Approaches to detecting tuberculosis in children and youth

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This practice point highlights when to suspect tuberculosis (TB) in children and youth and how to initiate investigations.

TB disease must always be considered in Indigenous children and youth who are living or have lived in areas with risk factors (i.e., overcrowded, poorly ventilated houses that exist in many Indigenous communities where TB has been endemic for decades) and in foreign-born children from countries with a high burden of TB (http://www.stoptb.org/countries/tbdata.asp). The incidence of TB between 2010 and 2016 in Canada overall was 4.5 to 4.8 per 100,000 population. However, in Nunavut during the same period, incidence was 120 to 299 per 100,000 population ^[1]-[3].

Latent tuberculosis infection (LTBI) implies that Mycobacterium tuberculosis (Mtb) bacteria are ‘dormant’, such that the infected individual is asymptomatic and non-infectious ^[4]. By contrast, TB ‘disease’ indicates that there is bacterial replication, such that the individual with infection is typically symptomatic.

Bacille-Calmette-Guérin (BCG) is a live, attenuated vaccine given at birth to infants residing in Canadian jurisdictions considered to have high rates of smear-positive TB ^[5]. BCG is contraindicated for infants with a family history of immunodeficiency or who are suspected of being immunodeficient ^[6][7].

Tuberculosis (TB) exposure and infection

Exposure commonly occurs through breathing household air that contains suspended aerosolized droplets of Mtb, usually from cough expectorations by an adult or adolescent (e.g., parents, grandparents, siblings). Exposure can also occur during sports events or community gatherings and in school or child care settings.

Source cases with cavitary disease are highly infectious and risk for transmission increases when sputum has a high density of Mtb (i.e., when bacilli are seen on the sputum smear) ^[8]-[14]. Table 1 illustrates some key points on history, along with their corresponding clinical significance.

Table 1. Key points in the history and their clinical significance
Relevant history	Clinical disease correlation
Known contact with an infectious source case	At highest risk for primary infection. Disease most likely to occur within one year of initial infection.
Remote residence in a TB-endemic area.	LTBI. Ongoing risk for reactivation as an otherwise healthy older child or as a child or youth with an immune-suppressing condition.
Residence in or travel to area with high TB rates, even when a child has been previously treated for LTBI.	Continued exposure to cases of clinical TB disease increases risk for acquiring new infection.
LTBI Latent tuberculosis infection; TB Tuberculosis

Mycobacterium tuberculosis (Mtb) infection

Primary infection is established when Mtb bacilli are inhaled and replicate in the pulmonary alveoli. There, they are engulfed by macrophages, leading to the formation of granulomas and causing hilar or mediastinal lymphadenopathy. The parenchymal site is a Ghon focus, whereas Ghon complex includes adjacent hilar lymphadenopathy. This initial infection may lead to spread of Mtb to other lymph nodes and/or hematogenous dissemination to other organs. Over time, granulomas may calcify, but Mtb is likely to remain viable though dormant ^[4].

Among children who have primary infection with Mtb, 90% to 95% experience minimal symptoms or are asymptomatic. They do not develop clinical disease and carry viable though dormant bacteria. This state of infection is commonly referred to as LTBI. Figure 1 describes the natural history of children infected with Mtb.

Early primary TB disease

Five to ten per cent of children infected with Mtb present with primary disease—either pulmonary or extra-pulmonary—with the vast majority (an estimated 90%) presenting clinically within one year after primary infection ^[15]. Infants and children <5 years old are especially vulnerable.

Pulmonary

Pulmonary symptoms may be acute, mimicking pneumonia, or indolent, with wheezing or subacute symptoms ^[15]. Both lateral and postero-anterior radiographs are required for diagnosis. Radiographs typically show focal pneumonitis or subtle ‘ground glass’ opacities, with (usually) hilar, mediastinal or subcarinal lymphadenopathy ^[16]-[18]. Chest computed tomography (CT), with or without contrast, is more sensitive and specific for detecting pulmonary TB, but this technique involves radiation and, possibly, sedation ^[19]-[21].

Disseminated disease or extra-pulmonary disease

When the immune system fails to contain early pulmonary infection, disseminated disease ensues. Infants are at particularly high risk ^[22].

In this context, constitutional symptoms may predominate, including weight loss, poor feeding, prolonged or recurrent fever, and lethargy or irritability. Syndromic presentations include pneumonia, meningitis, osteoarticular infections or sepsis unresponsive to antibiotics. Multiple organs can be involved, especially the lung, brain, retina, liver, spleen, bone marrow and muscle, making diagnosis challenging. Miliary nodules or a ‘tree-in-bud’ pattern on chest radiograph are typical, but a diffuse alveolar pattern or acute respiratory distress syndrome can also occur ^[16][17]. In meningitis, the cerebrospinal fluid (CSF) typically shows pleocytosis, with lymphocytic predominance. Magnetic resonance imaging (MRI) may be helpful. Because neonatal (congenital) TB is also commonly disseminated, diagnosis is often delayed when maternal diagnosis is missed.

Reactivation TB disease

An estimated 5% to 10% of children with LTBI, eventually reactivate the dormant infection and present with signs and symptoms of disease. Previously known as “post-primary” disease, reactivation can occur many years after the primary infection.

Although reactivation can occur in healthy young children, it occurs most commonly in adults or adolescents. Aside from likely host genetic factors, other risk factors include immunosuppression (e.g., human immunodeficiency virus (HIV) infection or diabetes), malnutrition or medications (especially steroids or biologics) ^[15][23]. Children and adolescents with pulmonary reactivation may present with ‘adult-type’ cavitary disease or infiltrates, often in the apical and upper lung zones. Other manifestations include tuberculous pleural effusions, lymphadenitis, central nervous system (CNS) tuberculous lesions, hepatic or splenic abscesses, osteoarticular infections, and (less commonly) disseminated disease.

Laboratory tests

When tuberculosis is suspected clinically, obtaining cultures is a vital next step. Cultures lead to a definitive diagnosis, permit drug resistance testing and may allow for molecular fingerprinting to link cases.

Specimens for microbiology

Sputum production can be induced by inhalation of hypertonic saline. In children who cannot expectorate sputum, fasting gastric aspirates obtained on three consecutive mornings are useful for culture ^[18][24].  The Curry International Tuberculosis Centre website describes the appropriate procedure: (http://www.currytbcenter.ucsf.edu/products/pediatric-tuberculosis-guide-gastric-aspirate-procedure). Bronchoscopy may be required to obtain specimens.

Appropriate specimens from fluid or tissues should be sent in sterile containers (without formalin) to the laboratory for acid-fast bacilli (AFB) stains and culture, with possible nucleic acid amplification testing (NAAT). Testing may be referred to accredited laboratories and protocols vary ^[25].  Specimens vary in quality, such that a negative smear or culture should not exclude a diagnosis of TB, when clinically compatible.

All patients with TB disease require serology for HIV.

Tuberculin skin testing and interferon-gamma release assays (IGRA)

Tuberculin is a purified protein derivative (PPD) from heat-inactivated Mtb. When injected intradermally as a tuberculin skin test (TST), a type IV hypersensitivity reaction (wheal) occurs if the recipient has been infected with Mtb or if they have cross-reactive antigens from non-tuberculous mycobacteria (NTM) or from BCG vaccine ^[26][27]. Cut-offs for TST induration indicative of possible infection are detailed in the Canadian Tuberculosis Standards, but generally are ≥5 mm induration for individuals who are immunocompromised and for contacts of cases and ≥10 mm for others. Of individuals who received BCG at or soon after birth, only 1% will have a TST of ≥10 mm after 10 years of age. Therefore, a TST of this size usually should not be attributed to past receipt of BCG vaccine ^[28].  Infants or young children with suspected TB disease may even have 0 mm or <5 mm induration.

The interferon-gamma release assays QuantiFERON-TB Gold In-Tube and the T-Spot.TB are in-vitro blood tests that evaluate immune response by measuring the release of interferon-gamma by T-cells in response to antigens specific for Mtb. There is no cross-reactivity with BCG and minimal reactivity with nontuberculous mycobacteria (NTM). Therefore, the specificity is >95%, compared with 60% for a TST ^[29].

Both IGRA and TST can yield false-negative results in the setting of immunosuppression, while IGRA can also signal falsely positive from a recent TST ^[29]. Neither test differentiates LTBI from active disease because in both situations, the child or youth is infected ^[26][27]. In children ≥2 years old, TST and IGRA were thought to have similar sensitivity and specificity for diagnosis of LTBI.  However,  IGRA is more specific than TST, especially in individuals who have received BCG, thus reducing the need for further testing and treatment if IGRA is negative. There are few studies of children <2 years old at the present time, but a TST is possibly  more sensitive than IGRA. Since this group is at higher risk for disease progression, the more sensitive TST is currently recommended over IGRA. Using clinical judgement on a case-by-case basis is paramount, however ^[27][30]. Provincial/territorial health authorities may or may not pay for IGRA tests, depending on indications.

Public health implications

The high incidence rate of TB among Indigenous peoples in Canada is a serious public health issue. Consideration of current and historical social determinants of health are critical to providing quality, culturally competent care and to addressing TB at the policy level.

Timely treatment of asymptomatic children with LTBI or of all contacts of TB cases is essential for preventing progression to active disease and subsequent transmission of Mtb. TB disease must be reported to local public health authorities within 48 h of diagnosis to prevent spread. Typically, when respiratory secretions from an index case smear positive, the individual is isolated in hospital or at home until three sputum specimens smear negative or, if initial smears are negative, after a full 2 weeks of directly observed therapy has been administered.

When the index case is a child with primary disease, the focus of contact tracing is to identify the source, which is usually an adult or youth because young children with primary disease are usually non-infectious ^[31].

When a child or youth is identified as a contact of an index case, conducting a history and physical exam, requesting chest radiographs and performing an initial TST are essential steps. Obtaining the index case’s drug sensitivities is also required. Child contacts <5 years of age with an initial TST of <5 mm should receive preventive prophylaxis (also known as ‘window prophylaxis’, with one TB drug), using a drug that has been identified as effective for treating the source case strain. A second TST is done at 8 to 10 weeks following last contact (sometimes termed “break of contact” ^[BOC]), while the index case was still infectious. A child ≥5 years old with an initial TST <5 mm in size needs a BOC TST 8 to 10 weeks later, although window prophylaxis is not recommended in this age group.

Child contacts <5 years old, with a BOC TST <5 mm in size at 8 to 10 weeks, can then have window prophylaxis discontinued. Child contacts ≥5 years who have no symptoms and whose physical exam and chest radiographs appear normal, with an initial or BOC TST of  ≥5 mm, should be treated for latent infection ^{[28][32]-[34]}.

Treatment

To prevent reactivation, individuals with LTBI are usually treated with isoniazid, rifampin or rifapentin/isoniazid, in collaboration with local public health authorities ^[32]-[35]. Patients with tuberculosis disease are usually started on a four-drug therapeutic regimen in accordance with the Canadian Tuberculosis Standards and in consultation with specialists in infectious diseases and/or respirology ^[36][37].

Acknowledgements

This practice point was reviewed by the First Nations, Inuit and Métis Health and Community Paediatrics Committees of the Canadian Paediatric Society, as well as the CPS Caring for Kids New to Canada Task Force. Special thanks are also due to Dr. Ian Kitai, tuberculosis specialist with the division of infectious diseases at the Hospital for Sick Children, in Toronto, Ontario.

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CPS INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE

Members: Michelle Barton-Forbes MD; Sean Bitnun MD; Natalie A Bridger MD; Shalini Desai MD (past member); Michael Forrester MD (Resident member); Ruth Grimes MD (Board Representative); Nicole Le Saux MD (Chair); Otto G Vanderkooi MD

Liaisons: Upton D Allen MBBS, Canadian Pediatric AIDS Research Group; Tobey Audcent MD, Committee to Advise on Tropical Medicine and Travel (CATMAT), Public Health Agency of Canada; Carrie Byington MD, Committee on Infectious Diseases, American Academy of Pediatrics; Fahamia Koudra MD, College of Family Physicians of Canada; Marc Lebel MD, IMPACT (Immunization Monitoring Program, ACTIVE); Jane McDonald MD, Association of Medical Microbiology and Infectious Disease Canada; Dorothy L Moore MD, National Advisory Committee on Immunization (NACI); Howard Njoo MD, Public Health Agency of Canada

Consultant: Noni E MacDonald MD

Principal author: Nicole Le Saux MD

CPS INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE (2023-24)

Members: Michelle Barton MD (Chair), Laura Sauvé MD (Past Chair), Raphael Sharon MD (Board Representative), Sean Bitnun MD, Sergio Fanella MD, Justin Penner MD, Jeannette Comeau MD MSC FRCPC FAAP                                            

Liaisons: Dorothy Moore MD (CPS Liaison to the National Advisory Committee on Immunization), Sean Bitnun MD (Canadian Paediatric and Perinatal HIV/AIDS Research Group), Isabelle Viel-Thériault MD (CPS Liaison to the Committee to Advise on Tropical Medicine and Travel), Marina Salvadori MD FRCPC (Public Health Agency of Canada), Sean O'Leary (American Academy of Pediatrics, Committee on Infectious Diseases), Rupeena Purewal MD (CPS Liaison to the Immunization Monitoring Program, ACTive), Cora Constantinescu MD (AMMI Canada, Pediatric Committee)

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.