1392 PART 5 Infectious Diseases

1.5 billion of the poorest people on Earth and have been widely

neglected in domains such as public policy, funding, and the development of diagnostics and treatments. Leprosy is the archetypical NTD,

featuring all of the common characteristics: a treatable infectious disease, a known population at risk, available preventive chemotherapy,

disease complications that may lead to severe disabilities, and a pervasive social stigma that leads to discrimination, social exclusion, and

severe mental health consequences. Nevertheless, the priority accorded

to leprosy on the public health agenda of most endemic countries is

very low. By joining hands in advocacy, fundraising, and development

of joint control strategies, health care organizations can substantially

raise the priority profile of NTDs, benefiting each of the individual

disease control programs. Such a joint approach serves the goal of

universal health coverage and helps to strengthen health services more

effectively than vertical programs are ever able to do on their own.

■ PREVENTION AND CONTROL

Interruption of Transmission and Novel Preventive Strate- gies Leprosy control was traditionally based on early case detection

and multidrug treatment. Apart from health education and leprosy

awareness campaigns, no preventive measures were available. In the

1990s, authorities hoped that the transmission of M. leprae in the community could be interrupted through timely detection of cases and provision of multidrug therapy, leading to a decline in leprosy incidence.

Unfortunately, this has not been the case (Fig. 179-1). The inability to

reduce leprosy incidence in many countries and the heightened interest in neglected tropical diseases have invigorated research into new

techniques for the diagnosis of disease and infection, leprosy vaccines,

enhanced postexposure chemoprophylaxis regimens, epidemiologic

tools (e.g., geographic information systems for identifying leprosy

hotspots), surveillance of antimicrobial resistance, and alternative

drugs and drug treatment regimens.

Vaccines against Leprosy The bacille Calmette-Guérin (BCG)

vaccine used against tuberculosis provides varying degrees of protection against leprosy and is used routinely as postexposure immunoprophylaxis for contacts of leprosy patients in Brazil. Two promising

vaccine candidates are in the pipeline: the MIP vaccine from India,

which is based on killed Mycobacterium indicus pranii, and the synthetic LepVax vaccine developed by the University of Washington’s

Infectious Disease Research Institute in the United States. If proven

effective, these vaccines, like the BCG vaccine, will be used as postexposure prophylaxis for contacts of leprosy patients. Trials are in early

stages, and sufficient proof of efficacy will take years.

Postexposure Chemoprophylaxis The introduction of postexposure chemoprophylaxis (PEP) for household and other close contacts

of leprosy patients is an important innovation. A large randomized

controlled trial has shown that single-dose rifampin, given once to

household contacts, neighbors, and social contacts, reduces the recipients’ risk of leprosy by ~60%. Implementation studies have shown that

PEP with single-dose rifampin is feasible and well accepted by patients,

contacts, and health workers in a variety of health care settings. Furthermore, modeling studies have indicated the potential impact of PEP on

transmission of M. leprae in endemic populations. This intervention was

included in the 2018 WHO Guidelines for the Diagnosis, Treatment,

and Prevention of Leprosy and is currently being introduced in many

countries. Research is ongoing into enhanced PEP regimens for those

close contacts who are at increased risk of leprosy (e.g., blood-related

household contacts and close contacts of multibacillary leprosy patients).

“Zero Leprosy” The WHO has formulated its new Global Leprosy

Strategy 2021–2030. As in the organization’s previous strategy, a holistic

approach to leprosy control is advocated, focusing on zero infection

and disease, zero disability, and zero stigma and discrimination. For

2030, the WHO is setting ambitious targets of achieving 120 countries with zero new autochthonous leprosy cases, reducing the annual

number of new cases detected by 70%, reducing the rate of new cases

with grade 2 disability per million population (as a proxy for detection

delay) by 90%, and reducing the rate of new child cases with leprosy

per million children (as a proxy for recent transmission) by 90%.

Widespread implementation of PEP with single-dose rifampin is one

of the key strategies to achieve these goals. The “Triple Zero Strategy”

(zeroleprosy.org) has also been embraced by the partners united in the

Global Partnership for Zero Leprosy, the International Federation of

Anti-Leprosy Associations, the Novartis Foundation, the Sasakawa

Health Foundation, and the International Association for Integration,

Dignity, and Economic Advancement.

The outlook for achieving “zero leprosy” in the coming decades is better than ever before, but this goal is admittedly very ambitious. It can be

reached only when all leprosy-endemic countries enhance their leprosy

control activities to include (1) active case-finding strategies, including

improved diagnosis; (2) contact screening; (3) implementation of PEP;

(4) improved prevention of disability services; and (5) activities to

reduce stigma and discrimination and to promote the social inclusion

and mental well-being of affected patients and their families. Coincident

with these efforts, an important threat must be confronted. With the

waning of interest in leprosy and the integration of management of the

disease into nonspecialized health systems, the number of medical doctors and health workers at the primary care level who have experience in

diagnosing and treating leprosy has decreased substantially all over the

world. Once lost, expertise is difficult to regain. Therefore, new energy

and resources need to be invested in bolstering technical capacity for

all aspects of leprosy services, with a view to strengthening the health

system in an integrated way and leaving no one behind.

Acknowledgement

We thank Dr. Colette L.M. van Hees, dermatologist at Erasmus MC,

University Medical Center Rotterdam, for critical review of this chapter.

■ FURTHER READING

Bratschi MW et al: Current knowledge on Mycobacterium leprae

transmission: A systematic literature review. Lepr Rev 86:142, 2015.

Kumar B, Kar HK (eds.): IAL Textbook of Leprosy, 2nd ed. New Delhi,

Jaypee Brothers Medical Publishers (P) Ltd, 2017.

Scollard DM, Gillis TP (eds): International Textbook of Leprosy. Available at https://internationaltextbookofleprosy.org. Accessed

February 7, 2021.

Smith WC et al: The missing millions: A threat to the elimination of

leprosy. PLoS Negl Trop Dis 9 e0003658, 2015.

World Health Organization: Guidelines for the diagnosis, treatment and prevention of leprosy. New Delhi, WHO Regional Office

for South-East Asia, 2018. Available at https://apps.who.int/iris/

handle/10665/274127. Accessed February 7, 2021.

Several terms—nontuberculous mycobacteria (NTM), atypical mycobacteria, mycobacteria other than tuberculosis, and environmental

mycobacteria—all refer to mycobacteria other than Mycobacterium

tuberculosis, 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 199. 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

180 Nontuberculous

Mycobacterial Infections

Steven M. Holland

1393CHAPTER 180 Nontuberculous Mycobacterial Infections

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 consequent 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 histocompatibility complex and Fc receptors, and to concentrate certain antibiotics 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 complex 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), SPP2A,

and IKBKG (which encodes NEMO) (Fig. 180-1). Despite the identification of genes associated with disseminated disease, 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 bestrecognized underlying condition for pulmonary infection with NTM

is bronchiectasis (Chap. 290). 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.

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 pulmonary

infection with NTM, mostly in association with bronchiectasis (Chap.

290), 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 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 individuals 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 identification 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 significant disease develops are highly likely to have specific susceptibility

factors 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

T/NK

1 2

NEMO

NRAMP1

ISG15

STAT1

GATA2

IL-15

IL-2 IL-2R

AFB

Salm.

MΦ

LPS

TLR

TNFαR

TNFα

IRF8

CD14

IFNγR

IFNγ

IL-12R

IL-12

IL-18 ?

β1

β2

FIGURE 180-1 Cytokine interactions of infected macrophages (MΦ) 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

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.

1394 PART 5 Infectious Diseases

Unlike disseminated or pulmonary infection, “hot-tub lung” represents 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 infections 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

infections 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 cultures 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 nontuberculous mycobacterial osteomyelitis. Dominant negative mutations in STAT1 and recessive mutations in IL-12RB1 can

produce variable 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 pathway that activates NF-κB through NEMO

(IKBKG). These patients may have associated immune globulin defects

as well. Patients with myelodysplasia 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 consequence of contaminated water. M. abscessus and M. fortuitum sometimes infect deep indwelling lines as well as fluids used in eye surgery,

subcutaneous 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 physicians multiple times and received symptom-based or transient therapy before the

diagnosis is entertained and samples are sent for mycobacterial 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. Predisposing

factors include underlying lung diseases such as bronchiectasis (Chap.

290), pneumoconiosis (Chap. 289), chronic obstructive pulmonary

disease (Chap. 292), primary ciliary dyskinesia (Chap. 290), α1

 antitrypsin deficiency (Chap. 292), and cystic fibrosis (Chap. 291). Bronchiectasis and nontuberculous mycobacterial infection often coexist

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 nontuberculous 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

disease 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 cavitary 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 nontuberculous 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,

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 antibiotic 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

opportunistic infections.

Skin and Soft Tissue Disease Cutaneous involvement with NTM

usually requires a break in the skin for introduction of the bacteria.

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 infections 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

cleaning 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

1395CHAPTER 180 Nontuberculous Mycobacterial Infections

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 admission to contaminated water.

The skin lesions are typically painless, clean ulcers that slough and can

cause osteomyelitis. The toxin mycolactone 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 unreliable.

(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 routine

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 growing

(≥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. genavense 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 categorize NTM. In contrast to NTM colonies, M.

tuberculosis colonies are 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 tuberculosis 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, bronchiectasis, 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 accurate 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

antigens. This test is variously referred to as the PPD test, the tuberculin skin test, and the Mantoux test, among other designations. Unfortunately, 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

mycobacterial 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 vaccine. Assays to measure the elaboration of IFN-γ

in response to the relatively 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. Conversely, in the setting of anti-IFNg

autoantibodies the IGRA test is indeterminate (failure of IFNg detection in response to specific antigens and mitogens, due to neutralizing

anti-IFNg autoantibodies).

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. haemophilum) for growth. Some NTM (e.g., M. tilburgii) remain noncultivable but can be identified molecularly in clinical samples.

The radiographic appearance of nontuberculous mycobacterial disease 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 has allowed the identification of characteristic changes

that are highly consistent with nontuberculous mycobacterial infection, such as the “tree-in-bud” pattern of bronchiolar inflammation

(Fig. 180-2). 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 findings;

a positive bronchoscopic alveolar sample, regardless of smear findings; or a pulmonary parenchyma biopsy sample with granulomatous

inflammation or mycobacteria found on section and NTM found on

culture. These guidelines probably apply to other NTM as well.

Although many laboratories use DNA probes to identify M. tuberculosis, MAC, M. gordonae, and M. kansasii, speciation of NTM helps

determine 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 have not been exposed to macrolides are almost always susceptible. NTM that have persisted beyond a course of antimicrobial therapy

FIGURE 180-2 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).