Mycobacterium tuberculosis

PART III  Etiologic Agents of Infectious Diseases SECTION A  Bacteria

134 Mycobacterium tuberculosis Silvia S. Chiang and Jeffrey R. Starke

The genus Mycobacterium consists of a diverse group of acid-fast bacilli (AFB) with a lipid-rich cell wall. The bacilli are aerobic, non–spore-forming, nonmotile, and slightly curved or straight organisms. Mycobacteria take up stain poorly but retain specific dyes despite treatment with acidalcohol solutions. This acid-fast property is demonstrated with fuchsin stain techniques, such as the Ziehl-Neelsen and Kinyoun methods, or the fluorochrome method using auramine and rhodamine stains. Tuberculosis (TB) disease results from infection with any member of the Mycobacterium tuberculosis complex: M. tuberculosis (which accounts for most human TB), M. bovis, M. africanum (which causes one half of pulmonary TB in West Africa), and M. canetti (which may be an ancestral strain of M. tuberculosis). The complex also includes several species that cause TB primarily in animals, and occasionally through animal exposure, in humans: M. microti (i.e., rodents), M. pinnipedii (i.e., aquatic mammals), and M. capral (i.e., animals in Europe). M. bovis, the primary cause of TB in cattle, causes a small but significant portion of human TB cases, which are acquired primarily through unpasteurized dairy products, although person-to-person transmission has been documented. The incidence of M. bovis likely is underestimated because most diagnostic tests cannot differentiate between M. bovis and M. tuberculosis. Disease caused by M. bovis is similar to that caused by M. tuberculosis, but M. bovis enteritis and other forms of extrapulmonary disease are more common among children and immunocompromised adults. M. bovis usually is identified by its intrinsic pyrazinamide resistance. Isolated pyrazinamide resistance occurs rarely in M. tuberculosis infection.

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IMMUNOLOGY AND PATHOGENESIS Exposure to M. tuberculosis can result in elimination of the bacteria, TB infection (an asymptomatic state evidenced only by a positive test of infection), or clinically significant TB disease (Box 134.1). TB diseases mirror a continuum of immunologic responses. At one end of the spectrum, severe disseminated disease represents a failure of T-lymphocyte proliferation in response to M. tuberculosis and often is associated with a negative tuberculin skin test (TST) result.1–5 In contrast, patients with TB pleuritis have an effective immune response. Few bacilli are found in the pleural fluid and tissue, and resolution without therapy is common.4 M. tuberculosis typically enters the body through the respiratory tract, where mucociliary transport and cough serve as the first line of defense. After M. tuberculosis reaches the alveolus, the Ghon focus develops. Bacilli drain from this granulomatous focus along local lymphatics to regional lymph nodes. Together, the Ghon focus, lymphangitis, and regional lymphadenopathy form the Ghon complex. Most immunocompetent persons contain the infection within the Ghon complex and never develop TB disease. However, failure to achieve initial control of the infection leads to early disease. In reactivation disease, tubercle bacilli are disseminated by bacteremia to lung fields and distant body sites. The host may successfully contain the infection but develop reactivation disease years later if there is disruption of the host-pathogen balance. Immunologic defenses against M. tuberculosis primarily are mediated by CD4+ T lymphocytes and macrophages. M. tuberculosis–specific CD4+ lymphocytes primarily produce type 1 helper T-lymphocyte (Th1)

Mycobacterium tuberculosis

BOX 134.1  Terminology Related to Mycobacterium tuberculosis Exposure, Infection, and Disease Exposure occurs when the child has had significant contact (“shared the air”) with an adult or adolescent with infectious tuberculosis. Not all children after exposure progress to infection. Infection indicates that M. tuberculosis has invaded the lung, draining lymphatics, as evidenced by a reactive TST or positive IGRA result, but has not resulted in any signs, symptoms, or chest radiograph abnormalities (except for calcifications in the lung parenchyma and/or regional lymph nodes). Not all children with tuberculosis infection progress to disease. Disease occurs when intrathoracic or extrathoracic signs or symptoms or radiographic manifestations (other than calcifications in the lung parenchyma and/or regional lymph nodes) caused by M. tuberculosis are apparent. IGRA, interferon γ release assay; TST; tuberculin skin test;

cytokines, which include interferon γ (IFNγ) and tumor necrosis factor-α (TNF-α). The protective roles of these cytokines against M. tuberculosis are demonstrated by the increased TB risk among patients treated with anti-TNF monoclonal antibodies and those with inherited defects in IFNγ pathways.6–9 Although CD8+ lymphocytes, neutrophils, and natural killer cells manifest mycobacteriostatic effects in vitro, their clinical significance remains unclear. The role of B lymphocytes also is undefined, although they are found in substantial numbers in granulomas. Several in-depth reviews describe the immune response to M. tuberculosis.1–5

EPIDEMIOLOGY Transmission Transmission of M. tuberculosis usually occurs person to person through mucous droplets that become airborne when an individual with pulmonary TB coughs or sneezes.10 Droplets containing tubercle bacilli dry and become droplet nuclei, which can remain suspended in air for hours. Only droplet nuclei less than 10 µm in diameter can reach the alveoli. In rare cases, transmission occurs by direct contact with infected body fluids (e.g., urine, wound drainage), fomites (e.g., syringes, gastric lavage tubes), or improperly cleaned bronchoscopes. The most important marker of contagiousness is the visualization of AFB in a sputum smear.11–14 Young children with pulmonary TB have paucibacillary endobronchial secretions and diminished force of cough, and they therefore rarely infect others.15,16 Because adolescents with reactivation pulmonary TB have a greater bacillary burden and stronger cough, they can be contagious and should be treated with the same infection control measures used for adults.17–19 Most TB outbreaks in pediatric healthcare facilities have been linked to adult or adolescent visitors.20,21 Adult and adolescent hospital visitors to children with suspected TB should be screened for cough, and coughing visitors should undergo chest radiography to exclude them as sources of transmissible infection.15,16,20,21 A patient is deemed no longer contagious on the basis of symptom improvement, decreased number of AFB in the sputum smear, radiographic improvement, and adherence to an effective treatment regimen.17 Epidemiologic and animal transmission studies indicate that most patients with drug-susceptible TB become noncontagious within 2 weeks of starting effective treatment. Many patients become noncontagious within several days, although some patients, especially those with multidrug-resistant organisms remain infectious for weeks to months.

Routes of Infection An estimated one third of the world’s population is infected with M. tuberculosis, including 66 million children younger than 15 years of age.22 In recent surveys from five Asian and African countries, the

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prevalence of childhood TB infection ranged from 7% (Nepal) to 23% (Somalia).23–27 In crowded parts of Cape Town, South Africa, which has one of the world’s highest TB rates, TB infection was documented among 28% of 5- to 10-year-old children and 42% of 11- to 15-year-old children.28 The overall prevalence of TB infection among US children is 1.1%; prevalence among foreign-born children is 12%, compared with 0.3% for US-born children.29 From 2007 to 2012, 13% of US immigrant and refugee children tested positive for TB infection.30 Most children acquire TB infection from close contact with a contagious adult or adolescent living in the same household. Consequently, the most efficient method of finding children infected with M. tuberculosis is household contact investigation of adults with contagious pulmonary TB.31 On average, 30% to 50% of household contacts of a case have a reactive TST result. The infectiousness of the source case and the degree and duration of contact mediate the likelihood of transmission. For instance, a child has a higher risk of infection if the source case is the primary caregiver or sleeps in the same room.32,33 Although children are less frequently infected from casual, nonhousehold contacts, outbreaks have occurred in schools, childcare facilities, churches, and on school buses. In most cases, a highly contagious adult working in the area was the source case. During a 1994 elementary school outbreak traced to a teacher with longstanding, unrecognized pulmonary TB, almost 50% of the students had M. tuberculosis infection, and 11% had radiographic evidence of disease.34

Disease Incidence and Epidemiology The World Health Organization (WHO) estimates about 10 million incident TB cases and 3 million TB-related deaths in the world every year. According to the WHO, approximately 550,000 of these cases occurred among children younger than 15 years of age.35–37 However, modeling studies have concluded that the true pediatric disease incidence is 800,000 to 1,000,000 cases per year.22,38 Epidemiology of childhood TB requires thorough knowledge of disease epidemiology for adults. From 1953 to 1984, the US TB (i.e., TB disease in this chapter unless stated otherwise) incidence declined by an average of 6% per year. However, from 1985 to 1993, the number of TB cases reported in the United States increased by 18%.39 The most important factors underlying the resurgence of TB were the human immunodeficiency virus (HIV) epidemic, influx of immigrants from high-prevalence countries, and inadequate implementation of public health policy. Fortunately, increased TB control efforts in the United States starting in the 1990s led to a steady decrease in TB incidence resulting in an all-time low of 9,582 cases in 2013 (Fig. 134.1).39 When TB was more prevalent in the United States, risk of exposure to a contagious adult was uniformly high throughout the population. With the currently low TB incidence, exposure to M. tuberculosis is more confined to well-defined populations. The proportion of patients with TB disease who are foreign born has risen steadily since 1993 and reached an all-time high of 65% in 2013. Five countries of origin (i.e., Mexico, Philippines, Vietnam, India, and China) accounted for 54% of the cases.39 Increased risk of TB infection historically has been associated with intravenous drug use and residence in jails, prisons, and homeless shelters, especially in large urban sites. Metropolitan areas with at least 500,000 people accounted for 67% of the US population and 80% of TB cases in 2013.39 The incidence of childhood TB in the United States declined by approximately 6% per year between 1953 and 1980. From 1980 through 1987, rates stabilized and then began a steady rise in 1988. In 1993, 1721 TB cases were reported in children younger than 15 years of age, a 40% increase over 1987. By 2013, the number of TB cases in children younger than 15 years had declined to 483, a 72% reduction since 1993.39 Of these 483 cases, 61% occurred in children younger than 5 years of age, reflecting this age group’s high risk of disease progression, and 20% occurred among foreign-born children.39 Hispanics and Asians had the highest percentage of cases among US-born children and foreign-born children, respectively.39 Fifty-seven percent of reported cases among children younger than 15 years occurred in seven states (i.e., California, Florida, Georgia, Illinois, Nevada, New York, and Texas), with 34% in California and Texas alone.39

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0 – 14 15 – 24 25 – 44  45 – 64  65 













5.0























2013



10.0

2011



2011



2010

15.0

2009

Cases per 100,000

20.0

2008

2007

2006

2005

2004

2003

2002

2001

2000

1999

1998

1997

1996

1995

1994

1993

0.0

Age group (year) FIGURE 134.1  Reported tuberculosis cases per 100,000 people by age group in the United States, 1993 to 2013. (Data from the Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 2013. Atlanta, GA, CDC, 2014.)

TABLE 134.1  Age-Specific Risk of Progression to Tuberculosis in Immunocompetent Children Percentage (%) of Children Who Do Not Develop Disease

Percentage (%) of Children Who Develop Pulmonary Disease

Percentage (%) of Children Who Develop Meningitis or Disseminated Disease

<1

50

30–40

10–20

1–2

85–90

10

2–5

2–5

95

5

0.5

Age at Primary Infection (yr)

5–10

98

2

<0.5

>10

80–90

10–20

<0.5

Data from Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402.

The risk of progression from M. tuberculosis infection to disease is age dependent and is highest among children younger than 2 years of age, likely due to a suboptimal immunologic response.1 Disease risk is low between 5 and 10 years of age, rising again during early adolescence (Table 134.1).40 Age also affects disease phenotype. Infants and young children are more likely to have pulmonary, meningeal, disseminated, and lymphatic TB, whereas older children and adolescents more commonly have reactivation pulmonary, pleural, genitourinary, or peritoneal disease.41–44 Among younger children, the sex ratio for TB disease is approximately 1 : 1, but girls have a higher incidence during early adolescence.42,45–49

Drug-Resistant Tuberculosis Drug-resistant TB poses a significant threat to global TB control. The spread of drug resistance stems from many factors: poor public health infrastructure (e.g., delays in the diagnosis of drug resistance, inconsistencies in TB medication supply), inadequate treatment (e.g., unmonitored therapy, nonadherence, incorrect use of anti-TB agents), inefficient infection control, and the HIV epidemic.50,51 India, China, and the former Soviet republics account for more than one half of the world’s cases of multidrug-resistant TB (MDR-TB) defined as resistance at least to isoniazid and rifampin (Fig. 134.2).37 In 2013, the WHO estimated that 8% of new TB cases and 14% of previously treated cases had isoniazid resistance without concurrent rifampicin resistance, and an additional 4% of new cases and 21% of

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previously treated cases had MDR-TB. Of greater concern, 30% of MDR-TB cases met criteria for pre-extensively drug-resistant TB (i.e., resistant to at least isoniazid, rifampin, and a fluoroquinolone or a second-line injectable agent) or extensively drug-resistant TB (XDR-TB) (i.e., resistant to at least isoniazid, rifampin, a fluoroquinolone, and a second-line injectable agent).37 Surveillance gaps, caused in large part by insufficient resources for drug susceptibility testing, limit the quality of drug-resistant TB epidemiology. Underdetection of resistant TB is greater for children, who frequently have culture-negative disease. Although the WHO has not published estimates of childhood drugresistant TB, modeling work estimated an annual incidence of 88,000 cases of isoniazid-resistant TB without concurrent rifampin resistance and 32,000 MDR-TB cases among children younger than 15 years of age. Southeast Asia and the Western Pacific regions bear the brunt of these cases.38,52 In the United States, isolated strains demonstrating multidrug resistance and isolated isoniazid resistance have hovered around 1% and 9%, respectively, for the past several years. Among children younger than 15 years of age with culture-confirmed disease, approximately 2% have MDR-TB.39,52,53 Patients with any of the following characteristics have a higher risk of drug-resistant TB: previous treatment for TB disease, birth in a country with a high drug-resistant TB prevalence (see Fig. 134.2), or contact with a source case previously treated for TB disease or born in a country with a high drug-resistant TB burden.

Tuberculosis in Immunocompromised Children The HIV epidemic has affected profoundly the epidemiology of childhood TB.54–56 HIV-infected adults are more likely to have TB infection, pulmonary disease, and lack of classic features allowing prompt diagnosis. Children with HIV infection have a higher risk of progressing from TB infection to disease. For adults and children, pulmonary TB is a defining condition for acquired immunodeficiency syndrome (AIDS). Studies have suggested that HIV-seronegative and HIV-seropositive adults with smear-positive pulmonary TB are equally infectious. However, HIV-infected adults with pulmonary TB may be less likely to have a positive acid-fast sputum smear than HIV-seronegative adults. A retrospective study in Florida observed a rise in childhood TB after an increase in pulmonary TB among HIV-infected adults in the community.57 Clinical and autopsy studies in countries with a high TB burden demonstrate excessive risk of TB disease among HIV-infected cohorts of children.58–61 In economically developing nations, the underdiagnosis of childhood TB likely is greater among HIV-infected children because of similarities in clinical presentation to other opportunistic infections, frequent skin test anergy, and elusive culture confirmation. All children with suspected TB disease should be tested for HIV infection.

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Percentage of cases 0–2.9 3–5.9 6–11.9 12–17.9 18 No data Subnational data only Not applicable FIGURE 134.2  Percentage of multidrug-resistant tuberculosis cases estimated to occur among notified pulmonary tuberculosis cases. (Data from the World Health Organization. Global Tuberculosis Report, 2015. Geneva, Switzerland, WHO, 2015.)

Other causes of immune suppression—including malignancies and their therapy and use of high-dose corticosteroids—have been associated with higher rates of TB disease. Anti-TNF drugs used to control inflammatory bowel and rheumatologic diseases greatly increase the risk of rapid progression from TB infection to disease in adults.62,63

CLINICAL MANIFESTATIONS Intrathoracic Disease Pulmonary Disease Most children infected with M. tuberculosis do not develop signs, symptoms, or radiographic abnormality.40 However, the occasional child may experience several days of low-grade fever and mild cough at the start of infection. Other children may have fever and mild systemic symptoms at 3 to 12 weeks after acquisition of infection; these symptoms resolve over 1 to 3 weeks. The Ghon complex affects lobes of the lung equally, and 25% of cases have multiple parenchymal foci.64 Initial inflammatory response is not usually visible radiographically, but a localized, nonspecific infiltrate can appear. Within days, infection spreads to regional lymph nodes. As tissue sensitivity develops, inflammation in lung and lymph nodes intensifies. The hallmark of childhood pulmonary TB is disproportionately enlarged regional lymph nodes compared with a relatively minor parenchymal focus (Fig. 134.3). Because approximately 70% of Ghon foci are subpleural, the initial presentation commonly includes localized pleural reaction. In most children, lung inflammation and adenopathy resolve spontaneously and quickly, often by the time the chest radiograph is obtained. These children have successfully contained the tubercle bacilli but can develop reactivation disease in the future. Other children, particularly infants, progress to disease. Lymph nodes continue to enlarge and can compress airways, causing partial or complete bronchial obstruction.64 The inflammatory response can erode the bronchial wall, leading to luminal infection. This process also can lead to partial or complete bronchial obstruction. A common radiographic sequence is adenopathy followed by localized hyperinflation and then

atelectasis of contiguous parenchyma, referred to as segmental lesions (Fig. 134.4). This radiographic picture is different from other bacterial pneumonias and mimics foreign body aspiration and other obstructive disorders. Although rare, obstructive emphysema of a lobar segment occurs most often in children younger than 2 years. Obstruction usually resolves spontaneously, but corticosteroids may hasten the process; complete resolution often takes several months. Up to 40% of children younger than 1 year of age with M. tuberculosis infection develop a segmental lesion, compared with 15% of children 11 to 15 years of age. Occasionally, the radiographic abnormality is lobar pneumonia, which is indistinguishable from acute bacterial pneumonia (Fig. 134.5). Enlarged subcarinal nodes can impinge on the esophagus, causing swallowing difficulty or the development of a bronchoesophageal fistula. Other

FIGURE 134.3  Right-sided hilar lymphadenopathy with minor parenchymal infiltrate in a 3-year-old boy with pulmonary tuberculosis. (Courtesy S. S. Long, St. Christopher’s Hospital for Children, Philadelphia, PA.)

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acute pericarditis with or without constriction). Before the advent of chemotherapy, 30% to 50% of children with progressive pulmonary TB died. With current treatment, the prognosis is excellent for full recovery. Older children can have reactivation (adult-type) pulmonary TB.41,72–76 This occurs more frequently when infection is acquired after 7 years of age, especially at the onset of puberty.40,72 Common symptoms include fever, anorexia, weight loss, night sweats, productive cough, chest pain, and hemoptysis. Physical examination findings usually are minor or absent, but the radiographic appearance is disproportionately abnormal (e.g., extensive upper lobe infiltrates, upper lobe cavities with or without calcification) (Fig. 134.8). Reactivation infection usually remains localized to the lungs. Most signs and symptoms improve within several weeks of the start of effective treatment, although cough can linger for several months. FIGURE 134.4  Mediastinal adenopathy and left upper-lobe segmental lesion in a child with pulmonary tuberculosis.

Pleural Disease Pleural TB is caused by the hypersensitivity response to the discharge of a few bacilli from a subpleural focus into the pleural space.77 Occasionally, a larger discharge causes a unilateral generalized pleural effusion, which usually occurs within 6 to 9 months of initial infection.78 Pleural TB is not associated with segmental pulmonary lesions and only rarely is associated with miliary TB. Symptoms usually begin abruptly and consist of fever, chest pain, and shortness of breath. Examination reveals dullness to percussion and diminished breath sounds on the affected side. Fever often is high and persists for several weeks despite effective treatment.79

FIGURE 134.5  Left upper-lobe consolidation in a 16-month-old child with pulmonary tuberculosis. (Courtesy S. S. Long, St. Christopher’s Hospital for Children, Philadelphia, PA.)

A

enlarged nodes can compress the subclavian vein, causing upper extremity edema. Nodes can rupture into the mediastinum and lead to supraclavicular adenitis (Fig. 134.6). The signs and symptoms of pulmonary TB in children usually are minor and occur more commonly in children younger than 5 years of age.65,66 Infants most frequently manifest nonproductive cough and mild dyspnea. Fever, night sweats, anorexia, and irritability are less common. Some infants have failure to thrive, which may not improve until months after initiation of appropriate chemotherapy. Tachypnea, localized wheezing, or decreased breath sounds can occur with bronchial obstruction, but respiratory distress is rare.67,68 Nonspecific signs and symptoms occasionally resolve after antibiotic therapy for more common bacterial pneumonias; this occurrence suggests superinfection distal to nodal obstruction. Progressive pulmonary TB, a rare but serious complication, occurs when the parenchymal focus enlarges and develops a large caseous center. The clinical course and radiographic appearance can resemble those of acute bacterial pneumonia (Fig. 134.7).69–71 Common findings include hyperpyrexia, moderate to severe cough, night sweats, dullness on chest percussion, rales, and decreased breath sounds over the affected area. Central liquefaction can produce a thin-walled cavity, which can cause rupture into the pleural space (i.e., causing a bronchopleural fistula or pyopneumothorax) or the pericardium (i.e., causing

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B FIGURE 134.6  An adolescent girl had biopsy performed of a supraclavicular mass (A) to exclude lymphoma because of a 1-month history of fever and weight loss and a chest radiograph showing a mediastinal mass. Histology (B) revealed caseous necrosis and granulomatous reaction (400×, hematoxylin and eosin stain). (Courtesy S. S. Long, St. Christopher’s Hospital for Children, Philadelphia, PA.)

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Pleural membrane biopsy is the most valuable diagnostic procedure because histopathologic examination demonstrates caseating granulomas in up to 90% of cases and tissue culture is positive in up to 70% of cases. Acid-fast smear of pleural fluid usually is negative; pleural fluid culture is positive in 30% to 50% of cases. Pleural fluid typically is yellow and occasionally is blood tinged, with a specific gravity of 1.012 to 1.025, protein level of 2 to 4 g/dL, glucose level of 20 to 40 mg/dL, and white blood cell count of 100 to 1000 cells/mm3. Cells classically are predominantly neutrophils early, followed by a high proportion of lymphocytes.

Cardiac Disease Occurring in 1% to 4% of childhood TB cases, pericarditis is the most common form of cardiac TB.80 In approximately 10% to 20% of cases, fibrosis leads to constrictive pericarditis over a period of months to years. Early symptoms of serofibrinous pericarditis are nonspecific and usually consist of low-grade fever, malaise, weight loss, and cough; in children, FIGURE 134.8  Multiloculated cavity with calcification in right upper lobe due to adult-type tuberculosis.

chest pain is unusual. Examination can reveal a pericardial friction rub, distant heart sounds, and pulsus paradoxus. Initially, pericardial fluid is serofibrinous or slightly hemorrhagic; it rarely stains positive for AFB but yields a positive culture in 30% to 70% of cases. Pericardial biopsy shows caseating granulomas in 50% to 75% of cases, and culture usually is positive. The detection of stranding on echocardiography can suggest the diagnosis of TB.81 The TST result is positive in 75% of cases.

Extrathoracic Disease Disseminated (Lymphohematogenous) Disease

A

B FIGURE 134.7  Pulmonary tuberculosis with hemoptysis. (A) Chest radiograph shows right lower-lobe consolidation. Bronchoscopy revealed hemorrhage and a large clot obscuring lumen to the right lower lobe. Computed tomography showed multiple nodes abutting airways and consolidation and atelectasis of the right lower lobe. A hilar node and the most rostral lower lobe infiltrate are shown (B). Bronchoalveolar lavage was smear negative but culture positive for Mycobacterium tuberculosis. (Courtesy S. S. Long, St. Christopher’s Hospital for Children, Philadelphia, PA.)

Clinical manifestations of early bacteremic spread, which occurs in all asymptomatic and symptomatic M. tuberculosis infections of the lung, depend on the continual balance between the pathogen and host’s immunologic containment. Infants and children with immunosuppression are more likely to have severe forms of disseminated disease.40,82 There are three forms of lymphohematogenous TB. The first and most common form is occult dissemination that remains clinically silent or manifests months to years later with metastatic, extrapulmonary TB. The second form is protracted bloodstream infection (rarely seen today), which arises from the intermittent release of bacilli from erosion of a caseous focus into a pulmonary vessel. Protracted bloodstream infection manifests more frequently with indolent, prolonged, intermittent fevers than with acute, spiking fevers. Initial mild pulmonary involvement becomes diffuse after several weeks. Multiorgan involvement is common and often includes hepatosplenomegaly, lymphadenitis of superficial or deep nodes, and appearance of papulonecrotic tuberculids in crops on the skin. Meningitis, which occurs late in the disease course, often was the cause of death in the prechemotherapy era. Gastric aspirate culture often is negative; blood or urine culture can be positive. Bone marrow or liver biopsy yields a high rate of positive stain and culture results. The third and most common clinically significant form of disseminated TB is miliary disease, which occurs when massive bloodstream infection causes disease in two or more organs.83–85 Miliary TB most often occurs as an early complication of M. tuberculosis infection (i.e., within 2 to 6 months) during infancy or early childhood. However, breakdown of a healed Ghon lesion can lead to miliary spread in older individuals. Clinical manifestations are protean and depend on the number and final location of disseminated organisms.83 Lesions usually are largest and most numerous in the lungs, spleen, liver, and bone marrow. The clinical onset of miliary TB usually is indolent, but it can be explosive over several days. Early manifestations consist of malaise, anorexia, listlessness, weight loss, and low-grade fever with normal physical findings. Higher fever, hepatosplenomegaly, and generalized lymphadenopathy develop within several weeks in approximately 50% of children. During this time, the patient has few respiratory symptoms and

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can have normal chest radiographic findings. A few weeks later, respiratory distress, cough, rales, or wheezing occurs as lungs often become filled with tubercles, and the classic radiographic finding appears (i.e., diffuse lung tubercles resembling millet seeds).83 If pulmonary disease progresses, alveolar-capillary block can result in respiratory distress, hypoxia, and pneumothorax. Timely diagnosis of miliary TB requires a high index of suspicion because premortem microbiologic confirmation is achieved in only one third of cases.85 The highest-yield tests of microbiologic confirmation are acid-fast smear and culture of bone marrow or liver tissue. Gastric aspirate culture usually is negative; blood or urine culture sometimes is positive. Ophthalmologic examination reveals choroid tubercles in 13% to 87% of children.84–86 Because more than 30% of children with miliary TB have a negative pretreatment TST result, eliciting a history of exposure to an adult with contagious TB is crucial. The differential diagnosis of miliary parenchymal disease includes lymphocytic interstitial pneumonia in HIV-infected children, histoplasmosis, disseminated neuroblastoma or thyroid carcinoma, and histiocytosis. Headache usually indicates TB meningitis, whereas abdominal pain or tenderness often heralds TB peritonitis.84,86 With timely treatment, children with miliary TB have an excellent prognosis. The general sense of well-being improves within 2 weeks of beginning therapy, but resolution of other signs and symptoms lags. For instance, weight gain may not occur for weeks to months, and chest radiograph abnormalities often persist for months.

Lymphatic Disease TB of the superficial lymph nodes (i.e., scrofula) is the most common form of childhood extrapulmonary TB, accounting for approximately 67% of cases. Historically, scrofula often resulted from drinking unpasteurized cow’s milk laden with M. bovis. Currently, most cases arise from M. tuberculosis acquired by aerosol or droplet nuclei. Supraclavicular, anterior cervical, tonsillar, and submandibular nodes most often are involved due to extension of a Ghon lesion of the upper lung fields or abdomen. Tuberculous inguinal, epitrochlear, or axillary lymphadenopathy usually results from cutaneous or skeletal TB and rarely occurs in children. Infected lymph nodes, which enlarge gradually in the early stages, are discrete and firm but not hard or tender. Nodes often feel fixed to underlying or overlying tissues.87,88 Involvement usually is unilateral but can be bilateral because of crossover drainage of lymphatic vessels in the chest and lower neck. Infection can involve several nodes, resulting in a matted mass. Other than low-grade fever, systemic signs and symptoms typically are absent. The TST result usually is reactive. Although usually present, a Ghon focus is visible radiographically in only 30% to 70% of cases and usually does not cause symptoms. Occasionally, lymphadenitis can progress more acutely, with rapid enlargement associated with high fever, tenderness, and fluctuation. Scrofula rarely manifests as a fluctuant mass with overlying cellulitis. Distinguishing scrofula from nontuberculous mycobacteria (NTM) lymphadenitis is challenging.87 Both conditions cause chronic, nontender adenopathy with tissue breakdown or sinus tracts. Chest radiographic findings usually are normal for both infections. If the lymphadenitis is caused by M. tuberculosis, the TST induration usually is more than 15 mm; in contrast, NTM usually produce a less intense reaction or no reaction. Two epidemiologic clues—history of exposure to a contagious TB case and the patient’s age—can help with the diagnosis. Whereas scrofula occurs in children of all ages, approximately 80% to 90% of NTM lymphadenitis occurs in children younger than 5 years of age.89,90 Excisional biopsy with culture of the lymph nodes often is required to establish the cause. Untreated lymphadenitis can resolve but more often progresses to caseating necrosis, capsular rupture, and spread to adjacent nodes and overlying skin, which becomes effaced, shiny, and erythematous (see Fig. 134.6A). Rupture through the skin creates a draining sinus tract, which may require surgical removal.88

Central Nervous System Disease Central nervous system (CNS) TB most commonly manifests as TB meningitis or tuberculoma. TB meningitis complicates 0.5% to 3% of

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untreated M. tuberculosis infection in children and occurs most frequently between the ages of 6 months and 4 years.91 Occurring 2 to 6 months after initial infection, TB meningitis is rare in infants younger than 4 months of age. TB meningitis arises from direct invasion during uncontrolled dissemination or from the renewed activity in a caseous lesion in the cerebral cortex or meninges that was established during early, occult lymphohematogenous dissemination.92–94 Lesions enlarge and discharge small numbers of bacilli into the subarachnoid space. The resulting exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction, and subsequent infarction of the cerebral cortex. The base of the brain is affected most commonly, accounting for frequent involvement of cranial nerves III, VI, and VII. Exudate can interfere with cerebrospinal fluid (CSF) flow at basilar cisterns, leading to communicating hydrocephalus.95 The combination of vasculitis, infarction, cerebral edema, and hydrocephalus causes severe brain injury. Hyponatremia and volume expansion due to the inappropriate secretion of antidiuretic hormone commonly occur and contribute to the pathophysiology.96 The clinical onset of TB meningitis can be rapid or gradual.97–103 The disease progresses more quickly among infants and young children, who may have symptoms only for several days before the onset of hydrocephalus, seizures, or cerebral edema. More often, the disease course progresses over several weeks and can be divided into three stages.104,105 Stage I typically lasts 1 to 2 weeks and is characterized by nonspecific symptoms such as fever, headache, irritability, and drowsiness. Focal neurologic signs are absent, but infants can lose developmental milestones. This stage usually can be recognized as early TB meningitis only in retrospect. Stage II often begins abruptly with lethargy and apathy, nuchal rigidity, a Kernig or Brudzinski sign, seizures, hypertonia, vomiting, cranial nerve abnormalities, and other focal neurologic signs. Some children have signs only of encephalitis, such as disorientation, abnormal movements, and speech impairment. If significant hydrocephalus occurs, early placement of a ventriculoperitoneal shunt or extraventricular device can relieve the symptoms.106 Stage III is marked by coma, hemiplegia or paraplegia, hypertension, decerebrate or decorticate posturing, progressive vital sign abnormalities, and eventual death. Microbiologic confirmation of TB meningitis can be difficult. Ideally, CSF should be sampled by lumbar puncture; ventricular CSF often is normal because the pathology occurs distal to the lateral ventricles. The likelihood of microbiologic confirmation directly correlates with the quantity of CSF sampled. Overall rates of positivity for acid-fast stain and culture are 9% and 35%, respectively.97 In contrast, with at least 10 mL of lumbar CSF, acid-fast stain and culture are positive in up to 30% and 70% of cases, respectively. Other CSF studies, such as nucleic acid amplification tests (NAATs), provide important diagnostic clues, as does microbiologic confirmation of pulmonary TB. The lumbar CSF leukocyte cell count ranges from 10 to 500 cells/mm3. Neutrophils can predominate early, but lymphocytic predominance is more typical. The CSF glucose level is usually between 20 and 40 mg/dL, but can be less than 10 mg/dL; CSF protein concentration is elevated, sometimes markedly (>400 mg/dL). Cranial computed tomography (CT) and especially magnetic resonance imaging help establish the diagnosis. Although CT findings can be normal early in the disease, basilar enhancement with communicating hydrocephalus and signs of cerebral edema or focal ischemia can occur later. Magnetic resonance imaging (MRI) is more sensitive and can show widespread areas of focal necrosis, ring enhancement, and edema (Fig. 134.9). Approximately 70% of cases have an abnormal chest radiograph. The TST result is less helpful because it can be nonreactive in up to 45% of cases.97 History of exposure to or newly identifying a contagious source case is a key diagnostic clue. Before the availability of anti-TB drugs, TB meningitis invariably caused death, usually within 3 weeks.107 Even with current treatment regimens and advanced life-support measures, the disease kills approximately 19% of the children it affects and leaves 54% of survivors with permanent neurologic complications, which include blindness, deafness, paraplegia, and behavioral and intellectual disabilities.97 The prognosis for TB meningitis correlates with the clinical stage of illness at the time effective treatment is begun.97 Patients whose treatment begins in stage I have a 1% risk of death. For patients whose treatment begins in stage II or III, the risks of death increase to 10% and 34%,

Mycobacterium tuberculosis

A

B

C

D

G

E

134

H

F

FIGURE 134.9  Tuberculous meningitis in a 6-month-old infant with a 2-week history of lethargy and acute onset of seizures, right facial paralysis, and right-sided hemiparesis. Some representative magnetic resonance images obtained at admission are shown. Axial short tau inversion recovery (STIR) sequence (A) shows ventriculomegaly and multiple bilateral supratentorial T2 hypointense lesions (arrows and circle). (B) Infratentorial T2 hypointense lesion with surrounding vasogenic edema. Axial postcontrast T1 sequence (C) shows corresponding ring enhancement of lesion in B. Coronal postcontrast T1 sequence (D) shows multiple supratentorial ring enhancing lesions (arrows). Sagittal image shows T2 hypointense intramedullary lesion with surrounding vasogenic edema that expands the spinal cord (E). Postcontrast T1 sequence image demonstrates the ring enhancement (F). The patient was given anti-tuberculosis drugs plus corticosteroids and improved. Neurosurgical spinal decompression was performed. Six weeks later, axial STIR sequence shows (G) regression of initial lesions (arrows and circle) but (H) new nodular lesions within the suprasellar cistern (circle). The corticosteroid dose was increased. Drug-susceptible Mycobacterium tuberculosis was isolated from gastric aspirates. (Courtesy A. Malik and S. S. Long, St. Christopher’s Hospital for Children, Philadelphia, PA.)

respectively. The risks of neurologic sequelae are 27%, 41%, and 71% for survivors whose treatment began in stage I, II, and III, respectively.97 Because of the diagnostic challenges and poor prognosis associated with TB meningitis, anti-TB treatment should be instituted empirically (while the diagnosis is being established) at least for any child with basilar meningitis accompanied by hydrocephalus, infarction, or cranial nerve involvement with no other apparent cause. Tuberculoma, another form of CNS infection, usually manifests as a space-occupying lesion and occurs most often in children younger than 10 years of age. The lesion typically is singular and infratentorial and is located at the base of the brain near the cerebellum.108 Tuberculoma and TB meningitis were once considered distinct entities, but neuroimaging has demonstrated that many young children have both (see Fig. 134.9). Tuberculoma most commonly manifests with headache, fever, and convulsions. The TST result usually is positive, and chest radiographic findings are normal. Although surgical excision is unnecessary, biopsy often is performed for diagnosis. Paradoxical appearance of tuberculomas during effective therapy for TB meningitis can occur109,110 (see Fig. 134.9). The pathogenesis of tuberculoma is similar to that of immune reconstitution inflammatory syndrome (IRIS), and the finding does not signify treatment failure. Tuberculoma should be suspected if focal neurologic abnormalities arise or change during treatment of TB meningitis. After consideration of optimized treatment and the possibility of drug-resistant infection,

corticosteroid therapy is appropriate, although optimal duration is unclear. Tuberculomas resolve slowly, typically over months to years.

Osteoarticular Disease Skeletal TB arises from direct lymphohematogenous seeding or extension of a caseous regional lymph node. The interval between infection and clinical manifestations can range from 1 month (i.e., TB dactylitis) to years (i.e., osteoarthritis of the hip). Infection usually begins in the metaphysis. The formation of granulation tissue and caseation can lead to bone necrosis. The bone infection may extend into adjacent soft tissue, leading to abscess formation, or a nearby joint, resulting in articular TB. Often, the infection becomes clinically apparent when the joint becomes involved. TB most commonly affects weight-bearing bones and joints, especially vertebrae. Spinal TB (i.e., Pott disease) can involve any or multiple vertebral bodies but has a predilection for the lower thoracic or upper lumbar spine. Affected vertebrae usually are contiguous, but there can be skip areas between lesions.111–113 Vertebral body infection leads to bone destruction and collapse, spondylitis of one or more disk spaces, collapse and wedging of the vertebral body with subsequent angulation of the spine (i.e., gibbus spine), or kyphosis. Infection can rupture into soft tissue, causing paraspinal, psoas, or retropharyngeal abscesses. In children, Pott disease most commonly manifests with low-grade fever,

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irritability, and restlessness; back pain (usually without significant tenderness); and abnormal positioning or refusal to walk. Rigidity of the spine results from involuntary immobilization and muscle spasm. Other common sites of skeletal TB include the knee, hip, elbow, and ankle.114,115 The extent of involvement ranges from mild joint effusion without bone destruction to frank bone destruction and joint restriction due to chronic fibrosis of the synovial membrane. Evolving over months to years, the process most commonly causes mild pain, stiffness, limping, and restrictive movement. The TST result is reactive in 80% to 90% of cases. Culture of joint fluid or bone biopsy usually yields the organism. TB dactylitis, one form of bony disease, is peculiar to infants. Affected children have distal endarteritis followed by painless swelling of hands or feet and cystic bone lesions. Abscesses are rare. The TST result usually is positive.

Abdominal and Gastrointestinal Disease TB enteritis, caused by hematogenous dissemination or swallowing of tubercle bacilli discharged from the patient’s lungs, most commonly involves the jejunum and ileum near Peyer patches and the appendix.116–118 Painful shallow ulcers, diarrhea or constipation, and weight loss are typical findings. Mesenteric lymphadenitis usually is prominent. Inflamed nodes can obstruct the intestines or erode through the omentum to cause generalized peritonitis. TB enteritis should be considered as a diagnosis for any child with chronic gastrointestinal complaints and a positive TST result.119 Diagnosis usually requires biopsy, stain, and culture of lesions. TB peritonitis is uncommon in adolescents and rare in young children. Generalized peritonitis can result from subclinical or miliary hematogenous dissemination. Localized peritonitis arises from direct extension from an infected intra-abdominal lymph node, an intestinal focus, or TB salpingitis.120 TB peritonitis typically manifests mild pain and tenderness, ascites, and low-grade fever. The TST result almost always is positive. Rarely, lymph nodes, omentum, and peritoneum become matted and manifest as a palpable, doughy, irregular, nontender mass. Diagnosis is confirmed by paracentesis or biopsy with stains and cultures, but the procedure must be performed with caution to avoid entering fixed bowel intertwined with matted omentum.

Genitourinary Disease Renal TB rarely occurs in children because the incubation period is at least several years.121 The disease process begins when tubercle bacilli reach the kidney during lymphohematogenous dissemination, as documented by recovery from urine in disseminated or pulmonary TB. Small caseous tubercles develop in the renal parenchyma and release M. tuberculosis into the tubules. A large mass can develop near the renal cortex; this focus of infection discharges large numbers of bacteria through a fistula into the renal pelvis. Infection spreads locally to the ureters, prostate, or epididymis. In early stages, renal TB often is clinically silent except for sterile pyuria and microscopic hematuria.122 As disease progresses, dysuria, flank or abdominal pain, and gross hematuria can develop. Superinfection frequently occurs and can delay recognition of underlying TB. Ureteral stricture or hydronephrosis complicates the disease.123 Urine mycobacterial culture results are positive in 80% to 90% of cases, but acid-fast stains of large volumes of sedimented urine are frequently less positive. The TST result usually is positive. TB of the genital tract is uncommon in both sexes before puberty. Infection usually originates from lymphohematogenous seeding, although it can spread contiguously from the intestinal tract or bone. Adolescent girls can develop hematogenous genital tract TB during the primary infection. Female genital tract TB most often involves the fallopian tubes, followed by the endometrium, ovaries, and cervix. Usual symptoms include lower abdominal pain and dysmenorrhea or amenorrhea. Male genital tract TB typically causes epididymitis or orchitis—manifesting as a unilateral, nodular, painless swelling of the scrotum—and rarely involves the glans penis. Both sexes have a positive TST result, absence of systemic manifestations, and normal chest radiographs. Because unrecognized female genital tract TB can lead to infertility and in vitro fertilization has been associated with congenital tuberculosis, women from endemic regions should have a TST before in vitro fertilization.124 Suspicion of congenital tuberculosis should rise when mother is from a

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country with high endemic TB prevalence and she was not tested during infertility evaluation.

Cutaneous Disease Cutaneous TB, more common decades ago, has four presentations: scrofuloderma, a lesion from direct inoculation, a site of hematogenous dissemination, or a hypersensitivity reaction to the tubercle bacillus.125 Scrofuloderma occurs when a caseous lymph node ruptures through the skin and leaves an ulcer or sinus tract. Direct inoculation of the skin through an abrasion, cut, or insect bite can cause a small, painless nodule, sometimes with tiny satellite lesions that soon turn into indolent ulcers without surrounding inflammation. Regional lymphadenitis is striking, but systemic symptoms usually are lacking. Direct inoculation also results in verrucosa cutis, a wart-like lesion that appears most commonly on the arms or legs in a person already sensitized to the organism.126 Hematogenous dissemination can lead to verrucosa cutis and papulonecrotic tuberculids, which are miliary tubercles in the skin that usually appear as tiny papules appearing most often on the trunk, thighs, and face. The characteristic apple-jelly center of papulonecrotic tuberculids is best demonstrated by covering it with a glass slide. The most common hypersensitivity reaction is erythema nodosum, characterized by large, painful, purple-brown nodules on the shins and extensor forearms.

Congenital Disease Congenital TB is rare, with fewer than 400 cases reported in the English language literature.127 The affected infant’s mother can have an existing diagnosis of TB, but the mother’s disease often is not diagnosed until delivery or later.128 Congenital infection depends on the presence and intensity of hematogenous dissemination of M. tuberculosis during pregnancy. Placental infection facilitates transmission to the fetus by blood or aspiration of amniotic fluid. However, even massive TB placentitis does not always lead to congenital infection. Congenital infection has been associated with maternal infertility (likely related to fibrosing TB salpingitis) and fetal infection after in vitro fertilization.124 In hematogenous congenital TB, M. tuberculosis reaches the fetus through the umbilical vein and disseminates widely. If bacilli infect the liver, a primary focus develops with involvement of periportal lymph nodes.129 Hematogenous primary focus in the fetal lung usually remains dormant until after birth, when oxygenation and circulation increase significantly. Congenital infection of the infant also occurs by aspiration or ingestion of infected amniotic fluid.130 Symptoms of hematogenous congenital TB can be present at birth but typically appear by the second or third week of life.127,128 The most common manifestations are respiratory distress, fever, hepatosplenomegaly, poor feeding, lethargy or irritability, lymphadenopathy, abdominal distention, ear drainage, and skin lesions. Clinical manifestations vary with lesion size and location. Some infants have a normal chest radiograph early in the course, but most have diffuse radiographic abnormalities as disease progresses. More common early radiographic findings are hilar lymphadenopathy and parenchymal infiltrates; approximately 50% of patients have a miliary pattern. Congenital TB should be suspected in any infant who has sepsis syndrome or other findings compatible with congenital infection with no response to antibiotic therapy and negative evaluation for another congenital infection. Suspicion is high if the mother is at risk for, has, or has had TB. Timely diagnosis of congenital or neonatal TB is difficult and often is delayed. The initial TST result usually is negative, frequently becoming reactive after 1 to 3 months of therapy. Positive results of acid-fast stains and cultures of body fluids and tissues (e.g., middle ear fluid, tracheal aspirate, bone marrow, lymph node) are needed to confirm the diagnosis.127 AFB in gastric or tracheal aspirates in a neonate is almost diagnostic because false-positive smear results are rare. Although only 20% of affected children have meningeal involvement, CSF examination and culture should be performed because a diagnosis of TB meningitis would change management. Endometrial specimens from the mother should be obtained because they usually yield positive culture results.

Mycobacterium tuberculosis

DIAGNOSIS Tests of Infection Diagnostic tests for TB detect M. tuberculosis in a clinical sample or the host’s immune response to the organism. TB diagnosis is complicated by the need to distinguish between asymptomatic infection and clinically significant disease. Current tests of infection, the TST and interferon γ release assays (IGRAs), are immune based and cannot discriminate between infection and disease.

Tuberculin Skin Test The definitive TST uses 5 tuberculin units of purified protein derivative (PPD) stabilized in Tween 80. A 26- or 27-gauge needle and a graduated syringe are used to inject 0.1 mL of PPD intradermally into the volar surface of the forearm; the immediate appearance of a wheal indicates correct technique.131 The delayed hypersensitivity reaction to the TST usually peaks at 48 to 72 hours. In some people, reaction occurs after 72 hours and should be measured. It may take up to 10 weeks after infection occurs for an immunocompetent individual to react to the TST. For accuracy, the TST result should be interpreted by trained healthcare providers. The diameter of induration—not erythema—is measured perpendicular to the axis of administration and recorded in millimeters. TST result should not be recorded as simply positive or negative. An allergic or Arthus-like reaction to TST components can cause erythema and induration within hours after application, peaking as late as 24 hours (for the Arthus reaction) and beginning to wane at 48 hours; these findings do not indicate M. tuberculosis infection. A nonreactive TST result does not exclude M. tuberculosis infection or disease because a variety of factors can lower tuberculin reactivity (Box 134.2).132 Approximately 10% of immunocompetent children with

BOX 134.2  Factors That Cause Decreased Response to Tuberculin Skin Test HOST-RELATED FACTORS Infection • Viral (rubella, rubeola, varicella, influenza) • Bacterial (typhoid fever, brucellosis, leprosy, pertussis, overwhelming tuberculosis) • Fungal (blastomycosis) Live virus vaccines Chronic renal failure Malnutrition Diseases affecting lymphoid organs (leukemia, lymphoma, human immunodeficiency virus infection) Immunosuppressive drugs (corticosteroids, antineoplastic agents) Age (infants <6 months of age and elderly) Stress (surgery, burns, mental illness)

culture-confirmed TB disease do not react at first to the TST.133 Most of these children have a positive test result after several months of treatment, suggesting that TB was acquired recently or that untreated disease depressed specific immune responses. Patients with immunocompromise due to a variety of causes, including disseminated TB and age younger than 6 months, often are anergic (i.e., have diminished cellular response to multiple stimuli).134 The measles vaccine can suppress TST response transiently. This suppression does not occur when the TST is done on the same day as measles vaccination. However, if the vaccine has already been administered, the TST should be delayed until 4 to 6 weeks after immunization unless the clinician is evaluating the child for recent exposure or TB disease. Due to theoretic concerns, this recommendation extends to other live viral vaccines.135 Improper storage, dilution, placement, and interpretation of the TST can cause false-negative results. The most significant causes of false-positive TST reactions are recent NTM infection and prior bacille Calmette-Guérin (BCG) vaccination.136–138 NTM infection, which occurs more frequently near the equator, usually causes a cross-reaction of 10 mm or less (but can be larger); crossreactivity can last for several months. In studies of BCG-vaccinated newborns, only 50% have a positive TST result, and 80% to 90% lose the reactivity within 5 years. Children or adults who receive BCG have higher initial and longer responses to TST, but most lose tuberculin reactivity within 10 years of vaccination.139 The degree of reactivity also is affected by BCG product and nutritional status.136,138 TST reactivity after BCG vaccination is expected to measure less than 10 mm of induration at 48 to 72 hours, although reactions of 10 to 15 mm can occur. Prior BCG vaccination is not a contraindication to tuberculin testing. In the United States, the TST result usually is interpreted similarly for persons with or without a history of vaccination.18 Countries that use BCG vaccine frequently have high rates of endemic TB, and studies have demonstrated that a positive TST result for a previously BCG-vaccinated child who is a close contact with an active TB case likely represents M. tuberculosis infection.137,140 Three cutoff values are used to interpret TST reactivity. The cutoff values represent a statistical attempt to minimize false-positive or falsenegative readings and vary according to individual and epidemiologic factors, of which exposure to M. tuberculosis is the most heavily weighted (Box 134.3). For children at highest risk for infection progressing to disease, an induration diameter of ≥5 mm is classified as a positive result. For other high-risk groups, an induration diameter ≥10 mm is a positive result. For low-risk children, an induration diameter ≥15 mm is a positive result.

BOX 134.3  Interpretation of Tuberculin Skin Test as Positive by Diameter of Induration and Risk Categorya INDURATION ≥5 MM IN DIAMETER Contact with an infectious case Abnormal chest radiograph Human immunodeficiency virus infection Immunosuppression from any cause

TUBERCULIN-RELATED FACTORS

INDURATION ≥10 MM IN DIAMETER

Improper storage (exposure to light or heat) Improper dilution Chemical denaturation Contamination Adsorption to glass or plastic

Birth in a tuberculosis high-prevalence country Frequent exposure to high-risk adultsb Illicit intravenous drug use Other medical risk factorsc Work in healthcare field Member of a locally identified high-risk population Age ≤4 years

ADMINISTRATION-RELATED FACTORS Incomplete injection of test dose Delayed administration after loading syringe Injection given subcutaneously READING-RELATED FACTORS Inexperienced reader (should measure induration only) Conscious or unconscious bias Error in recording

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INDURATION ≥15 MM IN DIAMETER Regardless of age or risk factors a

Single risk factor in a category is sufficient. Such as individuals who are HIV-infected, homeless, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized, or migrant farm workers. c Such as Hodgkin disease, lymphoma, diabetes mellitus, chronic renal failure, and malnutrition. b

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In the United States, it is preferable to screen children for M. tuberculosis infection risk factors with a questionnaire. The test of infection is performed only if there are risk factors.141

Interferon γ Release Assays QuantiFERON-TB Gold (QFT, Cellestis/Qiagen, Carnegie, Australia) and T-SPOT-TB (T-SPOT, Oxford Immunotec, Abingdon, UK) are the two commercially available IGRAs. In terms of performance, neither test is preferred.132 IGRAs measure IFNγ secreted by the patient’s T lymphocytes (QFT) or the number of IFNγ-secreting lymphocytes (T-SPOT) on ex vivo stimulation with M. tuberculosis-specific antigens that are not found in BCG vaccines or most NTM species (except M. marinum, M. kansasii, M. szulgai, and M. flavescens). Both IGRAs use positive and negative controls; if either control fails, the result is deemed indeterminate (QFT) or invalid (T-SPOT). Like the TST, IGRAs produce continuous results, and cutoff values are used to interpret results as positive or negative. For T-SPOT only, an intermediate result is classified as borderline. Unlike the TST, each IGRA has only one cutoff value regardless of the patient’s exposure history or immune status. However, multiple studies have questioned this lack of risk stratification and suggest a need for further refinement of IGRA cutoff values.142–148 Pediatric studies have demonstrated that IGRAs have a higher specificity than the TST for TB infection, particularly in settings of low TB burden and among BCG-vaccinated children.149–152 One meta-analysis estimated a specificity of 90% to 100% for IGRAs, compared with 56% for the TST.152 IGRAs and the TST have comparable sensitivities of 75% to 90% in immunocompetent individuals.149–152 However, like the TST, IGRAs have poor sensitivity among immunocompromised hosts and cannot differentiate TB infection from disease.153–157 A lack of data on IGRA performance in children younger than 5 years of age has prompted hesitancy to use these assays in this age group.132 In contrast, the TST is routinely used in children as young as 6 months of age.

Recommendations for Tests to Diagnose Tuberculosis Infection In high-income countries, a TST or IGRA may be used to diagnose TB infection in children at least 5 years of age. For children younger than 5 years of age, TSTs are preferred, although some experts use an IGRA for children 2 years or older, particularly if they have received BCG and have no significant TB risk factors. An IGRA can be used to confirm TB infection in a BCG-vaccinated child who has a positive TST result. Alternatively, an IGRA can be used in lieu of the TST for the initial evaluation. However, exposure to a contagious TB patient is the most important consideration in the interpretation of tests of infection. A positive TST result in a BCG-vaccinated child recently exposed to a person with contagious tuberculosis is most likely a true positive, and confirmation with an IGRA is not recommended. Because of their imperfect sensitivities, negative tests of infection cannot rule out TB disease and must be interpreted in concert with epidemiologic, clinical, and radiographic data.132 Some experts may use the TST and both IGRAs to maximize sensitivity in an immunocompromised child suspected of having TB disease. The WHO recommends against IGRA use in high-burden, resource-limited settings because IGRAs are more expensive than the TST, require greater laboratory infrastructure, and do not substantially improve diagnostic sensitivity.158

Microbiologic Confirmation and Drug Susceptibility Testing Methods of Specimen Collection Expectoration is the preferred specimen collection method for children who can produce sputum. However, for young children who cannot expectorate, other approaches are used to collect respiratory specimens. While a child sleeps, mucociliary transport sweeps respiratory secretions up the airways into the throat. The child swallows these secretions into the stomach.

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Gastric aspiration attempts to collect these swallowed respiratory secretions. To minimize the chance of stomach emptying, the procedure should be performed as early in the morning as possible, and the child should abstain from eating or drinking for the preceding 8 hours. The procedure begins with nasogastric tube insertion. If lubrication is required, sterile water or the patient’s own saliva should be used; commercially available lubricants can be bactericidal. The stomach contents should then be aspirated. If less than 10 mL of material is aspirated, 5 to 10 mL of normal saline should be injected through the tube, left for 2 to 3 minutes, and then aspirated and added to the first collection. Because the tubercle bacilli do not tolerate gastric acidity, the sample should be neutralized immediately. Concentration, decontamination, and culture also should be performed as soon as possible after collection. To optimize diagnostic yield, gastric aspirates should be performed on 3 consecutive mornings.159,160 Sputum induction, an alternative to gastric aspiration, works by increasing the child’s tussive force. Sputum induction requires the child to fast for 3 hours before the procedure. A 5-mL solution of 3% hypertonic saline is administered by nebulization with a flow of 6 to 8 L/min. Children with a history of airway reactivity may benefit from premedication with a β-agonist, which decreases the risk of bronchospasm. For infants and young children who cannot expel the resulting sputum, trained personnel must suction out the oropharynx to collect the specimen; two or three samples are recommended to increase diagnostic yield.160 Most studies demonstrate a lower yield of M. tuberculosis from bronchoalveolar lavage specimens compared with properly obtained gastric aspirates.161–163

Methods of Microbiologic Confirmation and Drug Susceptibility Testing Tests of microbiologic confirmation are divided into genotypic tests, which detect nucleic acid fragments from M. tuberculosis, and phenotypic tests, which detect whole microbes or their components. The sensitivity of both methods depends on bacterial burden and is therefore low for children due to the paucibacillary nature of childhood disease. Drug susceptibility testing (DST) methods also are characterized as phenotypic or genotypic. Phenotypic DST evaluates the strain’s growth or metabolic activity in the drug’s presence, and genotypic DST detects resistanceconferring mutations. Conventional Approach.  The conventional approach consists of acidfast stain and microscopy, mycobacterial culture, and the proportion method for DST. Acid-fast microscopy and mycobacterial culture have low sensitivity for detecting M. tuberculosis. Even with optimal specimen collection and laboratory processing, only 10% to 15% of children with clinically suspected pulmonary TB have smear-positive samples, and only 30% to 40% have culture-positive samples.160,164,165 Microbiologic confirmation of extrapulmonary TB also is elusive.44,97,166,167 For example, the proportions of smear-positive and culture-positive CSF samples for children treated for TB meningitis are approximately 9% and 35%, respectively.97 The proportion method for DST, which is the gold standard, can be performed only if M. tuberculosis has been isolated in culture. To perform the test, a critical concentration of each drug is placed in media with standardized inoculum. Resistance is diagnosed if the proportion of resistant bacilli exceeds 1%. The proportion method is performed routinely with more than one critical concentration of isoniazid—a clinically significant practice because higher concentrations (doses) of the drug may overcome low-level resistance. Different levels of isoniazid resistance correlate with specific genetic mutations; genotypic DSTs assess for different levels of isoniazid resistance by detecting the corresponding mutations. The proportion method lacks standardized techniques and interpretations for ethambutol, pyrazinamide, and second-line drugs.168 Obtaining a positive culture on solid media, such as Löwenstein-Jensen or Middlebrook agar, often requires 4 to 6 weeks, followed by an additional 2 to 4 weeks for DST. Automated liquid media systems have shortened the time to positivity to 1 to 3 weeks but have not increased culture sensitivity. Use of an automated liquid media system for the proportion method shortens time to result to 1 week. Nucleic Acid Amplification.  Several NAATs for mycobacteria have been developed with various target sequences, assay formats, and

Mycobacterium tuberculosis

specimen-processing procedures.169–177 Most NAATs use the insertion element IS6110 to detect M. tuberculosis.174 Xpert MTB/RIF (Xpert), the most widely used NAAT, uses an automated, cartridge-based polymerase chain reaction (PCR) platform and probes to detect in 2 hours the presence of M. tuberculosis and mutation of rpoB, the gene responsible for most rifampin resistance. Because rifampin resistance rarely occurs in the absence of isoniazid resistance, detection of a rpoB mutation serves as a proxy for the diagnosis of MDR-TB. Compared with culture, a meta-analysis showed that the Xpert overall sensitivity was only 66% for respiratory samples from 2600 children.178 In stratified analyses, Xpert had a sensitivity of 95% for AFB smear-positive samples but only 55% to 62% sensitivity for AFB smearnegative, culture-positive samples.178 HIV status and specimen type (i.e., sputum or gastric lavage) did not affect assay performance.178 Taken together, Xpert appears to be more sensitive than sputum smear microscopy but less sensitive than culture for confirming childhood pulmonary TB. Few reports have described Xpert’s diagnostic utility for childhood extrapulmonary TB. In a large cohort study that used culture as the reference standard, Xpert demonstrated sensitivities of 100% and 75% for lymph node tissue and CSF, respectively.179 In other studies that included children but did not disaggregate pediatric results, sensitivities ranged between 50% and 100% for both CSF and lymph node tissue.178,180–182 Xpert has demonstrated 95% or higher sensitivity and specificity for rifampin resistance, but false-positive results can result from the detection of silent rpoB mutations that do not affect phenotypic susceptibility.178,183,184 The line probe assay (LiPA), another NAAT, uses PCR to isolate and amplify genes with resistance mutations. LiPAs, which can be performed on patient samples or culture isolates, produce results in 1 to 2 days. Numerous LiPA models are commercially available and vary in the mutations detected. The newest models detect resistance to ethambutol and drugs used to treat MDR-TB. LiPAs have 98% or higher sensitivity and specificity for rifampin resistance. Although specificity for isoniazid resistance is consistently high, sensitivity varies with the LiPA model and ranges from 57% to 100%.185,186 Genetic Sequencing.  DNA sequencing, which has been used to identify M. tuberculosis strains for epidemiologic purposes, has been adapted for DST. Unlike NAATs, which use probes to detect a set number of resistance-conferring mutations fixed a priori into the product design, sequencing platforms can identify all possible mutations in target genes and be rapidly modified to add more genes. Sequencing can also distinguish between silent and phenotypically significant mutations. Studies have shown more than 90% sensitivity and specificity for isoniazid resistance and more than 95% sensitivity and specificity for rifampin resistance.184,187–189

Recommendations for Diagnosing Tuberculosis Disease and Drug Resistance The diagnostic approach for TB disease in children varies according to the patient’s clinical presentation and the available technology. Guiding principles include the following: 1. Although microbiologic confirmation of childhood TB disease is difficult, most cases can be diagnosed clinically. All children suspected of having TB should undergo a careful history, including identification of possible source cases, physical examination (including growth assessment), test of infection (i.e., TST or IGRA), and relevant radiologic exams (e.g., chest radiography for pulmonary disease, neuroimaging for TB meningitis). Each of these elements may provide important diagnostic clues. 2. In most cases of suspected childhood TB, microbiologic confirmation should be pursued with culture, which remains the most sensitive diagnostic tool. For children with a known source case, a positive test result for infection, and classic radiographic findings, microbiologic testing may not be necessary as long as the source case has a DST result that can guide treatment. 3. Although less sensitive than culture, molecular methods may shorten the time to microbiologic confirmation and diagnosis of drug resistance. Diagnostic speed is particularly important in instances of severe, life-threatening disease or in areas with high drug-resistant TB

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prevalence, particularly when no source case DST is available to guide therapy. When available, both culture and molecular testing should be obtained to increase diagnostic yield.190 Molecular methods also should be applied to known source cases to ensure timely initiation of appropriate therapy for themselves and their child contacts. 4. In the United States and other countries with a low prevalence of rifampin resistance, the detection of rifampin resistance by Xpert should be confirmed with phenotypic DST or sequencing.191 The diagnosis of MDR-TB should trigger testing for resistance to secondline drugs. In the United States, the Centers for Disease Control and Prevention (CDC) offers expanded DST through its Molecular Detection of Drug Resistance service, which employs sequencing methods.192

THERAPY Antituberculosis Agents Anti-TB drugs are bacteriostatic or bactericidal (Table 134.2). Isoniazid, rifampin, pyrazinamide, and ethambutol are the first-line agents for adults and children. Isoniazid.  Isoniazid, the most widely used anti-TB medication, is bactericidal, easily administered, inexpensive, and relatively nontoxic in children. Isoniazid is almost completely absorbed from the gastrointestinal tract, and the recommended dose achieves therapeutic levels in all body tissues and fluids, including the CSF. In adults, isoniazid has been associated with symptomatic deficiency of pyridoxine, which is mainly found in milk and meat. However, in pediatrics, this effect occurs almost exclusively in malnourished or HIV-infected children.193 Pyridoxine supplementation (25 to 50 mg/day) is not usually necessary in otherwise healthy, well-nourished children but is recommended for exclusively breastfed infants, HIV-infected children, pregnant adolescents, and children and adolescents with meat- and milk-deficient diets. The major toxicity of isoniazid is hepatitis. Almost 10% of children develop transiently elevated serum alanine aminotransferase (ALT) levels while taking isoniazid, but clinical toxicity is rare. Most children are followed clinically without serum biochemical monitoring, and ALT levels usually return spontaneously to normal without interruption of treatment.194 Isoniazid can interact with several other drugs and can increase serum phenytoin levels by blocking its metabolism in the liver, leading to toxicity.195,196 A dose of isoniazid exceeding 15 mg/kg/day or in combination with rifampin enhances toxicity.197 Rifampin.  Rifampin is bactericidal for M. tuberculosis and generally well tolerated at a dose of 15 mg/kg/day. Rifampin belongs to the rifamycin class of antibiotics. This class also includes rifabutin and rifapentene; the latter has a long half-life that allows for weekly administration. Although 75% of rifampin is protein bound, it penetrates well into most tissues and fluids except the CSF. Despite rifampin’s only modest CSF penetration—which improves in the setting of inflammation—its use has been associated with improved outcomes of childhood TB meningitis.198 Gastrointestinal upset is rifampin’s most common side effect. Other adverse events include skin eruptions, hepatitis, and occasional thrombocytopenia or cholestatic jaundice.193 Rifampin is excreted in bodily fluids and causes urine and stool to turn orange. Discoloration of tears may cause orange staining of contact lenses. This body fluid discoloration serves as a useful indicator of treatment adherence. Rifampin lowers the effectiveness of oral contraceptives and accelerates excretion of some hepatically metabolized drugs including HIV protease inhibitors. Pyrazinamide.  Pyrazinamide is bactericidal for M. tuberculosis, particularly when bacilli are found inside macrophages or other similarly acidic environments. Pyrazinamide exerts maximal effect during the first 2 months of therapy, and its use allows treatment duration to be shortened to 6 months.199 Pyrazinamide is well absorbed from the gastrointestinal tract and penetrates most tissues, including CSF.200,201 The optimal dose in children has not been established because of a lack of pharmacokinetic data. In children, hepatotoxicity occurs infrequently at the standard daily dose of 30 to 40 mg/kg but is more common with higher doses.202 Nonetheless, pyrazinamide causes hepatitis more often in children than does isoniazid or rifampin, particularly when given with rifampin. Adults taking pyrazinamide can experience symptomatic

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TABLE 134.2  Antituberculous Drugs Used for Children

Drug

Dosage Forms

Daily Dosage for Treatment of Infection or Disease (mg/kg/day)

Isoniazida

Scored tablets

10–20 (PO)

20–30

Daily: 300 mg Intermittent: 900 mg/dose

10–20 (PO or IV)

10–20

Daily: 600 mg Intermittent: 600 mg/dose

20–40 (PO)

50–70

2 g

20–40 (IM or IV)

20–40 (IM or IV)

1 g

20 (PO)

50

2.5 g

10–20 (PO)

No data to support intermittent dosing

1 g

15 (IM or IV)

15–25 (IM or IV)

1 g

15 (IM or IV)

15–25 (IM or IV)

1 g

15–30 (IM or IV)

15–30 (IM or IV)

1 g

10–20 (PO)

No data to support intermittent dosing

1 g

200–300 divided bid (PO)

No data to support intermittent dosing

10 g

15–20 (PO or IV)

No data to support intermittent dosing

1 g

10 mg (once daily ≥12 yr; divided bid <12 yr of age)

No data to support intermittent dosing

300 mg

Twice- or Thrice-Weekly Dosage for Treatment of Infection or Disease (mg/kg/dose)

• 100 mg

Maximum Dose

• 300 mg Syrup • 50 mg/5 mLb • 100 mg/5 mLb a

Rifampin

Capsules • 150 mg • 300 mg Syrup formulated from capsulesc Aqueous solution for IV injection

Pyrazinamide

Scored tablets • 500 mg

Streptomycin

Vials • 1 g • 4 g

Ethambutol

Scored tablets • 100 mg • 400 mg

Ethionamide

Tablets • 250 mg • 1 g

Amikacin

Vials • 500 mg • 1 g

Kanamycin

Vials • 75 mg/2 mL • 500 mg/2 mL • 1 g/3 mL

Capreomycin

Vials • 1 g

Cycloserine

Capsules • 250 mg

p-Aminosalicylic acid

Granule packets • 3 g

Levofloxacin

Tablets • 250 mg • 500 mg • 750 mg Vials • 25 mg/mL

e

Linezolid

Tablets • 400 mg • 600 mg IV solution

a

Rifamate is a capsule containing 150 mg of isoniazid and 300 mg of rifampin. Two capsules provide the usual adult (≥50 kg) daily dose of each drug. Rifater is a tablet containing 50 mg of isoniazid, 120 mg of rifampin, and 300 mg of pyrazinamide. Neither combination has been studied in children, and neither is available in a pediatric formulation. b Many experts recommend avoidance of isoniazid syrup because it is unstable and is associated with frequent gastrointestinal complaints, especially diarrhea. c Merrell Dow Pharmaceuticals (Cincinnati, OH) issues directions for preparation of this extemporaneous syrup. d Total adult daily dosage. Fluoroquinolones can cause gastrointestinal disturbance, rash, and headache. In theory, they damage growing cartilage, but in practice, this reaction is rarely observed. e Dosing recommendations from Garcia-Prats AJ, Rose PC, Hesseling AC, Schaaf S. Linezolid for the treatment of drug-resistant tuberculosis in children: a review and recommendations. Tuberculosis (Edinb) 2014;94:93–104.

hyperuricemia with arthralgia, arthritis, and overt gout; children rarely experience these symptoms. Other adverse events include gastrointestinal upset, rashes, and intense pruritis.193 Ethambutol.  Ethambutol is administered, easily absorbed well, and bacteriostatic against M. tuberculosis. Ethambutol has poor CSF

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penetration, even in the setting of inflammation.198,203,204 Ethambutol primarily is used as the fourth drug when there is a possibility of resistance to other first-line drugs. The most serious adverse effect is retrobulbar neuritis, which appears to be dose related and manifests with blurred vision, central scotoma,

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TABLE 134.3  Regimens for Treatment of Tuberculosis Infection Drugs Isoniazid

Duration (mo) 9

Pediatric Dose

Frequency

10–15 mg/kg; 300 mg maximum

Daily

Total Doses

20–30 mg/kg; 900 mg maximum

Twice or thrice weeklya

76 12

270

Isoniazid plus rifapentine

3

Children ≥2 yr old: Isoniazidb: 15 mg/kg rounded up to the nearest 50 or 100 mg; 900 mg maximum Rifapentineb: 10.0–14.0 kg, 300 mg 14.1–25.0 kg, 450 mg 25.1–32.0 kg, 600 mg 32.1–49.9 kg, 750 mg ≥50.0 kg, 900 mg maximum

Once weeklya

Rifampin

4c

10–20 mg/kg; 600 mg maximum

Daily

120

Isoniazid plus rifampin

3

Isoniazid: 10–20 mg/kg; 300 mg maximum Rifampin: 10–20 mg/kg; 600 mg maximum

Daily

90

Contraindications Source case with isoniazid resistance Source case with isoniazid or rifampin resistance; child with HIV infection receiving antiretroviral therapy; pregnancy; age <2 yr

Source case with rifampin resistance; child with HIV infection receiving antiretroviral therapy Source case with isoniazid or rifampin resistance; child with HIV infection receiving antiretroviral therapy

a

Intermittent regimens must be provided by directly observed therapy (DOT). Isoniazid is formulated as 100-mg and 300-mg tablets. Rifapentine is formulated as 150-mg tablets in blister packs that should be kept sealed until use. c Some experts recommend 6 months of daily rifampin (180 doses); the American Academy of Pediatrics endorses both the 6-month and the 4-month regimens. b

and red-green color blindness.193 At the standard daily dose of 20 mg/kg, neuritis is rare in children and all patients with normal renal function.205 A child’s inability to cooperate with vision testing or report visual changes should not preclude ethambutol use. Second-Line Agents.  Mostly used to treat MDR-TB, second-line agents may be useful for drug-susceptible disease in patients with CNS TB, a contraindication to first-line drugs, or a decreased ability to tolerate or absorb enteral medications (Table 134.3). Ethionamide and fluoroquinolones cross the blood-brain barrier well and appear to be effective for CNS TB.103,198,206 Amikacin, kanamycin, and streptomycin have some ability to penetrate the CNS and may be used as the fourth drug, but dose-dependent ototoxicity and nephrotoxicity may limit their use. For patients who cannot tolerate or absorb enteral drugs, rifampin, amikacin, kanamycin, streptomycin, capreomycin, fluoroquinolones, and linezolid have parenteral formulations. Optimal doses and dosing intervals for second-line agents have not been established for the treatment of childhood TB. Moreover, childfriendly formulations do not exist for most second-line agents. Secondline agents usually have less efficacy and greater toxicity, and they should be used only in consultation with a TB expert.

Principles of Approach to Antimicrobial Regimens Success of antimicrobial therapy against M. tuberculosis depends on antimicrobial susceptibility, bacillary number and activity level, and location of the organisms (e.g., open cavities, closed caseous lesions, within macrophages). The high oxygen tension and low pH in open cavities allows M. tuberculosis to grow to a density of more than 109 organisms. Reactivation TB is associated with a high density of organisms at all three sites. Most young children with pulmonary TB are infected with a smaller number of organisms because they do not have cavitary lesions. Any large population of a single M. tuberculosis strain has individual bacilli resistant to a particular antibiotic, even if the strain responds clinically to that drug.207 This phenomenon occurs because M. tuberculosis drug resistance mutations occur at predictable frequencies: for streptomycin, mutations per organism occur at a density of 10−6; for ethambutol, 10−7; for isoniazid, 10−6 to 10−7; and for rifampin, 10−8. A cavity containing 109 tubercle bacilli has thousands of drug-resistant organisms, and a closed caseous lesion with 106 bacilli has few or none.

Fortunately, because the genetic loci for resistance are unlinked on the mycobacterial chromosome, the chance occurrence of resistance to one drug is unrelated to that of any other drug. For a single bacillus to have primary drug resistance to two drugs, it would require a density of 1011 to 1016, which rarely occurs clinically. In adults and children with TB disease, high bacterial density assumes presence of many bacilli that are resistant to a single drug, and therapy requires two or more anti-TB drugs. A single effective drug would select for emergence of a dominantly resistant population and produce secondary drug-resistant TB. Conversely, in persons with M. tuberculosis infection, the low bacterial density allows the use of a single drug.

Treatment of Mycobacterium tuberculosis Infection The number of childhood TB cases occurring in even the poorest countries can be reduced drastically with timely evaluation and treatment of child contacts of pulmonary TB patients.208–210 Because most childhood disease occurs 2 to 9 months after infection, early intervention is highly beneficial and cost-effective.40,211 The decision to administer treatment should consider several aspects of the natural history of childhood TB. First, children younger than 5 years of age with TB infection were infected recently. Second, infants with untreated TB infection have up to a 40% chance of developing TB disease. Third, the risk for disease progression decreases gradually throughout childhood and then increases slightly in adolescence. Fourth, infants and young children are more likely to have life-threatening forms of TB, including meningitis and disseminated disease. Fifth, unlike adults, children with TB infection remain at risk for disease progression over many years. Treatment of TB infection significantly reduces the risk of TB disease. Treatment options are daily or twice-weekly isoniazid for 9 months, daily rifampin for 4 or 6 months, daily isoniazid plus rifampin for 2 to 3 months, or once-weekly isoniazid and rifapentine for 12 doses (see Table 134.3). The efficacy of isoniazid has been demonstrated by placebo-controlled trials involving more than 125,000 subjects. These studies showed a 60% median risk reduction for TB in adults after 1 year of treatment and follow-up. Among the subgroup of adults with good medication adherence, effectiveness approached 90%.212 Because infants, children, and

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PART III  Etiologic Agents of Infectious Diseases SECTION A  Bacteria

adolescents tolerate isoniazid better than adults and have a minimal risk of isoniazid-related hepatitis, the risk-benefit ratio for treatment of TB infection is especially favorable.197,213 One study of 2750 children with M. tuberculosis infection showed a 94% reduction in TB disease during the first year after treatment and a 70% reduction over the subsequent 9-year period.214 Other large clinical trials also demonstrated risk reductions of 70% to 90%.215,216 In the United States, most children receive a 9-month course of isoniazid as self-administered daily therapy or twice-weekly directly observed therapy (DOT).141 Twice-weekly isoniazid has been used extensively to treat TB infection in children, especially school children and close contacts of cases.217,218 Although no controlled clinical trials of intermittent treatment of childhood TB infection have been performed, an observational study of approximately 400 children younger than 18 years of age demonstrated high rates of efficacy and safety, despite the higher dose per day (see Table 134.3).219 Although a 6-month course of treatment is recommended by the WHO to lower cost, data from large placebocontrolled trials have shown that a 9-month course confers a greater risk reduction for developing TB disease.217 The 4-month rifampin regimen is an alternative to isoniazid for children who cannot tolerate isoniazid or have a source case with isoniazid-resistant but rifampin-susceptible disease. Adult and pediatric studies have shown 4 months of rifampin to be less toxic than 9 months of isoniazid; moreover, the shorter regimen has been associated with higher completion rates among adults and children.220–228 Some experts treat children younger than 12 years of age with rifampin for 6 months instead of 4 months. A randomized, controlled trial of 1058 children between 2 and 17 years of age showed a 12-week regimen of once-weekly isoniazid and rifapentine given under DOT was as efficacious as 9 months of daily selfadministered isoniazid.229,230 No hepatotoxicity or other severe adverse treatment events were reported for children in either arm. The rifapentine group had significantly lower rates of treatment discontinuation; however, the DOT may partly explain this finding.229 In randomized, controlled trials of treatment of adults, 3 months of daily isoniazid plus rifampin demonstrated equivalency to 9 months of isoniazid in efficacy, adverse events, and adherence.220,231,232 The WHO and CDC have not endorsed this regimen, but it is used in several European countries. Guidelines do not exist for treating MDR-TB exposure or infection. A TB expert should be consulted about the management of children with either condition.233 No controlled studies have been published regarding the efficacy of any form of treatment of TB infection in HIV-infected children. The recommended regimen is a 9-month course of daily isoniazid.141 Most experts recommend pyridoxine supplementation and routine monitoring of serum hepatic enzymes for HIV-infected children treated with isoniazid.

Window Prophylaxis Isoniazid should be given to children younger than 5 years of age who have negative TST results but known or suspected exposure to a contagious source case. The rationale for this therapy—known as window prophylaxis—is that an untreated child may develop severe TB disease before TST reactivity develops (8–10 weeks). Children receiving window prophylaxis should have a repeat TST at 8 to 10 weeks after contact with the source case has been broken by physical separation or adequate initial treatment of the source case. If the second TST result is positive, isoniazid therapy is continued for the full 9 months, but if it is negative, treatment can be stopped.

Treatment Regimens for Tuberculosis Disease Drug-Susceptible Pulmonary Tuberculosis Early regimens for pulmonary TB lasted 12 to 18 months. Although they were effective, poor adherence led to high failure rates. Extensive adult and pediatric studies have shown that short-course chemotherapy— 6-month regimens that typically consist of a 2-month intensive phase using 3 or 4 drugs followed by a 4-month continuation phase using 2 drugs—cures most forms of TB.199,234–238 The efficacy of short-course

804

chemotherapy depends on the use of multiple bactericidal drugs in the intensive phase and monitored adherence with DOT.239 To treat pulmonary TB, the American Academy of Pediatrics and the American Thoracic Society endorse standard RIPE therapy: 6 months of isoniazid plus rifampin supplemented during the first 2 months by pyrazinamide plus ethambutol (see Table 34.3).240,241 Ethambutol is safe in children and helps prevent the emergence of rifampin or isoniazid resistance.242 If the isolate from the child or the likely source case is susceptible to isoniazid and rifampin, ethambutol can be stopped. The WHO endorses decreasing the frequency of medication administration from daily to thrice-weekly at the start of the continuation phase for non-HIV–infected children in settings with strong DOT programs.190 Although not recommended by the WHO, daily therapy for the first 2 weeks followed by twice-weekly therapy under DOT has been shown to be as safe and effective (>95% cure rate) as longer durations of daily therapy.234,237 Treatment regimens for pulmonary TB depend on the extent of disease, medication adherence, adverse drug reactions, and clinical and bacteriologic response. Some experts consider a 6-month regimen of only isoniazid and rifampin adequate therapy for children with hilar adenopathy, no other radiographic abnormalities, and minimal risk of drug-resistant TB. If the chest radiograph shows pulmonary cavitation or slow improvement or sputum culture remains positive after 2 months of therapy, treatment duration should be extended to 9 months.

Extrapulmonary Tuberculosis No clinical trials comparing treatment regimens for childhood extrapulmonary TB have been conducted. Several pediatric trials of 6-month, three-drug regimens included cases of lymph node and disseminated TB; both disease types responded favorably to short-course chemotherapy.235,243 Most treatment data for extrapulmonary TB come from case series of adult patients; according to these reports, most non–lifethreatening forms respond well to the 6-month RIPE therapy used for pulmonary TB.244,245 One exception is bone and joint TB, for which 9 to 12 months of treatment is recommended because 6-month regimens (especially without surgical intervention) have been associated with a higher failure rate.246,247 Similarly, most experts treat childhood TB meningitis for 9 to 12 months. For a patient with a low likelihood of drug-resistant TB, isoniazid, rifampin, and pyrazinamide constitute the first three drugs. A study from Thailand demonstrated better survival and lower morbidity when pyrazinamide was added to the initial 2 months of treatment.248 Ethionamide, levofloxacin, amikacin, kanamycin, or streptomycin serves as the fourth drug. The fourth drug may be stopped after confirmation of susceptibility to isoniazid and rifampin. After the 2-month intensive phase, pyrazinamide may be discontinued if the patient has demonstrated good clinical response. An alternative regimen used extensively in South Africa is four drugs (i.e., isoniazid, rifampin, pyrazinamide, and ethionamide) given daily for 6 months (or 9 months for HIV-infected patients).98,103 Regimen recommendations for childhood TB meningitis derive from observational studies and clinician experience.97 The only component of therapy that has been supported by randomized, controlled trials is the administration of daily corticosteroids (1 to 2 mg/kg/day of prednisone or its equivalent) during the first month of therapy.249,250

Special Circumstances Treatment of Tuberculosis Infection in HIV-Infected Children.  The optimal therapy for TB in HIV-infected children has not been established; the only treatment outcome data are from small case series.55,251,252 Children and adults with HIV-TB coinfection usually achieve cure with RIPE therapy if total treatment duration is extended to 9 months (i.e., isoniazid plus rifampin for 9 months supplemented by pyrazinamide plus ethambutol for the first 2 months) or to 6 months after sputum smears and cultures become negative, whichever is longer.55,252,253 Intermittent, including thrice-weekly, therapy is not recommended for HIV-infected patients. Rifabutin can replace rifampin in patients receiving protease inhibitors; however, experience in children is limited.254–256 Infants of Mothers With Tuberculosis.  An infant whose mother or other household contact may have TB is at high risk for infection and disease.

Mycobacterium tuberculosis

If possible, separation of the mother or contact and infant should be minimized. Recommendations for various clinical scenarios follow.141 Infected Household Contact With No Evidence of Disease.  Other household and extended family members to whom the infant may be exposed should undergo evaluation for TB. If no other household or family members show evidence of disease, the infant does not need further assessment. Treatment for TB infection should be considered for the contact and any other household or family members with TB infection. Mother With Disease Who Is Noncontagious at Delivery.  Contact investigation of household and extended family members is mandatory. The neonate should have a chest radiograph and complete physical examination to evaluate for congenital TB. If the chest radiograph and examination are unremarkable, the infant should receive isoniazid. Separation of the mother and infant is unnecessary if treatment and follow-up are ensured. The infant can breastfeed safely. The infant should have a TST at 3 to 4 months. Isoniazid can be discontinued if the TST result and physical examination are normal, the mother adheres to therapy and shows satisfactory response, and no other close contacts have infectious TB. If the infant has a positive TST result, isoniazid should be continued for the full 9-month course. Mother With Disease Who Is Suspected to Be Contagious at Delivery.  Management is the same as for the infant of a mother who is noncontagious at delivery, with the exception that while the mother remains contagious, contact between mother and infant should be limited to short periods, during which the mother must wear a mask.

Drug-Resistant Tuberculosis The drug susceptibility pattern of the likely source case should guide empiric therapy while the child’s own DST results are pending. Most cases of childhood pulmonary TB that are isoniazid-resistant but rifampin- and pyrazinamide-susceptible can be treated with a 6-month regimen of rifampin plus pyrazinamide plus ethambutol given daily or thrice weekly. Because of its inherent pyrazinamide resistance, M. bovis, barring additional drug resistance, should be treated with isoniazid and rifampin for 9 months, accompanied by ethambutol for the first 2 months. MDR-TB regimens usually involve four or more drugs to which the patient’s strain is susceptible and last 12 to 24 months. The use of an injectable drug, such as amikacin, for the first 6 months has been associated with improved outcomes but also with ototoxicity.257–259 Intermittent administration of medications is not recommended for resistant TB, and daily DOT is critical to prevent emergence of additional resistance. Several resources provide a more comprehensive overview of the management of childhood drug-resistant TB.260–262 A TB expert should be involved in designing the treatment regimen for all drug-resistant cases. MDR-TB treatment guidelines for children are based on adult studies.258,263,264 Pediatric data are scarce, but clinical experience and observational reports support several generalizations. First, children tolerate second-line therapy well, despite the lack of pediatric dosages. Second, children with intrathoracic TB respond favorably when the regimen includes three or more drugs to which the isolate is susceptible. Third, children with TB meningitis, HIV infection, or poor access to health resources have worse outcomes. Fourth, outpatient therapy for most or all of the treatment course is not associated with worse outcomes.257,260,265 The US Food and Drug Administration has approved bedaquiline for adults with MDR-TB. No pediatric data exist for the drug’s safety, tolerability, efficacy, or pharmacokinetics.266

Adjunctive Measures and Monitoring Corticosteroid Therapy Corticosteroids are beneficial in the management of childhood TB when host inflammatory response contributes significantly to tissue damage or impaired function.267 Corticosteroids decrease mortality rates and longterm neurologic sequelae for patients with TB meningitis by reducing vasculitis, inflammation, and increased intracranial pressure.249,250,268 Corticosteroids also are used for a CNS inflammatory mass that arises during therapy for TB meningitis; enlarged hilar lymph nodes that compress the tracheobronchial tree, causing respiratory distress, localized emphysema, collapse, or consolidation269; and miliary disease associated

134

with alveolar-capillary block, pleural effusion, or pericardial effusion. The most commonly used agent is prednisone at 1 to 2 mg/kg/day for 4 to 6 weeks followed by a taper.

Follow-Up During Antituberculosis Therapy and Directly Observed Therapy The primary goals of treatment monitoring consist of ensuring adherence, watching for adverse drug reactions, and assessing clinical response. In the United States, TB cases must be reported to the local public health department, which assists with treatment monitoring, compiles statistics, and performs necessary contact investigations. Moreover, public health officials should be promptly alerted about nonadherence and missed appointments because they may be able to help patients overcome barriers to adherence to therapy and clinic visits. The use of DOT in adult populations with increased risk factors for nonadherence (e.g., homelessness, intravenous drug use, HIV infection, lower socioeconomic status) demonstrated reductions in drug resistance, overall relapse rates, and relapses with MDR organisms.270 Children and adolescents with TB should be managed with DOT whenever possible.190,218 Children have low rates of adverse reactions to anti-TB medications.141,193 Asymptomatic mild elevations (i.e., more than three times the normal level) of serum ALT occur frequently during isoniazid or rifampin therapy, do not predict hepatotoxicity, and are not indications for discontinuing drugs. With the exception of pregnant or postpartum adolescents, who may have an elevated risk of hepatotoxicity, pediatric TB patients do not usually require routine biochemical monitoring. Rather, their caregivers should receive education regarding signs and symptoms of adverse events (e.g., anorexia, vomiting, abdominal pain, jaundice), which should prompt discontinuation of all medications and evaluation by a physician. Children taking ethambutol require regular monitoring of visual acuity and color discrimination if they can cooperate with testing. While receiving chemotherapy, the patient should be seen periodically to encourage regular intake of the prescribed drugs and to assess treatment response and possible adverse drug effects. Because radiographic improvement of intrathoracic TB occurs slowly, routine chest radiographs typically need to be obtained only at diagnosis, 1 or 2 months into treatment, and at the conclusion of therapy. Normal chest radiograph appearance is not a necessary criterion for treatment completion. Hilar lymphadenopathy commonly persists for 2 to 3 years after therapy. Adults and children with HIV infection and tuberculosis may develop IRIS if antiretroviral drugs are started with or shortly after the initiation of anti-TB therapy.271,272 As the HIV load drops and the CD4+ lymphocyte count rises, TB disease appears to worsen, or new foci of infection (e.g., tuberculoma of the brain, abdominal lesions) appear despite effective chemotherapy. IRIS is an immunologically mediated phenomenon and does not indicate inadequate anti-TB treatment. The addition of corticosteroids to the treatment regimen usually hastens resolution of new lesions.

BACILLUS CALMETTE–GUÉRIN VACCINE Despite decades of routine use of BCG vaccines in every country except the Netherlands and the United States, TB remains a major cause of morbidity and mortality worldwide.273 The lack of known in vitro correlates for immunity to M. tuberculosis poses a major obstacle to TB vaccination. However, increased understanding of TB immunity has led to efforts to produce a more effective vaccine, and several vaccine candidates are in various stages of development.274 Studies suggest that BCG vaccination can confer some protection against infection with M. tuberculosis.275 Meta-analyses of published trials and case-control series suggest that BCG vaccination of children prevents about 50% of all cases of TB disease, 60% to 80% of severe cases (especially meningitis and miliary disease), and 60% to 80% of deaths from TB.91,276–278 Strong evidence supports the use of BCG vaccines in TB high-burden countries to prevent meningitis and disseminated disease in young children, but in 2011, vaccination rates in high-burden countries were only 47% to 85%.279 In the United States, the low risk of M. tuberculosis infection in the general population and the vaccine’s limited efficacy render universal

805

BCG vaccination inappropriate. However, BCG vaccination is recommended for infants and children with negative TST results who have a high risk of intimate and prolonged exposure to persistently untreated or ineffectively treated people with infectious pulmonary TB, cannot be removed from the source of exposure, and cannot be given appropriate preventive therapy. BCG vaccine is contraindicated in some patients: those whose immunologic responses are impaired because of HIV infection, congenital immunodeficiency, or generalized malignancy (e.g., leukemia, lymphoma); persons receiving corticosteroids, alkylating agents, antimetabolites, or irradiation; and pregnant women.280 Patients who are undergoing TB treatment or who receive BCG vaccine can be given measles or other live virus vaccines unless they are taking corticosteroids, are severely ill, or have specific vaccine contraindications. Complications of BCG vaccine include BCG lymphadenitis and abscesses. Immunosuppressed individuals and occasionally young children can develop infection at disseminated sites (e.g., bone, brain, liver, lung).281–289 Standard anti-TB therapy is recommended to treat osteitis and disseminated disease caused by BCG and can be considered for treatment of chronic suppurative lymphadenitis when surgical excision cannot be performed. All references are available online at www.expertconsult.com.

KEY REFERENCES 40. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402. 43. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc Lung Dis 2004;8:636–647. 55. Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis 2005;9:477–484. 71. Marais BJ, Gie RP, Schaaf HS, et al. A proposed radiological classification of childhood intra-thoracic tuberculosis. Pediatr Radiol 2004;34:886–894. 95. Andronikou S, Wieselthaler N. Modern imaging of tuberculosis in children: thoracic, central nervous system and abdominal tuberculosis. Pediatr Radiol 2004;34:861–875. 132. Starke JR, American Academy of Pediatrics Committee on Infectious Diseases. Interferon-gamma release assays for diagnosis of tuberculosis infection and disease in children. Pediatrics 2014;134:e1763–e1773. 178. World Health Organization. Xpert MTB/RIF Assay for the Diagnosis of Pulmonary and Extrapulmonary TB in Adults and Children. Policy update. Geneva, Switzerland: WHO, 2013. 229. Villarino ME, Scott NA, Weis SE, et al. Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr 2015;169:247–255. 241. American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Brady MT, Jackson MA, Long SS (eds) Red Book: 2015 Report of the Committee on Infectious Diseases. Elk Grove Village, IL, American Academy of Pediatrics, 2015, pp 805–831.

Mycobacterium tuberculosis

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