TB: Cases

Contents
• Cases

Case 1

     After a resurgence of tuberculosis in the late 80’s and early 90’s there has been a decline in the overall case rates of tuberculosis, including multidrug resistant tuberculosis. This has led to a change from universal screening of children to targeted tuberculin skin testing (TST).

     Pediatric tuberculosis disease is relatively rare in the United States with a fairly well defined epidemiology as delineated by multiple studies (see reference 1). This allows us to identify persons at risk for TB infection and those that would benefit from treatment for LTBI  (Latent  tuberculosis infection). Children at high risk include contacts with persons with active disease, those who are foreign-born, those who travel to countries with high TB prevalence or have visitors from those countries, contacts with high risk adults such as those who are homeless, are in jail, have HIV, use intravenous drugs. The definition of a high risk adult may vary somewhat from population to population. Using universal testing, where the positive predictive value is low, in a low prevalence population would lead to a large number of false positive tests and the need to follow and treat these individuals. Targeted TST allows more accurate identification of latent and active disease.

     Therefore mandated TST should not be routinely required for school entry, day care attendance, WIC, camp or college attendance. Instead children should be screened for relative risk factors for TB by using a risk assessment questionnaire developed by the Pediatric Collaborative Tuberculosis Group  that took into account the previously mentioned studies that were done in different populations but found to have fairly similar results. (see reference 1 page 1178, table 3, for detailed questionnaire).The following are the questions to ask.

1.      Was your child born outside the United States?

2.       Has your child traveled outside the United States?

3.      Has your child been exposed to anyone with TB?

4.      Does your child have close contact with a person who has had a positive TB skin test result?

5.      Does your child spend time with anyone who has been in jail, lives in a shelter, uses illegal drugs or has HIV? 

6.      Has your child drunk raw milk or eaten unpasteurized cheese?

7.      Does your child have a household member who was born outside the United States?

8.      Does your child have a household member who has traveled outside the United States?

The risk assessment questionnaire should be done every 6 months until 2 years old and then yearly. Anyone with one risk factor or more should have a TST placed. Children who need annual TSTs include children infected with HIV and incarcerated adolescents.

     Anyone with signs or symptoms of TB disease should be tested. The questionnaire is especially important in those at high risk for progression of disease such as children with diabetes mellitus, chronic renal disease, malnutrition and immunodeficiencies. An initial TST should be done before immunosuppressive therapy is begun including prolonged steroid administration, chemotherapy and agents active against tumor necrosis factor alpha.

Your answer to Mrs. Rodriguez would be to find out if her child has any risk factors for tuberculosis and if not to place no risk in the tuberculosis section of the school form. In New York City presumably the school form has been revised to reflect targeted TB screening guides but this new form has obviously not reached all schools.

 

Case 2

Tuberculin skin testing would be indicated in this child. Foreign travel risk includes travel within the last 12 months for greater than 1 week to a country with a high prevalence of TB or a household visitor from such a country. If the child does not have a history of TB contact during his visit  abroad and is healthy the TST should be delayed for up to 10 weeks after his return. TST is the most common method for diagnosing LTBI in an asymptomatic individual. The principle underlying TST is delayd type hypersensitivity (DTH) reaction induced by the antigenic components of M. tuberculosis. The incubation period from infection to development of a positive TST is 2-12 weeks, with a median of 3-4 weeks.

     In the past Multiple Puncture tests, such as tine were used. These are considered inaccurate and when positive required placement of a more accurate test for verification. The only reliable test now used is the Mantoux method which consists of 5 tuberculin units of purified protein derivative in 0.1 ml. This is  injected intradermally into the volar aspect of the forearm by a trained individual. Creation of a 6-10 mm wheal is important to get accurate testing.

     Quantiferon-TB (QFT) is a blood test that measures interferon production from an individual’s white blood cells in response to stimulation with M.TB antigens. The sensitivity of the QFT test is similar to TST in detecting untreated, culture confirmed infection. QFT has been approved for use in adults. Data is not available for children.

There are both false positives and false negative tests reported with Mantoux testing. 10% of immunocompetent children with TB will have a negative test.

     Reasons for a false positive test include infection with nontuberculous mycobacteria, previous BCG vaccination, incorrect method of TST administration, and incorrect interpretation of the reaction.

     Reasons for false negative tests include:

  1. Cutaneous annergy : Annergy testing as routine practice for assessing a patient’s ability to mount a DTH response is not recommended by the CDC. The diagnosis of annergy is not associated with high risk of developing TB disease and the antigens routinely administered and the reproducibility  of the DTH have not been standardized.
  2. Active infection with TB, measles, or varicella may temporarily suppress the DTH response to a TST.
  3. Recent TB infection (within 8-10 weeks of exposure)
  4. Very old TB infection ( many years)
  5. Very young age ( less than 6 months)
  6. Live attenuated virus vaccination such as measles, mumps, rubella, oral polio, BCG, and oral typhoid may temporarily suppress DTH response to TST. TST can be administered the same day of a live virus vaccine or should be placed 4-6 weeks later.
  7. Incorrect method of TST administration
  8. Incorrect interpretation of reaction
  9. Corticosteroids. A TST can be placed the same time as initiating corticosteroid therapy with both positive and negative results being reliable. If the TST is done after initiating therapy a positive test is reliable and a negative is unknown. The dose, dosing frequency, and length of treatment with corticosteroids that lead to a possible false negative TST have not been established in children.

This child is positive for one risk facto and needs to have TST. If the child is well he can receive his 1 year shots, have his WIC form done and return in 10 weeks for his PPD.

 

Case 3

  A TST should be placed regardless of the history of receiving BCG immunization.

     BCG stands for baccile Calmete-Guerin . It is a live vaccine prepared from attenuated strains of M. bovis. It is used to prevent disseminated disease and other life threatening manifestations of M. tuberculosis in children. BCG vaccines throughout the world differ in composition and efficacy. The vaccine appears to have a high protective efficacy against meningeal and miliary TB in children. The efficacy against pulmonary TB is variable.

     The WHO estimates that 79% of the world’s population has received BCG vaccine. 22 countries account for about 80% of the world’s TB cases (see reference 2). In countries that give BCG it is usually administered at birth. Some countries (Brazil, Russia) revaccinate during the school years.

     There are numerous studies that have tried to look at BCG vaccination and TST reactivity. Most of these studies are not comparable because different methods were used to document vaccine reception (scar on arm versus paper documentation), different vaccine strains were used for vaccination as well as different doses. In general BCG is thought to have a variable effect on TST reactivity. A minority of children will have a TST greater than or equal to 10 after receiving BCG. Children who receive BCG after infancy or who receive more than 1 BCG (see boosting question 4) have an increased rate of positive TST. The problem is that BCG reactivity cannot be distinguished from reactivity due to TB infection. However children from countries with high case rates of TB disease are more likely to have a positive TST from LTBI than from the BCG immunization. Consequently all positive TSTs in children who have received BCG are treated as positive for TB disease.

In this case you can explain to the mother that if the tuberculosis skin test is positive it might be from the BCG but is much more likely to be positive because of TB exposure. Therefore it is important both to check a TST and if it is positive to treat it as real and not a reaction from BCG.

Case 4

     A trained health professional should place, read and interpret TST. DTH reaction appears as an indurated area at the site of injection which reaches a maximum at 48-72 hours and then subsides over subsequent days. Proper reading includes measuring and recording the diameter of the induration in mm at 48-72 hours after placement. Immediate wheal and flare reactions may occur and usually disappear in 24 hours. They should not be interpreted as positive. Rarely the immediate reaction may be severe and experts recommend not to TB test that  person again. Negative tests should be recorded in mm as well. A TST read after 72 hours can underestimate the DTH response. If it is less than 10mm (negative) the  TST should be repeated immediately. However, a TST after 72 hours greater than 10 mm should be considered positive if risk factors for LTBI are present.

    If the TST is negative the reason to place a repeat test immediately is to avoid the boosting effect and a false positive test. Boosting, which is only seen in someone previously infected with mycobacterial antigens (non-tuberculous mycobacterial infection or BCG recipient), occurs when repeated TSTs  re-stimulate the DTH response and result in a false positive reaction. The effect is minimized if TSTs are placed less than 1 week apart.

The definition of a positive TST in children uses 3 cutoff levels (see reference 1 Table 4 page 1178 )

   Induration  greater than or equal to 5 mm

 Induration greater than or equal to 10 mm

Induration greater than or equal to 15 mm

        Children greater than or equal to 4 yo with no known risk factors

This child should have his TST site examined. If it is less than 10 mm he needs to have a repeat TST immediately. If it is greater than 10 mm he needs further evaluation.

Case 5

Children and adolescents with a +TST need to be further evaluated, most of which was presumably obtained prior to placement of the TST.

  1. Medical history

A medical history should be obtained to elicit symptoms of TB disease such as cough, fever, wheezing, and failure to gain weight. A history should also be gotten of preexisting or coexisting medical conditions that may complicate the treatment of LTBI.

      2.   Physical exam

            A targeted physical exam should be done with attention paid to the signs and symptoms of pulmonary and extrapulmonary TB including weight loss, scleral icterus, lymphadenopathy, and lung findings such as rales, wheezes and  hepatosplenomegaly.

3. Chest Radiographs - Both PA and lateral films should be gotten.

     Findings on CXR in children with LTBI are usually normal. Readings that include dense nodules with calcification (Ghon complex), calcified non-enlarged regional lymph nodes, pleural thickening (scarring) are also consistent with LTBI as they are not associated with disease or risk of progression to disease.

     CT evaluation of an aymptomatic child/adolescent is not indicated because the increased sensitivity of CTs may show enlarged or prominent mediastinal or hilar nodes that were not seen on CXR and are thought to be of no clinical significance. CTs may be helpful with equivocal radiographs. Routine LFT’s in the evaluation of a child with a +TST are not needed unless a preexisting condition exists which might increase the risk of hepatotoxicity with treatment for LTBI. These might include findings of liver disease on physical exam, ETOH abuse or drug abuse, HIV or a child on hepatotoxic drugs.

Treatment for LTBI

     Treatment for LTBI is with isoniazid (INH) for nine months in children/adolescents without a known source case or with a source case whose isolate is susceptible to INH. INH should be given daily for 9 months. If a dose is missed you don’t add it to the next day’s dose but instead extend the treatment to include any missing doses. The 9 month treatment needs to be completed within a 12 month period. If the patient receives less than 6 months of INH within a 9 month period he/she needs to be retreated. If therapy for LTBI is not started within 3 months of obtaining the CXR a repeat CXR should be gotten to make sure the disease has not progressed. In children who are already at increased risk of progression of TB (less than 1 year old, HIV, etc) a repeat radiograph should be done if treatment is not started within 1 month.

     Children being treated for LTBI should be evaluated monthly to reinforce adherence, to evaluate toxicity and to assess possible progression of disease. At the end of treatment written documentation should be given of completion of therapy.

     Intermittent regimens for the treatment of LTBI, where INH is given 2-3 times a week, are acceptable only if administered by the DOT program (directly observed therapy) run by the department of health. Those who should be prioritized for DOT are children less than 3 years old, HIV infected, close contacts of TB cases, immunocompromised, history of poor adherence, or LTBI with association with MDR (multidrug resistant) TB case.

     Rifampin can be given instead of INH. Rifampin is given for 6 months and is given if the isolate is resistant to INH and susceptible to Rifampin, or if the patient could not tolerate INH. Children exposed to a source case with MDR TB should have their management in consultation with an expert.

     In general INH is well tolerated in children. Liquid INH may cause abdominal pain and/or diarrhea. INH is available in100 and 300 mg scored tablets which can be easily crushed and given in soft foods.

     Toxicities associated with INH include:

  1. Hepatitis-  Aymptomatic transient elevation transaminases Clinical hepatitis, rare, resolves with stopping INH Very rare fulminant hepatitis with liver failure  Those at risk for hepatitis include preexisting liver disease, older age (esp adults), malnutrition, alcoholics, those on hepatotoxic drugs (ie anticonvulsants), pregnant women, postpartum women the first few weeks. Many physicians delay treating women for LTBI until 2-3 months postpartum unless the woman is HIV positive.

           Parents should be told to stop INH immediately if symptoms of hepatotoxicity appear, such as anorexia, nausea, vomiting, malaise, fatigue, abdominal pain, icterus, brown urine, clay colored stool. Patients considered at increased risk for hepatotoxicity should have LFTs done at 1 and 3 months into therapy.

         

2. Peripheral neuropathy- INH interferes with niacin metabolism causing increased excretion of pyridoxine (B6). Its effects are dose related. Peripheral neuropathy presents as tingling of the fingers and toes. It is rare in children. It is increased in people with certain risk factors-diabetes, uremia, diet low in milk and meat, nutritional deficiencies, symptomatic HIV, pregnancy, alcohol use, breastfed infants and their mothers. Vitamin B6 should be provided to breastfed infants, adolescents on meat and milk deficient diets and those with HIV or paresthesias while taking INH.

3. Hypersensitivity reactions- include skin rashes, maculopapular and morbilliform, secondary to INH. Stopping INH and then rechallenging can clarify the etiology of the drug rash. Fever, pruritis, arthralgia have also been described.

Documentation should be provided of the mm of induration of the +TST and completion of treatment. Someone presenting with a history of a positive TST without any documentation should have the TST repeated.

The child in case 5 should have a CXR done. If the CXR is normal, he is well, and there is no source case, he should be started on INH for 9 months, with monthly follow-ups to check on adherence. If his CXR is abnormal and there is no source case he should be admitted to the hospital in order to try to recover AFB from early morning gastric aspirates in consultation with infectious diseases. (see case 6) If there is a source case there is no need to recover organisms and his treatment can be determined by the sensitivities of the source case AFB in conjunction with the infectious disease specialists.

 

Case 6

 A source case investigation is where the Department of Health identifies all individuals exposed to a source case of tuberculosis. All close contacts are evaluated by physical exam, TST and/or CXR.

     The best way to prevent tuberculosis disease in children is by investigating close contacts of source cases and instituting appropriate therapy. The risk of developing disease is highest in the first 12 months after infection.

     Children 5 years old and under are at risk for progression to severe disease even if initially TST negative. As per previous discussion it takes 10-12 weeks to develop a +TST after infection while the incubation period for devastating disease, like meningitis, takes 4-6 weeks. This period following exposure and possible infection when the TST is not yet positive is called the window period. Even if the TST is negative during this period children 5 and under, and others  (DM etc) that are at high risk of progressive disease should be started on primary prophylaxis. The TST should then be repeated 12 weeks later.

     All persons with a TST greater than or equal to 5 should be considered positive if they are close contacts to a source case. A TST can be placed as young as 1 month of age but a TST result in a child under 6 months of age is unreliable. A negative TST obtained after 6 months of age can be considered truly negative. Children exposed to TB with a +TST and all children under 5 years old (whether the TST is positive or negative) should have a CXR and directed physical exam followed by window prophylaxis or treatment for LTBI.

     Those 5 and under on window prophylaxis should have a repeat TST in 12 weeks after the last exposure. If the TST is negative and the exposure has stopped, the treatment can be stopped. If the exposure is ongoing treatment needs to be continued and another TST placed 12 weeks after the last exposure. In a child less than 6 months old, if the repeat TST is negative and the child is well, and the exposure has stopped, the prophylactic treatment needs to continue until the child reaches 6 months of age. A repeat TST should be done at that time and if the TST is negative window prophylaxis can be stopped.

     If receiving window prophylaxis and the repeat TST is positive the child should be evaluated clinically for TB. If active disease is not present the child can be classified as having LTBI and treated for 9 months.

     Children older than 5 years of age who are TST negative initially do not need window prophylaxis but need to have a repeat TST done in 12 weeks (presumably the exposure has stopped). If positive they should be reevaluated for TB, if negative no treatment is needed.

     Children who are identified through a source case and have TB disease (+TST and +symptoms/CXR) can be treated according to the sensitivities of the source case TB in conjunction with the DOH or infectious disease specialist. In TB disease without a source case an attempt should be made to recover M. TB from the child. It is difficult to recover AFB from children because they have paucibillary disease. AFB smears and cultures of the sputum are often negative (<30% positive) and other body fluids areusually negative as well. Sputum samples are hard to get. Gastric washings are sometimes helpful but require hospitalization in order to collect a first morning specimen for three days. These are positive 30-40% of the time. Bronchial washings yield similar results to gastric aspirates and can be done as an outpatient but are more invasive. Treatment plans should be in conjunction with the infectious disease specialists and DOH as TB disease and treatment of source case contacts would be done by DOT to ensure compliance, especially in young children.

     In this case the 3 year old child was considered to have a positive TST and positive CXR and was started on treatment with INH, rifampin and pyrazinamide by DOT. The treatment regimen was reevaluated when the susceptibilities came back from the uncle’s AFB.

     The 7 week old was put on window prophylaxis with INH. A repeat TST 12 weeks later was negative. INH was continued (the source case AFB was sensitive to INH) and a repeat TST was scheduled for when the child reached 6 months of age. If the child was breastfeeding pyridoxine would have been added as well

 

Case 7

     Tuberculosis disease treatment during pregnancy should be managed by an expert. Prompt treatment should be initiated. Women with pulmonary TB are not as likely to infect the child in utero as they are after delivery. True congenital Tuberculosis in utero is extremely rare. (see reference 2 for further discussion)

Management of a newborn infant whose mother has LTBI or tuberculosis disease

  1. Mother has positive TST and normal CXR

      If the mother does not have any contagious contacts her treatment can wait until after delivery. No separation is needed between mother and child. After the initial postpartum period the mother should receive INH and pyridoxine. Maternal treatment with INH is not a contraindication to breastfeed. The newborn needs no special evaluation or treatment. Because a +TST can be a marker for unrecognized TB other household members and close contacts should be tested.

2. Mother with clinical signs, symptoms of TB disease or abnormal CXR consistent with TB disease

     This should be reported to the local health department which would probably initiate a contact investigation (see definitions).The infant should be evaluated for congenital TB and the mother for HIV. The mother and child should be separated until the appropriate evaluations are done and treatment has begun for both. The mother needs to wear a mask (until sputum cultures are negative x3) and needs to show a willingness to adhere to infection control procedures and treatment. Once the child is under treatment separation is no longer needed unless the mother has MDR TB, poor adherence or DOT is not possible. BCG might be considered under these circumstances.

     If the child does not have congenital TB INH is given until 3-4 months of age when a repeat TST is done. If the TST is negative and the mother has good adherence INH can be stopped. ( I’m not sure why this is the case since as previously stated a TST in a child under 6 months is unreliable but this is what the Redbook says). If the TST is positive the child needs to be reevaluated for TB disease. If the evaluation is negative the child should receive a total of 9 months of INH. If the evaluation is positive consultation with an infectious disease specialist is called for.

In this case one need do nothing for the child. The mother should be encouraged to follow-up with her doctor and receive a course of INH. Other household members should be tested.

Case 8

    Diagnosis of LTBI in a young child usually represents recent transmission of M. TB from an adult. Children less than 10 years old are rarely contagious because pulmonary lesions are small, cough non-productive and few or no bacilli are produced. The duration of contagiousness in an adult depends on receiving effective treatment, the drug susceptibility of the organism, the number of organisms in the sputum and the frequency of cough. Contagiousness usually lasts a few days to weeks after initiation of therapy but may last longer in cavitary disease, in someone not taking their medicines, or someone with MDR TB. If the sputum smears are negative on 3 separate days and the person is considered improved clinically they have low risk of transmission.

Associate investigations are usually performed by health departments where close contacts of children with LTBI are tested to detect undiagnosed cases of infectious TB. The AAP (Redbook) currently recommends that all associates of children with a +TST should have a TST. In general most health departments do associate investigations for children less than 5 years old with LTBI because young children are likely to have been recently infected so the likelihood of finding an active case among the associates is high.

In New York City the following is reportable to the DOH:

Positive AFB smear

Positive nucleic acid amplification test for M TB complex

Positive cultures for M TB complex

Susceptibility tests on M TB cultures

Pathology findings consistent with TB

Patients suspected of having TB

Patients started on 2 or more anti-TB drugs for the treatment of TB

Positive tuberculin skin test in children younger than 5 years old

In this case the LTBI in the 12 year old did not generate a contact investigation. The PMD offered TST for the child but the mother was unable to do so at that appointment. Another appointment was arranged for her to return for TST placement for the 4 month old which she did not keep. A few weeks later the child presented to the ED with 6th nerve palsy and hydrocephalus and was ultimately diagnosed with TB meningitis. The family was tested and the grandmother was found to be the source, with the mother and father now testing positive as well.