Update in the Diagnosis and Treatment of Tuberculosis in Children

Data from clinical and epidemiological studies have led to several new recommendations in the areas of diagnosis and treatment of pediatric tuberculosis in the past few years. Due to the low incidence of tuberculosis in the United States, many primary care providers may not be familiar with these new recommendations.After completing this article, readers should be able to: List the risk factors for tuberculosis (TB) in children in order to decide when further evaluation is required.Describe the difference between tuberculosis infection (TBI) and tuberculosis disease and identify the workup for each one.List the advantages and limitations of tests for TB infection and become familiar with the new recommendations for these tests.Identify the new preferred regimens recommended for TB infection in children.Describe the principles of therapy for TB disease, including treating multidrug-resistant TB and recognizing the most commonly used drugs and the new options for shorter duration of therapy.In the last decade, there have been many advances in the diagnosis of tuberculosis (TB), and for the first time in more than 5 decades, new drugs have been developed and others have been repurposed for the treatment of TB, including multidrug-resistant TB (MDR-TB). These developments have made TB treatment easier and shorter. Still, TB was the world’s second leading cause of death from an infectious agent, after COVID-19, with 1.3 million deaths in 2022. An estimated 10.6 million people developed TB in 2022 (including 410 000 with MDR-TB), with a global incidence of 133 cases/100 000 population.1 It has been estimated that approximately 1.7 billion people worldwide have asymptomatic TB infection, including nearly 100 million children.2 In the United States, there were 8331 reported cases of TB disease, with an incidence rate of 2.5 cases/100 000 persons in 2022.3 Given the low incidence in the United States, many pediatricians are not familiar with the new advances in the management of TB in children.Transmission of TB is mostly airborne and requires exposure to contagious adults or adolescents with active pulmonary (or laryngeal) TB, who actively cough. The factors that affect transmission are the susceptibility of the exposed person, the infectiousness of the person that has TB, proximity and duration of exposure, and environmental factors, such as poor air circulation, secondhand smoke, household crowding, and indoor wood-burning stoves.4,5 People with cavitary TB are usually more contagious than those with nodular TB. Children aged younger than 10 years are usually not contagious because they most commonly have paucibacillary disease (ie, affected lymph nodes and lung infiltrates have a low bacterial load), and they do not have the force to expel the organisms in droplet nuclei. The most important risk factor for TB in children is being a household contact of an active case.6 Other risk factors include place of birth, travel, residence or exposure to persons in countries that are endemic for TB, including countries from Africa, Asia, the Middle East, the former Soviet Union, and Latin America, and, to a lesser extent, exposure to individuals that experience homelessness, use illegal drugs, or have been residents of correctional facilities or other congregate settings.7After inhalation of Mycobacterium tuberculosis (MTB) droplet nuclei, the establishment of the infection depends on the level of efficiency of the clearance mechanisms of the airway, the innate immune system (phagocytosis and killing by alveolar macrophages), and the adaptive immune system (formation of granuloma, which undergoes caseous necrosis, encapsulation, fibrosis, and/or calcification).4,8 These processes can control TB infection in most cases. However, some organisms can survive in the granuloma for many years. This stage is generally called “latent tuberculosis infection” (LTBI) or, preferably, “tuberculosis infection” (TBI). In some children, hilar or paratracheal lymph nodes become enlarged by the inflammatory reaction to the tubercle bacilli, sometimes causing a partial obstruction of the airway, which can lead to hyperinflation, collapse of distal segments of the lung, and secondary bacterial pneumonia. Inflamed, caseous nodes may erode the bronchial wall, causing endobronchial TB.6When the infection is not controlled by the adaptive immune system, the bacilli are not contained in the granuloma and they spread via the bloodstream or via the lymphatic system to the lungs (pulmonary TB), distant organs (extrapulmonary TB), or multiple organ systems (disseminated TB).8 Spread can occur soon after the primary infection or years later (reactivation of a latent infection), and it is more common in the immunocompromised patient. In children, primary disease is more common than reactivation, but adolescents can present with reactivation.6Other forms of transmission include cutaneous, via ingestion of unpasteurized dairy products (M bovis), and vertical (congenital), but these forms of transmission are rare.6TB infection is defined by having a positive test for TBI, a normal chest x-ray (CXR), and no symptoms or abnormal findings on physical examination suggestive of TB disease. Most children are asymptomatic when they acquire primary TBI. A few children have mild to moderate signs and symptoms such as fever, cough, and malaise occurring a few weeks prior to testing positive for TBI and resolving within 5 to 7 days without specific treatment.The risk of advancing from TBI to TB disease is approximately 10% in the general population. However, the risk is higher in the first 2 years after the primary infection. It is estimated that 75% of patients with TB disease develop it within 1 year of contact with an index case and 97% within 2 years after exposure.9 If not treated for TBI, the estimated 2-year risk for developing TB disease is 19% in children younger than 5 years. Of the children that develop TB disease, 83% are diagnosed within the first 3 months of their known exposure.10This is the most common form of TB disease, accounting for approximately 80% of cases. The clinical presentation can be deceptive and varies among different age groups. Infants usually present with symptoms such as dry cough and wheezing secondary to airway obstruction due to external compression or internal narrowing of the airway due to endobronchial disease. Affected infants also usually have fever and weight stunting. On the other hand, school-aged children may be asymptomatic or may have mild cough with or without fever. The CXR typically shows perihilar lymphadenopathy with or without an associated infiltrate or atelectasis. Many children in this age group are discovered only via active contact investigation. A few patients at this age present with a clinical picture suggestive of bacterial pneumonia with signs of respiratory distress and a high fever. The CXR may show lobar infiltrates with or without significant pleural effusion. Adolescents more commonly present with the classic symptoms of prolonged fever, chronic productive cough, night sweats, and weight loss. Their CXR findings may be similar to those of school-aged children, but the CXR may show cavitation in the upper lobes similar to what is seen in adult patients.This form of TB can occur in almost any organ system, including superficial and visceral lymph nodes and the central nervous, gastrointestinal, osteoarticular, and genitourinary systems. The most common sites are the peripheral lymph nodes in the cervical region. The most severe form of extrapulmonary TB is meningitis, which occurs in only 0.5% to 2% of TBI cases, but it is important to recognize early because the prognosis relates in great part to the time of initiation of treatment. TB meningitis occurs more often in children younger than 2 years and in immunocompromised hosts.In miliary or disseminated TB, there is involvement of 2 or more organ systems. The clinical picture is often indolent, but it may be acute with fast progression. Early pulmonary involvement tends to be mild, but diffuse lung involvement becomes apparent if treatment is not given promptly. Generalized lymphadenopathy and hepatosplenomegaly develop in 50% of cases, and meningitis develops in 20% to 40%. The most common signs of miliary TB include malaise, anorexia, weight loss, and fever ranging from low to high grade. The CXR shows a particular nodular pattern with multiple very small opacities scattered bilaterally (called miliary due to the resemblance to millet seeds).In general, TB in a child can be discovered in 3 ways: through contact investigation of an active contagious TB case, through screening of children with other high epidemiological risks, and through evaluation of children presenting with symptoms and signs suspicious for TB.6 The first 2 ways allow for an early diagnosis, when children are asymptomatic or mildly symptomatic. Children identified in a contact investigation, with other epidemiological risks or with suspicious symptoms, should be tested for TB infection, using one of 2 different methods currently available: tuberculin skin test (TST) or interferon-γ release assays (IGRAs). Both methods are indirect because they test the individual’s adaptive immune response to MTB.Neither of them excludes TBI nor distinguishes TBI from TB disease. However, a positive IGRA correlates with progression to disease more strongly than a positive TST.11It involves intradermal injection of 0.1 mL of purified protein derivative containing 5 tuberculin units. The results are interpreted as the transverse diameter of induration present 48 to 72 hours after injection. This test has been used for decades. However, it has many disadvantages, including a low specificity. Factors such as very young age, malnutrition, immunosuppression by disease or drugs, viral infection, recent measles vaccination, and overwhelming TB can result in a false negative. False-positive results can be caused by cross-sensitization to antigens of nontuberculous mycobacteria and previous immunization with Bacille Calmette-Guérin (BCG) vaccine. To try to improve the specificity, there are 3 reaction size limits for determining a positive result based on epidemiological and clinical risk factors (Table 1). To interpret the results correctly, it is important to obtain an adequate history of possible risk factors for acquiring TBI.6 Other disadvantages include the need for a second visit to read the results, a lack of adequate training and experience in administration, a wide range of inter-reader variability, and boosting phenomenon (ie, a reaction to TST occurring in a person previously infected with TB or in children vaccinated with BCG whose immune response has waned over time and the tuberculin test stimulates or “boosts” their immune system; the reaction does not represent a new infection but a boosted immune response).These tests measure in vitro interferon gamma (IFN-γ) production from peripheral blood T-lymphocytes after stimulation with 2 purified antigens derived from the MTB complex. Two IGRAs are approved and commercially available in the United States: QuantiFERON-TB Gold Plus (QFT; Qiagen) and T-SPOT.TB test (T-Spot; Oxford Immunotec).These tests have higher specificity than the TST due to the use of more specific MTB antigens, which are not found in BCG vaccine or in most common nontuberculous mycobacteria, such as Mycobacterium avium complex. However, these antigens are found in other much less common species such as M kansasii, M marinum, M szulgai, and M IGRAs and positive in to the antigens to in test much response to the control or response to the positive control or These results be interpreted and should not be used in clinical Factors associated with or results include young age, immunocompromised and of the The results of the test to be less affected by these of IGRAs is similar to that of ranging from 80% to in patients with TB disease. The specificity of IGRAs from to which is higher than that of TST low as in with high BCG False-positive and results may occur due to in and with species of nontuberculous mycobacteria, such as M kansasii, M marinum, and can also cause a positive IGRA results may be false In with a positive the other IGRA or TST should be and only be as positive if 2 tests are IGRAs have many advantages over A of IGRAs and TST is in there has been to use IGRAs in very young children younger than 2 due to the of on this when these tests were and The has been the of of IGRAs with TST in these children, on the other hand, are at very high risk for developing severe TB disease if they In a by the for and TST IGRAs in asymptomatic children in the United States, the positive was 10% for TST with to for IGRAs in children younger than 5 and for TST to for IGRA in children aged 5 years and In if the TST is positive but the IGRA is in asymptomatic children without a history of exposure to an TB case, TBI is Data the use of IGRAs in children of have to and many pediatric TB have used IGRAs in children of for a few years In a of studies on the use of IGRAs in children that on children younger than 2 years found that after a of 3 to progression to TB disease not occur in any of children with including children with positive the of their from the use of IGRAs to children aged than 2 years to using these tests in children of any In IGRAs are preferred in most cases, but in children vaccinated with Other factors to when to use IGRAs in young children are the of a in in of and of to the in a testing with IGRA and TST is not However, results from tests may be in clinical such as when the test is in a child with TB, or in an immunocompromised child with epidemiological risk factors for TB. In these cases, a positive result from test should be interpreted as of TB infection. Of a result for an IGRA or a TST should be in infants aged younger than 3 a child tests positive for TST or the is to the child has TB disease or TBI. A history of symptoms and is of by a physical and should be in child that tests positive for TBI. the findings in primary pulmonary TB can be very it is recommended that be by an in pediatric TB, It is strongly recommended that a be to meningitis in children younger than 1 year with TB disease if they have no central system signs or symptoms, as as in any child with Other on the clinical TB disease is is to obtain to for and It is important to that often in children with TB may not be If a child is a known contact with an infectious case of TB, has a positive test of infection, and has clinical or findings suggestive of TB, that child should be treated for TB disease. The susceptibility testing results of a can be used to the treatment However, is recommended when the case is when there is known or when the child is and in cases of extrapulmonary TB is for include and other or to the age and clinical should be in the early the child and the of the and it is recommended to 3 for 3 The of bacilli in is low than The of of 3 is less than 50% in children and less than 75% in after with have been reported as having a and are in children than 5 to 7 In some after cough was and in via do not have a than those via using reaction of the of MTB in clinical The of has from to 83% when with clinical diagnosis in A result does not TB in a is the most available It can be in a wide of including and it is only approved in In a of pediatric using positive as the was in in in and in The specificity was high in high and specificity for the of and which it when TB is The is a test with reported in patients with paucibacillary disease (pulmonary TB with results and positive M tuberculosis results from respiratory such as children and patients with is not approved and is not available in the United The the use of in children as an test in and than and the use of in or The also the use of in other and and lymph of with and because an is to a susceptibility should not in the United However, the of the 2 methods is in the management of management of exposed children varies on the risk for acquiring the infection and the risk for developing TB disease a child with risk factors for TB infection is the factor to is the risk of developing TB disease, which is to the of their immune Children younger than 5 years are at high risk due to the of their immune or and also patients at high risk for TB younger than 5 years who are exposed to TB should be with a of systems and physical a test for infection or and a If evaluation is normal and/or these children should be on primary known as with or A test of infection is to 10 weeks after their last If the test is also the should be If it is these children should a for immunocompromised children, and are also In most cases, if the IGRA or TST is is However, the of the test may be low to infection when the of immunosuppression is In this case, TBI be and treatment should be other the evaluation should include IGRA or by a CXR if IGRA or TST is positive or if there are symptoms suggestive of TB. is not but IGRA or TST testing to 10 weeks after exposure is If the second test is no further evaluation or treatment is drugs used for the treatment of TB on the pattern of of the or MTB These are as MTB is to MTB is to at one of the MTB is to and MTB is to any and or (or MTB is to and a or a and a of for to months was the treatment for infection for many years. The is almost in TB disease. However, experience and studies have that and are using or in with are as with much and These regimens in are preferred over the infection, or with or without a second for to months is second drugs include or The of and has a higher risk of poor and/or and is not A recent of months of with in children and adolescents exposed to months may be for some However, an duration (ie, or is recommended by many TB for patients with children younger than 5 and individuals with other risk for progression to active TB disease. or with a pediatric TB is of an of 2 months with and also known as by a of months of to a treatment time of are usually given for the first 2 weeks to 2 months of this can be given and or therapy children without disease and no risks for TB, many using only 3 drugs and for the and for the other patients with cavitary pulmonary disease and/or patients with positive after 2 the is for 3 for a of This is used for pulmonary and most extrapulmonary TB, for meningitis and disease, for which the duration may be to to meningitis, the one of the drugs as the of or or for the However, the has a with the drugs as an to the The use of has been to improve in TB meningitis, and is strongly was by the and after an as with the It has been by in It is for children between the of 3 months and years with TB disease, defined as peripheral lymph lymph TB without significant airway TB pleural or disease, to less than one of the lungs (ie, pneumonia the be and without a miliary This of 2 months of 2 months of for a duration of with the in the first 2 months of treatment is recommended in with a high of or of that can be with only 3 a of this with the was by the in and the in It is an for children aged years and and with weight than or to with pulmonary also use it in other paucibacillary disease, such as peripheral lymphadenopathy or pleural TB. It of weeks of and given by a of the drugs without given for a duration of of is the of this with a pediatric TB is recommended when is or regimens for used a of and drugs for to The drugs used in these regimens 3 and based on their and experience of to the of new drugs and and of other drugs and new regimens for using from months to months have been and of and for The be to months when there is treatment response within the first is approved in persons aged years and without previous exposure to the 3 drugs However, because is not approved in children, this is not approved for children younger than years in the United of drugs in A and 1 from group the use of However, is available only through use in the United The duration is to This can be used in children of with without or severe extrapulmonary is very similar to the the recommendations for duration of therapy are to months for TB, to months for severe disease, and at months for are not for treatment of TB disease with or without involvement of sites with poor disseminated or meningitis, and TB), when there is or or or when the child is The treatment should be when the child or one or more of the drugs, when there is a clinical and when there are many treatment due to or is for the of a treatment The of the is for via and for of treatment of TBI and most cases of TB disease is not recommended because is a in previously However, these tests should be in children with clinical signs and symptoms of and children with disease, or children other using drugs, other tests specific to each be is an important for or may affect It is when using drugs that may not be in children, such as drugs or drugs used to or when there is a poor clinical response to what be an early and the prognosis of TB disease in children is This is in cases of with are seen in children with and in the diagnosis and treatment with in meningitis and disseminated disease. In cases of in children, the reported of have been to In a among children treated for the use of one or more of the new or repurposed drugs (ie, and in the treatment was associated with a higher of with regimens without any of those drugs for tuberculosis infection (TBI) should only be in children with risk factors for TB, recognizing that the most important risk factor is being a household contact of an active TB on and release assays are testing methods as the tuberculin skin test (TST) to TBI in children of on moderate and have many advantages over TST and in many is a in Bacille Calmette-Guérin on and tests including are for and of Mycobacterium tuberculosis (MTB) in clinical However, should be used in with on and to treatment for TBI is preferred over to regimens because of and with similar on and than 3 months with TB disease and without for multidrug-resistant TB can be treated with a using 3 to on and without or severe disease can be treated with a of drugs of using drugs and for to months of to on and