Infection by non-A, non-B acute viral hepatitis in hospital employees

The aim of this study is to evaluate the risk of infection of non-A, non-B acute hepatitis (NANB-AH) in hospital employees. Among 593 patients with acute viral hepatitis (AVH), hospital employees were 3/147 (2%) in type A, 19/174 (11%) in type B and 21/272 (8%) in non-A, non-B (NANB). All 43 patients were medical staffs such as doctors, nurses and laboratory technicians. Out of 21 patients with NANB hepatitis of hospital employees, 7 were doctors, 14 nurses and 6 laboratory technicians. Eight of them had preceding accidental needlestick exposures. Out of 17,290 employees of our hospital during 18 years, 27 medical persons developed AVH. They were 2 hepatitis A, 10 hepatitis B and 15 hepatitis NANB. No non-medical staff developed AVH. Out of 15 NANB hepatitis patients, 7 had needlestick accidents 4 to 6 weeks before development of the illness, and all donor patients showed liver diseases. During 3 years (1985 to 1987), there were 116 needlestick accidents in our hospital which happened in medical staffs alone, and 50 of them were NANB hepatitis-related accidents. Three ml of human immune serum globulin (ISG) was administered intramuscurally just after accidents to 23 persons but not to 27 persons. NANB hepatitis were developed in 2 doctors who were not treated with ISG. In conclusion, NANB hepatitis occurred in hospital employees especially in medical staffs.     

Acute onset hemoglobinemia and/or hemoglobinuria and sequelae following Rh(o)(D) immune globulin intravenous administration in immune thrombocytopenic purpura patients

Rh(o)(D) immune globulin intravenous (anti-D IGIV) was licensed by the United States Food and Drug Administration (FDA) in March 1995 to treat patients with immune thrombocytopenic purpura (ITP). Anti-D IGIV induces extravascular hemolysis, an expected adverse reaction that is consistent with the presumed mechanism of action. Between licensure and April 1999, the FDA received 15 reports of hemoglobinemia and/or hemoglobinuria following anti-D IGIV administration that met the case definition for this review. The mechanism responsible for hemoglobinemia and/or hemoglobinuria is unexplained. Review of these reports was prompted by the seriousness and the unexpectedness of treatment-associated sequelae experienced by 11 patients. Of these patients, 7 developed sufficient onset or exacerbation of anemia that orders were written for packed red blood cell transfusions, although only 6 patients were transfused. Eight patients experienced the onset or exacerbation of renal insufficiency, and 2 patients underwent dialysis. One patient died due to complications of exacerbated anemia. Six patients experienced 2 to 3 sequelae. Absent validated incidence data, a 1.5% estimated incidence rate from published clinical trial data and a 0.1% estimated reporting rate from FDA and drug utilization data were calculated for reported cases of hemoglobinemia and/or hemoglobinuria. This review presents the first case series of anti-D-IGIV-associated hemoglobinemia and/or hemoglobinuria and provides pretreatment and posttreatment clinical and laboratory findings of the case series patients. The primary purpose of this review is to increase awareness of this potentially serious occurrence among physicians and health care professionals who manage ITP patients treated with anti-D IGIV, thereby enabling prompt recognition and treatment of sequelae. (Blood. 2000;95:2523-2529)     

Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh(0)(D) immune globulin intravenous administration for immune thrombocytopenic purpura

The Food and Drug Administration (FDA) licensed Rh(o)(D) immune globulin intravenous (anti-D IGIV) on March 24, 1995, for treatment of immune thrombocytopenic purpura (ITP). A previous review described data on 15 patients who experienced acute hemoglobinemia or hemoglobinuria following anti-D IGIV administration for ITP or secondary thrombocytopenia. Eleven of those patients also experienced clinically compromising anemia, transfusion with packed red blood cells, renal insufficiency, dialysis, or death. That review suggested that patients receiving anti-D IGIV be monitored for those and other potential complications of hemoglobinemia, particularly disseminated intravascular coagulation (DIC). Through November 30, 2004, the FDA received 6 reports of DIC associated with "acute hemolysis" (or similar terms), 5 of which involved fatalities. The attending or consulting physicians assessed that acute hemolysis or DIC caused or contributed to each death. This review presents the first case series of DIC associated with acute hemoglobinemia or hemoglobinuria following anti-D IGIV administration for ITP. The purpose of this review is to increase awareness among physicians and other health care professionals that DIC may be a rare but potentially severe complication of anti-D IGIV treatment. Increased awareness of DIC as a diagnostic possibility may enable prompt recognition and medical intervention in affected patients.     

Evaluation of the specificity of an immunoprecipitin test for non-A, non-B hepatitis

The specificity of a new antigen-antibody system (devised at the International Center for Medical Research and Training [ICMRT], San José, Costa Rica) for non-A, non-B (NANB) hepatitis was evaluated. ICMRT antigen was found in eight (21%) of 38 patients with acute NANB hepatitis; 22 patients (58%) seroconverted, including three who were positive for ICMRT antigen. Five patients with chronic NANB hepatitis were persistently positive for ICMRT antigen and negative for ICMRT antibody during several years of observation. Neither ICMRT antigen nor seroconversion was found among 11 patients with hepatitis A and 19 with hepatitis B occurring concomitantly with NANB hepatitis; only two of 56 patients with other liver diseases had ICMRT antigen, both presumably with chronic antigenemia. Seven of 128 household contacts of patients with NANB hepatitis had ICMRT antigen; 27 had antibody initially, and 35 (37% of susceptible contacts) seroconverted during the observation period. Less than 4% of household contacts of patients with hepatitis A or B seroconverted.     

Prevalence of hepatitis G virus in hepatitis C virus (HCV)-infected patients and in HCV-contaminated intravenous immunoglobulin products

Hepatitis GB virus C/hepatitis G virus (HGV) is an RNA virus, which appears to be transmitted by parenteral exposure to contaminated blood and blood products, and may be associated with clinical hepatitis in humans. The prevalence of HGV was investigated in hepatitis C virus (HCV)-infected patients, and (HCV)-contaminated immune globulin intravenous products (IGIV), manufactured prior to the introduction of viral inactivation processing, and in recipients of these lots. Nested primers, specific for the 5' non-coding region of HGV, were designed and used to test 100 chronic HCV patients, 10 HCV RNA-positive IGIV lots and 36 of the recipients of these products. Hepatitis G virus specificity of the polymerase chain reaction (PCR) products was confirmed by sequencing a number of the amplified products and comparing the results with the published prototype sequence for HGV RNA. HGV RNA was detected in 23 of the 100 (23%) HCV-infected patients. The level of alanine aminotransferase (ALT) was lower in HCV–HGV coinfected patients than those with HCV infection alone. Hence, the severity of HCV infections is not influenced by HGV. Two of the 10 (20%) IGIV lots tested positive for HGV RNA; however, none of the serum samples from recipients of IGIV contained detectable HGV RNA although many were infected with HCV. This suggests that the transmission of HGV RNA from IGIV to the recipients is less efficient than that seen for HCV.     

Acute renal failure after intravenous anti-D immune globulin in an adult with immune thrombocytopenic purpura

Intravenous anti-D immune globulin (anti-D IGIV) is indicated for the treatment of immune thrombocytopenic purpura (ITP) in nonsplenectomized patients who are Rh(D)-positive. Recent reports have described episodes of intravascular hemolysis (IVH) and acute renal failure (ARF) after anti-D IGIV. We report the first adult patient with ITP who required and received dialysis after IVH and ARF complicating treatment with anti-D IGIV. Whether the transfusion of 2 units of Rh(D)-positive red cells, indicated for the resulting anemia, exacerbated the IVH and renal failure is unclear. Three weeks after the administration of anti-D IGIV (13 days after two hemodialysis treatments), the patient's renal function had returned to normal. This case highlights the infrequent but potentially serious side effects of anti-D IGIV and the need to monitor a patient's renal function closely if there is evidence of IVH after infusion of anti-D IGIV. If red cell transfusion is indicated, we recommend the use of Rh(D)-negative red cell products.     

Acute viral hepatitis in Lebanon: evidence for a HAV-like non-A non-B hepatitis

Ninety-three cases of acute viral hepatitis in adult Lebanese patients were followed-up prospectively for a period ranging from 6 to 18 months. These included 33 hepatitis A (HAV), 32 hepatitis B (HBV) and 21 non-A, non-B hepatitis (NANB) cases. The clinical and seroepidemiologic characteristics of the three types were evaluated. HAV was characterized by a short prodroma (less than 1 week) and a high IgM level. HBV did not differ from similar cases reported in the Western world except for a complete absence of male homosexuals and drug addicts as a possible route of transmission. NANB hepatitis in Lebanon is mainly a sporadic infection similar to HAV except that the prodromal phase is prolonged (greater than 14 days) and IgM levels are within normal limits. The failure to develop chronicity in NANB suggests that the virus of sporadic NANB may be different from that which causes post-transfusional (PTH) NANB.     

Anti-HCV immunoglobulin M antibody in patients with hepatitis C

Anti-hepatitis C virus (HCV) immunoglobulin M antibody titres were measured by an enzyme-linked immunosorbent assay method in 16 patients with non-A, non-B acute hepatitis (NANB AH), 13 with non-A, non-B fulminant hepatitis (NANB FH) and nine with type C chronic hepatitis. Anti-HCV IgM was positive in one of the 16 patients with NANB AH, six of the 13 with NANB FH, and five of the nine with type C chronic hepatitis. Anti-HCV IgG was positive in eight of the 16 patients with NANB AH and eight of the 13 with NANB FH. Either anti-HCV IgM or anti-HCV IgG were positive in 10 of the 13 patients with NANB FH. All of the five anti-HCV IgM positive patients with type C chronic hepatitis were undergoing an exacerbation of the diseases, while all of the anti-HCV IgM negative patients were in a remission stage which had lasted for more than 6 months. The findings of this study suggest that anti-HCV IgM is useful for the early diagnosis of type C FH and may be a useful marker of diseases activity in type C chronic hepatitis.     

Mechanisms of bacterial opsonization by immune globulin intravenous: correlation of complement consumption with opsonic activity and protective efficacy

To study the mechanism of bacterial opsonization by immune globulin intravenous (IGIV) complement consumption and polymorphonuclear leukocyte (PMNL) membrane receptor (FcRlo, CR1, and CR3)-mediated phagocytosis of Staphylococcus epidermidis, Klebsiella pneumoniae, and groups A and B streptococci were examined. IGIV alone did not consume complement and showed no opsonic activity by itself for these organisms. When these bacteria were preopsonized in IGIV, significant amounts of complement were consumed (44%-94%) and the uptake and killing of bacteria occurred. The in vitro opsonic activity of IGIV for these organisms was significantly correlated with the amount of complement consumed by the IGIV-opsonized bacteria (r = .85, P less than .05). The in vivo protective efficacy of IGIV also appeared to be directly associated with its ability to activate and consume complement (r = 1.0, P less than .001). Antibodies to FcRlo (Leu 11) markedly inhibited phagocytosis of bacteria opsonized in IGIV but not that of bacteria opsonized in specific IgM. Both CR1 and CR3 receptors on PMNLs were involved in uptake, but the contribution of each is different with different organisms.     

Prospective Study on the Hepatitis Safety of Intravenous Immunoglobulin, pH 4.25

Recent reports of transmission by intravenous gamma-globulin preparations of non-A non-B hepatitis (NANBH), including several cases that progressed to severe liver damage and death, have raised concerns about the safety of intravenous gamma-globulin. However, the problem does not seem to be widespread. To assess this issue, we previously reported the results of liver function tests monitored in 41 patients with primary immunodeficiency treated with intravenous immunoglobulin (IGIV), pH 4.25 over periods ranging from 6 to 15 months. Eighteen of these patients at two of the three centers have now had serial serum glutamic pyruvic transaminase (SGPT) levels performed regularly at intervals of 1-5 weeks while continuing monthly intravenous infusions of nonmodified IGIV, pH 4.25 for an additional 14-26 months. The standard dosage was 400 mg per kg body weight IGIV, pH 4.25. Six lots of IGIV, pH 4.25 were used. Transient minor SGPT elevations were observed in 5 of the patients on a total of 8 occasions. None of the elevations was considered indicative of NANBH or of any chronic hepatic disease. All patients remained negative for hepatitis B surface antigen throughout the study.     

Incidence of hepatitis and seroconversion to hepatitis C virus after open-heart surgery in transfused and non-transfused patients in Sweden

The transmission of non-A, non-B hepatitis (NANB)/hepatitis C virus (HCV) was studied in patients undergoing open-heart surgery and related to the reception of blood products and hospitalization and surgery per se. Posttransfusion hepatitis NANB was noticed in 17/390 (4.4%) patients receiving heterologous blood and 8/16 tested became positive for anti-HCV (Ortho HCV ELISA), all within 5 months after onset of hepatitis. Among patients with normal ALAT before surgery and during follow-up, who had received heterologous blood, 1/50 seroconverted after 6 months. This patient probably had a subclinical HCV infection, or possibly a temporary non-specific anti-HCV reactivity with a maximum optical density/cut-off ratio (OD/CO) of 1.2, whereas all posttransfusion hepatitis C cases had OD/CO ratios greater than 4. No hepatitis occurred among the 92 non-transfused patients and no seroconversion was found in any of 62 non-transfused patients tested 6 months after the operation. It was concluded that (1) hospitalization and surgery per se does not seem to offer a risk of hepatitis NANB/C, and (2) seroconversion to for HCV occurs in only 50% of Swedish patients with acute posttransfusion NANB hepatitis.     

Acute viral hepatitis in Lebanon: evidence for an HAV-like non-A non-B hepatitis

ABSTRACT— Ninety-three cases of acute viral hepatitis in adult Lebanese patients were followed-up prospectively for a period ranging from 6 to 18 months. These included 33 hepatitis A (HAV), 32 hepatitis B (HBV) and 21 non-A, non-B hepatitis (NANB) cases. The clinical and seroepidemiologic characteristics of the three types were evaluated. HAV was characterized by a short prodroma (<1 week) and a high IgM level. HBV did not differ from similar cases reported in the Western world except for a complete absence of male homosexuals and drug addicts as a possible route of transmission. NANB hepatitis in Lebanon is mainly a sporadic infection similar to HAV except that the prodromal phase is prolonged (>14 days) and IgM levels are within normal limits. The failure to develop chronicity in NANB suggests that the virus of sporadic NANB may be different from that which causes post-transfusional (PTH) NANB.     

The lack of transmission of NANB/C hepatitis between acute and chronically infected patients and their heterosexual partners

In order to study the risk of heterosexual transmission of non-A, non-B/C (NANB/C) hepatitis, 34 spouses and/or sexual partners to 34 index patients (13 women, 21 men; median age 39 years) with acute NANB/C hepatitis (anti-HCV positive 13/34) were repeatedly tested for antibodies to hepatitis C virus (anti-HCV) and serum alanine aminotransferase (S-ALAT) values. Spouses and/or sexual partners to 13 patients with chronic NANB/C hepatitis (11/13 anti-HCV positive) were also studied by determining anti-HCV and S-ALAT levels. No conclusive evidence of heterosexual transmission of NANB/C hepatitis was found.     

Antibody activity against Pseudomonas aeruginosa in immune globulins prepared for intravenous use in humans

Twenty-seven lots of human immune globulin for intravenous use (IGIV) from seven different producers, including one hyperimmune preparation, were examined for immunologic reactivity and opsonic and protective activity against Pseudomonas aeruginosa. All IGIVs contained hemagglutinating antibodies to seven immunotype-specific lipopolysaccharides of P. aeruginosa (geometric mean titer +/- SE, 14 +/- 3 for nonhyperimmune preparations and 420 for the hyperimmune product) and to exotoxin A (77 +/- 15). All IGIVs tested demonstrated opsonic activity against P. aeruginosa in an in vitro granulocyte-dependent bactericidal assay. All IGIVs conferred dose-dependent protection (hyperimmune more so than nonhyperimmune) against fatal burn-wound infections due to P. aeruginosa in mice. In contrast, single lots of hyperimmune and nonhyperimmune IGIV conferred limited protection against infections due to P. aeruginosa in granulocytopenic mice. These studies indicate the potential prophylactic efficacy of IGIV in human pseudomonas disease, and the possible need for high doses of hyperimmune IGIV in granulocytopenic patients.     

High risk of non-A non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin

After a first exposure to factor VIII concentrates, 9/9 British patients treated with U.S.A.-derived commercial products, and 10/12 treated with British volunteer (NHS) products, developed acute non-A, non-B (NANB) hepatitis. Hepatitis following commercial products was more severe, and of shorter incubation. High previous exposure to NHS blood products seemed to prevent NHS but not commercial factor VIII-induced hepatitis; the latter was also not attenuated by administration of U.S.A.-derived commercial immune serum globulin (ISG). After a first exposure to NHS factor IX concentrates without ISG, 4/4 patients developed short incubation NANB hepatitis; one also contracted prolonged incubation hepatitis B. One patient treated with ISG and factor IX of proven infectivity did not develop hepatitis, suggesting protection by ISG. Observed differences between concentrates might be attributable to their content of different NANB agents, but dose-related effects could provide alternative explanations. This data provides a basis for comparative assessment of new products of possible reduced infectivity in only small numbers of patients.     

Long-term sequelae of non-A, non-B hepatitis in experimentally infected chimpanzees

We have observed the development of long-term sequelae in four cases of experimentally induced non-A, non-B (NANB) hepatitis in chimpanzees. These sequelae were characterized by the following manifestations: nonprotection against challenge with autologous infectious plasma following acute disease and subtle histopathological alterations typical of long-lasting viral hepatitis. These manifestations were observed in animals infected with either of two human inocula. Whether or not these inocula represent sources of single or multiple etiologic agents is not known. However, our studies suggest that these inocula share at least one common etiologic agent. Further, these results may represent an atypical chronology of convalescence from viral hepatitis infection. For example, the convalescent stage of a type B hepatitis infection may be expected to occur within 6 to 8 months following exposure, whereas true convalescence in NANB hepatitis may be protracted over several months to several years. Thus, future efforts to identify the causative agent(s) of NANB hepatitis, and efforts to define the immune response in NANB, must take into consideration these studies.     

Intravenous immunoglobulin in the treatment of human immunodeficiency virus-related thrombocytopenia.

Fourteen patients with sexually transmitted human immunodeficiency virus (HIV)-related immune thrombocytopenia were treated with intravenous gammaglobulin (IVIG). The patients were treated with a uniform program consisting of 1 g/kg of IVIG on day 1 and day 2, followed by 1 g/kg on day 15. Most patients had pretreatment bleeding symptoms, which included petechiae, spontaneous and traumatic ecchymoses, gum bleeding, and epistaxis. Median baseline platelet count was 17,000/mm3 (range 3-61,000/mm3). After the infusion of the IGIV, all patients had a resolution of their bleeding by day 8. The median maximum platelet count achieved with the IGIV was 220,000/mm3 (range 76-426,000/mm3). No patient achieved either a sustained complete or partial remission after the conclusion of the IVIG therapy. Toxicities were minimal with the majority being headache and nausea. In conclusion, patients with sexually transmitted HIV infection and immune thrombocytopenia respond favorably to IVIG. This treatment should be considered as first-line therapy for patients with HIV-related immune thrombocytopenia who require immediate but temporary increase in their platelet count, attributable to symptoms or signs of clinical bleeding or because of the need for an invasive procedure.     

Cellular cytotoxicity against autologous hepatocytes in acute and chronic non-A, non-B hepatitis.

In a microcytotoxicity assay we tested lymphocyte cytotoxicity against autologous hepatocytes. The following cytotoxicity values were found (given mean +/- SEM): acute non-A, non-B (NANB) hepatitis 45.7 +/- 4.3% (n = 7), chronic NANB hepatitis 32.8 +/- 5.1% (n = 11), chronic active hepatitis B (CAH-B) 27.7 +/- 6.7% (n = 10), toxic lesions 18.1 +/- 4.2% (n = 18), controls with normal liver histology or minimal changes 4.9 +/- 2.5% (n = 8). Thus our study shows enhanced cellular cytotoxicity in acute and chronic NANB hepatitis and indicates that T cells as well as non-T cells have cytotoxic effector functions. These findings are similar to those obtained in CAH-B and suggest that cellular immune reactions play an important role in the course of NANB hepatitis. For comparison we tested cytotoxic reactions in toxic lesions. They were only moderate and well distinguishable from those observed in NANB hepatitis and CAH-B; they even may be unspecific. No correlation was seen between cytotoxicity and aminotransferase concentrations.     

Epidemiology of sporadic acute non-A, non-B hepatitis in Japan: a comparison with hepatitis A and B

Two hundred fifty-eight patients with clinically and serologically proven sporadic acute viral hepatitis during a period of past 7 years (January 1976-Deceniber 1982) were analyzed regarding epidemiology and outcome. The frequency of non-A, non-B (NANB) hepatitis mi the highest among the three categories of viral hepatitis; 118 patients had hepatitis NANB (467r), 70 hepatitis A (27%), and 70 hepatitis B (27%). In NANB hepatitis, the mean age was older than in other categories of hepatitis and both sexes were equally affected, in contrast to the male predominance in types A and B. Chronic liver disease developed in 32% of patients with NANB hepatitis, but in none of patients with hepatitis type A or B. these results suggest that in Japan the infectious sources of hepatitis NANB virus(es) are more prevalent than those of hepatitis A and B viruses, and also suggest that one of the possible important factors for the high tendency to chronicity may be concerned with intimate contact with, or evolution from, asymptomatic NANB virus carriers.     

The clinical behaviour of by immunology unique courses of NANB hepatitis (author's transl)

By means of both immunohistology and immunodiffusion a number of 7 by definition from NANB hepatitis suffering patients were found to belong to an unique antigen-antibody system. These patients responded to NANB infection with certain similarities: 1. The course of the disease exhibited a phasic pattern since increases in SGPT activity were observed at days 47 +/-- 10, 76 +/- 14, 117 +/- 18 and 157 +/- 7. 2. Increases of Gamma-GT were found to exceed values as observed in HAV and HBV infection. Thus, Gamma-GT increases are incriminated as further characteristic of NANB hepatitis.