Antje Knöll

Long‐term surveillance of haematopoietic stem cell recipients with resolved hepatitis B: high risk of viral reactivation even in a recipient with a vaccinated donor

Summary.  Reactivation of resolved hepatitis B virus (HBV) infection is increasingly recognized in patients with severe immunosuppression. We monitored seven patients with pretransplant antibodies to hepatitis B surface antigen (anti‐HBs) and hepatitis B core antigen (anti‐HBc) for HBV reactivation after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). Reverse seroconversion (from anti‐HBs to HBsAg) was observed in six recipients occurring 12, 14, 16, 22, 31 and 39 months after allo‐HSCT, respectively. The only patient without HBV reactivation had the highest pretransplant anti‐HBs titre and died after the shortest follow‐up period (25 months). A novel HBV surface mutant (D144G/G145E) was isolated from one recipient of stem cells from a donor vaccinated against HBV. Another surface mutant (P142L/G145R) was detected in a recipient from a non‐immune donor. Serum ALT elevation was measured in only two of the six patients with viral reactivation, followed by spontaneous clearance of HBsAg in one of them. Antiviral treatment reduced viral load in five patients, but the emergence of YMDD motif polymerase mutations resulted in lamivudine resistance in two patients. In conclusion, the risk of reactivation of a resolved HBV infection is close to 100% in allogeneic stem cell recipients and vaccination of the donor does not always warrant reliable protection.

SMARCB1(INI1)-deficient Sinonasal Basaloid Carcinoma A Novel Member of the Expanding Family of SMARCB1-deficient Neoplasms

Poorly differentiated sinonasal carcinomas are a heterogenous group of aggressive neoplasms that encompasses squamous cell carcinoma including basaloid variant, lymphoepithelial carcinoma, sinonasal undifferentiated carcinoma, and neuroendocrine-type small cell carcinoma. We herein describe 3 cases of a hitherto unreported variant combining features of basaloid carcinoma with variable intermingled rhabdoid cells. Patients were 2 women (aged 28 and 35) and a man (52 y) who presented with sinonasal masses. All had advanced local disease with bone involvement (pT4). None had a history of irradiation or a family history of rhabdoid tumors. Treatment was surgery and adjuvant chemoradiation. One patient developed liver, lung, pleural, and pericardial metastases (63 mo) and is currently (70 mo) alive under palliative treatment. Another developed recurrent cervical lymph node metastases and died of disease 8.5 years later. The youngest patient was disease-free at last follow-up 7 years later. Histologic features were very similar in all 3 cases and showed intimate admixture of compact basaloid cell nests with peripheral palisading, perivascular pseudorosettes, and a few scattered rhabdoid cells. Rhabdoid cells were more extensive in the metastasis in 1 case but formed a minor inconspicuous component in the primary tumors in all cases. Striking features common to all cases were (1) basaloid “blue” appearance at low power, (2) papilloma-like exophytic component, (3) extensive pagetoid surface growth with prominent denuding features, and (4) replacement of underlying mucous glands mimicking an inverted papilloma. Clear-cut origin from benign papilloma and overt squamous differentiation were lacking. Diffuse (2) or partial (1) p16 expression was noted, but all cases lacked human papillomavirus DNA by molecular tests. In situ hybridization was negative for Epstein-Barr virus. Immunohistochemistry showed diffuse expression of pancytokeratin. CK5 and vimentin showed intermingling of CK5+/vimentin− basaloid and CK5−/vimentin+ rhabdoid cells. Complete loss of nuclear SMARCB1 expression was seen in all cases including also the denuding carcinoma in situ–like surface lesions. To our knowledge, this variant of sinonasal carcinoma has not been reported before. The identical features in all 3 cases suggest a specific disease rather than a nonspecific dedifferentiated phenotype. Awareness of this rare variant and thus reporting of additional cases is necessary for defining its full morphologic and biological spectrum.

Hepatitis C - contamination of toothbrushes: myth or reality?

Summary.  Chronic hepatitis C patients are advised not to share toothbrushes, razors, nail‐scissors or other personal articles that potentially may have been in contact with blood, with others. This study examines the contamination of toothbrushes in patients with chronic hepatitis C as a model for a possible unconventional way of transmission. In 30 patients with chronic hepatitis C, 2 mL of saliva (before and after toothbrushing) and the toothbrush rinsing water after toothbrushing were tested for HCV‐RNA. Saliva before and after toothbrushing was positive for HCV‐RNA in nine (30%) and 11 patients (36.7%), respectively. Twelve of the toothbrush rinsing water specimens (40%) tested HCV‐RNA‐positive. In six of these 12 patients, the ‘native’ saliva had been negative for HCV‐RNA. Patients with HCV‐RNA‐positive toothbrush rinsing water showed no significant differences from those with negative rinsing water with respect to certain clinical, biochemical and virological parameters. In conclusion, our study demonstrates a contamination with HCV‐RNA of a considerable portion of toothbrushes used by hepatitis C patients, suggesting at least a theoretical risk of infection by sharing these objects and strengthening the recommendations to take care of a clear separation of these personal care objects between patients and their household members.

Prevalence of precore mutants in anti‐HBe‐positive hepatitis B virus carriers in Germany

Hepatitis B virus (HBV) precore mutants are associated often with highly productive infection in hepatitis B surface antigen (HBsAg) carriers lacking hepatitis B e antigen (HBeAg) but positive for anti‐HBe, rendering serological identification of infectious individuals unreliable. Although considered initially to be limited mostly to the Mediterranean area, more recent studies suggest a significant presence of these mutants in northern European countries. The sequence of the precore region was determined and examined for mutations from HBV isolates of 99 German chronic HBsAg carriers positive for HBV‐DNA and either HBeAg (n = 15) or anti‐HBe (n = 84). In addition, clinical data of individuals carrying wild‐type virus and those with precore mutants were compared. HBV precore mutants were found in more than half (44/84) of all HBeAg‐negative, anti‐HBe‐positive virus carriers. There was no difference between carriers of wild‐type and precore mutant HBV in the level of viremia or in the clinical course of chronic infection. In conclusion, HBV precore mutants are common in Germany and can therefore present a diagnostic problem for serological testing. However, precore mutants do not appear to have a detrimental effect on the course of chronic HBV infection. J. Med. Virol. 59:14–18, 1999.

Hepatocellular Carcinoma in Southern Germany: Epidemiological and Clinicopathological Characteristics and Risk Factors

The aetiology of chronic liver disease leading to hepatocellular carcinoma (HCC) and the clinical characteristics of patients with HCC vary considerably internationally and intranationally. This study analyses the characteristics of HCC patients in southern Germany, a low endemic area of HCC. Methods: The files of 118 consecutive patients with HCC observed in a single tertiary care hospital between 1994 and 2000 have been reviewed. Epidemiological and clinicopathological characteristics such as age at presentation, ethanol consumption, serological hepatitis virus markers, and fibrosis were studied. Additionally, serum levels of α-fetoprotein (AFP) were analysed at the time of diagnosis in 77 patients. Results: The male:female ratio was 4:1 and the mean age at presentation was 61.8 years. Alcohol abuse (49.2%) and chronic hepatitis C infection (17.8%) were the most frequent risk factors. Histologically proven liver cirrhosis in the surrounding non-tumorous tissue was present in only 59.0% of cases. AFP levels were elevated in 78% of cases, but only 34% reached >500 ng/ml, a value considered to be significant for the diagnosis of HCC. AFP levels correlated with the stage of fibrosis. Summary and Conclusions: The sensitivity of AFP serum levels as a tumour marker is poor but might help to detect at least a minority of cases. As in other populations within Europe, chronic alcohol abuse is frequently associated with HCC in southern Germany, confirming that alcohol is still the most important risk factor for hepatocarcinogenesis in areas with low hepatitis virus prevalence. Considering the poor prognosis of HCC, prevention is of pivotal importance, particularly for patients with chronic liver disease and other risk factors for the development of HCC.

Exposure of hematologic patients to parvovirus B19 as a contaminant of blood cell preparations and blood products

BACKGROUND: Patients with hematologic malignancies often require blood products, and parvovirus B19 is known to be transmitted by this route. Primary infection with parvovirus B19 shows a wide variety of disease manifestation. In immunocompromised patients, symptoms are severe and viral clearance is delayed or missing.

Immunogenicity of a combined hepatitis A and B vaccine in healthy young adults

Combining several vaccines in a single formulation can change the potency of the vaccine antigens. Previous studies suggested a higher immunogenicity of a new combined hepatitis A and B vaccine compared with the monovalent hepatitis B vaccine. We investigated the immune response to hepatitis B surface antigen 1 month after the third vaccine dose in 282 healthy adults who had received either a monovalent hepatitis B vaccine (n=148) or the combined hepatitis A/B vaccine (n=134). A slight trend towards higher geometric mean titres of anti HBs was found at this point in time in the group immunised with the combined vaccine, especially in the few vaccinees with preexisting antibodies against hepatitis A virus. However none of these differences was statistically significant, arguing against an advantage of the combined vaccine regarding hepatitis B immunisation.

Hepatitis C Virus Transmission in a Pediatric Oncology Ward: Analysis of an Outbreak and Review of the Literature

Hospital-related hepatitis C virus (HCV) infections continue to occur even after the introduction of blood donor screening. We report an outbreak of HCV in nine patients of a pediatric oncology ward in 1996/1997. Sequencing of the hypervariable genomic region 1 (HVR1) of the E2/NS1 region showed near identity between HCV isolates from these patients as evidence for infection with the same virus. Despite a detailed and careful investigation, the source of infection and the mode of virus transmission could not be established. Based on a review of the current literature about nosocomial HCV infection and HCV infection in children, hypotheses for possible means of transmission in this outbreak are discussed.

Can monovalent hepatitis A and B vaccines be replaced by a combined hepatitis A/B vaccine during the primary immunization course?

A combined hepatitis A/B vaccine (Twinrix Adult) has been licensed in Germany since 1997. We investigated possible differences in immunogenicity and safety when changing over from vaccinations with monovalent vaccines made by different manufacturers to vaccinations with the combined hepatitis A/B vaccine in an open, randomized, multicenter trial. We therefore compared four different schemes changing over from concomitant vaccinations with monovalent vaccines against hepatitis A and B (Havrix 1440+Engerix-B or Vaqta+Gen H-B-Vax) to combined vaccination against hepatitis A+B with three injections of the combined hepatitis A/B vaccine (0, 1, and 6 month schedule). Local and general symptoms were mostly mild in all five groups. With complete three-dose course using the combined vaccine or an early changeover from monovalent vaccines to the combined vaccine, higher overall anti-HBs seroprotection rates and geometric mean concentrations (GMCs) against hepatitis B could be achieved as early as after 2 months as compared to those groups switching later to the combined vaccine. This study demonstrated for the first time that switching from monovalent hepatitis A and B vaccinations to the combined hepatitis A and B vaccination has no negative influence on the tolerability and improves the immunogenicity.

Detection of Herpesvirus DNA in Cerebrospinal Fluid and Correlation with Clinical Symptoms

Background:Novel PCR techniques can detect minute quantities of herpesvirus DNA in cerebrospinal fluid (CSF). The clinical significance of such findings is not always clear.Patients and Methods:(a) Investigation of clinical characteristics of 76 patients with herpesvirus DNA detection in CSF. (b) Screening for herpesvirus DNA in CSF samples of 208 patients without clinical signs of herpesvirus infection.Results:(a) Eleven of 76 herpesvirus-DNA-positive patients did not show symptoms usually associated with the detected virus (HSV-1/2, n = 5; EBV, n = 6). (b) Two of 208 patients without hint for herpesvirus infection had HHV-6 DNA of low concentration in CSF.Conclusions:The detection of low-level herpesvirus replication in CSF by highly sensitive PCR assays requires critical evaluation.