Tuberculosis in Children

Etiology

Mycobacterium tuberculosis is an aerobic, slow-growing, nonmotile, acid-fast bacillus. Unlike other aerobes, M tuberculosis has a cell wall containing an elevated amount of high molecular weight lipids.[2] M tuberculosis is part of a group of closely related organisms (including Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium canetti) associated with human disease.[2] M tuberculosis is primarily found in the United States, while M bovis, M africanum, and M canetti are rare in the United States and are not routinely identified by clinical laboratories. If necessary, reference laboratories can distinguish M bovis from M tuberculosis. This differentiation may be relevant for a given case presentation since the epidemiology, treatment, and prevention are different, even though the clinical presentation is similar to M tuberculosis. Other mycobacteria in the M tuberculosis complex primarily cause animal disease.

Epidemiology

Most M tuberculosis infections and disease in children are found in areas of the world where adults have the greatest incidence of TB infection. The highest M tuberculosis disease burden is borne in countries in sub-Saharan Africa and Asia, particularly India and the Western Pacific. In the United States, which is a low-incidence country, children who develop TB are often either born outside the United States or have been exposed to close contact who are from outside the United States, particularly from a high-burden country. Another small percentage of cases result from travel to high-burden areas.[WHO 2023 Global TB Report][3] Drug resistance to first- and even second-line medications is an emerging public health problem globally. While data collection is variable, children with multidrug-resistant TB in some areas of the world reach as high as 13%.[WHO 2023 Global TB Report][4][5]

The 2023 WHO Global TB report indicated that 1.3 million children younger than 14  contracted TB in 2022, about 12% of the global total TB disease burden, while a quarter million have succumbed to TB-related disease.[WHO 2023 Global TB Report] Most likely, this is an underrepresentation of the actual number of pediatric cases and deaths, as childhood TB is often misdiagnosed or miscategorized.[1] Deaths from TB in many high-burden regions are frequently ascribed to pneumonia or meningitis without a specific diagnosis.[1]

The human immunodeficiency virus (HIV) epidemic has also affected the epidemiology of M tuberculosis, as coinfection with HIV is not an uncommon occurrence.[6] Although many children in the developing world have access to antiretroviral therapy (ART), children with HIV have a higher risk for M tuberculosis-associated disease even with a normal cluster of differentiation 4 lymphocyte counts and strong viral suppression compared with their non-HIV-infected cohort.[7] Several studies conducted in African nations documented that even though ART reduces TB risk and improves outcomes among children with HIV in sub-Saharan Africa, the risk of TB remains highly elevated compared to children without HIV in the same settings.[7] Children younger than 14 represent the lowest percentage of HIV-infected persons on ART (57% vs 77% for those older than 14).[7] This discrepancy also occurs at a time when both international and domestic funding for HIV initiatives has declined significantly [Global HIV and AIDS Statistics] and will impact not only HIV cases but also coinfections, including M tuberculosis that can accompany severe HIV disease.[8][9][10]

Pathophysiology

The pathophysiology of TB is well-documented. Please see StatPearls' companion resource, "Tuberculosis," for an overview of TB. However, clinicians should note that differences exist between children and adults with TB in terms of host control of the disease. Healthy adults with TB infection have only a 5% to 10% risk of developing TB disease during their lifetime and tend to develop their disease in the first 1 to 2 years after infection is established. However, infants and toddler-age children have a much higher risk of disease progression after exposure than school-age children if left untreated (40% to 50%, 25%, and 10% to 15%, respectively).[11]

Infants and young children have different immunologic responses to TB exposure than adults.[12] An infant's immune system has altered inflammatory responses to accommodate the transition to an extrauterine environment with inherent contact with beneficial and virulent pathogens.[12][13] They typically have lower numbers of macrophages, neutrophils, and tissue dendritic cells, and the function of these cells is different compared to that of adult cells. Production of proinflammatory cytokines, such as tumor necrosis factor and interleukins 1 and 12, is reduced, while anti-inflammatory cytokines are increased, including interleukin 10.[14] Infant T cells are less able to differentiate into interferon gamma-producing T cells, a key factor in M tuberculosis control.[14] 

Therefore, infants are 5 to 10 times more likely to develop active TB than adults, and they have significantly higher rates of severe disseminated disease, including miliary TB and meningitis.[15] Lack of T-cell responses with interferon-gamma release also interferes with tuberculin diagnostic testing for interferon-gamma release assay and tuberculin skin tests, even in the face of overwhelming disease. Children with immune deficiencies, particularly HIV, are at even greater risk for TB progression and severe disease.[7][Global HIV and AIDS Statistics]

Histopathology

Children tend to have paucibacillary disease yet a very brisk immunologic response to M tuberculosis.[10] The hallmark of M tuberculosis infection in tissue specimens is a caseating granuloma; children readily produce granulomas in M tuberculosis tissue disease. This granuloma comprises epithelioid histiocytes surrounding a central necrotic area and is accompanied by multinucleated giant cells and lymphocytes.[16] The function of these cells is to contain the mycobacterial infection and prevent its spread to surrounding healthy tissues and other organs.[16] 

Ziehl–Neelsen staining for acid-fast organisms can be applied to tissue samples for children, but their disease's paucibacillary nature makes visual diagnosis difficult. Fluorescent techniques utilizing auramine-rhodamine staining are often used for the ease of visualization in specimens with low numbers of mycobacteria. In situ, techniques using ribonucleic acid (RNA)scope adapted for M tuberculosis to identify intact and disintegrated mRNA in necrotic and nonnecrotic granulomata may also be useful as an adjunct in Ziehl–Neelsen-negative or fluorescence–negative tissue samples from children with suspected TB disease.[17]

History and Physical

TB has a wide variety of presentations in children and can produce disease in nearly all organ systems. Most TB disease in children takes a pulmonary form, with only approximately 20% manifesting as extrathoracic disease. An overlap is often seen between pulmonary disease and extrapulmonary manifestations, especially in children younger than 2, primarily including the following areas:

• Intrathoracic
• Pulmonary
• Pleural
• Cardiac (1% to 4%)
• Extrathoracic
• Disseminated (lymphohematogenous)
• Lymphatic
• Central nervous system
• Osteoarticular
• Abdominal and gastrointestinal
• Genitourinary
• Cutaneous
• Congenital 
• Other

Intrathoracic Manifestations

Pulmonary disease

The pulmonary system is the most affected in children with TB. After exposure, silent pulmonary infection without any obvious signs, symptoms, or imaging abnormalities ensues for many children. Some may have a prodrome consisting of several days of low-grade fever and cough resembling a viral illness, but these symptoms will resolve over several weeks. Ninety percent of newly infected older children will have an asymptomatic infection, whereas up to 50% of infected infants develop respiratory or constitutional symptoms with radiographic abnormalities during primary infection.[18] Clinicians must be aware of the age discrepancy in developing progressive severe disease.

Primary pulmonary infection in children includes infection of the lung tissue coupled with hyperplasia of regional lymph nodes, called the primary pulmonary complex. Unlike adults, all lung lobes are equally affected in children, and a quarter of the cases can have multiple parenchymal foci. Radiographic findings may note disproportionately enlarged regional lymph nodes compared with little to no parenchymal focus (see Image. Hilar Adenopathy).[19][20] 

Radiographic changes often resolve quickly, but in some children, particularly those younger than 2, lymph nodes will continue to enlarge, resulting in partial or complete bronchial obstruction from external compression. Such children may present with wheezing and shortness of breath due to the small caliber of their airways, similar to a foreign body aspiration or other obstructive disorders. Chest radiographs may demonstrate localized hyperinflation with atelectasis of contiguous parenchyma areas known as segmental lesions (see Image. Lymph Node Disease With Airway Compression).[19] Clinicians and radiologists must know that this finding is not typical of other types of bacterial pneumonia but can be M tuberculosis-related. 

Adolescents are frequently more symptomatic from pulmonary TB disease than school-aged children, especially when the disease is acquired near puberty. Adolescents may also present with reactivation disease like that seen in adults, with a classical picture consisting of progressive fatigue, loss of appetite, night sweats, weight loss, and fevers.[21] Chest pain and productive or nonproductive cough may occasionally be accompanied by hemoptysis. Physical findings may be absent, but chest radiographs demonstrate extensive upper lobe infiltrates and possibly even cavities (see Image. Adult-Type Cavitary Tuberculosis Disease).[18] Fortunately, M tuberculosis is localized well by the immune system if the teen is not immunocompromised, and anti-tuberculous treatment clears the signs and symptoms of infection rapidly if diagnosed and treated promptly.[22]

Pleural disease

Occasionally, pleural disease is seen in pediatric TB and may happen without segmental or miliary lesions in the lung parenchyma. This occurs when bacilli form a subpleural focus and erode into the pleural space. A hypersensitivity response ensues, stimulating the formation of a pleural effusion. Due to the brisk immune response, these collections may become large enough to be associated with abrupt onset of fever, chest pain, and shortness of breath with rapid respiratory compromise depending on the child's size and relative pleural effusion size. The physical examination will reveal dullness to percussion and diminished breath sounds on the affected side. Despite appropriate treatment, fevers are often very high and may persist for several weeks.[23][24] Microbiologic confirmation is often difficult due to low numbers of bacteria.[25] Pleural biopsy may demonstrate granuloma formation but requires surgical intervention or a fine needle biopsy. Newer techniques, such as polymerase chain reaction, may prove useful in such situations, but TB detection rates still fall below 50%.[26] Because true empyema rarely forms, it must be considered in the differential diagnosis of any culture-negative pleural specimen, especially in high-burden countries.[26]

Cardiac disease

Infection involving the cardiac system is unusual, occurring in less than 4% of all cases of pediatric TB.[27] The most common site of infection is pericardial tissue, which results in pericarditis and pericardial effusion. The presentation of pericardial involvement is similar to other forms of pericarditis with symptoms of fever, malaise, and weight loss; children are less likely to complain of chest pain than adults with TB pericarditis.[27] Generally, other organ systems are involved, and these features may overshadow the pericardial disease.[27] A physical examination may demonstrate a pericardial friction rub, distant heart sounds, and pulsus paradoxus, especially if the disease has progressed to the fibrinous stage. Chest radiography reveals a large globular heart, and ultrasonography demonstrates fluid collection in the pericardial space. When aspirated, pericardial fluid is serofibrinous or mildly hemorrhagic but rarely is acid-fast bacillus smear positive. Nonetheless, cultures are positive in 30% to 70% of cases, and a biopsy of the pericardium reveals caseating granulomas in 50% to 75% of the cases. Without early recognition and treatment of this condition, constrictive pericarditis from fibrosis over months to years will develop. In contrast to the outcomes of TB pericardial disease in adults, results from a recent study in South Africa found that the mortality was low and the residual morbidity among children in their cohort primarily resulted more from the concurrent disease at the time of presentation, particularly that of TB meningitis, than the pericardial involvement.[20]

Extrathoracic Manifestations

Disseminated disease

TB can disseminate to distant anatomic sites following the establishment of primary infection in young children or during reactivation disease in older children and adolescents, often triggered by the erosion of a previously healed primary pulmonary lesion. Depending upon the host's age and immune function, infection from this seeding to distant sites may become readily apparent or quiescent for years. Miliary TB is a highly lethal form of disseminated TB that results from a massive lymphohematogenous dissemination of M tuberculosis from an infected focus. The presentation varies depending on the organs involved and may resemble other common childhood diseases.[28] Fortunately, pediatric miliary TB is rare, comprising less than 1% of all pediatric TB cases, but this may be underestimated due to lack of recognition. A recent case report from Tunisia highlighted the complexities of miliary disease masquerading as multisystem inflammatory disease secondary to COVID-19 yet found to be caused by M tuberculosis.[29]

During early hematogenous dissemination of M tuberculosis, there may be an acute onset of high-spiking fevers, but a prolonged and intermittent fever is also possible. Classic features of TB infection may develop, including chronic weight loss, hepatosplenomegaly, and superficial or deep node lymphadenitis. Other unusual features, such as crops of skin lesions called papulonecrotic tuberculids and choroid tubercles seen on ophthalmological evaluation, are possible. Later in the clinical course, meningitis may also develop. Pulmonary disease, which may have been mild initially, can become more severe over time (see Image. Chest Radiograph and Computed Tomography, Tuberculosis). Due to the atypical multiple-organ involvement, a high index of suspicion is required for early recognition, followed by comprehensive investigation and prompt initiation of appropriate treatment for disseminated TB to mitigate the potential for severe complications and to reduce morbidity and mortality associated with this complex disease.[28][30]

Lymphatic disease

Tuberculous lymphadenitis (previously known as scrofula) is the most common form of extrapulmonary TB disease in children and constitutes nearly 60% of extrapulmonary cases. In the past, tuberculous lymphadenitis was often caused by drinking unpasteurized cow's milk contaminated by M bovis; pasteurization of milk and milk products has nearly eliminated M bovis as a cause of adenitis in low-burden countries. However, in high-burden regions of the world, particularly in pastoral areas, M bovis and other members of the M tuberculosis complex still warrant consideration.[31][32] Now, most cases of lymphadenitis are caused by M tuberculosis primary pulmonary infection acquired by aerosol or droplet contact.

Lymph nodes of the anterior cervical, supraclavicular, tonsillar, and submandibular areas are commonly involved due to extension from the primary lesion in the upper lung fields or the abdomen (see Image. Tuberculosis Disease, Cervical Lymph Node). Other areas of lymph node involvement include the inguinal, epitrochlear, and axillary chains. These generally are associated with skin lesions secondary to the M tuberculosis complex. Involved nodes often enlarge slowly but can become massive in size. They are discrete and firm but not hard or tender to touch. However, these affected nodes can feel fixed to adjacent tissue, suggesting a malignancy. Even though a primary pulmonary focus is invariably present, it is often asymptomatic and may be radiographically inapparent in as many as 30% of cases. Untreated lymphadenitis may resolve spontaneously or progress with fluctuance and an overlying purplish red hue indistinguishable from nontuberculous mycobacterial infections in children (see Image. Lymph Node Disease). A chest radiograph may be negative in tuberculous and nontuberculous lymphadenitis, but an interferon-gamma release assay will be unequivocally positive.[33] If untreated, the node may rupture and create a draining sinus tract that will require surgical resection. Clinicians need to maintain a high index of suspicion in low-burden countries to arrive at the proper diagnosis and treatment, especially for children of parents from high-burden nations.[34]

Central nervous system disease

The most deadly and debilitating form of TB is meningitis, which disproportionately affects young children. Without antibiotic therapy, corticosteroids, and critical care management of fluids, electrolytes, and elevated intracranial pressure, tuberculous meningitis is rapidly fatal within several weeks.[35] Despite advances in the care of children with tubercular meningitis, mortality is still high; more than 50% of survivors have neurodevelopmental disabilities.[35][36][37][38] Areas of the world with a high burden of TB may be more likely to recognize the disease than others but lack some tools for fully successful diagnosis and treatment. In contrast, high-resource areas lack knowledge and experience with the disease to recognize signs and symptoms early on.[38]

The clinical onset of tuberculous meningitis can be acute or gradual in the early stages. Nonspecific symptoms, such as flu-like illness, low-grade fever, malaise, and pulmonary symptoms, may overshadow central nervous system findings. Many children are initially seen with pneumonia that will not resolve, poor appetite, and vomiting before more serious signs of central nervous system disease become manifest. Advanced disease may demonstrate signs of meningeal irritation (eg, elevated intracranial pressure with a bulging fontanelle, sunsetting sign, and papilledema), cranial nerve palsies, neurologic deficits and loss of milestones, altered sensorium, and seizures.[39][40][41] The Glasgow Coma Scale can help assess the child's consciousness level and aid in determining the ultimate prognosis.[35]

Urgent evaluation of the central nervous system with head imaging is crucial, followed by lumbar puncture for cultures and fluid analysis.[42] Brain imaging commonly shows basilar meningeal enhancement, hydrocephalus, enhancement of basal ganglion, infarcts, or a combination of these.[43][44] Magnetic resonance imaging (MRI) is preferred over computed tomography for its improved ability to identify early infarcts, basal ganglia enhancement, and exudates in the basal cisterns.[45][46][47] However, MRI is not widely available in low-resource countries (see Image. Tuberculosis Meningitis). 

The treatment of tubercular meningitis requires a regimen of prolonged antituberculosis therapy, initially with 4 drugs. (Please refer to the Treatment section for more information on antituberculosis regimens). Management of increased intracranial pressure may require additional medications, including steroids, mannitol, and acetazolamide. The placement of a temporary or permanent ventriculoperitoneal shunt may be needed.[42][41] Close outpatient follow-up is required to manage adherence and potential adverse events from non TB medications, particularly electrolyte disturbances with the use of acetazolamide.

Skeletal disease

Osteoarticular TB also behaves differently in pediatrics than in adults. The primary focus of infection in children is generally the pulmonary system with dissemination to the osteoarticular system, but extension from either a caseous regional lymph node or an adjacent bone is also possible. Metaphyseal involvement develops initially, followed by necrosis from the pressure of granulation tissue and caseation. Extension into the joint space and adjacent soft tissues can complicate established bone infection, but the swollen joint makes the disease clinically apparent.[48]

Skeletal TB mainly involves weight-bearing bones and joints; the knee, hip, spine, elbow, and ankle are the most affected. The spectrum of presentation ranges from mild joint effusion without any bony destruction to significant destruction of bone and restriction of joint mobility caused by chronic synovial fibrosis. A single joint or many may be involved.[48][49][50][51] This slow process may evolve over months to years, causing mild pain, stiffness, limping, and restricted movement. A tuberculin skin test or interferon-gamma release assay is often reactive, and joint fluid culture or bone biopsy will usually be positive for M tuberculosis.

Dactylitis is more common in young infants and toddlers but is occasionally seen in older children and adults.[48][50] Distal endarteritis from M tuberculosis dissemination through the bloodstream leads to painless swelling of the hands or feet. In the case of digital involvement, a typical lesion involves the proximal phalanx of the index and middle fingers. Fusiform swelling of the digits may resemble juvenile idiopathic arthritis of the hands or feet but is painless. Radiographs showing lytic lesions in the involved digits, called spina ventosa, are typical for M tuberculosis dactylitis.[52] 

The vertebral bodies are a particular target of TB (Pott disease), and multiple vertebral bodies may become involved.[53] Infection in the lower thoracic or the upper lumbar vertebrae can lead to bone necrosis, with wedging and collapse; this can lead to gibbous or kyphotic spinal deformity (see Image. Vertebral Osteomyelitis Due to Tuberculosis). Rupture of the infection into adjacent soft tissue may lead to local abscess formation in the psoas muscle, paraspinal muscles, or retropharyngeal space. Paraspinal muscle spasms in children can be associated with low-grade fever, irritability, back pain, abnormal positioning of the back, refusal to bear weight, and movement difficulty. If significant bone destruction and collapse ensues, neurological complications are highly likely to occur, and neurologic impairment may be permanent.[54]

Radiographs of the involved bones generally reveal a lytic lesion, but an MRI should be performed to obtain further information.[48] Several characteristic MRI findings are often present, including synovial thickening, fluid collections, and bony erosions. T1 images show a low signal on the thickened synovium, and T2 images show a hypointense synovium. A confirmatory biopsy should be performed by either needle or open methods, but often, the bony cavity requires debridement of the necrotic bone and caseous material.

Cultures are frequently negative, as in other pediatric TB infections elsewhere in the body. However, biopsy material is critical to the diagnosis since caseating giant cell granulomas seen on histopathology are highly specific for TB and should be treated as such.[48] A history of TB contact is critical when evaluating a child with skeletal disease from a high-burden country or a child with HIV or other immunocompromising conditions who may have had an infectious contact. History is critical in younger age groups presenting with dactylitis.[48]

Abdominal and gastrointestinal disease

Abdominal TB in children may be more common than previously appreciated since it has nonspecific abdominal signs and symptoms, and the lack of available diagnostic tools makes the diagnosis difficult.[55][56] Abdominal TB tends to occur in slightly older children, usually older than 5 years. Abdominal TB can involve the mesenteric and intra-abdominal lymph nodes, the peritoneum, the intestines, and the intra-abdominal and pelvic organs. Lymphatic or hematogenous seeding, spread from adjacent lymph nodes, and the introduction of mycobacteria orally through M tuberculosis-contaminated animal milk, breast milk, or swallowed pulmonary secretions are the most common acquisition routes. The presentation may resemble other abdominal diseases such as appendicitis, intestinal perforation, and inflammatory bowel disease.[57]

TB enteritis generally results from hematogenous spread to the gut or from swallowing mycobacteria in contaminated milk or respiratory secretions. The jejunum and the ileum are the most common sites involved and may present with shallow ulcers that cause localized pain, diarrhea or constipation, and weight loss. A diagnosis of Crohn disease may be entertained before TB testing is completed as the signs and symptoms are similar. Mesenteric lymphadenitis is often present but generally not palpable on abdominal exam. Enlarged nodes can obstruct the intestines or erode through the omentum, resulting in generalized peritonitis. Tuberculous peritonitis can also result from TB of the genitourinary tract with extension, especially from infection in the fallopian tubes.[58] Intestinal obstruction is a common complication of intestinal TB resulting from mural thickening, ileal stricture, or adhesions. 

Abdominal ultrasound may aid in identifying enlarged lymph nodes, visceral disease with abscess formation, and the presence or absence of ascites.[56] Peritoneal fluid may demonstrate neutrophil or lymphocyte predominance. In a South African series, aspirated peritoneal fluid with an elevated adenosine deaminase level was present in three-quarters of the children with TB peritonitis; the children in this study were significantly more ill.[56]

Genitourinary disease

The genitourinary tract can be seeded by M tuberculosis during direct hematogenous or lymphatic spread from primary M tuberculosis lesions or reactivation disease elsewhere in the body.[59] M tuberculosis organisms can lodge in any portion of the genitourinary tract in both sexes. The disease progression is slow and insidious and is often missed clinically until the disease has caused significant organ damage.

Renal TB is the most common clinical presentation of urogenital TB. In the past, renal TB was believed to spare young children as the progression of the disease was slow. However, currently, several case series underscore the fact that renal TB may not be clinically obvious, though slow destruction of the organ is ongoing, even in infants and younger children.[60][61][62]

The intense vascularity of the kidney makes it an easy target for hematogenous spread, and M tuberculosis establishes foci with a granulomatous response. Small caseous tubercles develop and shed M tuberculosis into the tubules and, hence, into the urine. Large caseous masses can also develop and erode into the renal pelvis. Infection can readily spread to the ureters, prostate, epididymis, and adjacent organs like the uterus and fallopian tubes. Untreated, renal TB can lead to the destruction of the renal parenchyma, obstructive uropathy, and end-stage renal failure.[59][63]

The genital tract can be infected with M tuberculosis in both sexes. In young women of reproductive age (15 and older), infertility is the most common presentation of TB disease involving the genital tract in high-burden areas of the world.[59] In vitro fertilization for a woman with unrecognized genital tract TB can have severe consequences for the outcome of the procedure.[64] Adolescent females may complain of lower abdominal pain and experience dysmenorrhea or amenorrhea.[58] Adolescent males may present with unilateral, nodular, and painless scrotal swelling due to epididymitis or orchitis.[65] All parts of the male genital tract, including the prostate, seminal vesicles, bladder, urethra, and the penis, can be infected with M tuberculosis.[59] Fortunately, this is a rare situation for children.

Congenital and perinatal disease

Congenital TB is rare, but clinicians must always maintain a high index of suspicion when faced with a patient diagnosed with active TB during pregnancy. In-utero infections can occur following maternal bacteremia and have also been reported following in vitro fertilization of women from high-burden countries who likely had unrecognized or subclinical genital TB infection without treatment.[66] Perinatal TB carries up to a 50% mortality since many of the typical features, such as fever, respiratory distress, pulmonary infiltration, lethargy, enlarged liver and spleen, and hematologic abnormalities, cannot distinguish TB from other types of serious systemic infections in a newborn.[67][68] Further complicating the problem is that tuberculin skin test results are usually negative in infants with congenital or perinatally acquired infection, and the sensitivity of interferon-gamma release assay testing is unknown but also likely to be low due to the infant's immune response to M tuberculosis. If M tuberculosis is suspected, regardless of the tuberculin skin test or interferon-gamma release assay results, therapy for the infant should be initiated immediately with a 4-drug regimen. The placenta should be evaluated for granulomas and acid-fast bacilli and cultured for M tuberculosis. The parent should also have testing for tuberculosis as well as HIV since the risk of coinfection with HIV and TB in high-burden countries is significant.[67][68]

For patients with known or suspected TB, the following management of the parent-infant dyad is recommended depending on whether the parent has latent or active TB:

• The maternal parent has been diagnosed with TB infection in pregnancy (positive tuberculin skin test or interferon-gamma release assay with negative chest radiograph): 
  • This scenario suggests that the pregnant individual has TB infection (formerly latent TB) as opposed to TB disease. The pregnant patient does not have active TB and is noninfectious. Generally, the pregnant patient will be treated after the postpartum period for latent TB.
  • In this scenario, the infant needs no special testing and need not be separated from the maternal parent, who may breastfeed if she desires. However, the entire household and other potential contacts of the infant should be questioned and tested, especially if the index case for the maternal parent's positive TB test is not known since it will place the infant at risk from exposure.[69]

• The maternal parent has been diagnosed or treated for active TB disease during pregnancy (positive TST or IGRA with an abnormal chest radiograph consistent with tuberculosis): 
  • This is a high-risk situation for the infant to acquire TB disease through respiratory droplets or airborne transmission. Unfortunately, the infant and maternal parent need to be separated until both have been evaluated thoroughly for TB disease and placed on therapy.
  • The postpartum patient should begin antituberculosis therapy targeting her specific disease location. She needs to wear a mask and adhere to infection control measures. She may not breastfeed, but the infant could be fed expressed milk if the mother has no evidence of TB mastitis. Once the mother has been on therapy for 2 or more weeks AND she is no longer considered contagious, ie, has smear-negative sputum, she may breastfeed.
  • The infant requires evaluation for congenital tuberculosis, and if excluded, the infant should be started on isoniazid (INH) unless the M tuberculosis isolate is known or suspected to be INH resistant until the infant is 3 or 4 months of age when the TST should be performed. If this 3- to 4-month TST is negative AND the child has not developed any signs or symptoms of TB disease, INH can be discontinued as long as the postpartum parent has been adherent to medication and remains noninfectious. However, if the infant's 3-month TST is positive, they should be reassessed for M tuberculosis disease. Even if TB disease is excluded, the infant still requires further treatment for the positive TST. A full 9 months of INH, or 4 months of rifampin, is warranted.
  • Consultation with a specialist in pediatric infectious disease or a clinician with the local TB branch of the health department is recommended to ensure proper care.[69]

Other disease manifestations

TB can also present with rare and varied features that are often part of disseminated disease but may occasionally be seen in isolation. Otitis media and mastoiditis [70][71], cutaneous lesions called papulonecrotic tuberculids [72], and ophthalmologic findings of vitritis, keratitis, choroid tuberculids are the result of dissemination of M tuberculosis to distant sites.[73][74]

Evaluation

The initial step for TB evaluation should involve a TST or IGRA test. Proper placement, measurement, and interpretation are very important for accurate results (see Images. Mantoux Tuberculin Skin Test, Accurate Measurement). The TST should be read in the context of the child's history and potential exposure to active TB (see Table. Interpretation of Tuberculin Skin Testing in Children). Positive reactions should generate a chest radiograph.

Depending on the site of suspected M tuberculosis infection and the urgency of the evaluation, these tests may also be performed in conjunction with specimens from the most affected organ systems. For pulmonary TB, sputum collection is always of primary importance for a child who can expectorate. Children older than 10 years are generally able to provide an adequate amount of sputum, but children between 5 and 10 years of age may require assistance with induced sputum. For children younger than 5 years, specimens are generally collected by gastric aspiration or lavage of first morning specimens since young children usually swallow their respiratory secretions.

Specimens should always be sent for culture, drug susceptibilities, and for more rapid testing techniques where available. Culture of clinical specimens may take 3 to 8 weeks for visual growth to appear on solid media. Recent methods utilizing liquid media, such as the mycobacteria growth indicator tube (MGIT) system, have facilitated more rapid organism identification.[6][3] PCR technology remains a more useful and rapid modality but may not be widely available, especially in high-burden countries. Other types of detection methods are evolving, such as CRISPR detection of M tuberculosis in blood samples, that may prove to be of great benefit for children as they have paucibacillary disease, similar to that of reactivation disease for some adults.[75]

Another collection technique involves using a "string test," a highly absorbent nylon yarn packaged inside a gelatin capsule that is swallowed.[76] Feces may also contain swallowed M tuberculosis, and a nucleic acid amplification test (NAAT), eg, GeneXpert^® MTB/RIF (Cepheid, United States of America), can confirm approximately 45% of clinically diagnosed cases of pulmonary TB with less trauma for the child.[77][78] Bronchoalveolar lavage fluid (BAL) may also provide useful specimens for analysis in children suspected of having pulmonary TB, but less invasive methods should always be attempted first.[79] The utility of NAAT BAL has been demonstrated in adults with paucibacillary recurrent TB and may apply to the analysis of pediatric specimens.[80]

Similar techniques of in situ NAAT testing with the expert MTB/RIF assay can be performed on extrapulmonary specimens, fine needle aspirate or excisional biopsy specimens for lymph nodes, and in formalin-fixed, paraffin-embedded tissues for other types of extrapulmonary TB disease.[81][82] WHO recommends the use of GeneXpert^® testing to diagnose extrapulmonary TB, including TB meningitis of cerebral spinal fluid specimens for both adults and children.[83]

Treatment / Management

Treatment decisions regarding TB management are made based on a detailed medical history and a comprehensive physical examination. After careful consideration for TB in the differential diagnosis of a presenting child, one of the first tests that should be performed is a tuberculin test, either a purified protein derivative (PPD)/TST or a NAAT (eg, IGRA). (Please refer to the Evaluation section for more information.) Information from this test will guide subsequent testing.

A chest x-ray is warranted for evaluation following a positive PPD/TST or NAAT test to determine if pulmonary involvement is present; in cases of high suspicion for M tuberculosis in the absence of a positive screening test, imaging may be performed to assess for silent intraparenchymal disease or adenopathy. Other studies depend upon the location of potential infectious foci and can include ultrasonography of enlarged lymph nodes, imaging of the central nervous system followed by lumbar puncture, skeletal x-rays, imaging of the gastrointestinal or genitourinary tract, or a combination of these tests. Unfortunately, the lack of a positive reaction to a tuberculin test does not always exclude TB infection or TB disease, nor does a positive reaction distinguish between latent TB and actual disease. Up to 40% of immunocompetent children with culture-positive TB disease did not initially react to the tuberculin test. Host factors, particularly young age (younger than 2 years), poor nutrition, immunosuppression, and concurrent viral infections, can adversely affect a positive result. Recent TB infection and overwhelming disease (eg, those seen in disseminated disease) may also result in a negative reaction. Immunosuppression, particularly in children with advanced HIV disease, can also lead to a false negative PPD/TST result.

Treatment protocols for children parallel those of adults, except weight-based dosing is employed for all the needed medications. If directly observed therapy (DOT) is available or is required, as is the case for some regimens, it can be a helpful adjunct to adherence when children transition from the intensive phase with 3 or 4 drugs to the continuation phase with 2 drugs that can be administrated several times per week rather than daily (see Tables. Recommendations for Regimens to Treat Latent TB Infection, Recommended Drug Regimens and Therapy Length for Drug-Susceptible Tuberculosis Treatment, and Pediatric Drugs and Dosing for Drug Susceptible Tuberculosis Infection and Disease).[84][85][[86]

Table. Recommended Drug Regimens and Therapy Length for Drug-Susceptible Tuberculosis Treatment

 *Some experts recommend the use of a 3-drug regimen without ethambutol if the risk of drug-resistant Mtb (DR-Mtb) is low

¶ substitution of ethionamide or levofloxacin is more commonly used in practice, although WHO recommends the use of ethambutol

Φ Dose of Rifampin for meningitis is 30 mg/kg/d up to a max of 600 mg/d [84][85][[86]

Table. Recommended Pediatric Drugs and Dosing for Drug-Susceptible M tuberculosis Infection and Disease

†Dosing is based on lean body weight; doses for obese patients are not well-documented

Treatment of DR-Mtb in children is more difficult as some of the medications are not well-studied in children. Children are more likely to experience possible DR-Mtb if they or a close contact fit the following criteria:

• Reside in or emigrate from a country with high rates of resistance (eg, Russia and former Soviet bloc countries, Asia, Africa, and Latin America)
• Personal or contact history of prior incomplete drug treatment
• Personal or contact history of treatment for DR-Mtb
• Personal or contact history of persistently positive smear 2 months into therapy

The attached references can guide the treatment of DR-Mtb therapy, but consultation with an expert experienced in the treatment of DR-Mtb is highly recommended to prevent inadequate or partial treatment.[87][84] (A1)

Adherence can be significantly aided by home health nursing assistance where available. A care team consisting of the prescribing physicians, social workers, mental health clinicians, and local health department personnel is often needed to aid the family in completing successful treatment for a young child.[88] Home visits for DOT and intermittent visits to the office for the child and family to assess adverse effects, adherence, potential therapeutic barriers, and response to therapy may be needed for some types of TB treatment protocols. Unlike adults, children do not necessarily require monitoring of laboratory values, such as liver enzymes, unless they initially had abnormal testing or underlying conditions that may make tolerance of treatment regimens difficult without adverse effects.

Differential Diagnosis

Unfortunately, the differential diagnosis of TB is highly dependent upon the location of the disease. As noted in the clinical description of TB, many more common childhood diseases may be mistakenly diagnosed in a child with TB. Other viral, bacterial, and fungal types of pneumonia can present similarly, and M tuberculosis should always be considered in these cases. Cervical lymphadenitis can be viral, especially if multiple nodes are involved. Bacterial pathogens, eg, Bartonella and atypical mycobacteria, can also cause cervical, axillary, and inguinal lymphadenitis; atypical mycobacteria, like M tuberculosis, may produce purplish-red skin discoloration during the progression of the infection. M tuberculosis meningitis is often missed until late as it can mimic other more common childhood viral and bacterial infections that affect the central nervous system.

Furthermore, in high-burden countries, numerous vector-borne diseases (eg, malaria and encephalitis viruses) are present, in addition to parasites that infect the central nervous system. Disseminated TB, abdominal TB disease, and genitourinary tract TB disease can mimic inflammatory bowel disease, severe systemic viral, bacterial, and fungal infections, including multisystem inflammatory disease secondary to COVID-19, and even malignancy. Additionally, HIV should always be tested for in a patient diagnosed with M tuberculosis, and all persons with HIV should have yearly testing for M tuberculosis.

Prognosis

Tuberculosis is both curable and preventable. The overall prognosis for TB should be excellent for a healthy child with an early diagnosis and adequate treatment. Sadly, that is not often the case; morbidity and mortality from tuberculosis take their toll. Many complications, noted below, of late diagnosis or inadequate treatment occur worldwide, but especially in high-burden countries. This is especially true for children with disseminated disease with or without meningitis and for tuberculosis when coinfecting a child with impaired immunity, particularly HIV.[89] Overall mortality in children with HIV as a subset of high-risk children who are coinfected with TB have a disproportionate share of the overall TB mortality, estimated to be as high as 17%.[90] 

For children lacking access to early diagnosis and treatment, mortality can reach 21%, rivaling the M tuberculosis pretreatment era before 1946.[89] Mortality in tuberculous meningitis, even with treatment, can reach as high as 19%, and neurodisabilities are seen in >50% of survivors.[36] Survivors may suffer from significant complications related to their disease, the stage at which they started treatment, and any underlying conditions that compromise their immune system. Delays in diagnosis of other organ-specific involvement, eg, renal disease, can progress slowly with significant damage once the disease manifests.[91]

Complications

Most children with proper diagnosis and treatment will experience no complications related to their disease. However, children with immunodeficiencies, particularly HIV, children whose diagnosis was delayed, or children with poor adherence to therapy may lead to the following complications: 

• Pulmonary
  • Extensive lung damage with an increased risk of subsequent wheezing
  • Reduced lung function
  • Cavitary disease
• Lymphadenitis
  • Development of chronic fistula
• Central nervous system:
  • Hydrocephalus
  • Cerebrovascular diseases such as stroke and vasculitis
  • Tuberculoma
  • Coma
• Skeletal
  • Pott disease
  • Paraplegia related to spinal disease 
  • Epiphysial invasion, deformity, and bone shortening
  • Deformities of the affected limb
  • Spinal deformities
• Abdominal
  • Generalized peritonitis
  • Intestinal obstruction (from enlarged nodes and erosions)
• Genitourinary
  • Infertility in females
  • Hydronephrosis
  • Ureteral strictures
• Miliary spread (development of disseminated disease)
  • Meningitis
  • Rapid progression to death [20][30][92][93][94][95][96][97][98][99]