Introduction

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae) that affects peripheral nerves, skin, upper respiratory tract mucosa and eyes [1]. If the disease is treated too late, nerve damage can lead to preventable disability [2]. The incubation period of leprosy is relatively long and can vary widely, ranging from several months to more than twenty years [3]. Besides the slow incubation period of clinical manifestations, the variation in clinical presentation—also dependent on the immune response of the patient—contributes to the major challenges in early case detection, contact tracing, and interruption of the transmission of the disease. Since 1982, the World Health Organization (WHO) has recommended multidrug therapy (MDT) as the standard treatment for leprosy. MDT is provided free of charge by WHO to countries reporting new leprosy patients since 1995 [4,5].

MDT has transformed the treatment of leprosy leading to a reduced reported prevalence worldwide; people are no longer defined as “leprosy patients” after finishing MDT. However, evidence from the pre-treatment era suggests that certain cases of leprosy may also self-heal if left untreated [6]. The true global incidence of self-healing among leprosy cases is unknown, since it is not possible to determine how many people are infected. The reasons why only some leprosy patients may self-heal while others develop symptoms and further clinical manifestations are not fully understood. Furthermore, since effective treatment is available, it is not ethical to conduct longitudinal randomized studies to explore the phenomenon of leprosy self-healing in humans. Despite older studies indicating that leprosy shows a tendency to self-heal, no uniform definition has been established [6,7,8,9,10]. Research has solely suggested that spontaneous recovery from leprosy signs and symptoms can be the result of a slow and gradual development of immunity to the bacteria causing leprosy [9]. Furthermore, a study by Martinez et al. [11] has shown that Polymerase Chain Reaction (PCR) testing revealed high rates of exposure to M. leprae in certain populations. This study found a significant number of individuals testing positive for the presence of M. leprae in hotspot areas, suggesting infection [11]. However, despite high PCR and Phenolic Glycolipid 1 (PGL-1)—positivity rates, the actual reported incidence of individuals developing overt clinical symptoms of leprosy is much lower than the percentage of positive PCR results [11,12]. The meta-analysis of Penna et al. [12] to identify the presence of Immunoglobulin M (IgM) antibodies against the species-specific PGL-1 through enzyme-linked immunosorbent assay (ELISA) showed that the sensitivity of PGL-1 as a predictor of clinical leprosy varied from 2 to 39%. This suggests that a substantial proportion of individuals exposed to M. leprae do not progress to overt disease or may remain asymptomatic [12]. The difference between PCR and PGL-1 seropositivity rates and the reported incidence of leprosy supports the notion that a significant proportion of individuals indeed experiences resolving of the infection, preventing the progression to the clinical disease state [13,9]. Along with that, past studies have suggested the probability of self-healing to be associated with factors such as age, sex, type of infection, host’s immune response related to genetic factors or close contact in households and families, although a causal association is not confirmed [13].

Despite that self-healing or spontaneous regression in leprosy cases has been described by many researchers over the years [7,8,9,10], evidence remains limited. During the COVID-19 pandemic however, the incidence of leprosy cases decreased by a large percentage [14]. Between 2019 and 2020 there was a decline of 37% in new case detection (from 202,185 to 127,396) due to preventive measures related to the COVID-19 pandemic [14]. The restrictions of the COVID-19 pandemic significantly hindered global leprosy control measures such as active case finding, case detection, treatment, and prophylaxis [15]. Health facilities faced challenges in diagnosing and treating new leprosy patients and those with reactions, as they were overloaded by the pandemic. The supply of leprosy medication became challenging amid the disruptions caused by the ongoing health crisis [15]. While an impact of the pandemic on the new case detection of leprosy was therefore expected [16], it is noteworthy that some countries (e.g. Afghanistan and Bolivia) have not yet documented an increase in cases to the level before COVID-19, nor have the “missed cases” in other countries been accounted for up to the end of 2022 [14]. Although several factors might have contributed to this observation (e.g., ongoing health care providing backlogs, political changes, or effects secondary to low endemicity), one factor may be self-healing of leprosy cases over the course of the pandemic. Moreover, mathematical models have included self-healing when predicting trends in new case detection, thus emphasizing its possible relevance [17,18].

The aim of this systematic literature review is to provide more understanding of the role of self-healing in leprosy and to reveal existing knowledge gaps regarding this topic. Understanding the factors associated with self-healing could potentially shed light on novel control strategies and aid in the quest for leprosy elimination.

Methodology

Data extraction and analysis

The data extraction was done independently, whereby all researchers were involved. The found articles in the databases were deduplicated. Afterwards, articles were screened for eligibility, first by title, then by abstract and finally using full text (Fig 1). The data of the resulting six articles were extracted using Microsoft Excel. The developed spreadsheet included the title of the paper, author, and publication year as well as how the papers answered the set research question (S2 Table). A comprehensive analysis was conducted, differentiating between different themes of leprosy-healing in the found literature, such as demographic factors, country and incidence of self-healing. The analysis followed the methodology of the PRISMA guidelines [19].

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Fig 1. Flowchart of included studies.

https://doi.org/10.1371/journal.pntd.0012434.g001

Results

The initial literature search yielded 342 studies in three databases. Duplicate records were removed and the remaining articles were screened by title, abstract and assessed for eligibility by reading the full-text. Finally, we identified six studies that were eligible for review from three countries: India, Phillippines, the Democratic Republic of Congo and Brazil.

Discussion

We included six studies conducted between 1938 to 1978 exploring the incidence of self-healing in different countries and continents. Children and paucibacillary (PB) casesshowed a high probability of self-healing with an average healing time of two years.

The six studies provided an overview of the current state of knowledge regarding self-healing in leprosy cases. It was obvious that the evidence of self-healing in leprosy patients is scarce and that the studies are more than 45 years old [7,8,9,10]. This can be attributed to the fact that it is ethically problematic not to provide immediate treatment after the leprosy diagnosis has been confirmed, making it difficult to study the natural history of leprosy and thus to determine an accurate incidence of self-healing cases [22].

It may also relate to the lack of an agreed definition of self-healing. We propose the following definition, modifying the one proposed by Browne (1974) [7].

“Self-healing in leprosy is the disappearance of signs of active infection and/or the complete or partial resolution of lesions, with no redness in lesions or progression in size and or number, and disappearance of any other signs of the disease, including nerve involvement and/or any bacilli in a skin smear, for at least one year without administering anti-leprosy treatment, including MDT [7].”

Following this definition, self-healing is probably a relatively common phenomenon where the body’s immune system combats the causative agent, M. leprae, resulting in disappearance of the infection and remission of any signs or symptoms of disease without treatment or other medical intervention. Many studies have described evidence of infection in the form of seropositivity of antibodies to the M. leprae specific antigen PGL-1. In high endemic areas, rates of seropositivity of 30–40% have been described [23]. Yet, of these only a small minority go on to develop signs of leprosy, showing that the body was capable of resolving infection: preventing disease and clearing the infection without treatment [23].

Although self-healing appears to be described rarely, understanding this process and integrating it into research, might offer perspectives and inform potential avenues for future interventions. It would also add precision to mathematical models predicting the impact of interventions for the prevention of leprosy. Furthermore, awareness and knowledge about self-healing could help estimate the ramifications of phenomena such as the pandemic on untreated leprosy patient cohorts. With that, gaining insights from healthcare professionals and communities about the occurrence of self-healing may be beneficial for monitoring purposes.

In the literature reviewed, self-healing appears to be associated with the type of leprosy and age. While it is difficult to find a definite pattern due to the limited number of studies, most results point to an increased probability of self-healing among children and PB cases [7,8,9,10]. The suggested healing time of two years seems to be consistent in the three studies [10,20,7]. Furthermore, it is biologically plausible that a proportion of patients would self-heal in the absence of treatment. The body’s immune system can kill and clear a wide variety of pathogens, including M. leprae. It has been estimated that over 95% of individuals show resistance to leprosy. After exposure protection is believed to occur promptly, often without resulting in any visible signs of the disease [24]. PB cases are known to have a cell-mediated immune system capable of mounting a targeted attack on M. leprae. So, even if the innate immune system does not kill the bacteria at an early stage of the infection, persons with either sub-clinical disease or overt PB disease are likely to have the capacity to resolving the infection. In children, the bacterial load is often small, which may be a reason why they have an increased tendency to resolving the infection.

The phenomenon of self-healing also has operational implications for contact screening and control measures under low-endemic circumstances. Contact screening aims to find new cases among contacts of recently detected new cases. However, if these have minor symptoms and most likely PB disease, missing an occasional case is unlikely to have major consequences regarding M. leprae transmission and disease impact. Also, persons without clear signs of leprosy can thus be safely kept on observation. The exception to this is early Multibacillary (MB) disease, which may also present without anesthetic skin lesions or clearly enlarged nerves. A skin smear, quantitative Polymerase Chain Reaction (qPCR) test on a skin biopsy, or PGL-1 blood test may confirm that the person in fact has MB leprosy and should be treated without delay [23].

Conclusion and recommendations

Recent research on self-healing in leprosy is scarce and evidence limited. This is primarily due to ethical concerns regarding withholding effective treatment of diagnosed patients, and because of the absence of an agreed definition of self-healing. Nevertheless, self-healing appears to be a plausible phenomenon influenced by demographic factors, and the type of leprosy. There is no evidence that the rate of self-healing is impacted by geographical factors. However it is likely that the rate of self-healing is influenced by environmental and socio-economic factors, including poverty, since they affect the the immune system. The status of the latter is likely to play an important role in self-healing. We recommend further research on self-healing in leprosy if and when situations occur that patients have been unable to obtain treatment due to external reasons, as it provides insight into the human immune system and the determinants of this phenomenon.

Supporting information