Dottorato in TECNOLOGIE INNOVATIVE NELLE MALATTIE DELLO SCHELETRO,
DELLA CUTE E DEL DISTRETTO ORO-CRANIO-FACCIALE

Titolo della tesi: An epidemiological study on the prevalence of HEV infection in patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Introduction Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a heterogeneous, rare and treatable pathology of the peripheral nervous system with a plausible autoimmune pathogenesis. It is caused by an immune-mediated reaction against myelin antigens which, consequently, involves a non uniform slowdown in the conduction of the nerve impulse and clinically resulting in a symmetric, motor-predominant neuropathy with both proximal and distal muscle weakness. The variety of etiopathogenetic mechanisms accounts for its clinical heterogeneity: different phenotypes with different prognosis and response to treatment are described. The etiology is multifactorial as genetic and environmental factors seem to be involved. Among the environmental factors, a correlation with vaccines, diet and malignant tumors of the gastrointestinal tract has recently been reported. Another trigger may be infections as in AIDP variant of Guillain-Barrè Syndrome (GBS), an acute pathology with characteristics in common with CIDP. Some studies have supposed the association between CIDP and infections. The abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act synergistically to cause damage to peripheral nerves. Hepatitis E virus (HEV), an emerging pathogen widespread throughout the world, has already been associated with neuralgic amyotrophy, encephalitis/myelitis and GBS: its role as a probable autoimmune trigger was assumed. Purposes The goal of this study was to evaluate an eventual significative correlation between HEV infection and CIDP, by analyzing the prevalence of anti HEV IgG antibodies in a group of patients with CIDP. The primary purpose was to assess the prevalence of HEV infection in a group of patients with a diagnosis of defined CIDP compared to a general population group of controls through a serological evaluation of anti HEV IgG and IgM. The secondary purpose was to evaluate the prevalence of HEV infection in CIDP patients previously treated and untreated with human immunoglobulins (IG) and other immunosuppressive therapies. A possible analogy between HEV antigens and myelin antigens most implicated in demyelinating diseases was then investigated. An analysis of the risk factors for HEV infection was conducted, to establish their prevalence in the group of CIDP patients. Materials and Methods 45 patients with a diagnosis of “defined CIDP” were retrospectively analyzed. An analysis of risk factors for HEV in CIDP patients was performed by the administration of a screening questionnaire. Each enrolled patient was given a questionnaire, aimed at assessing the exposure to risk factors for HEV infection. Each patient underwent a venous sampling for serological research and a rectal swab. Serum prevalence of IgG and IgM anti-HEV were detected in CIDP patients and compared with the control group. The control group consisted of 301 blood donors enrolled by the Italian Health National Institute through the National Blood Center. The analogy between HEV antigens and myelin antigens most implicated in demyelinating diseases was then investigated by the comparison of HEV and myelin protein aminoacid sequences. Results This prevalence study showed a HEV IgG seropositivity of 33.3% (15/45) in CIDP patients compared to 8.97% of the control group (OR=5.07 p<0.0001); the statistical analysis of the comparison between CIDP patients and controls matched by age and sex was, also in this case, statistically significant. It was found that therapy with human immunoglobulins was correlated with seropositivity for anti-HEV IgG in a statistically significant way; the correlation was not significant for other immunomodulating treatments. Despite this, seropositivity for HEV IgG in CIDP patients not treated with human immunoglobulins in the two months prior to sampling (22.85%) resulted significantly higher than the same control group (OR=3.01 p=0.018). An analogy between viral and myelin amino acid sequences was detected. Among the risk factors for HEV, consumption of liver sausages, work in contact with animals and blood transfusions were found to be related to HEV infection in a statistically significant way. Conclusions The higher prevalence of IgG HEV antibodies in the CIDP patient group compared to the control population, regardless of immunoglobulin therapy, allows to hypothesize a role of HEV in the pathogenesis of CIDP. This evidence could be supported, in a model of molecular mimicry, by the detection of similarities between viral and myelin antigens. Among risk factors for HEV, transfusions, work with animals, and liver meat consumption has correlated, in a statistically significative way, with CIDP.