Nádia Cristina Duppre

Criteria for diagnosis of pure neural leprosy

Abstract.The clinical diagnosis of pure neural leprosy (PNL) remains a public health care problem mainly because skin lesions—the cardinal features of leprosy—are always absent.Moreover, the identification of the leprosy bacillus is not easily achieved even when a nerve biopsy can be performed. In an attempt to reach a reliable PNL diagnosis in patients referred to our Leprosy Outpatient Clinic, this study employed a variety of criteria. The nerve biopsies performed on the 67 individuals whose clinical, neurological, and electrophysiological examination findings strongly suggested peripheral neuropathy were submitted to M. leprae identification via a polymerase chain reaction (PCR). Mononeuropathy multiplex was the most frequent clinical and electrophysiological pattern of nerve dysfunction, while sensory impairment occurred in 89% of all cases and motor dysfunction in 81%. Axonal neuropathy was the predominant electrophysiological finding, while the histopathological nerve study showed epithelioid granuloma in 14% of the patients, acid fast bacilli in 16%, and nonspecific inflammatory infiltrate and/or fibrosis in 39%. PCR for M. leprae was positive in 47% of the nerve biopsy samples (n=23). PCR, in conjunction with clinical and neurological examination results, can be a powerful tool in attempting to identify and confirm a PNL diagnosis.

Epidemiologia da hanseníase em coorte de contatos intradomiciliares no Rio de Janeiro (1987-1991)

This study aimed to identify factors influencing the development of leprosy (Hansens disease) in household contacts. A dynamic cohort was analyzed from 1987 to 1991 at the Hansens Disease Department of the Oswaldo Cruz Foundation in Rio de Janeiro. The incidence rate was 0.01694 person-years of follow-up. Nevertheless, for subjects at the end of the first year of follow-up the incidence rate was 0.06385 (end of second year, 0.03299; end of third year, 0.02370; end of fourth year, 0.018622; and end of observation period, 0.01694). A stepwise multivariate logistic regression model was proposed to study the risk of developing leprosy, including co-prevalent cases, totaling 758 contacts. In the final model, the risk was associated with a negative Mitsuda skin test (OR = 3.093; CI 95% = 1.735-5.514), prior BCG vaccination (OR = 0.3802; CI 95% = 0.2151-0.66719), and multibacillary primary clinical form (OR = 2.547; CI 95% = 1.249-5.192). The results showed that both multibacillary leprosy and specific immune status are significant indicators for developing the disease in a cohort of household contacts.

Leprosy among Patient Contacts: A Multilevel Study of Risk Factors

Background This study aimed to evaluate the risk factors associated with developing leprosy among the contacts of newly-diagnosed leprosy patients. Methodology/Principal Findings A total of 6,158 contacts and 1,201 leprosy patients of the cohort who were diagnosed and treated at the Leprosy Laboratory of Fiocruz from 1987 to 2007 were included. The contact variables analyzed were sex; age; educational and income levels; blood relationship, if any, to the index case; household or non-household relationship; length of time of close association with the index case; receipt of bacillus Calmette-Guérin (BGG) vaccine and presence of BCG scar. Index cases variables included sex, age, educational level, family size, bacillary load, and disability grade. Multilevel logistic regression with random intercept was applied. Among the co-prevalent cases, the leprosy-related variables that remained associated with leprosy included type of household contact, [odds ratio (OR) = 1.33, 95% confidence interval (CI): 1.02, 1.73] and consanguinity with the index case, (OR = 1.89, 95% CI: 1.42–2.51). With respect to the index case variables, the factors associated with leprosy among contacts included up to 4 years of schooling and 4 to 10 years of schooling (OR = 2.72, 95% CI: 1.54–4.79 and 2.40, 95% CI: 1.30–4.42, respectively) and bacillary load, which increased the chance of leprosy among multibacillary contacts for those with a bacillary index of one to three and greater than three (OR = 1.79, 95% CI: 1.19–2.17 and OR: 4.07–95% CI: 2.73, 6.09), respectively. Among incident cases, household exposure was associated with leprosy (OR = 1.96, 95% CI: 1.29–2.98), compared with non-household exposure. Among the index case risk factors, an elevated bacillary load was the only variable associated with leprosy in the contacts. Conclusions/Significance Biological and social factors appear to be associated with leprosy among co-prevalent cases, whereas the factors related to the infectious load and proximity with the index case were associated with leprosy that appeared in the incident cases during follow-up.

Immunological Cytokine Correlates of Protective Immunity and Pathogenesis in Leprosy

The in vitro production of interferon (IFN)‐γ, interleukin (IL)‐5, tumour necrosis factor (TNF)‐α and IL‐10 by blood mononuclear cells in response to whole Mycobacterium leprae and polyclonal stimulii of 23 individuals, representing a variety of conditions in relation to exposure/susceptibility to M. leprae, was assayed. In most cases, healthy household contacts of newly diagnosed multibacillary leprosy patients, designated exposed household contacts (EC), showed low‐to‐undetectable in vitro IFN‐γ production in addition to substantial TNF‐α production in response to M. leprae. In contrast, peripheral blood mononuclear cells from previously exposed contacts (R) regarded as resistant‐to‐leprosy released low‐to‐moderate levels of IFN‐γ together with a mixed cytokine profile resembling a T helper (Th)0‐type response. TNF‐α/IL‐10 ratios in response to M. leprae and Concanavalin A were significantly higher in EC than in R contacts suggesting a role for the TNF‐α/IL‐10 ratio in restraining mycobacteria proliferation and spreading early in infection. The cytokine profiles of leprosy patients were taken as reference points. Post‐treatment lepromatous leprosy patients secreted relatively high levels of IL‐10 in response to M. leprae, whereas one self‐cured tuberculoid leprosy patient produced simultaneously high levels of IFN‐γ and TNF‐α. In addition, the quantitative changes in the cytokines released by peripheral blood mononuclear cells in EC contacts after Bacille Calmette‐Guérin (BCG) vaccination were investigated. Vaccination induced amplification of IFN‐γ production with a concomitant decrease in TNF‐α/IL‐10 ratios that resembled the cytokine pattern observed in R contacts. IFN‐γ production was observed in response to both a cross‐reactive antigen (Ag 85) and a M. leprae‐specific protein (MMP‐I), which attests to a BCG nonspecific stimulation of the immune system, thereby casting these antigens as likely candidates for inclusion in a subunit vaccine against leprosy. Finally, a model for protective × pathologic response to mycobacteria is presented.

Effectiveness of BCG vaccination among leprosy contacts : a cohort study

The study assessed the effectiveness of BCG vaccination against leprosy among the contacts of 1161 leprosy patients at the FIOCRUZ Leprosy Outpatient Clinic, RJ, Brazil, from June 1987 to December 2006. Following National Leprosy Program guidelines, the clinic has administered one-to-two doses to all healthy contacts since 1991. Among the 5680 contacts, 304 (5.4%) already had leprosy. Of the 5376 eligible healthy contacts, 3536 were vaccinated, 30 of whom were excluded due to previous or current tuberculosis, or HIV. In 18 years of follow up, 122 (2.15%) incident cases were diagnosed (58 vaccinated and 64 not), 28 occurring in the first year of follow up (21 vaccinated, 16 with no scar). The protection conferred by BCG was 56% and was not substantially affected by previous BCG vaccination (50% with a scar and 59% without). The risk of tuberculoid leprosy during the initial months was high among those vaccinated with no scar. However, it had substantially declined by the first year and in the following years, when the protection rate in this group reached 80%. Since Brazil is endemic for leprosy and the detection rate is not declining satisfactorily, vaccinating all contacts could be an effective means of substantially reducing the incidence of leprosy.

Detection of Mycobacterium leprae DNA by polymerase chain reaction in the blood and nasal secretion of Brazilian household contacts

DNA samples from blood and nasal swabs of 125 healthy household contacts was submitted to amplification by polymerase chain reaction (PCR) using a Mycobacterium leprae-specific sequence as a target for the detection of subclinical infection with M. leprae. All samples were submitted to hybridization analysis in order to exclude any false positive or negative results. Two positive samples were confirmed from blood out of 119 (1.7%) and two positive samples from nasal secretion out of 120 (1.7%). The analysis of the families with positive individuals showed that 2.5% (n = 3) of the contacts were relatives of multibacilary patients while 0.8% of the cases (n = 1) had a paucibacilary as an index case. All positive contacts were followed up and after one year none of them presented clinical signs of the disease. In spite of the PCR sensitivity to detect the presence of the M. leprae in a subclinical stage, this molecular approach did not seem to be a valuable tool to screen household contacts, since we determined a spurious association of the PCR positivity and further development of leprosy.

Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study.

Background Contacts of leprosy patients are at increased risk of developing leprosy and need to be targeted for early diagnosis. Seropositivity to the phenolic glycolipid I (PGL-I) antigen of Mycobacterium leprae has been used to identify contacts who have an increased risk of developing leprosy. In the present study, we studied the effect of seropositivity in patient contacts, on the risk of developing leprosy, stratified by Bacille Calmette Guerin (BCG) vaccination after index case diagnosis. Methodology/Principal Findings Leprosy contacts were examined as part of the surveillance programme of the Oswaldo Cruz Institute Leprosy Outpatient Clinic in Rio de Janeiro. Demographic, social, epidemiological and clinical data were collected. The presence of IgM antibodies to PGL-I in sera and BCG vaccination status at the time of index case diagnosis were evaluated in 2,135 contacts. During follow-up, 60 (2.8%; 60/2,135) leprosy cases were diagnosed: 41 among the 1,793 PGL-I-negative contacts and 19 among the 342 PGL-I-positive contacts. Among PGL-I-positive contacts, BCG vaccination after index case diagnosis increased the adjusted rate of developing clinical manifestations of leprosy (Adjusted Rate Ratio (aRR) = 4.1; 95% CI: 1.8–8.2) compared with the PGL-I-positive unvaccinated contacts (aRR = 3.2; 95% CI: 1.2–8.1). The incidence density was highest during the first year of follow-up for the PGL-I-positive vaccinated contacts. However, all of those contacts developed PB leprosy, whereas most MB cases (4/6) occurred in PGL-I-positive unvaccinated contacts. Conclusion Contact examination combined with PGL-I testing and BCG vaccination remain important strategies for leprosy control. The finding that rates of leprosy cases were highest among seropositive contacts justifies targeting this specific group for close monitoring. Furthermore, it is recommended that PGL-I-positive contacts and contacts with a high familial bacteriological index, regardless of serological response, should be monitored. This group could be considered as a target for chemoprophylaxis.

Contribuição ao diagnóstico e manejo dos estados reacionais: Uma abordagem prática

The early clinical recognition of reactional states brings great benefits to leprosy patients due to the possibility of appropriate and immediate therapeutic intervention, thus avoiding the development of disabilities that so much stigmatize and complicate the disease. There are three types of reactional episodes: types 1, 2 and neuritis. The latter may occur alone or together with the former forms. In some cases only neurological and/or skin manifestations are observed in the reactions; in others, patients present systemic alterations. The treatment with an association of immunosuppressors and anti-inflammatory drugs seems to be the most effective to avoid recurrences and side effects.

Current strategy for leprosy control in Brazil: time to pursue alternative preventive strategies?

La estrategia actual para el control de la lepra en Brasil se basa en dos actividades principales: la deteccion precoz de casos y el tratamiento de casos con farmacoterapia combinada. Ademas de dichas medidas, se realizan esfuerzos complementarios para identificar los contactos domesticos para el diagnostico precoz y la vacunacion con el bacilo de Calmette-Guerin (BCG). Sin embargo, la eficacia de estas acciones a la hora de reducir la incidencia de la lepra es aun discutible. Esto genera dudas acerca de la factibilidad de eliminar la lepra en Brasil e indica que deberian adoptarse otras medidas de prevencion. A pesar del hecho de que la vacunacion de los contactos se practica desde hace varios anos, falta informacion sobre el impacto de esta medida sobre la incidencia de la lepra en la comunidad. Ademas, con frecuencia no se tiene en cuenta el impacto de la vacunacion neonatal con la vacuna BCG. Sostenemos que hay lugar para la investigacion de metodos alternativos en el control y recomendamos que el programa brasileno de control haga un seguimiento esmerado de las tasas de cobertura para la vacunacion neonatal en aquellas zonas donde la lepra es endemica, con el fin de lograr que la cobertura siga siendo elevada. Ademas, recomendamos la realizacion de estudios, orientados hacia el desarrollo de politicas, sobre la eficacia, factibilidad e impacto de estrategias alternativas mas previsoras. Algunos posibles temas para estos estudios serian: 1) el impacto de la vacunacion de contactos sobre la incidencia de la enfermedad en la poblacion en general, 2) la factibilidad y el impacto de la quimioprofilaxis, y 3) el impacto de la identificacion de grupos de alto riesgo (o mediante la adopcion de una definicion amplia de los contactos expuestos a la lepra, o mediante la creacion de nuevas herramientas diagnosticas), y del diseno de programas para la deteccion precoz y la administracion de farmacoterapia combinada especificamente para estos grupos.

Leprosy exposure, infection and disease: a 25-year surveillance study of leprosy patient contacts

Contact surveillance is a valuable strategy for controlling leprosy. A dynamic cohort study of leprosy contacts was initiated in 1987 at Oswaldo Cruz Foundation. The objective of this work was to review the data on the major risk factors leading up to the infectious stage of the disease, estimate incidence rates of leprosy in the cohort and characterise the risk factors for the disease among the contacts under surveillance. The incidence rate of leprosy among contacts of leprosy patients was estimated at 0.01694 cases per person-year in the first five years of follow-up. The following factors were associated with acquiring the disease: (i) not receiving the BCG vaccine, (ii) a negative Mitsuda reaction and (iii) contact with a patient with a multibacillary clinical form of leprosy. The contacts of index patients who had high bacilloscopic index scores > 1 were at especially high risk of infection. The following factors were associated with infection, which was defined as a seropositive reaction for anti-phenolic glicolipid-1 IgM: (i) young age (< 20 years), (ii) a low measured Mitsuda reaction (< 5 mm) and (iii) contact with an index patient who had a high bacilloscopic index. BCG vaccination and re-vaccination were shown to be protective among household contacts. The main conclusions of this study indicate an urgent need for additional leprosy control strategies in areas with a high incidence of the disease.