Leprosy Mailing List – August 17, 2026
Ref.: (LML) Long-lasting adverse impact of chemoprophylaxis & what actually works
From: Isabela Goulart, Uberlândia, Brazil
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Dear Pieter and colleagues,
I fully agree with Claudio Salgado’s thoughtful comments, particularly with the fundamental question he raises at the end of his contribution: how certain are we that an apparently healthy contact truly does not already have Hansen’s disease, or early neural involvement, before chemoprophylaxis is administered?
I would like to add evidence generated over the past several years by our group at the National Reference Center for Sanitary Dermatology and Leprosy (CREDESH), Federal University of Uberlândia, Brazil. Our findings consistently indicate that the term “asymptomatic contact” should not be assumed to mean “individual without neural impairment”, nor necessarily an individual without evidence of Mycobacterium leprae infection.
This distinction is particularly important in the context of SDR-PEP.
In a study published by Santos et al. (2018) in PLoS Neglected Tropical Diseases, we evaluated 175 anti-PGL-I-seropositive and 35 seronegative household contacts using an integrated protocol combining clinical examination, anti-PGL-I IgM serology, molecular assays for M. leprae, and electroneuromyography (ENMG).
Among the seropositive household contacts, 31.4% (55/175) already showed electrophysiological evidence of neural impairment, compared with 13.3% (4/35) of seronegative contacts. Seropositive contacts had a 4.04-fold higher chance of neural impairment.
The molecular findings were equally relevant. Peripheral blood qPCR was positive in 40.6% (71/175) of seropositive contacts, compared with 8.6% (3/35) of seronegative contacts. In slit-skin smear samples, qPCR detected M. leprae DNA in 47.4% (83/175) of seropositive contacts, compared with 17.1% (6/35) of seronegative contacts (Santos et al., 2018).
Importantly, none of the evaluated contacts presented skin lesions.
Thus, individuals without a conventional clinical diagnosis of Hansen’s disease could already present molecular evidence of M. leprae infection together with objective neurophysiological abnormalities.
We subsequently expanded this investigation in a larger cohort.
Santos et al. (2023) evaluated 361 anti-PGL-I-seropositive household contacts considered clinically asymptomatic, using an extensive protocol including clinical, molecular and electroneuromyographic assessments. Individuals with clinical evidence of Hansen’s disease or neurological symptoms were excluded, as were individuals with other recognized causes of peripheral neuropathy.
ENMG demonstrated neural impairment in 23.5% (85/361) of these contacts, with a predominance of mononeuropathy, which accounted for 62.3% (53/85) of the abnormal examinations.
Perhaps even more important for the present discussion is the discrepancy between objective neurophysiological abnormalities and what could be detected by conventional clinical examination.
Clinical nerve thickening was found in 17.5% (63/361) of the seropositive contacts. However, among the 85 individuals with abnormal ENMG, only 25.9% (22/85) presented nerve thickening detectable on clinical examination (Santos et al., 2023).
In other words, approximately three-quarters of the contacts with objective electrophysiological evidence of peripheral nerve impairment did not have clinically detectable nerve thickening.
Furthermore, molecular investigation again demonstrated evidence of M. leprae among these apparently asymptomatic individuals. Slit-skin smear qPCR was positive in 35.5% (128/361) and skin-biopsy qPCR in 25.8% (93/361) of the seropositive contacts (Santos et al., 2023).
These were therefore not patients with an obvious clinical diagnosis who had simply been overlooked. They were contacts without clinical evidence of Hansen’s disease or neurological symptoms in whom more sensitive investigation disclosed molecular and/or neurophysiological abnormalities.
High-resolution peripheral nerve ultrasonography subsequently provided independent anatomical evidence supporting these neurophysiological findings.
Luppi et al. (2023) studied 49 anti-PGL-I-seropositive household contacts, 30 seronegative household contacts and 53 healthy volunteers, using high-resolution ultrasonography of the median, ulnar, common fibular and tibial nerves. The contacts underwent careful dermato-neurological and molecular evaluation, and individuals with other plausible causes of peripheral neuropathy were excluded. All selected household contacts had no skin lesions and underwent rigorous sensory evaluation.
Ultrasonographic nerve thickening was detected in 26.5% (13/49) of seropositive household contacts, compared with only 3.3% (1/30) of seronegative household contacts (Luppi et al., 2023).
The seropositive contacts had a 10.5-fold higher chance of neural impairment detected by ultrasonography. They also showed significantly greater cross-sectional areas in the common fibular and tibial nerves and greater nerve asymmetry at selected sites.
Thus, two different objective approaches — ENMG assessing nerve function and high-resolution ultrasonography assessing nerve structure — independently demonstrated peripheral nerve abnormalities in contacts who could otherwise remain outside the conventional clinical definition of Hansen’s disease.
Importantly, these findings are not restricted to our center.
Voltan et al. (2023) independently evaluated 83 household contacts of multibacillary patients, 49 healthy volunteers and 176 patients with Hansen’s disease using high-resolution peripheral nerve ultrasonography.
Household contacts showed greater peripheral nerve cross-sectional areas and greater nerve asymmetry than healthy volunteers. The authors characterized these findings as silent peripheral neuropathy. Their analysis demonstrated that ultrasonographic abnormalities in contacts may approach some of the patterns found in established Hansen’s disease, providing independent evidence that structural peripheral nerve abnormalities may already be present before conventional clinical diagnosis.
The convergence of these findings becomes even more relevant when we consider the limitations of the neurological examination traditionally used to identify nerve thickening.
A very recent study by Mendes et al. (2026) directly assessed the diagnostic performance of peripheral nerve palpation compared with ultrasonography in leprosy neuropathy.
Twenty-nine newly diagnosed, treatment-naïve patients with leprosy-related neuropathy underwent standardized palpation of the radial, ulnar, common fibular and posterior tibial nerves by three experienced examiners — a dermatologist, an orthopedist and a physiotherapist — with ultrasonographic cross-sectional area used as the comparative reference method.
Among 232 nerves evaluated, ultrasonography identified nerve thickening in 26%. However, the sensitivity of clinical palpation ranged from only 26% to 34%, depending on the examiner, while specificity ranged from 68% to 81%. Interobserver agreement for nerve thickening was only 60%, despite examination by experienced professionals (Mendes et al., 2026).
The problem was particularly relevant in pure neural leprosy, which represented 62% of their sample. Even in these patients, palpation sensitivity was only 43%, contributing to frequent misclassification.
Although Mendes et al. (2026) studied patients with established leprosy neuropathy rather than asymptomatic contacts, this distinction actually reinforces the question relevant to contact screening: if nerve palpation has such limited sensitivity even in patients who already have leprosy neuropathy, how confidently can a normal palpation examination exclude subtle or early neural involvement in an apparently asymptomatic contact?
This finding converges directly with our observations at CREDESH. In Santos et al. (2023), most seropositive contacts with objectively abnormal ENMG did not have clinically detectable nerve thickening.
Taken together, the neurophysiological findings of Santos et al. (2018, 2023), the ultrasonographic findings of Luppi et al. (2023), their independent corroboration by Voltan et al. (2023), and the demonstrated limitations of nerve palpation reported by Mendes et al. (2026) converge on the same fundamental concern: the absence of conventional clinical signs does not reliably exclude early peripheral nerve involvement.
This raises a fundamental issue for chemoprophylaxis programmes.
Before asking whether a single dose of rifampicin prevents Hansen’s disease in a contact, we must first ask whether that individual is truly disease-free.
A person may have no visible skin lesion, no neurological symptoms and no clinically detectable nerve thickening, yet objective investigation may disclose electrophysiological or ultrasonographic abnormalities of peripheral nerves.
Moreover, anti-PGL-I seropositivity identifies a subgroup in whom these abnormalities are considerably more frequent, while molecular assays may simultaneously demonstrate the presence of M. leprae DNA.
This is particularly important because peripheral nerve involvement is not merely a late complication of Hansen’s disease. It is a central component of its pathogenesis and the principal determinant of its long-term disability.
Waiting for conventional cardinal signs to become detectable may therefore mean waiting until an ongoing biological and neurological process has progressed sufficiently to cross the threshold of routine clinical recognition.
I would like to emphasize an important distinction.
Our findings do not, by themselves, demonstrate that SDR causes neurological damage.
Nor do these studies establish that chemoprophylaxis accelerates progression to multibacillary disease, reactions or disability.
What they demonstrate is something different, but highly relevant to the present discussion: some individuals operationally classified as asymptomatic household contacts already have measurable neural abnormalities and/or molecular evidence of M. leprae infection before any preventive intervention is considered.
This creates an important methodological problem for studies of chemoprophylaxis.
If eligibility for SDR-PEP is determined primarily by conventional clinical examination, individuals with subclinical infection and early neural involvement may inadvertently be included in the population classified as disease-free contacts.
If such individuals subsequently develop clinically recognizable Hansen’s disease, multibacillary disease, reactions, nerve function impairment or disability, how should that outcome be interpreted?
Without sufficiently sensitive baseline neurological and laboratory assessment, it may be impossible to determine whether this represents genuinely incident disease, progression of pre-existing subclinical disease, or a change in the natural history of an infection and neuropathy that were already present when chemoprophylaxis was administered.
This distinction becomes even more important when the principal endpoint of a study is simply subsequent detection of clinically diagnosed Hansen’s disease.
A reduction in case detection during a particular period does not necessarily tell us what is occurring biologically or neurologically among individuals who continue to be classified as disease-free.
The peripheral nerve may already be involved before the disease becomes recognizable by conventional clinical criteria.
For this reason, I strongly support Claudio’s call for a more rigorous definition of who is truly eligible for chemoprophylaxis and for substantially more comprehensive long-term safety assessment.
Future studies should not restrict baseline evaluation to the absence of conventional clinical signs.
Particularly in endemic settings and among household contacts, incorporation of biomarkers such as anti-PGL-I IgM and molecular detection of M. leprae, together with objective assessment of peripheral nerves by ENMG and/or high-resolution ultrasonography, could substantially improve characterization of the population receiving preventive interventions.
Likewise, longitudinal studies of chemoprophylaxis should include neurological outcomes — not merely incident case detection — including nerve conduction abnormalities, structural nerve changes, sensory and motor impairment, reactions and disability.
Long-term follow-up is also essential. Hansen’s disease has a prolonged and variable incubation period, and neurological involvement may evolve silently before conventional diagnostic criteria are fulfilled. Short-term reduction in case detection therefore cannot, by itself, establish long-term neurological safety.
In other words, the debate should perhaps move beyond the binary question of whether SDR-PEP “works” or “does not work.”
We must first define what population is actually receiving it and how confidently pre-existing Hansen’s disease, particularly early neural disease, has been excluded.
For those of us who have followed household contacts longitudinally and investigated them beyond routine clinical examination, the concept of the “healthy asymptomatic contact” becomes considerably more complex.
Our experience at CREDESH has repeatedly shown that: clinical silence does not necessarily mean neurological silence.
I believe this distinction should be central to any discussion of both the effectiveness and the long-term safety of chemoprophylaxis in Hansen’s disease.
Therefore, I fully agree with Claudio that perhaps the question preceding “Should SDR be given to this contact?” should be: “How certain are we that this individual truly does not already have Hansen’s disease?”
The available neurophysiological, ultrasonographic, serological and molecular evidence indicates that this question cannot always be answered by conventional clinical examination alone.
Kind regards,
Isabela Maria Bernardes Goulart, MD, PhD
Full Professor, School of Medicine
Federal University of Uberlândia
National Reference Center for Sanitary Dermatology and Leprosy – CREDESH/HC-UFU/HU Brazil
Uberlândia, Minas Gerais, Brazil
References
- Santos DF, Mendonça MR, Antunes DE, Sabino EFP, Pereira RC, Goulart LR, Goulart IMB. Molecular, immunological and neurophysiological evaluations for early diagnosis of neural impairment in seropositive leprosy household contacts. PLoS Negl Trop Dis. 2018;12(5). doi:10.1371/journal.pntd.0006494.
- Santos DF, Garcia LP, Borges IS, Oliveira TJ, Antunes DE, Luppi ADM, Goulart IMB. Early diagnosis of neural impairment in seropositive leprosy household contacts: The experience of a reference center in Brazil. Front Med (Lausanne). 2023;10:1143402. doi:10.3389/fmed.2023.1143402.
- Luppi ADM, Ferreira GE, Prudêncio DL, Antunes DE, Araújo L, dos Santos DF, Nogueira-Barbosa MH, Goulart IMB. High-resolution ultrasonography for early diagnosis of neural impairment in seropositive leprosy household contacts. PLoS One. 2023;18(5). doi:10.1371/journal.pone.0285450.
- Voltan G, Marques-Júnior W, Santana JM, Lincoln Silva CM, Leite MN, De Paula NA, Bernardes Filho F, Barreto JG, Da Silva MB, Conde G, Salgado CG, Frade MAC. Silent peripheral neuropathy determined by high-resolution ultrasound among contacts of patients with Hansen’s disease. Front Med (Lausanne). 2023;9:1059448. doi:10.3389/fmed.2022.1059448.
- Mendes JS, Montenegro da Silva T, Tavares Cruz P, dos Santos Cordeiro AG, da Mata Serique R, Alves MR, Lara FA, Talhari C, Miot HA, Talhari S. Diagnostic performance of peripheral nerve palpation compared with ultrasonography in leprosy neuropathy: A prospective real-world clinical evaluation. PLoS Negl Trop Dis. 2026;20(4). doi:10.1371/journal.pntd.0014234.
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LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << edit...@gmail.com
