Also known as Hansen's disease, leprosy has etched a long history as far back as modern civilization. The first case reports of leprosy with an express description of clinical presentation reportedly date from 600 B.C. to early 1400 B.C. in India.
To a large extent, leprosy is largely considered one of the oldest diseases ever documented in human colonies. With actual documentation dating back to at least the 5th century B.C., descriptions of different cases of a 'skin disfiguring condition' are found in Egyptian and Persian scripts. In the Middle Ages, more descriptions of the disease emerged throughout Europe, with different submissions describing the disease as 'incurable' and 'devilish.' As common practice during these times, individuals with these diseases were isolated as outcasts in different leper colonies located many miles away from uninfected populations.
Skin in Leprosy
In medieval times, despite measures to separate the infected individuals from the uninfected population, leprosy reportedly became endemic in Europe. Records exist documenting about 2,000 leper colonies in France alone by the 13th century. During the Renaissance, strict isolation of all infected individuals reportedly yielded results as records of new infections significantly reduced. In central Europe, isolation interrupted chain transmissions of the disease, and it reportedly 'vanished.'
However, the disease would resurface and persist into the 20th century in many parts of Europe. Regions particularly affected include Sicily, Scandinavia, the Iberian Peninsula, the Baltics, and the Balkans. Although there were exhaustive descriptions of the disease conditions, features, and characteristic manifestations in different groups, clinical investigations into pathophysiology and transmission were limited. The first recorded clinical interest in the diseases was published by Boeck and Danielsen - two Norwegian scientists who had authored pathological and anatomical descriptions of the disease in many people.
The discovery of M. leprae also confirmed the infectiousness of the condition, later described as "specdalsked" – a Norwegian term for leprosy. Since this discovery by Hansen, clinical studies on leprosy have focused largely on understanding the pathophysiology and possible treatment options of leprosy. In 1941, Guy Henry Faget documented the successful use of sulfonamides in treating early cases of leprosy. In 1947, Robert G. Cochrane would later introduce the drug 'dapsone' as the first largely studied bioactive agent for treating leprosy. Today, dapsone remains an integral component of different multidrug therapy regimens for the management of leprosy (Collin et al., 2023).
M. leprae, in its virulent state, exists as a non-motile, acid-fast rod with a length range of 4 – 7 microns. Microbial characterization of the bacterium shows it as reddish on the Ziehl-Neelsen staining – an observation attributed to the acid nature of its virulent state. In laboratory studies, M. leprae has shown no colony growth when cultured in growth mediums. However, animal cultures produced slowly multiplying colonies of the bacterium. Mouse paws and the nine-banded armadillo animal cultures are widely used in these studies. Growth conditions appear to be properly facilitated in low temperatures as cellular proliferation occurs slowly, only about every twelve days. Genomic studies conducted in 2001 revealed about 3.3 million base pairs with about 1,600 functional genes in the genetic code. With an incubation period lasting up to 11 years, M. leprae has been shown to affect different inflammatory reactions and dermatological manifestations in infected individuals (Ploemacher et al., 2020).
Depending on the clinical variants, the variability and virulence of M. leprae differ significantly. Clinical characteristics of an active infection are largely determined by the microorganism's tropism for the skin and the peripheral nervous tissues. The patients' susceptibility to the microorganism as genetically determined is also considered an important factor in infection onset. Also, the clinical variant of the causative organism determines the clinical morphology of the skin. Marked variabilities in the number, appearance, and distribution patterns of lesions in different patients seem to exist. Recent clinical studies on susceptibility and virulence suggest that active disease only occurs in about 5-10% of the infected population, with the level of susceptibility linked to a patient's immune status.
In 2008, bacilli from two cases of leprosy were isolated as a new species, Mycobacterium lepromatosis (M. lepromatosis). The new species was discovered and isolated following the death of a patient of Mexican origin who had been diagnosed with diffuse lepromatous leprosy (DLL) co-occurring with Lucio's phenomenon (LP) – a severe leprosy reaction. Sequencing studies conducted by PCR confirmed close genetic similarities between M. lepromatosis, M. leprae, and Mycobacterium haemophilum (M. haemophilum). Polymerase chain reaction (PCR) comparison results also confirmed M. lepromatosis as a causal agent of diffuse lepromatous leprosy and borderline lepromatous forms of leprosy (Collin et al., 2023). Since the first isolation in 2008, clinical studies have subsequently isolated M. lepromatosis samples from at least 15 confirmed cases of leprosy. Case distribution of the new species appears to be mostly in Mexico, the United States, Cuba, Canada, Paraguay, Singapore, Indonesia, and Myanmar (Deps & Collin, 2021).
Drawing observations from published reviews on leprosy transmission, it appears the exact mode of transmission in humans currently lacks sufficient evidence. Modes of transmission documented in different submissions range from tattooing to household contacts and exposure to armadillos. Household contact reportedly accounts for about 28% of new cases, with many of these contacts described as M. leprae by PCRs that were positive on skin and nasal swabs (Makhakhe, 2021). M. leprae infections also occur through air droplets expelled from infected individuals. In lepromatous leprosy patients, infected tissues reportedly house up to seven billion bacilli, making these individuals highly infectious.
Zoonotic transmissions also appear important in many regions where leprosy is considered endemic. In cases attributed to M. leprae in Mexico, zoonotic transmissions were suspected. Two affected individuals reportedly had direct contact with armadillos. Since this documentation, a history of contact with armadillos is now considered a valid investigation when presenting cases with clinical manifestations suggest leprosy. M. leprae samples have also been reportedly isolated from red squirrels in the British Isles. Isolated samples reportedly closely resemble those found in medieval human remains from Denmark and England (Schaub et al., 2020).
The pathophysiology of leprosy is properly documented in infected individuals with special cases of susceptibility to causal organisms. In active cases of infection, the bacilli primarily cause physiological deficiencies in the macrophage, keratinocytes, and histocytes of the skin.
Schwann cell axons are surrounded by lamina that interact with receptors to regulate cell activity and facilitate signal transduction in the central nervous system. Active cases of leprosy usually involve the rapid binding of the causal organism with laminin-2 isoforms – a key component of basal lamina consisting of alpha-2, beta-1, and gamma-1 chains. Early experimental models investigating this binding suggest that the neuronal tropism of M. leprae is mediated by laminin alpha-2 chain with the binding affinity to laminin alpha-1 chains despite its wide distribution in tissues (De Oliveira Brugger et al., 2023).
As part of bacilli invasion into healthy tissues, clinical studies identified alpha-Dystroglycan as the cell membrane receptor facilitating bacterium entry on Schwann cells. Similarly, beta-Dystroglycan has been identified to modulate cellular invasion in cytoskeletal proteins domiciled on peripheral nerves and muscles containing dystrophin. As documented by subsequent etiological studies, M. leprae appears to express a multi-dimensional approach to cell invasion in an active infection. Glycolipids and phthiocerol acids on the cell wall of M. leprae reportedly contain M. leprae-specific trisaccharides known to mediate binding on the laminin alpha-2 chain in the basal lamina of Schwann cells. In a typical physiological setup, Schwann cells have been demonstrated to depend on neuronal ligands for functionality and survival. The interdependence is mediated by an interaction facilitated in the binding of neuregulin to epidermal growth factor receptors ErbB2/ErbB3 – a receptor tyrosine kinase complex. To a large extent, this binding is considered primarily important in the differentiation and proliferation of Schwann cells. By binding and activating ErbB2, M. leprae induces early demyelination and, subsequently, downstream signaling pathways dependent on ErbB2. Deregulation of the Schwann cell axon signaling system leads to the eventual physiological collapse of the myelin sheath – a situation that directly initiates nerve injury and demyelination (Mungroo et al., 2020).
Clinical evidence documenting how M. leprae reprograms Schwan cells through epigenetic modification of key genes has slowly accumulated over the past few years. Schwann cell reprogramming follows a complex transcriptional process that produces multiple stem-like progenitor cells that ultimately facilitate the spread of the causal organism to other susceptible tissues. Beyond merely explaining how M. leprae infects muscle fibers and fibroblasts in humans, studies have also documented how the propagation of infection in fibroblasts is more efficient when M. leprae originates from reprogrammed Schwann cells compared to non-reprogrammed ones. By reprogramming Schwann cells, M. leprae ultimately improves its chances of continued survival and propagation in infected individuals (White & Franco-Paredes, 2015).
Depending on the parameter of description, the classification of leprosy has varied over the past few years. In 1982, the World Health Organization (WHO) proposed a simplified classification of leprosy based on the density of leprosy bacilli in slit-skin examinations at different stages of infection. Referred to as the 'bacterial index,' this classification method divided active cases of leprosy into paucibacillary and multibacillary. Multibacillary cases are characterized by a bacterial index equal to or higher than 2+, while paucibacillary cases have a bacterial index lower than 2+. Subsequently, in 1988, the WHO expert committee reviewed the definition of these classifications to make diagnosis more affordable and reduce the risk of cross-infection in front-line healthcare workers.
Today, this classification system is used mainly for treatment purposes and clinical studies comparing the efficacy of different treatment strategies. The individual's immune system integrity plays a large role in the form of leprosy that manifests during the clinical stage of an active infection. Multiple pieces of evidence suggest that individuals with a cell-mediated immune response against M. leprae eventually develop the paucibacillary form of leprosy. Conversely, those with an inadequate immune response develop the multibacillary form. Post-exposure documentation of active infection cases suggests that the common outcome after bacilli exposure is spontaneous cure. However, if active infection progresses, a single hypopigmented patch may appear as the first clinical manifestation of the lesion. Then, this is followed by mild anesthesia in the stage commonly referred to as indeterminate leprosy disease since the course of clinical manifestation cannot be predicted.
Concerning clinical presentation, the physical manifestations of leprosy as a disease occur between two stable forms, the tuberculoid and lepromatous forms. In every patient, these forms of leprosy do not change throughout the clinical presentation and remain the same throughout the course of infection.
Diagnosed as the early stage of bacilli invasion, indeterminate leprosy is characterized by prodromal symptoms almost unnoticed in many patients until the appearance of cutaneous lesions. In most cases, it presents primarily as numbness followed by loss of sensitivity to temperature extremes and light pressure as the earliest signs of sensory impairment. Variables in the level and type of sensory loss experienced first have been reported to be linked with the type of disease that is slowly evolving. However, in most cases, the dermatological presentation of indeterminate leprosy is similar across infected individuals.
A solitary, hypopigmented macule is often the first lesion noticed as it merges perfectly into the surrounding healthy skin patch. Erythematous macules may be present in some cases. Both clinical presentations are likely to be noticed on the cheeks, upper arm, thigh region, and buttocks. Sensory functions on these macules may be minimal or completely impaired, and compared to other forms, the macules may contain only a few or no bacilli on biopsy. From this form, the disease may evolve into either tuberculoid or borderline lepromatous leprosy.
In this form of leprosy, the presenting lesions are solitary, asymmetrically distributed, and may be five or fewer. On close physical examination, lesions appear dry, scaly, hairless, and hypopigmented. In some cases, a few lesions may be erythematous. Clinical studies have also reported typical large erythematous plaque-like presentations with elevated, rounded edges that slope down to a flattened atrophic center. Compared to those formed in indeterminate leprosy, lesions may also appear macular, erythematous, or hypopigmented in the early stages. The distinguishing feature, however, is the presence of palpable indurations accompanied by a completely altered neurological function at the site of lesion formation. In tuberculoid leprosy, the most common location for the formation of dermatological symptoms includes the trunk, limbs, and face.
In most cases, the groin, perineum, axilla, and scalp are not involved. Another presentation often reported in this form of leprosy is the enlargement or tenderness of superficial peripheral nerves serving or proximal to the lesions. In the same vein, the peroneal nerve and the greater auricular nerve may also present as enlarged or tender (Jariyakulwong et al., 2022).
Nerve involvement in tuberculoid leprosy implicates and initiates characteristic changes in the physiology of muscle groups in the affected region. The interosseous muscles of the hand may atrophy, leading to contracture of the fingers and wasting of the thenar and hypothenar eminences. Eventually, paralysis of the facial muscles may occur. As facial nerve paralysis progresses, the risk of vision loss and many ocular dysfunctions significantly increases. Although the emergence of lesions may be slow, spontaneous remission of dermatological presentation has been reported, and remission may be faster with adequate therapy.
Hand Wasting
Clinical presentations of borderline leprosy share multiple similarities with those of tuberculoid leprosy. The distinguishing factor, however, is that lesions in the borderline form are more numerous and are often reported as smaller in size. A typical presentation often reported is the appearance of satellite lesions around larger macules or plaques. If erythematous infiltrates are present, they form with prominent borders sharply demarcated and arranged asymmetrically. Sensory dysfunction and motor nerve involvement may also be present, although less pronounced than tuberculoid leprosy. Histologically, granulomatous infiltrates may extend to the cutis, and only a few bacilli are detected on biopsy.
Borderline borderline leprosy is characterized by numerous but countable skin lesions formed conspicuously with reddish plaques of no regular shape. The larger plaques may be surrounded by small satellite lesions largely distributed asymmetrically. Compared to those formed in tuberculoid leprosy, the lesions in this form are poorly defined. Nerve involvement presents as thickened and tendered nerves with moderate loss of sensory functions. Depending on the lesion, the biopsy may reveal a few or numerous bacilli. Normal hair growth and sweat gland function are primarily unaffected, and granulomas are often not reported in many cases.
The most reported clinical presentation of borderline lepromatous leprosy is the formation of lesions that are too numerous to count, formed on unaltered skin patches, and distributed asymmetrically. Papules, nodules, and infiltrated plaques are usually present as numerous, hypopigmented, and poorly demarcated. Sweating and hair growth in the affected skin region are hardly affected. In this form of leprosy, there is an extensive, symmetric involvement of peripheral nerves as they become enlarged and tender. Although dermatological symptoms may be slightly different in a few patients, they usually do not show the features of full-blown lepromatous leprosy as presentations such as leonine facies, loss of eyebrows, nasal ulceration, and keratitis are hardly present (Arunraghav et al., 2021).
As with tuberculoid leprosy, patients with clinical presentation of indeterminate leprosy may develop lepromatous leprosy. Often, a downgrade from borderline leprosy forms may also develop into lepromatous leprosy. Typically, lesions of lepromatous leprosy present with pale macules and diffuse infiltration of the skin distributed asymmetrically over the body.
Diagnosis conventions advise that the assignment of a patient to any of the chronic forms of leprosy, as discussed above, must not be definitive. About 30% of presenting cases reportedly develop acute, life-threatening exacerbations that may occur spontaneously or during treatment. These exacerbations, referred to as 'leprosy reactions', manifest as the sudden impairment of a patient's immunological functions and may occur at any time, even after a successful treatment.
Leprosy reactions are largely studied under three categories – type 1 reaction, type 2 reaction, and type 3 reaction.
Recently, the Lucio phenomenon has been primarily studied as a type of leprosy reaction. It is generally observed in patients with untreated lepromatous leprosy and characterized by extensive violaceous patches and bullous infiltrates. On histological examination, endothelial proliferation and extensive vasculitis with hemorrhages, cutaneous infarctions, and thromboses are common in the advanced stages of this reaction. Areas of the body affected ulcerate and become neurotic, and histological examination of endothelial cells may be positive for M. leprae bacilli (Ya et al., 2021).
Globally, the two most widely used treatment strategies for leprosy are the WHO's multidrug therapy regimen and the National Hansen's Disease Program strategy. The WHO multidrug therapy recommends different treatment regimens according to age and the type of leprosy disease diagnosed. Rifampicin, clofazimine, and dapsone are considered first-line treatment agents under this strategy (Lazo-Porras et al., 2020).
Synthesized in Italy from Amycolatopsis rifampycinica – a gram-positive soil bacteria, rifampicin has been commercially available since 1965. Pharmacologically, it exerts bioactivity by inhibiting bacteria RNA polymerase in mycobacteria. It is considered very active in leprosy cases as it significantly reduces bacteria count detectable in mucosal and cutaneous lesions of the leprosy types after a few days of administration. With a resistance rate currently estimated at 5%, rifampicin is not recommended as a monotherapy. High doses may cause severe side effects, including nausea, vomiting, and diarrhea. In patients who abuse alcohol while taking rifampicin, elevated liver function tests, intrahepatic cholestasis, and hepatotoxicity have been reported. In first-time users, erythematous macules on the face and scalp may occur within three hours of use.
Synthesized in Dublin in 1954 and first used as a leprosy treatment in Nigeria in 1959, clofazimine is considered in many anti-leprosy drug regimens for its anti-inflammatory and bactericidal effects. Many countries consider it a first-choice drug in treating multibacillary leprosy. It has also shown huge clinical results in treating type 2 leprosy reactions, making it an important component of the WHO treatment strategy. Typically, especially in Caucasians, clofazimine produces red-brown hyperpigmentation of leprosy lesions as the skin tone slowly changes. These effects are reversed over a few months or years once clofazimine is discontinued. Other side effects commonly reported include discoloration of the conjunctiva and body fluids, xerosis, and the accumulation of clofazimine crystals in the intestinal mucosa, causing multiple gastrointestinal symptoms (Riccardi et al., 2020).
Dapsone was first synthesized in Germany in 1908 and used as monotherapy for leprosy for the first time in 1941. It exerts bacteriostatic effects on M. leprae by inhibiting folic acid synthesis. It is widely considered a first-line drug for leprosy in many treatment regimens and is reported to have demonstrated significant clinical benefits in leprosy patients. It has no known teratogenic effects and can be used in pregnancy. Popularly reported side effects include fatigue, headache, gastrointestinal symptoms, hemolysis, and methemoglobin formation pronounced in patients with a clinical deficiency of glucose-6-phosphate dehydrogenase.
Population | Medication | Dose | Duration |
---|---|---|---|
Adults | Rifampicin | 600 mg/month | 6 months |
Dapsone | 100 mg/day | ||
Clofazimine | 300 mg/month + 50 mg/day | ||
Children (10-14 years) | Rifampicin | 450 mg/month | 6 months |
Dapsone | 50 mg/day | ||
Clofazimine | 150 mg/month + 50 mg/day | ||
Children (<10 years old or <40 kg) | Rifampicin | 10 mg/kg/month | 6 months |
Dapsone | 2 mg/kg/daily | ||
Clofazimine | 6 mg/kg/month + 1 mg/kg/day | ||
Lazo-Porras et al., 2020 |
Population | Medication | Dose | Duration |
---|---|---|---|
Adults | Rifampicin | 600 mg/month | 12 months |
Dapsone | 100 mg/day | ||
Clofazimine | 300 mg/month + 50 mg/day | ||
Children (10-14 years) | Rifampicin | 450 mg/month | 12 months |
Dapsone | 50 mg/day | ||
Clofazimine | 150 mg/month + 50 mg/day | ||
Children (<10 years old or <40 kg) | Rifampicin | 10 mg/kg/month | 12 months |
Dapsone | 2 mg/kg/daily | ||
Clofazimine | 6 mg/kg/month + 1 mg/kg/day | ||
Lazo-Porras et al., 2020 |
The Hansen Disease Program (NHDP) is commonly used in the United States. It is particularly popular for its longer treatment period and its exclusion of clofazimine in treating paucibacillary leprosy.
Population | Medication | Dose | Duration |
---|---|---|---|
Adults | Rifampicin | 600 mg/month | 12 months |
Dapsone | 100 mg/day | ||
Children | Rifampicin | 10–20 mg/kg/day (<600 mg) | 12 months |
Dapsone | 1 mg/kg/day | ||
Franco-Paredes et al., 2022; Lazo-Porras et al., 2020 |
Population | Medication | Dose | Duration |
---|---|---|---|
Adults | Rifampicin | 600 mg/month | 24 months |
Clofazimine | 50 mg/day | ||
Dapsone | 100 mg/day | ||
Children | Rifampicin | 10–20 mg/kg/day (<600 mg) | 24 months |
Clofazimine | 1 mg/kg/day | ||
Dapsone | 1 mg/kg/day | ||
Franco-Paredes et al., 2022; Lazo-Porras et al., 2020 |
Ryna, a 33-year-old female with no underlying medical conditions, presented to the New York Municipal Hospital dermatological unit in October 2022. She had lived in the United States for the past 15 years and had only taken a short trip to Mexico in 2009 on a vacation visit. She had presented to the clinic with hyperpigmentation and numerous lesions on her back and the trunk region. Ryna informed the dermatologist that she first noticed the strange formation on her back about two years before the presentation. Remembering vividly, she described macular lesions with no infiltration but with poorly demarcated edges.
She had self-medicated on a topical antimicrobial agent containing hydrocortisone, clindamycin, and clotrimazole. Two weeks after consistent use of the topical agent, the formation had resolved significantly. However, the pigmentation only faded slightly. A few months later, she explained how the pigmentation had slowly resolved, leaving a dry patch on the skin. Strangely, she noticed the dry patch was poorly sensitive to touch, heat, or needle pricks. She also noticed a significantly reduced sweating response to increased room temperature during this time.
Clinical Examination
On examination, Ryna's lesions presented as multiple, asymmetrically distributed, and hypopigmented plaques with poorly defined borders. She reported little to no sensory response to sensation on her trunk, back, and left cheek. There were infiltrated plaques on her earlobes and a few on the back. On neurological examination, the sensation of pain on the tips of her fingers and toes was minimal. Peripheral nerve examinations were unremarkable, as there were no signs of nerve enlargement.
Diagnosis and therapy plan
A provisional diagnosis of leprosy was made pending the result of laboratory investigations. The dermatology teams obtained slits of skin smears of plaques from her trunk and earlobes. The acid-fast staining of these samples confirmed the presence of acid-fast bacilli in all samples. With the presenting evidence – generalized distribution of plaque on the back, trunk, cheeks, and earlobes, the presence of bacilli in skin smears, and decreased sensory function on skin patches – the dermatological team made a confirmed diagnosis of lepromatous leprosy.
Following the WHO therapy regimen, Ryna was placed on the following:
About seven months after presentation, Ryna's lesion had significantly reduced, and sensory functions had improved. A follow-up visit plan was drafted annually for the next five years.
Leprosy is a long-standing disease that has been traced back through human history. Leprosy is chronically infectious and is caused by M. leprae. This disease affects the skin and nerves and can be diagnosed by dermatological and neurological examinations. Treatment is dependent on the type of leprosy and if any reactions occur.
CEUFast, Inc. is committed to furthering diversity, equity, and inclusion (DEI). While reflecting on this course content, CEUFast, Inc. would like you to consider your individual perspective and question your own biases. Remember, implicit bias is a form of bias that impacts our practice as healthcare professionals. Implicit bias occurs when we have automatic prejudices, judgments, and/or a general attitude towards a person or a group of people based on associated stereotypes we have formed over time. These automatic thoughts occur without our conscious knowledge and without our intentional desire to discriminate. The concern with implicit bias is that this can impact our actions and decisions with our workplace leadership, colleagues, and even our patients. While it is our universal goal to treat everyone equally, our implicit biases can influence our interactions, assessments, communication, prioritization, and decision-making concerning patients, which can ultimately adversely impact health outcomes. It is important to keep this in mind in order to intentionally work to self-identify our own risk areas where our implicit biases might influence our behaviors. Together, we can cease perpetuating stereotypes and remind each other to remain mindful to help avoid reacting according to biases that are contrary to our conscious beliefs and values.