308 Tuberkulosis

2000 CHAPTER 308 Tuberculosis
308
TUBERCULOSIS
JERROLD J. ELLNER AND KAREN R. JACOBSON
DEFINITION
Tuberculosis (TB) is a chronic granulomatous disease with a unique latent
stage caused by the acid-fast bacillus (AFB) Mycobacterium tuberculosis. The
lung is a site of disease in 75 to 80% of cases; frequent extrapulmonary sites
are the lymph nodes, pleura, bones, and joints. TB is spread from person to
person primarily by inhalation of infectious droplet nuclei aerosolized by
patients with active pulmonary TB. TB is the leading infectious disease killer
globally, with over 95% of cases and 99% of deaths occurring in resource-
limited settings. The human immunodeficiency virus (HIV) pandemic led to
a resurgence of TB worldwide and promoted explosive nosocomial outbreaks
of multiple-drug resistant TB. The result was increased attention to TB as a
global public health emergency and increased funding for TB control and
research. The problems posed for TB control are compounded by increasing
prevalence of drug-resistant disease that is expensive to treat and may be
refractory to available drugs.1
The Pathogen
TB is caused by infection with one of four members of the Mycobacterium
tuberculosis complex: M. tuberculosis, M. africanum, M. orygis or M. bovis. The
causative organism is a slender, non-motile, non–spore-forming, non–toxin-
producing bacillus that may be beaded in appearance and is approximately 2
to 4 µm in length. It is a slow-growing (doubling time of 18 to 24 hours)
facultative aerobe that can persist intracellularly for prolonged periods. The
organism is identified in clinical specimens as an acid-fast bacillus (AFB). M.
tuberculosis can be stained with carbol fuchsin by either alkalinization (Kinyoun)
or heat (Ziehl-Neelsen) methods. The waxy coat of M. tuberculosis, composed
of mycolic acid and other complex lipopolysaccharides, precludes decoloriza-
tion of the stain with a mixture of acid and alcohol.
DNA sequencing of M. tuberculosis and genetic manipulations have pro-
moted basic understanding of the metabolism and virulence of the organism,
its immunodominant antigens, and capacity to survive adverse conditions and
persist intracellularly. Clinical isolates of M. tuberculosis differ in their virulence,
potential for transmission in humans, and interaction with the host (immunopa-
thology, induction of host cytokines, delayed-type hypersensitivity). For example,
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CHAPTER 308 Tuberculosis

2000.e3
ABSTRACT KEYWORDS
Tuberculosis (TB) is a chronic infectious disease with a unique latent stage Mycobacterium tuberculosis
caused by the acid-fast bacillus (AFB) Mycobacterium tuberculosis. TB has had primary TB
a worldwide resurgence in incidence in contemporary times, complicated by reactivation TB
underlying HIV infection and drug resistance in many individuals. With treat- reinfection TB
ment, the prognosis of patients with TB depends on the extent of pulmonary pleural TB
TB, the sites of extrapulmonary TB, drug susceptibility of the isolate, and the military TB
presence of HIV infection and other comorbid conditions. Miliary TB is tuberculous meningitis
associated with a high case-fatality rate, in part related to delays in diagnosis. tuberculous lymphadenitis
TB meningitis is associated with serious neurologic residua, as well as high tuberculous pericarditis
mortality. Multidrug-resistant (MDR) TB and extensively drug-resistant TB tuberculous peritonitis
are accompanied by high rates of treatment failure, morbidity, and mortality. gastrointestinal TB
TB in HIV-infected persons is associated with high early mortality. The addi- renal TB
tion of ART can result in morbidities associated with concurrent administration vertebral osteomyelitis
of TB and HIV drugs and with TB-immune reconstitution inflammatory multidrug-resistant (MDR) TB
syndrome. extensively drug-resistant TB
HIV coinfection

2001
TABLE 308-1 RISK FACTORS FOR TUBERCULOSIS

INCREASED RISK OF INCREASED RISK OF PROGRESSION TST CUT
RISK FACTOR RECENT INFECTION* FROM INFECTION TO DISEASE POINT
Household contact of PTB X >5 mm
Solid organ transplant recipients, immunosuppressive treatment (TNF inhibitors, X >5 mm
prednisone >15 mg/day for >1 month), fibrotic lesions on chest radiograph
consistent with prior TB
HIV infection X X >5 mm
Foreign-born, injecting drug users, TST-positive children, adolescents, young adults X >10 mm
Residents or workers in hospitals, homeless shelters, correctional facilities, nursing X >10 mm
homes, residences for the HIV-infected
Underweight (>15%), silicosis, diabetes mellitus (particularly insulin-dependent or X >10 mm
poorly controlled), renal failure, hemodialysis, gastrectomy, jejuno-ileal bypass,
carcinoma of the head and neck, lung cancer, lymphoma, leukemia
None >15 mm
*Recent infection per se increases risk of progressing from infection to disease (12.9 cases per 1000 person-years in the first year compared to 1.6 per 1000 person-years in the subsequent 7 years).
HIV = human immunodeficiency virus; PTB = pulmonary TB; TNF = tumor necrosis factor; TST = tuberculin skin test.
the hypervirulent Beijing strain family overexpresses a phenolic glycolipid that origin whereas U.S.-born more likely acquired when TB was more common
inhibits innate immunity and may thereby contribute to its pathogenicity. domestically. There is a corresponding shift of age-specific prevalence of TB
There are six main phylogeographic lineages of M. tuberculosis, each associ- in the United States towards older adults.
ated with a specific human population. The families differ in geographic dis- Country of origin is a large determinant of both the risk of latent TB infec-
tribution and in some cases the potential for transmission and pathogenesis. tion and of TB disease. In a low-prevalence setting such as the United States,
Strain typing is particularly useful in outbreak investigations and can be per- the prevalence of latent TB infection (defined as a positive tuberculin skin
formed by several techniques, including restriction fragment length polymor- test or interferon-γ release assay [IGRA] but no active disease) is approximately
phism of the insertional element IS 6110 or spoligotyping, and increasingly 4%. An estimated 13 million people have latent TB in the United States.4
by deep DNA sequencing. The finding that multiple cases of TB are caused Those infected are at markedly increased risk of disease compared to unin-
by the same strain and constitute a “cluster” suggests that they are epidemio- fected, a risk that is further increased by medical comorbidities and other
logically linked although transmission may be recent or remote. Whole-genomic factors shown in Table 308-1. The risk is not homogeneous within groups
sequencing has emerged as a powerful tool to establish transmission even affected, for example, by extent of immunosuppression in HIV or duration,
absent strong epidemiologic links. severity, and control of diabetes. Smoking and alcoholism also confer an
TB caused by M. africanum is clinically identical to that caused by M. tuber- increased risk for TB, although smaller than the conditions listed. In the United
culosis. M. bovis has greater than 95% DNA homology with M. tuberculosis States in 2016, 16.4% of persons with TB had diabetes, 1.3% reported inject-
and causes disease in humans, cattle, deer, badgers, and other animals. The ing drugs, 6.8% reported using noninjectable drugs, and 10% reported excessive
main route of transmission of M. tuberculosis is person-to-person through alcohol use.
respiratory aerosols generated by coughing. Bacilli in small droplet nuclei (1 TB caused by drug-resistant organisms is a continuing threat.5 Multidrug-
to 5 µm in diameter) remain suspended in air for long periods and once resistant (MDR) TB (resistant to isoniazid [INH] and rifampin) and extensively
inhaled can reach the airways, where only 1 to 5 organisms are sufficient to drug-resistant TB (MDR plus resistance to fluoroquinolones [FQs] and to a
cause infection. Laryngeal involvement renders the patient highly infectious. second-line injectable [kanamycin, amikacin, or capreomycin]) are much more
Direct cutaneous inoculation (“prosector’s wart”) does occur. M. bovis can difficult and expensive to treat and in some cases may be incurable. In 2016,
be transmitted by the gastrointestinal route, usually through ingestion of con- there were 600,000 new TB cases with rifampin resistance, the most effective
taminated dairy products. first-line drug, of which 490,000 had MDR TB. Almost one-half (47%) of
these cases were in India, China, and the Russian Federation. About 6.2% of
EPIDEMIOLOGY MDR TB cases are extensively drug-resistant. Ninety-seven U.S. cases of MDR
The World Health Organization (WHO) estimates that in 2016 there were TB and one case of extensively drug-resistant TB were reported in 2016.
10.4 million new cases of TB (10% in HIV-infected persons) and 1.7 million Outcomes for drug-resistant TB remain poor, with only 54% of MDR TB
deaths (including 374,000 among people with HIV infection).2 An estimated patients and 30% of XDR TB patients successfully treated. This should improve
40% of deaths in persons with HIV were due to TB. Fifty-six percent of TB with the introduction of more active drugs and drug regimens. The majority
cases were in five countries: India, Indonesia, China, the Philippines, and of cases of XDR TB in an area with a high TB burden were found to be prob-
Pakistan. Worldwide, 65% of TB cases occur in males; the prevalence of disease ably due to transmission rather than to inadequate treatment, suggesting that
peaks in young adults, with major economic consequence. Globally, both TB control of the epidemic requires an increased focus on interruption of
incidence (declining 2% per year) and case-fatality rates have been falling. transmission.6
However, TB incidence decline needs to accelerate to 4 to 5% annually to
reach the WHO’s 2020 End TB Strategy Milestones of 20% incidence reduc- PATHOBIOLOGY
tion compared to 2015. Typically the chain of transmission of TB begins with an infectious case of
HIV infection has a profound effect on the epidemiology of TB, promoting pulmonary TB (Fig. 308-1). Infectiousness of a patient is determined by sputum
and accelerating progression from infection to active TB, and on both reactiva- smear status (3 to 4+ AFB), cough strength and frequency, the presence of
tion and reinfection disease. Seventy-four percent of HIV-infected TB cases cavitary lung disease, and the characteristics of the physical space shared with
are in sub-Saharan Africa, resulting in TB case rates as high as 1% in South the source (ventilation and air recirculation). However, not all strongly AFB
Africa and Swaziland. smear–positive patients with pulmonary TB are equally infectious, and there
In the United States in 2017 the incidence of TB was 2.8 per 100,000, with may be high transmitters, owing to host or bacterial factors or both. Only
about 9000 new cases reported (about 6% were HIV-infected, 5% homeless, about 50 to 60% of strongly sputum smear–positive persons with pulmonary
and 4.0% incarcerated).3 The incidence rate in foreign-born individuals was TB generate aerosols that contain viable organisms. Certain strains of M.
13-fold higher than in those born in the United States and foreign-born indi- tuberculosis also may be transmission-prone.
viduals accounted for 69% of new cases. Rates were 30-fold higher in non- In both low- and high-prevalence countries, exposure/infection may occur
Hispanic Asians than non-Hispanic whites. Of genotyped cases, 14% appear in the household. In this setting, where exposure may be intense and protracted,
due to recent transmission versus 86% that appear to be reactivation of previous 50 to 75% of contacts become infected. The higher numbers result from studies
infection, which in foreign-born was due to acquisition in their country of in which repeated testing identifies all tuberculin skin test convertors. In

Primary
progressive
TB (5%; 40%)
Treatment
Primary infection
No infection Cured TB
(50–75%)
Exposure
Reactivation
Latency TB (5%; 5–10%/year)
Exposure
Exposure
Reinfection TB
FIGURE 308-1. Natural history of TB. The proportion of individuals affected is shown in parentheses. Bolded figures are for HIV infection with severe immunosuppression. A number
of medical risk factors besides HIV promote progression from Mycobacterium tuberculosis infection to disease (see Table 308-1).
outbreaks occurring in residential shelters, hospitals, and prisons, M. tuberculosis

Clinical disease
Bacterial load?
Disease
infection or disease also has been documented after brief exposure. Recent
Symptoms
data suggest that in high prevalence settings, community transmission may
be more common than household transmission, although the sites in the com-
munity may not be known. Important variables that may explain differences Bacterial replication
in transmission include virulence of the organism, innate immunity, and sus- maintained at a subclinical Active infection
ceptibility of the exposed populations (e.g., HIV infected). Human genetic level by the immune system
Effect of HIV infection

factors such as polymorphisms in expression or regulation of toll-like receptors
(TLR), pattern recognition receptors important to innate immunity, may
modulate risk and expression of infection (interferon gamma release assay Infection controlled with some
[IGRA] or tuberculin skin test) as well as risk and expression of disease. Pre- bacteria persisting in Quiescent infection
disposition to disease is seen with defects in interferon (IFN)-γ and interleukin non-replicating form
(IL)-12 receptors, consistent with their role in adaptive immunity. Polymor-
phisms that modify inflammation (e.g., by affecting leukotriene A4 hydrolase)
also may affect disease manifestations and response to therapy. Infection eliminated in Acquired immune
Two models of the natural history of TB are shown in Figures 308-1 and association with T-cell priming response
308-2. There is increasing evidence that the natural history represents a con-
tinuum rather than distinct entities of latent and active TB. Diagnostic bio-
markers that stratify risk of progression from latent TB infection to active TB Infection eliminated without Innate immune
would be of enormous value for targeting public health interventions. Host priming antigen-specific T-cells response
blood RNA signatures are currently being studied as predictors of those most
at risk of developing active tuberculosis and therefore preferentially receive
prophylaxis. FIGURE 308-2. Tuberculosis infection as a spectrum. The outcome of infection by
Mycobacterium tuberculosis is generally represented as a bimodal distribution between
The lung is the site of most cases of reactivation TB. The hallmark of the active tuberculosis (TB) and latent TB on the basis of the presence or absence of clinical
pathology is granuloma formation with caseation necrosis and multinucleated symptoms. It is proposed that latent TB is usefully represented as part of a spectrum of
Langerhans giant cells. The caseous material found in necrotic cavities contains responses to infection. One consequence of this model is that there may be a subpopula-
AFB. M. tuberculosis multiplies exuberantly in the liquid caseum. Immunologi- tion within the group that is currently defined as having latent TB that should be pref-
erentially targeted for preventive therapy. A second consequence is that efforts to develop
cally, expectorated sputum contains cytokines and both upregulators and drugs for effective treatment of latent TB would overlap the search for drugs that shorten
downregulators of the immune and inflammatory response, the downregulation treatment times for active TB. (From Barry CE 3rd, Boshoff HI, Dartois V, et al. The spectrum
being dominant. Bronchoalveolar lavage shows a lymphocytic alveolitis, with of latent tuberculosis. Rethinking the biology and intervention strategies. Nat Rev Micro-
an influx of immature macrophages representing monocytes attracted from biol. 2009;7:845-855, Figure 1.)
blood. In sum, there is an active but well-regulated immune and inflammatory
response concomitant with bacterial replication. As a consequence of the
inflammation, extensive apoptosis occurs that might lead to the deletion of
M. tuberculosis-responsive T cells, that may play a role in the requirement for Several forms of extrapulmonary TB have a shared pathogenesis: discharge
a long duration of therapy. This is consistent with the recent finding of per- of a contiguous tuberculous focus into a serosal cavity, a brisk inflammatory
sistent areas of inflammation (by PET-CT scan) at the end of TB treatment, reaction based on preexisting delayed-type hypersensitivity, fever, frequently
and in the susceptibility to reinfection TB. In HIV-infected persons with negative smears of exudative fluid for AFBs, and sometimes a transiently nega-
advanced immunosuppression, granulomas may be poorly formed or absent. tive tuberculin skin test. The site of infection that discharges may be a long-
Lung tissue is infiltrated with foamy epithelioid cells that are macrophages standing focus or one that was seeded during recent dissemination associated
laden with AFBs. Caseation may or may not be present, but there is extensive with primary infection. This basic scenario occurs in pleural TB, TB pericarditis,
inflammation and necrosis. TB meningitis (the parameningeal focus is called a “Rich focus”), TB perito-
Extrapulmonary TB can involve any organ. Persistence of organisms in nitis, and TB arthritis.
areas that are relatively well oxygenated may explain the more frequent sites Pleural TB represents an in situ delayed-type hypersensitivity reaction with
of reactivation, such as the apices of the lung, cortices of the kidney, and activation of TH1 helper T cells, abundant cytokines, including IFN-γ and tumor
vertebral bodies. necrosis factor (TNF)-α, and apoptosis. In non–HIV-infected individuals,

2003
B C
D
FIGURE 308-3. A, Ghon complex. B, Moderately advanced pulmonary tuberculosis (TB). C, Far advanced pulmonary TB. D, Pulmonary (left) and extrapulmonary (right) TB. (Radiographs
courtesy Thomas M. Daniel, MD.)
organisms are sparse, which may be why self-cure of pleural TB can take place. of primary TB resolve without treatment, concurrent with the development
However, in the absence of chemotherapy for TB, there is a high risk for TB of an adaptive immune response. During the subsequent period of clinical
recurrence, usually as pulmonary TB on the side contralateral to the effusion. latency, evidence of the primary infection may be found as a small calcified
In addition to reactivation of a latent focus, reinfection with M. tuberculosis parenchymal scar in the mid-lung fields (Ghon complex), sometimes associ-
may occur and progress to disease. Reinfection is more likely if the host is ated with similar findings in the draining hilar nodes (Ranke complex) (Fig.
immunosuppressed or if there is repeated or intense exposure. Treated cases 308-3A). A small scar caused by an arrested lesion in the apices of the lung
of pulmonary TB also are predisposed to reinfection disease as discussed is called a Simon focus.
earlier. Latent TB infection is over 70% protective against reinfection TB.
Progressive Primary Tuberculosis
CLINICAL MANIFESTATIONS Failure to develop adaptive immunity is most common in young children, the
Primary Tuberculosis elderly, and the immunocompromised. Progressive primary TB manifested
Most cases of primary TB are unrecognized clinically except by conversion as TB meningitis, miliary TB, or disseminated TB may develop in this setting.
of the tuberculin skin test or IGRA. There may be fever, shortness of breath, Primary infection also may progress to pulmonary TB within the first 1 to 2
nonproductive cough, and rarely erythema nodosum. Crepitations and focal years. In this case pulmonary TB usually is in the upper lobe and cavitary,
wheezes may be present. Chest radiographs show small patchy opacities in distant from the site of primary infection. Recent data indicate that in high-
the mid-lung fields, often with unilateral hilar lymphadenopathy. Upper or prevalence areas most pulmonary TB cases represent progressive primary
middle lobe collapse may also be seen as a result of bronchial compression disease. Clinically, progressive primary and “post-primary” or reactivation TB
by enlarged nodes or transient pleural effusion. Studies with positron emis- are indistinguishable.
sion tomographic computed tomography (PET-CT) scan show that most
household contacts of infectious TB cases with a positive tuberculin skin test Reactivation (Post-primary) Tuberculosis
have mediastinal adenopathy that resolves with INH preventive therapy. HIV- The terms reactivation TB and post-primary TB are used interchangeably
infected and -uninfected persons with latent TB infection studied with this to connote that primary TB is followed by a variable period of at least 2
modality may show parenchymal uptake suggestive of subclinical disease. In years of clinical latency, after which TB develops in the setting of existing
most individuals (immunosuppression being the exception), the manifestations delayed-type hypersensitivity/adaptive immunity: existing sensitization to

mycobacterial antigens contributes importantly to the pathogenesis and clinical

manifestations.
Pulmonary TB is the most common form of reactivation TB. Typical clini-
cal findings in pulmonary TB consist of the insidious onset of a productive
cough, night sweats, anorexia, and weight loss. Fever is present in approximately
one half of those affected. Patients may be asymptomatic and the diagnosis
suggested only by a chest radiograph obtained for other reasons (subclinical
TB). The sputum may be purulent, blood streaked, or frankly bloody. Pleuritic
chest pain may occur when there is subpleural inflammation. Dyspnea is not
a hallmark of pulmonary TB, in part because thrombosis of vessels limits the
perfusion of inflamed areas, so that hypoxemia is not a prominent clinical
feature. Physical examination may show dullness to percussion, low-pitched
amphoric (hollow-sounding) breath sounds, and occasionally crepitations
that may be post-tussive. Chest radiographs often reveal more disease than
suggested by physical examination (see Fig. 308-3B and C). Typically (>95%
of cases), lesions are found in the apical and posterior segments of the upper
lobes and the superior (dorsal) segment of the lower lobe. There is a progression
from patchy opacities and consolidation to cavitation reflective of liquefac-
tion and caseation. Advanced imaging with PET-CT shows a heterogeneity
in metabolic activity of different lesions within the same patient (Fig. 308-4),
which may be associated with variable response to treatment and may in some
cases persist even after sterilization has been achieved. Rupture and discharge
into bronchi and intrabronchial spread may lead to disease in multiple areas,
including the other lung (so-called TB bronchopneumonia). There may be
involvement of the larynx and middle ear. Early cavities are thin walled and FIGURE 308-4. Positron emission tomographic computed tomography (PET-CT)
imaging. An 18F-fluorodeoxyglucose (FDG) PET-CT scan of a patient with tuberculosis
evolve into characteristic chronic thick-walled cavities. Ten percent of all with extensive bilateral disease and a complete collapse of the left lung. The right lung
cavities have an air-fluid level. There may be an associated pleural effusion also shows extensive disease throughout and illustrates the variability of FDG-PET uptake
or rarely, with rupture of cavities into the air space, pyopneumothorax. If the among lesions within even a single infected patient. The yellow star illustrates one lesion
disease is minimal, it may best be seen on apical lordotic chest radiographs that fails to take up FDG that lies immediately adjacent to a string of three lesions that
take up label avidly (red star). These different types of lesions respond to chemotherapy
or on CT scan. Rarely, chest radiographs are normal, and the accompanying with different kinetics, indicating that they represent distinct bacterial subpopulations
symptoms and positive sputum smears may be the result of endobronchial in different microenvironments. (From Barry CE 3rd, Boshoff HI, Dartois V, et al. The spec-
lesions or rupture of a tuberculous node into the bronchi. Healing, fibrosis, trum of latent tuberculosis. Rethinking the biology and intervention strategies. Nat Rev
and contraction obliterate small cavities, although large cavities may persist Microbiol. 2009;7:845-855, Figure 2.)
and even become the eventual nidus for an aspergilloma or a “scar” carcinoma.
In immunocompromised persons, the opacities may be located in the mid-
and lower lung fields and be manifested as poorly resolving lobar or segmental be concurrent pulmonary TB. Its peak occurrence is 3 to 6 months after primary
pneumonitis, atelectasis, nodules, and cavities. In individuals with HIV whose infection. The typical manifestation is abrupt onset of fever, pleuritic chest
CD4+ count exceeds 200/µL, pulmonary TB may be typical in its manifesta- pain, and cough. Occasionally there is an insidious presentation consisting of
tion. At lower CD4+ counts, mid- and lower lung abnormalities are more fever, weight loss, and malaise. If the pleural effusion is large enough, shortness
common. At a CD4+ count below 100/µL, the findings may be quite atypical, of breath may be seen. Physical examination shows dullness to percussion
with prominent hilar and mediastinal adenopathy, pleural disease, interstitial and decreased breath sounds. Above the area of dullness there may be true
or miliary opacities, or any combination of these manifestations. This picture egophony. Chest radiographs typically show unilateral pleural effusion, more
resembles primary TB and, in fact, may represent progressive primary TB or frequently in the right hemithorax. Bilateral disease occurs in 10% of cases.
reinfection disease. Chest radiographs are normal in up to 20% of persons Pleural effusions may be medium-sized, large, or, uncommonly, massive.
with culture-confirmed TB, sometimes in the presence of a smear that contains
AFB. In this CD4 strata, disseminated and extrapulmonary TB are the rule, Miliary Tuberculosis
with or without concurrent pulmonary TB. Miliary TB usually has an insidious manifestation consisting of fever, weight
loss, night sweats, and little in the way of localizing symptoms or signs. There
Reinfection Tuberculosis may be concurrent TB meningitis with associated symptoms. Physical exami-
Reinfection TB is clinically indistinguishable from other forms and an impor- nation may show choroidal tubercles (raised white-yellow plaques on fundu-
tant pathogenetic mechanism in high transmission settings. A documented scopic examination, present in 15% of cases), lymphadenopathy, and
change in the DNA fingerprint or sequence or occurrence in an outbreak hepatomegaly. Chest radiographs may show multiple bilateral small opacities
setting, including among patients hospitalized in TB wards, may be the only termed miliary infiltrates because of their resemblance to millet seeds. The
evidence supporting the diagnosis of reinfection TB. In high TB burden set- findings on initial chest radiographs are often subtle and may be clear-cut only
tings, individuals previously successfully treated for TB may have as high as in retrospect after 3 months of follow-up. Performance of CT or high-resolution
a five-fold risk compared to those with no history of developing TB disease, CT is useful because of its increased sensitivity (Fig. 308-5). A variant of
reflecting the high frequency of reinfection events that make up a high propor- miliary TB is disseminated areactive TB, as may occur in HIV-infected patients
tion of active cases. or those treated with TNF inhibitors. In this entity, chest radiographic findings
may be even more minimal or absent. In the HIV-infected individual with
Extrapulmonary Tuberculosis advanced immunodeficiency, blood cultures are positive for M. tuberculosis
Approximately 20% of cases of TB in non–HIV-infected populations are extra- in 20 to 40% of patients and may be the only laboratory manifestation of TB.
pulmonary (see Fig. 308-3D). In areas endemic for TB, extrapulmonary TB
often occurs concurrently with pulmonary TB and is more common in children Tuberculous Meningitis
and young adults, in whom it represents progressive primary infection. By TB meningitis is usually characterized by less than 2 weeks of fever, headache,
contrast, in low-prevalence areas, isolated extrapulmonary TB is more common, and meningismus.8 There may be depressed levels of consciousness, diplopia,
and there is a shift to the elderly that represents reactivation TB. HIV infection and (rarely) hemiparesis. Physical examination shows a stiff neck and occa-
is associated with a higher frequency of extrapulmonary disease, including sionally cranial neuropathy (VI, III, IV, VII in order of frequency) and long-
the more serious forms, disseminated TB and TB meningitis. tract signs. Chest radiographs may be consistent with pulmonary TB or miliary
TB. CT of the head may show contrast enhancement over the basilar meninges,
Pleural Tuberculosis hypodense areas consistent with infarcts, hydrocephalus, and sometimes focal
Pleural TB occurs by direct extension when a subpleural caseous focus dis- inflammatory lesions (tuberculomas). CT angiography may show entrapment
charges into the pleural space or through hematogenous seeding.7 There may of vessels or vasculitis.

2005
A B
FIGURE 308-5. Miliary tuberculosis in a 70-year-old man. A, Posteroanterior chest radiograph shows evenly distributed, discrete, uniformly millet-sized nodular opacities in both
lungs. B, High-resolution computed tomography (1.0-mm section thickness) at the level of the right upper lobar bronchus shows uniformly sized small nodules randomly distributed
throughout both lungs. Note the subpleural and subfissural nodules (arrows). (From Jeong YJ, Lee KS. Pulmonary tuberculosis: up-to-date imaging and management. AJR Am J Roent-
genol. 2008;191:834-844.)
Tuberculous Lymphadenitis often suggested by the finding of sterile pyuria or hematuria as initial abnor-
Lymphadenitis may be the sole manifestation of TB or, more frequently, par- malities that trigger evaluation. Physical examination is usually unremarkable.
ticularly in the HIV infected, may accompany pulmonary TB. Patients with CT shows renal cortical scarring, occasionally with mass or cavitary lesions,
isolated lymph node disease may be afebrile. The supraclavicular and posterior papillary necrosis with calyceal and ureteral dilation, or “beading” of the ureter
cervical lymph nodes are most frequently involved, referred to as scrofula. because of ureteral strictures.
This is in contrast to scrofula caused by atypical mycobacteria or M. bovis and
often seen in children, in whom submandibular and high anterior cervical Vertebral Osteomyelitis
adenopathy predominates. The lymphadenitis is not usually painful although The initial site of disease is the subchondral region of the anterior portion of
there may be tenderness and fluctuance, and aspiration of the lymph node the vertebral body.10 The lower thoracic and lumbar vertebrae are involved
with the finding of acid-fast bacilli (AFB) is an excellent approach to establish most commonly. The disc space is initially spared but becomes involved late
the diagnosis. with spread to adjacent vertebrae. Paravertebral “cold abscesses” may dissect
through tissue planes. Patients have back and sometimes radicular pain. Occa-
Tuberculous Pericarditis sionally and more often with cervical disease, there may be weakness of the
The usual manifestation of TB pericarditis is chronic but may occasionally be legs and incontinence of stool and urine. Physical examination may show a
subacute with fever, night sweats, chest pain, shortness of breath, pedal edema, gibbus deformity caused by anterior compression fractures or paraparesis.
and other signs of right heart failure.9 Physical examination shows signs of Radiographs of the spine, as well as CT and magnetic resonance imaging,
pericardial disease, right-sided heart failure, and tamponade (in ≈10%). Peri- may show abnormalities in adjacent vertebrae, with anterior compression (see
cardial aspiration and biopsy are the diagnostic procedures of choice. When Fig. 308-3D). Cold abscesses may be appreciated as well.
the pericardial effusion is large or tamponade is present, a pericardial window
can be both diagnostic and therapeutic. Other Forms of Extrapulmonary Tuberculosis
TB of the bone or joints may be manifested subacutely as a combination of
Tuberculous Peritonitis synovitis and osteomyelitis. The joints involved may have sustained previous
TB peritonitis may be accompanied by abdominal pain and fever, at times trauma. TB of the female genital tract may result in pelvic pain, menorrhagia,
mimicking an acute abdomen. Alternatively, there may be an insidious pre- vaginal discharge, or infertility. Males may have an epididymal mass, sometimes
sentation consisting of abdominal pain, swelling, night sweats, and weight seen in patients with miliary TB. TB also can cause granulomatous uveitis as
loss. The clinical syndrome is caused by discharge of tuberculous lymph nodes well as phlyctenular keratitis.
into the peritoneal space. Exudative ascites is usually present unless TB is
superimposed on preexisting transudative ascites, as in alcoholic liver disease. DIAGNOSIS
On physical examination, the abdomen has been described as “doughy,” because Infection with Mycobacterium Tuberculosis
matted loops of bowel may be palpable. A variant of this syndrome is perhaps The diagnosis of latent TB infection (we will use the term LTBI because
best termed abdominal TB. In this case, the abdominal pain is subacute, the it still is standard, although a better term is MTB infection) is based on
associated findings on physical examination less striking, and ascites less the finding of delayed-type hypersensitivity to mycobacterial antigens and
prominent or absent. The best method for diagnosis when ascites is present the absence of clinically active TB. The tuberculin skin test has been used
is laparoscopically guided peritoneal biopsy. In areas endemic for TB and widely, and there is strong epidemiologic evidence supporting its interpreta-
HIV, the finding of intra-abdominal lymphadenopathy on abdominal ultra- tion. Tuberculin purified protein derivative (PPD) derived from autoclaved
sound or CT is often used to support the diagnosis of abdominal TB. culture filtrates of M. tuberculosis is used to elicit delayed-type hypersensitivity.
The response elicited by PPD is nonspecific because of broad cross-reactivity
Gastrointestinal Tuberculosis among tuberculous and nontuberculous mycobacteria and other organisms
Patients with gastrointestinal TB have fever, abdominal pain, diarrhea, and as well. The tuberculin skin test is performed by injecting 5 tuberculin units
gastrointestinal bleeding or obstruction. Roentgenograms of the small bowel of PPD in 0.1 mL intradermally. The reaction is assessed as induration after
and abdominal CT show involvement of the terminal ileum, similar to Crohn 48 to 72 hours. Problems with the tuberculin skin test are legion. It is the
disease. The diagnosis is made on clinical suspicion in areas endemic for TB only bioassay used in clinical medicine, and its accuracy depends strongly on
and HIV or by the finding of TB elsewhere. Occasionally, intraluminal biopsy correct user application and interpretation The sensitivity of the tuberculin
of the terminal ileum or other involved sites is used to establish the skin test is less in immunosuppressed patients, such as those with HIV infec-
diagnosis. tion, and also less in the presence of active TB. The tuberculin skin test may
revert to negative over time, and it may be boosted by the repeat application
Renal Tuberculosis of PPD. On repeat testing the result is a “pseudoconversion” that does not
There may be few symptoms and signs associated with renal TB, although represent new infection with M. tuberculosis. The greatest limitation of the
occasionally dysuria, hematuria, and flank pain are present. The diagnosis is tuberculin skin test is its nonspecificity. There has been uncertainty in its

interpretation, particularly in the setting of previous vaccination with M. bovis tuberculin skin test in immunocompromised and perhaps all individuals, and
bacille Calmette-Guérin (BCG). In fact, BCG administered once at birth has that despite their increased cost, they are cost-effective in the United States.
little effect on the tuberculin skin test beyond the first year. By 10 years of Unfortunately, modeling currently is based on data that are quite variable
age, only 1% of positive tuberculin skin tests can be ascribed to previous BCG between studies. A fourth-generation test, Quantiferon-Gold PLUS also contains
administration. CD8 stimulatory antigens and is supplanting earlier generations of this IGRA.
The tuberculin skin test remains of value in the diagnosis of latent TB infec- Initial studies indicate similar performance to the Quantiferon-GOLD assay.
tion in at-risk individuals who are candidates for treatment (preventive therapy). In high TB–prevalence areas, the World Health Organization (WHO) rec-
Interpretation of the tuberculin skin test is based on a “sliding scale” that takes ommends preventive therapy for all HIV-infected persons because of the dif-
into account an individual’s a priori risk for M. tuberculosis infection (see Table ficulty in implementing a tuberculin skin test program that would identify
308-1). Changing the cut point for positives, in effect, modifies the sensitivity those who will achieve the greatest benefit of INH preventive therapy.
and specificity of the tuberculin skin test. Routine testing is not recommended
for low-risk populations; however, testing may be performed because of employ- Active Tuberculosis
ment. Certain populations should undergo annual testing, including staff or In countries with a high TB burden, the diagnosis of TB is often based on
individuals living or working in congregate settings (hospital staff, incarcerated, clinical symptoms and sputum microscopy. Clinical diagnosis without the
homeless, HIV-infected, correctional facility staff), injection drug users, and benefit of culture confirmation or radiography is the norm in endemic countries
others at risk because of sociodemographic factors. For individuals who will where access to diagnostics is limited. The diagnosis is also made on clinical
undergo an annual tuberculin skin test, a true baseline should be established grounds alone when smears are negative and suspicion for TB is high. Clinical
by two-step skin testing. After the initial negative tuberculin skin test, the test diagnosis is particularly important in HIV-infected persons because of the risk
is repeated in 1 to 3 weeks (there is no need to repeat the test if the first for rapid progression of the TB if left untreated, the more frequent occurrence
tuberculin skin test is positive). An increased reaction size on the second of AFB smear–negative pulmonary TB, and in those with forms of TB that are
tuberculin skin test is known as “boosting” and may be due to previous infec- “paucibacillary” (pediatric, meningeal, miliary, abdominal, pleural, pericardial),
tion with non-tuberculous mycobacteria or M. tuberculosis or vaccination with in which bacteria are few and AFB smears typically negative. The diagnosis
BCG. Tuberculin skin test conversion from negative to positive is the best of miliary, abdominal, pleural, and pericardial TB may be confirmed by the
indicator of intervening new infection with M. tuberculosis and is defined as finding of AFBs in biopsied tissue or by culture. In the absence of bacteriologic
an increase in reaction (induration) size of 6 mm or greater from less than confirmation, either because cultures (and GenXpert MTB/RIF) are unavail-
10 mm to 10 mm or greater. It also may be of value to perform a two-step able or because they are negative, the final diagnosis often relies on response
tuberculin skin test on individuals older than 60 years and therefore at risk to therapy or establishment of an alternative diagnosis. It should be noted
for tuberculin skin test reversion. that the empirical approach, taken of necessity in resource-limited settings,
In HIV infection, the tuberculin skin test may be negative before adminis- leads to overdiagnosis and overtreatment of TB, which expends TB program
tration of antiretroviral therapy (ART) and convert to positive with treatment. resources and delays treatment of other infections. It is therefore preferable
For this reason, it is recommended that the tuberculin skin test be repeated to attempt to establish a definite diagnosis based on the demonstration of M.
in tuberculin skin test–negative HIV-infected persons once their CD4+ count tuberculosis by smears, cultures, or nucleic acid amplification tests in infected
reaches 200/µL and annually thereafter. secretions or tissue specimens.
The sensitivity of the tuberculin skin test is decreased in individuals with Sputum microscopy is the standard approach to the diagnosis of pulmonary
active TB, more so in certain forms of extrapulmonary TB. Though insensitive TB. A smear requires 1000 to 10,000 bacilli/mL to be read as positive. Both
for the diagnosis of active TB, the tuberculin skin test has another application hot and cold carbol fuchsin methods (Ziehl-Neelsen and Kinyoun) are used
in low-prevalence areas. If the differential diagnosis of a clinical condition extensively. The use of fluorochrome stains such as auramine-rhodamine allows
includes TB, establishment of previous M. tuberculosis infection increases the more rapid screening of sputum smears and improves sensitivity by about
likelihood that the clinical findings represent TB. The tuberculin skin test is 10%. Three specimens, preferably early morning samples, should be examined
of particular value in the evaluation of smear-negative patients with pulmonary to establish the diagnosis. Yield is higher in the presence of cavitary lung
disease suggestive of pulmonary TB and in patients suspected of having extra- disease. Approximately one half of individuals with pulmonary TB are AFB
pulmonary TB. Confirmatory findings such as positive PCR, culture, or histol- sputum smear negative, and this proportion is higher in the HIV infected.
ogy, response to therapy, and lack of an alternative diagnosis are necessary to The quantity of AFBs present in the sputum smear is a rough measure of the
establish the diagnosis of TB. infectiousness of patients with pulmonary TB, and it is a convenient way to
Interferon gamma releasing assays (IGRAs) (QuantiFERON-TB PLUS, monitor response to treatment. On this basis, additional roles have evolved
T-test) have also been approved for the diagnosis of latent TB infection, and for the sputum smear as a tool to monitor the potential for transmission and
the CDC considers them interchangeable with the tuberculin skin test for response to therapy.
individuals over 2 years of age. The assays represent in vitro cell culture in HIV-infected persons with pulmonary TB carry a particular risk for trans-
which blood cells are stimulated with a mix of antigens present in M. tuber- mission to health care workers and have been documented as sources of
culosis but not in BCG and most nontuberculous mycobacteria. The main nosocomial outbreaks. Therefore, in the United States, in areas of high preva-
advantage of IGRAs is specificity and ability to have interpretable results with lence of TB, HIV-infected persons with pulmonary symptoms should be placed
only one patient visit. The disadvantages of IGRAs are expense, technical into respiratory isolation until infectious TB can be reasonably excluded by
requirements, and controversy over test sensitivity in certain situations such three negative sputum smears for AFB on specimens separated by at least 8
as HIV infection and in household contacts of patients with pulmonary TB. hours.
Another issue has been instability of the result in individuals undergoing annual The diagnosis of pediatric TB has always been problematic. Children do
testing with IGRAs close to the cut point. That said, IGRAs have come to not produce sputum readily, and TB is often noncavitary, extrapulmonary, or
replace TST in many settings due to the single visit requirement, lack of need both. Sputum samples may not be readily obtained from infants and children.
for operator experience, and higher specificity. Another factor is the current Options in this case include sputum induction and gastric aspiration. The
worldwide shortage of PPD. sensitivity of AFB smears of gastric aspirates and induced sputum is 25 to
Because treatment of latent TB infection is effective in tuberculin skin 30%. Recent studies indicate that induced sputum, culture of nasopharyngeal
test–positive HIV-infected persons, and the risk for progression of infection swabs, and GenXpert on stools have high enough yield so that gastric aspirates
is inordinately high in such individuals, it is important to perform tests with rarely are necessary. Nonetheless, the diagnosis often is based on clinical and
high negative predictive value. Therefore, both a tuberculin skin test and IGRA epidemiologic features as well as response to therapy.
should be performed in HIV-infected persons and others at high risk of pro- Bronchoscopy with bronchoalveolar lavage or transbronchial biopsy is
gression from M. tuberculosis infection to disease or of a poor outcome. Ideally another option for the diagnosis of TB and is useful in all severely ill individu-
the blood for IGRA should be drawn prior to TST placement to avoid false- als and the immunocompromised, in whom the diagnosis of TB or an alterna-
positive IGRA from the PPD. If either the tuberculin skin test or the IGRA tive infection must be made quickly if treatment is to have an impact on patient
is positive, the individual is a candidate for treatment of latent TB infection. outcome. Additionally, a post-bronchoscopy induced sputum has been shown
Recent studies indicate that IGRAs may be less sensitive than tuberculin skin to have higher yield.
test in household contacts recently infected with M. tuberculosis, a particularly AFB smears should be performed on normally sterile fluid obtained from
high-risk group. This may be due to delayed conversion of IGRAs relative to all patients suspected of having TB. The yield of smears from pleural fluid,
tuberculin skin test. Mathematical modeling suggests IGRAs should replace pericardial fluid, ascitic fluid, and cerebrospinal fluid (CSF) is low in patients

2007
with TB but may be higher in those with HIV coinfection, particularly if compared with 43% (23 to 66) for Xpert MTB/RIF, and 43% (23 to 66) for
immunodeficiency is advanced. In TB meningitis, CSF may clot spontane- culture.
ously, and AFB stains of the clot have increased yield. Rapid diagnosis of some There are other candidate nucleic acid amplification tests (NAATs) about
forms of extrapulmonary TB may be made by biopsy of tissue (pleural, peri- to undergo evaluation that are less expensive than GenXpert and may be truly
cardial, peritoneal, synovial, terminal ileum); the presence of granulomas, point of care. A1 For example, elevated blood levels of BATF2 (basic leucine
particularly if necrotizing, virtually confirms the diagnosis. Necrotizing granu- zipper transcription factor 2) are a sensitive biomarker for active TB.11 Diag-
lomas are seen in TB and fungal diseases (particularly histoplasmosis, blas- nostics for pediatric and extrapulmonary TB more sensitive than NAATs are
tomycosis, coccidioidomycosis, and sporotrichosis). AFBs may also be seen likely to be based on host responses. As regards host-based diagnostics, there
in tissue histology, and M. tuberculosis cultured from the specimen. are promising data based on transcriptomics, proteomics, and metabolomics.
The diagnosis of miliary TB can be suggested by CT of the chest and con- For example, a three-gene transcriptional signature proposed for the diagnosis
firmed by transbronchial lung biopsy (highest yield), as well as biopsy of the of TB is likely to be commercialized, and a 16-gene transcriptional signature
liver, bone marrow, or abnormal lymph nodes. If TB meningitis is suspected of risk indicates increased risk of developing TB within a 2-year time frame.
and the patient is immunosuppressed, it is particularly important to exclude As host-based diagnostics become available, a new category of subclinical TB
cryptococcal meningitis by performing a cryptococcal polysaccharide antigen may become easier to diagnose, a category which has been challenging because
test, as well as an India ink preparation on CSF sediment. by definition there are no symptoms and bacterial-based diagnostics are usually
The diagnosis of TB from specimens of normally sterile fluid can be difficult negative. The appropriate management of such patients is not clear because
and is increased by culturing relatively large volumes. In addition, the yield they may spontaneously resolve their minimal disease. If they are HIV infected
of biopsy and culture of tissue (pleura, pericardium) is additive. There are there will be the risk of “unmasking TB” with the start of ART. Even HIV-
particular diagnostic features for various forms of extrapulmonary TB. In TB uninfected patients they represent a high risk group with LTBI and probably
meningitis, the initial CSF examination may show neutrophil predominance, should be treated as such.
but this evolves into a lymphocytic meningitis (100 to 500 cells/µL) with TB in the HIV-infected patient poses particular diagnostic issues because
high protein and depressed glucose. TB of the pleura, pericardium, and peri- of the increased likelihood of smear-negative pulmonary TB, and in advanced
toneum is associated with an exudative effusion, often with a lymphocyte HIV, atypical presentation and extrapulmonary disease. The Alere Determine
predominance. Low glucose may be found in 20% of TB effusions but limits LAM TB test is a low-cost, rapid, lateral flow device (dipstick) that detects
the differential diagnosis considerably. For example, malignancy, empyema, lipoarabinomannan, the major cell wall glycolipid of M. tuberculosis. Its use
and rheumatoid arthritis are the other causes of pleural effusion with low as a TB diagnostic test improved survival of HIV-infected patients admitted
glucose. Pericardial fluid in patients with TB pericarditis may be bloody. to hospital with low CD4 counts (<100). The WHO has endorsed the test
Eosinophilic meningitis and chylous pleural effusions or ascites may also be for hospitalized HIV-infected individuals with CD4 lower than 100 and clinical
seen in TB. suspicion for TB.
Currently the gold standard for the diagnosis of TB is culture on solid New diagnostics also target rapid determination of drug susceptibility. The
(Löwenstein-Jensen) or in liquid (BACTEC MGIT 960 system) media. The Xpert MTB/RIF test described earlier detects the rpoB gene, where the major-
mycobacteria growth indicator tube (MGIT) system is non-radiometric and ity of mutations that confer rifampin resistance occur. A new cartridge allows
based on oxygen quenching in the presence of replicating mycobacteria. When rapid detection of mutations for isoniazid, fluoroquinolones, and second-line
compared with solid media, culture with liquid media is more sensitive and injectables.12 Similarly, the Hain Genotype MTBDRplus detects mutations
growth is more rapid (1 to 3 weeks vs. 3 to 8 weeks for solid media). Once for rifampin and for isoniazid (in katG and inhA promoter mutations) and
an isolate is available, drug susceptibility testing should be performed to guide more recently Genotype MTBDRsl detects mutations for fluoroquinolone
therapy. This takes an additional 2 to 4 weeks on solid media, although iso- and second-line injectables. The Genotype assays require the technician be
niazid (INH) and rifampin susceptibility results are available in several days trained in molecular methods, and results require several days. These molecular
when the molecular line probe assay (described later) is used. Liquid medium tests have been endorsed by the WHO for drug resistance detection. They
can be inoculated with smear-positive specimens for direct drug susceptibility allow drug susceptibility information to become available in many settings
testing, which also accelerates the process. Once mycobacterial growth occurs, for more patients than has been available with culture-based methods.
speciation is possible within hours with commercially available DNA probes.
Nuclear acid amplification tests are approved and commercially available for
use in TB diagnostics. Their sensitivity is somewhat higher than that of AFB TREATMENT
smears, and their specificity is excellent. Expense precludes routine use of
such tests, however. Comprehensive reviews of TB treatment provide complete information on
The Xpert MTB/RIF has transformed TB diagnosis globally. Through in drugs for TB, monitoring of therapy, management of adverse events, and treat-
situ DNA amplification reaction, this test allows a specific diagnosis of TB ment of pregnant women, children, and other special populations13:
https://www.cdc.gov/tb/publications/guidelines/pdf/clin-infect-dis.-2016-na-
and determination of susceptibility to rifampin within 90 minutes. After minimal
hid-cid_ciw376.pdf
processing, sputum is added to a cartridge. Gene amplification is done with Treatment of TB is both a clinical and a public health issue. The goals are to
primers based on the rpoB gene, which encodes the target of rifampin, and cure the patient and minimize transmission. For that reason, the treating physi-
resistance-conferring mutations are detected. This method is capable of estab- cian has the obligation to ensure that treatment is completed with good adher-
lishing the diagnosis of TB in 97% of patients with pulmonary TB, including ence to medications.14 Because of the declining number of TB cases in the
98% of AFB sputum smear–positive and 73% of smear-negative individuals, United States, with subsequent decline in expertise in TB management, treat-
thus rivaling the sensitivity of solid culture. It does not require molecular ment is more likely to occur in a public health clinic than in the private sector.
The cornerstone of TB treatment is multidrug therapy. This is necessary because
expertise by the technician and is not subject to amplicon (DNA) contamina-
M. tuberculosis undergoes spontaneous mutation to drug resistance at a fre-
tion, because it is a closed system. The uptake of GenXpert has been remark- quency such that most patients with cavitary lung disease—and therefore
able. The government of South Africa has replaced sputum smear analysis patients with a high burden of organisms—are likely to harbor resistant mutants.
with GenXpert for TB diagnosis. The government of Brazil is developing a For the treatment of TB caused by drug-susceptible organisms, there is an
similar policy. In Uganda, there will be a single reference laboratory for culture intensive phase of therapy for the first 2 months aimed at the rapidly dividing
and drug susceptibility testing (DST). GenXpert will be available regionally and metabolizing organisms and usually resulting in sterilization of sputum in
and used mainly for the diagnosis of smear-negative cases. GenXpert is priced those with pulmonary TB.15 This is followed by a 4- to 6-month continuation
differently for low-income countries, but cost still may be prohibitive in some phase that kills the slowly metabolizing persisting organisms. The four first-line
anti-TB drugs (all orally administered)—INH, rifampin, ethambutol, and pyra-
settings. The test allows more rapid diagnosis and initiation of treatment but zinamide—form the foundation of chemotherapy for TB. The precepts of therapy
has not led to more treated cases in high burden settings because many smear- have been largely defined by controlled clinical trials. Standard short-course
negative patients were receiving empiric treatment if clinical suspicion was therapy for pulmonary TB requires a 2-month intensive phase of four drugs
present. A new Xpert MTB/RIF Ultra cartridge was endorsed by the WHO (INH, rifampin, ethambutol, and pyrazinamide), followed by a 4-month continu-
as a replacement for the Xpert MTB/RIF cartridge in March, 2017. The car- ation phase with INH and rifampin. Pyridoxine should also be given to avoid
tridge has increased sensitivity, particularly among paucibacillary cases, but peripheral neuropathy from INH. Linezolid (600 mg daily) may be substituted
a slight decrease in specificity (from 98% to 96%). Encouraging is the test’s for ethambutol with equivalent results. A2
The use of intermittent dosing regimens increases the feasibility of directly
reported increased capacity to detect TB meningitis, in which sensitivity for observed therapy (DOT) but is controversial. Intermittent regimens may be
probable or definite infection was 70% (95% CI 47 to 87) for Xpert Ultra,

slightly less effective than daily 5/7 regimens (5 weekdays observed, 2 weekend non-nucleoside reverse transcriptase inhibitors (NRTIs). Because of its potency,
days self-administered). For patients with extensive cavitary disease and the simplicity, and proven clinical efficacy, efavirenz 600 mg with two NRTIs, along
severely immunosuppressed, daily therapy should be administered throughout with rifampin-based TB regimens, is the preferred strategy for co-treatment
the entire course. For HIV-infected persons with TB who are not severely immu- of HIV and TB. Rifabutin is off-patent and available as a less potent inducer of
nosuppressed, treatment should be daily during the intensive phase and at cytochrome enzymes, but its own pharmacokinetics can be affected by certain
least three times weekly during the continuation phase. Non–HIV-infected ARTs. Rifampin is the preferred rifamycin for efavirenz-containing regimens,
persons without extensive cavitary disease can be treated with intermittent whereas rifabutin should be used at a dose of 150 mg daily with a boosted
regimens throughout. The problem of nonadherence has led to the directive protease inhibitor. Rifampin can be used with dolutegravir at a doubled dose
to provide DOT. or rifabutin 300 mg daily can be used with daily dolutegravir. Patients should
The addition of pyrazinamide to the intensive phase allows for the so-called not be treated with tenofovir alafenamide (TAF) with rifamycins but switched
short-course chemotherapy; if pyrazinamide is not tolerated, comparable out- to alternative HIV regimens. Guidelines for other drug combinations to avoid
comes can be obtained with 9 months of INH-rifampin. Treatment of drug- drug interactions were updated in September 201417 and are available at https://
susceptible TB with this standard regimen can be expected to cure approximately www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/recommendations02.htm.
90 to 95% of cases. Routine monitoring of liver function test results is not Management of TB-HIV coinfection may be complicated for the clinician.
recommended unless there is preexisting liver disease. Patients should return For example, a new fever may be due to drug reaction, TB-IRIS, drug resistance,
to the clinic promptly with any signs of drug toxicity, particularly those of early or a complicating opportunistic infection.
hepatotoxicity (nausea, malaise, anorexia, upper abdominal discomfort). Visits
should be scheduled monthly and include clinical assessment and sputum
examinations. For those with pulmonary TB, sputum cultures are continued Drug-Resistant TB
until two consecutive cultures are negative. In uncomplicated pulmonary TB, Drug-resistant TB is more difficult to cure than drug-susceptible TB and in
defervescence is expected within 2 weeks, and there should be weight gain some instances may be incurable. Selection and monitoring of treatment for
and diminution of cough and chest pain. About 20% of patients with cavitary drug-resistant TB should be the responsibility of those experienced with the
pulmonary TB remain sputum culture positive after 2 months of therapy. A unique drug regimens and issues involved. It is clear that the addition of a
positive sputum culture at 3 months or failure to improve on chest radiographs single drug to a failing treatment regimen should never be done because it
suggests nonadherence with therapy, low drug levels due to malabsorption increases the risk of additional resistance development. A major problem is
or increased metabolism, drug-resistant TB, or an alternative or complicating the lack of information on drug susceptibility at the time of initiation of treat-
diagnosis. The etiology of the persistent positive culture should be pursued. ment. In resource-limited settings, drug susceptibility testing may not be avail-
Positive sputum culture at 4 months is defined as treatment failure. able at all. Although drug resistance can occur due to acquired resistance in
Extrapulmonary TB is usually associated with a smaller bacterial burden than an individual (the person is initially infected with a drug-susceptible strain that
is the case with pulmonary TB and can be treated with standard short-course becomes drug resistant due to poor adherence to medications, low quality
regimens of 6 to 9 months’ duration. However, because of the serious ramifica- drugs, weak regimen), recent molecular and modeling data show up to 70%
tions of treatment failure, more prolonged treatment of at least 9 to 12 months of drug-resistant strains occur due to transmission. Therefore, all individuals
is recommended for miliary, meningeal, and skeletal TB. Adjunctive surgical with TB disease would benefit from drug-susceptibility testing to ensure an
débridement and stabilization may be necessary for skeletal TB. Adjunctive effective regimen is given.
corticosteroids are indicated for TB pericarditis and severe pleurisy, as well as Monoresistance to INH has little effect on the outcome of TB treatment if
extensive pulmonary TB with clinical toxicity or respiratory failure. In TB men- identified early and adjustments to regimens are made. INH-monoresistant TB
ingitis, dexamethasone improves survival but has not had an impact on the can be treated with rifampin, pyrazinamide, and ethambutol for 6 months. A
proportion surviving with severe neurologic sequelae. Ventricular shunting may recent individual patient data meta-analysis suggests that addition of a fluo-
be necessary to relieve hydrocephalus. roquinolone to 6 to 9 months of rifampin, ethambutol, and pyrazinamide may
improve outcomes. A7 However, in much of the world INH resistance is not
detected unless an individual is failing a regimen, leading effectively to mono-
HIV-TB Coinfection therapy (rifampin alone) during the continuation phase. Ideally, routine testing
HIV-TB coinfection creates additional management issues. Fortunately, the for all relevant drugs should be seen as a critical step to improve TB outcomes.
response to treatment of TB is comparable to that in HIV-uninfected individuals, Acquisition of additional drug resistance is more likely if the initial isolate was
except for higher early mortality in individuals with low CD4 counts at treat- resistant to one drug (6%) or more than one drug (14%) versus being pansus-
ment initiation. Intermittent regimens have a tendency to lead to rifampin ceptible (0.8%).
resistance; therefore, daily administration of drugs is recommended throughout. MDR TB represents a more significant treatment challenge.18 Not only is cure
In a randomized trial among HIV-positive patients with pulmonary TB receiving difficult and extremely expensive, but unrecognized MDR TB can lead to noso-
antiretroviral therapy, a daily anti-TB regimen proved superior to a thrice-weekly comial outbreaks and rapid and high rates of fatality. In 2016, less than a quarter
regimen in terms of efficacy and emergence of rifampicin resistance. A3 In of the estimated 600,000 rifampin-resistant TB cases started MDR TB treatment
resource-limited settings, the administration of cotrimoxazole prophylaxis is and only 54% of those initiating care in 2014 had successful outcomes (cure
associated with improved survival. Integration of the treatment of TB and HIV or treatment completion). There is no substitute for performing drug suscep-
rather than sequential treatment of first TB and then HIV is associated with a tibility testing that includes all first-line and available second-line drugs on an
56% reduction in mortality. The results of three randomized controlled trials initial specimen in order to ensure an effective regimen is given. MDR TB is not
support the current U.S. Department of Health and Human Services and Infec- a homogeneous entity; some isolates are only resistant to INH and rifampin
tious Diseases Society of America guideline to start ART 2 weeks after initiation but half of MDR TB cases globally have resistance to pyrazinamide as well.
of TB treatment if CD4+ count is below 50 cells/µL. A4 Early ART in HIV-infected Patients with resistance to additional first- and second-line drugs benefit from
adults with newly diagnosed TB improves survival in patients with CD4+ T-cell more individualized regimens with newer drugs.19
counts lower than 50 cells/µL, although treatment is associated with a 2-fold In October 2016, the WHO published updated guidelines for drug-resistant
increased risk of TB-immune reconstitution inflammatory syndrome (TB-IRIS) TB. The biggest modification is the availability of the shorter MDR TB regimen
(Chapter 367).16 TB-IRIS is more likely to occur when the CD4+ count is low, the for adults and children, including those with HIV coinfection. The shorter regimen
viral load is high, and the interval between starting TB drugs and ART is short. is 7 drugs (moxifloxacin, kanamycin, ethionamide, clofazamine, high-dose iso-
Immune reconstitution is associated with inflammation and transient exacerba- niazid, pyrazinamide, and ethambutol) for 4 to 6 months followed by 4 drugs
tion of disease mimicking progression of TB. There may, for example, be fever, (moxifloxacin, clofazamine, pyrazinamide, and ethambutol) for another 5 to 6
lymphadenitis, and worsening parenchymal disease, including consolidation months, making the total course 9 to 12 months. A8 A8b These regimens are
,
and new or progressing nodular opacities on chest radiographs. In about one recommended in patients with rifampin-resistant or MDR TB who were not
third of dually infected patients, IRIS will develop within the first 2 months of previously treated with second-line drugs and in whom resistance to fluoro-
treatment and often within the first 2 to 3 weeks of starting ART. TB-IRIS usually quinolones and second-line injectable agents was excluded or is consider highly
is not an important cause of mortality. A controlled trial has shown that corti- unlikely. If resistance to any drugs other than isoniazid in the regimen are
costeroid therapy limits morbidity, A5 although it is not useful for treating tuber- known, then the short course is also not recommended.
culous pericarditis. A6 More problematic is IRIS associated with respiratory failure For all other patients, the cornerstone of treatment of MDR TB is the tradi-
or neurologic involvement. Initiation of ART in HIV-infected persons may also tional regimen which includes at least five drugs to which the isolate is sus-
be associated with “unmasking TB,” which occurs within 3 months. This may be ceptible. Typically, the regimen will include first-line drugs with retained activity,
due to a missed diagnosis of TB in screening, the development of inflammation a fluoroquinolone (FQ), an injectable (amikacin, kanamycin, or capreomycin),
at sites of mycobacterial replication in tissue, or progression of latent infection and second-line drugs (ethionamide, cycloserine, PAS) with the goal of five
consequent to ART. Unmasking TB is common in countries endemic for TB (5 effective drugs in the regimen. The duration of treatment is set at 18 to 24
to 10% in Uganda, for example, but about 25% in South Africa) and associated months. Residual susceptibility to FQ treatment and capreomycin has been
with morbidity, mortality, and risk for nosocomial transmission. shown to be a determinant of treatment outcome. Surgical resection is a con-
In general, TB does not affect the response of HIV to ART. A major issue, sideration if the disease is localized, sputum remains culture positive, medical
however, is the interactions between rifamycins that induce CYP3A hepatic therapy is not tolerated, or massive hemoptysis is present. Cure rates of 60 to
microsomal enzymes and protease inhibitors, integrase inhibitors, and some 80% can be expected if therapy is targeted to drug susceptibility test results

2009
and MDR organisms remain sensitive to enough chemotherapeutic drugs that

a reasonable regimen can be established. The U.S. Food and Drug Administra- TABLE 308-2 TREATMENT OF LATENT TUBERCULOSIS
tion (FDA) also approved both bedaquiline and delamanid for the treatment DRUG REGIMEN ADULT DOSE
of MDR TB, although bedaquiline is not yet recommended in children. Beda-
quiline, a diarylquinoline, targets mycobacterial ATP synthase, and delamanid, Isoniazid alone for 6 or 9 months 5 mg/kg (maximum 300 mg daily)
a nitrodihydro-imidazooxazole, inhibits M. tuberculosis mycolic acid synthesis. Rifampin alone for 4 months 10 mg/kg (maximum 600 mg daily)
Increasingly bedaquiline is being substituted for the aminoglycoside to avoid
Weekly rifapentine plus isoniazid Rifapentine, 15-30 mg/kg (maximum 900 mg);
the injectable agent and its toxicity. These are the first new classes of TB treat-
for 3 months isoniazid, 15 mg/kg (maximum 900 mg)
ment drugs to be approved by the FDA in 40 years. They are revolutionizing
management of MDR TB. Adapted from Getahun H, Matteelli A, Chaisson RE, et al. Latent Mycobacterium tuberculosis
The definition of extensively drug-resistant TB is an organism that is MDR infection. N Engl J Med. 2015;372:2127-2135.
with additional resistance to an FQ plus at least one of three injectables (ami-
kacin, kanamycin, capreomycin). The outcome of treatment of extensively
drug-resistant TB has been variable. The best reported results have been obtained absence of current fever, weight loss, or night sweats has a negative predictive
in Peru, with a comprehensive approach that included therapeutic regimens value of 97%, may obviate the need for chest radiography if it is not routinely
that were tailored according to drug susceptibility testing. Effective regimens available, and identifies a group that should be treated with INH preventive
included cycloserine, capreomycin, and PAS. Moxifloxacin may be active even
treatment regardless of tuberculin skin test status. Although INH preventive
if the isolate is resistant to first-generation FQs. Adjunctive surgery should be
considered. The newest drugs have become backbones for these regimens therapy is the preferred regimen, there is renewed interest in the possibility
where they are available. Studies indicate that linezolid has remarkable activity that rifamycin-containing regimens may confer more sustained protection.
against extensively drug-resistant TB, A9 and other oxazolidinones are in devel- A recently completed study of HIV-infected individuals reports that daily
opment for TB treatment. isoniazid plus rifapentine for one month was noninferior to 9 months of iso-
The emergence of drug resistance has emphasized the need for new drugs niazid, had fewer adverse events, and was more likely to be completed. A14 This
and new drug regimens. A drug regimen that shortens the course of TB would ultra-short course may become the standard in the future. Currently no standard
lessen the emergence of drug resistance, because adherence would increase recommended treatment is available for contacts of MDR TB cases. Experts
and DOT would be simplified. Once MDR TB develops, particularly in the setting
of extensively drug-resistant TB, new drugs are necessary to improve efficacy recommend considering fluoroquinolone-based preventive therapy. Three
and shorten treatment. randomized controlled trials are planned to evaluate the effectiveness of pre-
There are promising developments with existing classes of drugs and with ventive therapy for infected MDR TB contacts and include levofloxacin, iso-
new classes about to enter or already in clinical trials. Rifapentine, a rifamycin niazid, or delamanid.
with a longer half-life than rifampin, shows remarkable enhancement of ster- Secondary preventive therapy after completion of TB treatment is indicated
ilization of sputum at 2 months. Moxifloxacin has increased activity against M. in HIV-infected persons in the setting of intense exposure to M. tuberculosis.
tuberculosis, although data of its efficacy in 4-month regimens have been disap- Data demonstrating efficacy of secondary prevention largely result from studies
pointing. Pretomanid, a nitroimidazole, is now being trialed with bedaquiline
and linezolid as an all oral, short-course regimen for drug-resistant TB.
of adults in Congo and gold miners in South Africa.
A randomized controlled trial has demonstrated that in HIV-positive patients,
early initiation of ART as compared with delayed treatment (where there was
a decline in CD4 counts or AIDS-related illness had already occurred) led to
PREVENTION a significant decrease in the development of TB. A15
The CDC guidelines for treatment regimens for latent TB infection, updated Tracing of household contacts is a critical element of TB programs. The
June 2017, include recommendations for HIV coinfected individuals, children, household is a major site of TB transmission, particularly in an area of low
and pregnant women (https://www.cdc.gov/tb/topic/treatment/ltbi.htm). endemicity, so treatment of TST or IGRA converters is an important strategy
The approach taken in a low-prevalence setting such as the United States for elimination of TB. In a high TB prevalence setting in Vietnam, a cluster-
is to target testing to those at high risk for recent M. tuberculosis infection and randomized, controlled trial found that household-contact intervention plus
to those with comorbid conditions that predispose to progression from infec- standard passive case finding was more effective than standard passive case
tion to disease. In either category, a positive test (IGRA or TST) becomes an finding alone for the detection of sputum smear-positive TB. A16 It is essential
indication for treatment of latent TB infection. Providers should only test that transmission be limited in hospitals and other settings in which infectious
individuals for TB infection as part of a work-up for active TB or if they plan pulmonary TB patients may comingle with susceptible hosts. The risk of
to offer TB prophylaxis. transmission to health care workers should be ascertained annually by skin
Latent TB infection can be treated with rifampin for 4 months, INH for 6 testing. The finding of excessive risk for new TB infection should lead to
to 9 months, or INH plus rifapentine weekly for 3 months (12 doses), thereby focused measures for reducing transmission. All TB suspects should be placed
decreasing the lifetime risk for development of TB by approximately 75 to in respiratory isolation in negative-pressure rooms with at least six air exchanges
90%, depending on the level of adherence to treatment (Table 308-2).20 These per hour and high-efficiency particulate air (HEPA) filtration or ultraviolet
recommendations are consistent with an updated A10 network meta-analysis of irradiation. N-95 personnel respirator devices that are fit-tested are necessary
the best LTBI treatment options upon which these recommendations were for individuals entering areas with a known high risk for exposure.
originally based. A11 Pyridoxine should be administered to prevent INH-induced BCG vaccine is widely used and relatively safe except in the setting of
peripheral neuropathy in those at risk. Monitoring of liver function is indi- immunosuppression. Unfortunately, efficacy has been variable by age and by
cated in older individuals (the risk for hepatotoxicity increases beyond the latitude. A meta-analysis indicated an overall efficacy of 50%. It is approximately
age of 35 years) and in those with significant alcohol intake or underlying 80% effective in preventing the severe forms of TB in childhood, miliary TB,
liver disease (or both). INH should be discontinued if symptoms develop and TB meningitis. However, its failure to prevent adult TB, particularly at
(see Treatment) or hepatic transaminase levels rise to more than three to low latitudes that include the most endemic areas, means that BCG vaccine
five times the upper limit of normal. Rifapentine plus INH once weekly for does not have an impact on the public health problem of TB. An experimental
3 months (12 doses) is as effective as 9 months of INH alone in preventing protective vaccine has shown promise in reducing cases of active pulmonary
active TB in patients with latent infection. A12 Administration of this regimen tuberculosis. A17 However, the natural history of TB is such that large, lengthy,
should be directly observed, although more recent research has shown that and expensive trials may be needed to establish protective efficacy.
in the United States self-administration may be noninferior. A13 Side effects
from rifapentine, including hypersensitivity reaction, should be monitored. PROGNOSIS
In HIV-infected persons in high TB burden settings, treatment of latent TB In the pre-chemotherapeutic era, minimal pulmonary TB stabilized in about
infection confers short-term efficacy (≈1 year), but this may be extended if 50% of cases. Pleural TB also self-cured, with a risk for reactivation as noted
ART is administered. Treatment for 3 years with isoniazid in HIV-infected previously. With treatment, the prognosis of patients with TB depends on
persons confers an additional benefit that is most marked in the tuberculin the extent of pulmonary TB, the sites of extrapulmonary TB, drug susceptibil-
skin test positives in high TB burden settings. Unfortunately, treatment of ity of the isolate, and the presence of HIV infection and other comorbid
latent TB infection has not been applied broadly. This is in part due to the conditions. With extensive pulmonary TB, respiratory failure may supervene
concern that if screening is inadequate, patients with active TB will be treated with a poor prognosis. There is also increased risk for serious, sometimes
with a single drug and thereby acquire drug resistance. The available data do lethal, hemoptysis and pneumothorax. Miliary TB is associated with a high
not support this concern. In a low-resource setting in the HIV infected, the case-fatality rate, in part related to delays in diagnosis. TB meningitis is
associated with serious neurologic residua, as well as high mortality. MDR
TB and extensively drug-resistant TB are accompanied by high rates of treat-
ment failure, morbidity, and mortality. TB in HIV-infected persons is associated
with high early mortality that is poorly characterized. In the absence of ART,
there is increased risk for other opportunistic infections and progression of
HIV disease. The addition of ART, however, results in the morbidities associ-
ated with concurrent administration of TB and HIV medications and with
TB-IRIS. Long-term outcomes of South African patients with extensively
drug-resistant TB were poor irrespective of HIV status, and because of the
scarcity of long-stay or palliative care facilities, substantial numbers of patients
with extensively drug-resistant TB who had failed treatment and had positive
sputum cultures were being discharged to likely transmit disease into the
wider community.
Grade A References
A1. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert
MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised,
controlled trial. Lancet. 2014;383:424-435.
A2. Lee JK, Lee JY, Kim DK, et al. Substitution of ethambutol with linezolid during the intensive phase
of treatment of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label, phase
2 trial. Lancet Infect Dis. 2019;19:46-55.
A3. Gopalan N, Santhanakrishnan RK, Palaniappan AN, et al. Daily vs intermittent antituberculosis
therapy for pulmonary tuberculosis in patient with HIV: a randomized clinical trial. JAMA Intern
Med. 2018;178:485-493.
A4. Blanc F-X, Sok T, Laureillard D, et al. Earlier vs later start of antiviral therapy in HIV-infected adults
with tuberculosis. N Engl J Med. 2011;365:1471-1481.
A5. Meintges G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone
for paradoxical tuberculosis-associated immune reconstitution syndrome. AIDS. 2010;24:2381-2390.
A6. Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and Mycobacterium indicus pranii in tuberculous
pericarditis. N Engl J Med. 2014;371:1121-1130.
A7. Fregonese F, Ahuja SD, Akkerman OW, et al. Comparison of different treatments for isoniazid-
resistant tuberculosis: an individual patient data meta-analysis. Lancet Respir Med. 2018;6:265-275.
A8. Duan H, Chen X, Li Z, et al. Clofazimine improves clinical outcomes in multidrug-resistant tuber-
culosis: a randomized controlled trial. Clin Microbiol Infect. 2019;25:190-195.
A8b. Nunn AJ, Phillips PPJ, Meredith SK, et al. A trial of a shorter regimen for rifampin-resistant
tuberculosis. N Engl J Med. 2019;380:1201-1213.
A9. Lee M, Lee J, Carroll MW, et al. Linezolid for treatment of chronic extensively drug resistant tuber-
culosis. N Engl J Med. 2012;367:1508-1518.
A10. Menzies D, Adjobimey M, Ruslami R, et al. Four months of rifampin or nine months of isoniazid
for latent tuberculosis in adults. N Engl J Med. 2018;379:440-453.
A11. Zenner D, Beer N, Harris RJ, et al. Treatment of latent tuberculosis infection: an updated network
meta-analysis. Ann Intern Med. 2017;167:248-255.
A12. Sterling TR, Villarino ME, Borisov AS, et al. Three months of rifapentine and isoniazid for latent
tuberculosis infection. N Engl J Med. 2011;365:2155-2166.
A13. Belknap R, Holland D, Feng PJ, et al. Self-administered versus directly observed once-weekly iso-
niazid and rifapentine treatment of latent tuberculosis infection: a randomized trial. Ann Intern
Med. 2017;167:689-697.
A14. Swindells S, Ramchandani R, Gupta A, et al. One sent HIV-related tuberculosis. N Engl J Med.
2019;380:1001-1011.
A15. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of
antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN
052 randomised controlled trial. Lancet Infect Dis. 2014;14:281-290.
A16. Fox GJ, Nhung NV, Sy DN, et al. Household-contact investigation for detection of tuberculosis in
Vietnam. N Engl J Med. 2018;378:221-229.
A17. Van Der Meeren O, Hatherill M, Nduba V, et al. Phase 2b controlled trial of M72/AS01E vaccine
to prevent tuberculosis. N Engl J Med. 2018;379:1621-1634.
GENERAL REFERENCES
For the General References and other additional features, please visit Expert Consult
at https://expertconsult.inkling.com.

2010.e1
GENERAL REFERENCES 12. Xie YL, Chakravorty S, Armstrong DT, et al. Evaluation of a rapid molecular drug-susceptibility test
for tuberculosis. N Engl J Med. 2017;377:1043-1054.
1. Floyd K, Glaziou P, Zumla A, et al. The global tuberculosis epidemic and progress in care, prevention, 13. Horsburgh CR Jr, Barry CE 3rd, Lange C. Treatment of tuberculosis. N Engl J Med. 2015;373:
and research: an overview in year 3 of the End TB era. Lancet Respir Med. 2018;6:299-314. 2149-2160.
2. Daley CL. The global fight against tuberculosis. Thorac Surg Clin. 2019;29:19-25. 14. Nahid P, Dorman SE, Alipanah N, et al. Executive summary: official American Thoracic Society/
3. Stewart RJ, Tsang CA, Pratt RH, et al. Tuberculosis—United States, 2017. MMWR Morb Mortal Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice
Wkly Rep. 2018;67:317-323. Guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63:853-867.
4. Mancuso JD, Diffenderfer JM, Ghassemieh BJ, et al. The prevalence of latent tuberculosis infection 15. Furin J, Cox H, Pai M. Tuberculosis. Lancet. 2019;393:1642-1656.
in the United States. Am J Respir Crit Care Med. 2016;194:501-509. 16. Uthman OA, Okwundu C, Gbenga K, et al. Optimal timing of antiretroviral therapy initiation for
5. Park M, Satta G, Kon OM. An update on multidrug-resistant tuberculosis. Clin Med (Lond). HIV-infected adults with newly diagnosed pulmonary tuberculosis: a systematic review and meta-
2019;19:135-139. analysis. Ann Intern Med. 2015;163:32-39.
6. Shah NS, Auld SC, Brust JC, et al. Transmission of extensively drug-resistant tuberculosis in South 17. Centers for Disease Control and Prevention. Managing drug interactions in the treatment of HIV-
Africa. N Engl J Med. 2017;376:243-253. related tuberculosis. http://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/default.htm/.
7. Shaw JA, Irusen EM, Diacon AH, et al. Pleural tuberculosis: a concise clinical review. Clin Respir J. Accessed April 29, 2019.
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Curr Opin Infect Dis. 2017;30:123-128. drugs, treatment regimens, and host-directed therapies. Lancet Infect Dis. 2018;18:e183-e198.
9. Chang SA. Tuberculous and infectious pericarditis. Cardiol Clin. 2017;35:615-622. 20. Getahun H, Matteelli A, Chaisson RE, et al. Latent Mycobacterium tuberculosis infection. N Engl J
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tuberculosis. JCI Insight. 2016;1:1-15.
2010.e2 CHAPTER 308 Tuberculosis

REVIEW QUESTIONS 4. Which of the following is true concerning treatment of MDR TB:
1. The following is true of tuberculosis (TB) in the United States: A . The strategy of adding a single drug to retreatment regimens is
cost-effective.
A . Most cases are in the foreign born. B. Empirical therapy is as good as tailoring regimen to drug
B. Most cases are in the HIV infected. susceptibility.
C. The elderly are not at risk. C. Acquisition of additional drug resistance is unlikely.
D. The period of greatest risk of progression is 5 years and longer after D. Standard duration of therapy (6 months) is adequate.
infection. E. New drugs with potent activity now are available.
E. Outbreaks are a major source of multidrug-resistant (MDR) TB cases.
Answer: E Bedaquiline and delamanid have been approved by the FDA.
Answer: A Foreign-born individuals account for over 60% of U.S. TB cases. Adding a single drug to a retreatment regimen is inadequate in one fourth of
The greatest risk of progressing to disease is in the first and second years after cases.
infection. Outbreaks have been limited by application of infection control
measures.
5. Which of the following is true regarding treatment of latent TB infection
(LTBI)?
2. Advantages of interferon gamma release assays (IGRAs) such as Quantiferon-
Gold for the diagnosis of latent TB infection include all the following A . There is a prolonged effect in HIV-infected persons.
except: B. A 12-dose regimen of rifapentine-isoniazid is effective.
C. Treatment requires both a positive TST and IGRA.
A . More specific than tuberculin skin test (TST) D. There is no need to monitor for adverse events.
B. Reproducible results in health care workers E. Screening in HIV-infected patients in resource-limited settings requires
C. Does not require return visits chest x-ray and culture.
D. End points are objective.
E. Antigens are not found in BCG. Answer: B A 12-dose course of rifapentine-isoniazid is effective. The efficacy
of isoniazid preventive therapy in HIV-infected patients in high-transmission
Answer: B There is lack of reproducibility in serial testing, particularly if the settings wanes after 6 to 12 months.
“positive” is close to end point.
3. The advantages of GenXpert MTB/RIF for the diagnosis of TB include

all the following except:
A . Useful in monitoring therapy
B. More sensitive than smear
C. Does not require proficiency in molecular technology
D. More rapid than culture
E. Provides rifampin susceptibility
Answer: A Not useful in monitoring therapy; the presence of Mycobacterium
tuberculosis DNA in sputum does not indicate that there are viable
organisms.

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2000 CHAPTER 308 Tuberculosis

TABLE 308-1 RISK FACTORS FOR TUBERCULOSIS

outbreaks occurring in residential shelters, hospitals, and prisons, M. tuberculosis

Effect of HIV infection

mycobacterial antigens contributes importantly to the pathogenesis and clinical

and MDR organisms remain sensitive to enough chemotherapeutic drugs that

3. The advantages of GenXpert MTB/RIF for the diagnosis of TB include

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