AIDS Program's HIV liaison service, which is notified of all HIVinfected patients at the time of admission. Most of the patients were followed in the Boston City Hospital's Adult Clinical AIDS Program, which provides care to >850 HIV-infected patients, of whom >70% have a history of injection drug use, 65% are nonwhite, 30% are women, and 15% are homeless. Demographic information, medical history, laboratory data, description of the hospital course, results of diagnostic studies, em 1996;23 (August) Fever and HIV Infection and relevant outcomes were collected from a medical record review and recorded on standardized forms by one of the authors (L.B., C.P., or lG.). Data from autopsy reports were included for the two subjects on whom a postmortem examination was performed; both had non-Hodgkin's lymphoma. The most recent absolute CD4 lymphocyte count (from within 6 months of the admission) was used for analysis. Mortality rates were based on deaths during the admission. In our investigation, 168 HIV-infected study patients had 220 episodes of fever that required hospitalization; these 168 included all HIV-infected patients admitted for fever to the medical inpatient service during the study period. The cause of fever was determined on the basis of a clinical diagnosis proven by microbiological confirmation or a probable diagnosis without microbiological confirmation; some patients had multiple causes of fever. Diagnostic Criteria for Causes of Fever The diagnosis of bacterial infection as a cause of fever was made clinically, with microbiological confirmation by culture, if possible; infections caused by mycobacterial species were analyzed separately. The criteria for a diagnosis of bacterial pneumonia were a clinical history of cough with sputum production; radiographic evidence of a new, focal alveolar infiltrate or consolidation; and resolution of symptoms with antibiotic therapy. Endocarditis was diagnosed as either probable or possible, with use of the criteria of von Reyn et al. [22]. Central venous catheter infection was diagnosed either by the presence of local cellulitis or purulent drainage at the catheter site or by growth of a pathogen, such as Staphylococcus epidermidis, in cultures of both the blood and catheter. Pyuria and growth of a single species in urine culture (> 105 cfu/mL) were necessary for the diagnosis of urinary tract infection. Cellulitis was defined as a localized area of warmth, erythema, swelling, and tenderness, with or without purulent exudate, that responded to antibiotic therapy. A soft-tissue abscess was defined by aspiration or drainage of purulent material from the affected area. Osteomyelitis was defined by growth of a pathogen in cultures of bone or blood, with radiographic or radionuclide evidence of bone inflammation or destruction. Septic arthritis was diagnosed following growth of a pathogen in cultured joint fluid. A diagnosis of sinusitis was based on a history of localized headaches, the air-fluid level on a sinus radiograph or CT scan, and a clinical response to antibiotic therapy. Bacteremia was defined as growth of a pathogenic species in blood culture. For cases in which these organisms could be skin contaminants, two positive blood cultures were required. Only primary bacteremia (that lacking a primary focus of infection) was considered as a separate cause of fever. Opportunistic infections were diagnosed according to criteria established in 1987 by the CDC [21]. Tumors required histologic diagnosis. Pancreatitis was defined as hyperamylasemia 321 with sonographic or radiographic evidence of pancreatic inflammation. Diagnosis of drug fever required the exclusion of any other obvious potential sources of fever and the resolution of fever following withdrawal of the suspected medication. Comparative Analyses Demographic information, baseline clinical status, laboratory findings, and outcomes for episodes in which a cause of fever was identified were compared to those for episodes of unexplained fever. Episodes of fever with a single cause vs. those with multiple causes were analyzed in a similar fashion. An analysis was performed comparing 109 episodes caused by a single diagnosed bacterial infection (n = 104) or two bacterial infections (n = 5) with 69 episodes due to nonbacterial, or other, causes (65 of these had a single cause and 4 had two such causes). "Other" causes of fever included all parasitic, mycobacterial, viral, and fungal infections, as well as noninfectious diagnoses such as drug fever, pancreatitis, and tumor. Thirteen episodes of fever that were due to a bacterial infection and another cause were excluded from this analysis. Data Analysis Data were entered into a Foxpro (Microsoft Corp., Redmond, WA) database. Analysis was performed with use of the Statistical Package for the Social Sciences (SPSS, Chicago) [23]. A two-tailed X2 test was utilized to derive P values for discrete variables [24]. When cells contained less than five expected values, a Fisher's exact test was performed. Risk ratios were calculated as relative risks with 95% confidence intervals. Probabilities for nonparametric continuous variables were assessed with Wilcoxon's rank sum test. Results Study Population During the l l-month study period, 168 study subjects had 220 episodes of fever (figure 1). Of these 168 subjects, 131 (78%) had one episode, 26 (15%) had two episodes, 8 had three episodes, 2 had four episodes, and 1 had five episodes of fever requiring admission to the hospital. Of the 220 episodes, the majority involved patients who were male and nonwhite, had a history of injection drug use, and had AIDS or advanced HIV disease (table 1). Antiretroviral medications had been prescribed in 123 episodes (56%), and prophylactic regimens against PCP had been administered in 96 (44%), almost half of which were with aerosolized pentamidine. Causes of Fever A cause of fever was identified in 191 (87%) of the 220 episodes. A single cause of fever was diagnosed in 169 episodes 322 Barat et al. In 29 episodes, nodiagnosis was made 65 other diagnoses 10 bacterial infections in 5 episodes 13bacterial infections and 13other diagnoses in 13episodes 1996;23 (August) monary infections with S. pneumoniae accounted for 33% of all microbiologically confirmed bacterial infections and twothirds of all culture-positive episodes of pneumonia. S. aureus was the second most common blood pathogen isolated (25%); endocarditis, central venous catheter infection, and pneumonia were common primary sources. Escherichia coli was the causative agent in two-thirds of the episodes of fever due to urinary tract infections. Bacterial infections that were not confirmed by culture included 33 episodes of pneumonia, 8 skin and softtissue infections, and 5 episodes of sinusitis. A total of 43 bacterial, mycobacterial, and fungal pathogens were isolated from blood (figure 3). Two-thirds of all blood- 168patients admitted with fever 104 bacterial infections ern 8 other diagnoses in4 episodes Table 1. Demographic and clinical data from 220 episodes of fever in 168 HIV-infected inpatients at Boston City Hospital. Variable, with regard to patients Total of127 bacterial infections Figure 1. Summary of data regarding 168 patients with 220 episodes of fever requiring admission to the hospital: 131 patients who had a single episode and 37 patients who had multiple episodes (n = 89). No cause of fever was identified in 29 episodes (13%); in the remaining 191 episodes, either one (n = 169) or two (n = 44) causes of fever were diagnosed. Overall, we identified 127 bacterial infections and 86 other causes of fever (P. carinii pneumonia, 31 episodes; mycobacterial infection, 15; fungal infection, 9; viral infection, 8; parasitic infection, 3; tumor, 7; pancreatitis,S; drug fever, 2; aca1culous cholecystitis, 3; and miscellaneous, 3. (88%), and two causes were identified in 22 episodes. Compared with the 191 episodes of fever in which the cause was diagnosed, the 29 episodes in which no cause could be identified occurred significantly (P < .05) more often in males (90% vs. 70%), nonwhites (97% vs. 77%), and patients who had a serum albumin level of <3.3 mg/dL (39% vs. 74%), a serum aspartate aminotransferase level greater than three times the upper limit of normal (29% vs. 10%), a fever for <2 study days (82% vs. 50%), and a hospital stay of <7 days (72% vs. 35%). Bacterial Infections Of the 213 causes of fever identified in 191 episodes of fever, 60% were infections with common bacterial pathogens (table 2). Community-acquired bacterial pneumonia accounted for 73 (57%) of the total number of bacterial infections (figure 2). Bacterial infections were diagnosed in 88 (54%) of the 163 episodes of fever in patients with a baseline CD4 count of <200/mm3 ; 50 (57%) of these 88 episodes were due to pneumonia. Of the 127 bacterial infections, 65% were proved by microbiological confirmation and 35% were presumed (table 3). Pul- Age (y) 18-30 31-40 41-50 >50 Sex No. (%) of episodes 41 125 41 13 (19) (57) (19) (6) Male 159 (72) Female Race 61 (28) White Black Hispanic Risk factor Injection drug user (IDU) Homosexual or bisexual male Homosexual or bisexual male and IDU Heterosexual Other* Clinical status t AIDS Symptomatic (no AIDS) Asymptomatic No prior evaluation CD4 lymphocyte count <200/mm 3 200- 500/mm3 >500/mm3 Not available Prescribed medication Zidovudine Didanosine Trimethoprim-sulfamethoxazole Dapsone Aerosolized pentamidine Isoniazid Rifampin Ciprofloxacin Nystatin or miconazole troches Ketoconazole or fluconazole 45 (20) 145 (66) 30 (14) 140 20 3 51 7 (64) (9) (1) (23) (3) 104 65 39 12 (47) (30) (18) (5) 163 26 8 23 (74) (12) (4) (10) 103 20 19 31 46 (47) (9) (9) (14) (21) 20 7 5 58 34 (9) (3) (2) (26) (15) * Includes recipients of blood and blood products and unknown factors. On the basis of the 1987 CDC criteria (see text). t em 1996;23 (August) Fever and HIV Infection Table 2. Summary of 213 diagnosed causes of 191 episodes of fever involvingHIV-infectedsubjects admittedto Boston City Hospital during the periods of study. Cause of fever Bacterial Pneumonia Skin and soft-tissue infection Sinusitis Endocarditis Osteomyelitis or septic arthritis Catheter sepsis Urinary tract infection Salmonellosis Clostridium difficile colitis Mycobacterial Disseminated Mycobacterium avium complex infection Disseminated Mycobacterium tuberculosis infection Mycobacterium chelonae pneumonia Parasitic Pneumocystis carinii pneumonia Cerebral toxoplasmosis Viral Disseminated varicella infection Cytomegalovirus retinitis Herpes simplex (primary or esophagitis) Acute hepatitis B Enteroviral meningitis Fungal Cryptococca1 meningitis Candida endocarditis Candida esophagitis Tumor Lymphoma Kaposi's sarcoma (visceral) Carcinoma Other Pancreatitis Acalculous cholecystitis or sclerosing cholangitis Drug fever Lymphoid interstitial pneumonia Gouty arthritis Pneumothorax No. of episodes (% of all causes) 127 (60) 73 18 7 10 2 323 fever; nine patients with PCP had been prescribed prophylaxis. Disseminated MAC infection accounted for another 6% of the other causes of fever; ten of these infections were diagnosed by blood culture and two by bone marrow aspiration. Both patients whose blood yielded Mycobacterium tuberculosis had no evidence of pulmonary parenchymal disease. Except for one episode of PCP diagnosed in a patient with a CD4 lymphocyte count of 240/mm 3 , the 59 AIDS-defining opportunistic infections were seen solely in subjects with baseline CD4 lymphocyte counts of <200/mm3 . 6 9 1 1 15 (7) 12 2 1 34 (16) 31 Admissions Involving Multiple Diagnoses Of the 22 episodes in which there were two identified causes of fever, 5 each were due to two bacterial infections, 4 had two nonbacterial causes, and 13 had one of each (figure 1). No significant differences were found in demographic information, CD4 lymphocyte count, admission laboratory data, or outcome measures between episodes in which two fever sources were identified and those involving only one diagnosis. 3 8 (4) 2 2 2 1 1 9 (4) 6 1 2 7 (3) Outcomes Of the 10 episodes of fever lasting > 14 days, 3 were attributed to bacterial infections (lung abscess, sinusitis, and empyema), 6 had nonbacterial causes (PCP, pancreatitis, non-Hodgkin's lymphoma, acalculous cholecystitis, and disseminated 60 5 1 1 13 (6) 5 3 2 1 1 1 n =73 50 ;;g ~ (/) c: 40 0 13 ~ .s l1i "a5 t5 co 30 20 co 10 NOTE. For 29 fevers, no source was identified; for 22, two sources were identified. stream infections were caused by bacterial species, and S. aureus, S. pneumoniae, and other streptococcal species accounted for > 50% of the isolates. Other Infectious Causes Other infectious agents comprised 73 (34%) of the 213 causes of fever. Fifty-nine (81%) met the 1987 CDC criteria for AIDS-defining opportunistic infections (table 2) [21]. PCP accounted for 42% of the nonbacterial, or other, causes of Figure 2. Summaryof 127 episodes of fever attributedto bacterial infections,of which 83 (65%) were bacteriologically confirmed. Pneumonia accounted for 73 (57%) of the 127 bacterial infections, followed by skin and soft-tissue infection (14%), possible or probable endocarditis (8%), and urinary tract infection (7%). The black portion of each bar defines the percentage of infections that were associated with bacteremia. The number of episodes in which each type of infection was diagnosed (n) is indicated at the top of each bar ("other" includes mycobacterial, fungal, and viral infections as well as all noninfectious etiologies, as listed in the text). Barat et al. 324 Table 3. Pathogens isolated (and the primary site of infection) in 81 cases of culture-confirmed bacterial infection causing fever in patients admitted to Boston City Hospital. Organism(s): site or type of infection Gram-positive bacteria (n = 58) Streptococcus pneumoniae: pneumonia Staphylococcus aureus: Endocarditis Bone and joint Catheter sepsis Pneumonia Skin or soft tissue Sinusitis Streptococcus species* Endocarditis Skin or soft-tissue Pneumonia Staphylococcus epidermidis: catheter sepsis Enterococcus faecalis: urinary tract Bacillus cereus: endocarditis Clostridium difficile: colitis Gram-negative bacteria (n = 21) Escherichia coli: urinary tract Haemophilus influenzae (non-type b): pneumonia Pseudomonas aeruginosa: Pneumonia Sinusitis Skin or soft tissue Moraxella catarrhalis: pneumonia Klebsiella pneumoniae: urinary tract Proteus mirabilis: urinary tract Acinetobacter baumannii: catheter sepsis Eikenella corrodens: skin or soft tissue Salmonella enteritidis group G: bacteremia Mixed (n = 2) Bacteroides and Streptococcus species: skin or soft tissue E. coli and Klebsiella oxytoca: skin or soft tissue No. of episodes of fever 27 20 6 em 1996;23 (August) was due to nonbacterial or other causes (n = 69), they were significantly more likely (P < .05) to report a history of injection drug use; have an elevated admission leukocyte count, higher mean absolute CD41ymphocyte count (137 ± 182/mm 3 vs. 64 ± 107/mnr'), shorter duration of fever, and decreased hospital stays; and demonstrated a trend toward lower hospital mortality. As shown in figure 4, nonbacterial or other causes of fever, usually opportunistic infections, were more commonly noted in patients with a CD4 count of < 100/mm 3 than in patients with bacterial infections. 2 4 4 3 1 7 3 3 I 1 1 1 1 6 5 4 2 1 1 1 1 1 1 1 1 Discussion Although fever may occur at any stage of HIV infection, it is most commonly a symptom in people with advanced HIV infection, and it may be caused by a wide spectrum ofinfectious agents, tumors, or commonly prescribed drugs [17,20,25,26]. We were able to identify a cause in 87% of the 220 episodes of fever in this study of HIV-infected inpatients, which is consistent with the 83% reported by Sepkowitz and co-workers [20] with regard to a cohort of outpatients. Bacterial pneumonia, the single most common diagnosis, accounted for more than one-half of the bacterial infections identified and one-third of all causes overall. S. pneumoniae was the etiologic agent in 66% ofthe culture-confirmed cases of pneumonia. Thirty percent of the patients with pneumococcal pneumonia in our study had bacteremia, a rate that is consistent with that in other reports [5, 6, 8, 9]. Our data support earlier observations from this hospital and other centers, underscoring the increased susceptibility of HIV-infected patients to bacterial pneumonia [4, 5, 8-12]. Our findings, however, differ from those of Sepkowitz and co-workers [20], who reported a 20% incidence of pneumonia in their longitudinal study of outpatients, predominantly homo- NOTE. Forty-five bacterial infections were not bacteriologically confirmed. * Includes j3-hemolytic streptococci (n = 5) and viridans streptococci (n = 2). tuberculosis), and the remaining patient had cerebral toxoplasmosis and central venous catheter sepsis. Ten subjects died during hospitalization: 3 had bacterial infections (sinusitis, pneumonia, and empyema/cellulitis), 6 had nonbacterial conditions (2, non-Hodgkin's lymphoma; 2, PCP; and 1 each, candidal endocarditis and pancreatitis), and 1 died with unexplained fever. Four study subjects were febrile at the time of their death (one each had pneumonia and pancreatitis, and two had lymphoma). Bacterial Infections vs. Other Causes As shown in table 4, when patients with fever due to bacterial infection (n = 109) were compared with patients whose fever C. neoformans C. tropicalis M. avium complex (n = 10) M. tuberculosis (n =2) Figure 3. Summary of organisms isolated from blood cultures following 43 admissions of Hlv-infected patients with fever. Grampositive bacteria accounted for 25 (58%) of the pathogens isolated and 86% of the bacterial isolates. S. pneumoniae and S. aureus were the most common organisms isolated. Ten episodes of M avium complex infection, two episodes of M tuberculosis bacteremia, and two episodes of fungemia were identified. em 1996;23 (August) 325 Fever and HIV Infection Table4. Comparison of 109 HIV-infected subjects with fever due to bacterial infection and 69 with fever due to other conditions. No. (%) of patients with fever due to indicated cause Variable Age (y) 18-40 >40 Sex Male Female Race White Nonwhite Risk-related behavior Injection drug use Other Medication on admission Trimethoprim-sulfamethoxazole Dapsone Ciprofloxacin Rifampin Laboratory values WBC count, > 11,000/mm3 CD4 lymphocyte count, < 100/mm 3 Outcome Fever, ~3 d Hospital stay, ~7 d Death Bacterial Other* (n == 109) (n == 69) P value RR (95% CI) 80 (73) 29 (27) 51 (74) 18 (26) .9 0.99 (0.83-1.19) 73 (67) 36 (33) 54 (78) 15 (22) .1 0.86 (0.71-1.03) 27 (25) 82 (75) 14 (20) 55 (80) .5 1.22 (0.69- 2.16) 79 (72) 30 (28) 38 (55) 31 (45) .02 1.30 (1.02-1.66) (12) (10) (7) (7) .2 .3 .008 .03 0.55 (0.21 ~ 1.46) 1.54 (0.67 - 3.51) 0.13 (0.20-1.06) 7 (6) 17 (16) 0 1 (1) 8 7 5 5 24 (22)t 4 (6)+ 49 (52) 48 (76) .004 .002 3.74 (1.36-10.32) 0.68 (0.54-0.86) 76 (73) 52 (48) 3 (3) 34 (51) 13 (19) 6 (9) .003 .001 .09 1.44 (1.11-1.86) 2.53 (1.49-4.29) 0.32 (0.08-1.22) * Nonbacterial causes include viral (n == 5), fungal (n == 7), and mycobacterial (n == 8) infection; Pneumocystis carinii pneumonia (n = 31); toxoplasmosis (n = 1); tumors (n == 7); and noninfectious conditions (n == 10). t n == 95. + n == 63. sexual men, and found no cases attributable to S. pneumoniae or H influenzae. This disparity probably reflects differences in both study design and study populations. Our study population was primarily nonwhite; injection drug use was included as a risk-related behavior; and hospitalization was required for inclusion in this study. Our subjects who reported a history of injection drug use were significantly more likely to have a bacterial infection, especially pneumonia, than were patients with other risk-related behaviors (P < .02), a finding that confirms the recent report by Hirschtick and co-workers [16]. S. aureus, the second most common bacterial species isolated from our study patients, accounted for 10 (40%) of the 25 cases of gram-positive bacteremia, all of which were secondary to endocarditis and central venous catheter infections. High rates of S. aureus infections in HIV-infected patients have also been reported by other investigators [4, 13-15, 20, 27, 28]. Our data, and those of others, suggest that most bacterial infections occur in the setting of advanced immunosuppression (CD4 lymphocyte count, <200/mm3 ) [4-15, 20, 27, 28]. The increased susceptibility of HIV-infected individuals to bacterial infections is probably related to defects in lymphocytes, macrophages, and neutrophil function [26-30]. In those with advanced HIV disease, impairments of chemotactic and phagocytic activity of neutrophils and macrophages have been demonstrated. Defects in antibody production and in the activity of both classical and alternative complement pathways have also been reported [29-33]. In addition, the risk of bacterial infections and colonization in patients with AIDS may be altered by the use of prophylactic agents against opportunistic infections [27, 28, 34]. Some investigators have suggested that bacterial infections may accelerate the progression of HIV disease [14, 35, 36]. Selwyn and co-workers reported that injection drug users have a substantial rate of pre-AIDS morbidity from pyogenic bacterial infections, such as pneumonia and sepsis [14]. Serious bacterial infection or pulmonary tuberculosis accelerated the rate of progression to AIDS by 3.7-fold when CD4lymphocyte counts were >500/mm3 and by 220-fold when CD4+ lymphocyte counts were < 150/mm3 • The exact mechanism for this is unclear, but it may be related to a direct effect or upregulation, either through classical antigen presentation to the CD4 lym- Barat et al. 326 80 ~ n =48 60 ~ > .S! '0 40 til Q) ~ :::l 0 en 20 o <100 100-199 200-500 >500 CD4 cell count (lmm 3 ) Figure 4. Summary of the frequency of bacterial infection (solid bars) vs. other sources of fever (hatched bars), as related to absolute CD4+ T lymphocyte counts (zmrrr'), Frequencies were defined as the percentages of all bacterialinfections (n = 95) and of all other sources of fever (n = 63) among persons whose CD4 lymphocyte count was determined (see text). Bacterial infectionswere commonover a wide spectrumof CD4 counts. Other sources,which includedopportunistic infections, were more common when the CD4 count was < 1OO/mm3 • Thirteen episodes of fever caused by both a bacterial infection and another source were excluded. Other causes included mycobacterial, fungal, and viral infections, as well as all noninfectious etiologies(as listed in the text). The number at the top of each bar is the number of episodes. phocyte or indirectly via superantigens, cytokines, and other immune mediators [35-38]. In our study, other (nonbacterial) infections accounted for 34% of the causes of fever identified. Fifty-nine (82%) of these were AIDS-defining opportunistic infections that met the 1987 CDC criteria, and 76% occurred in patients whose CD4 lymphocyte count was < 100/mm3 • Most of these were PCP or disseminated MAC infections. Almost one-third of the patients with PCP had been prescribed prophylaxis, a proportion suggesting the possibility of poor compliance or drug failure [39]. Of the 12 patients with mycobacterial bacteremia, 10 had MAC infection and 2 had M tuberculosis infection with no evidence of pulmonary disease. More than one-half of the patients with disseminated MAC infection had another fever source identified. If lysis-centrifugation blood cultures had not been included in the admission evaluation of these patients, these mycobacterial infections might have remained undetected [3, 40]. Compared with patients with nonbacterial (other) causes of fever, the group with bacterial infection was significantly more likely to report a history of injection drug use and to have a significantly higher admission leukocyte count and baseline CD4 lymphocyte count, have more rapid resolution of fever, and have a 9% shorter hospital stay. The crude mortality rate for the 220 episodes of fever was 4.5%. In our comparative analysis, death was the outcome of 3% of the 109 episodes of fever due to bacterial infections and 6% of those due to nonbacterial causes. CID 1996;23 (August) Given the high rate of bacterial infections in people with AIDS, future studies should focus on the utility of specific prophylactic regimens, particularly against infection with S. pneumoniae, H influenzae, and S. aureus. Trimethoprim/sulfamethoxazole, when administered as prophylaxis for PCP, decreases the rate of bacterial colonization and infection and therefore is preferred to aerosolized pentamidine [16, 28, 34, 41]. However, a high rate of side effects and poor compliance with the use of oral medication in some risk groups remain problems [42]. In addition, the use of rifabutin or clarithromycin for prophylaxis against MAC infection may also reduce the rates of bacterial infection, but there remain concerns over the emergence of antibiotic-resistant strains of pneumococcus and other bacteria [43, 44]. The use of effective bacterial vaccines to prevent infection would be ideal, but to date the immune response of AIDS patients to pneumococcal polysaccharide and H infiuenzae type b conjugate vaccines has been unsatisfactory [4, 8, 11]. It is noteworthy that the H influenzae type b vaccine would not have protected against the nontypeable strains that accounted for all H influenzae infections in this study. All of the clinic patients in our program were offered pneumococcal vaccine at the time of our study, but recent concerns that pneumococcal vaccine may increase plasma levels of HIV-RNA have led us to reconsider the risk-benefit of routine vaccination [45]. Data from this study may not be generalizable because of the high proportions of injection-drug-using and homeless study patients, who may be less compliant with medications and who may be prescribed aerosolized pentamidine as prophylaxis for PCP, a less-effective agent than trimethoprim-sulfamethoxazole in preventing bacterial infection. In addition, this study was conducted over two different time periods, each including fall and winter seasons, when more bacterial infections occur. Finally, admission to the hospital was required for enrollment in the study, and with the changing health care delivery systems in the United States, in the future similar patients might be treated on an outpatient basis. Clinicians frequently feel overwhelmed when faced with possible causes of fever in HIV-infected patients. Our study indicates that the cause of the patient's fever is usually identified and that bacterial pathogens, particularly those causing pneumonia, are a common source of fever in patients with AIDS who require hospitalization. In contrast to opportunistic infections, such as PCP and MAC infection, which usually occurred in patients with CD4 lymphocyte counts of < 100/mm 3, bacterial infections occurred as both early and late complications of HIV infection. However, clinicians must realize that the relationship between bacterial infections and HIV infection is a dynamic process that may change with the population at risk, the natural history of the disease, and the use of antibiotics for prophylaxis against opportunistic pathogens, as well as the evolution of treatment and antimicrobial resistance. Acknowledgments The authors thank Drs. Peter Rice, Brant Viner, and Judith Steinberg for their assistance in the development of the study, Dr. em 1996;23 (August) Fever and HIV Infection Meg Sullivan for her careful review and comments, and Maria Tetzaguic for her assistance in preparation of the manuscript. 327 21. Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR Morb Mortal Wkly Rep 1987;36(suppl IS):3S-15S. 22. von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective References 1. Follansbee SE, Busch DF, Wofsy CB, et al. 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