Hansen’s Disease – Leprosy

Leviticus 13:45-13:46 – And the leper in whom the plague [is], his clothes shall be rent, and his head bare, and he shall put a covering upon his upper lip, and shall cry, Unclean, unclean. All the days wherein the plague [shall be] in him he shall be defiled; he [is] unclean: he shall dwell alone; without the camp [shall] his habitation [be]. 

Numbers 5:2 – Command the children of Israel, that they put out of the camp every leper, and every one that hath an issue, and whosoever is defiled by the dead.

Luke 5:13-5:14 – And he put forth [his] hand, and touched him, saying, I will: be though clean. And immediately the leprosy departed from him. And he charged him to tell no man: but go, and shew thyself to the priest and offer for thy cleansing, according as Moses commanded, for a testimony unto them.

The Bible

The origin of the disease known as leprosy is difficult to track down, as Mycobacterium leprae was not identified until 1873 by Dr. Gerhard Armauer Hansen (1). Many writings dating back to 600 BC to perhaps 1400 BC in India describe a similar disease to that of Leprosy, and some writings in 500 BC from China mention skin lesion, numbness, and loss of eyebrows. A clay pottery grain storage jar found at Beth-Shan in Jordan, Palestine finds a close portrayal of lepromatous leprosy, including leonine facies (2). Whether this represents leprosy is unknown, as similar water jars have been found in Peru, Bolivia, and Ecuador that portray destruction of lips and nose as well as foot deformities (2). It is believed the disease was not present in the New World before Columbus, and the earliest case reports suggest that leprosy was already established by the 1750s near New Orleans (3). 

Leprosy seems to be present during the time the Bible was written, as noted by the many references to the disease throughout the Authorized Version of the Old Testament scriptures. At the turn of the century, however, scholars concluded the Hebrew word tsara’ath, translated into leprosy in the Authorized version, is actually a generic term denoting defilement rather than a specific disease (2). This is believed to be due to a translation into the Greek word, lepra, which was used by Greek physicians to describe scaly skin conditions as well as bark and flakes (1). Despite this, given the deformities and disfigurement associated with untreated disease, there has been a history of fear and stigma towards patients suffering with leprosy (4). Throughout history, leprosy has been linked to sin, the ancient Chinese theory of feng shui (which links personal guilt to the presence of skin disease), and ancient Mesopotamian rituals of purification and quarantine (3).  Multiple examples of persecution exists (4):

• China, 1937: 80 leprosy patients were shot and thrown into a lime pit
• Korea, 1957: a mob beat 10 patients with leprosy to death
• India, 1939: a law forbade granting driver’s licenses to patients with leprosy
• Leprosy being a ground for divorce in the Abrahamic religions

Microbiology and Epidemiology

One of the things that people tend to know about Leprosy is its difficulty to culture. As a result, the study has been limited to the biochemical and physiologic characterization of bacteria isolated from infected nine-banded armadillos. M. leprae is a non-motile, non-spore forming, microaerophilic, acid fast staining bacteria that are either straight or slightly curved (5, 6). Doubling time of M. leprae in experimental models is around 11-13 days. As with other mycobacteria, its cell wall is significantly different, containing different types of lipids including an abundant antigenic glycolipid termed phenolic glycolipid 1 (PGL-1; 5, 6). 

While not terribly important (so feel free to skip this if you feel so inclined), one of the interesting things is its genome. Comparing it to that of tuberculosis, it seems it has undergone an extreme case of reductive evolution (6). It has a smaller genome compared to that of tuberculosis (3.3 Mb vs 4.4 Mb) with M. leprae’s genome having 1,133 inactivated genes, leaving it with <50% of its genome encoding functional genes. This is believed to have led to elimination of several metabolic pathways, leaving it with very specific growth requirements:

In terms of epidemiology, I would remiss to say this is not a disease of the Western world. Indeed, according to an WHO report from 2010, the United States recorded only 161 cases (7), with Mexico recording 114 new cases and Brazil 37,610 cases. An updated WHO report (8) found the vast majority of cases tended to be in Brazil and Southeast Asia. Worldwide, Brazil, India, and Indonesia account for a significant portion of the cases with the 23 global priority countries accounting for over 90% of worldwide cases:

How the Immune System Shapes Presentation

Leprosy should be considered a disease spectrum, which is largely shaped by the extent of the immune response. Indeed, M. leprae infection invokes distinct polarized T cell responses, which correlates with clinical presentation (9). At the one end, TT is characterized by few skin lesions, little bacteria and well formed granulomas with lots of CD4 T-cells. At the other end, LL is characterized by lots of bacteria, poorly formed granulomas with little lymphocytes (9):

Recall that antigen-presenting cells (usually macrophages) present a piece of leprosy to a naive helper CD4-T cell. These APCs, depending on what they’re presenting, will secrete cytokines that will dictate what happens to this naive CD4 T cell; it either becomes a Th1 or Th2 cell. If the organism is able to be phagocytosed, it is presented as an “intracellular” antigen and leads to the Th1 response, which is driven by IL-12 (indeed, those with tuberculoid lesions have IL-12 expression that is 10-fold higher than in lepromatous lesions). If the macrophages are not able to phagocytose the organism, then this leads to a Th2 response

• Th1 response – secrete IL-2, secreting CD8 cytotoxic cells. It also secretes IFN-gamma leading to production of more macrophages and IgG class switching. 
• Th2 response – secrete IL-4, IL-5, and IL-10. Usually increase mast cells, IgE class switching. 
• Th17 – increase IL-17 leading to more neutrophils.

The tuberculoid pole is characterized by a strong-mediated cell immunity and a Th1-response, driven by IFN-gamma and IL2. Meanwhile, the lepromatous pole is characterized by a Th-2 response which is driven by IL-4 mainly, leading to weak-cellular immunity (9, 10):

What causes this polarization is unknown. As mentioned before, perhaps the type of antigen presented drives the initial response, however other factors such as the cytokine milieu, the “strength of the signal” of the T-cell receptor, and presence of immunologically active hormone have also been proposed (9). Skin lesions of patients with LL tend to have high expression of IL-4, IL-5, and IL10. How this leads to manifestation of disease is beyond my comprehension, but I would assume that a Th1 response leads to the increased machinery of phagocytosis and more efficient organism killing compared to the Th2 response, which is responsible for controlling the immunopathology of parasites/worms and allergies (11). I am probably wrong about this, but just know the type of response drives the clinical manifestations, and most patients fall somewhere between here. 

Transmission:

There is evidence that leprosy can be transmitted via aerosol route. One study evaluated 113 patients with untreated leprosy and 104 household contacts (23). The presence of leprosy DNA was evaluated using PCR via nasal and blood samples 62.8% of patients with leprosy were positive overall (66% for nasal swab and 71.7% with nasal turbinate biopsies). During the study period, 6.7% of household contacts developed leprosy. Notably, 49% of household contacts were PCR positive by nasal swab, and 54% were positive by nasal turbinate biopsy. Notably, while presence of DNA in the nasal turbinates in the healthy cohort was not associated with development of disease later on, the presence of DNA in the blood in that cohort was:

Another cohort study evaluated 1037 patients with leprosy and over 21,000 contacts (24). Multivariate analysis found multivariate and paucibacillary leprosy with 2-5 lesions, close physical distance (sharing kitchen and roof) and being blood related were correlated with higher risk of leprosy in contacts:

It is likely leprosy is a zoonosis. For instance, a whole-genome analysis compared M. leprae obtained from wild armadillos and from patients in the US and found that one type of M. leprae was isolated from 33 armadillos and 26/29 patients who had no history of foreign residence (25). Another study using similar methodology found that 42% of patients with leprosy were infected with one of the 2 M. leprae genotype strains associated with armadillos (26). A comprehensive review describes several studies on animal vectors, with direct contact with an amarillo having an OR for leprosy of 2.01, 95% CI 1.36-2.99, though another study did not find increased risk for leprosy when consuming armadillo meat (27). Mosquitoes were not found to be a transmission risk, though adult female ticks were found to be a reservoir, and infected larvae attached to rabbit skin for five days lead to isolation of up to 10³ viable M. leprae. 

All in all, seems that person to person transmission is the main driver of infection, with some zoonotic contribution from mammals. 

Clinical Characteristics

More detail as to the classification scheme will come in the next section, but I think it is useful to bring the thing to look out for. Only around 95% of patients exposed to M. leprae develop the disease, and the incubation time is variable, ranging from 2 years to 20 years, even longer. The cardinal manifestations are hypopigmented, erythematous, or infiltrative skin lesions with or without neurological signs.  These range from hypoesthesia, weakness, autonomic dysfunction, and peripheral nerve thickening. In a retrospective analysis of 164 patients from Saudi Arabia (14) found the majority of patients presented with lepromatous leprosy, with around 84% presenting with skin manifestations and 87% presenting with neurological deficits.

Notably, all patients with tuberculoid leprosy presented with neurological deficits, with at least 80% in the lepromatous leprosy group presenting with neurological symptoms:

Another retrospective study from India (15) involving 101 patients found that 22 patients presented with neuropathic pain, with 45% having thickened nerves and 80% having some sort of sensory impairment. 44% of these patients also had some sort of disability:

Neuropathic pain in this study was also associated with psychological morbidity, tender nerves, and facial sensory impairment:

Diagnosis and Classification Schemes 

There are 2 general classification systems that are widely used. The first one that is the most widely used is the Ridley & Jopling classification. The other one is the WHO classification. The Ridley & Jopling classification (12) actually combines clinical characteristics with bacillary load and histopathology. For the sake of simplicity (and my own sanity) I will focus mostly on the clinical characteristics, since all these will end up being biopsied and looked at by a histopathologist anyways. Just know there is more than just clinical characteristics:

Group	Clinical Characteristic	Histopathology	Bacillary Load	WHO Classification
Tuberculoid (TT)	Usually single lesions. Large, red plaque with raised outer edge. Anesthetic, usually in the face or limbs, but can be anywhere. Can have nerve swelling.	No AFB; granuloma extend up to the epidermis. Lots of lymphocyte infiltration	0+	Paucibacillary
Borderline tuberculoid (BT)	Looks like TT, but more lesions and smaller. Thickened nerves, but not irregularly thickened and more of them	Similar to TT, but clear subepidermal zone. Nerve bundles can have granuloma	1-2+	Paucibacillary
Borderline borderline (BB)	Intermediate sized lesions and intermediate number. Moderate anesthesia, some “punched out” in appearance	Epithelioid cells spread through granuloma	3-4+	Multibacillary
Borderline lepromatous (BL)	Numerous lesions, but not bilateral and not really symmetric. Can have prominent peripheral neuropathy with secondary deformities (i.e. claw hand)	Granuloma with histiocytic cell. Foamy histiocyte with bacilli present.	As above	Multibacillary
Lerpomatous leprosy (LL)	Multiple macules/papules bilaterally and symmetric. Smooth/shiny surface, no anesthetic/anhidrotic. Can progress to plaques/nodules, with edema seen in feet. Thick facial skin -> leonine facies and saddle-nose deformities/nasal ulceration. Similar peripheral neuropathy damage as above, tend to have deformities as well.	Macrophages with fatty change and foam cells, scanty lymphocytes. No well-formed granulomas lots of AFB	Usually 5+	Multibacillary

The WHO classification simplifies this into paucibacillary leprosy (if patients demonstrated no positive smears) and multibacillary leprosy (if there are positive smears at any site) to allow simplification of treatment choices. This is largely based on counting lesions, with patients >5 lesions being defined as multibacillary and those with <5 lesions being defined as paucibacillary (12). Indeed, counting lesions does have a fairly good correlation with bacteriologic response in a review (12):

While there are clinical clues to the diagnosis, especially if the someone is coming from an endemic area, the differential here is broad:

• Infections: cutaneous TB, M. marinum infection, tertiary syphilis, post-kala-azar leishmaniasis
• Autoimmune: sarcoidosis, vitiligo (if hypopigmented patches are seen), granuloma multiforme
• Systemic: neurofibromatosis, keloids 

As such, we need a reliable method for diagnosis. As mentioned previously, the M. leprae is incredibly difficult to culture, with researchers relying on armadillos and athymic mouse foot-pads (6, 13). Indeed, armadillos tend to have cooler body temperatures (30 to 35C) and they tend to develop fully disseminated M. lepare infections. M. leprae usually requires cooler temperatures, around 33C (6). The gold-standard is a full-thickness skin biopsy obtained from the advancing margin, known as a slit-skin procedure (5, 6). Here, a small incision is made through the epidermis, scraping the dermal surface and smearing the scrapings on a glass slide and staining with either Fite staining or Ziehl-Neelsen staining. Histopathology with active lesion being embedded in paraffin is another option. 

Unfortunately, culture is not an option here. Antigen testing using ELISA against PGL-1 have been deployed for epidemiological studies, however the biggest drawback here is the fact  that in TT and BT patients, there are low levels of antibodies (6). For instance, a retrospective study found that 84% of patients with multibacillary leprosy were positive by antigen testing compared to only 17.8% of those with paucibacillary testing (14). A more robust study from Brazil (15) evaluated the performance of NDO-LID (which uses semi-synthetic disaccharide attached to octyl radical, mimicking PGL1) and PGL-1 rapid test in a group of 530 healthy subjects and 250 leprosy patients. The sensitivity of these tests was significantly higher in the multibacillary patients than in the paucibacillary patients:

Yet another study found an overall positivity of ~30% for several blood samples in a PGL-1 assay (16). Notably, here there was a weak correlation between bacterial load and antigen level, with the highest correlation seen in the capillary blood sample:

This suggest that as a diagnostic tool it fails for a certain percentage of patients with leprosy. As a result, PCR has emerged as another possible diagnostic tool in the past 20 years. One of the advantages is that the M. leprae genome is surprisingly conserved throughout the world. A 9 year review of PCR use for leprosy diagnosis revealed PCR positivity in 60% of all patients specimens diagnosed with leprosy, which increased to 93% in those with lepromatous leprosy (i.e. those with lots of bacilli, 13). Another review found multibacillary leprosy tended to have higher sensitivity in that Paucibacillary throughout multiple PCR methods and targets, though in certain studies the paucibacillary sensitivity was actually higher than previously reported (17):

PCR has also been used in household contacts of cases with specimens obtained from nasal swabs and blood, finding a positivity ranging from 1-11%:

Having said that, antigen and PCR are not widely available in the US and histological diagnosis is the way to go in the vast majority of patients. 

“Flares” – Leprosy Reactions

If you look into the literature, you will find “Leprosy Reactions.” These are acute systemic inflammatory complications that can occur prior to treatment, but commonly occurs either during treatment or years after (5, 6). I like to think of them as “leprosy flares” as it is an acute worsening of the disease. These are considered medical emergencies, as they can leave a patient significantly debilitated. 

Type 1 reaction aka reversal reaction – this is a consequence of Th1 cellular immunity and represents a vigorous host response within the skin and nerves with local IFN-gamma and TNF production. Typically seen in the borderline portion of the spectrum. This is marked by increased erythema, warmth, edema, and ulceration along with increased swelling and tenderness of peripheral nerves. You can think of it as a spontaneous enhancement of cellular immunity and delayed hypersensitivity. 

• Prevalence of reactions range from 30-50% (18, 19)
• No real trigger has emerged here. One case-control study evaluated 337 Vietnamese patients and found that the number of skin lesions, positive bacillary index, and BB and BL classification were associated with increased risk of a type 1 reaction (20):

• There are no known clinical markers here

Type II – also known as erythema nodosum leprosum. This is marked by the development of new painful, tender, and erythematous subcutaneous nodules. This is likely due to antibody-antigen complex deposition followed by complement activation. Here, systemic symptoms are the rule with high fevers and malaise and occasionally, presenting similar to septic shock. If you remember in the diagnostic section, the lepromatous end of the spectrum were the ones that had higher sensitivity for antigen testing. Indeed, these also have higher antibody levels and thus, end up being more susceptible to type II reactions. 

• Occurs in roughly 30-50% of patients with LL and 5-10% of patients with BL (21)
• The ENLIST ENL severity score is a 10 item system that has pretty good AUC (0.8372) to differentiate between mild and moderate-severe disease (21):
• 

Lucio’s phenomena – aka erythema necroticans aka leprosy vasculitis. This is a necrotizing vasculitis caused by endothelial invasion of M. leprae, which is manifested as hemorrhagic plaques followed by necrotic ulcerations (similar to pyoderma gangernosum). It is a very rare presentation and usually seen in Mexico and Carribean (22):

Treatment:

The basics of treatment are derived mostly from the latest WHO guidelines (28). Historically, dapsone was the mainstay of therapy from its discovery in the 1940s up to the 1970s, when resistance occurred (5). Since 1981, multidrug therapy has been adopted by the WHO, with the aforementioned classification being used to guide therapy. In general, therapy ranges anywhere from 6-24 months, depending on the guidelines you look at (29). The 3 drugs typically used include rifampicin, clofazimine, and dapsone. In terms of rifampicin resistance, ofloxacin/levofloxacin/moxifloxacin along with minocycline can be used.  

WHO Guidelines:

Treatment durations are shorter than the US guidelines. Part of this is cost in resource-limited settings, however there concerns about possible shorter treatment duration being associated with higher rates of relapse (30). Other studies did not find a difference between regimens (31). 

What about leprosy reactions? Treatment with high dose steroids (initial prednisone 60-80mg) tapered down over the next 2 weeks (40-60mg) is reasonable. Prolonged steroids tend to be the rule for type 1 reactions, usually over 2-6 months. Clofazamine daily for 6-12mo has also been used. 

For type 2 reactions, thalidomide is the drug of choice, with steroids and clofazimine also being used. 

TL;DR

• M. lepare is a gram positive rod, acid-fast staining, that is incredibly difficult to culture in vitro. Due to this, we typically use animal models such as armadillos and immunosuppressed rats
• Person-to-person transmission is the rule. Risk of infection is low overall.
• Clinical characteristics include multiple skin manifestations that can lead to patches, as well as peripheral neuropathy, autonomic disturbances, and anesthesia. 
• Clinical characteristics are dictated by the immune response to M. leprae. Th1 driven response leads to a tuberculoid presentation (usually one or few skin patches, lots of granulomas and little bacilli), while Th2 response leads to a lepromatous presentation (lots of bacilli, diffuse skin manifestation and peripheral nerve damage leading to deformities)
• Diagnosis is largey clinical + via biopsy
• Up to 50% can have “flares” during therapy, requiring high dose steroids, clofazimine, or thalidomide. 
• Treatment is with 3 drug combos, ranging from 6mo up to 24mo. 
• If nothing else, if you have a patient with leprosy, call the National Hansen’s disease Program at:

National Hansen’s Disease Program: 9181 Interline Avenue. Baton Rouge, Louisiana  70809. Phone Number: 1-800-642-2477

No, I didn’t write about Leprosy to make that reference about Hanson. Or maybe I did. I will never tell.

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