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 dedi-
cated programs and even the health sector is now essential. Therefore,
the new “End TB” strategy promoted by WHO since 2016 builds on
three pillars and relies on increased investments and efforts by all gov-
ernments, 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) intensi-
fied research and innovation. The first pillar incorporates all techno-
logical 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 highest-level 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 pov-
erty 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 implementation and rapid adop-
tion 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, diabe-
tes) 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
Falzon D et al: World Health Organization treatment guidelines for
drug-resistant tuberculosis, 2016 update. Eur Respir J 49:1602308,
2017.
Getahun H et al: Latent Mycobacterium tuberculosis infection. N Engl J
Med 372:2127, 2015.
Nahid P et al: Official American Thoracic Society/Centers for Dis-
ease 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.
Tameris MD et al: Safety and efficacy of MVA85A, a new tuberculosis
vaccine, in infants previously vaccinated with BCG: A randomized,
placebo-controlled phase 2b trial. Lancet 381:1021, 2013.
Uplekar M et al: WHO’s new end TB strategy. Lancet 385:1799, 2015.
■■WEBSITES
World Health Organization: Guidance for national tuberculo-
sis programmes on the management of tuberculosis in children.
2nd ed. Geneva, WHO, 2014. Available from http://www.who.int/tb
/publications/childtb_guidelines/en/. Accessed December 12, 2017.
World Health Organization: Global tuberculosis report 2017.
Geneva, WHO, 2017. Available from http://www.who.int/tb/publications
/global_report/en/. Accessed December 12, 2017.
World Health Organization: Treatment of tuberculosis. Guidelines
for treatment of drug-susceptible tuberculosis and patient care.
2017 update. Geneva, WHO, 2017. Available from http://apps.who.int
/iris/bitstream/10665/255052/1/9789241550000-eng.pdf?ua=1. Accessed
December 12, 2017.
Harrisons_20e_Part5_p0859-p1648.indd 1259
1259
174 Leprosy
Robert H. Gelber
Leprosy, first described in ancient Indian texts from the sixth century
b.c., is a nonfatal, chronic infectious disease caused by Mycobacterium
leprae, the clinical manifestations of which are largely confined to the
skin, peripheral nervous system, upper respiratory tract, eyes, and
testes. The unique tropism of M. leprae for peripheral nerves (from
large nerve trunks to microscopic dermal nerves) and certain immuno-
logically mediated reactional states are the major causes of morbidity
in leprosy. The propensity of the disease, when untreated, to result in
characteristic deformities and the recognition in most cultures that the
disease is communicable from person to person have resulted histori-
cally in a profound social stigma. Today, with early diagnosis and the
institution of appropriate and effective antimicrobial therapy, patients
can lead productive lives in the community, and deformities and other
visible manifestations can largely be prevented.
■■ETIOLOGY
M. leprae is an obligate intracellular bacillus (0.3–1 μm wide and
1–8 μm long) that is confined to humans, armadillos in certain locales,
and sphagnum moss. The organism is acid-fast, indistinguishable
microscopically from other mycobacteria, and ideally detected in
tissue sections by a modified Fite stain. Strain variability has been doc-
umented in this organism. M. leprae produces no known toxins and is
CHAPTER 174 Leprosy
well adapted to penetrate and reside within macrophages, yet it may
survive outside the body for months. In untreated patients, only ~1%
of M. leprae organisms are viable. The morphologic index (MI), a mea-
sure of the number of acid-fast bacilli (AFB) in skin scrapings that stain
uniformly bright, correlates with viability. The bacteriologic index (BI),
a logarithmic-scaled measure of the density of M. leprae in the dermis,
may be as high as 4–6+ in untreated patients and falls by 1 unit per
year during effective antimicrobial therapy; the rate of decrease is inde-
pendent of the relative potency of therapy. A rising MI or BI suggests
relapse and perhaps—if the patient is being treated—drug resistance.
Drug resistance can be confirmed or excluded in the mouse model of
leprosy, and resistance to dapsone and rifampin can be documented
by the recognition of mutant genes. However, the availability of these
technologies is extremely limited.
As a result of reductive evolution, almost half of the M. leprae
genome contains nonfunctional genes; only 1605 genes encode for
proteins, and 1439 genes are shared with Mycobacterium tuberculo-
sis. In contrast, M. tuberculosis uses 91% of its genome to encode for
4000 proteins. Among the lost genes in M. leprae are those for catabolic
and respiratory pathways; transport systems; purine, methionine, and
glutamine synthesis; and nitrogen regulation. The genome of M. leprae
provides a metabolic rationale for its obligate intracellular existence
and reliance on host biochemical support, a template for targets of drug
development, and ultimately a pathway to cultivation. The finding of
strain variability among M. leprae isolates has provided a powerful tool
with which to address anew the organism’s epidemiology and patho-
biology and to determine whether relapse represents reactivation or
reinfection. The bacterium’s complex cell wall contains large amounts
of an M. leprae–specific phenolic glycolipid (PGL-1), which is detected
in serologic tests. The unique trisaccharide of M. leprae binds to the
basal lamina of Schwann cells; this interaction is probably related to the
ability of M. leprae—unique among bacteria—to invade peripheral
nerves.
Although it was the first bacterium to be etiologically associated
with human disease, M. leprae remains one of the few bacterial species
that still has not been cultivated on artificial medium or tissue culture.
The regular multiplication of even a few M. leprae organisms in mouse
footpads (albeit limited, with a doubling time of ~2 weeks) has pro-
vided a sensitive means to evaluate antimicrobial agents, monitor clin-
ical trials, and screen vaccines. Several in vitro methods to assess the
6/1/18 12:06 PM
 1260 organisms’ viability, though promising, are many times less sensitive
than the mouse model in detecting viable M. leprae. M. leprae grows best
in cooler tissues (the skin, peripheral nerves, anterior chamber of the
eye, upper respiratory tract, and testes), sparing warmer areas of the
skin (the axilla, groin, scalp, and midline of the back).
Another distinct and recently discovered mycobacterial species,
M. lepromatosis, is genetically similar to M. leprae and evolved from a
common mycobacterial ancestor. M. lepromatosis has been identified in
tissue from a small number of leprosy patients in Mexico with diffuse
lepromatosis/Lucio’s phenomenon (see below) and in single leprosy
patients from Singapore and Canada. Of six Mexican patients studied,
four were infected with M. leprae and two with M. lepromatosis. Because
some new leprosy patients harbor both M. leprae and M. lepromatosis,
it is not entirely clear that the latter organism is, in fact, a causative
agent of leprosy. Fortunately, like M. leprae, M. lepromatosis is generally
sensitive to dapsone, rifampin, and fluoroquinolones.
■■EPIDEMIOLOGY
Demographics Leprosy is almost exclusively a disease of
the developing world, affecting areas of Asia, Africa, Latin
America, and the Pacific. While Africa has the highest disease
prevalence, Asia has the most cases. More than 80% of the world’s cases
occur in a few countries: India, China, Myanmar, Indonesia, Brazil,
Nigeria, Madagascar, and Nepal. Within endemic locales, the distribu-
tion of leprosy is quite uneven, with areas of high prevalence bordering
on areas with little or no disease. In Brazil the majority of cases occur in
the Amazon basin and two western states, while in Mexico leprosy is
mostly confined to the Pacific coast. Except as imported cases, leprosy
is largely absent from the United States, Canada, and northwestern
PART 5
Europe. In the United States, ~4000 persons have leprosy and 100–200
new cases are reported annually, most of them in California, Texas,
New York, and Hawaii among immigrants from Mexico, Southeast
Asia, the Philippines, and the Caribbean.
Infectious Diseases
The comparative genomics of single-nucleotide polymorphisms
support the likelihood that four distinct strains exist, having orig-
inated 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 global prevalence of leprosy is difficult to assess, given that
many of the locales with high prevalence lack a significant medical
or public health infrastructure. Estimates range from 0.6 to 8 million
affected individuals. The lower estimate includes only persons who
have not completed chemotherapy, excluding those who may be
TABLE 174-1 Clinical, Bacteriologic, Pathologic, and Immunologic Spectrum of Leprosy
FEATURE TUBERCULOID (TT, BT) LEPROSY
Skin lesions One or a few sharply defined annular
asymmetric macules or plaques with
a tendency toward central clearing,
elevated borders
Nerve lesions Skin lesions anesthetic early; nerve
near lesions sometimes enlarged;
nerve abscesses most common in BT
Acid-fast bacilli (BIa) 0–1+
Lymphocytes 2+
Macrophage differentiation Epithelioid
Langerhans giant cells 1–3+
Lepromin skin test +++
Lymphocyte transformation Generally positive
test
CD4+/CD8+ T cell ratio in 1.2
lesions
M. leprae PGL-1 antibodies 60%
See text.
a
Abbreviations: BB, mid-borderline; BL, borderline lepromatous; BT, borderline tuberculoid; TT, polar tuberculoid; LL, polar lepromatous; BI, bacteriologic index; NT, not
tested; PGL-1, phenolic glycolipid 1.
Harrisons_20e_Part5_p0859-p1648.indd 1260
physically or psychologically damaged from leprosy and who may
yet relapse or develop immune-mediated reactions. The higher figure
includes patients whose infections probably are already cured and
many who have no leprosy-related deformity or disability. Although
the figures on the worldwide prevalence of leprosy are debatable,
incidence is not falling; there are still an estimated 500,000 new cases
annually.
Leprosy is associated with poverty and rural residence. It appears
not to be associated with AIDS, perhaps because of leprosy’s long
incubation period. Most individuals appear to be naturally immune to
leprosy and do not develop disease manifestations after exposure. The
time of peak onset is in the second and third decades of life.
The most severe lepromatous form of leprosy is twice as common
among men as among women and is rarely encountered in chil-
dren. The frequency of the polar forms of leprosy in different
countries varies widely and may in part be genetically determined;
certain human leukocyte antigen (HLA) associations are known for
both polar forms of leprosy (see below). Furthermore, variations in
immunoregulatory genes are associated with an increased susceptibil-
ity to leprosy, particularly the multibacillary form. In India and Africa,
90% of cases are tuberculoid; in Southeast Asia, 50% are tuberculoid
and 50% lepromatous; and in Mexico, 90% are lepromatous. (For defi-
nitions of disease types, see Table 174-1 and “Clinical, Histologic, and
Immunologic Spectrum,” below.)
Transmission The route of transmission of leprosy remains uncer-
tain, and transmission routes may in fact be multiple. Nasal droplet
infection, contact with infected soil, and amoeba insect vectors have
been considered the prime candidates. Aerosolized M. leprae can cause
infection in immunosuppressed mice, and a sneeze from an untreated
lepromatous patient may contain >1010 AFB. Furthermore, both IgA anti-
body to M. leprae and genes of M. leprae—demonstrable by polymerase
chain reaction (PCR)—have been found in the nose of individuals from
endemic areas who have no signs of leprosy and in 19% of occupational
contacts of lepromatous patients. Several lines of evidence implicate
soil transmission. (1) In endemic countries such as India, leprosy is
primarily a rural and not an urban disease. (2) M. leprae products reside
in soil in endemic locales. (3) Direct dermal inoculation (e.g., during
tattooing) may transmit M. leprae, and common sites of leprosy in
children are the buttocks and thighs, suggesting that microinoculation
of infected soil may transmit the disease. Evidence for insect vectors
of leprosy includes the demonstration that bedbugs and mosquitoes
in the vicinity of leprosaria regularly harbor M. leprae and that exper-
imentally infected mosquitoes can transmit the infection to mice.
BORDERLINE (BB, BL) LEPROSY LEPROMATOUS (LL) LEPROSY
Intermediate between BT- and LL-type Symmetric, poorly marginated, multiple
lesions; ill-defined plaques with an infiltrated nodules and plaques or diffuse
occasional sharp margin; few or many infiltration; xanthoma-like or dermatofibroma
in number papules; leonine facies and eyebrow alopecia
Hypesthetic or anesthetic skin Hypesthesia a late sign; nerve palsies variable;
lesions; nerve trunk palsies, at times acral, distal, symmetric anesthesia common
symmetric
3–5+ 4–6+
1+ 0–1+
Epithelioid in BB; usually Foamy changes the rule; may be undifferentiated
undifferentiated but may have foamy in early lesions
changes in BL
— —
— —
1–10% 1–2%
BB: NT; BL: 0.48 0.50
85% 95%
6/1/18 12:06 PM
 Red squirrels from Brownsea Island, England, have recently been 1261
found to be commonly infected with a strain of M. leprae that circulated
in leprosy patients in medieval England. In addition, some red squir-
rels in England, Scotland, and Ireland have been found to be infected
with M. lepromatosis. Both of these mycobacterial species have been
found in overtly diseased red squirrels and in animals that appeared
to be well. It is unclear what role, if any, these zoonoses might play in
the propagation of human leprosy. Skin-to-skin contact generally is not
considered an important route of transmission.
In endemic countries, ~50% of leprosy patients have a history of
intimate contact with an infected person (often a household member),
while, for unknown reasons, leprosy patients in nonendemic locales
can identify such contact only 10% of the time. Moreover, household
contact with an infected lepromatous case carries an eventual risk of
disease acquisition of ~10% in endemic areas as opposed to only 1%
in nonendemic locales. Contact with a tuberculoid case carries a very
low risk. Physicians and nurses caring for leprosy patients and the
co-workers of these patients are not at risk for leprosy. FIGURE 174-1 Tuberculoid (TT) leprosy: a well-defined, hypopigmented, anesthetic
Although multilocus variable-number short-nucleotide tandem- macule with anhidrosis and a raised granular margin (arrowhead).
repeat (VNTR) analyses have generally demonstrated consider-
able variability among isolates, highly similar and even identical peripheral-nerve enlargement. Although any peripheral nerve may be
VNTR results have been obtained with isolates from a limited number enlarged (including small digital and supraclavicular nerves), those
of families with multiple cases. Moreover, VNTR results have been most commonly affected are the ulnar, posterior auricular, peroneal,
similar for isolates within certain geographic locales and divergent for and posterior tibial nerves, with associated hypesthesia and myopathy.
isolates within others. These findings suggest that genomic analyses In tuberculoid leprosy, T cells breach the perineurium, and destruc-
may prove useful in the future for defining M. leprae transmission tion of Schwann cells and axons may be evident, resulting in fibrosis of
patterns. the epineurium, replacement of the endoneurium with epithelial gran-
M. leprae causes disease primarily in humans. However, in Texas and ulomas, and occasionally caseous necrosis. Such invasion and destruc-

CHAPTER 174 Leprosy

Louisiana, 15% of nine-banded armadillos are infected, and armadillo
contact occasionally results in human disease. Armadillos develop dis-
seminated infection after IV inoculation of live M. leprae.
■■CLINICAL, HISTOLOGIC, AND IMMUNOLOGIC
SPECTRUM
The incubation period prior to manifestation of clinical disease can
vary between 2 and 40 years, although it is generally 5–7 years in
duration. This long incubation period is probably, at least in part,
a consequence of the extremely long doubling time for M. leprae
(14 days in mice versus in vitro doubling times of 1 day and 20 min for
M. tuberculosis and Escherichia coli, respectively). Leprosy presents as a
spectrum of clinical manifestations that have bacteriologic, pathologic,
and immunologic counterparts. The spectrum from polar tuberculoid
(TT) to borderline tuberculoid (BT) to mid-borderline (BB, which is
rarely encountered) to borderline lepromatous (BL) to polar lepro-
matous (LL) disease is associated with an evolution from asymmetric
localized macules and plaques to nodular and indurated symmetric
generalized skin manifestations, an increasing bacterial load, and loss
of M. leprae–specific cellular immunity (Table 174-1). Distinguishing
dermatopathologic characteristics include the number of lymphocytes,
giant cells, and AFB as well as the nature of epithelioid cell differenti-
ation. Where a patient presents on the clinical spectrum largely deter-
mines prognosis, complications, reactional states, and the intensity of
antimicrobial therapy required.
tion of nerves in the dermis by T cells are pathognomonic for leprosy.
Circulating lymphocytes from patients with tuberculoid leprosy
readily recognize M. leprae and its constituent proteins, patients have
positive lepromin skin tests (see “Diagnosis,” below), and—because
of a type 1 cytokine pattern in tuberculoid tissues—strong T cell and
macrophage activation results in a localized infection. In tuberculoid
leprosy tissue, there is a 2:1 predominance of helper CD4+ over CD8+
T lymphocytes. Tuberculoid tissues are rich in the mRNAs of the proin-
flammatory TH1 family of cytokines: interleukin 2 (IL-2), interferon γ
(IFN-γ), and IL-12; in contrast, IL-4, IL-5, and IL-10 mRNAs are scarce.
Lepromatous Leprosy Lepromatous leprosy patients present
with symmetrically distributed skin nodules (Fig. 174-2), raised
plaques, or diffuse dermal infiltration, which, when on the face, results
in leonine facies. Late manifestations include loss of eyebrows (initially
the lateral margins only) and eyelashes, pendulous earlobes, and dry
scaling skin, particularly on the feet. In LL leprosy, bacilli are numerous

Tuberculoid Leprosy At the less severe end of the spec-

trum is tuberculoid leprosy, which encompasses TT and BT
disease. In general, these forms of leprosy result in symptoms
confined to the skin and peripheral nerves. TT/BT leprosy is the most
common form encountered in India, and TT is most common in Africa,
while TT is virtually absent in Southeast Asia, where BT leprosy is
frequent.
The skin lesions of tuberculoid leprosy consist of one or a few
hypopigmented macules or plaques (Fig. 174-1) that are sharply demar-
cated and hypesthetic, often have erythematous or raised borders, and
are devoid of the normal skin organs (sweat glands and hair follicles)
and thus are dry, scaly, and anhidrotic. AFB are generally absent or few
in number. Tuberculoid leprosy patients may have asymmetric enlarge-
ment of one or a few peripheral nerves. Indeed, leprosy and certain rare
hereditary neuropathies are the only human diseases associated with FIGURE 174-2 Lepromatous (LL) leprosy: advanced nodular lesions.

Harrisons_20e_Part5_p0859-p1648.indd 1261 6/1/18 12:06 PM

 1262 in the skin (as many as 109/g), where they are often found in large
clumps (globi), and in peripheral nerves, where they initially invade
Schwann cells, resulting in foamy degenerative myelination and
axonal degeneration and later in Wallerian degeneration. In addition,
bacilli are plentiful in circulating blood and in all organ systems except
the lungs and the central nervous system. Nevertheless, patients are
afebrile, and there is no evidence of major organ system dysfunction.
Found almost exclusively in western Mexico and the
Caribbean is a form of lepromatous leprosy without visible
skin lesions but with diffuse dermal infiltration and a demon-
strably thickened dermis, termed diffuse lepromatosis.
In lepromatous leprosy, nerve enlargement and damage tend to be
symmetric, result from actual bacillary invasion, and are more insidi-
ous but ultimately more extensive than in tuberculoid leprosy. Patients
with LL leprosy have acral, distal, symmetric peripheral neuropathy
and a tendency toward symmetric nerve-trunk enlargement. They may
also have signs and symptoms related to involvement of the upper
respiratory tract, the anterior chamber of the eye, and the testes.
FIGURE 174-3 Moderately severe skin lesions of erythema nodosum leprosum,
In untreated LL patients, lymphocytes regularly fail to recognize some with pustulation and ulceration.
either M. leprae or its protein constituents, and lepromin skin tests
are negative (see “Diagnosis,” below). This loss of protective cellular
immunity appears to be antigen-specific, as patients are not unusually and increased levels of IFN-γ and IL-2. In addition, type 1 reactions
susceptible to opportunistic infections, cancer, or AIDS and maintain are associated with large numbers of T cells bearing γ/δ receptors—a
delayed-type hypersensitivity to Candida, Trichophyton, mumps virus, unique feature of leprosy.
tetanus toxoid, and even purified protein derivative of tuberculin. At TYPE 2 LEPRA REACTIONS: ERYTHEMA NODOSUM LEPROSUM Erythema
times, M. leprae–specific anergy is reversible with effective chemother- nodosum leprosum (ENL) (Fig. 174-3) occurs exclusively in patients
apy. In LL tissues, there is a 2:1 ratio of CD8+ to CD4+ T lymphocytes. near the lepromatous end of the leprosy spectrum (BL/LL), affecting
LL patients have a predominant TH2 response and hyperglobuline- nearly 50% of this group. Although ENL may precede leprosy diag-
mia, and LL tissues demonstrate a TH2 cytokine profile, being rich in
nosis and the initiation of therapy (sometimes, in fact, prompting the
PART 5

mRNAs for IL-4, IL-5, and IL-10 and poor in those for IL-2, IFN-γ, and
diagnosis), in 90% of cases it follows the institution of chemotherapy,
IL-12. It appears that cytokines mediate a protective tissue response in
generally within 2 years. The most common features of ENL are crops
leprosy, as injection of IFN-γ or IL-2 into lepromatous lesions causes
of painful erythematous papules that resolve spontaneously in a few
a loss of AFB and histopathologic conversion toward a tuberculoid
days to a week but may recur; malaise; and fever that can be pro-
pattern. Macrophages of lepromatous leprosy patients appear to be
Infectious Diseases

found. However, patients may also experience neuritis, lymphadenitis,

functionally intact; circulating monocytes exhibit normal microbicidal
function and responsiveness to IFN-γ.
Reactional States Lepra reactions comprise several common
immunologically mediated inflammatory states that cause consider-
able morbidity. Some of these reactions precede diagnosis and the insti-
tution of effective antimicrobial therapy; indeed, these reactions may
precipitate presentation for medical attention and diagnosis. Other
reactions follow the initiation of appropriate chemotherapy; these reac-
tions may cause patients to perceive that their leprosy is worsening and
to lose confidence in conventional therapy. Only by warning patients
of the potential for these reactions and describing their manifestations
can physicians treating leprosy patients ensure continued credibility.
TYPE 1 LEPRA REACTIONS (DOWNGRADING AND REVERSAL REACTIONS)
Type 1 lepra reactions occur in almost half of patients with borderline
forms of leprosy but not in patients with pure lepromatous disease.
Manifestations include classic signs of inflammation within pre-
viously involved macules, papules, and plaques and, on occasion,
the appearance of new skin lesions, neuritis, and (less commonly)
fever—generally low-grade. The nerve trunk most frequently involved
in this process is the ulnar nerve at the elbow, which may be painful
and exquisitely tender. If patients with affected nerves are not treated
promptly with glucocorticoids (see below), irreversible nerve damage
may result in as little as 24 h. The most dramatic manifestation is foot-
drop, which occurs when the peroneal nerve is involved.
When type 1 lepra reactions precede the initiation of appropriate
antimicrobial therapy, they are termed downgrading reactions, and the
case becomes histologically more lepromatous; when they occur after
the initiation of therapy, they are termed reversal reactions, and the case
becomes more tuberculoid. Reversal reactions often occur in the first
months or years after the initiation of therapy but may also develop
several years thereafter.
Edema is the most characteristic microscopic feature of type 1 lepra
lesions, whose diagnosis is primarily clinical. Reversal reactions are
typified by a TH1 cytokine profile, with an influx of CD4+ T helper cells
uveitis, orchitis, and glomerulonephritis and may develop anemia,
leukocytosis, and abnormal liver function tests (particularly increased
aminotransferase levels). Individual patients may have either a single
bout of ENL or chronic recurrent manifestations. Bouts may be either
mild or severe and generalized; in rare instances, ENL results in death.
Skin biopsy of ENL papules reveals vasculitis or panniculitis, some-
times with many lymphocytes but characteristically with polymorpho-
nuclear leukocytes as well.
Elevated levels of circulating tumor necrosis factor (TNF) have
been demonstrated in ENL; thus, TNF may play a central role in the
pathobiology of this syndrome. ENL is thought to be a consequence
of immune complex deposition, given its TH2 cytokine profile and its
high levels of IL-6 and IL-8. However, in ENL tissue, the presence of
HLA-DR framework antigen of epidermal cells—considered a marker
for a delayed-type hypersensitivity response—and evidence of higher
levels of IL-2 and IFN-γ than are usually seen in polar lepromatous
disease suggest an alternative mechanism.
LUCIO’S PHENOMENON Lucio’s phenomenon is an unusual
reaction seen exclusively in patients from the Caribbean and
Mexico who have the diffuse lepromatosis form of leproma-
tous leprosy, most often those who are untreated. Patients with this
reaction develop recurrent crops of large, sharply marginated, ulcera-
tive lesions—particularly on the lower extremities—that may be gener-
alized and, when so, are frequently fatal as a result of secondary
infection and consequent septic bacteremia. Histologically, the lesions
are characterized by ischemic necrosis of the epidermis and superficial
dermis, heavy parasitism of endothelial cells with AFB, and endothelial
proliferation and thrombus formation in the larger vessels of the
deeper dermis. Like ENL, Lucio’s phenomenon is probably mediated
by immune complexes.
Complications • THE EXTREMITIES Complications of
the extremities in leprosy patients are primarily a conse-
quence of neuropathy leading to insensitivity and myopathy.

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 Insensitivity affects fine touch, pain, and heat receptors but generally
spares position and vibration appreciation. The most commonly
affected nerve trunk is the ulnar nerve at the elbow, whose involvement
results in clawing of the fourth and fifth fingers, loss of dorsal interos-
seous musculature in the affected hand, and loss of sensation in these
distributions. Median nerve involvement in leprosy impairs thumb
opposition and grasp; radial nerve dysfunction, although rare in lep-
rosy, leads to wrist drop. Tendon transfers can restore hand function
but should not be performed until 6 months after the initiation of anti-
microbial therapy and the conclusion of episodes of acute neuritis.
Plantar ulceration, particularly at the metatarsal heads, is proba-
bly the most common complication of leprous neuropathy. Therapy
requires careful debridement; administration of appropriate antibi-
otics; avoidance of weight-bearing until ulcerations are healed, with
slowly progressive ambulation thereafter; and wearing of special shoes
to prevent recurrence.
Footdrop as a result of peroneal nerve palsy should be treated with
a simple nonmetallic brace in the shoe or with surgical correction
attained by tendon transfers. Although uncommon, Charcot’s joints,
particularly of the foot and ankle, may result from leprosy.
The loss of distal digits in leprosy is a consequence of insensitivity,
trauma, secondary infection, and—in lepromatous disease—a poorly
understood and sometimes profound osteolytic process. Conscientious
protection of the extremities during cooking and work and the early
institution of therapy have substantially reduced the frequency and
severity of distal digit loss in recent times.
THE NOSE In lepromatous leprosy, bacillary invasion of the nasal
mucosa can result in chronic nasal congestion and epistaxis. Saline
nose drops may relieve these symptoms. Long-untreated LL leprosy
may further result in destruction of the nasal cartilage, with consequent
saddle-nose deformity or anosmia (more common in the preantibiotic
era than at present). Nasal reconstructive procedures can ameliorate
significant cosmetic defects.
THE EYE Arising from cranial nerve palsies, lagophthalmos and
corneal insensitivity may complicate leprosy, resulting in trauma,
secondary infection, and (without treatment) corneal ulcerations and
opacities. For patients with these conditions, eye drops during the
day and ointments at night provide some protection from such conse-
quences. Furthermore, in LL leprosy, the anterior chamber of the eye
is invaded by bacilli, and ENL may result in uveitis, with consequent
cataracts and glaucoma. Thus leprosy is a major cause of blindness in
the developing world. Slit-lamp evaluation of LL patients often reveals
“corneal beading” that represents globi of M. leprae.
THE TESTES M. leprae invades the testes, while ENL may cause orchitis.
Thus males with lepromatous leprosy often manifest mild to severe
testicular dysfunction, with an elevation of luteinizing and follicle-
stimulating hormones, decreased testosterone, and aspermia or hypo-
spermia in 85% of LL patients but in only 25% of BL patients. LL
patients may become impotent and infertile. Impotence is sometimes
responsive to testosterone replacement.
AMYLOIDOSIS Secondary amyloidosis is a complication of LL leprosy
and ENL that is encountered infrequently in the antibiotic era. This
complication may result in abnormalities of hepatic and particularly
renal function.
NERVE ABSCESSES Patients with various forms of leprosy, but espe-
cially those with the BT form, may develop abscesses of nerves (most
commonly the ulnar), with a cellulitic appearance of adjacent skin. In
such conditions, the affected nerve is swollen and exquisitely tender.
Although glucocorticoids may reduce signs of inflammation, rapid
surgical decompression is necessary to prevent irreversible sequelae.
■■DIAGNOSIS
Leprosy most commonly presents with both characteristic skin lesions
and skin histopathology. Thus the disease should be suspected when
a patient from an endemic area has suggestive skin lesions or periph-
eral neuropathy. The diagnosis should be confirmed by histopathol-
ogy. In tuberculoid leprosy, lesional areas—preferably the advancing
Harrisons_20e_Part5_p0859-p1648.indd 1263
edge—must be biopsied because normal-appearing skin does not 1263
have pathologic features. In lepromatous leprosy, nodules, plaques,
and indurated areas are optimal biopsy sites, but biopsies of normal-
appearing skin also are generally diagnostic. Lepromatous leprosy
is associated with diffuse hyperglobulinemia, which may result in
false-positive serologic tests (e.g., Venereal Disease Research Labora-
tory, rheumatoid arthritis, and antinuclear antibody tests) and therefore
may cause diagnostic confusion. On occasion, tuberculoid lesions may
not (1) appear typical, (2) be hypesthetic, and (3) contain granulomas
(instead containing only nonspecific lymphocytic infiltrates). In such
instances, two of these three characteristics are considered sufficient for
a diagnosis. It is preferable to overdiagnose leprosy rather than to allow
a patient to remain untreated.
IgM antibodies to PGL-1 are found in 95% of patients with untreated
lepromatous leprosy; the titer decreases with effective therapy. How-
ever, in tuberculoid leprosy—the form of disease most often associ-
ated with diagnostic uncertainty because of the absence or paucity of
AFB—patients have significant antibodies to PGL-1 only 60% of the
time; moreover, in endemic locales, exposed individuals without clin-
ical leprosy may harbor antibodies to PGL-1. Thus PGL-1 serology is
of little diagnostic utility in tuberculoid leprosy. Heat-killed M. leprae
(lepromin) has been used as a skin test reagent. It generally elicits a
reaction in tuberculoid leprosy patients, may do so in individuals with-
out leprosy, and gives negative results in lepromatous leprosy patients;
consequently, it is likewise of little diagnostic value. Unfortunately,
PCR of the skin for M. leprae, although positive in LL and BL disease,
yields negative results in 50% of tuberculoid cases, again offering little
diagnostic assistance.
CHAPTER 174 Leprosy
■■DIFFERENTIAL DIAGNOSIS
Included in the differential diagnosis of lesions that resemble leprosy
are sarcoidosis, leishmaniasis, lupus vulgaris, dermatofibroma, histio-
cytoma, lymphoma, syphilis, yaws, granuloma annulare, and various
other disorders causing hypopigmentation (notably pityriasis alba,
tinea, and vitiligo). Sarcoidosis may result in perineural inflammation,
but actual granuloma formation within dermal nerves is pathogno-
monic for leprosy. In lepromatous leprosy, sputum specimens may
be loaded with AFB—a finding that can be incorrectly interpreted as
representing pulmonary tuberculosis.
TREATMENT
Leprosy
ANTIMICROBIAL THERAPY
Active Agents Established agents used to treat leprosy include
dapsone (50–100 mg/d), clofazimine (50–100 mg/d, 100 mg three
times weekly, or 300 mg monthly), and rifampin (600 mg daily or
monthly); see “Choice of Regimens,” below. Of these drugs, only
rifampin is bactericidal. The sulfones (folate antagonists), the fore-
most of which is dapsone, were the first antimicrobial agents found
to be effective for the treatment of leprosy and are still the mainstays
of therapy. With sulfone treatment, skin lesions resolve and num-
bers of viable bacilli in the skin are reduced. Although primarily
bacteriostatic, dapsone monotherapy results in a resistance-related
relapse rate of only 2.5%. When dapsone monotherapy was discon-
tinued in lepromatous patients treated for ≥18 years who had been
smear-negative for several years, relapses began to occur in the
first year after cessation and occurred in ~1% annually thereafter
during the next nine years (total, 10%). Dapsone is generally safe
and inexpensive. Individuals with glucose-6-phosphate dehydroge-
nase deficiency who are treated with dapsone may develop severe
hemolysis; those without this deficiency also have reduced red cell
survival and a hemoglobin decrease averaging 1 g/dL. Dapsone’s
usefulness is limited occasionally by allergic dermatitis and rarely
by the sulfone syndrome (including high fever, anemia, exfoliative
dermatitis, and a mononucleosis-type blood picture). When rifam-
pin has been included in finite regimens to treat multibacillary
6/1/18 12:06 PM
 1264 leprosy (including World Health Organization [WHO] multidrug
therapy), several studies have documented double-digit relapse
rates, particularly frequently in patients with a high BI. Relapses fol-
lowing the discontinuation of rifampin-containing regimens (unlike
those following the discontinuation of dapsone monotherapy)
generally begin only after 6 years and most commonly occur after
>10 years. It must be remembered that rifampin induces microso-
mal enzymes, necessitating increased doses of medications such
as glucocorticoids and oral birth control regimens. Clofazimine is
often cosmetically unacceptable to light-skinned leprosy patients
because it causes a red-black skin discoloration that accumulates,
particularly in lesional areas, and makes the patient’s diagnosis
obvious to members of the community.
Other antimicrobial agents active against M. leprae in animal
models and at the usual daily doses used in clinical trials include
ethionamide/prothionamide; the aminoglycosides streptomycin,
kanamycin, and amikacin (but not gentamicin or tobramycin); mino-
cycline; clarithromycin; and several fluoroquinolones, particularly
ofloxacin and moxifloxacin. After rifampin, the most bactericidal
agents against M. leprae in mice and patients appear to be minocy-
cline, clarithromycin, and ofloxacin, but these drugs have not been
used extensively in leprosy control programs. Most recently, rifap-
entine and moxifloxacin have been found to be especially potent
against M. leprae in mice. In a clinical trial in lepromatous leprosy,
moxifloxacin was profoundly bactericidal, matched in potency only
by rifampin.
Choice of Regimens Antimicrobial therapy for leprosy should be
individualized, depending on the clinical/pathologic form of the
disease encountered. Tuberculoid leprosy, which is associated with
PART 5
a low bacterial burden and a protective cellular immune response,
is the easiest form to treat and can be cured reliably with a finite
course of chemotherapy. In contrast, lepromatous leprosy may have
a higher bacillary load than any other human bacterial disease,
and the absence of a salutary T cell repertoire requires prolonged
Infectious Diseases
or even lifelong chemotherapy. Therefore, careful classification of
disease prior to therapy is important.
A reasoned approach to the treatment of leprosy is confounded
by several issues:
1. Even without therapy, TT leprosy may heal spontaneously, and
dapsone monotherapy is generally curative.
2. In tuberculoid disease, it is common for no bacilli to be found
in the skin prior to therapy. Thus there is no objective measure
of therapeutic success. Furthermore, despite adequate treat-
ment, TT and particularly BT lesions often resolve minimally or
incompletely, while relapse and late type 1 lepra reactions can
be difficult to distinguish.
3. LL leprosy patients commonly harbor viable M. leprae “persis-
ters” that are the source of relapse if therapy is discontinued.
Because leprosy may relapse many years after cessation of
antibiotic therapy, prolonged follow-up after completion of
treatment is recommended in order to prevent further disability
and deformity.
4. Even though primary dapsone resistance is exceedingly rare
and multidrug therapy is generally recommended (at least for
lepromatous leprosy), there is a paucity of information from
experimental animals and clinical trials on the optimal combi-
nation of antimicrobial agents, dosing schedule, and duration
of therapy.
In 1982, the WHO made recommendations for leprosy chemo-
therapy administered in control programs. These recommendations
recognized the limited resources available for leprosy care in the
very areas where it is most prevalent and the frustration and dis-
couragement of patients and program managers with the previous
requirement for lifelong therapy for many leprosy patients. Thus,
for the first time, and without supporting clinical-trial evidence
(particularly data on long-term relapse frequency), the WHO advo-
cated a finite duration of therapy for all forms of leprosy and—given
Harrisons_20e_Part5_p0859-p1648.indd 1264
the prohibitive cost of daily rifampin treatment in developing
countries—encouraged the monthly administration of this agent
as part of a multidrug regimen. The WHO treatment regimens
were specifically meant for control programs where implementa-
tion of a finite regimen for all forms of leprosy would substantially
decrease the operational burden of leprosy care; these regimens
were not claimed to be optimal in locales where more considerable
resources are available. Over the ensuing years, however, the WHO
recommendations have been broadly implemented worldwide. For
treatment purposes, the WHO originally classified patients with
few bacteria in the dermis (BI <2) as paucibacillary and those with
many bacteria (BI >2) as multibacillary. The WHO recommended
that paucibacillary leprosy in adults be treated with 100 mg of
dapsone daily and 600 mg of rifampin monthly (supervised) for
6 months (Table 174-2). As an alternative for patients with single-
lesion paucibacillary leprosy, the WHO recommended a single dose
of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg).
The recommendation for multibacillary leprosy in adults was 100
mg of dapsone plus 50 mg of clofazimine daily (unsupervised)
and with 600 mg of rifampin plus 300 mg of clofazimine monthly
(supervised). Originally, the WHO recommended that lepromatous
patients be treated for 2 years or until smears became negative (gen-
erally in ~5 years). In subsequent years, the WHO mandated several
modifications to their original multidrug-treatment recommenda-
tion, primarily related to leprosy classification criteria and treatment
duration (see “The Leprosy Elimination Campaign: Modifications of
the Multidrug Regimen and Their Consequences,” below).
Several factors have caused many authorities to question the
WHO recommendations and to favor a more intensive approach.
Among these factors are—for multibacillary patients—a high
(double-digit) relapse rate in several locales (reaching 20–40% in one
locale, with the rate directly related to the initial bacterial burden)
and—for paucibacillary patients—demonstrable lesional activity for
years in fully half of patients after the completion of therapy. The
more intensive approach (Table 174-2) calls for tuberculoid leprosy
to be treated with dapsone (100 mg/d) for 5 years and for leproma-
tous leprosy to be treated with rifampin (600 mg/d) for 3 years and
with dapsone (100 mg/d) throughout life.
With effective antimicrobial therapy, new skin lesions as well
as signs and symptoms of peripheral neuropathy cease appearing.
Nodules and plaques of lepromatous leprosy noticeably flatten in
1–2 months and resolve in one or a few years, while tuberculoid skin
lesions may disappear, ameliorate, or remain relatively unchanged.
Although the peripheral neuropathy of leprosy may improve some-
what in the first few months of therapy, rarely is it significantly
alleviated by treatment.
Although two of the three recommended drugs (dapsone and
clofazimine) are only bacteriostatic against M. leprae, and although
bactericidal agents have been identified since the WHO formulated
its recommendations, significant studies employing the available
alternatives in newly designed regimens have not been initiated.
TABLE 174-2 Antimicrobial Regimens Recommended for the
Treatment of Leprosy in Adults
MORE INTENSIVE WHO-RECOMMENDED
FORM OF LEPROSY REGIMEN REGIMEN (1982)
Tuberculoid Dapsone (100 mg/d) for Dapsone (100 mg/d,
(paucibacillary) 5 years unsupervised) plus
rifampin (600 mg/month,
supervised) for 6 months
Lepromatous Rifampin (600 mg/d) for Dapsone (100 mg/d) plus
(multibacillary) 3 years plus dapsone clofazimine (50 mg/d),
(100 mg/d) indefinitely unsupervised; and rifampin
(600 mg) plus clofazimine
(300 mg) monthly
(supervised) for 1–2 years
Note: See text for discussion and comparison of the WHO recommendations with
the more intensive approach as well as the alternative WHO regimen for single-
lesion paucibacillary leprosy.
6/1/18 12:06 PM
 Given that moxifloxacin, like rifampin, is profoundly bactericidal in
leprosy patients and that short-course chemotherapy for tuberculo-
sis is possible only when two or more bactericidal agents are used,
a moxifloxacin/rifamycin-based regimen including either minocy-
cline or clarithromycin (each more potent than either dapsone or
clofazimine) appears promising; such a regimen may prove to be
more reliably curative than WHO-recommended multidrug ther-
apy for lepromatous leprosy and may allow a considerably shorter
course of treatment.
THE LEPROSY ELIMINATION CAMPAIGN: MODIFICATIONS OF
THE MULTIDRUG REGIMEN AND THEIR CONSEQUENCES
The World Health Assembly resolution of 1991 proposed to “elimi-
nate leprosy as a public health problem” in all countries by the year
2000, with success defined as <1 in 10,000 persons with leprosy not
having completed a course of multidrug therapy. When leprosy
elimination appeared not to be occurring in that time frame, several
changes were made to WHO multidrug therapy recommenda-
tions to simplify leprosy diagnosis and treatment, ease operational
requirements for control programs, and facilitate attainment of the
elimination target:
1. The duration of treatment of multibacillary leprosy was reduced
from 2 years to 1 year in 1995 and to only 6 months in 2002. Nei-
ther duration was supported by prior clinical trials, and neither
has been demonstrated in trials with prolonged follow-up to
provide a reliable cure. However, this reduction in duration of
therapy for multibacillary leprosy had the effect of reducing for
elimination purposes the number of multibacillary cases by a
factor of four.
2. The recommendation for multibacillary treatment was first
changed to mandate therapy for any patient whose skin smear
was positive. By 1995, skin biopsies and even skin smears were
no longer advocated for leprosy diagnosis and classification.
For treatment purposes, classification henceforth was to be
determined on clinical grounds alone: more than five anesthetic
skin lesions or enlarged nerves were to be considered multi-
bacillary and fewer lesions paucibacillary. Unfortunately, such
classification often led to under-treatment for some patients
and over-treatment for others. Although leprosy often can be
diagnosed on clinical grounds alone, it is not infrequently con-
fused with other dermatologic disorders, and the diagnosis not
uncommonly remains uncertain even for seasoned leprologists.
Skin smears and biopsies often clarify a leprosy diagnosis and
earmark those patients most prone to relapse after the comple-
tion of therapy. With these diagnostic tests abandoned, leprosy
diagnosis has been profoundly compromised.
3. The WHO advocated the integration of leprosy into national gen-
eral health services. In most countries where leprosy is endemic,
those services are already overburdened, and the prospects that
their leprosy patients will receive optimal care is most unlikely.
Unfortunately, in endemic countries, medical education often
ignores leprosy. Therefore, in general health services, a leprosy
diagnosis is frequently delayed or missed, and a rise in leprosy
disability and deformity has consequently been encountered
worldwide.
4. The WHO now promotes “accompanied multidrug therapy,”
which allows a newly diagnosed patient—if accompanied by
a companion who will offer assistance and encourage drug
compliance—to receive the full complement of the leprosy regi-
men at the time of diagnosis; thereafter, the patient is no longer
counted as a case and often is no longer entitled to receive further
leprosy services. Accompanied multidrug treatment entirely elim-
inated directly observed therapy—a cornerstone of effective treat-
ment for tuberculosis—from the leprosy treatment regimen. Like
that for all chronic diseases, including tuberculosis, compliance
with leprosy treatment has proved consistently unreliable. Com-
pliance was previously ameliorated to some extent by the directly
observed monthly component of the WHO leprosy regimen.
Harrisons_20e_Part5_p0859-p1648.indd 1265
5. The WHO now encourages “uniform multidrug therapy,” 1265
whereby all leprosy patients receive the same 6 months of treat-
ment previously reserved for multibacillary cases. This treatment
duration for multibacillary cases (or an even longer duration)
has not proved reliable in preventing relapse. Moreover, patients
whose cases were previously classified as paucibacillary receive
clofazimine—a drug whose use is not necessary and is often
cosmetically and psychosocially unacceptable, marking patients
with a leprosy diagnosis.
6. Since 1995, the WHO went on record as not advocating for
patient follow-up after completion of multidrug treatment.
Thus, relapse is assuredly underreported, and its impact is not
appreciated.
7. A by-product of the elimination campaign and the public per-
ception that leprosy elimination is at hand is the substantial
diminution of funding for both patient care and research. An
older generation of leprologists is retiring, specialized leprosy
facilities are disappearing, and recruitment of professionals for
careers as leprosy clinicians and researchers has been substan-
tially reduced. As a consequence, leprosy research has been
largely abandoned. In particular, though there are real prospects
for improving chemotherapy for leprosy and evaluating new
antimicrobial agents both in mice and in clinical trials, almost no
such efforts have commenced in the past decade. Furthermore,
the mouse footpad laboratories required for such work world-
wide are few and lack the capacity to monitor those efforts.
THERAPY FOR REACTIONS
CHAPTER 174 Leprosy
Type 1 Type 1 lepra reactions are best treated with glucocorticoids
(e.g., prednisone, initially at doses of 40–60 mg/d). As inflamma-
tion subsides, the glucocorticoid dose can be tapered, but steroid
therapy must be continued for at least 3–6 months lest recurrence
supervene. Because of the myriad toxicities of prolonged glucocor-
ticoid therapy, the indications for its initiation are strictly limited
to lesions whose intense inflammation poses a threat of ulceration;
lesions at cosmetically important sites, such as the face; and cases
in which neuritis is present. Mild to moderate lepra reactions that
do not meet these criteria should be tolerated, with glucocorticoid
treatment withheld. Thalidomide is ineffective against type 1 lepra
reactions. Clofazimine (200–300 mg/d) is of questionable benefit
but in any event is far less efficacious than glucocorticoids.
Type 2 Treatment of ENL must be individualized. If ENL is mild
(i.e., if it occurs without fever or other organ involvement and with
occasional crops of only a few skin papules), it may be treated with
antipyretics alone. However, in cases with many skin lesions, fever,
malaise, and other tissue involvement, brief courses (1–2 weeks)
of glucocorticoid treatment (initially 40–60 mg/d) are often effec-
tive. With or without therapy, individual inflamed papules last for
<1 week. Successful therapy is defined by the cessation of skin
lesion development and the disappearance of other systemic signs
and symptoms. If, despite two courses of glucocorticoid therapy,
ENL appears to be recurring and persisting, treatment with tha-
lidomide (100–300 mg nightly) should be initiated, with the dose
depending on the initial severity of the reaction. Because even a sin-
gle dose of thalidomide administered early in pregnancy may result
in severe birth defects, including phocomelia, the use of this drug in
the United States for the treatment of fertile female patients is tightly
regulated and requires informed consent, prior pregnancy testing,
and maintenance of birth control measures. Although the mecha-
nism of thalidomide’s dramatic action against ENL is not entirely
clear, the drug’s efficacy is probably attributable to its reduction
of TNF levels and IgM synthesis and its slowing of polymorpho-
nuclear leukocyte migration. After the reaction is controlled, lower
doses of thalidomide (50–200 mg nightly) are effective in preventing
relapses of ENL. Clofazimine in high doses (300 mg nightly) has
some efficacy against ENL, but its use permits only a modest reduc-
tion of the glucocorticoid dose necessary for ENL control.
6/1/18 12:06 PM
 1266 Lucio’s Phenomenon Neither glucocorticoids nor thalidomide is
effective against this syndrome. Optimal wound care and therapy
for bacteremia are indicated. Ulcers tend to be chronic and heal
poorly. In severe cases, exchange transfusion may prove useful.
■■PREVENTION AND CONTROL
Multidrug Treatment and Leprosy Elimination Between
2000 and 2006, the worldwide annual case-detection rate of leprosy fell
from 700,000 to 280,000. Because India alone was estimated to carry
60% of the world’s leprosy burden and was slow to reach the elimina-
tion goal, additional operational policies were instituted:
1. Single-lesion leprosy, which accounts for one-third of leprosy cases
in India, was no longer classified as leprosy at all.
2. A case of leprosy was no longer counted if diagnosed by the treating
physician but not verified (as required) by program managers at
the district or state level—individuals who were under pressure to
produce improved statistics.
3. Active case finding, which had been extensive and successful in
India, was discouraged. Because of the stigma of leprosy, self-
reporting often does not occur.
In India between 2000 and 2006, the annual leprosy case-detection
rate fell from 560,000 to 140,000, and “elimination” was achieved in
2004. However, since the incubation period of leprosy in the large
majority of cases is 5–7 years or longer, and since most new cases
reported in 2006 were already incubating in 2000, the claim of a
dramatic fall in the incidence of leprosy—and, as a consequence, of
multidrug therapy—both in India and worldwide is epidemiologi-
PART 5
cally unreasonable. Rather, millions of cases were undiagnosed and
untreated, while new leprosy cases, disability, and deformity have been
documented to be on the rise.
Vaccination Vaccination at birth with bacille Calmette-Guérin
Infectious Diseases
(BCG) has proved variably effective in preventing leprosy: the results
have ranged from total inefficacy to 80% efficacy. The addition of
heat-killed M. leprae to BCG does not increase the effectiveness of the
vaccine. Because whole mycobacteria contain large amounts of lipids
and carbohydrates that have proved in vitro to be immunosuppressive
for lymphocytes and macrophages, M. leprae proteins may prove to be
superior vaccines. Data from a mouse model support this possibility.
Chemoprophylaxis Chemoprophylaxis with dapsone may
reduce the number of tuberculoid leprosy cases but not the number
of lepromatous cases and therefore is not recommended, even for
household contacts. In addition, single-dose rifampin prophylaxis is of
doubtful efficacy.
Isolation Because leprosy transmission appears to require close
prolonged household contact, hospitalized patients need not be
isolated.
■■LEPROSY: THE PRESENT SITUATION
During most of the twentieth century, nongovernmental organizations,
particularly Christian missionaries, provided a medical infrastructure
devoted to the care and treatment of leprosy patients—the envy of
those with other medical priorities in the developing world. With the
public perception that leprosy is near eradication, resources for patient
care are rapidly being diverted, and the burden of patient care is being
transferred to nonexistent or overloaded national health services and
to health workers who lack the tools and skills needed for the disease’s
diagnosis and classification and for the selection of nuanced therapy
(particularly in cases of reactional neuritis). Furthermore, after the com-
pletion of therapy, when a patient is no longer considered to represent a
case, half of all patients continue to manifest disease activity for years;
relapse rates (at least for multibacillary patients) are unacceptably
high; disabilities and deformities go unchecked; and the social stigma
of the disease persists. Thus the prerequisites for a salutary outcome
increasingly go unmet.
Harrisons_20e_Part5_p0859-p1648.indd 1266
■■FURTHER READING
Gelber RH et al: The relapse rate in MB leprosy patients treated with
2-years of WHO-MDT is not low. Int J Lepr Other Mycobact Dis
72:493, 2004.
Gelber RH, Grosset J: The chemotherapy of leprosy: An interpretive
history. Lepr Rev 83:221, 2012.
Pardillo FE et al: Powerful bactericidal activity of moxifloxacin in
human leprosy. Antimicrob Agents Chemother 52:3113, 2008.
Ridley DS, Jopling WH: Classification of leprosy according to immu-
nity. A five-group system. Int J Lepr Other Mycobact Dis 34:255, 1964.
Smith WC et al: The missing millions: A threat to the elimination of
leprosy. PLoS Negl Trop Dis 9:e0003658, 2015.
175 Nontuberculous
Mycobacterial Infections
Steven M. Holland
Several terms—nontuberculous mycobacteria (NTM), atypical myco-
bacteria, mycobacteria other than tuberculosis, and environmental
mycobacteria—all refer to mycobacteria other than Mycobacterium tuber-
culosis, its close relatives (M. bovis, M. caprae, M. africanum, M. pinnipedii,
M. canetti), and M. leprae. The number of identified species of NTM is
growing and will continue to do so because of the use of DNA sequence
typing for speciation. The number of known species currently exceeds
170. NTM are highly adaptable and can inhabit hostile environments,
including industrial solvents.
■■EPIDEMIOLOGY
NTM are ubiquitous in soil and water. Specific organisms have
recurring niches, such as M. simiae in certain aquifers, M. fortuitum
in pedicure baths, and M. immunogenum in metalworking fluids.
Most NTM cause disease in humans only rarely unless some aspect
of host defense is impaired, as in bronchiectasis, or breached, as by
inoculation (e.g., liposuction, trauma, cardiac surgery). There are few
instances of human-to-human transmission of NTM, which occurs
almost exclusively in cystic fibrosis. Because infections due to NTM are
rarely reported to health agencies and because their identification is
sometimes problematic, reliable data on incidence and prevalence are
lacking. Disseminated disease denotes significant immune dysfunction
(e.g., advanced HIV infection), whereas pulmonary disease, which is
much more common, is highly associated with pulmonary epithelial
defects but not with systemic immunodeficiency.
In the United States, the incidence and prevalence of pulmo-
nary infection with NTM, mostly in association with bronchiectasis
(Chap. 284), have for many years been several-fold higher than the
corresponding figures for tuberculosis, and rates of the former are
increasing among the elderly as rates of tuberculosis continue to fall.
Among patients with cystic fibrosis, who often have bronchiectasis,
rates of clinical infection with NTM range from 3 to 15%, with even
higher rates among older patients. Although NTM may be recovered
from the sputa of many individuals, it is critical to differentiate active
disease from commensal harboring of the organisms. A scheme to help
with the proper diagnosis of pulmonary infection caused by NTM has
been developed by the American Thoracic Society and is widely used.
The bulk of nontuberculous mycobacterial disease in North America
is due to M. kansasii, organisms of the M. avium complex (MAC), and
M. abscessus.
In Europe, Asia, and Australia, the distribution of NTM in
clinical specimens is roughly similar to that in North America,
with MAC species and rapidly growing organisms such as
M. abscessus encountered frequently. M. xenopi and M. malmoense are
especially prominent in northern Europe. M. ulcerans causes the
6/1/18 12:06 PM
 distinct clinical entity Buruli ulcer, which occurs throughout tropical
zones, especially in western Africa. M. marinum is a common cause of
cutaneous and tendon infections in coastal regions and among individ-
uals exposed to fish tanks or swimming pools.
The true international epidemiology of infections due to NTM is
hard to determine because the isolation of these organisms often is not
reported and speciation often is not performed for M. tuberculosis or
NTM. The latter issue poses an especially important problem during
therapy for tuberculosis when smears positive for acid-fast bacilli are
considered evidence of treatment failure. The increasing ease of iden-
tification and speciation of these organisms is already having a major
impact on the description of the dynamic international epidemiology
of tuberculosis and NTM infections.
■■PATHOBIOLOGY
Because exposure to NTM is essentially universal and disease is rare,
it can be assumed that normal host defenses against these organisms
must be strong and that otherwise healthy individuals in whom signifi-
cant disease develops are highly likely to have specific susceptibility fac-
tors that permit NTM to become established, multiply, and cause disease.
At the advent of HIV infection, CD4+ T lymphocytes were recognized as
key effector cells against NTM; the development of disseminated MAC
disease was highly correlated with a decline in CD4+ T lymphocyte
numbers. Such a decrease has also been implicated in disseminated
MAC infection in patients with idiopathic CD4+ T lymphocytopenia.
Potent inhibitors of tumor necrosis factor α (TNF-α), such as infliximab,
adalimumab, certolizumab, golimumab, and etanercept, neutralize this
critical cytokine, with consequent inhibition of granuloma formation.
The occasional result is severe mycobacterial or fungal infection; these
associations indicate that TNF-α is a crucial element in mycobacterial
control. However, in cases without the above risk factors, much of the
genetic basis of susceptibility to disseminated infection with NTM
is accounted for by specific mutations in the interferon γ (IFN-γ)/
interleukin 12 (IL-12) synthesis and response pathways.
Mycobacteria are typically phagocytosed by macrophages, which
respond with the production of IL-12, a heterodimer composed of
IL-12p35 and IL-12p40 moieties that together make up IL-12p70.
IL-12 activates T lymphocytes and natural killer cells through binding to
its receptor (composed of IL-12Rβ1 and IL-12Rβ2/IL-23R), with conse-
quent phosphorylation of STAT4. IL-12 stimulation of STAT4 leads to
secretion of IFN-γ, which activates neutrophils and macrophages to
produce reactive oxidants, to increase expression of the major histocom-
patibility complex and Fc receptors, and to concentrate certain antibiot-
ics intracellularly. Signaling by IFN-γ through its receptor (composed of
IFN-γR1 and IFN-γR2) leads to phosphorylation of STAT1, which in turn
regulates IFN-γ-responsive genes, such as those coding for IL-12 and
TNF-α. TNF-α signals through its own receptor via a downstream com-
plex containing the nuclear factor κB (NF-κB) essential modulator
(NEMO). Therefore, the positive feedback loop between IFN-γ and
IL-12/IL-23 drives the immune response to mycobacteria and other
intracellular infections. These genes are known to be the critical ones in
the pathway of mycobacterial control: specific Mendelian mutations
have been identified in IFNGR1, IFNGR2, STAT1, GATA2, ISG15, IRF8,
IL-12A, IL-12RB1, IL-12RB2, CYBB (which encodes the gp91phox protein of
the NADPH oxidase), and IKBKG (which encodes NEMO) (Fig. 175-1).
Despite the identification of genes associated with disseminated dis-
ease, only ~70% of cases of disseminated nontuberculous mycobacterial
infections that are not associated with HIV infection have a genetic
diagnosis; the implication is that more mycobacterial susceptibility
genes and pathways remain to be identified.
In contrast to the recognized genes and mechanisms associated
with disseminated nontuberculous mycobacterial infection, the best-
recognized underlying condition for pulmonary infection with NTM
is bronchiectasis (Chap. 284). Most of the well-characterized forms of
bronchiectasis, including cystic fibrosis, primary ciliary dyskinesia,
STAT3-deficient hyper-IgE syndrome, and idiopathic bronchiectasis,
have high rates of association with nontuberculous mycobacterial
infection. The precise mechanism by which bronchiectasis predisposes
to locally destructive but not systemic involvement is unknown.
Harrisons_20e_Part5_p0859-p1648.indd 1267
IL-2
IL-2R
1267
T/NK IFNγ
β1
IL-12R
β2
IL-18 ?
IL-15
IFNγR
STAT1
GATA2 1 2
IL-12 ISG15 IRF8
AFB NEMO
Salm. TNFα
NRAMP1
MΦ TNFαR
TLR
CD14 LPS
FIGURE 175-1 Cytokine interactions of infected macrophages (MF) with T
and natural killer (NK) lymphocytes. Infection of macrophages by mycobacteria
(AFB) leads to the release of heterodimeric interleukin 12 (IL-12). IL-12 acts on
its receptor complex (IL-12R), with consequent STAT4 activation and production of
homodimeric interferon γ (IFNγ). Through its receptor (IFNγR), IFNγ activates STAT1,
stimulating the production of tumor necrosis factor α (TNFα) and leading to the
killing of intracellular organisms such as mycobacteria, salmonellae (Salm.), and
some fungi. Homotrimeric TNFα acts through its receptor (TNFαR) and requires
nuclear factor κB essential modulator (NEMO) to activate nuclear factor κB, which
also contributes to the killing of intracellular bacteria. Both IFNγ and TNFα lead
to upregulation of IL-12. TNFα-blocking antibodies work either by blocking the
CHAPTER 175 Nontuberculous Mycobacterial Infections
ligand (infliximab, adalimumab, certolizumab, golimumab) or by providing soluble
receptor (etanercept). Mutations in IFNGR1, IFNGR2, IL12B, IL12RB1, IL12RB2,
STAT1, GATA2, ISG15, IRF8, CYBB, and IKBKG (NEMO) have been associated with
predisposition to mycobacterial infections. Other cytokines, such as IL-15 and
IL-18, also contribute to IFNγ production. Signaling through the Toll-like receptor
(TLR) complex and CD14 also upregulates TNFα production. IRF8, interferon
regulatory factor 8; ISG15, interferon-stimulated gene 15; LPS, lipopolysaccharide;
NRAMP1, natural resistance-associated macrophage protein 1.
Unlike disseminated or pulmonary infection, “hot-tub lung” rep-
resents pulmonary hypersensitivity to NTM—most commonly MAC
organisms—growing in underchlorinated water, often in indoor hot
tubs.
■■CLINICAL MANIFESTATIONS
Disseminated Disease Disseminated MAC or M. kansasii infec-
tions in patients with advanced HIV infection are now uncommon
in North America because of effective antimycobacterial prophylaxis
and improved treatment of HIV infection. When such mycobacterial
disease was common, the portal of entry was the bowel, with spread
to bone marrow and the bloodstream. Surprisingly, disseminated infec-
tions with rapidly growing NTM (e.g., M. abscessus, M. fortuitum) are
very rare in HIV-infected patients, even in those with advanced HIV
infection. Because these organisms are of low intrinsic virulence and
disseminate only in conjunction with impaired immunity, disseminated
disease can be indolent and progressive over weeks to months. Typical
manifestations of malaise, fever, and weight loss are often accompanied
by organomegaly, lymphadenopathy, and anemia. Because special cul-
tures or stains are required to identify the organisms, the most critical
step in diagnosis is to suspect infection with NTM. Blood cultures may
be negative, but involved organs typically have significant organism
burdens, sometimes with a grossly impaired granulomatous response.
In a child, disseminated involvement (i.e., involvement of two or
more organs) without an underlying iatrogenic cause should
prompt an investigation of the IFN-γ/IL-12 pathway. Recessive
mutations in IFNGR1 and IFNGR2 typically lead to severe infection
with NTM. In contrast, dominant negative mutations in IFNGR1, which
lead to over-accumulation of a defective interfering mutant receptor on
the cell surface, inhibit normal IFN-γ signaling and thus lead to nontu-
berculous mycobacterial osteomyelitis. Dominant negative mutations
in STAT1 and recessive mutations in IL-12RB1 can produce variable
6/1/18 12:06 PM
 1268 phenotypes consistent with their residual capacities for IFN-γ synthesis
and response. Male patients who have disseminated nontuberculous
mycobacterial infections along with conical, peg, or missing teeth and
an abnormal hair pattern should be evaluated for defects in the path-
way that activates NF-κB through NEMO (IKBKG). These patients may
have associated immune globulin defects as well. Patients with myelo-
dysplasia and mycobacterial disease should be investigated for GATA2
deficiency. A recently recognized group of patients who often develop
disseminated infections with rapidly growing NTM (predominantly
M. abscessus) as well as other opportunistic infections have high-titer
neutralizing autoantibodies to IFN-γ. Thus far, this syndrome has been
reported most frequently in East Asian female patients.
IV catheters can become infected with NTM, usually as a conse-
quence of contaminated water. M. abscessus and M. fortuitum sometimes
infect deep indwelling lines as well as fluids used in eye surgery, sub-
cutaneous injections, and local anesthetics. Infected catheters should
be removed.
Pulmonary Disease Lung disease is by far the most common
form of nontuberculous mycobacterial infection in North America and
the rest of the industrialized world. In North America, rates of NTM
lung disease far exceed rates of tuberculosis. The clinical presentation
typically consists of months or years of throat clearing, nagging cough,
and slowly progressive fatigue. Patients will often have seen physi-
cians multiple times and received symptom-based or transient therapy
before the diagnosis is entertained and samples are sent for mycobac-
terial stains and cultures. Because not all patients can produce sputum,
bronchoscopy may be required for diagnosis. The typical lag between
onset of symptoms and diagnosis is ~5 years in older women. Predis-
posing factors include underlying lung diseases such as bronchiectasis
PART 5
(Chap. 284), pneumoconiosis (Chap. 283), chronic obstructive pul-
monary disease (Chap. 286), primary ciliary dyskinesia (Chap. 284),
α1 antitrypsin deficiency (Chap. 286), and cystic fibrosis (Chap. 285).
Bronchiectasis and nontuberculous mycobacterial infection often coex-
Infectious Diseases
ist and progress in tandem. This situation makes causality difficult to
determine in a given index case, but bronchiectasis is certainly among
the most critical predisposing factors that are exacerbated by infection.
MAC organisms are the most common causes of pulmonary non-
tuberculous mycobacterial infection in North America, but rates vary
somewhat by region. MAC infection most commonly develops during
the sixth or seventh decade of life in women who have had months
or years of nagging intermittent cough and fatigue, with or without
sputum production or chest pain. The constellation of pulmonary dis-
ease due to NTM in a tall and thin woman who may have chest wall
abnormalities is often referred to as Lady Windermere syndrome, after
an Oscar Wilde character of the same name. In fact, pulmonary MAC
infection does afflict older nonsmoking white women more than men,
with onset at ~60 years. Patients tend to be taller and thinner than the
general population, with high rates of scoliosis, mitral valve prolapse,
and pectus anomalies. Whereas male smokers with upper-lobe cavi-
tary disease tend to carry the same single strain of MAC indefinitely,
nonsmoking females with nodular bronchiectasis tend to carry several
strains of MAC simultaneously, with changes over the course of their
disease.
M. kansasii can cause a clinical syndrome that strongly resembles
tuberculosis, consisting of hemoptysis, chest pain, and cavitary lung
disease. The rapidly growing NTM, such as M. abscessus, have been
associated with esophageal motility disorders such as achalasia.
Patients with pulmonary alveolar proteinosis are prone to pulmonary
nontuberculous mycobacterial and Nocardia infections; the underlying
mechanism may be inhibition of alveolar macrophage function due
to the autoantibodies to granulocyte-macrophage colony-stimulating
factor found in many of these patients.
Cervical Lymph Nodes The most common form of nontubercu-
lous mycobacterial infection among young children in North America
is isolated cervical lymphadenopathy, caused most frequently by MAC
organisms but also by other NTM. The cervical swelling is typically
firm and relatively painless, with a paucity of systemic signs. Because
the differential diagnosis of painless adenopathy includes malignancy,
Harrisons_20e_Part5_p0859-p1648.indd 1268
many children have infection with NTM diagnosed inadvertently
at biopsy; cultures and special stains may not have been requested
because mycobacterial disease was not ranked high in the differential.
Local fistulae usually resolve completely with resection and/or anti-
biotic therapy. Likewise, the entity of isolated pediatric intrathoracic
nontuberculous mycobacterial infection, which is probably related to
cervical lymph node infection, is usually mistaken for cancer. In neither
isolated cervical nor isolated intrathoracic infections with NTM have
children with underlying immune defects been commonly identified,
nor do the affected children usually go on to develop other opportu-
nistic infections.
Skin and Soft Tissue Disease Cutaneous involvement with
NTM usually requires a break in the skin for introduction of the bacte-
ria. Pedicure bath–associated infection with M. fortuitum is more likely
if skin abrasion (e.g., during leg shaving) has occurred just before
the pedicure. Outbreaks of skin infection are often caused by rapidly
growing NTM (especially M. abscessus, M. fortuitum, and M. chelonae)
acquired via skin contamination from surgical instruments (especially
in cosmetic surgery), injections, and other procedures. These infec-
tions are typically accompanied by painful, erythematous, draining
subcutaneous nodules, usually without associated fever or systemic
symptoms.
M. marinum lives in many water sources and can be acquired from
fish tanks, swimming pools, barnacles, and fish scales. This organism
typically causes papules or ulcers (“fish-tank granuloma”), but the
infection can progress to tendinitis with significant impairment of
manual dexterity. Lesions appear days to weeks after inoculation of
organisms by a typically minor trauma (e.g., incurred during the clean-
ing of boats or the handling of fish). Tender nodules due to M. marinum
can advance up the arm in a pattern also seen with Sporothrix schenckii
(sporotricoid spread). The typical carpal-tendon involvement may be the
first presenting manifestation and may lead to surgical exploration or
steroid injection. The index of suspicion for M. marinum infections must
be high to ensure that proper specimens obtained during procedures
are sent for culture.
M. ulcerans, another waterborne skin pathogen, is found
mainly in the tropics, especially in tropical areas of Africa.
Infection follows skin trauma or insect bites that allow admis-
sion to contaminated water. The skin lesions are typically painless,
clean ulcers that slough and can cause osteomyelitis. The toxin myco-
lactone accounts for the modest host inflammatory response and the
painless ulcerations.
■■DIAGNOSIS
NTM can be detected on acid-fast or fluorochrome smears of sputum
or other body fluids. When the organism burden is high, the organisms
may appear as gram-positive beaded rods, but this finding is unreli-
able. (In contrast, nocardiae may appear as gram-positive and beaded
but filamentous bacteria.) Again, the requisite and most sensitive step
in the diagnosis of any mycobacterial disease is to think of including
it in the differential. In almost all laboratories, mycobacterial sample
processing, staining, and culture are conducted separately from rou-
tine bacteriologic tests; thus many infections go undiagnosed because
of the physician’s failure to request the appropriate test. In addition,
mycobacteria usually require separate blood culture media. NTM are
broadly differentiated into rapidly growing (<7 days) and slowly grow-
ing (≥7 days) forms. Because M. tuberculosis typically takes ≥2 weeks
to grow, many laboratories refuse to consider culture results final until
6 weeks have elapsed. Newer techniques using liquid culture media
permit more rapid isolation of mycobacteria from specimens than is
possible with traditional media. Species more readily detected with
incubation at 30°C include M. marinum, M. haemophilum, and M. ulcerans.
M. haemophilum prefers iron supplementation or blood, whereas M. gena-
vense requires supplemented medium with the additive mycobactin J.
Bacterial formation of pigment in light conditions (photochromogenicity)
or dark conditions (scotochromogenicity) or a lack of bacterial pigment
formation (nonchromogenicity) was historically used to help catego-
rize NTM. In contrast to NTM colonies, M. tuberculosis colonies are
6/1/18 12:06 PM
 beige, rough, dry, and flat. Current identification schemes reliably
use biochemical, nucleic acid, or cell wall composition, as assessed
by high-performance liquid chromatography or mass spectrometry,
for speciation. With the remarkable decline in U.S. cases of tubercu-
losis over recent decades, NTM have become the mycobacteria most
commonly isolated from humans in North America. However, not
all isolations of NTM, especially from the lung, reflect pathology and
require treatment. Whereas identification of an organism in a blood or
organ biopsy specimen in a compatible clinical setting is diagnostic, the
American Thoracic Society recommends that pulmonary infection due
to NTM be diagnosed only when disease is clearly demonstrable—i.e.,
in an appropriate clinical and radiographic setting (nodules, bronchiec-
tasis, cavities) and with repeated isolation of NTM from expectorated
sputum or recovery of NTM from bronchoscopy or biopsy specimens.
Given the large number of species of NTM and the importance of accu-
rate diagnosis for the implementation of proper therapy, identification
of these organisms is ideally taken to the species level.
The purified protein derivative (PPD) of tuberculin is delivered
intradermally to evoke a memory T cell response to mycobacterial anti-
gens. This test is variously referred to as the PPD test, the tuberculin
skin test, and the Mantoux test, among other designations. Unfortu-
nately, the cutaneous immune response to these tuberculosis-derived
filtrate proteins does not differentiate well between infection with some
NTM and that with M. tuberculosis. Because intermediate reactions
(~10 mm) to PPD in latent tuberculosis and nontuberculous myco-
bacterial infections can overlap significantly, the progressive decline
in active tuberculosis in the United States means that NTM probably
account for increasing proportions of PPD reactivity. In addition, bacille
Calmette-Guérin (BCG) can cause some degree of cross-reactivity, posing
problems of interpretation for patients who have received BCG vac-
cine. Assays to measure the elaboration of IFN-γ in response to the rel-
atively tuberculosis-specific proteins ESAT6 and CFP10 form the basis
for IFN-γ-release assays (IGRAs). These assays can be performed with
whole blood or on membranes. It is important to note that M. marinum,
M. kansasii, and M. szulgai also have ESAT6 and CFP10 and may cause
false-positive reactions in IGRAs. Despite cross-reactivity with NTM,
large PPD reactions (>15 mm) most commonly signify tuberculosis.
Isolation of NTM from blood specimens is clear evidence of disease.
Whereas rapidly growing mycobacteria may proliferate in routine
blood culture media, slow-growing NTM typically do not; thus it is
imperative to suspect the diagnosis and to use the correct bottles for
cultures. Isolation of NTM from a biopsy specimen constitutes strong
evidence for infection, but cases of laboratory contamination do occur.
Identification of organisms on stained sections of biopsy material
confirms the authenticity of the culture. Certain NTM require lower
incubation temperatures (M. genavense) or special additives (M. haemo-
philum) for growth. Some NTM (e.g., M. tilburgii) remain noncultivable
but can be identified molecularly in clinical samples.
The radiographic appearance of nontuberculous mycobacterial dis-
ease in the lung depends on the underlying disease, the severity of the
infection, and the imaging modality used. The advent and increase in
the use of CT have allowed the identification of characteristic changes
that are highly consistent with nontuberculous mycobacterial infec-
tion, such as the “tree-in-bud” pattern of bronchiolar inflammation
(Fig. 175-2). Involvement of the lingual and right-middle lobes is
commonly seen on chest CT but is difficult to appreciate on plain
film. Severe bronchiectasis and cavity formation are common in more
advanced disease. Isolation of NTM from respiratory samples can be
confusing. M. gordonae is often recovered from respiratory samples
but is not usually seen on smear and is almost never a pathogen.
Patients with bronchiectasis occasionally have NTM recovered from
sputum culture with a negative smear. The American Thoracic Society
has developed guidelines for the diagnosis of infection with MAC,
M. abscessus, and M. kansasii. A positive diagnosis requires the growth
of NTM from two of three sputum samples, regardless of smear find-
ings; a positive bronchoscopic alveolar sample, regardless of smear
findings; or a pulmonary parenchyma biopsy sample with granuloma-
tous inflammation or mycobacteria found on section and NTM found
on culture. These guidelines probably apply to other NTM as well.
Harrisons_20e_Part5_p0859-p1648.indd 1269
1269
FIGURE 175-2 Chest CT of a patient with pulmonary Mycobacterium avium
complex infection. Arrows indicate the “tree-in-bud” pattern of bronchiolar
inflammation (peripheral right lung) and bronchiectasis (central right and left
lungs).
Although many laboratories use DNA probes to identify M. tuberculosis,
MAC, M. gordonae, and M. kansasii, speciation of NTM helps deter-
mine the antimycobacterial therapy to be used. Only testing of MAC
organisms for susceptibility to clarithromycin and of M. kansasii for
susceptibility to rifampin is indicated; few data support other in vitro
susceptibility tests, attractive though they appear. MAC isolates that
CHAPTER 175 Nontuberculous Mycobacterial Infections
have not been exposed to macrolides are almost always susceptible.
NTM that have persisted beyond a course of antimicrobial therapy are
often tested for antibiotic susceptibility, but the value and meaning of
these tests are undetermined.
■■PREVENTION
Prophylaxis of MAC disease in patients infected with HIV is started
when the CD4+ T lymphocyte count falls to <50/μL. Azithromycin
(1200 mg weekly), clarithromycin (1000 mg daily), or rifabutin (300 mg
daily) is effective. Macrolide prophylaxis in immunodeficient patients
who are susceptible to NTM (e.g., those with defects in the IFN-γ/IL-12
axis) has not been prospectively validated but seems prudent.
TREATMENT
Nontuberculous Mycobacteria
NTM cause chronic infections that evolve relatively slowly over a
period of weeks to years. Therefore, it is rarely necessary to initiate
treatment on an emergent basis before the diagnosis is clear and
the infecting species is known. Treatment of NTM is complex, often
poorly tolerated, and potentially toxic. Just as in tuberculosis, inad-
equate single-drug therapy is almost always associated with the
emergence of antimicrobial resistance and relapse.
MAC infection often requires multidrug therapy, the foundation
of which is a macrolide (clarithromycin or azithromycin), etham-
butol, and a rifamycin (rifampin or rifabutin). For disseminated
nontuberculous mycobacterial disease in HIV-infected patients, the
use of rifamycins poses special problems—i.e., rifamycin interac-
tions with protease inhibitors. For pulmonary MAC disease, thrice-
weekly administration of a macrolide, a rifamycin, and ethambutol
has been successful. Therapy is prolonged, generally continuing for
12 months after culture conversion; typically, a course lasts for at
least 18 months. Other drugs with activity against MAC organisms
include IV and aerosolized aminoglycosides, fluoroquinolones, and
clofazimine. In elderly patients, rifabutin can exert significant tox-
icity. However, with only modest efforts, most antimycobacterial
regimens are well tolerated by most patients. Resection of cavitary
lesions or severely bronchiectatic segments has been advocated for
some patients, especially those with macrolide-resistant infections.
The success of therapy for pulmonary MAC infections depends on
6/1/18 12:06 PM
 1270 whether disease is nodular or cavitary and on whether it is early or
advanced, ranging from 20 to 80%.
M. kansasii lung disease is similar to tuberculosis in many ways
and is also effectively treated with isoniazid (300 mg/d), rifampin
(600 mg/d), and ethambutol (15 mg/kg per day). Other drugs
with very high-level activity against M. kansasii include clarith-
romycin, fluoroquinolones, and aminoglycosides. Treatment should
continue until cultures have been negative for at least 1 year. In
most instances, M. kansasii infection is easily cured. Bulky, severe,
necrotizing M. kansasii lymphadenopathy, especially in the medias-
tinum, is strongly associated with GATA2 deficiency.
Rapidly growing mycobacteria pose special therapeutic prob-
lems. Extrapulmonary disease in an immunocompetent host is
usually due to inoculation (e.g., via surgery, injections, or trauma)
or to line infection and is often treated successfully with a macrolide
and another drug (with the choice based on in vitro susceptibility),
along with removal of the offending focus. In contrast, pulmonary
disease, especially that caused by M. abscessus, is extremely diffi-
cult to cure. Repeated courses of treatment are usually effective in
reducing the infectious burden and symptoms. Therapy generally
includes a macrolide along with an IV-administered agent such
as amikacin, a carbapenem, cefoxitin, or tigecycline. Other oral
agents (used according to in vitro susceptibility testing and toler-
ance) include fluoroquinolones, doxycycline, and linezolid. Because
nontuberculous mycobacterial infections are chronic, care must be
taken in the long-term use of drugs with neurotoxicities, such as
linezolid and ethambutol. Prophylactic pyridoxine has been sug-
gested in these cases. Durations of therapy for M. abscessus lung dis-
ease are difficult to predict because so many cases are chronic and
PART 5
require intermittent therapy. Expert consultation and management
are strongly recommended.
Once recognized, M. marinum infection is highly responsive
to antimicrobial therapy and is cured relatively easily with any
combination of a macrolide, ethambutol, and a rifamycin. Ther-
Infectious Diseases
apy should be continued for 1–2 months after clinical resolution
of isolated soft-tissue disease; tendon and bone involvement may
require longer courses in light of clinical evolution. Other drugs with
activity against M. marinum include sulfonamides, trimethoprim-
sulfamethoxazole, doxycycline, and minocycline.
Treatment of the other NTM is less well defined, but macrolides
and aminoglycosides are usually effective, with other agents added
as indicated. Expert consultation is strongly encouraged for difficult
or unusual infections due to NTM.
■■PROGNOSIS
The outcomes of nontuberculous mycobacterial infections are closely
tied to the underlying condition (e.g., IFN-γ/IL-12 pathway defect,
cystic fibrosis) and can range from recovery to death. With no or inad-
equate treatment, symptoms and signs can be debilitating, including
persistent cough, fever, anorexia, and severe lung destruction. With
treatment, patients typically regain strength and energy. The optimal
duration of therapy when NTM persist in sputum is unknown, but
treatment in this situation can be prolonged. In general, for severe
underlying immunodeficiencies, hematopoietic stem cell transplanta-
tion is recommended and may be helpful in the resolution of severe
mycobacterial disease.
■■GLOBAL CONSIDERATIONS
In many countries, pulmonary tuberculosis is diagnosed by
smear alone, which is also the method used for monitoring
of response and relapse. However, examination of mycobac-
teria from the affected patients shows that a significant proportion of
isolates are actually NTM. Overall, as rates of tuberculosis decline,
the proportion of positive smears caused by NTM will increase.
Advances in speciation will distinguish tuberculosis from nontuber-
culous mycobacterial infections and thereby affect rates of assumed
relapse and resistance, leading to more targeted and appropriate
therapy.
Harrisons_20e_Part5_p0859-p1648.indd 1270
■■FURTHER READING
Aksamit TR et al: Adult patients with bronchiectasis: A first look at the
US Bronchiectasis Research Registry. Chest 151:982, 2017.
Browne SK et al: Adult-onset immunodeficiency in Thailand and
Taiwan. N Engl J Med 367:725, 2012.
Fleshner M et al: Mortality among patients with pulmonary non-
tuberculous mycobacteria disease. Int J Tuberc Lung Dis 20:582, 2016.
Holland SM et al: Case 28-2017. A 13-month-old girl with pneumonia
and a 33-year-old woman with hip pain. N Engl J Med 377:1077, 2017.
Kim RD et al: Pulmonary nontuberculous mycobacterial disease: Pro-
spective study of a distinct preexisting syndrome. Am J Respir Crit
Care Med 178:1066, 2008.
Lovell JP et al: Mediastinal and disseminated Mycobacterium kansasii
disease in GATA2 deficiency. Ann Am Thorac Soc 13:2169, 2016.
Olivier KN et al: Inhaled amikacin for treatment of refractory pul-
monary nontuberculous mycobacterial disease. Ann Am Thorac Soc
11:30, 2014.
Spinner MA et al: GATA2 deficiency: A protean disorder of hemato-
poiesis, lymphatics, and immunity. Blood 123:809, 2014.
Szymanski EP et al: Pulmonary nontuberculous mycobacterial infec-
tion. A multisystem, multigenic disease. Am J Respir Crit Care Med
192:618, 2015.
Wu UI, Holland SM: Host susceptibility to non-tuberculous mycobac-
terial infections. Lancet Infect Dis 15:968, 2015.
176 Antimycobacterial Agents
Divya Reddy, Max R. O’Donnell
Agents used for the treatment of mycobacterial infections, includ-
ing tuberculosis (TB), leprosy, and infections due to nontuberculous
mycobacteria (NTM), are administered in multiple-drug regimens for
prolonged courses. Currently, >160 species of mycobacteria have been
identified, the majority of which do not cause disease in humans. While
the incidence of disease caused by Mycobacterium tuberculosis has been
declining in the United States, TB remains a leading cause of morbidity
and mortality in developing countries—particularly in sub-Saharan
Africa and Asia, where the HIV epidemic rages. Not only effective
drug regimens are needed; without a well-organized infrastructure
for diagnosis and treatment of TB, therapeutic and control efforts
are severely hampered (Chaps. 460 and 462). Infections with NTM
have gained in clinical prominence in the United States and other
developed countries. These largely environmental organisms often
establish infection in immunocompromised patients or in persons with
structural lung disease.
TUBERCULOSIS
■■GENERAL PRINCIPLES
The earliest recorded human case of TB dates back 9000 years. Early
treatment modalities, such as bloodletting, were replaced by sanato-
rium regimens in the late nineteenth century. The discovery of strep-
tomycin in 1943 launched the era of antibiotic treatment for TB. Over
subsequent decades, the discovery of additional agents and the use of
multiple-drug regimens allowed progressive shortening of the treat-
ment course from years to as little as 6 months for drug-susceptible
TB. Latent TB infection (LTBI) and active TB disease are diagnosed by
history, physical examination, radiographic imaging, tuberculin skin
test, interferon γ release assays, acid-fast staining, mycobacterial cul-
tures, and/or new molecular diagnostics. LTBI is treated with isoniazid
(optimally daily or weekly for 9 months), rifampin (daily for 4 months),
isoniazid plus rifampin (daily for 3 months), or isoniazid plus rifapen-
tine (weekly for 3 months) (Table 176-1).
For active or suspected TB disease, clinical factors, including HIV
co-infection, symptom duration, radiographic appearance, and public
6/1/18 12:06 PM