Frederick Koster

Hantavirus Pulmonary Syndrome: A Clinical Description of 17 Patients with a Newly Recognized Disease

Background In May 1993 an outbreak of severe respiratory illness occurred in the southwestern United States. A previously unknown hantavirus was identified as the cause. In Asia hantaviruses are associated with hemorrhagic fever and renal disease. They have not been known as a cause of human disease in North America. Methods We analyzed clinical, laboratory, and autopsy data on the first 17 persons with confirmed infection from this newly recognized strain of hantavirus. Results The mean age of the patients was 32.2 years (range, 13 to 64); 61 percent were women, 72 percent were Native American, 22 percent white, and 6 percent Hispanic. The most common prodromal symptoms were fever and myalgia (100 percent), cough or dyspnea (76 percent), gastrointestinal symptoms (76 percent), and headache (71 percent). The most common physical findings were tachypnea (100 percent), tachycardia (94 percent), and hypotension (50 percent). The laboratory findings included leukocytosis (median peak cell count, 26,000 per cu...

Hemolytic-uremic syndrome after shigellosis. Relation to endotoxemia and circulating immune complexes.

To investigate three possible causes of the acute hemolysis in the hemolytic-uremic syndrome, we studied prospectively 207 children and 34 adults with shigellosis in Bangladesh. Nineteen children showed acute hemolytic anemia, a leukemoid reaction, thrombocytopenia and oliguria; nine other had, in addition, a serum urea nitrogen level of over 100 mg per diciliter. Eight of the nine had pseudomembranous colitis, and six of the nine died. The frequency of bacteremia was similar in all grades of shigellosis. Circulating immune complexes were found in 10 of 20 patients with uncomplicated shigellosis and in four of six with severe hemolytic-uremic syndrome. Limulus assay for endotoxemia was positive in nine of 18 patients with hemolysis (50 per cent) and three of 61 with uncomplicated shigellosis (5 per cent) (P less than 0.001). These data support the hypothesis that severe colitis in shigellosis is associated with circulating endotoxin from the colon producing coagulopathy, renal microangiopathy and hemolytic anemia.

Hantavirus pulmonary syndrome in the United States: A pathological description of a disease caused by a new agent

An outbreak of an acute respiratory disease in the southwestern United States has led to the recognition of a new hantaviral illness. This report describes a unique spectrum of antemortem and postmortem pathological findings seen in a case series of nine surviving patients and 13 who died. Clinical, laboratory, and autopsy findings were derived from a consecutive series of individuals confirmed to have hantavirus pulmonary syndrome. Laboratory studies included chemical, hematological, and bone marrow analyses as well as flow cytometric and immunohistochemical phenotyping. Autopsy tissues were examined by routine histological stains, immunohistochemical methods, and transmission electron microscopy. The lung is the primary target organ in this illness. Pulmonary abnormalities include pleural effusions, alveolar edema and fibrin, and an interstitial mononuclear cell infiltrate. Large immunoblast type cells are seen in the lungs, blood, bone marrow, lymph nodes, liver, and spleen. A tetrad of hematological findings includes left-shifted neutrophilic leukocytosis, thrombocytopenia, hemoconcentration in severe cases, and circulating immunoblasts. In contrast to previously described nephropathic hantaviral syndromes, hantavirus pulmonary syndrome is characterized by a unique constellation of pulmonary, hematological, and reticuloendothelial pathological findings. The pulmonary findings are distinguishable from fatal adult respiratory distress syndrome. The data suggest a capillary leak syndrome restricted to the pulmonary circulation. Likewise, the hematological picture is unique and may be valuable in the rapid identification of cases for further diagnostic studies.

High Levels of Cytokine-Producing Cells in the Lung Tissues of Patients with Fatal Hantavirus Pulmonary Syndrome

Hantavirus pulmonary syndrome (HPS) is characterized by the rapid onset of pulmonary edema and a high case-fatality rate. Hantavirus antigens have been demonstrated in pulmonary capillary endothelial cells, but the mechanisms causing capillary leakage remain unclear. Immunohistochemical staining was used to enumerate cytokine-producing cells (monokines: interleukin [IL]-1alpha, IL-1beta, IL-6, and tumor necrosis factor [TNF]-alpha; lymphokines: interferon-gamma, IL-2, IL-4, and TNF-beta) in tissues obtained at autopsy from subjects with HPS. High numbers of cytokine-producing cells were seen in the lung and spleen tissues of HPS patients, but only low numbers in the livers and kidneys. A modest increase in the numbers of cytokine-producing cells was detected in the lungs of patients who died with non-HPS acute respiratory distress syndrome (ARDS), and very few (or no) cytokine-producing cells were detected in the lungs of patients who died of causes other than ARDS. These results suggest that local cytokine production may play an important role in the pathogenesis of HPS.

Cardiopulmonary manifestations of hantavirus pulmonary syndrome.

OBJECTIVE To describe the clinical characteristics of a group of patients infected with the newly recognized hantavirus in the Southwestern United States. DESIGN Case series. SETTING Tertiary referral center. PATIENTS All patients with confirmed hantavirus infection admitted to the University of New Mexico Hospital between May 1, 1993 and January 1, 1994. INTERVENTIONS Records of patients with hantavirus infection were reviewed to collect all pertinent clinical data. MEASUREMENTS AND MAIN RESULTS Pulmonary disease in these patients was characterized by hypoxemia covering a wide range of severity. The cause of hypoxemia was an increased permeability (noncardiac) pulmonary edema which could be differentiated from hydrostatic (cardiac) pulmonary edema by its association with low pulmonary artery occlusion pressures and increased protein content of edema fluid. Hemodynamic measurements in severe cases showed a shock state characterized by a low cardiac index (range 1.6 to 3.0 L/min/min2), a low stroke volume index (range 10.5 to 29 mL/m2), and high systemic vascular resistance index (range 1,653 to 2,997 dyne.sec/cm5.m2). Progression to death was associated with worsening cardiac dysfunction unresponsive to treatment and causing oxygen debt and lactic acidosis. CONCLUSIONS The two major life-threatening pathophysiologic changes in Hantavirus Pulmonary Syndrome are increased permeability pulmonary edema, and an atypical form of septic shock caused by myocardial depression and hypovolemia.

Role of Specific CD8 + T Cells in the Severity of a Fulminant Zoonotic Viral Hemorrhagic Fever, Hantavirus Pulmonary Syndrome

We report on the role of specific CD8+ T cells in the pathogenesis of a highly lethal human viral disease, hantavirus pulmonary syndrome (HPS). HPS is a zoonotic disease caused by transmission of Sin Nombre virus (SNV) from chronically infected deer mice. In humans, this fulminant infection is characterized by lung capillary leakage, respiratory failure, and cardiogenic shock. Individuals with HLA-B*3501 have an increased risk of developing severe HPS, suggesting that CD8+ T cell responses to SNV contribute to pathogenesis. We identified three CD8+ T cell epitopes in SNV presented by HLA-B*3501 and quantitated circulating SNV-specific CD8+ T cells in 11 acute HPS patients using HLA/peptide tetramers. We found significantly higher frequencies of SNV-specific T cells in patients with severe HPS requiring mechanical ventilation (up to 44.2% of CD8+ T cells) than in moderately ill HPS patients hospitalized but not requiring mechanical ventilation (up to 9.8% of CD8+ T cells). These results imply that virus-specific CD8+ T cells contribute to HPS disease outcome. Intense CD8+ T cell responses to SNV may be induced by the encounter of the unnatural human host to this zoonotic virus without coevolution. This may also be the immunopathologic basis of other life-threatening human virus infections.

Recombinant Human Growth Hormone, Insulin-like Growth Factor 1, and Combination Therapy in AIDS-Associated Wasting: A Randomized, Double-Blind, Placebo-Controlled Trial

Wasting associated with the acquired immunodeficiency syndrome (AIDS) is a serious complication of human immunodeficiency virus (HIV) infection that causes progressive loss of both lean body mass and, more variably, fat mass [1-4]. The pathogenesis is probably multifactorial and includes the underlying viral infection, tissue cytokines, intercurrent infections, and poor intake of calories [1, 2]. Recombinant human insulin-like growth factor 1 (rhIGF-1) alone and recombinant human growth hormone (rhGH) alone have been administered to humans during various catabolic states, including fasting, the period immediately after surgery, and trauma, and have had positive effects on lean body mass [5-7]. The beneficial effects of rhGH on body composition and metabolism are reportedly mediated by increased levels of IGF-1 [4, 5]. Furthermore, animal studies have shown that rhIGF-1 has beneficial effects on lymphopoieses [8]. Limited studies of rhGH or rhIGF-1 treatment alone in patients with AIDS have also been promising, resulting in an increase in circulating IGF-1 levels, lean body mass, and muscle function [9-11]. We hypothesized that treating AIDS-associated wasting with rhIGF-1, alone or in combination with rhGH, would reverse the catabolic effects characteristic of this wasting. We further hypothesized that if rhGH therapy increased lean body mass, then physical strength, immune function, and quality of life would improve. We therefore did a randomized, double-blind, placebo-controlled trial to assess the effects of rhGH and rhIGF-1 therapy in patients with AIDS-associated wasting. The primary end points were changes in weight and lean body mass. The secondary end points were changes in muscle function, immune status, quality of life, and protein catabolism. The Institutional Review Boards of the University of New Mexico and the University of Texas Southwestern Medical Center approved the study, and all patients gave written informed consent before entering the study. Methods Patients We recruited 60 patients (58 men and 2 women) with AIDS (as defined by the Centers for Discase Control and Prevention [12]), unexplained wasting (defined as weight loss 10% of the weight before diagnosis or body mass index 19.8 kg/m2), and a CD4 count less than 200 cells/mm3. Weight before diagnosis was defined as the weight that an adult patient maintained for at least 2 years during the time the patient believed that he or she was healthy. In New Mexico, patients were recruited by postings at the University of New Mexico Hospital Infectious Disease Clinic and Veterans Administration Hospital and by physician referral from private practices in Albuquerque and Santa Fe. In Texas, patients were recruited from the University of Texas Southwestern Medical Center at Dallas, a collaborating institution, and private practices throughout the Southwest. In addition, an advertisement was placed in the directory of the American Federation for AIDS Research. The patients were admitted to the University of New Mexico Clinical Research Center for a 2-day inpatient screening assessment. This assessment included physical examination, neurologic examination, electrocardiography, and chest radiography. Additional inclusion criteria were a hematocrit of 0.28 or greater, negative result of a pregnancy test (in women), negative 7-day blood culture for Mycobacterium avium intracellulare within 4 weeks before study entry, negativity for cryptococcal antigen in serum within 4 weeks before study entry, and a chest radiograph showing no evidence of acute cardiopulmonary disease within 28 days before study entry. Exclusion criteria were body mass index of 26.0 kg/m2 or greater, opportunistic infection that resolved less than 4 weeks before study entry, diarrhea (defined as five or more bowel movements per day or identification of an enteric pathogen), history of endocrine disease associated with hypoglycemia or hyperglycemia, any disorder associated with moderate or severe edema, history of cancer within 3 years of study entry, active Kaposi sarcoma, diagnosed cardiovascular disease (including congestive heart failure and cardiomyopathy), medically significant liver dysfunction (serum alanine aminotransferase level > 200 IU, total bilirubin level > 51.3 mmol/L) and renal dysfunction (creatinine level > 176.8 mmol/L). Baseline dietary histories were analyzed; at study entry, all patients were consuming at least 25 kcal/kg of body weight and none was receiving intravenous or tube feeding. None had received therapy with anabolic or catabolic agents, including interferon, megestrol, dronabinol, oxandrolone, and corticosteroids, within 30 days of study entry. No patient had received any experimental agent or procedure within 30 days of enrollment other than prophylactic antimicrobial therapy directed at fungal, bacterial, viral, mycobacterial, or parasitic infections. All patients had been receiving antiretroviral therapy for at least 3 months before study entry and received prophylaxis for Pneumocystis carinii throughout the treatment period. Genentech, Inc. (South San Francisco, California), randomly assigned the 60 patients into four groups of 15 patients each so that balance was maintained across the groups with respect to body mass index, CD4 count, type of antiretroviral therapy, and age. The type of antiretroviral therapy was divided into five categories: zidovudine alone, didanosine alone, simultaneous administration of zidovudine and didanosine, simultaneous administration of zidovudine and zalcitabine, and other. The schedule for the subcutaneously injected therapy was as follows: Group 1 received 1.4 mg of rhGH once daily and 1 mL of placebo twice daily; group 2 received 5 mg of rhIGF-1 twice daily and 1 mL of placebo once daily; group 3 received 5 mg of rhIGF-1 twice daily and 1.4 mg of rhGH once daily; and group 4 received 1 mL of placebo three times daily. All patients received three subcutaneous injections per day for 12 weeks. Both patients and clinicians were blinded to treatment group assignments. The rhGH dosage used in this study was approximately one half the dosage used in our previous study [9]. The decision to use this dosage was based on the 2 2 analysis of variance (ANOVA) design and concern about the potential for increased incidence and severity of side effects if full doses of rhGH and rhIGF-1 were used in the patients receiving rhGH plus rhIGF-1. Patients were withdrawn from the study if they did not administer all three injections each day for 7 continuous days throughout the treatment period. Injection compliance was assessed by counting vials and interviewing the study clinician during assessment visits. In addition, IGF-1 levels were monitored in all patients and were compared with values at baseline and those in placebo recipients. The intended duration of all treatments was 12 weeks. Body Composition Lean body mass, fat mass, and percentage of body fat were measured by using dual-energy x-ray absorptiometry (Hologic QDR-1000/W, Waltham, Massachusetts), as described elsewhere [13]. Total Body Water We measured total body water using bioelectric impedance analysis (model 106, bioelectrical impedance analysis, RJL Systems, Detroit, Michigan). Testing was done between 1300 and 1500 hours, and all patients were fed and well hydrated before testing. We calculated body water by fitting the impedance measurements of resistance and reactance into previously derived prediction equations [14]. Protein Catabolism Protein catabolism was estimated by turnover of [2H5]phenylalanine (Cambridge Isotope Laboratories, Woburn, Massachusetts), as described elsewhere [15, 16]. The plasma phenylalanine level was measured by using gas chromatography mass spectrometry after being derivatized to its t-butyldimethylsilyl ester [17]. The concentration and level of [2H5]phenylalanine in plasma were analyzed by using multiple ion detection under electron-impact ionization conditions [17]. Muscle Function Computerized isotonic dynamometry (Baltimore Therapeutic Equipment, Baltimore, Maryland) was used to evaluate maximal voluntary contraction and maximum power (20%, 40%, and 60% maximal voluntary contraction) for a knee extension and a compound movement of the upper body. Quality of Life We measured quality of life using a self-administered 36-item Medical Outcomes Study questionnaire, which was previously validated in HIV-positive patients with AIDS-associated complex [18]. We accounted for missing values by averaging scores across completed items in the same scale for a particular patient. Eleven domains and three generalized domains were analyzed: 1) Total score was the average of the scores for all 36 questions; 2) functional status was the average of the scores in the domains for physical functioning, role functioning, social functioning, and cognitive functioning; and 3) well-being was the average of the scores in the domains for pain, mental health, energy and fatigue, health distress, and quality of life. Endocrine Assays Serum insulin levels were measured by using double-antibody radioimmunoassay (Pharmacia Diagnostics AB, Piscataway, New Jersey), and growth hormone levels were measured by using Tandem-R human growth hormone immunoradiometric assay (Hybritech, Inc., San Diego, California). Total IGF-1 levels were measured by double-antibody radioimmunoassay using rabbit antihuman IGF-1 antibody generated by Peter Gluckman (Auckland, New Zealand) at Genentech, Inc. Immunologic Studies Levels of HIV p24 antigen were measured in serum after acid dissociation by solid-phase sand-wich-type immunoassay that used a signal amplification technique (acid dissociated enzyme-linked immunoassay, DuPont Co., Boston, Massachusetts) [19]. CD3, CD4, and CD8 counts and percentage of total lymphocytes were measured in Ficol-separated peripheral blood mononuclear cell by flow cytometry using appropriate monoclonal antibodies and FACscan IV (Becton-Dickinson, Mountain Vi

Humoral Immune Responses in the Hantavirus Cardiopulmonary Syndrome

The immunologic responses that mediate viral clearance of and recovery from hantavirus cardiopulmonary syndrome (HCPS) due to Sin Nombre (SN) virus are unknown. Serial serum samples from 26 patients with acute SN virus infection were tested for IgG, IgA, and IgM reactivity to recombinant viral nucleocapsid (N) and glycoprotein G1 antigens by a novel strip immunoblot assay. The titers of antibodies capable of neutralizing SN virus in vitro also were determined for each sample. At admission, patients with severe disease had lower titers of IgG antibodies to SN virus N antigen (P<.033) and lower neutralizing antibody titers (P<3.4x10-5), compared with patients with mild disease. These data suggest that a strong neutralizing antibody response may be a predictor of effective clearance of and recovery from SN virus infection and raise the possibility that passive immunotherapy may be useful in HCPS.

Placebo-Controlled, Double-Blind Trial of Intravenous Ribavirin for the Treatment of Hantavirus Cardiopulmonary Syndrome in North America

UNLABELLED BACKGROUND. Ribavirin is active in vitro against hantaviruses, but the findings of an open trial of the use of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome (HCPS) were inconclusive. METHODS Subjects with suspected HCPS in the prodrome or cardiopulmonary phase but without shock were eligible for randomization to receive either intravenous ribavirin (33 mg/kg [<or=2 g], followed by 16 mg/kg [<or=1 g] given every 6 h for 4 days and by 8 mg/kg [<or=.5 g] given every 8 h for 3 days) or placebo (administered for 7 days or until the initial Sin Nombre virus antibody test result was confirmed to be negative). The primary outcome was survival at day 28 of the study without the need for extracorporeal membrane oxygenation (ECMO). RESULTS Thirty-six subjects were enrolled in the trial from March 1996 through July 2001, at which point the study was terminated prematurely because of both the slow rate of accrual of subjects and the findings of a futility analysis. Of the 36 subjects enrolled, 23 (all of whom were enrolled during the cardiopulmonary stage of HCPS) had HCPS confirmed by serologic testing. The severity of illness at entry into the study was similar among the 10 subjects with HCPS who received ribavirin and the 13 subjects with HCPS who received placebo. The proportion of subjects who survived and who did not require ECMO was similar among ribavirin recipients and placebo recipients (70% vs. 62%, respectively); 2 ribavirin recipients and 2 placebo recipients died, including 3 of 7 subjects treated with ECMO. The frequency of adverse events, including anemia, was similar between treatment groups. CONCLUSIONS The rate of accrual of subjects in the present study was inadequate to clearly assess the safety or efficacy of ribavirin in the treatment of HCPS. However, ribavirin was well tolerated, and the lack of trends supporting the use of intravenous ribavirin suggests that it is probably ineffective in the treatment of HCPS in the cardiopulmonary stage.

High Levels of Viremia in Patients with the Hantavirus Pulmonary Syndrome

Hantavirus pulmonary syndrome (HPS) is a rare but acute fulminant disease caused by Sin Nombre virus (SNV). To understand the role of the viral load in the pathogenesis of HPS, the load of virus in the blood of patients with HPS was measured. A quantitative reverse transcription-polymerase chain reaction assay was developed for SNV, because SNV is difficult to grow in cell culture. Thirty-eight samples from 26 patients with HPS were analyzed. Twenty of the 26 initial samples were positive for viral RNA (7 of 9 samples were obtained from patients with fatal cases, and 13 of 17 were obtained from survivors). Mean viral RNA copy numbers were 106.1+/-1.4/mL in positive cases (106.7+/-1.4/mL in fatal cases, 105.8+/-1.3/mL in survivors) and were correlated with peak hematocrit (P<.05) and with the lowest platelet count (P=.05). In 8 survivors who had serial samples obtained, viral RNA copy numbers decreased promptly after resolution of fever.