Hepatitis B Virus Infection Among Leprosy Patients: A Case for Polymorphisms Compromising Activation of the Lectin Pathway and Complement Receptors.

Thousands of leprosy patients not only suffer from physical deformities, but also either have or have had hepatitis B virus (HBV) coinfection. Polymorphisms of the complement system modulate susceptibility to leprosy, but genetic susceptibility to past or present HBV infection is unknown. We used sequencing and multiplex sequence-specific PCR to genotype 72 polymorphisms of seven genes (MBL2, FCN1, FCN2, FCN3, MASP1, MASP2, C3) encoding components of the lectin pathway, and two genes encoding complement receptors (CR1, VSIG4) in 190 patients, of which 74 were positive for HBsAg and/or anti-HBc (HBV+, 93.2% with a resolved infection) and 116 lepromatous patients, and 408 HBV-blood donors. In addition, we tested for levels of proteins of the lectin pathway. We found no difference between serum concentrations of mannan-binding lectin (MBL), MBL-associated serine proteins (MASP-1, MASP-2, MASP-3, MAp44), ficolin-3 (FCN-3), soluble complement receptor 1 (sCR1) and MBL mediated C4 activation, measured by ELISA or TRIFMA in up to 167 HBV+ and HBV- patients. Haplotypes lowering protein levels or encoding dysfunctional proteins increased susceptibility to HBV infection: MBL2*LYQC (OR = 3.4, p = 0.02), MASP1*AC_CC (OR = 4.0, p = 0.015) and MASP2*1C2-l (OR = 5.4, p = 0.03). Conversely, FCN1*3C2 haplotype, associated with higher gene expression, was protective (OR = 0.56, P = 0.033). Other haplotypes associated with HBV susceptibility were: MASP2*2B1-i (OR = 19.25, P = 0.003), CR1*3A (OR = 2.65, P = 0.011) and VSIG4*TGGRCG (OR = 12.55, P = 0.014). Some polymorphisms in ficolin genes associated with lower protein levels increased susceptibility to leprosy/HBV infection: FCN*1 (OR = 1.66, P = 0.029), FCN2*GGGCAC (OR = 6.73, P = 0.008), and FCN3*del_del_C (OR = 12.54, P = 0.037), and to lepromatous disease/HBV infection: FCN2*TA (OR = 2.5, P = 0.009), whereas FCN2*MAG was associated with increased FCN-2 expression and resistance against coinfection (OR = 0.29, P = 0.026). These associations were independent of demographic factors and did not increase susceptibility to leprosy per se, except MASP2*1C2-l. Associations for FCN2, FCN3, MASP1, MASP2, and VSIG4 variants were also independent of each other. In conclusion, polymorphisms compromising activation of the lectin pathway of complement increase susceptibility to HBV infection, with ficolin polymorphisms playing a major role in modulating the susceptibility among leprosy patients.

Prevalence of hepatitis B and C virus infection among leprosy patients in a leprosy-endemic region of central Brazil.

Leprosy and hepatitis B virus (HBV) are highly endemic in some regions of the state of Mato Grosso, in central Brazil. The association of leprosy with HBV and hepatitis C virus (HCV) was assessed using a seroprevalence study and 191 leprosy outpatients were included. Demographic data and the clinical classification of leprosy were recorded. Evidence of previous HBV infection was present in 53 patients (27.7%, 95% confidence interval: 21.9-34.5) and two (1%) were HBsAg positive. Five (2.6%) had antibodies to HCV. The prevalence of previous exposure to HBV was higher than expected for an adult population in central Brazil. In contrast, the prevalence of anti-HCV antibodies was not much higher regarding the age range of participants. HBV markers were associated with a higher number of sex partners and the use of injections without proper sterilisation of the syringes. The number of HBV carriers was small, suggesting that there was no increased likelihood of chronification among these patients.

Prevalence of hepatitis B and C virus infection among leprosy patients in a leprosy-endemic region of central Brazil

Leprosy and hepatitis B virus (HBV) are highly endemic in some regions of the state of Mato Grosso, in central Brazil. The association of leprosy with HBV and hepatitis C virus (HCV) was assessed using a seroprevalence study and 191 leprosy outpatients were included. Demographic data and the clinical classification of leprosy were recorded. Evidence of previous HBV infection was present in 53 patients (27.7 percent, 95 percent confidence interval: 21.9-34.5) and two (1 percent) were HBsAg positive. Five (2.6 percent) had antibodies to HCV. The prevalence of previous exposure to HBV was higher than expected for an adult population in central Brazil. In contrast, the prevalence of anti-HCV antibodies was not much higher regarding the age range of participants. HBV markers were associated with a higher number of sex partners and the use of injections without proper sterilisation of the syringes. The number of HBV carriers was small, suggesting that there was no increased likelihood of chronification among these patients.

Association between leprosy and hepatitis B infection: a survey in Goiânia, central Brazil

This investigation presents the results of hepatitis B virus screening among leprosy patients conducted in central Brazil as a preliminary information for a HBV vaccination programme. The main objectives were to assess the seroprevalence of HBV serum markers among lepromatous patients and to analyse institutionalization as risk factor for HBV infection in this population. Two groups of lepromatous patients were studied, 83 outpatients and 171 institutionalized ones. Screening for HBV serum markers included the detection of HBsAg, anti-HBc by radioimmune assay (RIA). The prevalence of carrier state (HBsAg) was 4.8% and 8.8% among outpatients and institutionalized, respectively, (p > 0.05). Seroprevalence of exposure (all markers) was statistically significant different between outpatients (16.9%) and institutionalized ones (50.3%). Institutionalized patients had an almost four fold risk of HBV infection when compared to the outpatients, and the highest risks were among patients with more than 21 years of residence in the colony, after adjusting for age and sex

Association between leprosy and hepatitis B infection. A survey in Goiânia, central Brazil.

This investigation presents the results of hepatitis B virus screening among leprosy patients conducted in central Brazil as a preliminary information for a HBV vaccination programme. The main objectives were to assess the seroprevalence of HBV serum markers among lepromatous patients and to analyse institutionalization as risk factor for HBV infection in this population. Two groups of lepromatous patients were studied, 83 outpatients and 171 institutionalized ones. Screening for HBV serum markers included the detection of HBsAg, anti-HBc by radioimmune assay (RIA). The prevalence of carrier state (HBsAg) was 4.8% and 8.8% among outpatients and institutionalized, respectively, (p > 0.05). Seroprevalence of exposure (all markers) was statistically significant different between outpatients (16.9%) and institutionalized ones (50.3%). Institutionalized patients had an almost four fold risk of HBV infection when compared to the outpatients, and the highest risks were among patients with more than 21 years of residence in the colony, after adjusting for age and sex.

Biological false positive test for syphilis in lepromatous leprosy patients with concomitant hepatitis B virus infection.

Within the wide range of immunological abnormalities occurring in lepromatous leprosy (LL), antiphospholipid antibodies unrelated to treponemal infection, the so-called biological false positive test for syphilis (BFP), have long been recognized. Considering that BFP may also be encountered in different clinical situations, the fact that whether BFP in LL occurs solely or is associated with other concomitant infections or serological abnormalities was investigated. For this purpose, two groups of LL patients with similar clinical features and no evidence of treponemal infection were studied, one group with BFP (n = 21) and the other without BFP (n = 13). At the time of study, patients underwent the following tests: hepatitis B surface antigen (HBsAg), anti-Trypanosoma cruzi specific antibodies, infectious mononucleosis-associated heterophil antibodies, rheumatoid factors, antinuclear antibodies, anti-dsDNA antibodies and gamma-globulin serum levels. Except for HBsAg, which was more frequently detected in patients with BFP (p < 0.02), the other variables showed no significant differences between groups. This finding suggests the possibility that simultaneous infection with hepatitis B virus could contribute, to some extent as an additional factor, to the generation of an altered humoral immune response. The possible physiopathologic significance of anti-phospholipid antibodies, in the light of current knowledge, is also discussed.

Hepatitis B virus infection among immunocompromised patients in Egypt.

Several workers reported an increased susceptibility to hepatitis B virus (HBV) in immunosuppressed patients. A study was carried out on 4 groups of supposedly immunocompromised patients for hepatitis B surface antigen (HBsAg), and anti-HBs. The 4 groups of patients were suffering from: Leprosy, Bronchial asthma, Diabetes and hepatosplenic Schistosomiasis. Serum specimens were obtained from 137 patients representing the 4 groups and from a control group of 25 healthy individuals. All sera were tested by ELISA technique for HBsAg and anti-HBs. Results indicated that HBsAg carrier rate was 4% for the control healthy group, 7% for Bronchial asthma, 10% for Diabetes, 24% for Leprosy and 28% for hepatosplenic Schistosomiasis. On the other hand, the anti-HBs was 21% for the control group, 29% for Schistosomiasis, 55% and 58% for Diabetes and Bronchial asthma respectively and 74% for Leprosy. This study shows that immunosuppressed patients particularly those suffering from leprosy and hepatosplenic Schistosomiasis experience higher HBsAg carrier rate than the control group for the endemic hepatitis B (6-7 times higher for leprosy and Schistosomiasis). An important observation was the diminished anti-HBs rate in hepatosplenic Schistosomiasis patients, despite the highest HBsAg carrier rate they exhibited. This may be due to an immunological defect, resulting in an unsatisfactory antibody response and chronic hepatitis B antigenemia. In Egypt, where Schistosomiasis is prevalent (40-50%), the problems caused by hepatitis B infection are increased.

Hepatitis B antigen and antibody in patients with leprosy: a study of three resettlement villages in Thailand.

It remains uncertain whether the cellular immune abnormalities of patients with lepromatous leprosy interfere with resolution of hepatitis B virus (HBV) infections. To investigate this question in an area coendemic for the two diseases, we determined the prevalence of hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) in: 1) 204 leprosy patients living in three leprosy resettlement villages; 2) 198 contacts living in the same villages; and 3) 44 newly diagnosed leprosy patients in Thailand. Within the villages, the prevalence of HBsAg positivity was inversely related to age, tended to be more frequent in patients with tuberculoid than lepromatous leprosy, and was similar after age adjustment among persons with and without leprosy. The prevalence of HBV markers found in newly diagnosed patients was similar to that in the villagers. We conclude that extensive HBV transmission had occurred in the resettlement villages and that the natural history of HBV infection was similar in persons with, whether tuberculoid or lepromatous, and without leprosy.

Serological pattern of hepatitis B virus markers (HBsAg, anti-HBs, IgM anti-HBc and HBV specific DNA polymerase) in leprosy patients.

Sera of 134 lepromatous (LL/BL) and 57 tuberculoid (TT/BT) leprosy patients were analysed for four HBV markers. HBsAg was detected in 6.71% of lepromatous and 3.5% of tuberculoid sera. The per cent positivity of lepromatous and tuberculoid sera for anti-HBs antibodies was 30.59% and 35.08%, respectively. The positivity of normal sera for HBsAg and anti-HBs was 3.60% and 21.69%, respectively. The difference in the positivity of three groups of sera (lepromatous, tuberculoid and normal) for HBsAg or anti-HBs was not statistically significant. Anti-HBc (IgM) antibodies were detected in 6% of lepromatous sera. HBV-specific DNA-polymerase activity was found in 22.22% of HBsAg positive (but anti-HBc negative) sera, and 66.66% of anti-HBc positive (but HBsAg negative) sera. The pattern of acute HBV infection in leprosy patients followed the typical pattern prevalent in the normal population.

Hepatitis B virus (HBV) serum markers in Greek leprosy patients.

The prevalence of HBsAg, anti-HBs, and anti-HBc in the sera of 217 patients with the two polar types of leprosy and 382 hospital controls was studied in order to investigate the degree of exposure of Greek leprosy patients to HBV and the ability of these patients to clear HBV from the blood. Two distinct serological patterns were analyzed: effective exposure, characterized by the presence of one or more of the three serological markers, and active infection, characterized by the presence of HBsAg. From the statistical analysis it was found that TT as well as LL cases had a higher prevalence of effective exposure in comparison to controls (p less than 10(-5) and p less than 10(-6)). No significant difference was found between the two polar leprosy types (p greater than 0.30) or between bacteriologically positive and negative LL cases (p greater than 0.30). As far as the prevalence of active infection is concerned among the effectively exposed subjects of all groups, no significant difference existed between TT cases and controls, LL cases and controls, the two polar leprosy cases combined and controls, the two polar leprosy groups, and LL cases positive and negative for Mycobacterium leprae (p for all comparisons greater than 0.30). It is concluded that leprosy cases are at a high risk of HBV infection, but the prevalence of active infection among those effectively exposed does not differ between leprosy cases and hospital controls.

[Leprosy and hepatitis B]. / Lèpre et hépatite B.

In 1966, B. S. Blumberg, investigating for carriers of the "Australia" antigen which he had discovered two years before, finds that the percentage is significantly more elevated in a group of leprous patients than in controls. In this initial work, realized at Cebu, Philippines, he mentions a higher percentage of this antigen carriers among the lepromatous than among the tuberculoid patients. He explains his findings by a genetic hypothesis and by the fact that lepromatous patients are more often hospitalized than the tuberculoid ones, thus narrowest contacts could favour the antigen transmission. Later, the established relation between Australia antigen and hepatitis B incites the authors to disregard the very deceiving genetic hypothesis and to build up the most important characteristic of lepromatous leprosy--cell immunity--as opposed to the tuberculoid form where cell immunity is normal. Investigation for seric markers of hepatitis B virus in patients with tuberculoid or lepromatous leprosy provides a model for the study on "cell immunity and hepatitis B". The juxtaposition of geographic areas with high prevalence of leprosy patients and of HBs Ag carriers is a supplementary argument for the study of their connection. Up to now, about fifty works have been published on this subject. Most of them investigate detection of HBs Ag and a few of HBe Ag and HBs Ac. This bibliographical study, including a personal study, reviews markers of hepatitis B virus replication in leprosy patients, incidence of hospitalization and age of these patients, as well as the methodology used.

Hepatitis-B virus infection in patients with leprosy: a serological study in a leprosarium in Northern Nigeria.

The prevalence rates of hepatitis-B surface antigen (HGsAg) and its homologous antibody (anti-HBs) were determined in 62 patients in a leprosarium (42 tuberculoid and 20 lepromatous) and in 40 adults living near the locality. The exposure rate (HBsAg + anti-HBs) was high in both controls and patients, 72.5% and 70.9% respectively, The frequency of HBsAg was significantly higher in patients with lepromatous leprosy (40%) compared with controls (10%) (chi 2 = 5.7 p less than 0.025) but there was no difference in the prevalence rate of HBsAg between patients with lepromatous leprosy (40%) compared with those with tuberculoid leprosy (23.8%) (chi 2 = 1.7 p greater than 0.1). The exposure rate was higher in the lepromatous group (80%) compared with the tuberculoid group (59.5%) but the difference was not significant (chi 2 = 2.87 p greater than 0.05). It is concluded that the high rate of infection in patients with leprosy if not due to a peculiar genetic defect but the result of living in an environment where the virus is highly endemic. The observed significance increase in carriage of HBsAg in lepromatous leprosy is probably due to depressed cellular immune function characteristic of this group of patients. The slightly increased exposure rate to HBV of lepromatous versus the tuberculoid type of leprosy is probably due to increased opportunity for infections from repeated and prolonged stay in hospital.

Imbalance in T cell subsets in human diseases.

T cell subsets have been evaluated in 232 patients with various immunological diseases and 41 normal individuals used as a control group. An increase in the helper/suppressor ratio (OKT4:OKT8) was often noted in multiple sclerosis (acute attacks and progressive forms), autoimmune hemolytic anemia (without steroids), membranous and IgA-deposit glomerulonephritis, HBs-negative chronic active hepatitis, lepromatous patients with erythema nodosum, and myasthenia gravis. Ratios were usually normal in membranoproliferative nephritis, in lupus erythematosus (at least in steroid treated cases) and in nephrotic syndrome. High values of helper cells have been found in Sezary's syndrome (with low or no suppressor cells) and in mycosis fungoides. Variable data have been obtained in immunodeficiency syndromes. These data have been correlated with age, sex and clinical parameters, as well as with other immunological tests (E rosettes, mitogen responses, mixed lymphocyte reaction, Concanavalin A-induced suppression). From our investigations we have concluded that the study of OKT antibody-defined T cell subsets offers a valuable technique for the further investigation of human immunological diseases.

Lymphocytotoxins in leprosy and in asymptomatic hepatitis B virus infection.

Serum lymphocytotoxic antibodies (LCAs) were detected in 67% of Papua New Guinean lepromatous leprosy patients who were persistent carriers of hepatitis B surface antigen (HBsAg). Lymphocytotoxins were not associated with asymptomatic HBsAg in either healthy controls or tuberculoid leprosy patients. It was apparent that, although HBsAg itself is a poor indicator of in vitro lymphocytotoxicity, when the antigen occurred in a host with impaired immune response, lymphocytotoxicity, when the antigen occurred in a host with impaired immune response, lymphocytotoxicity was enhanced. In contrast to this finding, lepromatous leprosy patients without HBsAg had significantly depressed LCA production in comparison with tuberculoid patients and controls. The interaction between leprosy and hepatitis B virus was highly significant (P = 0.001) in an analysis of variance of cytotoxicity scores. It is proposed that the previously reported equivocal results regarding autoantibodies in leprosy patients may be explained by this unusual interaction between lepromatous leprosy and hepatitis B virus infection.

[Distribution of HBs antigen in Tananarive (author's transl)]. / Répartition de l'antigène HBs à Tananarive.

This survey has been conducted among blood donors and patients with hepatitis, cirrhosis, liver carcinomas and various causes of liver dysfunction or enlargement. The frequency is 5,4 p. 100 among blood donors and 50 p. 100 among cases of hepatitis.