AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 September 8, 1995 Opportunistic Infections (Part VIII) Fever Information Sheet for Patient Education June 16, 1995 Fever occurs when your body temperature rises above normal. It may be accompanied by chills, increased sweating, muscle and joint aches, and fatigue. You should see your doctor if fever lasts more than three days, is unusually high, or is associated with other symptoms and signs of serious illness. Fever has many causes, including infections, tumors, inflammatory conditions, and prescription and alternative medications. In people with early HIV disease, fever does not usually indicate a serious HIV-related condition. In people with advanced HIV disease, fever is more likely to be caused by unusually or opportunistic diseases, such as Pneumocystis carinii pneumonia (PCP), Mycobacterium avium complex infection (MAC), or lymphoma. What is fever? Fever is a higher than normal body temperature. Usually the human body temperature is controlled within a narrow range near 37 degrees Centigrade or 98.6 degrees Fahrenheit by turning on and off mechanisms that produce and release heat. Normally a person's temperature is lower in the morning and rises during the day by about one degree Fahrenheit (0.5 degrees Centigrade). What are the common causes of fever? Fever occurs in response to a variety of infections caused by viruses, bacteria, fungi, and parasites. It may occur in association with infection of the blood and other organs or tissues, such as the gums (gingivitis, tooth abscesses), upper respiratory tract (colds, sinusitis), heart (endocarditis), lungs (bronchitis, pneumonia), liver (hepatitis), gut (gastroenteritis), kidney (pyelonephritis, cystitis), skin (cellulitis, abscess), and brain and spinal cord (meningitis, encephalitis). Certain tumors such as lymphomas may cause fever. Fever also occurs with some inflammatory conditions, such as blood clots in large vessels (thrombophlebitis) and red and swollen joints (arthritis). In addition, fever may be a side effect of many medications. What conditions cause fever in HIV-infected persons? In person with early stages of HIV disease (T-cell count greater than 500), fever is usually caused by the same self-limited conditions, such as viral upper respiratory infections, as in non- HIV infected persons. However, it may also be associated with more serious problems including bacterial pneumonia, sinusitis, and shingles (herpes zoster). Tuberculosis (TB) is a highly contagious, treatable infection that is a potential cause of fever in persons who live in crowded conditions or who have been in contact with others with TB. In persons with later stage HIV disease (T-cell count less than 200), any of the above problems may cause fever, but it may also indicate the presence of unusual conditions such as PCP, MAC, and cytomegalovirus (CMV). An abnormally low white blood cell count (neutropenia) and a permanent intravenous catheter are common conditions in advanced HIV disease that increase the risk for serious infections associated with fever. Prescription, nonprescription, or alternative medications are also possible causes of fever. Other conditions should always be ruled out before attributing fever to HIV disease itself. What should you do if you have a fever? A new fever is a reason for concern because it may indicate a serious infection that can cause harm if not identified and treated rapidly. You should see your doctor if you develop a mild fever that lasts more than three days. For a new fever that is unusually high (above 39.5 degrees Centigrade or 103 degrees Fahrenheit) or associated with other symptoms and signs of significant illness, it is important to contact your doctor immediately. In order to help your doctor determine what is causing the fever, you should think about and have ready the following information: 1) Is the fever a continuing problem or has it been present only a few days? 2) Do you have other signs of illness, such as cough, diarrhea, or localized pain, that will give clues about the medical condition causing the fever? 3) Are you severely ill or only mildly uncomfortable? 4) What prescription and alternative medications are you taking? The answers will guide your doctor to choose what tests to do and how quickly they should be done. Tests may include blood tests; cultures of blood, sputum, or urine; skin tests; x-rays or scans; or diagnostic bronchoscopy (insertion of a flexible tube into the lungs). In general, if you are only mildly ill, then simple, noninvasive (not painful or risky) tests will be done. If the condition is an emergency or if you have advanced HIV disease, extensive testing and hospital admission are much more likely. How can fever be controlled? Fever is a symptom. The best way to treat fever is to work with your doctor to identify and treat the condition causing it. Fever can usually be controlled with medications, including acetaminophen (Tylenol), or nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen (Motrin), or naproxen (Naprosyn). NSAIDs tend to have more side effects, particularly stomach distress, than acetaminophen. Drinking plenty of liquids when you have a fever is important to prevent dehydration from increased body fluid loss. [Editor's Note: This is one of a series of Information Sheets prepared by the National AIDS Treatment Information Project (NATIP) with funding from the Henry J. Kaiser Family Foundation. The materials are designed for self-education by HIV-infected persons and for counseling by community advisors, case managers, social workers, and clinicians. For more information about NATIP, call 617-667-5520 or write: Helen E. Woods Wogan, Project Manager, Libby 317, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. Fax: 617-667-2885. Internet: hwoods@bih.harvard.edu] Fever - References AU - Barat LM ; Gunn JE ; Steger KA ; Perkins CJ ; Steinberg JL ; Viner BL ; Craven DE TI - Bacterial infections are the most common cause of fever in HIV-infected patients admitted to a municipal hospital. AB - OBJECTIVE: To determine the etiology of fever and its relationship to risk category in HIV-infected people admitted with a febrile illness to the medical inpatient service of a municipal hospital. METHODS: We prospectively monitored all HIV-infected patients admitted with fever (greater than 100.4 degrees F) to determine the source of their illness and outcome. RESULTS: Of the 204 patients followed, a fever source was documented in 177 patients (87%), who were predominantly male (70%), non-white (78%), and reported a history of injecting drug use (IDU-66%); 83% had CD4 counts of less than 200/mm3. Of 195 documented fever sources, 117 (60%) were bacterial infections (BI). Pneumonia accounted for 59%, skin and soft tissue infections for 10% and endocarditis for 8% of all BI. Streptococcus pneumoniae (N = 23) and Staphylococcus aureus (N = 15) were the most frequently isolated pathogens. Twenty-seven patients (23%) had bacteremia, S. pneumoniae (26%) and S. aureus (33%) were again the predominant isolates. Patients with a history of IDU were more likely to have a BI (p = 0.05). When compared to 65 patients with other diagnoses (tumors, opportunistic infections, etc.), those with BI had significantly higher median white blood cell (WBC) count (6.4 vs. 4.0/mm3, p less than 0.0001) and CD4 count (95 vs 20/mm3, p less than 0.005). Patients with BI also had shorter median duration of fever (2.0 vs 3.0 days, p less than 0.01) and hospital stays (8 vs 12 days, p less than 0.0001). Although mortality rates of patients with BI were three-fold higher than those with other diagnoses, the difference was not statistically significant (3% vs 9%, p = 0.07). CONCLUSIONS: BI were the most common diagnoses in HIV-infected patients requiring hospitalization for fever, particularly in those with a history of IDU. BI occurred at usual sites and common pathogens were isolated. Patients with BI had distinct presentations and improved outcomes, as compared to those with fever from other sources. SO - Int Conf AIDS. 1992 Jul 19-24;8(2):B229 (abstract no. PoB 3832). AU - Bissuel F ; Leport C ; Perronne C ; Longuet P ; Vilde JL TI - Fever of unknown origin in HIV-infected patients: a critical analysis of a retrospective series of 57 cases. AB - OBJECTIVES. The aim of the study was to assess the incidence and aetiology of fever of unknown origin in human immunodeficiency virus (HIV)-infected patients, and to evaluate the usefulness of the main diagnostic procedures. DESIGN. A retrospective study. SETTING AND SUBJECTS. We reviewed the records of 270 HIV-infected patients who were hospitalized for the first time in a department of infectious and tropical diseases during the 27 month study period. MAIN OUTCOME MEASURES. Fifty-seven patients (21%) had a history of fever of unknown origin. RESULTS. The aetiology was found in 49 cases (86%). The major cause of the fever was mycobacteriosis: atypical mycobacteria in 10 cases, Mycobacterium tuberculosis in 10, mycobacteria of unspecified type in two, and BCG strain in one. A liver biopsy and a thoracic CT scan greatly contributed to the diagnosis of mycobacterial infection. Seventeen patients were given empiric antimycobacterial therapy as a therapeutic test, of whom seven had a favourable response. The other main causes of fever were cytomegalovirus infection in five patients, leishmaniasis in four, and lymphoma in four. CONCLUSIONS. Fever of unknown origin is a frequent occurrence in the course of HIV infection, and mycobacterial infection should be considered as a first-line diagnosis in such cases. The place of empiric antimycobacterial therapy in the diagnostic strategy requires further evaluation, but appears to be an alternative to multiple investigative procedures. SO - J Intern Med. 1994 Nov;236(5):529-35. AU - Durack DT ; Street AC TI - Fever of unknown origin--reexamined and redefined. SO - Curr Clin Top Infect Dis. 1991;11:35-51. AU - Hambleton J ; Aragon T ; Modin G ; Northfelt DW ; Sande MA TI - Outcome for hospitalized patients with fever and neutropenia who are infected with the human immunodeficiency virus. AB - We conducted a retrospective cohort study to evaluate the occurrence of bacteremia and associated mortality among hospitalized patients who were seropositive for the human immunodeficiency virus (HIV) and who developed fever and neutropenia following antineoplastic chemotherapy or for other reasons. Review of medical records revealed 224 episodes in 142 patients. Of these episodes, 57% occurred following antineoplastic chemotherapy, and 43% occurred under other circumstances. Members of the chemotherapy group had significantly less-advanced HIV disease, a lower mean absolute-neutrophil-count nadir, and a shorter duration of hospitalization. There was no difference between the two groups in the frequency of bacteremia or mortality due to all causes when they were compared by multivariate analysis. Statistically significant univariate and multivariate predictors of bacteremia included sepsis syndrome and concurrent infection. Predictors of mortality included sepsis syndrome, concurrent infection, bacteremia, and antimicrobial therapy. This study suggests that the cause of neutropenia in HIV-seropositive patients is not a predictor of the outcome of fever and neutropenic episodes. Instead, clinical presentation and concomitant illnesses have a greater impact on outcome for a patient. SO - Clin Infect Dis. 1995 Feb;20(2):363-71. AU - Kirby AJ ; Munoz A ; Detels R ; Armstrong JA ; Saah A ; Phair JP TI - Thrush and fever as measures of immunocompetence in HIV-1-infected men. AB - The occurrence of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus type 1 (HIV-1)-infected individuals with high CD4+ counts indicates poor immunologic function. Thrush and persistent fever, easily recognized clinically, are potential measures of immunocompetence. This analysis establishes the complex interactions of CD4+ count, thrush, and persistent fever to predict the occurrence of PCP. Analyses used 20,632 person visits from 2,568 HIV-1-seropositive homosexual or bisexual men participating in the Multicenter AIDS Cohort Study (MACS). Comprehensive examinations were conducted semiannually, while occurrences of PCP were assessed continuously. The occurrence of thrush and fever increase in frequency as CD4+ levels decrease. The relative hazard of PCP in the presence of thrush compared with the absence of thrush rises (p < 0.05) from 1 for the lowest CD4+ category to approximately 5 in the highest categories. The relative hazard of PCP in the presence of fever compared with the absence of fever is above one (p < 0.05) in all CD4+ categories. No cases of PCP occurred in individuals on PCP prophylaxis with CD4+ counts > 200/mm3. These results suggest that HIV-1-related symptoms provide a measure of failing immune function that is not reflected by enumeration of CD4+ lymphocytes alone and support the United States Public Health Service recommendation that symptomatic individuals with CD4+ counts > 200/mm3 should be considered for PCP prophylaxis. SO - J Acquir Immune Defic Syndr. 1994 Dec;7(12):1242-9. AU - Leach RM ; Davidson AC ; O'Doherty MJ ; Nayagam M ; Tang A ; Bateman NT TI - Non-invasive management of fever and breathlessness in HIV positive patients. AB - In a prospective study of 72 human immunodeficiency virus (HIV) positive patients presenting with fever and breathlessness, a non-invasive management protocol, incorporating a scanning technique using radioactively labelled diethylenetriamine penta acetate (DTPA) and sputum induction, was found to be highly sensitive and specific in the early detection of Pneumocystis carinii pneumonia (PCP). At presentation, the DTPA scan was abnormal in 34 of 36 cases of PCP, irrespective of smoking history, whilst the chest radiograph was diffusely abnormal in 21 cases. Sputum induction identified 7 of 14 patients with PCP in the first six months of its use and 7 of 10 patients over the last six months. The DTPA lung scan and induced sputum examination are non-invasive techniques which can be used to investigate out-patients. In combination they detected all cases of PCP at presentation, reduced the need for bronchoscopy, resulted in a low case fatality (5.4%) and reduced the need for admission. SO - Eur Respir J. 1991 Jan;4(1):19-25. AU - Levin M ; Hertzberg L TI - Kaposi's sarcoma of the bone marrow presenting with fever of unknown origin. AB - Kaposi's sarcoma (KS) has become more common in the United States with the spread of the Acquired Immunodeficiency Syndrome (AIDS) epidemic. The epidemic form associated with AIDS involves primarily skin and visceral organs. Bone marrow involvement is rare. We present a case of Kaposi's sarcoma that was diagnosed upon bone marrow biopsy, without skin or visceral involvement, that presented with fever of unknown origin which responded to indomethacin and anti-KS chemotherapy. Kaposi's sarcoma of the bone marrow should be considered in the differential of febrile illness of unknown origin in patients with AIDS. SO - Med Pediatr Oncol. 1994;22(6):410-3. AU - Liu YC ; Cheng DL ; Liu WT ; Liu CY ; Yen MY ; Wang RS ; Lin HH ; Chen YS TI - AIDS presenting as fever of undetermined origin: report of four cases. SO - Int J STD AIDS. 1993 Sep-Oct;4(5):303-6. AU - Lozano F ; Pujol E ; Torres-Cisneros J ; Bascunana A ; Canas E ; Garcia-Ordonez MA ; Hernandez-Quero J ; Vergara A ; Marquez M ; Diez F ; et al TI - Fever of unknown origin in HIV-infected patients. A multicentric-prospective study of 116 cases. Andalusian Group for Study of Infectious Diseases. AB - OBJECTIVE: HIV-associated FUO is an entity with peculiar significance and not yet adequately studied till now. Our purpose was to document the occurrence, etiology, prognosis and profitability diagnosis of FUO. METHODS: A prospective 2-year (92-93) study was realized with 116 in-patients from 14 hospitals of Andalusia. They fullfilled following criterion: 1) Proved HIV infection, 2) Fever > 38.3 degrees C, more of three weeks of duration, 3) Not etiologic diagnosis after one week hospitalization, 4) Not evidence of clinical or radiologic data of focal point infection at admission moment. RESULTS: Frecuency of HIV-associated FUO was 3.1%. The average patient's age was 31.2 + 8.4 years. 88% of them were males, 82% intravenous drug abusers and 40% were AIDS diagnosis previously. Mean duration of fever and hospitalization was 68 + 38.3 days and 40.1 + 25.3 respectively. Mean number of CD4 lymphocites was 98.7 + 145/mm3 (76% had < 100/mm3 and 59% had < 50/mm3). A sure diagnosis was achieved in 75% of patients. Most common entities were: tuberculosis (37%), visceral leishmaniasis (19%), MAI infection (8%) and lymphomas (7%). Diagnosis was probably suspected in 19% of patients (tuberculosis was suspected in 65% of them) and in a 6% any etiologic diagnosis was obtained. The most valuable investigations was hepatic biopsy (67%) and bone marrow puncture (38%). During hospitalization period 10% of patients died. DISCUSSION AND CONCLUSIONS: 1) HIV-associated FUO is a relatively common entity that appears in advanced HIV-infection and bears a high economic cost. 2) More prevalent etiologies in our country are tuberculosis and visceral leishmaniasis. SO - Int Conf AIDS. 1994 Aug 7-12;10(2):197 (abstract no. PB0803). AU - Mijch AM ; Hoy JF TI - Unexplained fever and drug reactions as clues to HIV infection. AB - Unexplained fever, usually self-limiting and often due to a viral infection, is commonly seen in many medical practices. When should a doctor consider HIV in relation to a patient's fever? SO - Med J Aust. 1993 Feb 1;158(3):188-9. AU - Oehler R ; Loos U ; Ferber J ; Fischer HP TI - Diagnostic value of liver biopsy in HIV patients with unexplained fever. AB - A common problem in HIV patients is fever which remains unexplained even with careful diagnostic examination. Besides the lungs and brain which show a broad spectrum of diseases, the liver is most often involved in HIV-related diseases. During the last 2 years 15 patients with serum antibodies to HIV underwent diagnostic liver biopsy in our department because of fever which could not be explained by non-invasive procedures. Seven of the 15 patients were HIV-positive but without AIDS prior to admission. Thirteen of 15 patients had abnormal biochemical liver function tests, but only in one patient ultrasound showed focal lesions in the liver. We found Pneumocystis carinii in the biopsy of the patient with multiple small focal lesions in the liver, one patient had Hodgkin's disease which had not been diagnosed prior to liver biopsy. Four patients were diagnosed of having disseminated mycobacteriosis in the liver with granuloma and acid-fast bacilli. In two of the patients with mycobacteriosis epithelioid-cell granuloma could also be found in bone marrow biopsy, and in two patients acid-fast bacilli were found in duodenal biopsy at endoscopic examination. Only 2 of the 4 patients with mycobacteriosis had AIDS prior to liver biopsy. We found non-specific toxic hepatopathy in 2 cases, hepatosteatosis in 2 and cirrhotic parenchymal lesions due to hepatitis C in 2 patients. Three patients had a nondiagnostic liver biopsy. In one of them we could find meningitis due to cryptococcosis, one had cerebral toxoplasmosis and in the other patient fever was possibly due to disseminated Kaposi's sarcoma which did not involve the liver. RESULTS: In 40% of our patients liver biopsy led to the diagnosis of a specific AIDS-related disease. Additional 40% of the patients were diagnosed of having liver diseases that had not been diagnosed before. Only in 20% of the patients liver biopsy did not show any abnormalities. In conclusion, liver biopsy proved to give important additional information with therapeutic consequences in HIV-positive patients with fever which remained unexplained after non-invasive diagnostic procedures. SO - Int Conf AIDS. 1992 Jul 19-24;8(2):B211 (abstract no. PoB 3722). AU - Rogeaux O ; Priqueler L ; Hoang C ; Cadranel JF ; Opolon P ; Gentilini M TI - Diagnostic usefulness of liver biopsy for unexplained fever in HIV patients. AB - OBJECTIVE: Isolated fever or fever (F) with abnormalities of liver function tests (LFT) are common in HIV patients (pts). The aim of this prospective work was to evaluate the utility of liver biopsy (LB) with microbiological studies for unexplained fever in HIV pts. PATIENTS: From January 1991 to June 1992, 21 pts (20 male) underwent LB. A liver biopsy was performed during the same period in 4 pts with LFT abnormalities and without F. In the remaining 17 pts (T4 < or = 100/mm3; n = 12), LB was performed for unexplained F. These pts were separated in 2 groups (G). G1: 15 pts had unexplained F for at least 15 days with LFT abnormalities, ie: alkaline phosphatase 1.5 x upper limit of normal range and/or ALT > or = 2N. In all pts AIDS related cholangiopathy had been ruled out by morphological methods. Group 2 consisted of 2 pts without LFT abnormalities. METHODS: The diagnosis of unexplained F required the absence of pathogens in a location outside the liver. RESULTS: G1: in 7 pts out of 15 (46.6%) LB showed epithelioid granuloma. The discovery of hepatic granuloma was followed by antituberculosis therapy that led to relief of fever in all 7 pts. In one pt in this group, LB showed inclusions consistent with cytomegalovirus infection. G2: LB was not contributory in these 2 pts. CONCLUSION: LB enabled a positive diagnosis in 53.3% of pts (8/15) when F was associated with LFT abnormalities. It authorized a diagnosis of infection leading to the immediate institution of specific therapy. SO - Int Conf AIDS. 1993 Jun 6-11;9(1):446 (abstract no. PO-B19-1867). AU - Sepkowitz KA ; Telzak EE ; Carrow M ; Armstrong D TI - Fever among outpatients with advanced human immunodeficiency virus infection. AB - BACKGROUND: Fever is common among persons with human immunodeficiency virus (HIV) infection. However, the clinical implications of fever in this population have not been evaluated. We therefore undertook a prospective study of fever in persons with advanced HIV infection to determine the incidence and etiology of fever in this patient group. METHODS: Prospective natural history study of 176 patients with advanced HIV infection followed up at Memorial Sloan-Kettering Cancer Center, New York, NY, from April 1, 1990, through December 31, 1990. RESULTS: Fever occurred in 46% of patients. A diagnosis was made in 83% of episodes, with acquired immunodeficiency virus-defining illnesses accounting for half of the diagnosed cases. Patients whose conditions required more than 2 weeks to diagnose most often had lymphoma, Mycobacterium avium- intracellulare bacteremia, or Pneumocystis carinii pneumonia. Four patients had persistent unexplained fever without a clear source. Only one patient had fever that clearly responded to antiretroviral therapy. CONCLUSIONS: Fever is common among outpatients with advanced HIV infection. Human immunodeficiency virus itself is rarely the cause of fever in such patients; the cause of the fever should be thoroughly evaluated. SO - Arch Intern Med. 1993 Aug 23;153(16):1909-12. AU - Zylberberg H ; Le Gal FA ; Robert F ; Zylberberg L ; Dupouy-Camet J ; Viard JP TI - Isolated fever due to disseminated toxoplasmosis under cotrimoxazole prophylaxis. AB - We report a case of prolonged and clinically unexplained fever in one AIDS patient with a CD4 cell count of 70/mm3, and who had received cotrimoxazole for several months as primary prophylaxis. Tests performed to investigate this fever and especially the presence of Toxoplasma infection included chest X-rays, BAL, ophthalmoscopy, cerebral CT scan and MRI, cardiac echography, blood cultures for mycobacteria, fungi and CMV, cryptococcus antigenemia, bone marrow biopsy, liver function tests, LDII and CPK blood levels, and were normal or negative, except the polymerase chain reaction (PCR) for Toxoplasma gondii, which was positive in the blood on two occasions. After a few days of anti-toxoplasmic therapy (pyrimethamine plus clindamycin) the patient became afebrile and the Toxoplasma PCR became repeatedly negative. This patient probably had disseminated toxoplasmosis attenuated by cotrimoxazole. We point out the interest of Toxoplasma PCR in the screening of unexplained fever in AIDS patients, particularly when they receive cotrimoxazole prophylaxis. SO - Int Conf AIDS. 1994 Aug 7-12;10(2):154 (abstract no. PB0631).