1365CHAPTER 178 Tuberculosis

administration may reduce the duration of fever and/or chest pain but

is not of proven benefit.

Tuberculous empyema is a less common complication of pulmonary

TB. It is usually the result of the rupture of a cavity, with spillage of a

large number of organisms into the pleural space. This process may

create a bronchopleural fistula with evident air in the pleural space.

CXR shows hydropneumothorax with an air-fluid level. The pleural

fluid is purulent and thick and contains large numbers of lymphocytes.

Acid-fast smears and mycobacterial cultures are often positive. Surgical

drainage is usually required as an adjunct to chemotherapy. Tuberculous empyema may result in severe pleural fibrosis and restrictive lung

disease. Removal of the thickened visceral pleura (decortication) is

occasionally necessary to improve lung function.

TB of the Upper Airways Nearly always a complication of

advanced cavitary pulmonary TB, TB of the upper airways may involve

the larynx, pharynx, and epiglottis. Symptoms include hoarseness,

dysphonia, and dysphagia in addition to chronic productive cough.

Findings depend on the site of involvement, and ulcerations may be seen

on laryngoscopy. Acid-fast smear of the sputum is often positive, but

biopsy may be necessary in some cases to establish the diagnosis. Carcinoma of the larynx may have similar features but is usually painless.

Genitourinary TB Genitourinary TB, which accounts for ~10–

15% of all extrapulmonary cases in the United States and elsewhere,

may involve any portion of the genitourinary tract. Clinical manifestations are cryptic and protean. Patients may be asymptomatic and their

disease discovered only after destructive lesions of the kidneys have

developed. Symptoms are often nonspecific, and include those of urinary tract infection with frequency, dysuria, nocturia and hematuria,

and abdominal or flank pain. Without a high index of suspicion, this

form of TB may result in delayed diagnosis with irreversible organ

damage. Up to 75% of patients have abnormalities on CXR suggesting

previous or concomitant pulmonary disease. Urinalysis gives abnormal

results in 90% of cases, revealing pyuria and hematuria. The documentation of culture-negative pyuria in acidic urine should raise the

suspicion of TB. IV pyelography, abdominal CT, or MRI (Fig. 178-9)

may show deformities and obstructions; calcifications and ureteral

strictures are suggestive findings. Culture of three morning urine

specimens yields a definitive diagnosis in nearly 90% of cases. Severe

ureteral strictures may lead to hydronephrosis, serious renal damage,

and, ultimately, renal failure. Genital TB is diagnosed more commonly

in female than in male patients. In female patients, it affects the fallopian tubes and the endometrium and may cause infertility, pelvic pain,

and menstrual abnormalities. Diagnosis requires biopsy or culture of

specimens obtained by dilation and curettage. In male patients, genital

TB preferentially affects the epididymis, producing a slightly tender

mass that may drain externally through a fistulous tract; orchitis and

prostatitis may also develop. In almost half of cases of genitourinary

TB, urinary tract disease is also present. Genitourinary TB responds

well to chemotherapy.

Skeletal TB In the United States, TB of the bones and joints is

responsible for ~10% of extrapulmonary cases. In bone and joint disease, pathogenesis is related to reactivation of hematogenous foci or

to spread from adjacent paravertebral lymph nodes. Weight-bearing

joints (the spine in 40% of cases, the hips in 13%, and the knees in 10%)

are most commonly affected. Spinal TB (Pott’s disease or tuberculous

spondylitis; Fig. 178-10) often involves two or more adjacent vertebral

bodies. Whereas the upper thoracic spine is the most common site of

spinal TB in children, the lower thoracic and upper lumbar vertebrae

are usually affected in adults. From the anterior superior or inferior

angle of the vertebral body, the lesion slowly reaches the adjacent body,

later affecting the intervertebral disk. With advanced disease, collapse

of vertebral bodies results in kyphosis (gibbus). A paravertebral “cold”

abscess may also form. In the upper spine, this abscess may track to and

penetrate the chest wall, presenting as a soft tissue mass; in the lower

spine, it may reach the inguinal ligaments or present as a psoas abscess.

CT or MRI reveals the characteristic lesion and suggests its etiology.

The differential diagnosis includes tumors and other infections. Pyogenic bacterial osteomyelitis, in particular, involves the disk very early

and produces rapid sclerosis. Aspiration of the abscess or bone biopsy

confirms the tuberculous etiology, as cultures are usually positive and

histologic findings highly typical. A catastrophic complication of Pott’s

disease is paraplegia, which is usually due to an abscess or a lesion compressing the spinal cord. Paraparesis due to a large abscess is a medical

emergency and requires rapid drainage. TB of the hip joints, usually

involving the head of the femur, causes pain; TB of the knee produces

pain and swelling. If the disease goes unrecognized, the joints may be

destroyed. Diagnosis requires examination of the synovial fluid, which

is thick in appearance, with a high protein concentration and a variable

cell count. Although synovial fluid culture is positive in a high percentage of cases, synovial biopsy and tissue culture may be necessary

to establish the diagnosis. Skeletal TB responds to chemotherapy, but

severe cases may require surgery.

Tuberculous Meningitis and Tuberculoma TB of the central

nervous system (CNS) accounts for ~5% of extrapulmonary cases in

FIGURE 178-9 MRI of culture-confirmed renal tuberculosis. T2-weighted coronary

plane: coronal sections showing several renal lesions in both the cortical and the

medullary tissues of the right kidney. (Courtesy of Dr. Alberto Matteelli, Department

of Infectious Diseases, University of Brescia, Italy; with permission.)

FIGURE 178-10 CT scan demonstrating destruction of the right pedicle of T10 due

to Pott’s disease. The patient, a 70-year-old Asian woman, presented with back pain

and weight loss and had biopsy-proven tuberculosis. (Courtesy of Charles L. Daley,

MD, University of California, San Francisco; with permission.)

1366 PART 5 Infectious Diseases

the United States. It is seen most often in young children but also develops in adults, especially those infected with HIV. Tuberculous meningitis results from the hematogenous spread of primary or postprimary

pulmonary TB or from the rupture of a subependymal tubercle into

the subarachnoid space. In more than half of cases, evidence of old

pulmonary lesions or a miliary pattern is found on CXR. The disease

often presents subtly as headache and slight mental changes after a prodrome of weeks of low-grade fever, malaise, anorexia, and irritability. If

not recognized, tuberculous meningitis may evolve acutely with severe

headache, confusion, lethargy, altered sensorium, and neck rigidity.

Typically, the disease evolves over 1–2 weeks, a course longer than that

of bacterial meningitis. Because meningeal involvement is pronounced

at the base of the brain, paresis of cranial nerves (ocular nerves in particular) is a frequent finding, and the involvement of cerebral arteries

may produce focal ischemia. The ultimate evolution is toward coma,

with hydrocephalus and intracranial hypertension.

Lumbar puncture is the cornerstone of diagnosis. In general, examination of cerebrospinal fluid (CSF) reveals a high leukocyte count (up

to 1000/μL), usually with a predominance of lymphocytes but sometimes with a predominance of neutrophils in the early stage; a protein

content of 1–8 g/L (100–800 mg/dL); and a low glucose concentration.

However, any of these three parameters can be within the normal

range. AFBs are infrequently seen on direct smear of CSF sediment,

and repeated lumbar punctures increase the yield. Culture of CSF is

diagnostic in up to 80% of cases and remains the gold standard. Realtime automated nucleic acid amplification (the Xpert MTB/RIF assay)

has a sensitivity of up to 80% and is the preferred initial diagnostic

option. Treatment should be initiated immediately upon a positive

Xpert MTB/RIF result. A negative result does not exclude a diagnosis

of TB and requires further diagnostic workup. Imaging studies (CT

and MRI) may show hydrocephalus and abnormal enhancement of

basal cisterns or ependyma. If unrecognized, tuberculous meningitis

is uniformly fatal. This disease responds to chemotherapy; however,

neurologic sequelae are documented in 25% of treated cases, in most

of which the diagnosis has been delayed. Clinical trials have demonstrated that patients given adjunctive glucocorticoids may experience

faster resolution of CSF abnormalities and elevated CSF pressure,

resulting in lower rates of death or severe disability and relapse. In one

study, adjunctive dexamethasone significantly enhanced the chances

of survival among persons >14 years of age but did not reduce the

frequency of neurologic sequelae. The dexamethasone schedule was

(1) 0.4 mg/kg per day given IV with tapering by 0.1 mg/kg per week

until the fourth week, when 0.1 mg/kg per day was administered; followed by (2) 4 mg/d given by mouth with tapering by 1 mg per week

until the fourth week, when 1 mg/d was administered. The WHO

now recommends that adjuvant glucocorticoid therapy with either

dexamethasone or prednisolone, tapered over 6–8 weeks, should be

used in CNS TB.

Tuberculoma, an uncommon manifestation of TB of the CNS,

presents as one or more space-occupying lesions and usually causes

seizures and focal signs. CT or MRI reveals contrast-enhanced ring

lesions, but biopsy is necessary to establish the diagnosis.

Gastrointestinal TB Gastrointestinal TB is uncommon, making

up only 3.5% of extrapulmonary cases in the United States. Various

pathogenetic mechanisms are involved: swallowing of sputum with

direct seeding, hematogenous spread, or (largely in developing areas)

ingestion of milk from cows affected by bovine TB. Although any portion of the gastrointestinal tract may be affected, the terminal ileum

and the cecum are the sites most commonly involved. Abdominal pain

(at times similar to that associated with appendicitis) and swelling,

obstruction, hematochezia, and a palpable mass in the abdomen are

common findings at presentation. Fever, weight loss, anorexia, and

night sweats are also common. With intestinal wall involvement,

ulcerations and fistulae may simulate Crohn’s disease; the differential

diagnosis of this entity is always difficult. Anal fistulae should prompt

an evaluation for rectal TB. Because surgery is required in most cases,

the diagnosis can be established by histologic examination and culture

of specimens obtained intraoperatively.

Tuberculous peritonitis follows either the direct spread of tubercle

bacilli from ruptured lymph nodes and intraabdominal organs (e.g.,

genital TB in women) or hematogenous seeding. Nonspecific abdominal pain, fever, and ascites should raise the suspicion of tuberculous

peritonitis. The coexistence of cirrhosis (Chap. 342) in patients with

tuberculous peritonitis complicates the diagnosis. In tuberculous peritonitis, paracentesis reveals an exudative fluid with a high protein content and leukocytosis that is usually lymphocytic (although neutrophils

occasionally predominate). The yield of direct smear and culture is

relatively low; culture of a large volume of ascitic fluid can increase the

yield, but peritoneal biopsy (with a specimen best obtained by laparoscopy) is often needed to establish the diagnosis.

Pericardial TB (Tuberculous Pericarditis) Due either to

direct extension from adjacent mediastinal or hilar lymph nodes or

to hematogenous spread, pericardial TB has often been a disease

of the elderly in countries with low TB prevalence. However, it also

develops frequently in HIV-infected patients. Case–fatality rates are

as high as 40% in some series. The onset may be subacute, although

an acute presentation, with dyspnea, fever, dull retrosternal pain, and

a pericardial friction rub, is possible. An effusion eventually develops

in many cases; cardiovascular symptoms and signs of cardiac tamponade may ultimately appear (Chap. 270). In the presence of effusion,

TB must be suspected if the patient belongs to a high-risk population

(HIV-infected, originating in a high-prevalence country); if there is

evidence of previous TB in other organs; or if echocardiography, CT,

or MRI shows effusion and thickness across the pericardial space. A

definitive diagnosis can be obtained by pericardiocentesis under echocardiographic guidance. The pericardial fluid must be submitted for

biochemical, cytologic, and microbiologic evaluation. The effusion is

exudative in nature, with a high count of lymphocytes and monocytes.

Hemorrhagic effusion is common. Direct smear examination is very

rarely positive. Culture of pericardial fluid reveals M. tuberculosis in up

to two-thirds of cases, whereas pericardial biopsy has a higher yield.

High levels of adenosine deaminase, lysozyme, and IFN-γ may suggest

a tuberculous etiology.

Without treatment, pericardial TB is usually fatal. Even with treatment, complications may develop, including chronic constrictive pericarditis with thickening of the pericardium, fibrosis, and sometimes

calcification, which may be visible on a chest radiograph. Systematic

reviews and meta-analyses show a trend toward benefit from glucocorticoid treatment with regard to death and constrictive pericarditis.

However, the largest and most recent study—the IMPI study—failed

to show such a benefit. Of the patients enrolled in this trial, 67% were

infected with HIV, and only a fraction were receiving antiretroviral

treatment (ART). A supplemental analysis among HIV-negative people

showed a small mortality benefit, as did another small study among

HIV-infected people. The WHO currently recommends that, in patients

with tuberculous pericarditis, initial adjuvant glucocorticoid therapy

may be used. The 2016 guidelines of the American Thoracic Society (ATS), the CDC, and the Infectious Diseases Society of America

(IDSA), on the other hand, suggest that glucocorticoid therapy should

not be routinely administered.

Caused by direct extension from the pericardium or by retrograde

lymphatic extension from affected mediastinal lymph nodes, tuberculous myocarditis is an extremely rare disease. Usually, it is fatal and is

diagnosed postmortem.

Miliary or Disseminated TB Miliary TB is due to hematogenous

spread of tubercle bacilli. Although in children it is often the consequence of primary infection, in adults it may be due to either recent

infection or reactivation of old disseminated foci. The lesions are usually yellowish granulomas 1–2 mm in diameter that resemble millet

seeds (thus the term miliary, coined by nineteenth-century pathologists). Clinical manifestations are nonspecific and protean, depending

on the predominant site of involvement. Fever, night sweats, anorexia,

weakness, and weight loss are presenting symptoms in the majority

of cases. At times, patients have a cough and other respiratory symptoms due to pulmonary involvement as well as abdominal symptoms.

1367CHAPTER 178 Tuberculosis

Physical findings include hepatomegaly, splenomegaly, and lymphadenopathy. Eye examination may reveal choroidal tubercles, which are

pathognomonic of miliary TB, in up to 30% of cases. Meningismus

occurs in fewer than 10% of cases.

A high index of suspicion is required for the diagnosis of miliary TB.

Frequently, CXR (Fig. 178-5) reveals a miliary reticulonodular pattern

(more easily seen on underpenetrated film), although no radiographic

abnormality may be evident early in the course and among HIVinfected patients. Other radiologic findings include large infiltrates,

interstitial infiltrates (especially in HIV-infected patients), and pleural

effusion. Sputum-smear microscopy is negative in most cases. Various hematologic abnormalities may be seen, including anemia with

leukopenia, lymphopenia, neutrophilic leukocytosis and leukemoid

reactions, and polycythemia. Disseminated intravascular coagulation

has been reported. Elevation of alkaline phosphatase levels and other

abnormal values in liver function tests are detected in patients with

severe hepatic involvement. TST results may be negative in up to half

of cases, but reactivity may be restored during chemotherapy. Bronchoalveolar lavage and transbronchial biopsy are more likely to provide

bacteriologic confirmation, and granulomas are evident in liver or

bone-marrow biopsy specimens from many patients. If it goes unrecognized, miliary TB is lethal; with proper early treatment, however, it

is amenable to cure. Glucocorticoid therapy has not proved beneficial.

A rare presentation seen in the elderly, cryptic miliary TB has a

chronic course characterized by mild intermittent fever, anemia,

and—ultimately—meningeal involvement preceding death. An acute

septicemic form, nonreactive miliary TB, occurs very rarely and is due

to massive hematogenous dissemination of tubercle bacilli. Pancytopenia is common in this form of disease, which is rapidly fatal. At

postmortem examination, multiple necrotic but nongranulomatous

(“nonreactive”) lesions are detected.

Less Common Extrapulmonary Forms TB may cause chorioretinitis, uveitis, panophthalmitis, and painful hypersensitivity-related

phlyctenular conjunctivitis. Tuberculous otitis is rare and presents

as hearing loss, otorrhea, and tympanic membrane perforation. In

the nasopharynx, TB may simulate granulomatosis with polyangiitis.

Cutaneous manifestations of TB include primary infection due to

direct inoculation, abscesses and chronic ulcers, scrofuloderma, lupus

vulgaris (a smoldering disease with nodules, plaques, and fissures),

miliary lesions, and erythema nodosum. Tuberculous mastitis results

from retrograde lymphatic spread, often from the axillary lymph

nodes. Adrenal TB is a manifestation of disseminated disease presenting rarely as adrenal insufficiency. Finally, congenital TB results from

transplacental spread of tubercle bacilli to the fetus or from ingestion of

contaminated amniotic fluid. This rare disease affects the liver, spleen,

lymph nodes, and various other organs.

Post-TB Complications TB may cause persisting pulmonary

damage in patients whose infection has been considered cured on

clinical grounds. Chronic impairment of lung functions, bronchiectasis, aspergillomas, and chronic pulmonary aspergillosis (Chap. 217)

have been associated with TB. Chronic pulmonary aspergillosis may

manifest as simple aspergilloma (fungal ball) or chronic cavitary aspergillosis. Early studies revealed that, especially in the presence of large

residual cavities, Aspergillus fumigatus may colonize the lesion and produce symptoms such as respiratory impairment, hemoptysis, persistent

fatigue, and weight loss, often resulting in the erroneous diagnosis of

TB recurrence. The detection of Aspergillus precipitins (IgG) in the

blood suggests chronic pulmonary aspergillosis, as do radiographic

abnormalities such as thickening of the pleura and cavitary walls or

the presence of a fungal ball inside the cavity. Treatment is difficult.

Recent preliminary studies on the use of itraconazole for ≥6 months

indicate improvement or stabilization of 60–75% of the radiologic and

clinical manifestations. Surgical removal of lesions is risky except in

simple aspergilloma.

HIV-Associated TB (See also Chap. 202) TB is one of the

most common diseases among HIV-infected persons worldwide.

Responsible for up to 30% of all HIV-related mortality (208,000 deaths

per year), TB is likely the main cause of death in this population. In certain urban settings in some African countries, the prevalence of HIV

infection among TB patients reaches 70–80% (Fig. 178-11).

A person with a positive TST who acquires HIV infection has

a 3–13% annual risk of developing active TB, with the exact risk

depending on the degree of immunosuppression when observation

begins. Furthermore, a new TB infection acquired by an HIV-infected

individual may evolve into active disease in a matter of weeks rather

HIV prevalence in

new and relapse TB

cases, all ages (%)

0–4.9

5–9.9

10–19

20–49

≥50

No data

Not applicable

FIGURE 178-11 Estimated HIV prevalence in new and relapse tuberculosis (TB) cases in 2018. (See disclaimer in Fig. 178-2. Reproduced with permission from Global

Tuberculosis Report 2019. Geneva, World Health Organization; 2019.)

1368 PART 5 Infectious Diseases

than months or years. TB can appear at any stage of HIV infection, and

its presentation varies with the stage. When cell-mediated immunity is

only partially compromised, pulmonary TB presents in a typical manner (Figs. 178-6 and 178-7), with upper-lobe infiltrates and cavitation

and without significant lymphadenopathy or pleural effusion. In late

stages of HIV infection, when the CD4+ T-cell count is <200/μL, a

primary TB–like pattern, with diffuse interstitial and subtle infiltrates,

little or no cavitation, pleural effusion, and intrathoracic lymphadenopathy, is more common. However, these forms are becoming less

common because of the expanded use of ART. Overall, sputum smears

are less frequently positive among TB patients with HIV infection than

among those without; thus the diagnosis of TB with traditional technology may be difficult, especially in view of the variety of HIV-related

pulmonary conditions mimicking TB. Extrapulmonary TB is common

among HIV-infected patients. In various series, extrapulmonary TB—

alone or in association with pulmonary disease—has been documented

in 40–60% of all cases in individuals co-infected with HIV. The most

common forms are lymphatic, disseminated, pleural, and pericardial.

Mycobacteremia and meningitis are also common, particularly in

advanced HIV disease. The diagnosis of TB in HIV-infected patients

may be complicated not only by the increased frequency of sputumsmear negativity (up to 40% in culture-proven pulmonary cases) but

also by atypical radiographic findings, a lack of classic granuloma formation in the late stages, and a negative TST. The Xpert MTB/RIF assay

is the preferred initial diagnostic option for pulmonary TB ensuring

a sensitivity of 81% and a specificity of 98%, and therapy should be

started on the basis of a positive result because treatment delays may

be fatal. A negative Xpert MTB/RIF result, however, does not exclude a

diagnosis of TB. Culture remains the gold standard. Recent assessment

of a test based on the detection of mycobacterial lipoarabinomannan

antigen in urine has shown favorable results in assisting with the

detection of TB in HIV-positive people (see “Additional Diagnostic

Procedures,” below).

The immune reconstitution inflammatory syndrome (IRIS) or TB

immune reconstitution disease consists of exacerbations in systemic

manifestations (lymphadenopathy, fever) or respiratory signs (worsening of pulmonary infiltrations, pleural effusion) as well as laboratory or radiographic manifestations of TB. This syndrome has been

associated with the administration of ART and occurs in ~10% of

HIV-infected TB patients. Usually developing 1–3 months after initiation of ART, IRIS is more common among patients with advanced

immunosuppression and extrapulmonary TB. “Unmasking IRIS”

may develop after the initiation of ART in patients with undiagnosed

subclinical TB. The earlier ART is started and the lower the baseline

CD4+ T-cell count, the greater the risk of IRIS. Death due to IRIS is

relatively infrequent and occurs mainly among patients who have a

high preexisting mortality risk. The presumed pathogenesis of IRIS

consists of an immune response that is elicited by antigens released as

bacilli are killed during effective chemotherapy and that is temporally

associated with improving immune function. There is no diagnostic

test for IRIS, and its confirmation relies heavily upon case definitions

incorporating clinical and laboratory data; a variety of case definitions

have been suggested. The first priority in the management of a possible

case of IRIS is to ensure that the clinical syndrome does not represent

a failure of TB treatment or the development of another infection.

Mild paradoxical reactions can be managed with symptom-based

treatment and do not worsen outcomes of treatment for TB. However,

IRIS can result in serious neurologic complications or death in patients

with CNS TB. Therefore, ART should not be initiated during the first

8 weeks of TB treatment in patients with TB meningitis. Glucocorticoids have been used for severe paradoxical reactions; prednisolone

given for 4 weeks at a low dosage (1.5 mg/kg per day for 2 weeks and

half that dose for the remaining 2 weeks) has reduced the need for hospitalization and therapeutic procedures and has hastened alleviation of

symptoms, as reflected by Karnofsky performance scores, quality-of-life

assessments, radiographic response, and C-reactive protein levels.

The effectiveness of glucocorticoids in alleviating the symptoms of

IRIS is probably linked to suppression of proinflammatory cytokine

concentrations as these medications reduce serum concentrations of

IL-6, IL-10, IL-12p40, TNF-α, IFN-γ, and IFN-γ-inducible protein 10.

Recommendations for the prevention and treatment of TB in HIVinfected individuals are provided below.

DIAGNOSIS

The key to the early diagnosis of TB is a high index of suspicion. Diagnosis is not difficult in persons belonging to high-risk populations who

present with typical symptoms and a classic chest radiograph showing

upper-lobe infiltrates with cavities (Fig. 178-6). On the other hand, the

diagnosis can easily be missed in an elderly nursing-home resident or a

teenager with a focal infiltrate. Often, the diagnosis is first entertained

when the chest radiograph of a patient being evaluated for respiratory

symptoms is abnormal. If the patient has no complicating medical conditions that cause immunosuppression, the chest radiograph may show

typical upper-lobe infiltrates with cavitation (Fig. 178-6). The longer

the delay between the onset of symptoms and the diagnosis, the more

likely is the finding of cavitary disease. In contrast, immunosuppressed

patients, including those with HIV co-infection, may have “atypical”

findings on CXR—e.g., lower-zone infiltrates without cavity formation—

or interstitial disease only.

The several approaches to the diagnosis of TB require, above all, a

well-organized microbiology laboratory network with an appropriate

distribution of tasks at different levels of the health care system. Besides

clinical assessment and radiography, screening and referral are the

principal tasks at the peripheral and community levels. Diagnosis at a

secondary level (e.g., a traditional district hospital in a high-incidence

setting) can be accomplished nowadays through real-time automated

nucleic acid amplification technology (e.g., the Xpert MTB/RIF assay,

which also allows detection of drug resistance) or through traditional

AFB microscopy, where new tools have not yet been introduced. At a

tertiary level, additional technology is necessary, including molecular

tests, rapid culture, and DST.

■ NUCLEIC ACID AMPLIFICATION TECHNOLOGY

Several test systems based on amplification of mycobacterial nucleic

acid have become available in the past few years and are now the preferred first-line diagnostic tests. These tests are progressively replacing

smear microscopy, as they ensure rapid confirmation of all types of

TB. One system that permits rapid diagnosis of TB with high specificity and sensitivity (approaching that of liquid culture) is the fully

automated, real-time nucleic acid amplification technology known as

the Xpert MTB/RIF assay. Xpert MTB/RIF can simultaneously detect

TB and rifampin resistance in <2 h and has minimal biosafety and

training requirements. Therefore, it can be housed in nonconventional

laboratory settings as long as a stable and uninterrupted power supply

can be assured. The WHO recommends its use worldwide as the firstline diagnostic test in all adults and children with signs or symptoms of

active TB. Given the test’s high sensitivity, the WHO also recommends

its use as the initial diagnostic test for people living with HIV in whom

TB is suspected. In the diagnosis of pulmonary TB, this test has an

overall sensitivity of 85% reaching 98% among AFB-positive cases and

~70% among AFB-negative specimens; its specificity is 98%. When

compared to phenotypic drug susceptibility testing for simultaneous

detection of rifampin resistance, Xpert MTB/RIF has an overall sensitivity of 96% and a specificity of 98%. The newer Xpert MTB/RIF Ultra

assay (Ultra), which uses the same GeneXpert diagnostic platform, has

an overall sensitivity of 90% including “trace calls” (i.e., the “noise”

produced by detection of DNA from nonviable bacilli) as positive with

the greatest increases among smear-negative, culture-positive cases

(+17%) and among HIV-infected persons (+12%). If “trace calls” are

excluded, sensitivity decreases to 86%. Because of this greater sensitivity and the capacity to also detect nonviable bacilli, the new Ultra

cartridge has 2% lower specificity than the original test. However,

excluding “trace calls,” specificity increases to 98%. Among people with

HIV co-infection, Ultra sensitivity is 88% and specificity 95%. Sensitivity and specificity for detection of rifampin resistance by Ultra are 94%

and 99%, respectively, similar to those by the Xpert MTB/RIF assay.

In the diagnosis of extrapulmonary TB, Xpert MTB/RIF and Ultra

should be the initial test applied to CSF from patients in whom TB