AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Tuberculosis (TB) is the most common cause of infection-related death worldwide. In 1993, the World Health Organization (WHO) declared TB to be a global public health emergency. Mycobacterium tuberculosis is the most common cause of TB. Other rare causes are Mycobacterium bovis and Mycobacterium africanum. Tubercle bacilli belong to the family Mycobacteriaceae and order Actinomycetales. The acid-fast characteristic of the mycobacteria is their unique feature. M tuberculosis is an aerobic, non–spore-forming, non-motile slow-growing bacillus with a curved and beaded rod-shaped morphology. It is a very hardy bacillus that can survive under adverse environmental conditions. Humans are the only known reservoirs for M tuberculosis.

Pathophysiology

TB occurs when individuals inhale the bacteria aerosolized by infected persons. The organism is slow growing and tolerates the intracellular environment, where it may remain metabolically inert for years before reactivation and disease. The main determinant of the pathogenicity of TB is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses. Among the several virulence factors in the mycobacterial cell wall are the cord factor, lipoarabinomannan (LAM), and a highly immunogenic 65-kd M tuberculosis heat shock protein. Cord factor is a surface glycolipid present only in virulent strains that causes M tuberculosis to grow in serpentine cords in vitro. LAM is a heteropolysaccharide that inhibits macrophage activation by interferon-gamma and induces macrophages to secrete tumor necrosis factor-alpha, which causes fever, weight loss, and tissue damage.

The infective droplet nucleus is very small, measuring 5 micrometers or less, and may contain approximately 1-10 bacilli. Although a single organism may cause disease, 5-200 inhaled bacilli are usually necessary for infection. The small size of the droplets allows them to remain suspended in the air for a prolonged period of time. Primary infection of the respiratory tract occurs as a result of inhalation of these aerosols. The risk of infection is increased in small enclosed areas and in areas with poor ventilation. Upon inhalation, the bacilli are deposited (usually in the midlung zone) into the distal respiratory bronchiole or alveoli, which are subpleural in location. Subsequently, the alveolar macrophages phagocytose the inhaled bacilli. However, these naïve macrophages are unable to kill the mycobacteria, and the bacilli continue to multiply unimpeded.

Thereafter, transportation of the infected macrophages to the regional lymph nodes occurs. Lymphohematogenous dissemination of the mycobacteria to other lymph nodes, the kidney, epiphyses of long bones, vertebral bodies, juxtaependymal meninges adjacent to the subarachnoid space, and, occasionally, to the apical posterior areas of the lungs. In addition, chemotactic factors released by the macrophages attract circulating monocytes to the site of infection, leading to differentiation of the monocytes into macrophages and ingestion of free bacilli. Logarithmic multiplication of the mycobacteria occurs within the macrophage at the primary site of infection.

A cell-mediated immune (CMI) response terminates the unimpeded growth of the M tuberculosis 2-3 weeks after initial infection. CD4 helper T cells activate the macrophages to kill the intracellular bacteria with resultant epithelioid granuloma formation. CD8 suppressor T cells lyse the macrophages infected with the mycobacteria, resulting in the formation of caseating granulomas. Mycobacteria cannot continue to grow in the acidic extracellular environment, so most infections are controlled. The only evidence of infection is a positive tuberculin skin test (TST) result. However, the initial pulmonary site of infection and its adjacent lymph nodes (ie, primary complex or Ghon focus) sometimes reach sufficient size to develop necrosis and subsequent radiographic calcification.

Most persons infected with M tuberculosis do not develop active disease. In healthy individuals, the lifetime risk of developing disease is 5-10%. In certain instances, such as extremes of age or defects in CMI (eg, human immunodeficiency virus [HIV] infection, malnutrition, administration of chemotherapy, prolonged steroid use), TB disease may develop. For patients with HIV infection, the risk of developing TB is 7-10% per year.

Progression of the primary complex may lead to enlargement of hilar and mediastinal nodes with resultant bronchial collapse. Progressive primary TB may develop when the primary focus cavitates and organisms spread through contiguous bronchi. Lymphohematogenous dissemination, especially in young patients, may lead to miliary TB when caseous material reaches the bloodstream from a primary focus or a caseating metastatic focus in the wall of a pulmonary vein (Weigert focus). Tubercular meningitis also may result from hematogenous dissemination. Bacilli may remain dormant in the apical posterior areas of the lung for several months or years, with later progression of disease resulting in the development of reactivation-type TB (ie, endogenous re-infection TB).

Frequency

United States

Approximately 15 million people are infected with M tuberculosis in the United States. The number of TB cases reported annually in the United States dropped 74% (ie, 84,304 to 22,201) between 1953 and 1985. Subsequently, resurgence in the number of TB cases was reported, with a peak of 26,673 cases in 1992. While the incidence increased by approximately 13% in all ages from 1985-1994, the rate among children younger than 15 years increased by 33%. This resurgence was attributed to the HIV epidemic, which increased the risk of developing active TB among persons with HIV and latent TB infection. Other contributory factors were emigration from developing countries and transmission in settings such as endemic hospitals and prisons.

Development of multidrug-resistant (MDR) organisms and deterioration of the public health infrastructure for TB services further contributed to the rise in the number of cases.

Recently, a 44% decrease in the incidence of tuberculosis in the United States from 1993-2003 has been noted, with the lowest number of cases reported in 2003 (14,874).The decline in case numbers since 1992 has been attributed to increased awareness of the disease, the institution of more aggressive preventive measures, improvement in health care strategies (eg, prompt identification and treatment of patients with TB), and highly active antiretroviral therapy for HIV-positive patients. Although the case rate has declined since 1992, a huge reservoir of individuals who are infected with M tuberculosis remains.

International

According to the WHO, more than 8 million new cases of TB occur each year. Currently, 19-43.5% of the world's population is infected with M tuberculosis. TB occurs disproportionately among disadvantaged populations, such as homeless individuals, malnourished individuals, and those living in crowded areas. According to the WHO, developing countries including India, China, Pakistan, Philippines, Thailand, Indonesia, Bangladesh, and the Democratic Republic of Congo account for nearly 75% of all cases of TB.

Mortality/Morbidity

The mortality rate from TB in the United States is currently 0.6 deaths per 100,000 individuals, which represents approximately 1,700 deaths per year and an annual mortality rate of approximately 7% per newly identified case. In 1953, the mortality rate was 12.5 per 100,000 individuals. This decrease in mortality is attributed to improved health care and prompt initiation of therapy. MDR-TB cases have a reported fatality rate of greater than 70%. Worldwide, deaths due to TB are estimated at 3 million per year.

Race

According to the Centers for Disease Control and Prevention (CDC), rates of TB are 10 times higher among Asians and Pacific Islanders, 8 times higher among non-Hispanic blacks, and 5 times higher among Hispanics, Native Americans, and Native Alaskans compared to non-Hispanic whites. However, race may not be an independent risk factor, and risk is best defined on the basis of social, economic, and medical factors as well.

Sex

TB equally affects females and males.

Age

An increased risk of mortality from TB exists at the extremes of age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• While the natural history of TB in children follows a continuum, the American Thoracic Society (ATS) definition of stages is useful:
• • Stage 1: Exposure has occurred, implying that the child has had recent contact with an adult who has contagious TB. The child has no physical signs or symptoms and has a negative TST result. The chest radiograph (CXR) does not show any changes at this stage. Not all patients who are exposed become infected, and it may take 3 months for the TST result to become positive. Unfortunately, children younger than 5 years may develop disseminated TB in the form of miliary disease or tubercular meningitis before the TST result becomes positive. Thus, a very high index of suspicion is required when a young patient has a history of contact.
  • Stage 2: This stage is heralded by a positive TST result. No signs and symptoms occur, although an incidental CXR may show the primary complex.
  • Stage 3: Tuberculous disease occurs and is characterized by the appearance of signs and symptoms depending on the location of the disease. Radiographic abnormalities also may be seen.
  • Stage 4: This stage is defined as TB with no current disease. This implies that the patient has a history of previous episodes of TB or abnormal, stable radiographic findings with a significant reaction to the TST and negative bacteriologic studies. No clinical findings suggesting current disease are present.
  • Stage 5: TB is suspected, and the diagnosis is pending.
• Asymptomatic infection: Patients with asymptomatic infection have a positive TST result but do not have any clinical or radiographic manifestations. Children with asymptomatic infection may be identified on a routine well-child physical examination, or they may be identified subsequent to TB diagnosis in household or other contacts (eg, children who recently have immigrated, adopted children).
• Disease evaluation: Any patient with pneumonia, pleural effusion, or a cavitary or mass lesion in the lung that does not improve with standard antibacterial therapy should be evaluated for TB. Also, patients with fever of unknown origin, failure to thrive, significant weight loss, or unexplained lymphadenopathy should be evaluated for TB.
• Pulmonary TB may manifest itself in several forms, including endobronchial TB with focal lymphadenopathy, progressive pulmonary disease, pleural involvement, and reactivated pulmonary disease. Symptoms of primary pulmonary disease in the pediatric population often are meager. Fever, night sweats, anorexia, nonproductive cough, failure to thrive, and difficulty gaining weight may occur.
• • Endobronchial TB with enlargement of lymph nodes: This is the most common variety of pulmonary TB. Symptoms are the result of impingement on various structures by the enlarged lymph nodes. Persistent cough may be indicative of bronchial obstruction, while difficulty in swallowing may result from esophageal compression. Vocal cord paralysis may be suggested by hoarseness or difficulty breathing.
  • Tubercular pleural effusion: Pleural effusions due to TB usually occur in older children and rarely are associated with miliary disease. Typical history reveals an acute onset of fever, chest pain that increases in intensity on deep inspiration, and shortness of breath. Fever usually persists for 14-21 days.
  • Progressive primary TB: Progression of the pulmonary parenchymal component leads to enlargement of the caseous area and may lead to pneumonia, atelectasis, and air trapping. This is more likely to occur in young children than in adolescents. The child usually appears ill with symptoms of fever, cough, malaise, and weight loss.
  • Reactivation TB: This condition usually has a subacute presentation with weight loss, fever, cough, and, rarely, hemoptysis. Reactivation TB typically occurs in older children and adolescents. The condition is more common in patients who acquire TB when aged 7 years and older.
• Extrapulmonary TB includes peripheral lymphadenopathy, tubercular meningitis, miliary TB, skeletal TB, and other organ involvement.
• • Lymphadenopathy: Patients with lymphadenopathy (ie, scrofula) may have a history of enlarged nodes. Fever, weight loss, fatigue, and malaise are usually absent or minimal. Lymph node involvement typically occurs 6-9 months following initial infection by the tubercle bacilli. More superficial lymph nodes commonly are involved. Frequent sites of involvement are the anterior cervical, submandibular, and supraclavicular nodes. TB of the skeletal system may lead to involvement of the inguinal, epitrochlear, or axillary lymph nodes.
  • Tubercular meningitis: One of the most severe complications of TB is tubercular meningitis. Tubercular meningitis develops in 5-10% of children younger than 2 years; thereafter, the frequency drops to less than 1%. A very high index of suspicion is required to make a timely diagnosis because of the insidious onset of the disease. A subacute presentation usually occurs within 3-6 months after the initial infection. Nonspecific symptoms such as anorexia, weight loss, and fever may be present. After 1-2 weeks, patients may experience vomiting and seizures or alteration in the sensorium. Deterioration of mental status, coma, and death may occur despite prompt diagnosis and early intervention.
  • Miliary TB: This is a complication of primary TB in young children. It may manifest subacutely with low-grade fever, malaise, weight loss, and fatigue. A rapid onset of fever and associated symptoms also may be observed. History of cough and respiratory distress may be obtained.
  • Bone or joint TB: This may present acutely or subacutely. Vertebral TB may go unrecognized for months to years because of its indolent nature.
  • Additional sites: Other unusual sites for TB include the middle ear, gastrointestinal tract, skin, kidneys, and ocular structures.
• Congenital TB is rare. Symptoms typically develop during the second or third week of life and include poor feeding, poor weight gain, cough, lethargy, and irritability. Other symptoms include fever, ear discharge, and skin lesions. To make a diagnosis of congenital TB, the infant should have proven TB lesions and at least one of the following:
• • Skin lesions during the first week of life, including papular lesions or petechiae
  • Documentation of TB infection of the placenta or the maternal genital tract
  • Presence of a primary complex in the liver
  • Exclusion of the possibility of postnatal transmission

Physical

• Primary TB is characterized by the absence of any signs on clinical evaluation. These patients are identified by a positive TST result. Tuberculin hypersensitivity may be associated with erythema nodosum and phlyctenular conjunctivitis.
• Signs of disease are dependent on the site involved (pulmonary or extrapulmonary).
• Pulmonary disease may manifest itself in several forms, including endobronchial TB with focal lymphadenopathy, progressive pulmonary disease, pleural involvement, and reactivated pulmonary disease.
• • Endobronchial disease: Enlargement of lymph nodes may result in signs suggestive of bronchial obstruction or hemidiaphragmatic paralysis. Vocal cord paralysis may occur as a result of local nerve compression. Dysphagia due to esophageal compression also may be observed.
  • Progressive primary pulmonary TB: This condition presents with classic signs of pneumonia, including tachypnea, nasal flaring, grunting, dullness to percussion, egophony, decreased breath sounds, and crackles.
  • Pleural effusion: Signs include tachypnea, respiratory distress, dullness to percussion, decreased breath sounds, and, occasionally, features of mediastinal shift.
  • Reactivation TB: Physical examination results may be normal or may reveal posttussive crackles.
• Extrapulmonary TB: Manifestations include peripheral lymphadenopathy, tubercular meningitis, miliary TB, skeletal TB, and other organ involvement.
• • Lymphadenopathy: This usually involves the anterior or posterior cervical and supraclavicular nodes. Less-commonly involved lymph nodes include: submandibular, submental, axillary, and inguinal lymph nodes. Typically, infected lymph nodes are firm and nontender with nonerythematous overlying skin. The nodes are initially nonfluctuant. Suppuration and spontaneous drainage of the lymph nodes may occur with caseation and the development of necrosis.
  • Tubercular meningitis: Three stages of tubercular meningitis have been identified.
    • Stage 1: No focal or generalized neurologic signs are present. Possibly, only nonspecific behavioral abnormalities are found.
    • Stage 2: This stage is characterized by the presence of nuchal rigidity, altered deep tendon reflexes, lethargy, and/or cranial nerve palsies. Tubercular meningitis most often affects the sixth cranial nerve, resulting in lateral rectus palsy. This is due to the pressure of the thick basilar inflammatory exudates on the cranial nerves or to hydrocephalus. The third, fourth, and seventh cranial nerves also may be affected. Funduscopic changes may include papilledema and the presence of choroid tubercles, which should be sought carefully.
    • Stage 3: This final stage comprises major neurologic defects, including coma, seizures, and abnormal movements (eg, choreoathetosis, paresis, paralysis of one or more extremities). In the terminal phase, decerebrate or decorticate posturing, opisthotonus, and/or death may occur. Patients with tuberculomas or tubercular brain abscesses may present with focal neurologic signs. Spinal cord disease may result in the acute development of spinal block or a transverse myelitis–like syndrome. A slowly ascending paralysis may develop over several months to years.
  • Miliary TB: Physical examination includes lymphadenopathy, hepatosplenomegaly, and systemic signs including fever. Respiratory signs may evolve to include tachypnea, cyanosis, and respiratory distress. Other signs, which are subtle and should be sought carefully in the physical examination, are papular, necrotic, or purpuric lesions on the skin or choroidal tubercles in the retina.
  • Bone TB: Common sites involved are the large weightbearing bones or joints including the vertebrae (50%), hip (15%), and knee (15%). Destruction of the bones with deformity is a late sign of TB. Manifestations may include angulation of the spine (gibbus deformity) and/or Pott disease (severe kyphosis with destruction of the vertebral bodies). Cervical spine involvement may result in atlantoaxial subluxation, which may lead to paraplegia or quadriplegia.
• Congenital TB: Signs of congenital TB include failure to thrive, icterus, hepatosplenomegaly, tachypnea, and lymphadenopathy.

Causes

Risk factors for the acquisition of TB are usually exogenous to the patient. Thus, likelihood of being infected depends on the environment and the features of the index case. However, the development of TB disease depends on inherent immunologic status of the host.

• Infection
• • The number of bacilli in the inoculum and the relative virulence of the organism are the major factors determining transmission of the disease. TB is transmitted by inhaling the tubercle bacilli.
  • The infectiousness of the source case is of vital importance in determining likelihood of transmission. Bacillary population of TB lesions varies and depends on the morphology of the lesion. Nodular lesions have 100-10,000 organisms, whereas cavitary lesions have 10 million to 1 billion bacilli. Thus, persons with cavitary lesions are highly infectious. Also, contacts of persons with sputum-positive smears have an increased prevalence of infection as opposed to contacts of those with sputum-negative smears.
  • Persons who have received anti-TB drugs are much less infectious than those who have not received any treatment. This decline in infectiousness is due primarily to reduction in the bacillary population in the lungs.
  • Environmental factors also contribute to the likelihood of acquiring the infection. The concentration of bacilli depends on the ventilation of the surroundings and exposure to ultraviolet light. Thus, overcrowding, congregation in prison settings, poor housing, and inadequate ventilation predispose individuals to the development of TB.
• Disease
• • Defects in cell-mediated immunity and level of immunocompetence are major determinants for development of disease.
  • HIV infection is one of the most significant risk factors for TB infection. Case rates for persons who are dually infected with HIV and M tuberculosis exceed the lifetime risk of persons with TB infection who are not infected with HIV.
  • Steroid therapy, cancer chemotherapy, and hematologic malignancies increase the risk of TB.
  • Malnutrition interferes with the CMI response and therefore accounts for much of the increased frequency of TB in impoverished patients.
  • Non-TB infections, such as measles, varicella, and pertussis, may activate quiescent TB.
  • Individuals with certain human leukocyte antigen (HLA) types have a predisposition to TB. Hereditary factors, including the presence of a Bcg gene, have been implicated in susceptibility to acquisition of TB.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Making the diagnosis of TB in children is extremely challenging because of the difficulty in isolating M tuberculosis. Definitive diagnosis of TB depends upon isolation of the organism from secretions or biopsy specimens.
• Despite innovations in rapid diagnosis, many of the classic diagnostic tools remain useful and continue to be used in the evaluation of patients with TB.
• Detection and isolation of the mycobacterium are accomplished as follows:
• • The initial step is to obtain appropriate specimens for bacteriologic examination. Examination of sputum, gastric lavage, bronchoalveolar lavage, lung tissue, lymph node tissue, bone marrow, blood, liver, cerebrospinal fluid (CSF), urine, and stool may be useful, depending on the location of the disease.
  • Gastric aspirates are used in lieu of sputum in very young children (<6 y) who usually do not have a cough deep enough to produce sputum for analysis.
  • • Using the correct technique for obtaining the gastric lavage is important because of the scarcity of the organisms in children compared to adults. An early morning sample should be obtained, before the child has had a chance to eat or ambulate, as these activities dilute the bronchial secretions accumulated during the night.
    • Initially, the stomach contents should be aspirated, and then a small amount of sterile water injected through the orogastric tube. This aspirate also should be added to the specimen.
    • Since gastric acidity is poorly tolerated by the tubercle bacilli, neutralization of the specimen should be performed immediately with 10% sodium carbonate or 40% anhydrous sodium phosphate. Even with careful attention to detail and meticulous technique, the tubercle bacilli can be detected in only 70% of infants and in 30-40% of children with disease.
  • Sputum specimens may be used in older children. Nasopharyngeal secretions and saliva are not acceptable. In older children, bronchial secretions may be obtained by the stimulation of cough by an aerosol solution of propylene glycol in 10% sodium chloride.
  • Bronchoalveolar lavage also may be used to provide bronchial secretions for detection of tubercle bacilli.
  • Decontamination of other microorganisms in the specimens obtained may be performed by the addition of sodium hydroxide, usually in combination with N-acetyl-L-cysteine. Other body fluids (eg, CSF, pleural fluid, peritoneal fluid) also can be centrifuged; the sediment can be stained and evaluated for presence of acid-fast bacilli (AFB). Smears of CSF are positive in fewer than 10% of patients in some series. Enhancement of the yield may be possible by staining any clot that may have formed in standing CSF specimens, as well as using the sediment of a centrifuged specimen. Increased yield also may be obtained from cisternal or ventricular fluid.
  • Obtain overnight urine specimens in the early morning. Send immediately for analysis since the tubercle bacilli tolerate the acidic pH of urine poorly.
• Staining of the specimen is as follows:
• • Since M tuberculosis is an AFB, staining of AFB provides preliminary confirmation of the diagnosis.
  • Staining also can give a quantitative assessment of the number of bacilli being excreted (eg, 1+, 2+, 3+). This can be of clinical and epidemiologic importance in estimating the infectiousness of the patient and in determining the discontinuation of respiratory isolation. However, for reliably producing a positive result, smears require approximately 10,000 organisms per milliliter. Therefore, in early stages of the disease or in children in whom the bacilli in the respiratory secretions are sparse, the results may be negative. A single organism on a slide is highly suggestive and warrants further investigation.
  • A significant drawback of AFB smears is that they cannot be used to differentiate M tuberculosis from other acid-fast organisms such as other mycobacterial organisms or Nocardia species.
  • Conventional methods include the Ziehl-Neelsen staining method. The Kinyoun stain is modified to make heating unnecessary. Fluorochrome stains, such as auramine and rhodamine, are variations of the traditional stains. The major advantage of these is that slides can be screened faster because the acid-fast material stands out against the dark, nonfluorescent background. However, fluorochrome-positive smears must be confirmed by Ziehl-Neelsen staining.
• Conventional growth techniques are as follows:
• • Culture of mycobacterium is the definitive method to detect bacilli. It is also more sensitive than examination of the smear. Approximately 10 AFB per millimeter of a digested concentrated specimen are sufficient to detect the organisms by culture.
  • Another advantage of culture is that it allows specific species identification and testing for recognition of drug susceptibility patterns. However, since M tuberculosis is a slow-growing organism, a period of 6-8 weeks is required for colonies to appear on conventional culture media.
  • Conventional solid media include the Löwenstein-Jensen medium, which is an egg-based medium, and the Middlebrook 7H10 and the 7H11 media, which are agar-based media. Liquid media (eg, Dubos oleic-albumin media) also are available, and they require incubation in 5-10% carbon dioxide for 3-8 weeks. These media usually have antibacterial antibiotics, which are slightly inhibitory for tubercle bacilli.
• Modern approaches in diagnosis are as follows:
• • Since mycobacteria require 6-8 weeks for isolation from conventional media, automated radiometric culture methods (eg, BACTEC) are increasingly being used for the rapid growth of mycobacteria. The methodology employs a liquid Middlebrook 7H12 medium containing radiometric palmitic acid labeled with radioactive carbon 14 (¹⁴C). Several antimicrobial agents are added to this medium to prevent the growth of nonmycobacterial contaminants. Production of ¹⁴CO₂ by the metabolizing organisms provides a growth index for the mycobacteria. Growth generally is detected within 9-16 days.
  • Another rapid method for isolation of mycobacteria is SEPTICHEK. This nonradiometric approach has a biphasic broth-based system that decreases the mean recovery time versus conventional methods.
  • Mycobacterial growth indicator tubes (MGITs), which presently are used as a research tool, have round-bottom tubes with oxygen-sensitive sensors at the bottom. MGITs indicate microbial growth and provide a quantitative index of M tuberculosis growth.
• Identification of species is as follows:
• • M tuberculosis can be reliably differentiated from other species on the basis of culture characteristics, growth parameters, and other empiric tests. M tuberculosis produces heat-sensitive catalase, reduces nitrates, produces niacin, and grows slowly. Serpentine cording is demonstrated on smears prepared from the BACTEC system.
  • Addition of p-nitro-acetyl-amino-hydroxy-propiophenone (NAP) inhibits the growth of M tuberculosis complex (including M bovis and M africanum) but does not inhibit growth of other mycobacteria. This provides the basis for the NAP differentiation test.
  • Chromatographic analysis of mycobacterial cell wall lipids can provide further speciation. The most useful approaches include gas-liquid chromatography and high-performance liquid chromatography (HPLC). The unique mycolic acid pattern associated with the species can be detected by the chromatographic separation of the ester. A significant drawback of these methods is the requirement of bacterial colonies grown in conventional solid media, a process that takes at least 3 weeks. However, the recent combination of HPLC with fluorescence detection has made the method more sensitive, thus BACTEC broth culture can be used instead of conventional solid media. This may make the method comparable to the NAP and AccuProbe tests. The expense of the initial equipment limits the availability of HPLC.
• Nucleic acid probes are used as follows:
• • Since biochemical methods are time-consuming and laborious, nucleic acid hybridization using molecular probes has become widely accepted. Commercially available probes, including the AccuProbe technology, help advance identification of the M tuberculosis complex. Sensitivity and specificity approach 100% when at least 100,000 organisms are present.
  • The basic principle is the utilization of a chemiluminescent, ester-labeled, single-strand DNA probe. A luminometer is used to assess the chemiluminescence.
  • Positive test results should be reported as M tuberculosis complex because the probe does not reliably differentiate between M tuberculosis and other members of the complex (eg, M bovis). Final identification to species level is required because pyrazinamide should not be included in the treatment regimen if the isolate is M bovis.
  • Niacin production, nitrate reduction, pyrazinamidase, and susceptibility to thiophene-2-carboxylic acid hydrazide can help differentiate between M bovis and M tuberculosis.
• Polymerase chain reaction (PCR) and other amplification tests are used as follows:
• • Nucleic acid amplification allows the direct identification of M tuberculosis in clinical specimens, unlike the nucleic acid probes, which require substantial time for bacterial accumulation in broth culture.
  • The US Food and Drug Administration has approved 2 tests, the amplified M tuberculosis direct test and the AMPLICOR M tuberculosis test. The AMPLICLOR test targets the DNA. The most commonly used target sequence for the detection of M tuberculosis has been the insertion sequence IS6110. The amplified M tuberculosis direct test is an isothermal transcription-mediated amplification that targets RNA.
  • Although amplification techniques are promising tools for the rapid diagnosis of TB, several caveats remain. Contamination of samples by products of previous amplification and the presence of inhibitors in the sample may lead to false-positive or false-negative results.
  • Although the sensitivity and specificity of the nucleic acid techniques in smear-positive cases exceed 95%, the sensitivity of smear-negative cases varies from 40-70%. Thus, discordance between the acid-fast smear result and the nucleic acid amplification techniques requires careful clinical appraisal and judgment.
• A new test, Quantiferon (QFT-g), has been recently approved (May, 2005) by the US Food and Drug Administration (FDA). The test is an enzyme-linked immunoassay (ELISA) test, which basically detects the presence of interferon gamma release protein (IFN-g) from the blood of sensitized patients when incubated with the early secretory antigenic target-6 (ESAT6) and culture filtrate protein 10 (CFP10) peptides. The test is as sensitive as, and more specific than, the tuberculin skin test and has been recommended as a screening tool in all situations where the tuberculin skin test has been used (ie, for diagnosing disease as well as infection).
• M tuberculosis drug susceptibility is determined as follows:
• • Because of the emergence of MDR organisms, determination of the drug susceptibility panel of an isolate is important so that appropriate treatment can be ensured.
  • Numerous chromosomal mutations are associated with drug resistance. Genotypic methods now being evaluated to identify these mutations include DNA sequencing, solid phase hybridization, and PCR–single-strand combination polymorphism analysis.
  • Mutations of the catalase peroxidase gene katG, the inhA gene involved in fatty acid biosynthesis, the ahpc gene, and the oxyR gene have been identified as major determinants for isoniazid (INH) resistance.
  • Resistance to rifampin is determined by mutations in the rpoB gene encoding the beta subunit of the RNA polymerase.
  • Phenotypic susceptibility assays, which remain experimental, employ mycobacteriophages to type the mycobacteria grown in the presence of antituberculous agents.
• Serology is as follows:
• • M tuberculosis increases the levels of antibody titers in the serum.
  • No available serodiagnostic test for TB has adequate sensitivity and specificity for routine use in diagnosing TB in children.

Imaging Studies

• Chest radiograph
• • Chest radiograph (CXR) is a classic diagnostic tool when evaluating patients for pulmonary TB.
  • Initial studies include posteroanterior and lateral views. Apical-lordotic and oblique views may be helpful if further evaluation of the extent of lung involvement is indicated (eg, patients with apical lesions or extensive hilar adenopathy).
  • If pleural effusion is present, lateral decubitus views aid in the determination of the nature of effusion (ie, free moving, loculated).
• Computed tomographic scan and magnetic resonance imaging
• • CT scan and MRI are not routinely indicated when CXR findings are unremarkable.
  • However, in patients with pulmonary TB, these imaging studies can help demonstrate hilar lymphadenopathy, endobronchial TB, pericardial invasion, and early cavitations or bronchiectasis.

Other Tests

• The TST is a widely used diagnostic test for evaluation of patients who have symptoms of TB or in whom infection with M tuberculosis is suspected. Although the sensitivity and the specificity of the TST are less than 100%, no better diagnostic test is widely available.
• The American Academy of Pediatrics (AAP) has issued the following guidelines for pediatric testing:
• • Immediate skin testing is indicated for the following children:
    • Those who have been in contact with persons with active or suspected TB
    • Immigrants from countries in which TB is endemic (eg, Asia, Middle East, Africa, Latin America) or children with travel histories to these countries
    • Those who have radiographic or clinical findings suggestive of TB
  • Annual TST is indicated for the following children:
    • Children who are infected with HIV or those living in a household with persons infected with HIV
    • Incarcerated adolescents
  • Testing at 2- to 3-year intervals is indicated if the child has been exposed to high-risk individuals including those who are homeless, institutionalized adults who are infected with HIV, users of illicit drugs, residents of nursing homes, and incarcerated adolescents or adults.
  • Testing when children are aged 4-6 years and 11-16 years is indicated for the following children:
    • Children without risk factors residing in high-prevalence areas
    • Children whose parents emigrated from regions of the world with a high prevalence of TB or who have continued potential exposure by travel to the endemic areas and/or household contact
  • Performing an initial TST before the initiation of immunosuppressive therapy is recommended in any patient.
• Administration of TST is as follows:
• • The recommended TST is the Mantoux test. The dosage of 0.1 mL or 5 TU purified protein derivative (PPD) should be injected intradermally into the volar aspect of the forearm using a 27-gauge needle. A detergent called Tween 80 to prevent loss of efficacy on contact and adsorption by glass stabilizes the PPD. A wheal should be raised and should measure approximately 6-10 mm in diameter.
  • Skilled personnel always should read the test 48-72 hours after administration. Measure the amount of induration and not erythema. This should be measured transverse to the long axis of the forearm.
  • Multiple puncture tests (eg, tine test, Heaf test) lack sensitivity and specificity and hence are not recommended.
• The CDC and the AAP have provided recommendations on the size of the induration created by the TST that is considered a positive result and indicative of disease. The TST is interpreted on the basis of rule of 5, 10, and 15 mm.
• • Induration of 5 mm or more is considered a positive TST result in the following children:
    • Children having close contact with known or suspected contagious cases of the disease, including those with household contacts with active TB whose treatment cannot be verified before exposure
    • Children with immunosuppressive conditions (eg, HIV) or children who are on immunosuppressive medications
    • Children who have an abnormal CXR finding consistent with active TB, previously active TB, or clinical evidence of the disease
  • Induration of 10 mm or more is considered a positive TST result in the following children:
    • Children who are at a higher risk of dissemination of tuberculous disease, including those younger than 5 years or those who are immunosuppressed because of conditions such as lymphoma, Hodgkin disease, diabetes mellitus, and malnutrition
    • Children with increased exposure to the disease, including those who are exposed to adults in high-risk categories (eg, homeless, HIV infected, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized persons); those who were born in or whose parents were born in high-prevalence areas of the world; and those with travel histories to high-prevalence areas of the world
  • Induration of 15 mm or more is considered a positive TST result in children aged 5 years or older without any risk factors for the disease.
• False-positive reactions and false-negative results can have various causes.
• • False-positive reactions often are attributed to asymptomatic infection by environmental nontuberculous mycobacteria (due to cross-reactivity).
  • False-negative results may be due to vaccination with live-attenuated virus, anergy, immunosuppression, immune deficiency, or malnutrition. Other factors that may cause a false-negative result include improper administration (eg, subcutaneous injection, injection of too little antigen), improper storage, and contamination. PPD has been recognized to have an initial false-negative rate of 29%.
• The following are important when administering the TST to prior recipients of bacille Calmette-Guérin (BCG) vaccine:
• • Immunization with BCG is not a contraindication to the TST. BCG vaccination is used in many parts of the world, especially in developing countries.
  • Differentiating tuberculin reactions caused by vaccination with BCG versus reactions caused by infection with M tuberculosis is difficult. History of contact with a person with contagious TB or emigration from a country with a high prevalence of TB suggests that the positive results are due to infection with M tuberculosis. However, multiple BCG vaccinations may increase the likelihood that the positive TST result is due to BCG vaccination. The positive reactivity caused by BCG vaccination generally wanes with the passage of time. With the administration of TST, this positive tuberculin reactivity may be boosted.
  • A prior BCG vaccination does not affect interpretation of a TST result for a person who is symptomatic or in whom TB is strongly suspected.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The ATS and CDC have provided standard guidelines for the treatment of TB. The ultimate goal of treatment is to achieve sterilization of the TB lesion in the shortest possible time. The general rule is strict adherence to TB treatment regimens for a sufficient period of time. To prevent the emergence of resistance, the regimens for the treatment of TB always should consist of multiple drugs.

Current recommendations for the treatment of pulmonary TB include a 6-month course of INH and rifampin, supplemented during the first 2 months with pyrazinamide. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) may need to be included in the initial regimen until the results of drug susceptibility studies are available. Drug susceptibility studies may not be required if the risk of drug resistance is not significant. Significant risk factors include residence in a community with greater than 4% primary resistance to INH, history of previous treatment with anti-TB drugs, history of exposure to a drug-resistant case, and origin in a country with a high prevalence of drug resistance. The purpose of this recommendation is to decrease the development of MDR-TB in areas where primary INH resistance is increased.

Another treatment option is a 2-month regimen of INH, rifampin, and pyrazinamide daily, followed by 4 months of INH and rifampin twice a week. Effective treatment of hilar adenopathy when the organisms are fully susceptible is a 9-month regimen of INH and rifampin daily or a 1-month regimen of INH and rifampin once a day followed by 8 months of INH and rifampin twice a week.

Since poor adherence to these regimens is a common cause of treatment failure, directly observed therapy (DOT) is recommended for treatment of TB. DOT means a health care provider or other responsible person must watch the patient ingest the medications. Intermittent regimens should be monitored by DOT for the duration of therapy because poor compliance may result in inadequate drug delivery.

• Most cases of extrapulmonary TB, including cervical lymphadenopathy, can be treated with the same regimens used to treat pulmonary TB. Exceptions include bone and joint disease, miliary disease, and meningitis.
  • For these severe forms of drug-susceptible disease, the recommendation is a regimen of 2 months of INH, rifampin, pyrazinamide, and streptomycin once a day, followed by 7-10 months of INH and rifampin once a day.
  • The other recommended regimen is 2 months of INH, rifampin, pyrazinamide, and streptomycin, followed by 7-10 months of INH and rifampin twice a week. Streptomycin may be administered with initial therapy until drug susceptibility is known.
  • Consider administering capreomycin or kanamycin instead of streptomycin in patients who may have acquired TB in areas where resistance to streptomycin is common.
• Optimal therapy for TB in children with HIV infection has not been established.
• • According to the current guidelines provided by the CDC, effective treatment of TB for patients infected with HIV should include DOT and consultation with a specialist.
  • Use of a regimen that uses rifabutin instead of rifampin has been advised when treating HIV disease and TB simultaneously. This situation may occur (1) when antiretroviral treatment is recommended for a newly diagnosed HIV infection in a patient with active TB or (2) when a patient with active TB has established HIV infection, and continuation of antiretroviral therapy is recommended. This recommendation is based on the fact that the use of rifampin with protease inhibitors or nonnucleoside reverse transcriptase inhibitors is contraindicated.
  • The treatment regimen for TB initially should include at least 3 drugs and should be continued for at least 9 months. INH, rifampin, and pyrazinamide with or without ethambutol or streptomycin should be administered for the first 2 months. Treatment of disseminated disease or drug-resistant TB may require the addition of a fourth drug.
• Therapy for drug-resistant TB is as follows:
  • Infection caused by MDR organisms, defined as organisms resistant to at least INH and rifampin, has reached critical levels worldwide.
  • Two categories of drug resistance exist, primary and secondary. Primary resistance is defined as the occurrence of resistance to anti-TB treatment in an individual who has no history of prior treatment. Secondary resistance involves the emergence of resistance during the course of ineffectual anti-TB therapy.
  • Risk factors for the development of primary drug resistance include patient contact with drug-resistant contagious TB, residence in areas with a high prevalence of drug-resistant M tuberculosis, birth outside the United States, ethnicity other than non-Hispanic white, young age, HIV infection, and the use of intravenous drugs.
  • Secondary drug resistance reflects patient nonadherence to the regimen, inappropriate drug regimens, and/or interference with absorption of the drug.
  • The current guidelines endorsed by the CDC state that if a child is at risk of or has disease resistant to INH, at least 2 drugs to which the isolate is susceptible should be administered.
  • Another important management principle is to never add a single drug to an already failing regimen. The resistance pattern, toxicities of the drugs, and patients' responses to treatment determine duration and the regimen selected.
  • The initial treatment regimen for patients with MDR-TB should include 4 drugs. At least 2 bactericidal drugs (eg, INH, rifampin), pyrazinamide, and either streptomycin or another aminoglycoside (also bactericidal) or high-dose ethambutol (25 mg/kg/d) also should be incorporated into the regimen.
  • Six-month treatment regimens are not advocated for patients with strains resistant to INH or rifampin. Intermittent therapy with twice-a-week regimens also is not recommended.
  • In the instance of isolated INH resistance, the 4-drug, 6-month regimen should be started initially for the treatment of pulmonary TB. INH should be discontinued when resistance is documented. Continue pyrazinamide for the entire 6-month course of treatment.
  • In the 9-month regimen, INH should be discontinued upon the documentation of isolated INH resistance. If ethambutol was included in the initial regimen, continue treatment with rifampin and ethambutol for a minimum of 12 months. If ethambutol was not included, then repeating susceptibility tests is advocated, as are discontinuation of INH and the addition of 2 new drugs (eg, ethambutol and pyrazinamide).
  • Resistance to both INH and rifampin presents a complex problem that often necessitates consultation with a specialist. It is preferable to at least continue the initial drug regimen (with 2 drugs to which the organism is susceptible) until bacteriologic sputum conversion is documented; then administer at least 12 months of 2-drug therapy. The role of new agents such as quinolone derivatives and amikacin in MDR cases remains unclear.
• Management of a neonate whose mother or other household contact has TB is as follows:
• • The AAP and CDC guidelines advocate avoidance of separation of the mother and infant if possible. Authorities have endorsed the following recommendations:
    1. The mother has a positive TST result and no evidence of current disease: Since the positive TST result may be evidence of an unrecognized case of contagious TB within the household, careful screening and evaluation of the other members of the household should be performed. Perform a Mantoux test when the infant is aged 4-6 weeks and 3-4 months. Consider administration of isoniazid (10 mg/kg/d) to the infant if the family cannot be promptly tested.
    2. The mother is having current disease but is noncontagious at delivery: In this situation, separation of the mother and infant is not necessary, and the mother can breastfeed the infant. Evaluation of the infant includes CXR and Mantoux test at age 4-6 weeks; if negative, a repeat test is warranted at age 3-4 months and at age 6 months. INH should be administered even if the TST result and CXR do not suggest TB because sufficient CMI to prevent progressive disease may not develop until age 6 months.
    3. The mother has current disease and is contagious at delivery: In this situation, separation of the mother and infant is recommended until the mother is noncontagious. The rest of the management is the same as for category 2.
    4. The mother has hematogenous spread: Congenital TB is possible in this scenario. Promptly perform a Mantoux test and CXR, and immediately begin treatment for the infant. INH should be administered until the infant is aged 6 months, at which time evaluation of the infant with a TST should be repeated. If the TST result is positive, the infant should be treated with INH for a total of 9 months.
• Monitoring for adverse effects is as follows:
  • Adverse effects of INH (eg, hepatitis) are rare in children; therefore, routine determination of serum aminotransferase levels is not necessary.
  • Consider monthly monitoring of hepatic function tests in the following patients: (1) those with severe or disseminated TB; (2) those with concurrent or recent hepatic disease; (3) those receiving high daily doses of INH (10 mg/kg/d) in combination with rifampin, pyrazinamide, or both; (4) women who are pregnant or within the first 6 weeks postpartum; (5) those with clinical evidence of hepatotoxic effects; and (6) those with hepatobiliary tract disease from other causes.

Surgical Care

Pulmonary resection in patients with TB may be required in drug-resistant cases because of the high likelihood of failure of the medication regimen. Surgical resection also may be required in patients with advanced disease with extensive caseation necrosis. Hemoptysis, though rare in children, may necessitate surgical intervention. Tubercular abscesses and bronchopleural fistulae also should be removed surgically.

Consultations

Infectious diseases consultation may be helpful.

Diet

Diet is as tolerated.

Activity

The advisability of bed rest varies with the type and severity of the disease. No limitation of activity is required in patients with TB infection or asymptomatic primary pulmonary TB. Severely ill patients with miliary TB and tubercular meningitis may require complete bed rest.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Antituberculous medications kill mycobacteria, thereby preventing further complications of early primary disease and progression of disease. However, disappearance of caseous or granulomatous lesions does not occur even with therapy.

Antitubercular drugs are classified as first-line and second-line drugs. First-line drugs have less toxicity with greater efficacy than second-line drugs. All first-line agents are bactericidal with the exception of ethambutol.

First-line agents include rifampin, isoniazid (INH), pyrazinamide, ethambutol, and streptomycin. Second-line agents are capreomycin, ciprofloxacin, cycloserine, ethionamide, kanamycin, ofloxacin, levofloxacin, and para-aminosalicylic acid.

INH and rifampin are effective against bacilli in necrotic foci and intracellular populations of mycobacteria. Streptomycin, aminoglycosides, and capreomycin have poor intracellular penetration. MDR-TB is defined as resistance to at least INH and rifampin. The emergence of drug-resistant strains has necessitated use of second-line agents.

Naturally drug-resistant organisms occur with a frequency of approximately 10^-6; however, individual resistances may vary. The resistance to streptomycin is 10^-5, to INH is 10^-6, and to rifampin is 10^-8. The chance that an organism is naturally resistant to both INH and rifampin is on the order of 10^-14. Because populations of this size do not occur in patients, organisms naturally resistant to 2 drugs are essentially nonexistent. If only a single medication is administered to a patient with TB, the subpopulations susceptible to that medication are destroyed, but the other categories continue to multiply. Thus, the use of multiple agents in the treatment of TB is essential.

Drug Category: Antitubercular drugs

Antimycobacterial agents are a miscellaneous group of antibiotics whose spectrum of activity includes Mycobacterium species. They are used to treat TB, leprosy, and other mycobacterial infections.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Public health authorities should be notified of all cases of TB.
• DOT is mandatory for the treatment of patients with coexistent HIV disease, those with MDR-TB, and those who may be noncompliant.
• A regular follow-up appointment every 4-8 weeks should be scheduled to ensure compliance and to monitor the adverse effects of and response to the medications administered. Adherence to the regimen is of vital importance to its success. Therefore, every measure should be taken to provide language-specific and culturally appropriate material to ensure compliance. Clear and written instructions regarding the timing of medication and the quantity to be administered should be provided.
• Monitoring of liver function test results is not indicated routinely. However, it may be requi