A Clinical guide to pediatric infectious disease

12

Pediatric Tuberculosis

Epidemiology

After years of decline in the national rates of tuberculosis, there were discussions in the early 1980s regarding the elimination of the disease in the United States. However, from the mid-1980s to the early 1990s, there was a 15% increase in reported cases. Children were even more greatly affected by this trend, with an increase in reported cases in children 5 to 14 years of age of almost 40%. The increase in cases of tuberculosis was thought to be the result of an increase in medically underserved populations, an increased number of patients from endemic areas, and an increase in patients infected with human immunodeficiency virus (HIV) resulting in large numbers of contagious patients. Although infection control efforts have been somewhat successful in controlling tuberculosis, it remains a major cause of morbidity and mortality in selected areas of the United States. This chapter discusses both the pathophysiology of pediatric tuberculous infection and the diagnosis and therapy of latent and active disease.

Etiology

Infection with Mycobacterium tuberculosis (MTB) begins with the inhalation of airborne bacilli. After inhalation, the bacilli reach the pulmonary alveoli and are transported through pulmonary lymphatic channels to hilar lymph nodes. They can then enter the bloodstream by way of the thoracic duct. Although the entrance of MTB into the host is respiratory, the organism can thus be spread to virtually every organ in the body. Spread of small numbers of bacilli result in clinically inapparent foci of infection. Regions most commonly seeded include the meninges, the pleura, and the bone. A reaction involving macrophages, lymphocytes, and ingested organisms then occurs, and tubercles are formed. When this reaction occurs, a tuberculin skin test will become positive, indicating that exposure to MTB has occurred.

The initial immune containment of clinically inapparent infection may not be permanent, and reactivation is possible at any time. Infants younger than 1 year of age have about a 50% chance of developing active disease. In children younger than 5 years of age, the risk for reactivation to active disease is about 25%.

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Presentation of Latent Tuberculosis

A child who is infected with MTB without clinical or radiographic signs is defined as having latent infection. There is a great advantage in diagnosing and treating latent infection because it can avoid subsequent reactivation and the development of active disease.

Diagnosis

Tuberculin skin testing (TST) is the method used for diagnosing latent infection. The TST used is the Mantoux test, containing five tuberculin units administered intradermally. This test is read as millimeters of induration at 48 to 72 hours.

The definition of a positive TST is based on a variety of epidemiologic and clinical factors. Induration of greater than 15 mm is considered positive in children older than 4 years of age without specific risk factors. A TST of greater than or equal to 10 mm is positive in children younger than 4 years of age and in children with other medical conditions, including renal failure, diabetes, or malignancy. This is also considered positive in children with increased risk for exposure, including those residing in areas with a high prevalence of tuberculosis. An induration of greater than 5 mm is considered positive in children receiving immunosuppressive therapy or with underlying immunodeficiency conditions. This induration is also considered positive if one has close contact with a case of active tuberculosis or has clinical or radiographic evidence of the disease (Table 12.1).

Use of Anergy Testing

Up to 20% of patients with active tuberculosis have a negative TST at initial presentation. In the 1970s, the idea of evaluating negative tuberculin tests results by assessing reactions to a panel of unrelated antigens (such as candida or tetanus) was proposed. This concept ofanergy testing became a routine adjunct to tuberculin

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skin testing. Despite its widespread use, the validity of this approach has never been proved. The ability to respond to other antigens has been shown not to improve the reliability of a negative TST test. Studies have also shown that the results of anergy testing do not predict the risk for progression to active disease in either HIV-negative or HIV-positive patients. For this reason, routine anergy testing, used as a validation to tuberculin skin testing, is not recommended by most infectious disease specialists.

TABLE 12.1. Criteria for Positive Tuberculin Skin Test

Reaction

Population

1. Greater than 5-mm induration

1. Human immunodeficiency virus (HIV) positive

2. Radiographic evidence of tuberculosis

3. Contacts of contagious patients

4. Immunosuppressive individuals including organ transplantation and/or patients receiving ≥ 15 mg/d prednisone

2. Greater than 10-mm induration

1. Children younger than 4 yrs

2. Recent immigrants (i.e., within past 5 yrs) from high-prevalence countries

3. Residents of high-risk settings including nursing homes, jails, homeless shelters

3. Greater than 15-mm induration

1. Persons with no risk factors for tuberculosis

2. Children older than 4 yrs

Although Bacille Calmette-Guérin (BCG) vaccine is not routinely given in the United States, the pediatrician will need to interpret TST in children who have received this vaccine. After BCG vaccination, distinguishing a positive reaction secondary to latent infection from reactivity to BCG is difficult. One study found that only 8% of persons who had received BCG vaccine at birth had a positive TST 15 years later. It is for this reason that the American Academy of Pediatrics recommends the same criteria for TST interpretation in patients who have received BCG.

Booster Phenomenon

Reactivity from TST resulting from MTB exposure may actually decrease over time in some patients, resulting in a nonreactive test despite a history of past exposure and latent infection. In these cases, the stimulus of a tuberculin test may actually “boost” or increase the size of any subsequent TST. This positive TST may be misleading because it may suggest recent tuberculin conversion when in fact latent infection has been present for years. Adults who undergo annual TST, particularly health care workers, often undergo two-step testing on initial evaluation with a second TST administered 1 week after the initial test. In this way, the boosting phenomenon can be appropriately evaluated and not mistaken for a recent skin test conversion.

Management of Latent Infection

Children who have a positive TST require a chest x-ray. In children younger than 18 years of age with a positive TST and negative chest x-ray, the diagnosis of latent tuberculous infection is made. Monotherapy is acceptable only in the case of latent tuberculosis infection. Patients younger than 18 years of age who have latent infection with an isoniazid-sensitive organism are treated with isoniazid for 9 months. Latent infection with an isoniazid-resistant organism is treated with a 6-month course of oral rifampin. Children younger than 5 years of age have a very high risk for severe tuberculosis when exposed to a contagious index case. Even if such a child's first TST is negative, it is recommended that antituberculosis medication be given. Medication can then be discontinued if a second TST 3 months later remains negative and the child has no clinical signs of tuberculosis.

Previously, the Centers for Disease Control (CDC) recommended prophylaxis with pyrazinamide and ethambutol for patients exposed to isoniazid- and rifampin-resistant mycobacteria. Surveillance done by the CDC has reported numerous cases of severe liver injury in patients receiving this prophylaxis. The updated recommendation

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is for clinicians to practice extreme caution in treating latent infection with the combination of pyrazinamide and ethambutol, especially if there are risk factors for liver injury, including concurrent hepatotoxic medications or alcohol consumption. Patients who elect to take this regimen should be followed closely, both clinically and with frequent measurement of serum aminotransferase levels.

Active Tuberculous Infection

In a percentage of cases after exposure to MTB, the latent tuberculous infection can reactivate. At this point, the child is considered to have active tuberculous infection. It is important to note that there are a variety of clinical syndromes associated with active disease.

Common Clinical Manifestations of Active Pediatric Tuberculosis

·         Pulmonary disease

·         Miliary disease

·         Meningitis

·         Pleural effusion

Tuberculous Pneumonia

Epidemiology

The most common clinical manifestation of active pediatric tuberculous disease is pulmonary tuberculosis. Unlike adults who present with cavitary disease, pediatric pulmonary tuberculosis usually presents as hilar adenopathy.

Presentation

The hilar enlargement of pulmonary tuberculosis typically produces little or no symptoms in older children; up to 80% of children older than 5 years of age are asymptomatic. Unlike older children, infants with hilar adenopathy may become symptomatic. The smaller caliber of bronchi in infants is more easily compressed by the enlarging lymph nodes, and the progressive lymphadenopathy can cause obstruction with resultant air trapping and wheezing (Figs. 12.1 and 12.2).

Diagnosis

The diagnosis of pulmonary tuberculosis in the child often rests on a positive TST and a chest radiograph that shows pulmonary disease. Therefore, accurate radiographic diagnosis is crucial for correct diagnosis of pediatric pulmonary tuberculosis.

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When there is uncertainty about whether hilar adenopathy is present, computed tomography (CT) has been shown to be helpful in confirming the diagnosis.

 

FIG. 12.1. Large hilar adenopathy seen in child with tuberculosis.

 

FIG. 12.2. Early hilar adenopathy representing typical pediatric pulmonary tuberculosis.

Isolation of MTB from clinical specimens remains the gold standard for diagnosis. Isolation of MTB in children is more difficult than in adults, who frequently have cavitary disease and can produce large amounts of sputum for culture. An aggressive workup aimed at isolation of infective mycobacteria should always be attempted because this will guide subsequent therapy.

Even in tertiary medical centers, the diagnosis in children of MTB is confirmed by culture no more than 40% of the time. Bronchoalveolar lavage (BAL) yields a pathogen in about 20% of cases. The low yield for BAL is likely due to the specimen collected over a brief time period and only in selected pulmonary segments. The fact that children often swallow respiratory secretions can be used in the isolation of MTB. Gastric lavage of early-morning stomach contents contains material collected over an entire evening and can yield the positive culture in up to 50% of cases. A recent study also suggested that this procedure could be successfully done during serial outpatient visits, provided appropriate support systems were in place. The use of proper technique in the collection of gastric aspirate is crucial in maximizing the yield of this procedure. Gastric aspiration should be performed in the early morning when the patient has been without food for at least 8 hours. Stomach contents are aspirated first through an 8 French feeding tube. Following this, 30 mL of sterile water (not saline) is placed into the stomach and then removed and added to the first collection. Gastric pH should be neutralized within 30 minutes because MTB does not tolerate acid environments. Gastric pH is typically neutralized with a 10% sodium bicarbonate solution. Specimens need to be refrigerated and transported within 4 hours of collection.

Pulmonary Manifestations of Tuberculosis

1.   Hilar adenopathy is the most common manifestation.

2.   CT can help in the diagnosis.

3.   Gastric aspirate and BAL cultures.

Miliary Tuberculosis

Epidemiology

Miliary tuberculosis represents one of the most severe manifestations of tuberculosis. It represents unchecked dissemination of bacilli to secondary sites, including the liver, brain, and bones.

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Presentation

Fever, poor weight gain, and increased respiratory rate are common presenting signs of miliary tuberculosis. Patients with miliary disease may also have diffuse lymphadenopathy and organomegaly.

Diagnosis

Appearance of too-numerous-to-count nodules in the chest x-ray suggests miliary tuberculosis. The nodules may be visualized on CT of the brain even in the absence of cerebrospinal pleocytosis. It is important to realize that, in the setting of an ineffective immune response to tuberculosis, skin testing is frequently negative in miliary disease (Figs. 12.3 and 12.4).

In the setting of miliary disease, cultures bronchoscopy and gastric aspirate are often positive. Biopsy samples of affected organ sites, such as liver, lung, or bone marrow, can also yield the organism.

Miliary Tuberculosis

1.   Presentation may include fever, weight loss, or organomegaly.

2.   Initial TST may be negative.

3.   Central nervous system can be involved without meningitis.

4.   Steroids may be helpful if hypoxia is present.

 

FIG. 12.3. Chest radiograph showing too numerous to count lesions seen in military tuberculosis.

 

FIG. 12.4. Computed tomograph of the chest in a child with military tuberculosis.

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Tuberculous Meningitis

Etiology

Tuberculosis meningitis arises from hematogenous dissemination that forms tubercles in the brainstem. After reactivation, these foci may rupture, discharging bacilli into the spinal fluid. A thick exudate subsequently develops, which then impedes the flow of cerebrospinal fluid (CSF).

Presentation

A typical history for tuberculous meningitis is one of progressive lethargy and vomiting over several weeks as hydrocephalus develops and intracranial pressure increases. The chronicity of tuberculosis meningitis helps distinguish it from the more common self-limited pediatric illnesses, such as viral meningitis or gastroenteritis.

 

FIG. 12.5. MRI of brain showing hydrocephalous, brainstem inflammation in a child with tuberculosis meningitis.

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Diagnosis

In tuberculosis meningitis, CSF examination reveals several hundred cells, most of which are lymphocytes. Cerebrospinal glucose is low, and protein is often elevated. CT of the brain often shows basilar enhancement with hydrocephalus (Fig. 12.5). CT can also be helpful in suggesting the diagnosis because hydrocephalus is a rare occurrence in viral or uncomplicated bacterial meningitis. Acid-fast staining and culture of 1 mL of CSF rarely shows organisms; obtaining a larger volume of up to 15 mL and then cytocentrifuging this larger volume can result in positive acid-fast stain and culture in up to 90% of cases. Although there has been considerable experience in the use of nucleic acid amplification tests for the detection of MTB in respiratory specimens, the use of this technology in CSF is still investigational.

Tuberculous Meningitis

1.   Progressive history of lethargy and vomiting indicates increased intracranial pressure.

2.   Lymphocytic pleocytosis is found in CSF; profile can resemble viral meningitis.

3.   CSF glucose level is low in majority of patients.

4.   Chest radiograph is positive in 50% of patients; PPD is positive in 50% of patients.

5.   CT reveals hydrocephalus in 80% to 100% of patients.

6.   Ventriculoperitoneal shunting is often required.

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Tuberculous Pleural Effusion

Etiology

Tuberculous pleural effusion is secondary to rupture of subpleural foci into the pleural space. The rupture of subpleural foci into the pleural space 6 to 12 weeks after primary infection then promotes a delayed hypersensitivity response to the mycobacterial proteins, resulting in a pleural effusion.

Presentation

Patients can present with fever, cough, and pleuritic pain. Night sweats and hemoptysis are occasionally seen. The chest radiograph often reveals a unilateral pleural effusion (Fig. 12.6). The natural history of tuberculous pleural effusion is complete or significant clearance of the effusion, even without treatment. However, untreated patients have a high rate of developing active pulmonary or extrapulmonary disease within a year. Progression to active disease is greater in young children and immunocompromised patients.

Diagnosis

The diagnosis is suggested in a patient with a unilateral pleural effusion who has a history of exposure to tuberculosis. A one-time thoracentesis is usually indicated because it allows examination of the pleural fluid for diagnostic purposes and can help exclude other etiologies. The pleural fluid usually reveals several hundred cells, most of which are lymphocytes. Less than one third of patients have a positive acid-fast stain or acid-fast culture from pleural fluid. Yield of pleural biopsy is significantly higher and approaches 75%. Adenosine deaminase (ADA) is an enzyme involved in purine catabolism; high levels of ADA have been reported in pleural fluid of patients infected with tuberculosis. Elevated levels of ADA can also be found in patients with an increased number of lymphocytes in the pleural fluid; thus, patients

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with leukemias and lymphomas can have misleading results. Polymerase chain reaction for the detection of mycobacterial DNA in pleural effusions is increasingly performed and has a sensitivity of 70% with a specificity of 100%. Most patients with tuberculous pleural effusion have strongly reactive skin tests, and empiric treatment is often given to a patient with a unilateral pleural effusion, a strongly reactive TST, and no other obvious etiology for the effusion.

 

FIG. 12.6. Progressive unilateral pleural effusion seen in child with tuberculosis. Tuberculosis skin test strongly positive.

Pleural Effusion

1.   Progressive unilateral effusion is seen with lymphocytic predominance.

2.   PPD is often reactive.

3.   Natural history is of resolution with high incidence of subsequent pulmonary or extrapulmonary disease.

Management of Active Pediatric Tuberculosis

Critical to effective therapy of tuberculosis is the understanding of the presence of naturally occurring mutant organisms within a large population of tuberculous bacilli.

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Subpopulations of drug-resistant bacteria are always present within a population of drug-susceptible bacteria. Effective treatment of tuberculosis requires the administration of at least two drugs to which the bacilli is sensitive. If only one effective medication is given, secondary resistance develops within the entire bacilli population.

There was a time when effective two-drug therapy could be guaranteed with the administration of isoniazid and rifampin. The incidence of drug-resistant tuberculous disease continues to increase, largely the result of improper treatment and poor compliance. When initiating treatment for tuberculosis, one can no longer assume isoniazid sensitivity.

When initiating treatment, there should always be an aggressive workup to determine susceptibilities of the infecting mycobacteria. Often, this can be done by finding the index case and obtaining sensitivities on that isolate. This is successful in about one half of cases. If this process is unsuccessful, gastric aspirates and bronchoscopy are often used in an effort to isolate infecting organisms.

In an effort to ensure the use of at least two drugs to which the infecting organism is sensitive, the initial regimen often includes four drugs. The following is a summary of the front-line medications used in pediatric tuberculosis (Table 12.2):

  • Isoniazid.This drug is bactericidal and penetrates the CSF. Dosage is 10 to 15 mg/kg per day. INH is metabolized in the liver by acetylation. In children, there is no correlation between acetylation efficiency rate and the rate of adverse reaction. The side effects of hepatitis are extremely rare in children. The routine monitoring of liver function tests and vitamin supplementation in patients taking isoniazid alone is not recommended.
  • Rifampin.This drug is bactericidal and again metabolized by the liver. Dosage is 15 mg/kg per day. Major side effects include orange discoloration of body fluids and interference with oral contraceptives.
  • Pyrazinamide.This is a well-tolerated drug that penetrates the CSF well. The dose is 20 to 40 mg/kg per day. The major side effects, which are extremely rare, include hepatitis and an increase in uric acid levels.

TABLE 12.2. Front-line Therapy for Pediatric Tuberculosis

Drug

Daily dose (mg/kg/d)

Twice weekly dose (mg/kg/dose)

Adverse reactions

Isoniazid

15–25

20–30

1. Hepatitis

2. Peripheral neuropathy

Rifampin

10–20

10–20

3. Body secretion discoloration

4. Interference with oral contraception

Pyrazinamide

20–40

40–60

5. Hepatitis

6. Hyperuricemia

Ethambutol

15

25–50

7. Optic neuritis, decreased red-green color discrimination

Streptomycin (intramuscular)

20–40

20–4—0

8. Nephrotoxicity

9. Auditory and vestibular toxicity

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  • Ethambutol.Reports of optic neuritis, which manifests clinically as color blindness, previously precluded use in children because it was thought that children may not be able to verbalize any early visual changes. It has been shown that, at a lower dose of 15 mg/kg per day, the optic neuritis does not occur. Ethambutol is now considered the front-line fourth drug when a fourth drug is indicated.

Duration of Treatment

Using data from thousands of children being treated for tuberculous disease, the American Academy of Pediatrics has issued guidelines for treatment. A 6-month regimen consisting of isoniazid, rifampin, and pyrazinamide for the first 2 months, followed by isoniazid and rifampin for the remaining 4 months, is recommended for the treatment of drug-susceptible pulmonary MTB disease. Extrapulmonary tuberculosis, including meningitis and miliary disease, is generally treated for a total of 12 months.

Selected Readings

Abernathy RS. Tuberculosis: an update. Pediatr Rev 1997;18(2):50–8.

Janner D, Rutherford M, Azimi P. Tuberculous meningitis in children. Pediatr Emerg Care 1993;9(5):281–284.

Jasmer RM, Nahid P, Hopewell, PC. Latent tuberculosis infection. N Engl J Med 2002;347(23):1860–1866.

Lobato MN, Loeffler AM, Furst K, et al. Detection of Mycobacterium tuberculosis in gastric aspirates collected from children: hospitalization is not necessary. Pediatrics 1998;102(4):E40.

Neu N, Saiman L, San Gabriel P, et al. Diagnosis of pediatric tuberculosis in the modern era. Pediatr Infect Dis J 1999;18(2):122–126.

Slovis BS, Plitman JD, Haas DW. The case against anergy testing as a routine adjunct to tuberculin skin testing. JAMA2000;283(15):2003–2007.