Leprosy ( Mycobacterium leprae )

History and Society

Descriptions of leprosy have been found in texts written over 2000 years ago in China, India, and Egypt. Skeletal remains from centuries ago show bony changes consistent with leprosy and M. leprae DNA is detectable in skeletal remains from the 4th century. Genetic epidemiology studies show correlation of leprosy strain types with patterns of human migration and trade routes, and confirm the ancient origin of this bacterium.

M. leprae was discovered in 1873 by Gerhard Henrik Armauer Hansen in Norway, in a time when leprosy incidence was increasing. Hansen visualized bacteria in tissue from a nodule, but was unable to culture the bacteria or infect animals, which would have been proof of disease causation. Hansen inoculated the eye of a leprosy patient with a knife that had incised a leprous nodule from another patient. He admitted doing this without her consent, and lost physician privileges but remained the Chief Medical Officer for Leprosy in Norway.

Fear of leprosy led to compulsory isolation of people suspected to have leprosy. There is no indication for isolation of people with leprosy at any stage of disease. The current goals of the World Health Organization (WHO) for 2020 are zero new cases of leprosy in children where deformity is present at diagnosis, reduction in the rate of leprosy with disability at diagnosis in all ages, and zero countries with laws permitting discrimination against leprosy (“Triple Zero Campaign”). WHO guidelines for eliminating discrimination against people with leprosy recommend that discriminatory language, including the term leper, be removed from government publications. Leper is a stigmatizing term and should not be used to refer to someone with M. leprae infection.

Epidemiology

Leprosy is an underrecognized and underdiagnosed disease. Challenges to prompt diagnosis include reluctance of patients to seek care because of leprosy-related stigma and failure of physicians to recognize the disease at the time of clinical presentation. Additionally, there are no definitive laboratory tests to determine who has had exposure, has infection, or is at risk for progressing from infection to clinical leprosy. Experts hypothesize that most of the world's population has a natural immunity to leprosy, and it is unknown what factors make some people more susceptible to M. leprae infection and subsequent development of clinical leprosy. The prolonged incubation periods between exposure, infection, and development of symptoms are challenging for studies of M. leprae.

Studies on M. leprae transmission are also limited by the inability to propagate M. leprae in culture and the lack of an animal model that replicates human leprosy and leprosy pathologic immune reactions. It is thought that transmission occurs with close, long-term exposure from a person with a disseminated leprosy to a person who has an innate susceptibility to the infection. The primary mode of transmission is thought to be by the respiratory route, from either respiratory droplets or nasal secretions.

Rees and McDougall showed that athymic mice could be infected with M. leprae when the respiratory exposure was 60 minutes to M. leprae aerosolized in a 1.2 × 10 ⁸ M. leprae /mL suspension. Even in a laboratory setting with high concentrations of M. leprae, only 33% of mice had any tissues positive for M. leprae 14 to 24 months after exposure. M. leprae DNA is detectable in the nasal secretions of people with leprosy and in those who live in leprosy-endemic areas, but the role of this carriage in transmission has not been definitively established. After respiratory introduction of M. leprae, the bacteria likely disseminate throughout the body. One hypothesis is that this is due to reprogramming of infected cells into stem cells, which migrate and affect immune response. In untreated lepromatous leprosy with high bacillary load, M. leprae bacteremia can be detected.

Antibodies to M. leprae have been detected in cord blood, although M. leprae bacteremia in cord blood has not been reported. Studies of placentas from mothers with lepromatous leprosy do not show pathologic changes associated with leprosy, although small numbers of acid-fast bacilli (AFB) have been found in placental tissues. Thus vertical transmission of leprosy from a mother with lepromatous leprosy is possible, but extremely unlikely if she has been treated. Skin-to-skin contact as a route of transmission has not been confirmed. Multiple publications have reported leprosy lesions developing in the area of a tattoo, suggesting inoculation leprosy from unsterilized needles.

Global Epidemiology

The adoption of multidrug therapy for leprosy in 1981 dramatically decreased the rate of leprosy new case detection worldwide. In 2016, the WHO reported 214,783 new cases of leprosy diagnosed worldwide, a new case detection rate of 2.9 per 100,000 population ( Fig. 250.1 ); 22 countries accounted for 95.03% of new cases. The greatest number of cases are reported from India (63%), Brazil (12%), and Indonesia (8%). Six percent of new cases already have severe disability with visible deformity, an indicator of significant delay in diagnosis. Millions of people worldwide are living with sequelae of leprosy.

Leprosy is an underdiagnosed disease. This is related to the chronic nature of the infection with insidious onset of symptoms, fear and stigma deterring contact with the health care system, or delay in diagnosis when signs and symptoms are not identified as being compatible with leprosy. In places with endemic leprosy, active case-finding activities diagnose more leprosy than would be expected from the baseline new case detection rate. Delay in diagnosis results in increased physical and functional disability from further nerve damage. Delay in diagnosis may also increase risk of transmission of M. leprae from someone with multibacillary leprosy with a high bacterial index. Awareness among medical professionals and communities is essential for timely diagnosis and initiation of treatment.

Epidemiology in the United States

Since 1894, 13,950 cases of leprosy have been registered in the United States. The NHDP estimates that approximately 9000 people who have or had leprosy are alive, many with long-term sequelae of leprosy and who could benefit from specialized care. There were 178 new cases reported in 2015, which continues a trend of increased case reporting. Most cases were reported from Florida, California, Texas, Louisiana, Hawaii, and New York. Fig. 250.2 shows the distribution of reported leprosy cases from 2005 to 2014. There are “indigenous foci” of leprosy transmission in Hawaii, Puerto Rico, and the region of the western Gulf of Mexico. There were 96 cases reported from Texas, Louisiana, Arkansas, Mississippi, Alabama, Georgia, and Florida. These are states where M. leprae has been isolated from nine-banded armadillos; 65% of cases from these states were in people who were born in and had never lived outside the United States. Country-wide, 57% of people with leprosy reported being born outside of the United States, with most cases in people coming from the South Pacific region. In 2015, new cases ranged in age from 7 to 95 years and were 66% male. Over half of new cases had lepromatous leprosy, the most disseminated form of leprosy, which increases risk for complications and sequelae.

Microbiology

M. leprae is not culturable on standard laboratory growth media. Isolation and propagation of M. leprae in the laboratory requires experimental infection of armadillos or footpads of immunodeficient mice. The doubling time of M. leprae is 14 days during the logarithmic growth phase, and up to 40 days during mouse footpad infection. M. leprae are Gram stain positive and carbol fuschin acid-fast stain positive. They are straight or slightly curved, 2.1 µm long, and 0.25 to 0.3 µm in width. The cell wall of M. leprae is rich in lipids and glycolipids, including phenolic glycolipid 1 (PGL-1). Antibody to PGL-1 is used to assess exposure to M. leprae and sometimes as part of diagnostic evaluation. There is no evidence of plasmids or bacteriophages that contribute to M. leprae pathogenesis.

M. leprae is an obligate intracellular pathogen, with macrophages and Schwann cells most frequently infected. The genome of M. leprae is much smaller than Mycobacterium tuberculosis (3.27 vs. 4.41 Mb, respectively), and appears to have undergone reductive evolution with loss of portions of the oxidative, microaerophilic, and anaerobic respiratory chains, such that it is unable to utilize certain carbon sources. Protein-coding genes comprise only half of the M. leprae genome. The M. leprae cell wall components are less diverse than in M. tuberculosis, and M. leprae has fewer enzymes available to facilitate scavenging of host cell lipids. It lacks many of the enzymes used by M. tuberculosis to survive in macrophages. M. leprae has an extremely conserved genome, with 99.995% sequence identity in M. leprae strains from four geographically distant countries. The frequency of SNPs is very low at 1 in 28,400 base pairs. A survey of 84 SNPs in M. leprae from 28 geographic regions separate M. leprae into 4 SNP types and 16 SNP subtypes. These SNP subtypes have been used for phylogeographic studies charting the dissemination of leprosy with human migration routes throughout history.

Recently, a new species of mycobacteria, M. lepromatosis, has been implicated as a cause of leprosy in humans. It is reported to have association with diffuse lepromatous leprosy, and with erythema necroticans, also known as Lucio phenomenon, a potentially fatal complication of leprosy. M. lepromatosis was first characterized in two patients from Mexico who had diffuse lepromatous leprosy and erythema necroticans that was fatal. In one study, 6 of 227 leprosy biopsies collected worldwide had M. lepromatosis ; all were from people from Mexico. M. lepromatosis has also been identified in red squirrels in the United Kingdom that had leprosy-like syndromes. M. lepromatosis and M. leprae genomes are similar sizes and have 93% nucleotide sequence identity in protein-coding genes, but only 82% in pseudogenes. To date, no mutations have been identified in M. lepromatosis that correspond to drug resistance mutations in M. leprae .