Open Access

Unsolved matters in leprosy: a descriptive review and call for further research

Annals of Clinical Microbiology and Antimicrobials201615:33

https://doi.org/10.1186/s12941-016-0149-x

Received: 3 February 2016

Accepted: 11 May 2016

Published: 21 May 2016

Abstract

Leprosy, a chronic mycobacterial infection caused by Mycobacterium leprae, is an infectious disease that has ravaged human societies throughout millennia. This ancestral pathogen causes disfiguring cutaneous lesions, peripheral nerve injury, ostearticular deformity, limb loss and dysfunction, blindness and stigma. Despite ongoing efforts in interrupting leprosy transmission, large numbers of new cases are persistently identified in many endemic areas. Moreover, at the time of diagnosis, most newly identified cases have considerable neurologic disability. Many challenges remain in our understanding of the epidemiology of leprosy including: (a) the precise mode and route of transmission; (b) the socioeconomic, environmental, and behavioral factors that promote its transmission; and (c) strategies to achieve early diagnosis and prevent neurologic impairment to reduce the large burden of disability among newly identified cases; and among those who endure long-term disability in spite of completing multidrug therapy.

Keywords

Leprosy Mycobacterium leprae Hansen’s disease Sequelae Peripheral nerve Schwann cell Histiocytes Leprosy reactions Disability Elimination

Background

Leprosy is a chronic mycobacterial infection caused by Mycobacterium leprae leading to a plethora of clinical manifestations ranging from cutaneous manifestations to disfigurement, deformity, stigma, and disability (neurologic and blindness). The burden of disease associated with M. leprae infection in humans stems from the ability of this bacterial pathogen to induce severe injury of peripheral nerves (Schwann cells) and skin (keratinocytes and histiocytes) [17]. The clinical spectrum of disease of leprosy is further defined by the immune response to the leprosy bacillus ranging from tuberculoid, to borderline, and to lepromatous forms (Ridley-Jopling) [1, 2]. Once the infection is established, the occurrence of leprosy reactions, because of their inflammatory impact on the peripheral nerve, constitutes an important contributor to sensory loss and dysfunction [2, 3, 8, 9].

Leprosy trends

Leprosy does not constitute the ancestral plague that once used to be. However, the elimination of leprosy as a public health problem as defined by the World Health Organization, has not been achieved in any meaningful and sustainable manner [6, 7]. Besides its measurable medical consequences, leprosy hampers the freedoms and capabilities of individuals and affected communities [10]; and often excludes individuals from social life due to the often associated stigma [1113]. The early tales of fear and pity that leprosy in its severe forms elicited among many human groups, continues to transpire to a similar degree into modern societies [6, 7, 13].

Leprosy continues to be an important infectious disease in many endemic settings as demonstrated by: (a) a growing number of new cases [7, 14, 15]; (b) many patients completing multi-drug therapy but subsequently developing leprosy reactions [16, 17]; or (c) microbiologically treated individuals but with long-term neurologic dysfunction and disability originated by irreversible peripheral nerve injury [2, 16].

Since 1981, multi-drug therapy (MDT) has been universally instituted through active case finding in highly affected communities [6, 14]. These programs have achieved some degree of success by decreasing the prevalence of the disease [14], however, there are many continuing challenges including: (a) yearly, new cases continue to be detected in highly endemic areas [7]; (b) since 2005, the number of reported new cases has remained consistently stable despite continuous use of MDT concomitantly with a substantial decrease in the prevalence of the disease [7]; (c) a rising number of new cases are expected to reach the 4 million mark by the year 2020 [7]; and (d) From 2007 to 2013, new cases continue to be identified with grade 2 disability with no evidence of this indicator decreasing [7].

There are two major potential reasons for the persistent detection of new cases of leprosy in endemic areas. The first one is that the “elimination phase” has transitioned into an era of complacency [6, 7, 14]. The reported rate of new case detections suggests that the rate of new cases decreased by 60 % from 2000 to 2005 [7]. However, there is evidence to suggest that the detection of cases did not truly decreased to such degree during this period; and that current reports may actually represent an underestimation of newly detected cases [7]. Secondly, persistent transmission of M. leprae calls for reassessing our long-held notions about its mechanism and routes of transmission [1820]. Current epidemiologic trends reinforce old disagreements regarding the portal of entry and the pathways of M. leprae into the human body [19, 20]. Neither person-to-person transmission nor host-susceptibility explains the patchy distribution of leprosy, and new cases are detected in persons who have had no know contact with human leprosy (30–60 % of cases) [5, 6]. Transmission of leprosy to close contacts has been documented and it is considered a major risk factor for developing leprosy among susceptible individuals [2123]. Nonetheless, the precise mode and route of transmission has not been satisfactorily defined [22, 23]. It has been assumed that person-to-person transmission occurs by nasal secretions or cutaneous lesions under circumstances such as overcrowding, inadequate housing and lack of hygiene [2123].

There is sufficient ecological data to suggest that the transmission of leprosy is potentially influenced by environmental factors such as soil and water exposures, insect vectors playing a role [2435], and the free-living amoebas (e.g., Acanthamoeba spp.) may participate in the environmental viability of leprosy in some biotopes [30, 31]. Zoonotic transmission from natural infection of armadillos in the Southeast United States has been confirmed as responsible for the majority of autochthonous transmission of cases in this area [32]. It is likely that armadillos may also play an important role in the transmission of leprosy in some areas of Latin America such as in Colombia, Venezuela, Mexico, and Brazil [33]. Understanding how environmental factors influence host-pathogen interactions in complex natural systems [34, 35], where multiple feedbacks between biotic and abiotic factors take place, is especially important in the context of environmentally persistent pathogens such as M. leprae.

Human migration and the spread of Mycobacterium leprae

The mycobacterial ancestor of M. leprae diverged from the tuberculosis bacilli approximately 66 million years ago, long before the origin of the Homo genus [3642]. Estimates of the intracellular adaptation of M. leprae related to reductive evolution and pseudogene development has been estimated to occur around 9 million years ago [37, 38]. Our current understanding based on recent genetic and molecular clock data indicates that leprosy the human species prior or during the Paleolithic [37]. In turn, human migration has been crucial in the global spread of leprosy [38]. In this evolutionary journey, M. leprae has migrated with human populations through expeditionary, military, colonialist, and other human endeavours [3841]. The earliest clinical descriptions of leprosy are said to be from Egypt and India from records dating back to 600 B.C.E [38]. Older descriptions of disfiguring cutaneous illnesses possibly including leprosy under the Hebrew Tsar’ath (zarath) contained in the Old Testament; however, this fact remains controversial since there is scant skeletal evidence for leprosy in human remains from Israel [13]. Humans are natural reservoirs in the transmission of M. leprae and therefore the global spread of leprosy is tied to historical milestones of human migration [10, 3739]. Recent comparative genomic evidence points to the origin of the leprosy in Eastern Africa [38, 39]. The cohabitation of M leprae with human hosts has provided M. leprae with different social and biological attributes that facilitated the selection of different traits conferring different adaptive biological properties [3739]. Phyleogeographic studies have demonstrated an association between the spread of leprosy and migration patterns of earlier human societies and trade routes (i.e., the Silk Road that united Europe to China contributed to the spread of leprosy) [38, 39, 41, 43]; or to historical events corresponding to the returning expeditionary forces of antiquity spreading the pathogen from the Middle-Eastern strain of M. leprae to Medieval Europe [38]. Subsequently, European explorers spread the disease westward to the New World or through the Atlantic slave route [37, 39]. Overall, genomic comparisons of ancient and modern strains of M. leprae remain remarkably similar, indicating it was probably improvements in social conditions that led to a substantial reduction of leprosy in Europe in the 16th Century [40, 41]. While these events indicate the crucial role of humans as reservoirs of disease and potentially transmitting to their close contacts, it is also feasible that nasal discharges or cutaneous lesions of populations migrating into previously leprosy-free biotopes may have caused a spillover of M. leprae into environmental niches with optimal biotic and abiotic factors that subsequently amplified the cycle of transmission of leprosy.

In modern times, it is likely that the clustering of cases of leprosy occurs among individuals living in resource-poor areas with favorable ecological niches for M. leprae to thrive [2123]. In turn, the human host acquires M. leprae by an increased exposure to mycobacteria by their low socioeconomic standing combined with their biologic susceptibility to acquire the infection and develop the disease. In these settings, poverty operates by promoting low schooling, poor housing in often-unstructured settlements with overcrowding, lack safe water, absence of water management systems and sewage, and, as a result most experience poor hygienic practices [2123]. Additionally, most individuals who have been diagnosed with leprosy have also experienced food shortages and malnutrition. Suffering from leprosy and other neglected tropical diseases becomes part of their biological destiny and their way of life. Therefore, it is important to consider the larger social drivers that underlie the unequal distribution of life choices of individuals living in the highest endemic areas that place them at risk of suffering from leprosy and other neglected diseases.

Mycobacterial ecology

Humanity is irremediably imbedded in a matrix of natural and man-made ecologies of living organisms [44]. Mycobacteria are ubiquitous microorganisms that live in natural waters, soils, and engineered water systems that have role in nutrient cycling. A major determinant of the ecology and epidemiology of mycobacterial species is the presence of a lipid-rich outer membrane leading to biofilm formation, antibiotic/disinfectant resistance, aerosolization, and surface adherence [20, 44]. A few species have evolved from this environmental pools to become major human pathogens such as M. tuberculosis, M. leprae and M. ulcerans [13, 4549]. Searching for common ecological patterns and transmission dynamics among these three closely phylogenetically related species may assist in identifying environmental sources of persistent infection [4549]. For the two major human pathogens, M. tuberculosis and M. leprae, it is crucial to adapt to the intracellular lifestyle and to modulate the lipid metabolism of sanctuary cells [44] (Table 1). M. tuberculosis and M. leprae have evolved pathogenic mechanisms through complex evolutionary negotiations between these pathogens and their hosts, while the acquisition of a large plasmid encoding the toxin mycolactone relates to the underlying mechanism of pathogenicity of M. ulcerans [4850]. This mycobacterial pathogen is causative agent of Buruli ulcer, which is a chronic destructive necrotizing infection of subcutaneous tissue that has been reported to occur in more than 30 countries [4850]. In contrast to M. tuberculosis and M. leprae, M. ulcerans adaptation mechanisms have involved the selection of certain genes that facilitate its livelihood occupying aquatic aerobic, dark, and osmotically stable environments and its ability to reside in the extracellular matrix of the subcutaneous tissues where it unleashes the production of its toxin [50]. Genetic analyses of M. ulcerans have shown that it had a common ancestor with M. marinum and that it diverged around a million years ago [45, 49, 50]. M. marinum produces a relatively milder nodular cutaneous lesions compared with Buruli ulcer [50].
Table 1

Comparison of the three major pathogenic species within the Mycobacterium genus

Features

M. tuberculosis a

M. leprae

M. ulcerans b

Genome

Genome of 4.4 Mb with 4000 genes and only six pseudogenes (91 % coding capacity)

No evidence of major reductive evolution

Reductive evolution and large pseudogene (1116) formation resulting in a 3.31-Mb genome

Only 50 % coding capacity by 1605 genes

M. ulcerans downsized from 6.6 MB (M. marinum) to 5.8 Mb genome

M. marinum and M. ulcerans share 97 % of genes since they share a common ancestor and evolved from M. marinum by lateral gene transfer and reductive evolution (~771 pseudogenes)

Selected genes facilitate occupying an aerobic niche environment, osmotically stable, dark, and extracellular environments

Target cell of infection

Intracellular

Macrophages (alveolar) and in the reticuloendothelial system

Non-classical immune cells (epithelial cells, endothelial cells, fibroblasts, adipocytes, glia and neurons) [70]

Intracellular

Schwann cells

Histiocytes

Keratinocytes

Extracellular

Extracellular matrix in subcutaneous tissues where M. ulcerans directs the production of the polyketide toxin mycolactonec leading to tissue necrosis and local tissue and systemic immunosuppression

Pathogenic mechanisms

Intracellular persistence in macrophages causes necrotizing granulomas that cause tissue destruction in the lung or other organs

Infection of Schwann cells leads to peripheral nerve dysfunction secondary to demyelination

Reprogramming of Schwann cells linked to disseminated disease

Destructive ulcerative ulcers (Buruli ulcer) with subcutaneous fat necrosis

Environmental determinants

Members of the Mycobacterium tuberculosis complex can be shed by infected hosts to the environment in sputum, feces, and urine by humans; in milk from dairy animals (cattle) and infected body tissues from other domestic and wild animals

Free-living amoebas may act as macrophage-like niches in the environment

Clustering of cases by geospatial assessments of thermal-hydrological determinants in Ethiopia and India

Armadillo is a natural host in the Western Hemisphere and causes a zoonosis in the Southern USA

In some settings some primates species may become reservoirs of M. leprae

There is evidence of viable M. leprae found in soil, water, and free-living amoebas (Acanthamboeba spp.)

Sphagnum and other moss vegetation may have facilitated transmission in the second half o the 19th and the beginning of the 20th century living in isolated farms in coastal Norway

Ecological studies have linked contaminated water with M. leprae in polluted surface water in the tropics

M. leprae contaminates clothes by washing in streams and incomplete drying in the humid tropical climate; or by bathing and washing clothes or dishes in a report from Indonesia

In Brazil, bathing twice weekly, infrequent changing of bed linens or hammock among impoverished populations in Northern Brazil

Mycobacterium ulcerans transmission cycle involves aquatic insect vectors, aquatic plants, and aquatic animals

Aquatic plants (e.g., Rhizoclonium sp., H. reticulatum) favor the growth and biofilm production of M. ulcerans

There are two different ways that M. ulcerans persists in the environment and infect aquatic animals (in the savanna landscape residing in stagnant or slowly moving waters; and in tropical rainforests dwelling in alkaline waters and its growth is dependent on climate changes)

Vector transmission

M. canettii the ancestor of M. tuberculosis complex (MTC) was probably transmitted by an unidentified ancestral vector (e.g., plant or insect) prior to the Neolithic revolution (>12,000 years ago)d

Some mosquitoese

(Culex fatigans and Cimex hemipterus caught in the field in an endemic area in India harbor viable M. leprae

Laboratory-bred Culex fatigans and Cimex hempterus are able to take up leprosy bacilli from blood of patients with untreated lepromatous leprosy

The feasibility of biting arthropods amplifying the transmission of leprosy through mechanical studies demonstrated that large numbers of bacilli are readily available to the biting apparatus of arthropods among individuals with untreated multibacillary leprosy

Bacteremia in cases of leprosy may make viable bacilli available to biting arthropods

Naucoridae (aquatic insects) in West African Countries (Ghana, Benin, Togo)

Effect of BCG (Bacille-Calmette-Guérin)

Protection for disseminated tuberculosis including tuberculous meningitis in children <4 years of age

Variable degree of protection from different reports

Offers important protection against Buruli ulcer

Many mycobacterial species may cause skin and soft tissue infections including M. tuberculosis, M. leprae, M. ulcerans, M. marinum, M. hemophilus, M. kansasii, M. abscessus, M. fortuitum, and M. chelonei (Refs. [73])

a Mycobacterium tuberculosis complex consists of seven species capable of causing tuberculosis (M. canetti, M. pinnipedii, M. africae (subtypes Ia, Ib and II), M. microti, M. caprae, M. bovis, M. bovis BCG, Dassie bacillus)

b Mycobacterium marinum is a closely related species to M. ulcerans. Mycolatone is the toxin produced by M. ulcerans is responsible for causing cutaneous and subcutaneous ulceration (tissue necrosis) and associated local and systemic immunosuppression

cMycolactone produced inhibition of protein translocation into the endoplasmic reticulum resulting in a deficit release of innate immune system cytokines, membrane receptors, adhesion molecules, and specific immune system cytokines

dOf the Mycobacterium tuberculosis complex, M. bovis and M. caprae are found in hosts domesticated 10,000–12,000 years ago, earlier ancestral species infected humans many years before that era and subsequently spread to other hosts directly from humans or through an unknown vector

eThere are several biting arthropods residing in leprosy endemic areas of which any could potentially act as a vector for the transmission of leprosy

Proverbial human-to-human transmission via respiratory droplets of M. leprae infection has been traditionally considered the driving engine of transmission of leprosy [18, 19, 51, 52]. While leprosy bacilli are present in the nasopharynx of individuals with multibacillary leprosy [51] and from cutaneous lesions [52], and that these bacilli are able to infect other susceptible human hosts [18, 19], the precise mechanism and route of transmission remain to be completely elucidated. Indeed, the current epidemiology of the persistent transmission of leprosy along with collected evidence made since the 19th Century suggest that environmental factors such as soil and water, vegetation, arthropods [20], free-living amoebas [30, 31], and animal reservoir host such as the nine-banded armadillo (Dasypus novemcintus) play an influential role in the ongoing transmission of M. leprae [32, 33].

In 1895, Hansen and Looft made the initial observation regarding the possibility of environmental factors involved in the transmission of leprosy [24]. They suggested that the initial site of cutaneous lesions often involved sites with direct contact with environmental surfaces (e.g., wading in streams and rivers in patients with lesions in calves). Subsequently, 27 years after Hansen’s description of M. leprae, Sand proposed that the transmission of leprosy between humans takes place indirectly. His findings were the result of analyzing 1221 patients in the Norwegian leprosarium of Reitgjaerdet in whom the transmission within household was relatively low and most cases occurred in men who had more contact with environmental sources. He further proposed that perhaps a living organism or ground containing decomposing material were factors involved in the transmission cycle [25].

Environmental factors such as climate, type of soil and water, environmental degree of acidity [20], etc.; along with spillover of M. leprae from human cases (e.g., nasal discharges contaminating soil or water) may facilitate the amplification of the transmission cycle in biotopes with existing suitable ecological abiotic and biotic determinants (i.e., tropical and subtropical settings) [34, 35]. In this hypothetical model, we can postulate that chemoprophylaxis (or preemptive treatment) of contacts of multibacillary cases and effective treatment of leprosy cases decreases spillage of M. leprae into environmental reservoirs (soil, water, plants, or free-living amoebas) [24, 25, 27]. Preliminary evidence from a leprosy-endemic area in India has shown that genetic material of M. leprae was detected near washing and bathing areas where cases of leprosy were detected and genetic fingerprinting correlated between human cases and DNA detected in soil samples [24, 29]. The spillover of M. leprae into soil and water may explain the acquisition of this pathogen by armadillos acting as scavengers, and ultimately linking a reverse cycle of transmission from armadillos back to humans [32]. Nevertheless, it is possible that there are other unidentified environmental reservoirs or vectors influencing the occurrence of new human infections in highly endemic areas. Zoonotic transmission of M. leprae from armadillos in the Golf Coast of the United States contributes to endemic human infections detected in this geographic area every year, supporting the fact that leprosy is not exclusively transmitted person-to-person [32].

Free-living amoebas as environmental sanctuaries of M. leprae

There is some evidence that the obligate intracellular M. leprae may spill over onto environmental niches and survive endosymbiotically inside free-living amoebae similar to the mechanism described of Legionella pneumophila residing inside Acanthamoeba [30, 31]. Large numbers of viable leprosy bacilli are expelled into the environment in the nasal secretions or to a lower degree from skin lesions of individuals diagnosed with multibacillary leprosy [52]. There is also evidence that M. leprae may invade and infect the nasal mucosa or into abraded/punctured skin [5254]. In this regard, it is feasible that free-living pathogenic amoebae potentially act as “external” reservoirs capable of ingesting and supporting the environmental viability of M. leprae expelled by infectious patients into the environment and thus acting as a macrophage-like niches [30, 31]. Further evidence has demonstrated that M. leprae remains viable for prolonged periods inside Acanthamoeba castellani and Acanthamoeba polyphaga; and it is able to survive encystment and retain infectivity in the nu/nu mouse model [33]. It remains to be tested if M. leprae infected amoebae is able to transport the bacilli through nasal mucosa or through intact or abraded skin to produce clinical disease [31].

Arthropods as vectors of M. leprae transmission

The possibility of arthropods as vectors of M. leprae has not been conclusively ruled out [5]. As early as 1915, Adolpho Lutz suggested that “the erratic manner of the propagation of leprosy” might be explained by the bites of biting arthropods, particularly of Culex mosquitoes (i.e., Culex fatigans) [20]. In fact, there are several biting arthropods residing in highly endemic areas of leprosy that theoretically might act as a vector of M. leprae [5566]. In some studies, the distribution of single lesions of tuberculoid leprosy correlated with exposed skin areas [60, 61]. Mechanical studies have demonstrated the feasibility of biting arthropods to uptake M. leprae since large numbers of bacilli are readily available within cutaneous lesions to the biting apparatus of many species of arthropods among individuals with untreated multibacillary leprosy [59, 6166]. Additionally, it has been shown that patients with lepromatous leprosy by developing bacteremia may make viable bacilli available to biting arthropods [6365]. Sandflies have been ruled out as vectors of leprosy transmission [66].

There is evidence that mycobacterial species constituting the Mycobacterium tuberculosis complex (i.e., M. canetti) infected humans before the Neolithic period (< than 12,000 years ago) and that a non-mammalian vector may have played a role (e.g., plants or insects) [4446]. Tuberculosis infection later spread to dairy animals as a result of human transmission during their domestication and involving a mechanism of transmission either through direct contact or through an unrecognized vector [44].

Mycobacterium ulcerans transmission cycle involves aquatic insect vectors, aquatic plants, and aquatic animals [45, 4750]. Similarly, survival of M leprae in environmental niches may also involve natural reservoirs (e.g., free-living amoebas) or it may be transmitted by arthropods (e.g., mosquitoes). It is also possible that species of the Mycobacterium tuberculosis complex may use environmental sanctuaries such as free-living amoebas to resist the external environment by acting as a macrophage-like niche [20]. Further studies using novel molecular assays need to be conducted to assess the potential contribution of arthropods to the transmission of leprosy in endemic areas.

Early diagnosis and neurologic disability

Peripheral nerve involvement occurs in all patients with M. leprae infection. At the time of a diagnosis of leprosy, up to 60 % of cases have evidence of peripheral nerve damage enough to require prolonged course of corticosteroids [6]. Neural tropism of the leprosy bacillus is through its binding and entry into Schwann cells causing demyelination [8, 9, 6769]. These events results in demyelination of myelinated Schwann cells that manifests clinically with decreased sensorimotor function and its associated complications [69, 70]. Additionally, M. leprae leads to a dedifferentiation process of Schwann cells transforming them into Trojan horses for the systemic dissemination of the bacilli [3, 69, 70]. Peripheral nerve sensorimotor dysfunction in patients with leprosy is frequently exacerbated by episodes of leprosy reactions [8, 9]. Indeed, even after effective antibacterial therapy, a large number of dead bacterial cells remain within nerves and continue to elicit immunologic responses manifested as acute or chronic neuritis [8, 71]. Early detection and treatment of neuropathy in leprosy has important preventive potential. Preventing leprosy reactions or effectively treating them is therefore an important consideration in any strategy attempting to reduce peripheral nerve injury. We need to expand our understanding of factors that predispose individuals to develop leprosy reactions and the mechanisms that trigger their occurrence. One important consideration is the potential role of the microbiome in modulating the inflammatory response, particularly of herpes viruses [2]. While there is little research in this area, there is ample evidence in other clinical scenarios to illustrate that herpes viruses modulate inflammatory responses during pathologic conditions [72] (Table 2). Early identification of leprosy cases remains a central priority in controlling this disease. In this regard, school-screening programs employing clinical assessments combined with serological and molecular surveys in endemic areas have been shown to increase the early detection of cases [73]. These programs have the greatest potential for reducing transmission by early instituting of treatment early in the course of the disease; and by identifying household contacts and household cases. Similarly, geospatial analyses of risk assessments of leprosy based on thermal and hydrological environments have demonstrated useful in predicting clustering of cases in studies conducted in Ethiopia and India [34, 35] (Table 2). Efforts to scale up school-based screenings and geospatial risk assessments based on ecological determinants in hyperendemic settings may offer so far, the best opportunity to reduce the occurrence of new cases.
Table 2

A potential research and policy roadmap to reduce leprosy transmission

Categories

Key considerations

Suggestions

Understanding pathogenic mycobacterial ecosystems

M. tuberculosis complex, M. leprae and M. ulcerans are phylogenetically closely related

These three pathogenic species cause three major diseases: tuberculosis, leprosy, and Buruli ulcer, respectively

Mycobacterium ulcerans transmission cycle involves aquatic insect vectors, aquatic plants, and aquatic animals. Buruli ulcer is transmitted by aquatic fleas (Naucoridae)

Insect vectors or plants may have played a role in much earlier transmission of tuberculosis to humans that that occurring during the neolithic revolution, where the disease spread likely from human to human and from humans to domesticated dairy animals

Armadillos are responsible for the majority of autochthonous cases of human leprosy in the Southeast USA

Further studies to address zoonotic transmission by armadillos in Latin America

Assess the role of armadillo control strategies to reduce leprosy transmission

Potential role for household-insecticide spraying or other vector-prevention or vector-control strategies for vector control among patients diagnosed with multibacillary leprosy

Epidemiological clues linked to historical population migration events

There are important associations between the spread of leprosy to migration patterns of earlier human societies and trade routes (i.e., the Silk Road that United Europe to China contributed to the spread of leprosy); or to historical events corresponding to the returning expeditionary forces of antiquity spreading the pathogen from the Middle-Eastern strain of M. leprae to Medieval Europe

Subsequently, European explorers spread the disease westward to the New World and through the Atlantic Slave Trade

Evaluate transmission networks

Historical reassessments of important population migrations to identify potentially missed epidemiologic clues

Early diagnosis, treatment and prevention of neurologic disability

Early identification of subclinical cases may assist in interrupting the course of the natural history of the disease by preventing the occurrence of clinical manifestations including and its associated nerve injury; and from a public health perspective to potentially decrease spillage of M. leprae by instituting chemophrophylaxis of contacts; treatment of those with latent infection; or preemptive treatment of those with subclinical disease

Epidemiologic mapping of hot zones of transmission

Rigorous contact investigation of patients with leprosy

Development of a diagnostic test for early-stage or subclinical infectiona

Early identification of leprosy cases in endemic areas through school-based surveys

Implement post-exposure treatment of contacts, latent infection, or subclinical infection (chemoprophylaxis versus latent treatment versus preemptive treatment)

Preventing leprosy reactions

Leprosy reactions may occur during multi-drug therapy (MDT) or even after completing MDT

Leprosy reactions are often precipitated by stress (e.g., surgery, infections, trauma) or after the initiation of MDT

Herpes viruses reactive in the human host during stress

Leprosy reactions exacerbate peripheral nerve injury and therefore may lead to neurologic sequelae

Herpes viruses have host immunomodulatory properties and there is increasing evidence that the reactivation of some herpes viruses is responsible for drug reactions (i.e., Epstein-Barr virus (EBV) infection reaction to amoxicillin during an episode of infectious mononucleosis; or herpes human virus 6 reactivation linked to drug reaction eosinophilic systemic syndrome (HHV-6); or cytomegalovirus (CMV) causing immunologic rejection in transplant recipients

Early diagnosis of leprosy cases

Close clinical follow-up of patients initiating MDT

Long-term period follow up of patients that completed MDT, particularly those with borderline and lepromatous forms of leprosy

Effective management of leprosy reactions to prevent further nerve injury

Research to confirm the association between herpes viruses and the occurrence of leprosy reactions: evaluate patients presenting with newly diagnosed leprosy reactions with molecular testing (i.e., PCR) for herpes virus reactivation including HHV-6, Epstein-Barr virus, Varicella-Zoster virus, cytomegalovirus or others

Evaluate the potential role for the institution of antiviral suppressive therapy among those with evidence of herpes virus reactivation

a Mycobacterium leprae has the ability to reprogram the Schwann cell into a stem-cell-like cell that carries the bacilli into other tissues to ensure its dissemination. Given this systemic dissemination it seems feasible to search for the development of assays such as an interferon—assay employing a similar approach to the one used for detection of cytokine-production patterns by M. tuberculosis

Conclusions

Our understanding of the transmission dynamics of M. leprae is incomplete. While person-to-person transmission may play a role, there is a possibility of other modes of transmission involved. Therefore, there is a need for a fresh reexamination of the historical, phyleogeographic, sociocultural, and environmental factors linked to the spread of M. leprae among human populations. We need to consider mycobacterial ecologies of other pathogenic mycobacteria such as M. ulcerans; and to expand our exploration for environmental determinants including thermal-hydrological factors (i.e., soil, vegetation, water); intermediate reservoirs or vectors including free-living amoebas, arthropods, and zoonotic transmission. Identifying epidemiologic clues from these analyses may facilitate designing effective control or elimination interventions.

Declarations

Authors’ contributions

CFP: Participated in the design, review of the literature, and writing of the manuscript. AJRM: Participated in the design, review of the literature, and writing of the manuscript. Both authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Infectious Diseases Clinic, Phoebe Putney Memorial Hospital
(2)
Hospital Infantil de México, Federico Gómez
(3)
Public Health and Infection Research Group, Faculty of Health Sciences, Universidad Tecnológica de Pereira

References

  1. Britton WJ, Lockwood DNJ. Leprosy. Lancet. 2004;363:1209–19.View ArticlePubMedGoogle Scholar
  2. White C, Franco-Paredes C. Leprosy in the 21st century. Clin Microbiol Rev. 2015;28(1):80–94.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Polycarpou A, Walker SL, Lockwood DN. New findings in the pathogenesis of leprosy and implications for the management of leprosy. Curr Opin Infect Dis. 2013;26:413–9.PubMedGoogle Scholar
  4. Rodrigues LC, Lockwood DNJ. Leprosy now: epidemiology, progress, challenges, and research gaps. Lancet Infect Dis. 2011;11(6):464–70.View ArticlePubMedGoogle Scholar
  5. Gay FP. The unsolved problems in leprosy transmission. Science. 1935;81(2099):2083–5.View ArticleGoogle Scholar
  6. Lockwood DNJ, Shetty V, Oliveira Penna G. Hazards of setting targets to eliminate disease lessons from the leprosy elimination campaign. Brit Med J. 2014;348:g1136.View ArticlePubMedGoogle Scholar
  7. Smith WC, van Brakel W, Gillis T, Saunderson P, Richardus JH. The missing millions: a threat to the elimination of leprosy. PLoS Negl Trop Dis. 2015;9(4):e0003658.View ArticlePubMedPubMed CentralGoogle Scholar
  8. Scollard DM, Truman RW, Ebenezer GJ. Mechanisms of nerve injury in leprosy. Clin Dermatol. 2015;33:46–54.View ArticlePubMedGoogle Scholar
  9. Scollard DM. The biology of nerve injury in leprosy. Lepr Rev. 2008;79:242–53.PubMedGoogle Scholar
  10. Franco-Paredes C, Santos-Preciado JI. Freedoms, justice, and the neglected tropical diseases. PLoS Negl Trop Dis. 2011;5(8):e1235.View ArticlePubMedPubMed CentralGoogle Scholar
  11. White C. Leprosy and stigma in the context of international migration. Lepr Rev. 2011;82(2):147–54.PubMedGoogle Scholar
  12. Jacob J, Franco-Paredes C. The stigmatization of leprosy in India and its impact on future approaches to elimination and control. PLoS Negl Trop Dis. 2008;30:e113.View ArticleGoogle Scholar
  13. Stone AC, Wilbur AK, Buikstra JE, Roberts CA. Tuberculosis and leprosy in perspective. Am J Phys Anthropol. 2009;52:66–94.View ArticleGoogle Scholar
  14. Lockwood DNJ, Suneetha S. Leprosy: too complex a disease for a simple elimination paradigm. Bull World Health Org. 2005;83(3):230–5.PubMedPubMed CentralGoogle Scholar
  15. Smith CS, Kahder Noordeen S, Richardus JH, Sansarricq H, Cole ST, Baruaf S, Soares RS, Savioli L, Aertsh A. A strategy to halt leprosy transmission. Lancet Infect Dis. 2014;14:96–7.View ArticlePubMedGoogle Scholar
  16. Jacob J, Kozarsky P, Dismukes R, Bynoe V, Margoles L, Leonard M, Tellez I, Franco-Paredes C. Five-year experience with type 1 and type 2 reactions in Hansen’s disease at a US travel clinic. Am J Trop Med Hyg. 2008;79:452–4.PubMedGoogle Scholar
  17. Pocaterra L, Jain S, Reddy R, Muzaffarullah S, Torres O, Suneetha S, Lockwood DNJ. Clinical course of erythema leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med. 2006;74(5):868–79.Google Scholar
  18. Bratschi MW, Steinmann P, Wickenden A, Gillis TP. Current knowledge on Mycobacterium leprae transmission: a systematic literature review. Lepr Rev. 2015;86:142–55.PubMedGoogle Scholar
  19. Mensah-Awere D, Bratschi MW, Steinmann P, Fairley JK, Gillis TP. Developing straegies to block the transmission of leprosy. Lepr Rev. 2015;86:156–64.PubMedGoogle Scholar
  20. Blake LA, West BC, Lary CH, Todd JR IV. Environmental nonhuman sources of leprosy. Rev Infect Dis. 1987;9(3):561–77.View ArticleGoogle Scholar
  21. Kerr-Pontes LRS, Barreto ML, Evangelist CMN, Rodrigues LC, Heukelbach J, Feldmeier H. Socioeconomic, environmental, and behavioural risk factors for leprosy in Northeast Brazil: results of a case-control study. Int J Epidemiol. 2006;35:994–1000.View ArticlePubMedGoogle Scholar
  22. Kerr-Pontes LRS, Montenegro ACD, Barreto ML, Werneck GL, Feldemeier H. Inequality and leprosy in Northeast Brazil: an ecological study. Int J Epidemiol. 2004;33:262–9.View ArticlePubMedGoogle Scholar
  23. Lockwood DNJ. Commentary: leprosy and poverty. Int J Epidemiol. 2004;33:269–70.View ArticlePubMedGoogle Scholar
  24. Lavania M, Katoch K, Katoch VM, Gupta AK, Chauhan DS, Sharma R, Gandhi R, Chauhan V, Bansal G, Sachan P, Sachan S, Yadav VS, Jadhav R. Detection of viable Mycobacterium leprae in soil samples: insights into possible sources of transmission of leprosy. Infect Genet Evol. 2008;8:627–31.View ArticlePubMedGoogle Scholar
  25. Kazda J, Pavlik I. Obligate pathogenic mycobacteria. In: Kazda J, Pavlik I, Falkinham JO, Hruska K, editors. The ecology of mycobacteria: impact on animal’s and human’s health. 2nd ed. Berlin: Springer; 2009. p. 1–19.View ArticleGoogle Scholar
  26. Sreevatsa. Leprosy and arthropods. Indian J Lepr. 1993;65(2):189–200.PubMedGoogle Scholar
  27. Desikan KV, Sreevatsa. Extended studies on the viability of M. Leprae outside the human body. Lepr Rev. 1995;66:287–95.PubMedGoogle Scholar
  28. Turankar RP, Lavania M, Singh M, Siva Sai KSR, Jadhav RS. Dynamics of Mycobacterium leprae transmission in environmental context: deciphering the role of environment as potential reservoir. Infect Gen Evol. 2012;12:121–6.View ArticleGoogle Scholar
  29. Matsuoka M, Izumi S, Budiawan T, Nakata N, Saeki K. Mycobacterium leprae DNA in daily using water as a possible source of leprosy infection. Indian J Lepr. 1999;71:61–7.PubMedGoogle Scholar
  30. Lahiri R, Krahenbuhl JL. The role of free-living pathogenic amoeba in the transmission of leprosy: a proof of principle. Lepr Rev. 2008;79:401–9.PubMedGoogle Scholar
  31. Wheat WH, Casali AL, Thomas V, Spencer JS, Lahiri R, Williams DL, McDonnell GE, Gonzalez-Juarrero M, Brennan PJ, Jackson M. Long-term survival and virulence of Mycobacterium leprae in amoebal cysts. PLoS Neglec Trop Dis. 2014;8(12):e3405.View ArticleGoogle Scholar
  32. Balamayooran G, Pena M, Sharma R, Truman RW. The armadillo as an animal model and reservoir host for Mycobacterium leprae. Clin Dermatol. 2015;33:108–15.View ArticlePubMedGoogle Scholar
  33. Cardona-Castro N, Beltran JC, Ortiz-Bernal A, Vissa V. Detection of Mycobacterium leprae DNA in nine-banded armadillos (Dasypus novemcinctus) from the Andean region of Colombia. Lepr Rev. 2009;80:424–31.PubMedGoogle Scholar
  34. Tadesse Argaw A, Sannon EJ, Assefa A, Mikru FS, Mariam BK, Malone JB. A geospatial risk assessment model for leprosy in Ethiopia based on environmental thermal-hydrological regime analysis. Geospat Health. 2006;1(1):105–13.View ArticlePubMedGoogle Scholar
  35. Joshua V, Mehendale S, Gupte MD. Bayesian model, ecologial factors and transmission of leprosy in an endemic area of South India. Indian J Med Res. 2016;143:104–6.View ArticlePubMedPubMed CentralGoogle Scholar
  36. Gomez-Valero L, Rocha EPC, Latorre A, Silva F. Reconstructing the ancestor of Mycobacterium leprae: the dynamics of gene loss and genome reduction. Genome Res. 2007;17:1178–85.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Trueba G, Dunthorn M. Many neglected tropical diseases may have originated in the Paleolithic or before: new insights from genetics. PLoS Neglect Trop Dis. 2012;6(3):e1393.View ArticleGoogle Scholar
  38. Monot M, Honore N, Garnier T, Zidane N, Sherafi D, Paniz-Mondolfi A, Matsuoka M, Taylor GM, Donoghue HD, Bouwman A, Mays S, Wason C, Lockwood D, Khamesipour A, Dowlati Y, Jianping S, Rea TH, Vera-Cabrera L, Stefani MM, Banu S, Macdonald M, Spakota BR, Spencer JS, Thomas J, Harshman K, Singh P, Busso P, Gattiker A, Rougemont J, Brennan PJ, Cole ST. Comparative genomic and phyleogeographic analysis of Mycobacterium leprae. Nat Genet. 2009;41(12):1282–9.View ArticlePubMedGoogle Scholar
  39. Monot M, Honore N, Garnier T, Araoz R, Coppee JY, Lacroix C, Sow S, Spencer JS, Truman RW, Williams DL, Gelber R, Virmond M, Flageul B, Cho SN, Ji B, Paniz-Mondolfi A, Convit J, Young S, Fine PE, Rasolofo V, Brennan PJ, Cole ST. On the origin of leprosy. Science. 2005;308(5724):1040–2.View ArticlePubMedGoogle Scholar
  40. Singh P, Cole ST. Mycobacterium leprae: genes, pseudogenes, and genetic diversity. Future Microbiol. 2011;6(1):57–71.View ArticlePubMedPubMed CentralGoogle Scholar
  41. Schuenemann VJ, Singh P, Mendum TA, Krause-Kyora B, Jager G, Bos KI, Herbig A, Economou C, Benjak A, Busso P, Nebel A, Boldsen JL, Kjellstrom A, Wu H, Stewart GR, Taylor M, Bauer P, Lee OYC, Wu HHT, Minnikin DE, Besra GS, Tucker K, Roffey S, Sow SO, Cole ST, Nieselt K, Krause J. Genome-wide comparison of medieval and modern Mycobacterium leprae. Science. 2013;341:179–83.View ArticlePubMedGoogle Scholar
  42. Prasanna AN, Mehra S. Comparative phylogenomics of pathogenic and non-pathogenic Mycobacterium. PLoS One. 2013;8(8):e71248.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Cardona-Castro N, Cortes N, Beltran C, Romero M, Badel-Mogollon JE, Bedoya G. Human genetic ancestral composition correlates with the origin of Mycobacterium leprae strains in a leprosy endemic population. PLoS Neglect Trop Dis. 2015;9(9):e0004045. doi:https://doi.org/10.1371/journal.pntd.0004045.View ArticleGoogle Scholar
  44. Falkinham JO. Surrounded by mycobacteria: nontuberculous mycobacteria in the human environment. J Appl Microbiol. 2009;107(2):356–67.View ArticlePubMedGoogle Scholar
  45. Garchitorena A, Guegan JF, Lege L, Eyangoh S, Marsollier L, Roche B. Mycobacterium ulcerans dynamics in aquatic ecosystems are driven by a complex interplay of abiotic and biotic factors. eLife. 2015;4:e07616.View ArticlePubMedGoogle Scholar
  46. Boritsch EC, Supply P, Honore N, Seeman T, Stinear TP, Brosch R. A glimpse into the past and predictions for the future: the molecular evolution of the tuberculosis agent. Mol Microbiol. 2014;93(5):835–52.View ArticlePubMedGoogle Scholar
  47. Mostowy S, Behr MA. The origin and evolution of Mycobacterium tuberculosis. Clin Chest Med. 2005;26:207–16.View ArticlePubMedGoogle Scholar
  48. Marsollier L, Stinear T, Aubry J, Saint Andre JP, Robert R, Legras P, Manceau AL, Audrain C, Bourdon S, Kouakou H, Carbonnelle B. Aquatic plants stimulate the growth of and biofilm formation by Mycobacterium ulcerans in axenic culture and harbor these bacteria in the environment. Appl Environ Microbiol. 2004;70(2):1097–103.View ArticlePubMedPubMed CentralGoogle Scholar
  49. Röltgen K, Stinear TP, Pluschke G. The genome, evolution and diversity of Mycobacterium ulcerans. Infect Genet Evol. 2012;12:522–9.View ArticlePubMedGoogle Scholar
  50. Doig KD, Holt KE, Fyfe JAM, Lavender CJ, Eddyani M, Portaels F, Yeboah-Manu D, Pluschke G, Seeman T, Stinear TP. On the origin of Mycobacterium ulcerans, the causative agent of Buruli ulcer. BMC Genomics. 2012;13:258.View ArticlePubMedPubMed CentralGoogle Scholar
  51. Davey TF, Res RJW. The nasal discharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974;45:121–34.PubMedGoogle Scholar
  52. Job CK, Jayakumar J, Kearney M, Gillis TP. Transmission of leprosy: a study of skin and nasal secretions of household contacts of leprosy patients using PCR. Am J Trop Med Hyg. 2008;78(3):518–21.PubMedGoogle Scholar
  53. Chehl S, Job CK, Hastings RC. The nose: a site for the transmission of leprosy in nude mice. Am J Trop Med Hyg. 1985;34:1161–6.PubMedGoogle Scholar
  54. Job CK, Harris EB, Allen JL, Hastings RC. Thorns in armadillo ears and noses and their role in the transmission of leprosy. Arch Pathol Lab Med. 1986;110:1025–8.PubMedGoogle Scholar
  55. Dungal N. Is leprosy transmitted by arthropods? Lepr Rev. 1961;32:28–35.PubMedGoogle Scholar
  56. Manja KS, Narayanan E, Kasturi G, Kirchheimer WF, Balasubramanyan M. Non-cultivable mycobacteria in some field collected arthropods. Lepr India. 1973;45:231–4.Google Scholar
  57. Narayanan E, Sreevatsa, Kirchheimer WF, Bedi BMS. Transfer of leprosy bacilli from patients to mouse foot pads by Aedes aegypti. Lepr India. 1977;49:181–6.PubMedGoogle Scholar
  58. Narayanan E, Sreevatsa, Raj AD, Kirchheimer WF, Bedi BMS. Persistence and distribution of M. leprae in Aedes aegyptii and Culex fatigans experimentally fed on leprosy patients. Lepr India. 1978;50:26–36.PubMedGoogle Scholar
  59. Saha K, Jain M, Mukherjee MK, Chawla WM, Chaudhary DS, Prakash N. Viability of Mycobacterium leprae within the gut of Aedes aegypti after they feed on multibacillary lepromatous patients: a study by fluorescent and electron microscopes. Lepr Rev. 1985;56:279–90.PubMedGoogle Scholar
  60. McDougall AC, Cologlu AS. Lepromatous leprosy in man; depth of the cellular infiltrate and bacillary mass in relation to the possibility of transmission of leprosy by biting arthropods. Ann Trop Med Parasitol. 1983;77(2):187–93.PubMedGoogle Scholar
  61. Narayanan E, Manja KS, Bedi BM, Kirchheimer WF, Balasubrahmanyan M. Arthropod feeding experiment in lepromatous leprosy. Lepr Rev. 1972;43(4):188–93.PubMedGoogle Scholar
  62. Kirchheimer WF. The role of arthropods in the transmission of leprosy. Int J Lepr Other Mycobact Dis. 1976;44(1–2):104–7.PubMedGoogle Scholar
  63. Manja KS, Bedi BM, Kasturi G, Kirchheimer WF, Balasubrahmanyan M. Demonstration of Mycobacterium leprae and its viability in the peripheral blood of leprosy patients. Lepr Rev. 1972;43(4):181–7.PubMedGoogle Scholar
  64. Sreevatsa, Sengupta U, Ramu G, Desikan KV. Evaluation of bacteraemia in leprosy patients. Lepr India. 1978;50(3):381–7.PubMedGoogle Scholar
  65. Reis EM, Araujo S, Lobato J, Neves AF, Costa AV, Gonçalvez MA, Goulart LR, Goulart IMB. Mycobacterium leprae DNA in peripheral blood may indicate a bacilli migration route and high-risk for leprosy onset. Clin Microbiol Infect. 2014;20:447–52.View ArticlePubMedGoogle Scholar
  66. Sreevatsa, Girdhar BK. Can sandflies be the vector for leprosy? Int J Lepr Other Mycobact Dis. 1992;60(1):94–6.PubMedGoogle Scholar
  67. Rambukkana A. Molecular basis for the peripheral nerve predilection of Mycobacterium leprae. Curr Opin Microbiol. 2001;4:21–7.View ArticlePubMedGoogle Scholar
  68. Lockwood DN, Saunderson PR. Nerve damage in leprosy: a continuing challenge to scientists, clinicians, and service providers. Int Health. 2012;4(2):77–85.View ArticlePubMedGoogle Scholar
  69. Masaki T, Qu J, Cholewa-Waclaw J, Burr K, Raaum R, Rambukkana A. Reprogramming adult Schwann cells to stem cell-like cells by leprosy bacilli promotes dissemination of infection. Cell. 2013;152(1–2):51–67.View ArticlePubMedPubMed CentralGoogle Scholar
  70. Randall PJ, Hsu NJ, Quesniaux V, Ryffel B, Muazzam J. Mycobacterium tuberculosis infection of the ‘non-classical immune cell’. Immunol Cell Biol. 2015;93:789–95.View ArticlePubMedGoogle Scholar
  71. Van Brakel WH, Nicholls PG, Wilder-Smith EP, Das L, Barkataki P, Lockwood DNJ. On behalf of the INFIR Study Group. PLoS Negl Trop Dis. 2008;2(4):e212.View ArticlePubMedPubMed CentralGoogle Scholar
  72. Sorbara MT, Giardin SE. Emerging themes in bacterial autophagy. Curr Opin Microbiol. 2015;23:163–70.View ArticlePubMedGoogle Scholar
  73. Goncalvez Barreto J, Bisanzio D, Cipriani Frade MA, Pires Moraes TM, Gobbo AR, de Souza Guimaraes L, et al. Spatial epidemiology and serologic cohorts increase the early detection of leprosy. BMC Infect Dis. 2015;15:527.View ArticleGoogle Scholar

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