Pediatrics

Mycobacterial infections

OVERVIEW: What every practitioner needs to know

Are you sure your patient has tuberculosis disease? What are the typical findings for this disease?

Tuberculosis (TB) is one of the three great infectious disease killers worldwide. It is estimated that one-third of the global population harbors the TB bacillus asymptomatically (termed latent TB infection, or LTBI). These individuals, whose lifetime risk of developing (active) TB disease is 5-10%, serve as the reservoir for future disease cases. Over 95% of the burden of TB occurs in developing nations. The United States' case rates have declined annually since the early 1990s, and the TB incidence in the United States is currently 3 per 100,000.

Table I. Key Signs and Symptoms of Tuberculosis Disease

Table I.

Key Signs and Symptoms of Tuberculosis Disease
Infants Children Adolescents
Pulmonary Symptoms FeverCoughDyspnea Cough FeverCoughProductive cough
Signs RalesWheezing Cough Cough
Extrapulmonary Sites MeningitisMiliary disease Extrapulmonary disease uncommon Cervical lymphadenopathy

Tuberculosis Definitions

Childhood tuberculosis can be classified into three groups: exposure, infection, and disease.

Children with exposure are preschool-aged children who have been in contact with a person with suspected TB disease. Given their rapid risk of disease progression, they are typically started on prophylactic monotherapy while awaiting sequential tuberculin skin tests (TSTs).

Children with infection (e.g., latent TB infection, LTBI) have a positive TST and/or the interferon gamma release assay IGRA, but without physical examination or radiographic findings consistent with TB. These children have a 5-10% chance of developing TB disease if untreated. Consequently, these children are offered chemoprophylaxis, usually with a single agent, for a 6-9-month period (see below) to decrease risk of progression to TB disease.

Children with TB disease have examination and/or radiographic anomalies consistent with TB. These children receive at least 6 months of directly observed multidrug therapy administered through a dispassionate third party, typically a health department.

Table II. TB Classification

Table II.

TB Classification
Classification Age group Symptoms consistent with TB TST IGRA Examination findings CXR
Exposure < 4 years No - - - -
Infection1 All No +/- +/- - -
Disease All Yes +/- +/- +/- +/-2

Table III. Risk of progression to TB disease

Table III.

Risk of progression to TB disease
Age at Primary Infection (years) No Disease (%) Pulmonary Disease (%) Miliary or CNS Disease (%)
< 1 50 30-40 10-20
1-2 75-80 10-20 2.5
2-5 95 5 0.5
5-10 98 3 <0.5
>10 80-90 10-20 <0.5

What other disease/condition shares some of these symptoms?

Differential Diagnosis by Site of TB Disease:

  • Pulmonary (non-miliary, non-cavitary): pyogenic bacteria (Streptococcus, Staphylococcus), viral pneumonia

  • Hilar/mediastinal lymphadenopathy: fungal pneumonia; lymphoma

  • Cavitary pulmonary disease: pyogenic lung abscess, nontuberculous mycobacterial disease, cavitating fungal pneumonia, parasitic (e.g., Echinococcus, Entamoeba); congenital lung anomalies; sarcoidosis; malignancy

  • Pleural effusion: pyogenic bacteria (Staphylococcus, Streptococcus), fungal; malignancy; autoimmune

  • Miliary disease: fungal pneumonia, viral pneumonitis (varicella, measles, cytomegalovirus), Legionella, tularemia, Brucella; lymphoma; hypersensitivity pneumonitis; sarcoidosis; alveolar hemorrhage; parasitic

  • Peripheral (predominantly cervical) lymphadenopathy: nontuberculous mycobacterial disease; fungal infection; cat scratch disease; lymphoma and other malignancy; sarcoidosis; Kikuchi's disease

  • Skeletal: subacute pyogenic osteomyelitis (staphylococcal, streptococcal), brucellosis, fungal osteomyelitis, actinomycosis; malignancy

  • Gastrointestinal: actinomycosis, Yersinia enterocolitica, amebiasis; lymphoma; inflammatory bowel disease

What caused tuberculosis disease to develop at this time?

TB risk factors can be divided into 2 groups: 1) risk for coming into contact with an individual with TB disease and converting the tuberculin skin test (TST) and 2) risk for progressing from TB infection to TB disease. Additionally, there are persons without risk factors who need to be screened for other reasons; while these persons would never be screened for TB infection under optimal circumstances, nonetheless for these persons there also needs to be TST cut-off for positivity.

Risk Factors for TST Conversion: epidemiologic factors

  • Close contact of person with contagious TB

  • Birth in or travel to high-prevalence nation (e.g., outside United States, Canada, Western Europe, Scandinavia, Australia, and New Zealand)

  • Residence in congregate living facilities (e.g., correctional facilities, long-term care units, homeless shelters)

  • Children exposed to adults with risk factors

Risk Factors for Progression from TB Infection to TB Disease: host immunologic factors

  • Immunosuppression / Immunocompromise

  • Age <5 (highest risk seen in infancy)

  • Recent TST conversion (within the last 2 years)

  • Certain medical conditions (e.g., diabetes mellitus)

  • Person with history of inadequately treated TB infection

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Tests that aid in diagnosis:

  • Sputum (or gastric aspirate, for the younger child) for acid-fast bacilli (AFB) stain and culture; these are generally obtained serially

  • Lumbar puncture for routine studies (cell count/differential, protein, glucose, Gram stain/culture), as well as AFB stain/culture, should be considered in any infant diagnosed with TB disease, as well as any older child with neurologic symptoms

  • Tuberculin skin test (TST)

  • Interferon gamma release assay (IGRA) [QuantiFERON and/or T-SPOT.TB]

Adjunctive tests that do not assist in diagnosis, but do aid in long-term care of the child:

  • Human immunodeficiency virus (HIV) ELISA: does not help establish diagnosis, but it is important to screen every person with a new diagnosis of TB for HIV

  • For children with TB meningitis, serum sodium should be checked

  • In children on other hepatically metabolized medications (e.g., antiepileptics), hepatic transaminases should be checked prior to initiation of therapy

Tuberculin Skin Test (TST) Induration Interpretation

There is perpetual confusion over the interpretation of the TST, as there is a sliding scale for positivity. The take-home message is that we want to optimize sensitivity for persons at high risk for progressing from TB infection and for individuals with suspected TB disease (in the latter instance, it is because anergy to the TST in children with overwhelming disease has been well-documented).

So, for the first group (below), we consider false positives to be acceptable because we do not want to risk not diagnosing a child. The children in the second group have TB risk factors, but without contact with an identifiable person with contagious TB. The third group are individuals without TB risk factors. In a perfect world, these individuals would never be screened for TB by skin test (but rather would be screened by history). However, as sometimes patients are screened for various and sundry reasons, we must have a cut-off for positivity. For this last group, the idea is to optimize specificity and decrease the number of false positive results.

Tuberculin skin test results that should be considered positive:

>=5mm:

  • Human immunodeficiency virus infection or other immunocompromising condition (e.g., solid organ or bone marrow transplantation, immunodeficiency, long-term steroid recipient)

  • Contact with a person with suspected TB disease

  • Abnormal chest radiograph or other imaging/clinical findings consistent with TB

>=10 mm:

  • Age <4 years

  • Birth or residence in high-prevalence nation (e.g., outside United States, Canada, Western Europe, Scandinavia, Australia, and New Zealand)

  • Residence in correctional or long-term care facility

  • Healthcare workers

  • Certain medical conditions (e.g., diabetes mellitus, renal failure, silicosis)

>= 15mm:

  • Considered positive even in individuals lacking specific risk factors

A new class of tests for TB (infection and disease) have become available since 2005. These tests, termed interferon gamma release assays (IGRAs), test the immune response to antigens that are quite specific to Mycobacterium tuberculosis. While these proteins are shared by a few nontuberculous mycobacterial (NTM) species (e.g., M. marinum), they are not found on the most common NTM species seen in the United States, e.g., Mycobacterium avium complex (MAC), and are not present in the BCG vaccine. What these blood tests offer is not increased sensitivity, but rather, enhanced specificity.

The two FDA-approved tests are the QuantiFERON assay and the T-SPOT. TB assay. These tests have been studied for older, immunocompetent children, but there are few data on their performance in young children and in immunocompromised hosts. Current recommendations of the American Academy of Pediatrics advocate the use of IGRAs in children 5 years of age and older, with specific emphasis on the advantage of these tests in children who have received the BCG vaccine or who are unlikely to return for TST interpretation.

Would imaging studies be helpful? If so, which ones?

Chest radiograph (PA and lateral): While pulmonary TB radiographic findings can overlap with those of community-acquired pneumonia, certain findings may help differentiate the two. In young children, hilar and/or mediastinal lymphadenopathy is commonly seen. In infants, the thymic shadow can preclude adequate evaluation of the mediastinum on the frontal radiograph, and lateral radiographs are critical. Atelectasis/volume loss can be seen in the collapse/consolidation pattern of TB in these children. Here, lymphadenopathy may be not be apparent by chest radiography and can result in compression of a peripheral bronchus and collapse of the lung distally. This is more often seen in younger children, in whom airway diameters are smaller.

Calcifications can be commonly seen in children with pulmonary tuberculosis, and generally indicate that disease has been present at least 2-6 months (these calcifications may take months/years to resolve radiographically despite effective therapy). Tuberculous pleural effusions are free-flowing, nonseptated, non-debris-laden effusions that can be seen in the presence or absence of concomitant pulmonary parenchymal disease.

Miliary disease leads to a very characteristic (although non-pathognomonic) diffuse pattern on radiograph, and is particularly important to recognize in infants, as up to 50% of infants with miliary TB have concomitant TB meningitis. Cavitary lesions can be seen at the extremes of the pediatric age ranges, but are much less commonly noted than in adults and in the pediatric age range are most commonly seen in adolescents. Any child with cavitary disease should be treated as potentially contagious. This means that healthcare workers should use N95 respirators and patients should be moved to negative-pressure rooms and should wear simple facemasks when not in their rooms.

For children with suspected TB meningitis, computed tomography (CT) can be helpful in evaluating for hydrocephaly, but an MRI brain (contrasted study) will be more helpful for delineating the basilar exudate and ischemic watershed regions consistent with TB meningitis, as well as to evaluate for infratentorial tuberculomas which may not be adequately visualized by CT. Up to 80-90% of children with tuberculosis meningitis will also have an abnormal chest radiograph, and M. tuberculosis is one of the few pathogens to cause concomitant meningitis and chest radiograph abnormalities.

Confirming the diagnosis

As microbiologic confirmation is possible for only a minority of children with suspected TB disease, the diagnosis often is contingent upon 1) positive TST or IGRA, 2) compatible clinical or radiographic findings, and 3) contact with a person suspected of having contagious TB, after exclusion of reasonable alternative diagnoses.

There are no good clinical decision algorithms for confirming the diagnosis of TB disease in children in industrialized nations. The excellent algorithms for pulmonary and lymphatic tuberculosis that have been described in high-prevalence environments such as South Africa have limited applicability in the United States and other low-prevalence nations. In low-prevalence nations, cold abscesses/lymphadenopathy and subacute pneumonias are more likely to be caused by nontuberculous mycobacterial species than by Mycobacterium tuberculosis.

If you are able to confirm that the patient has tuberculosis disease, what treatment should be initiated?

In the stable child in whom an adult with contagious TB cannot be identified (e.g., the child whose adult contact is not available or has no available culture), clinicians should attempt to obtain cultures from the child prior to the initiation of therapy.

The stages of TB disease therapy are subdivided into the intensive regimen (more drugs administered, and therapy is initially given daily), followed by a longer period of consolidation therapy (see Table IV). TB drugs are broken down into first-line and second-line medications. The differentiation is based on relative efficacy and side effect profiles. Second-line medications often are used for patients with drug-resistant TB isolates or patients who have medication intolerance of the first-line agents.

Table IV.

First-line Drugs Used to Treat Tuberculosis
Medication Daily dose Daily dose Biweekly dose Biweekly dose Dosing formulations Duration*
mg/kg/day Maximum dose (mg) mg/kg/day Maximum dose (mg)
Isoniazid 10-15 300 20-30 900 Scored tablets (100, 300mg)Suspension (10mg/mL) Entire duration of therapy
Rifampin 10-20 600 10-20 600 Capsules (150, 300mg)Suspension Entire duration of therapy
Pyrazinamide 30-40 2000 50 2000 Scored tablets (500mg) First 2 months
Ethambutol 20 2500 50 2500 Tablets (100, 400mg) First 2 months of therapy, or until susceptibility to first-line medications is confirmed (whichever comes first)

The first-line TB medications are isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA). These medications are administered daily for the first 2-4 weeks of therapy, then can be spaced to twice weekly therapy. They should always be administered by the health department to prevent selection of drug resistance. INH and RIF are the backbone of TB therapy and are continued through the entire course (assuming drug-susceptible TB). PZA is an agent that, if used from the initiation of therapy, enables clinicians to treat drug-susceptible disease (excluding meningitis, miliary disease) for 6 months instead of 9 months. EMB is utilized at the beginning of therapy as additional coverage in the event that unexpected drug resistance is seen. Once an isolate is shown to be pan-susceptible, EMB may be stopped.

Second-line TB medications include injectable agents with associated nephro- and ototoxicity (e.g., streptomycin, amikacin), fluoroquinolones, and older medications with unfavorable side effect profiles (e.g., para-aminosalicylic acid, cycloserine). In contrast to first-line medications, second-line medications require frequent laboratory monitoring for side effects. Consultation with a tuberculosis or infectious disease expert should be considered if a child requires these medications.

Adjunctive therapy with corticosteroids should be initiated for children with TB meningitis, pericarditis, severe pleural or miliary disease, endobronchial TB, and abdominal TB. The dose is 2mg/kg/day (maximum 60mg/day) prednisone or prednisolone for 4-6 weeks, followed by a slow taper.

The duration of therapy depends upon the site and extent of disease, drug-resistance (if any), and host immunocompetence. Medications are considered second-line because of either decreased efficacy or increased side effect profile relative to first-line medications. Use of second-line medications should be considered for children with drug-resistant TB disease, children with LTBI whose source case has multidrug-resistant TB, or children with TB disease who are intolerant of first-line medications.

Table V. Tuberculosis Disease Regimens

Table V.

Tuberculosis Disease Regimens
TB Patient Intensive Regimen Consolidation Regimen Notes
Immunocompetent; pulmonary or non-meningeal extrapulmonary TB 2 months HRZE 4 months HR If source case is known to have pan-susceptible TB, E may be eliminated from the regimen
Severe disease, considerable disease at the conclusion of 6 months of therapy 2 months HRZE >=4-7 months HR Cavitary disease at the end of 6 months of therapy is a risk factor for disease relapse
TB meningitis 2 months HRZ + (Eth or I) 7-10 months HR Adjunctive corticosteroids should be initiated
HIV-infected, uncomplicated pulmonary TB 2 months HRZE 7 months HR Risk of relapse is higher in HIV-infected persons treated for 6 versus 9 months
HIV-infected, extrapulmonary TB 2 months HRZE 10 months HR Beware interaction between rifampin and antiretrovirals
Isolated INH resistance 2 months RZE 4-7 months RZE F may be added for children with extensive disease
Isolated Rifampin resistance 2 months HZEF 10-16 months HEF Injectable agent may be added for children with extensive disease
MDR-TB or XDR-TB 3-5 drugs to which isolate is susceptible Expert consultation should be sought

What are the adverse effects associated with each treatment option?

Table VI. Medications Used for the Treatment of Tuberculosis

Table VI.

Medications Used for the Treatment of Tuberculosis
Drug Adverse Effects Comment Dose adjustment for hepatic or renal insufficiency
First-line medications Isoniazid Hepatitis, peripheral neuropathy Neuropathy (but not hepatitis) preventable with pyridoxine Hepatic
Rifampin Hepatitis Multiple drug interactions Hepatic
Pyrazinamide Gout, rash Increases in serum uric acid seldom accompanied by gout symptoms Hepatic
Ethambutol Optic neuritis Uncommon in children, who metabolize the drug faster than adults Renal
Second-line medications Injectable agents (streptomycin, amikacin, capreomycin) Oto- and nephro-toxicity Requires central venous catheter in most children, who do not have the muscle mass to tolerate IM injections Renal
Ethionamide Vomiting, hypothyrodism, peripheral neuropathy, hepatitis, optic neuritis Make sure child not vomiting medications before hospital discharge Renal
Fluoroquinolones Theoretical risk of arthropathy Renal
Cycloserine Rash, seizures, psychosis Monthly neuropsychiatric evaluation needed; serum levels available Renal
Para-aminosalicylic acid GI distress, hepatotoxicity, hypothyroidism Need to check TSH monthly Renal

What are the possible outcomes of tuberculosis disease?

The prognosis for the immunocompetent child with non-meningeal TB disease is excellent. Survival rates for adults with pulmonary TB (~80-85%) are depressed due to mortality from underlying comorbid medical conditions in these patients, and these mortality rates do not reflect prognosis for childhood TB (survival rates >95%). While up to two-thirds of children with pulmonary TB will continue to have pulmonary scarring at the end of therapy, this does not generally impact pulmonary function.

Mortality rates are increased in at least two subgroups with TB disease: children with TB meningitis and persons with multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Children with TB meningitis have a prognosis that is contingent upon how far into their disease course they are at the time of presentation. Children with altered mentation and increased intracranial pressure at the time of presentation have a poor prognosis for neurologically intact recovery. The 5-year survival rate for MDR and XDR TB in HIV-seronegative adults averages 60-70%. HIV-infected persons with MDR/XDR TB have substantially higher mortality rates (one study had 98% mortality among HIV-infected adults with XDR TB). Few longitudinal data are available for immunocompetent children with MDR/XDR TB.

From a risk/benefit standpoint, TB medications clearly fall into the overwhelming benefit category, both for TB disease and infection. First-line TB medications have all been used for upwards of 40 years, and are very well tolerated by children. The hepatic side effects seen in adults are very infrequent in children. In part, this is because children are less likely to be receiving other hepatotoxic medications, are less likely to have incurred prior liver damage, and (we hope) are less likely to consume alcohol along with their TB medications. For this reason, baseline liver function tests are not mandated in the otherwise healthy child who is not receiving hepatically metabolized medications. This being said, the threshold for checking hepatic transaminases should be justifiably low in a child with abdominal complaints not readily attributable to other causes.

What causes tuberculosis disease and how frequent is it?

About 9,500 cases of TB disease are seen annually in the United States. Of these, over 50% occur in 4 states: New York, California, Texas, and Florida. These states share the characteristic of having large populations of persons born abroad. In fact, over 65% of all persons diagnosed with TB in the United States were born internationally. Approximately 5-6% of all TB cases occur in children.

In contrast to the number of TB disease cases, the numbers of persons with positive TSTs without symptoms or abnormal radiographs (TB infection) is unknown, as TB infection is not reportable. It has been estimated that approximately 4% of the United States population has TB infection, compared with global estimates of 25-30%.

Mycobacterium tuberculosis is airborne in its transmission, and along with varicella, measles, SARS, and smallpox, is one of the few reasons for placing patients in negative-pressure rooms. In contrast to adults with cavitary TB, most children are not contagious. This is due to a number of factors, including weaker coughs by young children, lower bacillus inoculum in the lungs, decreased frequency of cavitary disease (with the attendant large numbers of organisms harbored in cavities). That being said, any child with cavitary disease should be treated as contagious.

Predisposing conditions to TB include any immunodeficiency (a more recently recognized comorbidity is diabetes mellitus, particularly in patients with poor glycemic control) and certain pre-existing lung damage (e.g., silicosis). Most children who develop TB disease have no identifiable immunodeficiency or other predisposing condition.

Several groups have attempted to identify genetic polymorphisms that may predispose a person to progress from TB infection to disease. However, while identification of genes may enable targeted treatment of persons with TB infection, multiple polymorphisms with variable penetrance exist, currently precluding efforts at genomic-based prophylactic strategies.

How do these pathogens/genes/exposures cause the disease?

After the bacillus enters the lungs, several outcomes are possible:

  • Bacterial may be encapsulated without subsequent disease

  • Bacteria may replicate locally, termed primary progressive disease

  • Bacteria may spread along the bronchial tree, termed endobronchial TB

  • Bacteria may be drained to local intrathoracic lymph nodes, resulting in hilar or mediastinal lymphadenopathy

  • Bacteria may disseminate widely within (and outside) the lungs, resulting in a miliary pattern

Other clinical manifestations that might help with diagnosis and management

A child with lymphocytic meningitis with elevated cerebrospinal fluid (CSF) protein should have a chest radiograph. Several case series have shown that upwards of 90% of children with TB meningitis have abnormal radiographs. This is due to the short incubation period for TB meningitis (versus, for example, skeletal or renal TB), so the lungs have not had a chance to heal before the disease disseminates and seeds the meninges. Given the long time frame for cultures to return, an abnormal radiograph may be the first clue that a child's CSF pleocytosis may be due to TB.

What complications might you expect from the disease or treatment of tuberculosis disease?

Immune reconstitution inflammatory syndrome (IRIS) is a complication that may be expected in a child on appropriate therapy for TB disease. IRIS is a paradoxical worsening of symptoms, and has been described for pulmonary infiltrates, peripheral and visceral lymphadenopathy, and intracranial tuberculomas. While IRIS has been best described in HIV-infected and other immunocompromised patients, it can occur in immunocompetent hosts as well. Symptoms generally worsen 4-8 weeks after initiation of therapy. Nonsteroidal anti-inflammatory drugs are used for mild reactions, where as significant worsening of symptoms may require corticosteroids.

Are additional laboratory studies available; even some that are not widely available?

GeneXpert: is a rapid PCR-based technology that can identify mutations conferring resistance to rifampin. This identification can be done in a few hours and is important, because rifampin mono-resistance is uncommon. Rather, almost all isolates displaying rifampin resistance are also resistant to isoniazid. Therefore, this technique enables the rapid identification of multidrug resistant (MDR-TB) isolates, which are defined as isolates resistant to both isoniazid and rifampin.

How can tuberculosis disease be prevented?

Tuberculosis disease can be prevented in two ways:

1) by the treatment of young children with TB exposure to a person with contagious TB (termed a 'source case') until they have had their definitive skin test (performed 8-10 weeks after the child has either no longer been around the individual or 8-10 weeks after the individual is deemed, by serial sputum cultures, to be noncontagious)

2) by the treatment of children with TB infection

Table VII. Regimens for Tuberculosis Exposure and Infection

Table VII.

Regimens for Tuberculosis Exposure and Infection
Classification Initial treatment Duration of therapy Other
Exposure, >= 4 years old and immunocompetent None N/A Repeat TST 8-10 weeks after contact with source case is broken; if 2nd TST is positive, see section on TB infection
Exposure, < 4 years old or immunocompromised 1st line: INH2nd line: RIF Variable Repeat TST 8-10 weeks after contact with source case is broken; if 2nd TST is positive, see section on TB infection
Exposure, infant 1st line: INH2nd line: RIF Variable See above. Because TSTs are less reliable in infants compared to older children, the TST results of other children in the family should be considered when making decisions about terminating chemoprophylaxis; expert opinion should be sought
Infection 1st line: INH2nd line: RIF INH: 9 monthsRIF: 6 months Can be administered daily through family or biweekly through health department. Consider health department administration for young children or for children in whom an identifiable source case is found

What is the Evidence?

Epidemiology

"Global Tuberculosis Report 2015". http://www.who.int/tb/publications/global_report/gtbr15_main_text.pdf.

(WHO report on the global epidemiology of TB, where it is estimated that there are 10 million new cases of TB disease annually.)

"Leveling of tuberculosis incidence – United States, 2013-2015". MMWR. vol. 65. 2016. pp. 273-278.

(CDC report on the epidemiology of tuberculosis disease in the United States. In 2015, there were approximately 9500 cases of TB disease, of which 5-6% occurred in children.)

Clinical Manifestations

Chintu, C, Mwaba, P.. "Tuberculosis infection in children with human immunodeficiency virus infection". Int. J. Tuberc. Lung Dis.. vol. 9. 2005. pp. 477-484.

(Reviews the differences in clinical presentation, diagnosis, and management of TB in the HIV- infected child.)

Marais, BJ, Gie, RP, Schaaf, HS. "Childhood pulmonary tuberculosis: old wisdom and new challenges". Am J Resp Crit Care Med.. vol. 173. 2006. pp. 1078-1090.

Diagnosis

Starke, JR. "Interferon-gamma release assays for diagnosis of tuberculosis infection and disease in children". Pediatrics. vol. 134. 2014. pp. e1763-1773.

(Reviews the updated American Academy of Pediatric recommendations on the use of IGRAs in children.)

Froehlich, H, Ackerson, LM, Morozumi, PA.. "Targeted testing of children for tuberculosis: validation of a risk assessment questionnaire". Pediatrics. vol. 107. 2001. pp. e54.

Treatment

Pickering, LJ. "Tuberculosis". Red Book report of the Committee on Infectious Diseases. American Academy of Pediatrics. 2006. pp. 678-698.

(Pediatric specific guidelines for treatment strategies in the United States.)

Guidance for national tuberculosis programmes on the management of tuberculosis in children. World Health Organization. 2006.

(Helps guide treatment strategies with more global views and more resource-poor settings.)

"Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America". MMWR. vol. 52. 2003.

(Helps guide treatment strategies in locations where chest radiography, cultures, susceptibilities, and second-line agents are available.)

Chiang, SS, Khan, FA, Milstein, MB. "Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis". Lancet Infect Dis. vol. 14. 2014. pp. 947-957.

(Overall mortality rates of up to 20% were seen, and more than one-half of survivors had neurological sequelae.)

Villarino, ME, Scott, NA, Weis, SE. "Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid". JAMA Pediatr. vol. 169. 2015. pp. 247-255.

(RCT of a combination, short-course regimen for latent TB infection demonstrated that no child progressed to TB disease, completion rates were higher, and hepatotoxicity was not seen when this regimen was compared to a 9-month course of isoniazid.)

Prevention

"Targeted tuberculin testing and treatment of latent tuberculosis infection". Am. J. Respir. Crit. Care Med.. vol. 161. 2000. pp. 1376-1395.

Zar, HJ, Cotton, MF, Straus, S. "Effect of isoniazid prophylaxis on mortality and the incidence of tuberculosis in children with HIV: randomized controlled trial". BMJ. vol. 334. 2006. pp. 136-142.

(Large survival advantage seen in HIV-infected children on INH prophylaxis, even without a known exposure; study conducted in an area of hyperendemicity for TB and HIV.)

Ongoing controversies regarding etiology, diagnosis, treatment

Controversies exist in several areas of childhood TB diagnosis, prevention, and treatment.

Perhaps the greatest weakness in childhood TB surrounds the difficulty in cementing a microbiologic diagnosis. Young children rarely produce sputum, and when they do, the paucibacillary nature of disease results in low culture yields. Consequently, we are often left to diagnose a child by using the triad of a positive TST (or IGRA), contact with an adult suspected of having contagious TB, and compatible radiographic and clinical findings.

The newest test to assist in the diagnosis of TB infection and disease (though it does not differentiate between the two), is the IGRA. However, this test has not been well-studied in the highest-risk children: preschool-aged children and immunocompromised hosts. In the latter population, studies indicate that IGRAs have a high proportion of indeterminate test results. Since the advent of these assays, it is recognized that there is no longer a reference standard for the diagnosis of tuberculosis infection. However, it is also not clear what to do when children have discordant results between the TST and the IGRA. One strategy is to define positivity as either test being positive in a high-risk child (see above categories for TST cut-offs), and to utilize the more specific test (the IGRA) in low-risk children.

Preventive strategies for TB are driven by economic and logistical considerations, as well as by the rates of drug resistance seen in different areas. In the United States, treatment of children with TB infection with isoniazid monotherapy is a viable option; the drug is cheap, safe, and effective. In resource-limited nations, this may not be the case. One excellent study by Heather Zar and colleagues distributed INH to HIV-infected children in South Africa; this was done irrespective of specific TB risk factors, and the TST was not used to risk-stratify children. The study was terminated after an interim analysis showed it was unethical to proceed with randomization, as the children who received INH had significantly lower mortality rates than the control group.

Another controversy with preventive therapy relates to the duration of therapy. There are discrepancies between United States and World Health Organization recommendations, and many national thoracic societies have advocated short-course multidrug therapy for TB infection. The rationale here is that the duration of therapy is strongly inversely correlated with patient adherence.

Finally, any widespread chemoprophylaxis plan should take local drug resistance rates into consideration. It is known that treating a child with TB infection with INH when the person who infected them had INH resistance does not decrease their risk of disease progression. However, it is not clear what the prevalence of INH resistance should be in a community before the decision is made to switch to rifampin or other empiric therapy. This scenario is complicated further because in many developing countries, a child may be exposed to more than one adult with contagious TB, and these persons may have isolates with disparate susceptibility patterns.

The treatment of drug-susceptible strains of Mycobacterium tuberculosis is well-accepted. However, for drug-resistant strains, particularly MDR-TB, there are no accepted treatment regimens. The recommendation is that the child receive several medications to which the isolate has demonstrated susceptibility. However, given the disparate drug resistance pattern of isolates and the limited pharmacologic armamentarium, finding an effective therapy that is tolerated by the patient may be challenging. Additionally, many countries bearing most of the burden of TB disease are countries that often cannot obtain drug susceptibility testing at the time of initiation of therapy. In these nations, the true rates of drug resistance are not well-documented. Finally, finding optimal treatment regimens for a given susceptibility pattern would require multicenter studies.

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