Mycobacterial infections

Table III.

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.