1380 PART 5 Infectious Diseases

previously untreated persons whose chest radiograph shows fibrotic

lesions consistent with old TB, and persons receiving drugs that suppress the immune system are defined as an area of induration ≥5 mm

in diameter. A 10-mm cutoff is used to define positive reactions in most

other at-risk persons. For persons with a very low risk of developing TB

if infected, a cutoff of 15 mm is used. (Except for employment purposes

where longitudinal screening is anticipated, the TST is not indicated for

these low-risk persons.) A positive IGRA is based on the manufacturer’s

recommendations. Good clinical practice requires that, in addition to

test results, epidemiologic and clinical factors also guide the decision to

implement TPT and that active TB be definitively excluded before the

initiation of a prophylactic regimen. The WHO recommends systematic testing for infection and TPT for the following groups at high risk

of progression from infection to disease or of exposure and infection:

adults, adolescents and children older than 12 months living with HIV;

infants with HIV aged <12 months who are contacts of persons with TB;

all household contacts of patients with infectious pulmonary TB including children <5 years of age; patients with silicosis, patients starting antiTNF treatment, patients on dialysis, and patients preparing for organ or

hematologic transplantation. In addition, testing and TPT may be considered for persons living or working in at-risk institutional or crowded

settings, such as prisoners, health care workers, recent immigrants from

high-TB-burden countries, and homeless people who use drugs.

Some TST- and IGRA-negative individuals are also candidates for

TPT. Once an appropriate clinical evaluation has excluded active TB,

infants and children <5 years of age who were in contact with infectious cases should be offered TPT even in the absence of a positive

test for TB infection. HIV-infected persons >1 year of age who have

been exposed to an infectious TB patient should receive TPT regardless of the TST result. Any HIV-infected candidate for TPT must be

screened carefully to exclude active TB, which would necessitate full

disease treatment. The use of a clinical algorithm based on four signs/

symptoms (current cough, fever, weight loss, and night sweats) helps

to decide which HIV-infected person can start TPT. The absence of all

four symptoms tends to exclude active TB in people living with HIV.

The presence of one of these four manifestations, on the other hand,

warrants further investigation for active TB before TPT is started.

Although a test of TB infection is prudent before starting TPT, this

test is not an absolute requirement—given the logistical challenges—

among contacts aged <5 years and people living with HIV in highTB-incidence and low-resource settings.

Among people living with HIV and receiving ART, conversion of the

TST from negative to positive can occur during the first few months

of TPT. Conversions (from negative to positive) and reversions (from

positive to negative) are more common with IGRAs than with TSTs

among serially tested health care workers in the United States.

TPT in selected persons at risk aims at preventing active disease

and, in the absence of an immunizing vaccine, is a critical component

of TB elimination strategies. Potential candidates for TPT are listed in

Table 178-6. This intervention is based on the results of a large number

of randomized, placebo-controlled clinical trials demonstrating that

a 6- to 9-month course of isoniazid reduces the risk of active TB in

infected people by up to 90%. Analysis of available data indicated that

the optimal duration of treatment with this drug was ~9 months. In the

absence of reinfection, the protective effect is believed to be lifelong.

Clinical trials have shown that isoniazid reduces rates of TB among

TST-positive persons with HIV infection. Studies in HIV-infected

patients have also demonstrated the effectiveness of shorter TPT regimens containing a rifamycin. Several TPT regimens (Table 178-7) can

be used. The most widely used has been that based on isoniazid alone at

a daily dose of 5 mg/kg (up to 300 mg/d) for 9 months. On the basis of

cost–benefit analyses and concerns about feasibility, a 6-month period

of treatment at the same dose is considered adequate by the WHO.

An alternative regimen for adults is 4 months of daily rifampin, which

should also be effective against isoniazid-resistant strains. A 3-month

regimen of daily isoniazid and rifampin is used in some countries (e.g.,

the United Kingdom) for both adults and children who are known not

to have HIV infection. A previously recommended 2-month regimen

of rifampin and pyrazinamide has been associated with serious or even

fatal hepatotoxicity and is not recommended. The rifampin-containing

regimens should be considered for persons who are likely to have been

infected with an isoniazid-resistant strain. A clinical trial showed that

a regimen of isoniazid (900 mg) and rifapentine (900 mg), given once

weekly for 12 weeks, is as effective as the standard 9-month isoniazid

regimen. This regimen was associated with higher rates of treatment

completion (82% vs 69%) and less hepatotoxicity (0.4% vs 2.7%) than

isoniazid alone, although the rate of permanent discontinuation due to

an adverse event was higher (4.9% vs 3.7%).

Currently, the isoniazid–rifapentine regimen is not recommended

for children <2 years of age or pregnant women. Recently, an openlabel, randomized, phase 3 noninferiority trial has shown that among

HIV-infected persons, a 1-month regimen of daily rifapentine plus

isoniazid was noninferior to the 9-month daily isoniazid regimen and

ensured a higher treatment completion. As a result, the WHO has

included a 1-month regimen composed of daily isoniazid (300 mg)

and rifapentine (600 mg) among the available options for people aged

13 years or more. Rifampin and rifapentine are contraindicated in

HIV-infected individuals receiving protease inhibitors, most nonnucleoside reverse transcriptase inhibitors (e.g., nevirapine), and, for those

with chronic hepatitis B, tenofovir alafenamide. However, efavirenz

and tenofovir disoproxil can be used for simultaneous administration

with a rifamycin without dose adjustment. However, the dose of the

integrase inhibitor dolutegravir needs to be increased to 50 mg twice

daily when given together with rifampin, a dose that is usually well tolerated and gives equivalent efficacy in viral suppression and recovery

of CD4+ cell count compared with efavirenz. Administration of rifapentine with raltegravir was found to be safe and well tolerated. A recent

phase 1/2 trial of the 3-month regimen isoniazid plus rifapentine and

dolutegravir in adults with HIV reported good tolerance and viral

load suppression, no adverse events of grade >3, and did not indicate

that rifapentine reduced dolutegravir levels sufficiently to require dose

adjustment. Clinical trials to assess the efficacy of long-term isoniazid

administration (i.e., for at least 3 years) among people living with

HIV in high-TB-transmission settings have shown that this regimen

can be more effective than 9 months of isoniazid and is therefore

TABLE 178-7 Recommended Regimens and Drug Dosages for

Tuberculosis Preventive Treatmenta

REGIMEN DOSE ADVERSE EVENTS

Isoniazid alone for

6 or 9 months

Adults: 5 mg/kg (max,

300 mg) per day

Children <10 years of

age: 10 mg/kg per day

(range, 7−15 mg)

Drug-induced liver injury,

nausea, vomiting, abdominal

pain, skin rash, peripheral

neuropathy, dizziness,

drowsiness, seizure

Rifampin alone for

4 months

Adults: 10 mg/kg per day

Children <10 years of

age: 15 mg/kg (range,

10−20 mg) per day

Flulike syndrome, skin

rash, drug-induced liver

injury, anorexia, nausea,

abdominal pain, neutropenia,

thrombocytopenia, renal

reactions (e.g., acute tubular

necrosis and interstitial

nephritis)

Isoniazid plus

rifampin for

3 months

As above As above

Rifapentine plus

isoniazid for

3 months

Adults and children:

Isoniazid: 15 mg/kg

(900 mg) weekly

Rifapentine: 15–30 mg/kg

(900 mg) weekly

Hypersensitivity reactions,

petechial skin rash, druginduced liver injury

Anorexia, nausea, abdominal

pain

Hypotensive reactions

Rifapentine plus

isoniazid for

1 month

Age >13 years only:

Isoniazid 300 mg and

rifapentine 600 mg daily

(28 doses)

Essentially like those

of isoniazid alone with

neutropenia more common and

elevation in liver enzyme levels

and neuropathy less common

a

See text for full description of evidence on and limitations of these regimens.

Source: Reproduced with permission from World Health Organization.

1381CHAPTER 178 Tuberculosis

recommended under those circumstances. Studies looking at whether

briefer treatment with rifapentine-based regimens could achieve similar efficacies have been undertaken. Isoniazid should not be given to

persons with active liver disease. All isoniazid recipients at increased

risk of hepatotoxicity (e.g., those abusing alcohol daily and those with

a history of liver disease) should undergo baseline and then monthly

assessment of liver function; they should be carefully educated about

hepatitis and instructed to discontinue use of the drug immediately

should any symptoms develop. Moreover, these patients should be seen

and questioned monthly during therapy about adverse reactions and

should be given no more than a 1-month supply of drug at each visit.

Persons receiving high-dose isoniazid and who are at risk of vitamin

B6 (pyridoxine) deficiency, as listed above, should receive pyridoxine

to prevent peripheral neuropathy.

TPT among persons likely to have been infected by a multidrugresistant strain is a challenge because no clinical trial results are available to guide treatment. Close observation for early signs of disease

is one option. However, in selected high-risk household contacts of

patients with MDR-TB (e.g., children, recipients of immunosuppressive therapy), TPT may be considered on the basis of individualized

risk assessment and clinical criteria. In the absence of evidence of efficacy of any regimen, important factors in the decision to treat include

intensity of exposure, certainty about a source case, information on the

drug resistance pattern of the index case, and potential adverse events.

Confirmation of infection with available testing is generally required.

Drug selection should be based on the drug susceptibility profile of the

index case. One regimen recommended by the WHO is daily levofloxacin (750−1000 mg daily among adults) for 6 months.

It may be more difficult to ensure adherence to TPT than when

treating those with active TB. If family members of patients with active

TB are being treated, adherence and monitoring may be easier. When

feasible, supervised therapy may increase the likelihood of completion.

As in active cases, the provision of incentives may also be helpful.

Currently, no evidence shows that large-scale use of TPT leads to significant development of drug resistance. However, before TPT begins,

it is mandatory to carefully exclude active TB in order to prevent

undertreatment and promote development of drug resistance.

■ PRINCIPLES OF TB CONTROL

The highest priority in any TB control program is the prompt detection

of cases and the provision of treatment to all TB patients under proper

case-management conditions, including DOT and social support. In

addition, screening of high-risk groups, including immigrants from

high-prevalence countries, migrant workers, prisoners, homeless individuals, substance abusers, and HIV-seropositive persons, is recommended. TST- or IGRA-positive high-risk persons should receive TPT

as described above. Contact investigation is an important component

of efficient TB control. In the United States and other countries worldwide, a great deal of attention has been given to the transmission of

TB (particularly in association with HIV co-infection) in institutional

settings such as hospitals, homeless shelters, and prisons. Measures to

limit such transmission include respiratory isolation of persons with

suspected TB until they are proven to be noninfectious (at least by

sputum AFB smear negativity), proper ventilation in rooms of patients

with infectious TB, use of ultraviolet irradiation in areas of increased

risk of TB transmission, correct use of personal protective equipment,

and periodic screening of personnel who may come into contact with

known or unsuspected cases of TB. In the past, radiographic surveys,

especially those conducted with portable equipment and miniature

films, were advocated for case finding. Today, however, the prevalence

of TB in industrialized countries is sufficiently low that “mass miniature radiography” is not cost effective.

In high-prevalence countries, most TB control programs have made

remarkable progress in reducing morbidity and mortality since the

mid-1990s by adopting and implementing the standards and strategies

internationally promoted by the WHO. Between 2000 and 2018, more

than 60 million lives are estimated to have been saved. The essential

elements of good TB care and control were established in the mid1990s and consist of well-defined interventions that were the basis

of the “DOTS strategy”: early detection of cases and bacteriologic

confirmation of the diagnosis; administration of standardized shortcourse chemotherapy, with direct supervision to ensure adherence to

treatment and the provision of social support to patients; availability

of drugs of proven quality, with an effective supply and management

system; and a monitoring and evaluation system, including assessment

of treatment outcomes—e.g., cure, completion of treatment without

bacteriologic proof of cure, death, treatment failure, and default—in all

cases registered and notified as well as measurement of the impact of

control methods on classical TB indicators such as mortality, incidence,

prevalence, and drug resistance. In 2006, the WHO indicated that,

besides pursuing these essential elements that remain the fundamental

components of any control strategy, additional steps had to be undertaken in order to reach international TB control targets. These steps

included addressing HIV-associated TB and MDR-TB with additional

measures; operating in harmony with general health services; engaging

all care providers beyond the public providers; empowering people

with TB and their communities; and enabling and promoting research.

Evidence-based International Standards for Tuberculosis Care—

focused on diagnosis, treatment, and public health responsibilities—

were introduced for wide adoption by medical and professional

societies, academic institutions, and all practitioners worldwide.

Care and control of HIV-associated TB are particularly challenging

in poor countries because existing interventions require collaboration

between HIV/AIDS and TB programs as well as standard services. TB

programs must test every patient for HIV in order to provide access to

trimethoprim-sulfamethoxazole prophylaxis against common infections and ART. HIV/AIDS programs must regularly screen persons

living with HIV/AIDS for active TB, provide TPT, and ensure infection

control in settings where people living with HIV congregate.

Early and active case detection is considered an important intervention not only among persons living with HIV/AIDS but also

among other vulnerable populations, as it reduces transmission in a

community and provides early effective care. Additional measures are

indicated for the management of MDR-TB, RR-TB, and other forms

of drug-resistant TB; they include upgrades of laboratory capacity to

perform rapid DST and ensure surveillance of drug resistance; availability of drug regimens that are recommended for RR/MDR-TB, with

assured quality of drugs; and infection control measures in all settings

where patients with drug-resistant forms of TB may congregate. In

the new era of the United Nations Sustainable Development Goals

(2016–2030), the approach to TB control and care needs to evolve

further and become multisectoral and more holistic. Engagement

beyond dedicated programs and even the health sector is now essential. Therefore, the new “End TB” strategy promoted by the WHO

since 2016 builds on three pillars and relies on increased investments

and efforts by all governments, their national programs, and a multitude of partners within and beyond the health sector: (1) integrated,

patient-centered care and prevention; (2) bold policies and supportive

systems; and (3) intensified research and innovation. The first pillar

incorporates all technological innovations, such as early diagnostic

approaches (including universal DST and systematic screening of

identified, setting-specific, high-risk groups); well-designed treatment

regimens for all forms of TB; proper management of HIV-associated

TB and other comorbidities; and preventive treatment of persons at

high risk. The second pillar is fundamental and is normally beyond the

scope of dedicated programs, relying on policies forged by the highestlevel health and governmental authorities: availability of adequate

human and financial resources; engagement of civil organizations

and all relevant public and private providers to pursue proper care for

all patients and prevention for all people at risk; a policy of universal

health coverage (which, together with social protection, implies avoidance of catastrophic expenditures caused by TB among the poorest);

regulatory frameworks for case notifications, vital registration, quality

and rational use of medicines, and infection control; social protection

mechanisms as part of poverty alleviation strategies; and promotion

of interventions against the broader determinants of TB. Finally, the

third pillar of the new strategy emphasizes intensification of research

and development on new tools and interventions as well as optimal

1382 PART 5 Infectious Diseases

implementation and rapid adoption of new tools in endemic countries.

Besides specific clinical care and control interventions as described

in this chapter, elimination of TB in a society ultimately will require

control and mitigation of the multitude of direct risk factors (e.g., HIV

infection, smoking, alcohol abuse, diabetes) and socioeconomic determinants (e.g., extreme poverty, inadequate living conditions and poor

housing, malnutrition, indoor air pollution) with clearly implemented

policies within the health sector and other sectors linked to human

development and welfare.

■ FURTHER READING

Conradie F et al: Treatment of highly drug-resistant pulmonary

tuberculosis. N Engl J Med 382:893, 2020.

Dorman SE et al: Four-month rifapentine regimens with or without

moxifloxacin for tuberculosis. N Engl J Med 384:1705, 2021.

Getahun H et al: Latent Mycobacterium tuberculosis infection. N Engl

J Med 372:2127, 2015.

Nahid P et al: An Official American Thoracic Society/Centers for

Disease Control and Prevention/European Respiratory Society/

Infectious Diseases Society of America clinical practice guideline:

Treatment of drug-resistant tuberculosis. Am J Respir Crit Care Med

200:e93, 2019.

Nahid P et al: An Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America

clinical practice guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis 63:853, 2016.

Pai M et al: Tuberculosis. Nat Rev Dis Primers 2:16076, 2016.

Swindells S et al: One month of rifapentine plus isoniazid to prevent

HIV-related tuberculosis. N Engl J Med 380:1001, 2019.

Tait DR et al: Final analysis of a trial of M72/AS01 vaccine to prevent

tuberculosis. N Engl J Med 381:2429, 2019.

Uplekar M et al: WHO’s new End TB strategy. Lancet 385:1799, 2015.

■ WEBSITES

World Health Organization: Global tuberculosis report

2020, Geneva, WHO, 2020. https://www.who.int/publications/i/

item/9789240013131

World Health Organization: Treatment of tuberculosis. Guidelines for treatment of drug-susceptible tuberculosis and patient

care. 2017 update. Geneva, WHO, 2017. https://apps.who.int/iris/

bitstream/handle/10665/255052/9789241550000-eng.pdf?sequence=1

World Health Organization: WHO Consolidated Guidelines on

Tuberculosis, Module 4: Treatment. Drug-Resistant Tuberculosis

Treatment. Geneva, WHO, 2020. https://www.who.int/publications/i/

item/9789240007048

World Health Organization: WHO consolidated guidelines on

tuberculosis. Module 3: Diagnosis. Rapid diagnostics for tuberculosis

detection. 2021 update. Geneva, WHO, 2021. https://www.who.int/

publications/i/item/9789240029415

Leprosy, also referred to as Hansen’s disease, is a chronic infectious disease caused by Mycobacterium leprae. The clinical manifestations are

largely confined to the skin, peripheral nervous system, eyes, and upper

respiratory tract. The differing immune responses to M. leprae result in

a spectrum of disease ranging from tuberculoid to lepromatous leprosy.

M. leprae has a predilection for peripheral nerves, and immunologically mediated reactional states can cause nerve damage to the face,

arms, and legs; this damage often results in disability, which in turn

can lead to stigma and social exclusion. The physical disfigurement

179 Leprosy

Jan H. Richardus, Hemanta K. Kar,

Zoica Bakirtzief, Wim H. van Brakel

that accompanies leprosy has left marks on society that have endured

long after the disease’s disappearance in many countries. In everyday

language, leprosy has become a metaphor for a horrible condition

that warrants social exclusion. Leprosy is a neglected disease and is

often thought no longer to exist. However, 202,185 new cases from

150 countries were reported in 2019. A general lack of awareness

among both the public and medical practitioners often delays diagnosis and treatment and thus results in irreversible impairments. Early

diagnosis and treatment of leprosy and leprosy reactions can cure the

disease and prevent most chronic complications.

■ ETIOLOGY

M. leprae is an obligate, intracellular, acid-fast staining, rod-shaped

bacterium, measuring 1–8 μm in length and 0.3 μm in diameter.

M. leprae mostly appears irregularly stained and fragmented or granular, in which case the organism is usually considered to be dead. The

few bacteria that are brightly and uniformly stained are thought to be

solid, viable bacilli. The morphologic index is a measure of uniformly

stained solid bacilli on slit-skin smear examination and is calculated

as the percentage of viable bacilli among the total number of bacilli

counted under oil-immersion microscopy. On slit-skin smear examination at the lepromatous end of the disease spectrum, M. leprae is predominantly found in clumps or globi within macrophages (lepra cells).

Inside these cells, M. leprae multiplies in unrestricted fashion, and hundreds of bacilli may be present; the organisms are arranged in parallel

arrays placed side by side as a result of the presence of surface lipids

(glial substances). The bacteriologic index is a logarithmic-scaled measure of the density of bacilli of all forms found in the dermis upon slitskin smear examination, varying from 0 to 6+ (with or without globi)

from the tuberculoid to the lepromatous end of the disease spectrum.

The bacteriological index falls an average of 1 log unit per year with

multidrug therapy. M. leprae infects mainly macrophages and Schwann

cells. It has never been grown in artificial media. Reproduction occurs

by binary fission, and the organism grows slowly (over 12–14 days)

in the footpads of mice. The temperature required for survival and

proliferation—between 27°C and 30°C—explains the greater impact of

the disease on surface areas such as the skin, peripheral nerves, testicles, and upper airways, with less inner visceral involvement. M. leprae

remains viable for 9 days in the environment.

Ultrastructural Characteristics of M. leprae Electron microscopy reveals that M. leprae has a cytoplasm, plasma membrane, cell

wall, and capsule. The cytoplasm contains structures common in

gram-positive microorganisms. The plasma membrane has a permeable lipid bilayer containing interacting proteins—the protein

surface antigens. Similar to that of other mycobacteria, M. leprae’s

cell wall, which is attached to the plasma membrane, is composed of

peptidoglycans bound to branched-chain polysaccharides; these peptidoglycans are arabinogalactans, which support mycolic acids, and

lipoarabinomannan (LAM). The capsule—the outermost structure—

contains lipids, particularly phthiocerol dimycocerosate and phenolic

glycolipid (PGL-1), which has a trisaccharide bound to lipid by a

molecule of phenol. Because this trisaccharide is antigenically specific

for M. leprae, its detection is helpful in serologic diagnosis of leprosy.

Genome of M. leprae Comparative analysis of the genomics

of single-nucleotide polymorphisms indicates that four distinct

strains of M. leprae originated in East Africa or Central Asia.

A mutation spread to Europe and subsequently underwent two separate mutations that were then followed by spread to West Africa and

the Americas. The genome of M. leprae is circular. Its estimated molecular mass is 2.2 × 109

 Da, with 3,268,203 base pairs and a guanine-pluscytosine content of 57.8%.

Culture Difficulties Compared to the genome of Mycobacterium

tuberculosis, that of M. leprae underwent reductive evolution, resulting

in a smaller genome rich in inactive or entirely deleted genes. This

reductive evolution, gene decay, and genome downsizing all may

explain the unusually long generation time and may account for the

inability to culture the leprosy bacillus in artificial media. As a result,

1383CHAPTER 179 Leprosy

prevalence, which would include existing cases that have not yet been

detected. The two factors that determine the registered prevalence are

the new case detection rate and the duration of treatment; changes in

either factor will affect the registered prevalence.

The WHO leprosy disability grading system scores patients according to the presence of disabilities of the eyes, hands, and feet. For the

hands and feet, grade 0 means no anesthesia and no visible impairment; grade 1 signifies anesthesia but no visible impairment; and grade

2 indicates visible impairment. For the eyes, grade 0 signifies no eye

problems due to leprosy and no evidence of visual loss; grade 1 signifies

eye problems due to leprosy without severe effects on vision; and grade

2 indicates severe visual impairment (vision score worse than 6/60;

inability to count fingers at 6 meters) and also includes lagophthalmos,

iridocyclitis, and corneal opacities. The sum score for these six body

sites is called the Eye-Hand-Foot (EHF) score and is used as an overall

indicator of the impairment status of a person with leprosy. Leprosyrelated grade 2 disability is usually reported as the proportion of people

with such disability at any site among patients newly diagnosed with

leprosy in a specific year.

The global trend in new case detection since 1985 is presented

in Fig. 179-1. The trend was remarkably static up to the year 2001,

with a peak around the year 2000; fell dramatically between 2001

and 2005; and has leveled off since 2006. The most important factor

contributing to the fast downward trend was the decline in leprosy

control activities following the declaration by the WHO in 2000 that

leprosy was eliminated as a “public health problem.” Elimination was

defined as a prevalence of <1 case per 10,000 population at the global

level. The attainment of this target was a great achievement but led

many to believe that the problem of leprosy was solved altogether. This

misunderstanding in turn led to reduced political commitment to leprosy control programs and facilities, with consequent downsizing and

decreased funding. The stabilization of the new case detection rate at

just over 200,000 cases annually since 2006 indicates that transmission

of M. leprae is continuing unabated, posing an enormous challenge in

leprosy control.

Sex, Age, and Geographic Distribution Approximately 40%

of all reported leprosy patients are women, but the low proportion in

some countries raises concerns about underdiagnosis in women due to

poor access to health services, illiteracy, low status, and other cultural

factors. The age-specific incidence often shows a bimodal pattern, with

peaks in the teenage years and in adulthood. Around 8% of all newly

detected cases are found in children (<15 years of age), a measure that

is often taken as an indicator of continued (recent) transmission. Leprosy is rare among children <5 years of age. Around 5% of all patients

have a grade 2 disability.

propagation of M. leprae has been restricted to animal models, including the armadillo and normal, athymic, and gene-knockout mice.

These systems have provided the basic resources for genetic, metabolic,

and antigenic studies of the bacillus. Growth of M. leprae in mouse

footpads also provides a tool for assessing the viability of the bacteria

and testing the drug susceptibility of clinical isolates.

Immunologic Properties of M. leprae M. leprae induces both

humoral and cell-mediated immune responses. The immunogenic

components of M. leprae include polysaccharides and proteins. Polysaccharide components induce mainly a humoral immune response,

whereas protein components induce both humoral and cell-mediated

immune responses. The immunogens in M. leprae form two distinct

groups: cytoplasmic antigens and antigens from the mycobacterial cell.

As mentioned above, a species-specific phenolic glycolipid, PGL-1,

has been identified in M. leprae. Other varieties of M. leprae antigens

identified with monoclonal antibodies include antigens of 18, 28, 7,

14, 36, 65, and 70 kDa that may possibly induce an immune response.

Mycobacterium lepromatosis In 2008, a new mycobacterial species,

M. lepromatosis, was isolated from patients with a special type of diffuse lepromatous leprosy known as diffuse leprosy of Lucio and Latapí.

This clinical variety of leprosy is found mainly in Mexico and Central

America. M. lepromatosis is very similar to M. leprae microbiologically

and clinically. Microbiologically, both species are acid-fast and noncultivable and preferably infect skin and peripheral nerves. Clinically,

differentiation of M. lepromatosis from M. leprae in individual patients

is not diagnostically necessary since both organisms respond well to

the same antimycobacterial regimens.

■ EPIDEMIOLOGY

Incidence, Prevalence, and Disability The true incidence

of leprosy is difficult to establish because the figure is very low and

because the initial signs and symptoms are often insidious, and thus

not all cases are detected as they occur. In 2019, as stated earlier,

202,185 new cases were reported to the World Health Organization

(WHO) from 150 countries. New case detection per year is commonly

used as a proxy for incidence, but operational factors, such as the intensity of case detection, the use of surveys, the use of contact tracing, the

level of community awareness, and the quality and availability of health

care, have a profound effect on case detection rates. In nonendemic

countries around the world, leprosy is often misdiagnosed simply

because it is not considered.

The registered prevalence of leprosy is defined as the number of

patients receiving treatment at a point in time (usually at the end of a

calendar year). The registered prevalence is a proxy measure for true

1985

0

100,000

200,000

300,000

400,000

500,000

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

600,000

700,000

800,000

900,000

FIGURE 179-1 Global trend in leprosy new-case detection, 1985–2019.

1384 PART 5 Infectious Diseases

There are large variations among world regions and countries in

new case detection rates. Approximately 80% of global new case detection is reported from India, Brazil, and Indonesia. There are also distinct geographic variations within countries, with differences between

urban and rural communities and clustering of cases at the village or

neighborhood level. Geographic variations can be due to differences

in health service provision, socioeconomic development, isolation,

and poverty. Figure 179-2 depicts the geographic distribution of new

leprosy cases in 2018.

Transmission Understanding of the transmission of M. leprae is

limited. The existing evidence is largely circumstantial because of the

long incubation period from exposure to disease, the inability to culture

M. leprae, and the difficulty of diagnosing both infection and early disease. M. leprae organisms can be shed in large numbers from the mouth

and nose of patients with untreated multibacillary leprosy (droplet

infection) and sometimes from damaged skin, but it is unclear whether

patients with paucibacillary leprosy can spread the bacillus. There is evidence for transmission between humans and—in southern U.S. states—

for zoonotic transmission through wild armadillos. The main route of

entry into the body is assumed to be the respiratory tract, but in patients

with wounds or tattoos, transmission through the skin also is possible.

Reservoirs of Infection It is assumed that humans are the main

reservoir of infection for M. leprae. The armadillo is also a reservoir

for human infection. Certain species of monkeys and red squirrels

are infected with M. leprae in the wild, but there is no evidence of

transmission to humans through contact with these animals. Evidence

is weak for the potential of water and soil as environmental sources of

M. leprae. The higher incidence rate of leprosy among household contacts of multibacillary cases than among those of paucibacillary cases

suggests that multibacillary cases represent an important reservoir for

undetected and untreated cases in the community; that is, a prolonged

period between the onset of signs of leprosy and treatment due to a

delay in diagnosis and initiation of multidrug therapy increases exposure in the community. Persons with subclinical leprosy are likely to

be a main source of infection, given that multidrug therapy for clinical

leprosy apparently has not made an impact on transmission.

Incubation Period, the Role of Contacts, and Genetic

Susceptibility The incubation period of leprosy is estimated to

range from 2 to ≥10 years. The incubation period for multibacillary

leprosy appears to be longer (5 to ≥10 years) than that for paucibacillary leprosy (~2–5 years). Poverty-associated factors such as low level

of education, poor hygiene, and food shortages have been identified as

risk factors for leprosy, but the most important risk factors are associated with intimacy and duration of contact with a leprosy patient,

in particular with an index case with multibacillary leprosy, and the

intensity of contact with and physical distance from the index patient.

Increasing evidence from studies in twins and from observational studies supports host genetic susceptibility to leprosy. Ongoing studies are

exploring the mechanism underlying genetic susceptibility to leprosy

and its clinical manifestations.

■ PATHOGENESIS

Whatever the route of M. leprae’s entry into the human body, the

pathogenic process usually starts in the peripheral nerves. Once bacilli

are engulfed by Schwann cells, the histopathologic changes in nerve

and skin—and thus the type of leprosy that develops—depend on the

immunologic resistance of the person infected, in particular on the

cell-mediated immune (CMI) response to the bacillus and its antigens.

Ridley-Jopling Classification of Leprosy In 1962, Ridley and

Jopling described five overlapping categories of leprosy: tuberculoid

(TT), borderline tuberculoid (BT), mid-borderline (BB), borderline

lepromatous (BL), and lepromatous (LL). An early clinical manifestation is recognized and referred to as indeterminate leprosy (IL).

Immunologic resistance is strong at the tuberculoid end of the spectrum, gradually diminishes through the borderline spectrum, and is

weakest in lepromatous leprosy. The LL and TT types of leprosy are

relatively stable, with little or no change in clinical disease expression

over time, while the BL, BB, and BT types are unstable both clinically

and immunologically. Further distinction indicates that subpolar types

of TT and LL leprosy (TTs and LLs) are less stable than polar types

(TTp and LLp). The immune reaction depends on predisposing genetic

factors and the extent of exposure to M. leprae. The host tissue’s reaction and related damage are largely due to delayed hypersensitivity. In

response to the presence of M. leprae, a granuloma is formed either

by macrophage–lymphocyte interaction when there is immunity or

otherwise by macrophages only. The formation of a granuloma is preceded by a stage of infiltration by lymphocytes alone, as is seen in IL.

Because of the strong immune response toward the tuberculoid end of

0 6 1,500 3,000 ,000 Kilometers

New leprosy cases–2018–

0

1–10

11–100

101–1000

1001–10,000

>10,000

No data

FIGURE 179-2 Geographic distribution of new leprosy cases, 2018. (Reproduced with permission from Global leprosy update, 2018: moving towards a leprosy-free world.

Wkly Epidemiol Rec 35/36:389, 2019.)

1385CHAPTER 179 Leprosy

the spectrum, macrophages, along with many lymphocytes, become

fixed epithelioid cells, and groups of these cells become giant cells. The

tuberculoid granuloma leads to nerve destruction resulting in anesthesia and muscle weakness. The cellular response is less focal and less

destructive in the borderline portion of the spectrum; consequently,

there is less damage to nerves and few bacilli are present. In BL leprosy,

there are macrophage granulomas along with lymphocytes, but little

nerve damage and more bacilli. In LL leprosy, bacilli multiply within

Schwann cells and perineural cells. Liberated bacilli from these cells are

engulfed by histiocytes, becoming wandering macrophages and traveling throughout the body to other nerves and tissues via blood, lymph,

and tissue fluids. In addition, there are diffuse lepromas in LL leprosy

that consist of histiocytes and/or macrophages, with very few lymphocytes and plasma cells. The bacilli are packed within macrophages

called globi and outside macrophages either singly or in small groups.

WHO Simplified Clinical Classification of Leprosy RidleyJopling classification requires clinical and pathologic expertise that

does not exist in many settings. The WHO has therefore introduced

a simplified classification system based on slit-skin smear: patients

with negative slit-skin smear results at all body sites are classified as

having paucibacillary leprosy, whereas patients with positive smears at

any body site are classified as having multibacillary leprosy. However,

because slit-skin smear facilities are not available or dependable in

many countries, most leprosy control programs use clinical criteria

only for classifying leprosy and deciding on the appropriate treatment

regimen for individual patients. In this circumstance, paucibacillary leprosy is defined as one to five skin lesions and no or only one

involved peripheral nerve, while multibacillary leprosy is defined as six

or more skin lesions and/or more than one involved peripheral nerve.

■ CLINICAL MANIFESTATIONS

Leprosy is a disease affecting mainly the skin, cutaneous and peripheral

nerves, mucous membranes, and, less commonly, other sites such as

joints, lymph nodes, eyes, and testes. Other systemic manifestations

may occur, particularly in BL and LL disease, with or without leprosy

reactions. Most dermal and cutaneous nerves feeding skin lesions are

affected—e.g., the supraorbital, great auricular, radial cutaneous, infrapatellar, superficial fibular, and sural nerves and the cutaneous nerves

of the thigh. The peripheral nerves involved include the ulnar, median,

radial (in upper limbs), lateral popliteal, and posterior tibial (in lower

limbs). The cranial nerves commonly involved are the trigeminal and

facial.

Indeterminate Leprosy (IL) This early clinical type manifests

as one or a few hypopigmented or faintly erythematous, ill-defined

to well-defined macular lesions measuring 1–5 cm in diameter. These

lesions invariably occur on the external aspects of the limbs, buttocks,

and face, with mild to moderate impairment of touch and/or thermal

sensations. There is no thickening of the corresponding cutaneous

and peripheral nerves. IL is often, but not always, the first clinical

sign of leprosy. This type either heals spontaneously or progresses to

a determinate form of the disease (TT, BT, BB, BL, or LL), depending

on CMI status.

Tuberculoid (TT) Leprosy TT leprosy (Fig. 179-3) presents

either as a well-defined, hypopigmented macule or as a raised, erythematous/brown/copper-colored plaque with a well-defined edge. The

lesions may be found on any part of the skin and are characterized

by complete loss of fine touch and temperature sensations over their

surface. Skin lesions are single or few (up to three) in number and can

be of any size, but they seldom measure >10 cm in diameter. In plaquetype lesions, the raised clear-cut edge often slopes inward to a flattened

and sometimes hypopigmented central area, acquiring an annular configuration. The skin surface of both macular and plaque lesions is dry,

hairless, and anesthetic because of destruction of underlying superficial

cutaneous nerves. Larger corresponding cutaneous nerves are thickened in a limited number of cases. On the face, sensory impairment

may be difficult to demonstrate because of the generous and bilateral

supply of sensory nerve endings. Autonomic nerve damage within the

lesion is responsible for surface dryness and loss of sweating over the

lesion. A solitary peripheral-nerve trunk in the vicinity of a lesion may

be thickened, with sensory loss of the area supplied and with or without motor disfigurement. On slit-skin smear examination, no acid-fast

bacilli (AFB) are normally found. The lepromin skin test is strongly

positive, signifying good host CMI status.

Borderline Tuberculoid (BT) Leprosy BT leprosy (Fig. 179-4)

is characterized by either macular or plaque-type lesions numbering

three to nine or more and asymmetrically located on any part of the

body, with variable sizes and contours. The margins of the lesions range

from poorly defined to well defined; sometimes both forms of margin

are seen in one lesion. There may be smaller satellite lesions around

a larger one, especially on sides where the margin is less defined; this

characteristic indicates downgrading of the lesion from TT to BT

leprosy. The edges of plaque lesions may slope outward in contrast to

TT lesions, which slope inward; plaques may gradually fade outward

and eventually blend into normal-looking skin. Loss of sensation is

less intense than it is in TT lesions and dryness on the surface less

conspicuous. Several peripheral nerves are likely to be enlarged in an

asymmetrical pattern, with sensory and motor deficits. One of the

most striking features of BT leprosy is susceptibility to a type 1 leprosy

reaction (T1R; see below) that exacerbates skin lesions and/or peripheral nerves. If not diagnosed and treated early, disease in these patients

tends to downgrade across the spectrum to BB, BL, or LLs leprosy, with

an increasing bacteriologic index and a regressed CMI response causing nerve damage along the way. Slit-skin smears show bacteriologic

indices varying from negative to 1+.

FIGURE 179-3 Tuberculoid (TT) leprosy. Hypopigmented macular lesion with a welldefined edge and loss of fine-touch sensation. (From Dr. H. K. Kar, with permission.)

FIGURE 179-4 Borderline tuberculoid (BT) leprosy. Macular lesion with irregular,

moderately defined edge and satellite lesion, with loss of sensation. (From Dr. W. H.

van Brakel, with permission from NLR.)

1386 PART 5 Infectious Diseases

FIGURE 179-5 Borderline lepromatous (BL) leprosy. Numerous diffusely infiltrated

erythematous and hypopigmented macules, downgrading from borderline

tuberculoid to lepromatous leprosy. (From Dr. C. L. M. van Hees, Department of

Dermatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands,

with permission.)

FIGURE 179-6 Lepromatous (LL) leprosy. Multiple nodules on ears and face and loss

of eyebrows. (From Dr. K. Mponda, Department of Dermatology, Queen Elisabeth

Central Hospital, Blantyre, Malawi, with permission.)

Mid-Borderline (BB) Leprosy This form of leprosy is unstable.

Many cases downgrade toward BL and LLs disease, especially if not

treated. There are multiple plaque lesions and, not infrequently, macular lesions; the lesions are of various shapes and sizes, are bilateral, and

usually occur in a more or less symmetrical distribution. In annular

lesions, the inner edge is well demarcated and “punched out,” and the

outer edge is ill defined and merges with normal-looking skin. The

surface of the lesions is moderately shiny and the central area looks

pale. There is minimal loss of sensation over the lesions. Nerve damage

is variable in BB leprosy. Many nerves may be thickened, and this effect

may be asymmetrical. BB leprosy is not commonly observed and rapidly changes its spectrum—rarely to BT leprosy but more often to BL

disease. The lepromin test is negative. Slit-skin smears of lesions show

a moderate number of AFB (2+ to 3+).

Borderline Lepromatous (BL) Leprosy In BL leprosy

(Fig. 179-5) there are numerous bilateral, round or oval, macular, diffusely infiltrated, erythematous or hypopigmented lesions with moderately defined borders. The lesions are usually 2–3 cm in diameter, may

have a coppery hue, and tend to become symmetrical. Some loss of

sensation may be detected, particularly over older lesions; however, no

loss of sensation is observed over fresh lesions. With disease progression, papules, nodules, and plaques develop over the macular lesions.

In untreated patients, new ill-defined skin lesions continue to develop.

Widespread but asymmetrical thickening of peripheral nerves, with or

without tenderness, leads to sensory and motor deficits. The lepromin

test gives negative results, as it does in all degrees of lepromatous leprosy. Slit-skin smear examination of lesions shows a bacteriologic index

varying from 3+ to 4+.

Lepromatous (LL) Leprosy LL leprosy (Fig. 179-6) presents

with innumerable bilateral, symmetrically distributed, diffusely

indurated, erythematous, copper-colored or skin-colored patches or

plaques. There is no loss of sensation over these lesions, which have

a smooth, shiny surface. The lesions spread over the face, earlobes,

ears, extensor aspects of the upper and lower extremities, back, and

buttocks. Induration can readily be recognized when lesions are viewed

tangentially under natural sunlight. The induration initially is of a

finer type but gradually becomes coarse, and lesions then progress to

papules, plaques, and nodules. Bilateral earlobe thickening and eyebrow loss occur. Coarse induration on the face sometimes results in

gross skin folds that lead to an appearance referred to as “lion face,”

particularly when associated with loss of eyebrows and thickening of

earlobes. Of all cases of LL leprosy, 10–15% are of the polar type (LLp)

from the time of lesion onset; the remaining cases downgrade from

the untreated borderline spectrum to subpolar LLs leprosy. Patients

with LLs disease develop nerve damage during the borderline stages.

In LLp disease, involvement of peripheral nerves occurs late and is

bilateral and symmetrical, with sensory loss in a “glove-and-stocking”

distribution. Slit-skin smear examination shows a bacteriologic index

of 4+ to 6+ with globi.

SYSTEMIC INVOLVEMENT In LL leprosy, AFB are found in the lymph

nodes, spleen, liver, bone marrow, adrenal glands, smooth and striated

muscles, tooth pulp, testes, oral cavity, nose, larynx, and eyes. Involvement of the testes leads first to sterility and then to gynecomastia and

impotence. Eye involvement includes corneal anesthesia; early on, this

manifestation is due to bacillary infiltration of corneal nerves, while

later it arises from damage to the ophthalmic division of the trigeminal

nerve. In addition, eye involvement includes episcleritis, iridocyclitis,

iris atrophy, cataract and glaucoma, lagophthalmos, corneal ulceration

and perforation, and blindness. The nose is the portal of entry for

M. leprae and is the earliest site of involvement in LL leprosy. Edema

and mucosal thickening occur in the inferior turbinate and nasal

septum, with crusting and epistaxis. Later, patients develop chronic

rhinitis with loss of smell sensation. Septal perforation due to bony

destruction, with typical saddle-nose disfigurement, is common in

advanced LL disease. In late-stage LL leprosy, ulceration of the tongue,

pharynx, hard and soft palates (leading to palate perforation), tonsillar

pillars, and uvula occurs. In the hands, slow resorption sets in, starting

from the distal end of the terminal phalanx and proceeding proximally

to involve the middle and proximal phalanges.

HISTOID LEPROSY Histoid leprosy is a rare form of LL leprosy in which

waxy, shiny, firm, symmetrical or asymmetrical nodules and plaques

are observed over normal-looking skin. Histologic examination of

these lesions shows specific spindle-cell granulomas. Slit-skin smear

examination reveals high bacteriologic and microbiologic indices without globi in most cases.