Maria Rapicetta

Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study

Abstract Objective: To investigate if markers of exposure to foodborne and orofecal microbes versus airborne viruses are associated with atopy and respiratory allergies. Design: Retrospective case-control study. Participants: 240 atopic cases and 240 non-atopic controls from a population sample of 1659 participants, all Italian male cadets aged 17-24. Setting: Air force school in Caserta, Italy. Main outcome measures: Serology for Toxoplasma gondii, Helicobacter pylori, hepatitis A virus, measles, mumps, rubella, chickenpox, cytomegalovirus, and herpes simplex virus type 1; skin sensitisation and IgE antibodies to relevant airborne allergens; total IgE concentration; and diagnosis of allergic asthma or rhinitis. Results: Compared with controls there was a lower prevalence of T gondii (26% v 18%, P=0.027), hepatitis A virus (30% v 16%, P=0.004), and H pylori (18%v 15%, P=0.325) in atopic participants. Adjusted odds ratios of atopy decreased with a gradient of exposure to H pylori, T gondii, and hepatitis A virus (none, odds ratio 1; one, 0.70; two or three, 0.37; P for trend=0.000045) but not with cumulative exposure to the other viruses. Conversely, total IgE concentration was not independently associated with any infection. Allergic asthma was rare (1/245, 0.4%) and allergic rhinitis infrequent (16/245, 7%) among the participants (245/1659) exposed to at least two orofecal and foodborne infections (H pylori, T gondii, hepatitis A virus). Conclusion: Respiratory allergy is less frequent in people heavily exposed to orofecal and foodborne microbes. Hygiene and a westernised, semisterile diet may facilitate atopy by influencing the overall pattern of commensals and pathogens that stimulate the gut associated lymphoid tissue thus contributing to the epidemic of allergic asthma and rhinitis in developed countries.

Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis a virus

Abstract Objective: To investigate the working hypothesis that common infections occurring early in life prevent atopy. Design: Cross sectional, retrospective study of young Italian men with results for hepatitis A serology and atopy. Setting: Air force school for military students in Caserta, Italy. Subjects: 1659 male students aged 17-24, most of whom (90%) were from central and southern Italy. Main outcome measures: Skin sensitisation and specific IgE antibodies to locally relevant airborne allergens; diagnosis of respiratory allergy (asthma or rhinitis, or both); hepatitis A seropositivity. Results: 443 of the 1659 subjects (26.7%) were positive for hepatitis A virus antibody. Atopy was less common among seropositive than seronegative subjects according to skin sensitization (weal reaction ≥3 mm) to one or more allergens (21.9% (97/443) v 30.2% (367/1216), P<0.001); polysensitisation (sensitive to three or more allergens) (2.7% (12/443) v 6.4% (78/1216), P<0.01); high specific IgE concentration (9.7% (43/443) v 18.4% (224/1216), P<0.00005); and lifetime prevalence of allergic rhinitis or asthma, or both (8.4% (37/443) v 16.7% (203/1216), P<0.001). Hepatitis A seropositivity remained inversely associated with atopy after adjusting for fathers education, the number of older siblings, and the area of residence (based on the number of inhabitants). The prevalence of atopy was constantly low among seropositive subjects, whatever the number of older siblings; by contrast, it increased with a decreasing number of older siblings among seronegative subjects. Conclusion: Indirect but important evidence is added to the working hypothesis as common infections acquired early in life because of the presence of many older siblings (among seronegative subjects) or because of unhygienic living conditions (among seropositive subjects) may have reduced the risk of developing atopy. Key messages Young men with antibodies to hepatitis A virus had a lower prevalence of atopy and atopic respiratory diseases, and this was independent of the number of older siblings and other relevant risk factors The prevalence of atopy was as low in seronegative as in seropositive subjects only when they had three or more older siblings Among seropositive subjects the prevalence of atopy was low, whatever the number of older siblings Common infections acquired early in life because of the presence of many older siblings (among seronegative subjects) or because of unhygienic living conditions (among seropositive subjects) may have reduced the risk of development of atopy This study adds indirect but important evidence to the hypothesis that improvements in hygiene and reduced recirculation of common infections may be a major cause of the increasing prevalence of atopy and atopic diseases in Western countries

Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis : a case-control study

OBJECTIVE To determine whether chronic hepatitis C virus (HCV) infection is an independent risk factor for hepatocellular carcinoma and whether it increases the cirrhosis-related risk for hepatocellular carcinoma. DESIGN Two pair-matched case-control studies. SETTING A referral-based hospital. PATIENTS In study I, 212 patients with hepatocellular carcinoma (197 of whom had known underlying cirrhosis) were compared with controls who had chronic nonhepatic diseases. In study II, the 197 patients with hepatocellular carcinoma and cirrhosis were compared with 197 pair-matched controls who had cirrhosis but not hepatocellular carcinoma. MEASUREMENTS Levels of antibody to HCV (anti-HCV), hepatitis B surface antigen (HBsAg), and antibody to hepatitis B core antigen (anti-HBc) were assayed, and alcohol abuse was assessed by history. MAIN RESULTS In study I, 151 patients (71%) with hepatocellular carcinoma were anti-HCV positive compared with 11 controls (5%) with chronic nonhepatic diseases (odds ratio, 42; 95% CI, 22 to 95). Multivariate analysis showed that anti-HCV was an independent risk factor for hepatocellular carcinoma (odds ratio, 69; CI, 15 to 308). The analysis also showed that HBsAg (odds ratio, 8.7; CI, 1.5 to 50) and anti-HBc (odds ratio, 4.2 (CI, 1.7 to 11) were risk factors for hepatocellular carcinoma. No statistically significant interaction was found between anti-HCV and the markers of HBV infection. In study II, 146 patients (74%) with hepatocellular carcinoma and cirrhosis were anti-HCV positive compared with 122 patients (62%) with cirrhosis alone (odds ratio, 1.8; CI, 1.1 to 2.8). Multivariate analysis confirmed that anti-HCV (odds ratio, 2.0; CI, 1.3 to 32) and HBsAg (odds ratio, 2.0; CI, 1.0 to 4.2) were independent risk factors for hepatocellular carcinoma. CONCLUSIONS Hepatitis C virus infection is a risk factor for hepatocellular carcinoma, apparently by inducing cirrhosis and, to a lesser extent, by enhancing the risk in patients with cirrhosis. Hepatitis C virus infection acts independently of HBV infection (another risk factor) and of alcohol abuse, age, or gender.

Hepatitis C virus infection and alanine transaminase levels in the general population : a survey in a southern Italian town

BACKGROUND/AIM The aim of the study was to estimate the prevalence, risk factors and genotype distribution of hepatitis C virus (HCV) in the general population older than 5 years of age in a southern Italian town. The positive predictive value of alanine transaminase (ALT) screening in identifying HCV positive subjects was also assessed. METHODS Cluster random sampling from the census of the general population was used. ELISA and RIBA tests assessed the presence of anti-HCV; nested reverse transcription polymerase chain reaction (RT-PCR) was used to identify HCV-RNA; genotyping was performed by INNO-LIPA III. The association linking anti-HCV seropositivity with potential risk factors was assessed by multiple logistic regression analysis. RESULTS Among the 488 subjects enrolled, 79 (16.2%) were anti-HCV positive. The prevalence increased from 1.2% in subjects 6-29 years of age to 42.1% in those > or = 60 years. Forty percent of these positive subjects also had abnormal ALT level and 54.4% were HCV RNA positive by PCR. The positive predictive value of the ALT test in identifying anti-HCV positive subjects was 65%; however, it was 46.7% in subjects younger than 60 years of age and 90.5% in those 60 or older. Genotype 1b was detected in 74% of subjects, type 2c in 23.3%, and type 1a in 2.3%. The only two variables significantly associated with HCV seropositivity in multivariate analysis were age older than 45 years (O.R. 8.5; CI 95%=3.0-24.1) and past use of glass syringes (O.R. 3.4; CI 95%=1.5-7.6). CONCLUSIONS These findings confirm that HCV infection is endemic in southern Italy, particularly among the elderly. Percutaneous exposure, such as injections with nondisposable, multiple-use, glass syringes used in the past for medical purposes may have played a major role in the spread of HCV infection. ALT screening is not useful in detecting HCV positive subjects in the general population, particularly among subjects who could benefit from antiviral therapy.

Correlation between virus genotype and chronicity rate in acute hepatitis C

BACKGROUND/AIMS Forty-two patients with the diagnosis of acute hepatitis C virus hepatitis were studied to investigate the relationship between hepatitis C virus genotype and progression to chronic infection. METHODS The patients were followed for more than 1 year (mean age 29 years, male/female ratio 2.5). Intravenous drug use was documented in 15 cases, blood transfusion in four, surgical intervention, dental therapy or other parenteral exposure in 15, and unknown factors in the remaining eight. The evolution to chronicity was diagnosed on the basis of a persistent increase in transaminase levels, the presence of HCV-RNA and the histological pattern of chronic hepatitis. RESULTS The majority of cases presented hepatitis C virus infection of subtype 1a (38.1%) or 1b (33.9%). Six cases showed the presence of genotype 3a (14.3%). Subtype 2c was observed in three out of four cases infected with genotype 2. No significant association was demonstrated with documented risk factors. The overall chronicity rate was 59.5%. This value increased to 92% in individuals infected with genotype 1b. By multivariate analysis the age-adjusted odds ratio for infection with genotype 1b as compared with all other genotypes was 14.4 (95% confidence interval; 1.52-137). Moreover, significant differences (p= 0.0002) were present in this group for histological activity index (8.7 as compared with 5-7). CONCLUSIONS The results of this prospective study are consistent with an independent association between hepatitis C virus genotype 1b and a poor prognosis.

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

ABSTRACT Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferon-stimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.

Hepatitis C virus infection in an endemic area of Southern Italy 14 years later: Evidence for a vanishing infection

BACKGROUND In a 1996 survey, prevalence of hepatitis C virus antibodies (anti-HCV) in a southern Italian town was 12.6%. AIMS To identify changes in the epidemiology of hepatitis C virus (HCV) infection. METHODS Anti-HCV, HCV-RNA (PCR, detection limit 15 IU/mL), HCV genotype (Innolipa). Were performed in a random 1:4 systematic sample of the general population. Multiple logistic regression analysis was used to estimate factors independently associated with the likelihood of anti-HCV positivity. RESULTS Of 1012 subjects, 58 (5.7%) were anti-HCV-positive, compared to 12.6% 14 years earlier. Prevalence was 0.4% in individuals <30 years old and 31.8% in those ≥ 70 years old. Among 139 HCV-negative in 1996 re-sampled in 2010, only one had seroconverted (incidence: 0.05 × 100 persons/year). Alanine transaminase levels were elevated in 8 (13.8%). HCV-RNA was detected by PCR in 46.5% anti-HCV-positive subjects. In 2010 59% were genotype 2-infected, in 1996 50.7% genotype 1-infected. Previous use of non-disposable glass syringes was a strong independent predictor (OR 3.2; CI 95%=1.4-7.3). CONCLUSION Epidemiology of HCV infection in an endemic area of south Italy has changed over 14 years, now largely confined to the oldest age group; this seems to be due to the disappearance of its past main mode of transmission, namely the use of glass syringes.

Epidemiological and virological characterization of a large community-wide outbreak of hepatitis A in southern Italy

A large outbreak of hepatitis A virus (HAV) infection occurred in 2004 in Campania, a region of southern Italy, with 882 cases reported between 1 January and 1 August. The local public health authorities and the Italian National Institute of Health carried out investigations in order to characterize the agent, identify the source of infection and the route of transmission, and implement appropriate control measures. A web-based reporting system enhanced the flow of information between public health authorities, providing real-time epidemic curves and frequency distributions. The same 1B HAV genotype was found in 90% of sera from a subset of patients with acute disease, suggesting a local common source. A case-control study in the municipality with the highest attack rate showed that raw seafood consumption, in particular if illegally sold in water, was strongly associated with HAV illness. Samples of seafood systematically collected from retailers were found contaminated by HAV.

Liver targeting of antiviral nucleoside analogues through the asialoglycoprotein receptor.

Summary. In order to reduce the extrahepatic side‐effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl‐terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with the asialoglycoprotein receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The validity of this chemotherapeutic strategy has been endorsed by a clinical study. Adenine arabinoside monophosphate (ara‐AMP), conjugated with lactosaminated human serum albumin (L‐HSA) and administered to hepatitis B virus (HBV)‐infected patients for 28 days, exerted an antiviral activity to the same extent as the free drug without producing any clinical side‐effects, including the severe neurotoxicity caused by the free drug. Preclinical studies are now underway with conjugates obtained using lactosaminated poly‐L‐lysine (Lacpoly(Lys)) as the hepatotropic carrier. These new conjugates have some advantages over those prepared with L‐HSA: they can be administered by the intramuscular route; they are obtained entirely by chemical synthesis, thus eliminating the problems involved in the use of haemoderivatives; they have a heavy drug load, which permits administration of smaller quantities of conjugate that are more easily digested in lysosomes; and they enable higher quantities of drug to be introduced into hepatocytes. The results of the experiments with two Lac‐poly(Lys) conjugates, one with ara‐AMP and one with ribavirin, are reported in this review.

Switched memory B cells maintain specific memory independently of serum antibodies: the hepatitis B example.

The immunogenicity of a vaccine is conventionally measured through the level of serum Abs early after immunization, but to ensure protection specific Abs should be maintained long after primary vaccination. For hepatitis B, protective levels often decline over time, but breakthrough infections do not seem to occur. The aim of this study was to demonstrate whether, after hepatitis B vaccination, B‐cell memory persists even when serum Abs decline. We compared the frequency of anti‐hepatitis‐specific memory B cells that remain in the blood of 99 children five years after priming with Infanrix®‐hexa (GlaxoSmithKline) (n=34) or with Hexavac® (Sanofi Pasteur MSD) (n=65). These two vaccines differ in their ability to generate protective levels of IgG. Children with serum Abs under the protective level, <10 mIU/mL, received a booster dose of hepatitis B vaccine, and memory B cells and serum Abs were measured 2 wk later. We found that specific memory B cells had a similar frequency in all children independently of primary vaccine. Booster injection resulted in the increase of memory B cell frequencies (from 11.3 in 106 cells to 28.2 in 106 cells, p<0.01) and serum Abs (geometric mean concentration, GMC from 2.9 to 284 mIU/mL), demonstrating that circulating memory B cells effectively respond to Ag challenge even when specific Abs fall under the protective threshold.