There is no point of care diagnostic test for infection with M. Leprae or for leprosy, although ELISA anti PGL-1 has been considered and sometimes used as a means to identify infection. A systematic review of all cohort studies, which classified healthy leprosy contacts, at entry, according to anti-PGL1 positivity, and had at least one year follow up. The outcome was clinical diagnosis of leprosy by an experienced physician. The meta-analysis used a fixed model to estimated OR for the association of PGL-1 positivity and clinical leprosy. A fixed model also estimated the sensibility of PGL-1 positivity and positive predictive value. Contacts who were anti PGL-1 positive at baseline were 3 times as likely to develop leprosy; the proportion of cases of leprosy that were PGL-1 positive at baseline varied but was always under 50%. Although there is a clear and consistent association between positivity to anti PGL-1 and development of leprosy in healthy contacts, selection of contacts for prophylaxis based on anti PGL1 response would miss more than half future leprosy cases. Should chemoprophylaxis of controls be incorporated into leprosy control programmes, PGL1 appears not to be a useful test in the decision of which contacts should receive chemoprophylaxis.
Leprosy remains a neglected disease, in some parts of the world [1], with a high new case detection rate in spite of worldwide control efforts [2]. Most cases are concentrated in remote areas [3,4]. At primary care, leprosy diagnosis is clinical: presence of skin lesion (s) with altered or absent sensibility. Early detection and treatment would reduce transmission. More recently, the idea of leprosy prophylaxis is being promoted as a way of reducing transmission. As in the case of many other neglected diseases, new tools are needed for early detection of cases, if we are to achieve a marked reduction in incidence in a short timeframe. An accurate point of care test for the diagnosis of leprosy disease or infection could have a major impact in detection. Point of care diagnostic tests target biomarkers of infection or disease. In the early 1980’s, Brett et al. described an ELISA test to detect IgM and IgG antibodies against the phenolic glycolipid (PGL) component of Mycobacterium leprae. Earlier serological tests for M. leprae antigens had shown low specificity and the discovery of PGL test created a substantial expectation, given the high specificity reported initially [5] In 1998 a dipstick assay was developed to detected anti-PGL-1 [6], as a convenient point of care test. The expectation at the time was that a positive anti-PGL-1 result would indicate infection, and a negative result absence of infection. Recent publications still offer this interpretation [7,8, 9]. However, evidence produced since does not confirm such a straightforward interpretation, with variations reported in the validity of the test as a predictor of who will develop leprosy. In this paper, we present results of a systematic review and meta-analysis of the risk of developing leprosy, in leprosy contacts according to anti-PGL-1 test results. This could inform any decision of incorporating or not the dipstick assay for IgM anti-PGL1 in leprosy control programmes.
A systematic literature review protocol strategy was developed based on the ‘Preferred Reporting Items for Systematic reviews and Meta-Analyses’ (PRISMA) checklist. The protocol was published in Prospero International prospective register of systematic reviews before its implementation (PROSPERO 2013: CDRD42013005285). We aimed to include all cohort studies, which classified, at entry, healthy leprosy contacts according to anti-PGL1 positivity and had at least one year follow up. The outcome was clinical diagnosis of leprosy by an experienced physician. Studies with no leprosy cases in one of the groups, and those using any antigen other than PGL1 conjugated with bovine serum albumin (BSA) met the exclusion criteria. When more than one paper described the same cohort, we included the one with most information. We searched PUBMED, EMBASE, LILACS, IMSEAR, WPRIM, WHOLIS, IMEMR and INDMED from 1983, when the technique for detection of anti-PGL-1 was published, to April 2015. The electronic search strategy on PUBMED was: ( (" Contact" [Journal] OR" contact" [All Fields] OR" Contact" [Journal] OR" contact" [All Fields]) OR contacts[All Fields]) AND ( (" leprosy" [MeSH Terms] OR" leprosy" [All Fields]) OR (" leprosy" [MeSH Terms] OR" leprosy" [All Fields] OR (" hansen" [All Fields] AND" disease" [All Fields]) OR" hansen disease" [All Fields]) ) AND (anti-phenolic[All Fields] OR (phenolic[All Fields] AND (" glycolipids" [MeSH Terms] OR" glycolipids" [All Fields] OR" glycolipid" [All Fields]) ) OR anti-PGL-1[All Fields] OR PGL-1[All Fields] OR (" immunology" [Subheading] OR" immunology" [All Fields] OR" serology" [All Fields] OR" serology" [MeSH Terms] OR" serology" [All Fields] OR" serologic tests" [MeSH Terms] OR (" serologic" [All Fields] AND" tests" [All Fields]) OR" serologic tests" [All Fields]) ) We decided to include papers written in English, French, Spanish or Portuguese. Endnote files kept all selected references and abstracts. Two authors (SN and PI) read the abstracts and selected the papers for inclusion in the review. When they disagreed, a third author (MLFP) reviewed it based on the paper’s full text. These three authors assessed the paper’s full text defining those to include in the systematic review. One of the authors (MLFP) abstracted the data and another (SN) checked it. Our main measure of association was the odds ratio (OR) and its log transformation (LOR) based on the number of patients at the beginning of follow up in each category (anti_PGL1 positives and negatives) and the number of cases in each category. We used the Tool to Assess Risk of Bias in Cohort Studies from Cochrane Bias Methods Group to classify each paper. We did not apply items 4 and 5 since these items were about the presence and control of other prognostic factors, which was not relevant for this review. We also abstracted data about the site of the study, proposed time of follow up, type of antigen used, technique of the test, dilution used and cut off point. We estimated the summary LOR as the combined inverse-variance weighted LOR of the individual studies, i. e. , used a fixed effect model. As a measure of heterogeneity, we used Cochran’s Q (this has the same distribution as chi square with n -1 degrees of freedom, where n is the number of studies). The set of studies was considered heterogeneous if p<0. 1. The inconsistency index was estimated (I2) and if the index was 40% or less, we considered that the inconsistency was not important. A funnel plot evaluated publication bias Sensitivity analysis was based on the variation of the summary OR when one study was removed. We present a ROC plane plot with the results of each study. Ulrich et al. was excluded from the plot because in this study included all contacts with negative reactions to M leprae and only a sample of those with positive reaction. The study sample is not balanced in respect of all possible immunological response among contacts, although it has internal validity.
We retrieved abstracts of 462 papers and we selected 27 for full-text reading. From those, 9 were selected for the systematic review and 8 entered for the meta-analysis (Fig 1). We accepted the authors’ definition of household contacts and considered neighbourhood contact if the study selected their sample due to the presence of leprosy cases in an area. Table 1 presents some characteristics of the selected the studies [10,11,12,13,14,15,16,17,18]. Table 2 shows the extracted data for each study. Table 3 shows the bias assessment of the papers. Brasil et al. paper [14] was excluded from the meta-analysis because the follow up procedures were not the same in those who were PGL-1 positive and those who were negative: the anti-PGL-1 positive group had annual medical consultation scheduled during the four years follow up period, but the anti-PGL-1 negative group received the test result with information about leprosy signs and symptoms, and the PGL-1 results and interpretation, but there was no active follow up and leprosy diagnosis in this group depended on the individual demand for medical consultation. We considered this to be differential follow-up as the leprosy diagnosis strategy introduced severe ascertainment bias and thus excluded the study from the meta-analysis. We considered this differential follow-up. Leprosy diagnosis strategy introduced severe ascertainment bias and excluded the study. Fig 2 shows the forest plot of the included studies. The total number of contacts included in these studies was 18197, with 4140 anti PGL1 positives and 14057 anti PGL1 negatives. The summary ORs with Brasil et al. (14) study removed varied from 2. 72 to 3. 53, but all the 95% confidence interval included 3. 11, the fixed model point estimate. The summary measure with random effects estimate was 3. 05 CI95% [1. 99–4. 67]. The point out of the confidence limit of the funnel plot (Fig 3) represents the excluded paper that had an OR of 10. 18. Fig 4 graphically represents the sensitivity and 1-specificity of each study. The sensitivity varied from 2% [16] to 39% [17] and the specificity from 83% [13]to 98% [16]. Table 4 presents these values and the positive predictive value (PPV) of each study, i. e. , the proportion of positives results that developed clinical leprosy. Douglas 2004 is the study with higher PPV due to a high specificity and a moderate sensibility. Chanteau 1993 and Sinha 2004 had higher specificity but a very low sensibility.
Although there is a clear and consistent increase in risk of development of leprosy in anti PGL-1 positive healthy contacts, selection of cases for prophylaxis intervention based on anti PGL1 response would reach less than half of future leprosy cases, and result in much unnecessary treatment. Leprosy research must explore the role of antibody production in leprosy and it is similar to that in tuberculosis.
Contacts of leprosy cases are more likely to be infected and develop leprosy. But not everyone infected with M. Leprae develops clinical leprosy. into clinical disease. We examined and summarized all the eight studies that evaluated how well PGL-1 predicts which contacts of leprosy will become cases. PGL-1 positive contacts were 3 times more likely to develop leprosy; a variable proportion, but less than 30% of the cases were attributed to PGL-1 and less than 45% of the PGL-1 contacts developed leprosy. PGL1 would not be an appropriate test to decide which contacts of leprosy should receive preventive therapy if this was proposed in leprosy control programmes.
mycobacterium leprae
medicine and health sciences
enzyme-linked immunoassays
immune physiology
pathology and laboratory medicine
immunology
tropical diseases
preventive medicine
bacterial diseases
mathematics
statistics (mathematics)
neglected tropical diseases
vaccination and immunization
immunologic techniques
antibodies
bacteria
research and analysis methods
public and occupational health
immune system proteins
infectious diseases
serology
proteins
mathematical and statistical techniques
immunoassays
actinobacteria
research assessment
biochemistry
prophylaxis
meta-analysis
systematic reviews
physiology
leprosy
biology and life sciences
physical sciences
statistical methods
organisms
Anti-PGL-1 Positivity as a Risk Marker for the Development of Leprosy among Contacts of Leprosy Cases: Systematic Review and Meta-analysis