5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

Anti-inflammatory therapy

Corticosteroids are useful in treating some children with tuberculosis disease but only when used in combination with effective antituberculosis drugs. They are beneficial for tuberculosis in children where the host inflammatory reaction contributes significantly to tissue damage or impairment of organ function (Table 18.6). There is convincing evidence that corticosteroids decrease mortality rates and long-term neurologic sequelae in some patients with tuberculous meningitis by reducing vasculitis, inflammation, and, ultimately, intracranial pressure.172 Lowering the intracranial pressure limits tissue damage and favors circulation of antituberculosis drugs through the brain and meninges. Short courses of corticosteroids also may be effective for children with enlarged hilar lymph nodes that compress the tracheobronchial tree causing respiratory distress, localized emphysema, or segmental pulmonary lesions.173,174 Several randomized clinical trials have shown that corticosteroids can help relieve symptoms and constriction associated with acute tuberculous pericardial effusion.175 In patients with tuberculous pleural effusion in whom there is a shift of the mediastinum and acute respiratory compromise, corticosteroids may cause dramatic improvement in symptoms, although the long-term course is probably unaffected.176 Some children with severe miliary tuberculosis have dramatic improvement with corticosteroids if the inflammatory reaction is so severe that alveolocapillary block is present. There is no convincing evidence that one corticosteroid is superior over the other. The most commonly used regimen is prednisone, 1–2 mg/ kg/day divided in one or two doses orally for 4–6 weeks, followed by a gradual taper. Thalidomide (3–5 mg/kg/day), a potent TNF-α inhibitor of monocytes and macrophages, has been used as a successful adjuvant therapy for the treatment of children with tuberculous arachnoiditis of the optic chiasm leading to visual loss, and large tuberculous pseudo-abscesses in the brain and spinal

cord.83,148

Treatment of tuberculosis infection

The goal of treatment of children with asymptomatic tuberculosis infection is to prevent progression to disease. This treatment is an established practice. The effectiveness of isoniazid therapy in children infected by a source case with an isoniazid-susceptible isolate has approached 100%.177

The following aspects of the natural history and treatment of tuberculosis infection in children must be considered in the formulation of recommendations about therapy: (1) recently infected immunocompromised children and children younger than 5 years have a high risk of progression to disease with untreated infants having up to a 40% chance of developing tuberculosis disease; (2)

Table 18.6  Manifestations of tuberculosis that may benefit from corticosteroid therapy

•Tuberculous meningitis

•Tuberculoma with edema or mass effect

•Miliary disease with alveolar-capillary block

•Constrictive pericarditis

•Massive pleural effusion

•Pott’s disease (vertebral tuberculosis) with nerve compression

infants and young children are more likely to have life-threaten- ing forms of tuberculosis, including meningitis and disseminated disease; (3) the risk for progression from tuberculosis infection to disease decreases gradually through childhood, until adolescence when the risk increases; and (4) children with tuberculosis infection have more years at risk for the development of disease than adults. Because of these factors, and the excellent safety profile of antituberculosis drugs in children, children and adolescents with tuberculosis infection should always be treated.

The standard treatment regimens for the treatment of tuberculosis infection in children include: 6–9 months of isoniazid (daily, or twice weekly via DOT); 3 months of daily rifampin and isoniazid; 4 months of daily rifampin; and once weekly isoniazid and rifapentine for 12 weeks.7,178

Isoniazid therapy for tuberculosis infection appears to be more effective for children than adults, with several large clinical trials demonstrating risk reduction of 70%–90%. Analysis of data from several studies has demonstrated a 20%–30% decreased efficacy of isoniazid treatment if it was taken for 6 months rather than 9 months. However, due to resource constraints on the international scale, the WHO-recommended duration of isoniazid therapy for tuberculosis infection is 6 months.179 Isoniazid given twice weekly for 9 months via DOT has been used extensively and is as effective as daily therapy. For healthy children taking isoniazid but no other potentially hepatotoxic drugs, routine biochemical monitor- ing and supplementation with pyridoxine are not necessary. Three months of daily rifampin and isoniazid has been used throughout Europe, with programmatic data suggesting that the regimen is effective, but this regimen is not recommended in the United States.180 Rifampin alone is a safe, well tolerated, acceptable alternative to daily or twice weekly isoniazid for 9 months. A multicenter, open-label trial randomized 844 children (<18 years of age) to receive either 4 months of daily rifampin or 9 months of isoniazid; 13% more children completed 4 months of rifampin compared to isoniazid, and no children in either group discontinued the drug due to a serious adverse event.181 Due to superior treatment completion rates compared to 9 months of isoniazid, 4 months of rifampin is now considered by many experts to be a better treatment option.178,181–184 Rifapentine is a rifamycin with a very long half-life, allowing for weekly administration in conjunction with high-dose isoniazid. Twelve doses of once weekly high-dose isoniazid and rifapentine are as safe and effective for treating tuberculosis infection as 9 months of daily isoniazid for children down to 2 years of age.129,183,185 Traditionally, this regimen has been given via DOT. In areas of the United States where DOT and funding are available, this is becoming the preferred regimen for the treatment of tuberculosis infection in age-eligible children who are exposed to a contact with a pansusceptible isolate of M. tuberculosis.

For children who develop tuberculosis infection after being in contact with a source case with a MDR strain of M. tuberculosis, the treatment regimen depends on the drug-susceptibility profile of the source case’s organism. The most commonly used regimen includes a fluoroquinolone—often levofloxacin—with or without other oral drugs.186 In most cases, an expert in tuberculosis should be consulted.

Few controlled studies have been published regarding the efficacy of treatment regimens other than isoniazid for tuberculosis

infection in HIV-infected children. The most commonly used regimen is a 6–9-month course of daily isoniazid. Most experts recommend that routine monitoring of serum hepatic enzyme concentrations be performed and pyridoxine be given when HIVinfected children are treated with isoniazid. In children who are not receiving protease inhibitor or nonnucleoside reverse transcriptase inhibitors, the optimal duration of rifampin therapy is not known, but most experts recommend at least a 6-month course if isoniazid cannot be used.

Postexposure treatment “window prophylaxis”

Serious tuberculosis disease can develop rapidly in a young child, even before a test of infection becomes positive. Therefore, children younger than 5 years of age who are initially TST or IGRA negative but have been in contact with a potentially contagious adult should receive isoniazid therapy until 8–10 weeks after contact has been broken by either physical separation from the source case or chemotherapy.187 This practice is often referred to as “window prophylaxis.” For these children, TST or IGRA testing is repeated after 8–10 weeks; if the second test result is positive, isoniazid therapy is continued for 9 months, but if the result is negative, treatment can be stopped.

Supportive and follow-up care

Children receiving treatment should be followed carefully to promote adherence to therapy, to monitor for adverse reactions to medications, and to ensure that the tuberculosis is being adequately treated. The clinician must report all clinically suspected and microbiologically confirmed childhood tuberculosis cases to the local health authority. This is to ensure that the child and the family receive appropriate care and evaluation. Adequate nutrition is important during the treatment of tuberculosis. Activity restriction is not necessary unless the child develops respiratory embarrassment or immobilization is necessary (in some cases of vertebral tuberculosis). Patients should be clinically evaluated every 4–6 weeks while receiving therapy. Anticipatory guidance with regard to the administration of medications to children is crucial. The clinician should foresee difficulties that the family might have in introducing several new medications in inconvenient dosage formulations to a young child. Pill forms of isoniazid, rifampin, pyrazinamide, and ethambutol can be crushed and given with small amounts of food.

Nonadherence to treatment is a major problem due to the long-term nature of treatment and sometimes difficult social circumstances of the patients. The child or adolescent and family must know what is expected of them through verbal and written instructions in their primary language. Approximately 30%–50% of children taking long-term treatment are nonadherent with selfadministered medications, and clinicians are usually not able to determine in advance which children or adolescents will be nonadherent. Preferably, DOT should be instituted by the local health authority.130

The rates of adverse reactions to antituberculosis medications are low enough in children and adolescents that routine baseline and monitoring of hepatic function tests is not necessary. If there is a previous history of hepatitis, obesity (fatty liver) or other chronic illness, it is advisable to obtain a baseline hepatic function

panel. If the patient or family reports any symptoms that could be adverse reactions to antituberculosis medications, the child should have a complete physical examination and a hepatic function panel (including bilirubin level determination). Serum liver enzyme elevations of 2 times normal are fairly common and do not necessitate discontinuation of medications if all other findings are normal. Pyrazinamide may cause mild arthralgia or arthritis that is usually transient. Rash and severe pruritus are less common in children. Children receiving ethionamide should have baseline thyroid function testing and monitoring every 6 months to evaluate for hypothyroidism. Rifapentine can cause muscle aches that are generally self-limited and require no intervention. Adverse reactions with fluoroquinolones are uncommon.

Radiographic improvement of intrathoracic disease in children occurs very slowly. A common practice is to obtain a chest radiograph at diagnosis and 4–8 weeks into therapy to be sure that no progression or unusual changes have occurred. If these radiographs are satisfactory, interim chest radiographs are not necessary, and an end of treatment radiograph is recommended. A significant proportion of children with intrathoracic adenopathy have abnormal radiographic findings for 1–3 years, after effective antituberculosis treatment has been completed. If clinical and radiographic improvement has occurred after 6 months of therapy, medications can be discontinued, and the child can be followed at intervals of 6–12 months with appropriate chest radiographs to determine continued improvement in radiographic appearance.

TUBERCULOSIS IN PREGNANT WOMEN

AND THE NEWBORN

Introduction

The influence of pregnancy on the incidence and prognosis of tuberculosis has been debated since antiquity.188 At various times, pregnancy has been thought to improve, worsen, or have no effect on the prognosis of tuberculosis. This controversy has lost some of its importance since the advent of effective antituberculosis therapy. With adequate treatment, a pregnant woman with tuberculosis has a prognosis equivalent to that of a comparable nonpregnant woman. If untreated, tuberculosis disease during pregnancy may result in unfavorable outcomes for both the pregnant woman and the fetus. Tuberculosis during pregnancy increases the risk of premature birth, low birth weight, intrauterine growth retardation, and perinatal death. Infants born to mothers with tuberculosis disease should be evaluated and treated to prevent the development of serious tuberculosis.189

Pathogenesis

The pathogenesis of pulmonary tuberculosis during pregnancy is similar to that for nonpregnant women. Shortly after the initiation of infection, some organisms enter the lymphatic and blood vessels and disseminate throughout the body. During this phase of infection, the genitalia, endometrium, or placenta may become involved. Genital tuberculosis is most likely to occur at the time

of menarche and can have a very long and relatively asymptomatic course. The fallopian tubes are most often involved (90%– 100%), followed by the uterus (50%–60%), ovaries (20%–30%), and cervix (5%–15%).190 Sterility is often the presenting complaint of tuberculous endometritis, which diminishes the likelihood of congenital tuberculosis occurring.191 Worldwide estimates are that tuberculosis is the cause of infertility in 1%–13% of women. An Egyptian study of 420 infertile women who were admitted for diagnostic laparoscopy, endometrial biopsy, and M. tuberculosis PCR testing192 identified tuberculosis as the cause in 24 women (5.7%); 17 of these women (71%) were found to have fallopian tube involvement (beading, sacculation or rigid appearance), 7 (29%) had ovarian disease, and 6 (25%) had peritoneal seeding. Tuberculous endometritis can lead to congenital infection in the newborn, but it results more frequently from disseminated tuberculosis in the mother than from direct extension from endometritis.193,194

The potential modes of inoculation of the newborn infant with tuberculosis from the mother are listed in Table 18.7. Infection of the neonate through the umbilical cord is a rare event. These infants’ mothers frequently suffer from pleural effusion, meningitis, or disseminated disease during pregnancy or soon after- wards.195–199 In many of these cases, a diagnosis of tuberculosis in the child leads to the discovery of the mother’s tuberculosis. The intensity of lymphohematogenous spread during pregnancy is one of the factors that determines if congenital tuberculosis will occur. Hematogenous dissemination in the mother leads to the infection of the placenta with subsequent transmission to the fetus. Tubercle bacilli have been demonstrated in the decidua, amnion, and chorionic villi of the placenta.191 However, even massive involvement of the placenta with tuberculosis does not always give rise to congenital infection. It is not clear whether the fetus can be directly infected from the mother’s bloodstream without a caseous lesion first forming in the placenta.

In hematogenous congenital tuberculosis, M. tuberculosis reaches the fetus via the umbilical vein. If some bacilli infect the liver, a primary focus develops with involvement of the periportal lymph nodes. However, the bacilli can pass through the liver into the main circulation leading to a primary focus in the fetus’ lung. The tubercle bacilli in the lung often remain dormant until after birth when oxygenation and circulation increase significantly, leading to pulmonary tuberculosis in the young infant.

Congenital infection of the infant may also occur via aspiration or ingestion of amniotic fluid.199 The fetus may inhale or ingest the tubercle bacilli when the caseous lesion in the placenta ruptures directly into the amniotic cavity. Inhalation or ingestion of infected amniotic fluid is the most likely the cause of tuberculosis

Table 18.7  Potential modes of inoculation of a neonate or infant with M. tuberculosis

if the infant presents with multiple primary foci in the lung, liver, gastrointestinal tract, or middle ear.200

The pathology of tuberculosis in the fetus and newborn usually demonstrates the predisposition to dissemination and fatal disease.201 The liver and lungs are primarily involved followed by the bone marrow, bone, gastrointestinal tract, adrenal glands, spleen, kidney, abdominal lymph nodes, and skin. The histologic patterns of involvement are similar to those in adults; tubercles and granulomas are common.202 CNS involvement occurs in fewer than 50% of cases. The mortality of congenital tuberculosis reaches 50% due primarily to the failure to suspect the correct diagnosis. Most fatal cases are diagnosed at autopsy.197,198

Postnatal acquisition of tuberculosis via airborne inoculation is the most common route of infection for the neonate. It may be impossible to differentiate postnatal infection from prenatal acquisition on clinical grounds alone. It is important to remember that any adult in the neonate’s environment can be a source of airborne tuberculosis. Since newborns infected with tuberculosis are at extremely high risk of developing severe forms of disease, investigation of an adult with tuberculosis whose household contains a pregnant woman should be considered a public health emergency. In addition, all adults in contact with an infant suspected of having infection or disease should undergo a thorough investigation for tuberculosis.

Epidemiology: Interaction of tuberculosis and pregnancy

The true burden of tuberculosis disease among pregnant women is unknown. An estimate of the global burden of tuberculosis disease during pregnancy that was extrapolated from the WHO tuberculosis case incidence data in 2011 from 217 countries estimated that 216,500 (range 192,100–247,000) tuberculosis cases occurred among pregnant women worldwide.203 The greatest burdens of disease were found in the WHO African region (89,400 cases) followed by the South East Asian region (67,500 cases). The lowest burden of disease occurred in the WHO region of the America with 4800 cases. Due to nonspecific signs and symptoms that occur in pregnant women with tuberculosis, this is thought to be an underestimate of the true burden of disease.

From ancient times, medical opinions regarding the interaction of pregnancy and tuberculosis have varied considerably. Hippocrates thought that pregnancy had a beneficial effect on tuberculosis, a view that persisted virtually unchallenged into the nineteenth century, when an opposite view emerged. In 1850, Grisolle reported 24 cases of tuberculosis that developed during pregnancy.204 In all patients, the progression of tuberculosis was more severe than usually seen in nonpregnant women of the same age. Shortly thereafter, further reports were published that implied pregnancy had a deleterious effect on tuberculosis. This view gained so much support that by the early twentieth century, the concept of induced abortion as a solution to avoid the consequences­ of tuberculosis during pregnancy became accepted practice.

The opinion that pregnancy had a deleterious effect on tuberculosis predominated until the late 1940s. In 1943, Cohen detected no increase rate of progression of tuberculosis among 100 pregnant

women with abnormal chest radiographs.205 In 1953, Hedvall presented a comprehensive review of the published studies concerning tuberculosis in pregnancy in the prechemotherapy era.206 He cited studies totaling over 1000 cases that reported negative effects of pregnancy on tuberculosis. However, he discovered a nearly equal number of reported cases in which a neutral or favorable relationship between pregnancy and tuberculosis was observed. In his own study involving 250 pregnant women with abnormal chest radiographs consistent with tuberculosis, he noted that 9% improved, 7% worsened, and 84% remained unchanged during pregnancy. In follow-up, during the first postpartum year, 9% improved, 15% worsened, and 76% were stable. Crombie noted that 31 of 101 pregnant women with quiescent tuberculosis experienced a relapse after delivery; 20 of the 31 relapses occurred in the first postpartum year.207 Several other investigators observed a higher risk of relapse during the puerperium. However, other studies failed to support an increased risk of progression of tuberculosis in the postpartum period. Cohen’s study failed to show a major increase in activity of tuberculosis during pregnancy or any postpartum interval.208 Other studies had similar results and, although they did not have controlled populations, it was estimated that the rates of progression would be comparable to nonpregnant age-matched control subjects.208,209 From these and other studies it became clear that the anatomic extent of disease, the radiographic pattern, and the susceptibility of the individual patient to tuberculosis are more important than pregnancy itself in determining the course and prognosis of the pregnant woman with tuberculosis.

The controversy concerning the effect of pregnancy or the postpartum period on tuberculosis has lost most of its importance since the advent of effective chemotherapy. With adequate treatment, pregnant women with tuberculosis have the same excellent prognosis as nonpregnant women. Several studies could document no adverse effects of pregnancy, birth, the postpartum period, or lactation on the course of tuberculosis in women receiving chemotherapy.189,210

In the prechemotherapy era, active tuberculosis at an advanced stage carried a poor prognosis for both the mother and the child. Shaefer et al. reported that the infant and maternal mortality from untreated tuberculosis was between 30% and 40%.189 In the chemotherapy era, the outcome of pregnancy rarely is altered by the presence of tuberculosis in the mother, except in rare cases of congenital tuberculosis. One study from Norway revealed a higher incidence of toxemia, postpartum hemorrhage, and difficult labor in mothers with tuberculosis compared to controls.211 The incidence of miscarriage was almost 10 times higher in mothers with tuberculosis, but there was no significant difference in the rate of congenital malformations between children born to mothers with and without tuberculosis. One study reported an incidence of prematurity among infants born to untreated mothers in a tuberculosis sanatorium ranging from 23%–64%, depending on the severity of tuberculosis in the mother.212 However, most experts now believe that with adequate treatment of the pregnant woman with tuberculosis, the prognosis of pregnancy should not be affected adversely by the presence of tuberculosis. Because of the excellent prognosis for both mother and child, the recommendation for the therapeutic abortion has been abandoned.

Clinical manifestations, diagnosis, and management

PREGNANT WOMAN

The clinical manifestations of tuberculosis in pregnant women can overlap with those related to pregnancy (including tiredness, fatigue, shortness of breath, sweating, and low-grade fevers) which may lead to a delay in a diagnosis of tuberculosis.213,214 In one series of 27 pregnant and postpartum women with pulmonary tuberculosis, the most common clinical findings were cough, fever, weight loss, malaise, and fatigue.215 However, almost 20% of pregnant women lacked significant symptoms. The TST was positive in 26 of 27 patients. Diagnosis was established in all cases by culture of sputum for M. tuberculosis. Sixteen of these patients had drug-resistant tuberculosis and their clinical course was marked by more extensive pulmonary involvement, higher incidence of pulmonary complications, longer sputum conversions times, and a higher incidence of death. In another series, approximately 5%–10% of pregnant women with tuberculosis had extrapulmonary disease, a rate comparable to the nonpregnant population.216

The indications for treatment and the basic principles for management of tuberculosis disease in the pregnant women are not much different from those in the nonpregnant patient. However, the recommended drug regimens and drugs used are slightly different, mostly due to possible toxic effects of several drugs on the developing fetus. There is no doubt that untreated tuberculosis disease represents a far greater risk to the pregnant woman and her fetus than dose appropriate treatment of the disease.217 However, if there is a delay in diagnosis, there is great risk of morbidity and mortality in both the woman (including a higher risk of abortion, postpartum hemorrhage, labor difficulties, and preeclampsia) and her developing fetus (including low birth weight, prematurity, and neonatal mortality).213 The currently recommended treatment for drugsusceptible tuberculosis in pregnancy is 6 months of isoniazid and rifampin daily, supplemented by ethambutol and pyrazinamide for the first 2 months.218,219 The drugs are usually given daily for the first 2 weeks to 2 months; then they can be given daily or intermittently for the remainder of therapy with equal effectiveness. Pyridoxine should also be given because of increased requirements for this vitamin in pregnancy.220 Extensive experience with isoniazid, rifampin, and ethambutol has shown that they are safe in both the mother and the fetus.218–220 Several antituberculosis drugs are not used in pregnancy because of possible toxicity to the fetus.221 Streptomycin should be avoided during pregnancy, if possible, since almost 20% of infants will have eighth nerve damage if the drug is given to their mothers during pregnancy.219,222 Other injectable drugs with antituberculosis activity, including capreomycin, kanamycin, and amikacin, could have the same toxic potential as streptomycin.

In women with multidrug-resistant tuberculosis, second-line agents (cycloserine, ethionamide, fluoroquinolones, para-amino- salicylic acid, and aminoglycosides) have been used successfully for treatment, and short term follow-up analyses found no evidence of teratogenicity, toxicity, or transmission of tuberculosis to the infant.223,224 The treatment of any form of drug-resistant tuberculosis during pregnancy is extraordinarily difficult and should be handled by an expert with great experience with the disease.

NEWBORN

The clinical manifestations of tuberculosis in the fetus or newborn are listed in Table 18.8. Most newborns with tuberculosis have an abnormal chest radiograph and approximately 50% have a miliary pattern of disease. Some infants with a normal chest radiograph early in the course develop profound radiographic abnormalities as the disease progresses. The most common findings are adenopathy and parenchymal infiltrates. Occasionally, the pulmonary involvement progresses very rapidly, leading to the development of a thin-walled cavity.

The clinical presentation of tuberculosis in the newborn is similar to that caused by bacterial sepsis and other congenital infections such as syphilis and cytomegalovirus. The diagnosis of congenital tuberculosis should be suspected in any infant with appropriate signs and symptoms who does not respond to vigorous antibiotic therapy and whose evaluation for other congenital infections is unrevealing. Of course, clinical suspicion should be high if the mother has or has had tuberculosis or if she has tuberculosis risk factors. If possible, an examination of the placenta for granulomatous inflammation, acid-fast bacilli, and by PCR and culture should be performed.225

The timely diagnosis of congenital or neonatal tuberculosis is often difficult. The TST is always negative initially, although it may become positive after 1–3 months. Occasionally, an IGRA is positive. The diagnosis must be established by finding acid-fast bacilli in body fluids or tissue and by culturing M. tuberculosis. A positive acid-fast smear of an early morning gastric aspirate in a newborn should be considered indicative of tuberculosis, although falsepositive smears occur. Direct acid-fast smears, PCR, and culture from middle ear fluid, bone marrow, tracheal aspirate, or tissue biopsy can be useful and should be attempted. One study found positive cultures for M. tuberculosis in 10 of 12 gastric aspirates, 3 of 4 liver biopsies, 3 of 3 lymph node biopsies, and 2 of 4 bone marrow biopsies from children with congenital tuberculosis.226 Open lung biopsy has also been used to establish a diagnosis. The CSF should be examined, sent for routine studies, cultured for mycobacteria, and sent for molecular testing; however, the yield for isolation of M. tuberculosis is low.226,227

The most important clue to rapidly establish the diagnosis of congenital or neonatal tuberculosis is the maternal and family

Table 18.8  Most frequent signs and symptoms of congenital tuberculosis

Source: Adapted from Hageman J et al. Pediatrics. 1980;66:980.

history. Suspicion should increase if the mother of other family members suffer from unexplained pneumonia, bronchitis, pleural effusion, meningitis, or endometritis shortly before, during, or after pregnancy. Testing of both parents and other family members can yield important clues about the presence of tuberculosis in the family. The importance of this epidemiologic information cannot be overemphasized. The need for thorough investigation of the mother was emphasized by Hageman et al. who found that only 10 of 26 mothers who gave birth to neonates with congenital tuberculosis were diagnosed prior to their infants; the other 16 were discovered as part of the investigation of the infant.226

The optimal treatment of congenital tuberculosis has not been established since the rarity of the condition precludes formal treatment trials. The basic principles for treatment of older children also apply to the treatment of congenital tuberculosis. All neonates with suspected congenital tuberculosis should be started on four antituberculosis medications (isoniazid, rifampin, pyrazinamide plus either ethambutol or an aminoglycoside) until the diagnostic evaluation and susceptibility testing of isolated organisms are concluded.227 Although the optimal duration of therapy has not been established, many experts treat infants with congenital tuberculosis for a total duration of 9–12 months. Young infants receiving multidrug therapy should have serum liver enzymes and uric acid (for pyrazinamide) monitored. Hearing screens and renal function testing should be obtained for infants receiving long-term aminoglycoside therapy. All neonates and infants should receive tuberculosis treatment under DOT.

Screening and testing for tuberculosis during pregnancy

For all pregnant women, the history obtained in an early visit should include questions about tuberculosis risk factors (including birth in or regular travel to a country with a high burden of tuberculosis or known exposure to an adult with known tuberculosis disease), previous positive test for tuberculosis infection (either TST or IGRA), previous treatment for tuberculosis, and current symptoms compatible with tuberculosis. The WHO recommends systematic tuberculosis screening of pregnant women who live in settings where the tuberculosis prevalence is 100 cases per 100,000 population or higher.228 In the United States, the CDC and the American College of Obstetrics and Gynecology (ACOG) recommend screening for tuberculosis in women at high risk at the time of prenatal care visits.229 Any pregnant woman with risk factors for tuberculosis and all HIV-infected women should be tested with either a TST or IGRA. An IGRA is the preferred method for testing women who have received a BCG vaccination and in those who are less likely to return for a TST reading. It must be emphasized that HIV-infected women and M. tuberculosis may have a falsely negative TST or IGRA, especially if her HIV infection is poorly controlled; these women should be screened for symptoms of tuberculosis with a low threshold for chest imaging to evaluate for pulmonary tuberculosis. For many high-risk women, prenatal or peripartum care represents their only contact with the health-care system and the opportunity to test them for tuberculosis infection or disease should not be lost. Any pregnant

woman with a positive TST or IGRA result should receive a chest radiograph with appropriate abdominal shielding. In addition, a thorough review of systems and physical examination should be carried out to exclude extrapulmonary tuberculosis.

The principles of treatment of asymptomatic tuberculosis infection are similar for pregnant women and other adults of comparable age. Although treatment of tuberculosis disease during pregnancy is unquestioned, the treatment of the pregnant woman who has an asymptomatic tuberculosis infection is more controversial. As pregnancy does not seem to increase the risk of a woman progressing from infection to disease, some clinicians prefer to delay treatment of tuberculosis infection until after delivery. Others believe that because recent infection can be accompanied by hematogenous spread to the placenta, it is preferable to treat without delay or defer initiating treatment until the second trimester.230 The benefits of immediate treatment may be greater in high-risk patients such as HIV-infected women or close contacts to a person with tuberculosis. There appears to be an increased risk of isoniazidassociated hepatoxicity during the postpartum period.231–233 This was highlighted in multicenter, randomized, non-inferiority trial including HIV-infected pregnant women. The women were randomized to receive isoniazid during pregnancy (immediate group) or in the postpartum period (deferred group). Approximately 6% of women developed hepatotoxicity of grade 3 or higher, including four who were symptomatic and two (0.2%) died of hepatotoxicity. More women in the immediate group experienced hepatotoxicity than those in the deferred group. All of the events occurred during the postpartum period in participants receiving efavirenz-based antiretroviral treatment (ART) regimens.233 If isoniazid treatment is started or continued during pregnancy or the postpartum period, women should be followed closely for signs, symptoms, and abnormalities in liver enzymes. The possible increased risk of isoniazid-associated hepatotoxicity must be weighed against the risk of developing tuberculosis disease as well as the subsequent consequences to both the mother and the baby.

In mothers who are continued on tuberculosis treatment following the delivery of the infant, questions arise regarding the safety of breastfeeding while the mother is receiving antituberculosis drugs. Snider and Powell showed that a breastfeeding infant would receive no more than 20% of the usual therapeutic dosage of isoniazid and less than 11% for other antituberculosis drugs.234 Potential toxic effects of drugs delivered via breast milk have not been reported. However, because pyridoxine deficiency in the neonate can cause seizures, and breast milk contains relatively low levels of pyridoxine, the infant whose breastfeeding mother is taking isoniazid should receive supplemental pyridoxine. This is often administered in the form of an infant multi-vitamin.235

Management of a mother with a positive test for tuberculosis infection

NEGATIVE CHEST RADIOGRAPH AND ASYMPTOMATIC

If the mother has a positive TST or IGRA, a negative chest radiograph, and is clinically well, no separation of the infant and the mother is needed after delivery. The child needs no

special evaluation or treatment if the child remains asymptomatic. Because the mother’s test of infection may be a signal that there is infectious tuberculosis within the household, all other household members and close contacts should undergo testing for tuberculosis infection­ and further evaluation as indicated. The mother is usually a candidate for therapy for tuberculosis infection.

ABNORMAL CHEST RADIOGRAPH

If the mother has suspected tuberculosis at the time of delivery (based on her tuberculosis risk factors, symptoms with or without a positive TST or IGRA), the newborn should be separated from the mother until the chest radiograph is obtained. If the mother’s chest radiograph is abnormal, separation should be maintained until the mother has been evaluated thoroughly, including examination of her sputum. If possible, the placenta should be examined for evidence of granulomoatous inflammation and tissue specimens should be sent for acid fast smear and mycobacterial culture. If the mother’s chest radiograph is abnormal but the history, physical examination, sputum examination, and evaluation of the radiograph show no evidence of current active tuberculosis, it is reasonable to assume that the infant is at low risk for infection. The radiographic abnormality may be due to another cause or a quiescent focus of past tuberculosis. If the mother remains untreated, she may develop active tuberculosis and expose her infant (who is at very high risk of a tuberculosis infection progressing to disease).236 The untreated mother should receive appropriate treatment, and she and her infant should receive careful follow-up care. In addition, all other household members and close contacts should undergo testing for tuberculosis infection and further evaluation as indicated.

If the mother’s chest radiograph, acid-fast sputum smear, or rapid molecular testing shows evidence of current tuberculosis disease, additional steps are necessary to protect the infant. Isoniazid therapy for newborns has been so effective that separation of the mother and the infant is no longer considered mandatory.237,238 Separation should occur only if the mother is ill enough to require hospitalization, she has been or is expected to become nonadherent to treatment, or she has confirmed or suspected drug-resistant tuberculosis. As isoniazid resistance is increasing, it is not always clear if isoniazid therapy will be effective. If, due to epidemiologic factors, isoniazid resistance is suspected or the mother’s adherence with medication is in question, rigorous separation of the infant from the mother must be considered. The duration of the separation will vary but must be as long as it takes to render the mother noninfectious. An expert in tuberculosis should be consulted if the young infant has potential exposure to the mother or another adult with tuberculosis disease caused by an isoniazid-resistant strain of M. tuberculosis. A conservative suggestion for the duration of separation would be 6–12 weeks of culture negativity for the mother. In cases when the organism is drug-susceptible, isoniazid should be continued in the infant at least until the mother is sputum culture negative for 3 months. At that time, a TST should be performed; if the test is positive, the infant should be evaluated for the presence of tuberculosis disease with a physical examination and chest radiograph and further evaluation

for extrapulmonary sites of disease. If disease is absent, the infant should continue isoniazid for a total duration of 6–9 months. If the TST is negative, and the mother has good adherence and response to treatment, isoniazid can be discontinued.

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