Joseph A. Kovacs

The cardiovascular response of normal humans to the administration of endotoxin.

Marked abnormalities in cardiovascular function accompany septic shock, and bacterial endotoxin is believed to be one of the principal mediators of these abnormalities. To evaluate the cardiovascular effects of endotoxemia in humans, we measured hemodynamic variables in nine normal subjects given an intravenous bolus dose of endotoxin (Escherichia coli, 4 ng per kilogram of body weight) and in six normal subjects given a bolus dose of saline, before and three hours after administration. All the subjects then underwent volume loading with normal saline (mean, 2217 ml) during the fourth and fifth hours after administration of the bolus, and the measurements were repeated. Three hours after the administration of endotoxin and before volume loading, the cardiac index had increased by 53 percent and the heart rate by 36 percent (both changes were significant; P less than or equal to 0.008), and the systemic vascular-resistance index had decreased by 46 percent (P = 0.004). After volume loading (five hours after the administration of endotoxin), the left ventricular ejection fraction decreased by 1 percent of the base-line value in the subjects given endotoxin, but increased by 14 percent in the controls (P = 0.008). The left ventricular end-diastolic and end-systolic volume indexes increased by 18 percent (P = 0.07) and 24 percent (P = 0.042), respectively. Left ventricular performance, as measured by the ratio of the peak systolic pressure to the end-systolic volume index, was depressed (a decrease of 0.90 in the subjects given endotoxin vs. an increase of 0.76 in the controls; P = 0.024). We conclude that the administration of endotoxin to normal subjects causes a depression of left ventricular function that is independent of changes in left ventricular volume or vascular resistance. The changes in function are similar to those observed in septic shock and suggest that endotoxin is a major mediator of the cardiovascular dysfunction in this condition.

Pneumocystis carinii Pneumonia: A Comparison Between Patients with the Acquired Immunodeficiency Syndrome and Patients with Other Immunodeficiencies

Clinical features of 49 episodes of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome were compared with those of 39 episodes in patients with other immunosuppressive diseases. At presentation patients with the syndrome were found to have a longer median duration of symptoms (28 days versus 5 days, p = 0.0001), lower mean respiratory rate (23.4 versus 30, p = 0.005), and higher median room air arterial oxygen tension (69 mm Hg versus 52 mm Hg, p = 0.0002). The survival rate from 1979 to 1983 was similar for the two groups (57% and 50% respectively). Patients with the syndrome had a higher incidence of adverse reactions to trimethoprim-sulfamethoxazole (22 of 34 versus 2 of 17, p = 0.0007). Survivors with the syndrome at initial presentation had a significantly lower respiratory rate, and higher room air arterial oxygen tension, lymphocyte count, and serum albumin level compared to nonsurvivors. Pneumocystis carinii pneumonia presents as a more insidious disease process in patients with the syndrome, and drug therapy in these patients is complicated by frequent adverse reactions.

Cryptococcosis in the Acquired Immunodeficiency Syndrome

The clinical course and response to therapy of 27 patients with cryptococcosis and the acquired immunodeficiency syndrome were reviewed. Cryptococcosis was the initial manifestation of the syndrome in 7 patients, and the initial opportunistic infection in an additional 7. Meningitis was the commonest clinical feature (18 patients). Blood cultures and serum cryptococcal antigen were frequently positive. In patients with meningitis, leukocyte count, protein level, and glucose level in cerebrospinal fluid were frequently normal; cerebrospinal fluid India ink test (82%), culture (100%), and cryptococcal antigen (100%) were usually positive. Only 10 of 24 patients had no evidence of clinical activity of cryptococcal infection after completion of therapy; 6 of these 10 had relapses shown by clinical findings or at autopsy. Standard courses of amphotericin B alone or combined with flucytosine were ineffective. Cryptococcosis in patients with the syndrome is a debilitating disease that does not respond to conventional therapy; earlier diagnosis or long-term suppressive therapy may improve the prognosis.

Guidelines for preventing opportunistic infections among HIV-infected persons - 2002

Introduction In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV) (1-3). These guidelines, which are intended for clinicians and health-care providers and their HIV-infected patients, were revised in 1997 (4) and again in 1999 (5), and have been published in MMWR (1, 4, 5), Clinical Infectious Diseases (2, 6, 7), Annals of Internal Medicine (3, 8), American Family Physician (9, 10), and Pediatrics (11); accompanying editorials have appeared in JAMA (12, 13). Response to these guidelines (e.g., a substantial number of requests for reprints, website contacts, and observations from health-care providers) demonstrates that they have served as a valuable reference for HIV health-care providers. Because the 1995, 1997, and 1999 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the relative importance of each recommendation. Since acquired immunodeficiency syndrome (AIDS) was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life for HIV-infected persons in the industrialized world. During the first decade of the epidemic, this improvement occurred because of improved recognition of opportunistic disease processes, improved therapy for acute and chronic complications, and introduction of chemoprophylaxis against key opportunistic pathogens. The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAART) as well as continuing progress in preventing and treating OIs. HAART has reduced the incidence of OIs and extended life substantially (14-16). HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy (14-16). However, certain patients are not ready or able to take HAART, and others have tried HAART regimens but therapy failed. Such patients will benefit from prophylaxis against OIs (15). In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART (15). Clearly, since HAART was introduced in the United States in 1995, chemoprophylaxis for OIs need not be lifelong. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by CD4+ T lymphocyte counts for patients who are receiving HAART. Thus, a strategy of stopping primary or secondary prophylaxis for certain patients whose immunity has improved as a consequence of HAART is logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care, and potentially facilitate adherence to antiretroviral regimens. In 1999, the USPHS/IDSA guidelines reported that stopping primary or secondary prophylaxis for certain pathogens was safe if HAART has led to an increase in CD4+ T lymphocyte counts above specified threshold levels. Recommendations were made for only those pathogens for which adequate clinical data were available. Data generated since 1999 continue to support these recommendations and allow additional recommendations to be made concerning the safety of stopping primary or secondary prophylaxis for other pathogens. For recommendations regarding discontinuing chemoprophylaxis, readers will note that criteria vary by such factors as duration of CD4+ T lymphocyte count increase, and, in the case of secondary prophylaxis, duration of treatment of the initial episode of disease. These differences reflect the criteria used in specific studies. Therefore, certain inconsistencies in the format of these criteria are unavoidable. Although considerable data are now available concerning discontinuing primary and secondary OI prophylaxis, essentially no data are available regarding restarting prophylaxis when the CD4+ T lymphocyte count decreases again to levels at which the patient is likely to again be at risk for OIs. For primary prophylaxis, whether to use the same threshold at which prophylaxis can be stopped (derived from data in studies addressing prophylaxis discontinuation) or to use the threshold below which initial prophylaxis is recommended, is unknown. Therefore, in this revision of the guidelines, in certain cases, ranges are provided for restarting primary or secondary prophylaxis. For prophylaxis against Pneumocystis carinii pneumonia (PCP), the indicated threshold for restarting both primary and secondary prophylaxis is 200 cells/L. For all these recommendations, the Roman numeral ratings reflect the lack of data available to assist in making these decisions (Box). Table. System Used to Rate the Strength of Recommendations and Quality of Supporting Evidence During the development of these revised guidelines, working group members reviewed published manuscripts as well as abstracts and material presented at professional meetings. Periodic teleconferences were held to develop the revisions. Major Changes in These Recommendations Major changes in the guidelines since 1999 include the following: Higher level ratings have been provided for discontinuing primary prophylaxis for PCP and Mycobacterium avium complex (MAC) when CD4+ T lymphocytes have increased to >200 cells/L and >100 cells/L, respectively, for 3 months in response to HAART (AI), and a new recommendation to discontinue primary toxoplasmosis prophylaxis has been provided when the CD4+ T lymphocyte count has increased to >200 cells/L for 3 months (AI). Secondary PCP prophylaxis should be discontinued among patients whose CD4+ T lymphocyte counts have increased to >200 cells/L for 3 months as a consequence of HAART (BII). Secondary prophylaxis for disseminated MAC can be discontinued among patients with a sustained (e.g., 6-month) increase in CD4+ count to >100 cells/L in response to HAART, if they have completed 12 months of MAC therapy and have no symptoms or signs attributable to MAC (CIII). Secondary prophylaxis for toxoplasmosis and cryptococcosis can be discontinued among patients with a sustained increase in CD4+ counts (e.g. 6 months) to >200 cells/L and >100200 cells/L, respectively, in response to HAART, if they have completed their initial therapy and have no symptoms or signs attributable to these pathogens (CIII). The importance of screening all HIV-infected persons for hepatitis C virus (HCV) is emphasized (BIII). Additional information concerning transmission of human herpesvirus 8 infection (HHV-8) is provided. New information regarding drug interactions is provided, chiefly related to rifamycins and antiretroviral drugs. Revised recommendations for vaccinating HIV-infected adults and HIV-exposed or infected children are provided. Using the Information in This Report For each of the 19 diseases covered in this report, specific recommendations are provided that address 1) preventing exposure to opportunistic pathogens, 2) preventing first episodes of disease, and 3) preventing disease recurrences. Recommendations are rated by a revised version of the IDSA rating system (17). In this system, the letters AE signify the strength of the recommendation for or against a preventive measure, and Roman numerals IIII indicate the quality of evidence supporting the recommendation (Box). Because of their length and complexity, tables in this report are grouped together and follow the references. Tables appear in the following order: Table 1 Dosages for prophylaxis to prevent first episode of opportunistic disease among infected adults and adolescents; Table 1. Prophylaxis to Prevent First Episode of Opportunistic Disease among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV) Table 2 Dosages for prophylaxis to prevent recurrence of opportunistic disease among HIV-infected adults and adolescents; Table 2. Prophylaxis to Prevent Recurrence of Opportunistic Disease, after Chemotherapy for Acute Disease, among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV) Table 3 Effects of food on drugs used to treat OIs; Table 3. Effects of Food on Drugs Used to Prevent Opportunistic Infections Table 4 Effects of medications on drugs used to treat OIs; Table 4. Effects of Medications on Drugs Used to Prevent Opportunistic Infections Table 5 Effects of OI medications on drugs commonly administered to HIV-infected persons; Table 5. Effects of Opportunistic Infection Medications on Antiretroviral Drugs Commonly Administered to Persons Infected with Human Immunodeficiency Virus (HIV) Table 6 Adverse effects of drugs used to prevent OIs; Table 6. Adverse Effects of Drugs Used in Preventing Opportunistic Infections Table 7 Dosages of drugs for preventing OIs for persons with renal insufficiency; Table 7. Dosing of Drugs for Primary Prevention of or Maintenance Therapy for Opportunistic Infections Related to Renal Insufficiency Table 8 Costs of agents recommended for preventing OIs among adults with HIV infection; Table 8. Wholesale Acquisition Costs of Agents Recommended for Preventing Opportunistic Infections among Adults Infected with Human Immunodeficiency Virus Table 9 Immunologic categories for HIV-infected children; Table 9. Immunologic Categories for Human Immunodeficiency Virus-Infected Children, Based on Age-Specific CD4+ T Lymphocyte Counts and Percentage of Total Lymphocytes Table 10 Immunization schedule for HIV-infected children; Table 10. Recommended Immunization Schedule for Human Immunodeficiency Virus (HIV)-Infected Children Table 11 Dosages for prophylaxis to prevent first episode of opportunistic disease among HIV-infected infants and children; Table 11. Prophylaxis to Prevent First Episode of Opportunistic Disease among Infants and Children Infected with Human Immunodeficiency Virus Tabl

CONTROLLED TRIAL OF INTERLEUKIN-2 INFUSIONS IN PATIENTS INFECTED WITH THE HUMAN IMMUNODEFICIENCY VIRUS

BACKGROUND Interleukin-2 is a cytokine that regulates the proliferation and differentiation of lymphocytes. In preliminary studies, intermittent infusions of interleukin-2 led to increases in CD4 counts in patients with human immunodeficiency virus (HIV) infection and more than 200 CD4 cells per cubic millimeter. We conducted a controlled study to evaluate the long-term effects of such therapy on both CD4 counts and the viral burden. METHODS Sixty HIV-infected patients with base-line CD4 counts above 200 cells per cubic millimeter were randomly assigned to receive either interleukin-2 plus antiretroviral therapy (31 patients, 1 of whom was lost to follow-up) or antiretroviral therapy alone (29 patients). Interleukin-2 was administered every two months for six cycles of five days each, starting at a dosage of 18 million i.u. per day. Safety and immunologic and virologic measures were monitored monthly until four months after the last treatment cycle. RESULTS In patients treated with interleukin-2, the mean (+/-SE) CD4 count increased from 428 +/- 25 cells per cubic millimeter at base line to 916 +/- 128 at month 12, whereas in the control group, the mean CD4 count decreased from 406 +/- 29 cells per cubic millimeter to 349 +/- 41 (P < 0.001). There were no significant differences between the groups in serial measurements of the plasma HIV RNA or p24 antigen concentration during the 12 months of treatment. Constitutional symptoms (fever, malaise, and fatigue) and asymptomatic hyperbilirubinemia were the chief dose-limiting toxic effects of interleukin-2 therapy. CONCLUSIONS In patients with HIV infection and base-line CD4 counts above 200 cells per cubic millimeter, intermittent infusions of interleukin-2 produced substantial and sustained increases in CD4 counts with no associated increase in plasma HIV RNA levels.

Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection : a preliminary study

BACKGROUND Interleukin-2 is an important regulatory cytokine of the immune system, with potent effects on T cells, B cells, and natural killer cells. In vitro, interleukin-2 can induce the proliferation and differentiation of peripheral-blood mononuclear cells from patients infected with the human immunodeficiency virus (HIV). METHODS We treated 25 HIV-infected patients with interleukin-2 administered as a continuous infusion at a dosage of 6 to 18 million IU per day for 5 days every 8 weeks during a period of 7 to 25 months. All patients also received at least one approved antiviral agent. Immunologic and virologic variables were monitored monthly. RESULTS In 6 of 10 patients with base-line CD4 counts higher than 200 per cubic millimeter, interleukin-2 therapy was associated with at least a 50 percent increase in the number of CD4 cells. Changes ranged from -81 to +2211 cells per cubic millimeter. Interleukin-2 therapy resulted in a decline in the percentage of CD8 lymphocytes expressing HLA-DR and an increase in the percentage of CD4 lymphocytes that were positive for the p55 chain of the interleukin-2 receptor. Four patients had a transient but consistent increase in the plasma HIV RNA level at the end of each infusion. In the remaining 15 patients, who had CD4 counts of 200 or fewer cells per cubic millimeter, interleukin-2 therapy was associated with increased viral activation, few immunologic improvements, and substantial toxic effects. CONCLUSIONS Intermittent courses of interleukin-2 can improve some of the immunologic abnormalities associated with HIV infection in patients with more than 200 CD4 cells per cubic millimeter.

Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy

The size of the pool of resting CD4+ T cells containing replication-competent HIV in the blood of patients receiving intermittent interleukin (IL)-2 plus highly active anti-retroviral therapy (HAART) was significantly lower than that of patients receiving HAART alone. Virus could not be isolated from the peripheral blood CD4+ T cells in three patients receiving IL-2 plus HAART, despite the fact that large numbers of resting CD4+ T cells were cultured. Lymph node biopsies were done in two of these three patients and virus could not be isolated. These results indicate that the intermittent administration of IL-2 with continuous HAART may lead to a substantial reduction in the pool of resting CD4+ T cells that contain replication-competent HIV.

CD4 Counts as Predictors of Opportunistic Pneumonias in Human Immunodeficiency Virus (HIV) Infection

STUDY OBJECTIVE To determine if circulating CD4+ lymphocyte counts are predictive of specific infectious or neoplastic processes causing pulmonary dysfunction. DESIGN Retrospective, consecutive sample study. SETTING Referral-based clinic and wards. PATIENTS We studied 100 patients infected with human immunodeficiency virus (HIV) who had had 119 episodes of pulmonary dysfunction within 60 days after CD4 lymphocyte determinations. MEASUREMENTS AND MAIN RESULTS Circulating CD4 counts were less than 0.200 X 10(9) cells/L (200 cells/mm3) before 46 of 49 episodes of pneumocystis pneumonia, 8 of 8 episodes of cytomegalovirus pneumonia, and 7 of 7 episodes and 19 of 21 episodes of infection with Cryptococcus neoformans and Mycobacterium avium-intracellulare, respectively. In contrast, circulating CD4 counts before episodes of nonspecific interstitial pneumonia were quite variable: Of 41 episodes, 11 occurred when CD4 counts were greater than 0.200 X 10(9) cells/L. The percent of circulating lymphocytes that were CD4+ had a predictive value equal to that of CD4 counts. Serum p24 antigen levels had no predictive value. CONCLUSIONS Pneumocystis pneumonia, cytomegalovirus pneumonia, and pulmonary infection caused by C. neoformans or M. avium-intracellulare are unlikely to occur in HIV-infected patients who have had a CD4 count above 0.200 to 0.250 X 10(9) cells/L (200 to 250 cells/mm3) or a CD4 percent above 20% to 25% in the 60 days before pulmonary evaluation. Patients infected with HIV who have a CD4 count below 0.200 X 10(9) cells/L (or less than 20% CD4 cells) are especially likely to benefit from antipneumocystis prophylaxis.

Persistence of HIV in Gut-Associated Lymphoid Tissue despite Long-Term Antiretroviral Therapy

Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.

A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS

OBJECTIVE To evaluate foscarnet sodium in treating cytomegalovirus retinitis in patients with AIDS. PATIENTS Twenty-four previously untreated persons with AIDS and cytomegalovirus retinitis who were at low risk for loss of their visual acuity. INTERVENTION PATIENTS were randomly assigned to receive either no therapy (delayed treatment, control group) or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. MEASUREMENTS PATIENTS were examined weekly until they reached the primary clinical end point, defined as progression of their retinitis border by 750 microns or the development of a new retinal lesion due to cytomegalovirus. Progression was evaluated using retinal photographs by masked readers. Secondary evaluations included changes in visual acuity, cytomegalovirus shedding in the blood and urine, serum levels of human immunodeficiency virus type 1 (HIV-1) p24 antigen, and total CD4 T lymphocyte counts. RESULTS The mean time to progression of retinitis was 3.2 weeks in the control group (n = 11) compared with 13.3 weeks in the treatment group (n = 13) (P less than 0.001). Nine of 13 patients in the treatment group had positive blood cultures for cytomegalovirus at entry and all nine cleared their blood of cytomegalovirus by the end of the induction period (P = 0.004) compared with one of six patients in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet treatment were seizures (2 of 13 patients), hypomagnesemia (9 of 13), hypocalcemia (11 of 13), and elevations in serum creatinine above 176.8 mumol/L (2.0 mg/dL) (3 of 13). The control patients received an average of 0.2 units of blood per week compared with an average of 0.6 units of blood per week for the patients on treatment. CONCLUSIONS The administration of foscarnet decreases the rate of progression of cytomegalovirus retinitis in persons with AIDS. Its judicious use is likely to prevent loss of vision in these patients. In this study, however, there was little change in visual acuity in patients in either the immediate or delayed treatment group because only patients with non-sight-threatening disease were selected.