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W2075887079 abstract "Despite the availability of effective antituberculosis drugs since 1952,tuberculosis remains an important cause of morbidity, mortality, and health care cost in the United States. Tuberculosis case rates declined at a rate of 6% annually for more than 20 years until 1985 when they leveled off(Fig. 1). Factors responsible for this include human immunodeficiency virus (HIV)infection; immigration of individuals from countries where tuberculosis rates are 10 to 30 times that of the United States; transmission of disease in hospitals, homeless shelters, and prisons; and poverty, overcrowded living, and poor access to medical care. While all this was occurring, funds for tuberculosis control by public health programs declined. Fortunately,the number of cases reported annually has decreased by 8.7% in the past 2 years, probably due to recently increased federal funds to public health programs.The Centers for Disease Control and Prevention (CDC) reported 24,361 cases of tuberculosis in the United States in 1994, a case rate of 9.4 cases per 100,000 population. This was a slight decline from 1993, but still is 9.7% more cases than reported in 1985. Foreign-born persons accounted for 31.9% of all cases of tuberculosis in 1994. The 1,695 cases of tuberculosis among children under 15 years of age accounted for almost 7% of the total. The continuing transmission of tuberculosis to children, the future reservoir of the disease, represents at least a partial failure of tuberculosis control efforts.Tuberculosis among children occurs primarily in minorities,particularly in large cities. Geographic areas that have case rates of tuberculosis above the national rate include most states in the southeast and south central United States, Hawaii, Alaska, New York, California, and Illinois. New York City leads the cities in reporting 161 cases of childhood tuberculosis in 1994, followed by Los Angeles with 145, Chicago with 75,Houston with 67, San Diego with 53, and Atlanta with 44. The nonuniformity of case distribution is illustrated by the fact that 87.5% of counties in the United States reported no tuberculosis cases among children younger than 15 years of age in 1994.In 1994, 60% of the 1,695 childhood cases of tuberculosis were younger than 5 years, 23% were foreign-born, and 85% were minorities. Blacks accounted for 33% and Hispanics for 38% of cases.Tuberculosis is transmitted when a person who has contagious tuberculosis coughs, sneezes, spits, or sings and releases infected droplets of mucus into the air. These become droplet nuclei of less than 5 mu, which may remain viable and suspended in the air for several hours. Several factors determine infectivity. A person who has a positive sputum smear for acid-fast bacilli is much more contagious than one who is culture-positive but sputum smear-negative. The presence of cough; high-volume, low-viscosity sputum; and prolonged duration of symptoms without any adequate treatment increases the risk. Exposure indoors under crowded living circumstances and when there is poor ventilation is more concentrated.Children who have tuberculosis have very few organisms in their lesions and usually do not cough or produce sputum. Therefore, they virtually never infect other children. Any childhood case represents transmission from an adult case of infectious pulmonary tuberculosis.The age and ethnic composition of adult cases of tuberculosis has developed a bimodal distribution over the past 20 years (Fig. 2). Non-Hispanic whites present primarily in old age,having acquired their infection many decades earlier. Patients from minority populations have their peak incidence of presentation between 20 and 45 years when they are more likely to live in homes that include small children. Minority adults are more likely to be medically indigent, intravenous drug users, or in prison. The most potent risk factor for the development of tuberculosis is infection with HIV, which also is increasing in the minority population. Whereas immunocompetent adults infected with the tubercle bacillus have a 5% to 10% chance of developing tuberculosis in their lifetime, an individual who has HIV infection has a 5% to 10% rate of developing the disease each year. Tuberculosis in the HIV-infected adult is fully contagious to children.Tuberculosis infection begins when the infected droplet nucleus reaches a pulmonary alveolus in the lung of a susceptible child. All lobar segments are equally at risk for becoming involved. The organism is ingested by a neutrophil or pulmonary macrophage,where it multiples at a slow rate. Within a few weeks there are enough bacilli to spread via the regional lymphatics to the hilar lymph nodes. A few organisms enter the bloodstream and are distributed throughout the body. Within 3 to 10 weeks of the initial implantation, specifically sensitized T lymphocytes begin to liberate lymphokines. Monocytes begin to migrate to the area, the host macrophages show increased capacity for phagocytosis and intracellular killing of the organism, and hematogenous dissemination stops. By this time, the tuberculin skin test is positive, and the primary complex may be visible on the chest radiograph.Making a positive diagnosis of tuberculosis in children is very difficult; positive cultures often are not obtained. The chest radiograph, however, may be very suggestive of the diagnosis. The diagnostic tools are shown in Table 1. The tuberculin skin test is the most specific readily available test. A positive reaction indicates infection with Mycobacterium tuberculosis. An asymptomatic child who has a positive reaction but a normal chest radiograph and physical examination is considered to be infected but without disease and would be a candidate for chemoprophylaxis. Symptoms, abnormal physical examination, or chest radiographic abnormalities suggestive of tuberculosis indicate disease and require multiple drug therapy.The Mantoux skin test, in which 0.1 mL of tuberculin solution containing 5 tuberculin units of purified protein derivative (PPD) is injected intradermally into the volar surface of the forearm to produce a 6- to 10-mm wheal, is the definitive diagnostic test for tuberculosis in children. A positive reaction is necessary to establish the diagnosis.Multiple-puncture skin tests have been used in the past to screen low-risk groups, but these have unacceptably high false-positive and false-negative rates. Because public health authorities strongly recommend that no skin test screening be performed on truly low-risk children, these tests no longer are needed.The Mantoux test is read as millimeters of induration found 48 to 72 hours after application of the test. Erythema is not significant. The importance of an accurate reading should be evident from the three levels of “positive” tuberculin reactions now existing (Table 2). The ballpoint pen method of measurement originally described by Sokol has been shown to be comparable to the palpation method when used by skilled, experienced skin test readers. It also was noted to be quicker. It is a reasonably reliable method of reading for busy pediatricians who read a positive skin test once a year or less. A medium ballpoint or felt-tip pen is used to approach the site of induration from above or distal to the area, slowly progressing until resistance is felt. The pen then is lifted and a similar procedure is carried out on the opposite side. The distance between the ends of the lines is measured in millimeters(Figs. 3A and 3B).False-positive reactions occur from cross-reactions to nontuberculosis mycobacterial (NTM)infections or following vaccination with bacillus Calmette-Guérin (BCG). If the latter is given in infancy, the PPD reading rarely exceeds 5 mm by 3 to 5 years of age, and reactions to NTM infections infrequently exceed 10 mm. The skin test will be negative before the child develops his or her tuberculin sensitivity after initial infection, but the child also will not show any evidence of disease. False-negative reactions can occur after viral infections or administration of live viral vaccines or in the presence of overwhelming tuberculosis, malnutrition, or immunosuppression due to lymphoma, HIV, or corticosteroids. The injection also may be given too deeply, not producing a superficial wheal in the skin, or the reading could be inaccurate. A Mantoux test given at the time of instituting corticosteroid therapy will be valid, and reactivity will be restored 7 to 10 days after the conclusion of the steroid course. Many children who are PPD-negative during acute tuberculosis infection will show reactivity after treatment. However, 5% of children who have culture-positive tuberculosis can show a persistently negative skin test. Therefore, one should never rule out tuberculosis on the basis of a negative skin test if other findings support the diagnosis.Induration of the PPD skin test more than 5 mm is considered positive if the child is a contact of an infectious case of tuberculosis, has an abnormal chest radiograph, or is HIV-infected or otherwise immunocompromised (Table 2). In other high-risk groups, induration of 10 mm or greater should be considered a positive reaction. This includes any child at risk for dissemination of disease, such as those younger than 4 years of age or those who have diabetes, chronic renal disease, or malnutrition. Also,children whose parents were born in high prevalence areas of the world are included in this high-risk grouping. Travel to areas of high prevalence also increases risk. Other environmental risks include being a medically indigent city dweller or being exposed to high-risk adults,such as those infected with HIV,users of illicit drugs, residents of prisons or nursing homes, homeless persons, or migrant farm workers. The American Academy of Pediatrics (AAP) states that for children older than 4 years who have none of these risk factors, a reaction must be 15 mm or greater to be positive. Because only a minority of children who have tuberculosis lack risk factors, probably 10 mm could be considered a positive reaction.Skin testing with 250 tuberculin units of PPD is not indicated. Control skin tests to assess anergy are only indicated in patients in whom immunosuppression is suspected or proven. Tetanus toxoid is the antigen used most widely in children for this purpose. These tests never are warranted in initial diagnostic evaluation for tuberculosis or in routine screening of high-risk children. In the past, greater reactivity to specific PPD antigens from NTM over the reaction to standard PPD suggested that cervical adenitis was due to NTM infection rather than to tuberculosis. Unfortunately, these NTM antigens currently are not available clinically for testing.After the tuberculin reaction becomes positive, a Ghon complex,consisting of a small parenchymal infiltrate and enlarged hilar lymph nodes, may be visible on the chest radiograph. Often, only the hilar nodes can be seen. This represents simple primary tuberculosis, usually an asymptomatic condition. It is essential to obtain lateral films to detect hilar adenopathy because even large nodes may not be seen easily on the posterioanterior (PA)view (Figs. 4A and 4B).Wallgren described the chronology of tuberculosis infection in children in Sweden(Fig. 5). The earliest complications of primary tuberculosis—miliary disease and tuberculosis meningitis—are the most deadly. They occur within a few months of the appearance of the primary lesion, which is why it is imperative to complete the diagnosis of childhood tuberculosis,particularly in the very young, and begin treatment without delay.Pleural effusion, rarely seen in children younger than 6 years,appears after about 6 months of infection. Tuberculous pleurisy usually causes a sudden onset of fever, chest pain, and shortness of breath. Physical findings include dullness to percussion and diminished breath sounds over the effusion. Symptoms may persist 1 to 3 weeks and can be alleviated by thoracentesis and drainage.Meanwhile, pulmonary infiltrates can continue to progress. As an enlarging hilar lymph node impinges on a nearby bronchus, infection spreads through the bronchial wall,penetrating the bronchus to cause endobronchial disease. In infants,partial bronchial obstruction can cause a ball-valve action, with distal airtrapping and hyperinflation of the lobe. Respiratory distress and loud wheezing often occur (Fig. 6). More commonly, the bronchus becomes completely obstructed, with resultant segmental collapse-consolidation(Fig. 7). Despite the very dramatic appearance of this lesion, these children rarely are very ill. If any symptom is present, it usually is cough. Abnormal findings on physical examination also are extremely rare. Finding a large pulmonary consolidation in a minimally ill child always suggests tuberculosis.Disease occurs after infection in only a small number of children between 5 years of age and adolescence; case rates are the lowest in this age range—approximately one fifth the rate for the entire population. However, following infection in the adolescent years, there is a much greater incidence of progression to adult-type chronic pulmonary disease, often within 1 to 2 years. This disease is identical to that seen in adults and is characterized by fever, cough, sputum production,and weight loss. The radiologic appearance is of classic upper lobe disease, often with a cavity. Organisms usually are found easily in the smear or by culture of the sputum.Scrofula, tuberculous cervical adenitis, is the most common tuberculous disease seen outside the chest cavity in children. It presents with large, nontender, rubbery, often multiple and matted anterior cervical or submandibular lymph nodes. Usually a course of antibiotics has been given without benefit. The diagnosis is made by demonstrating a positive PPD skin test. It is impossible to differentiate this disease from NTM adenitis. Excision of the infected node cures infection with NTM and also allows for confirmation of the diagnosis by culture. Biopsies are not advised because draining sinus tracts may ensue. Cervical adenitis in conjunction with a positive PPD always requires antituberculous chemotherapy.Skeletal tuberculosis develops in 1% to 6% of untreated children, but not until 1 to 3 years following primary disease. The vertebrae are affected in 40%; hips or knees are affected in fewer than 10%.Miliary tuberculosis usually occurs very early after primary infection in very young children. Symptoms may be minimal but usually include fever, loss of appetite, rapid breathing, and nearly always, a palpable spleen. Within 1 to 3 weeks of onset, multiple tiny miliary lesions can be seen uniformly throughout the lung fields and are most visible in the retrocardiac space on the lateral film. The PPD skin test usually is positive. Prior to the availability of drug therapy, most of these children eventually developed tuberculous meningitis and died. Now the prognosis,with treatment,is excellent. The cerebrospinal fluid always should be examined before initiating treatment.Tuberculous meningitis is the most serious form of tuberculosis; it also occurs soon after the primary infection. It is more common than pure miliary disease. Before medical therapy was available,all patients died. Even today, there is still significant mortality and a high incidence of serious neurologic residua if the child has stage III disease, with altered consciousness, at admission.Initial symptoms are nonspecific and include low-grade fever,anorexia,intermittent vomiting, irritability,apathy, and loss of interest in play. As the disease progresses to stage II, cranial nerve palsies,more vomiting, drowsiness, and seizures can occur. The neck is stiff to flexion in only one third of those affected; infants may have a bulging fontanelle. Characteristic findings in the cerebrospinal fluid are 50 to 500 cells/μL, which are polymorphonuclear leukocytes early and mononuclear cells later; an elevated protein level; and a glucose level less than 50% of that in the serum. The diagnosis of tuberculous meningitis is extremely difficult to make because 40% of children will have a negative tuberculin skin test, 25% to 50% may have normal chest films,and 67% of the source cases are not identified until after the child becomes ill. If the diagnosis is suspected, a trial of empiric treatment for tuberculosis is advisable.Recently, among 14,038 children followed at 70 National Institutes of Health-sponsored study sites for pediatric acquired HIV infection,75 children were found to have tuberculosis and 40 had positive PPD skin tests. Had the current criteria for a positive reaction in HIV-infected children been used (>5 mm induration), the latter figure no doubt would have been higher. Cultures from 47 adult source cases showed that 15% had isoniazid (INH) and rifampin (RIF) resistance. The case rates of tuberculosis ranged from 58/100,000 children at the centers opened in the early 1980s to 478/100,000 at 15 centers opened between 1990 and 1992. The overall case rate among children younger than 5 years in the United States is 5.5/100,000; in Houston, Texas, the rate is 20/100,000.The most definitive laboratory test for diagnosis of tuberculosis is the mycobacterial culture. In adults, isolating the organism confirms the diagnosis of tuberculosis, and drug susceptibility studies direct the therapy. If full bacteriologic information is available on the adult source case, cultures from the child add little to the management. However, if no source case is known, if the child is very ill, or if drug resistance is present in the community, every effort should be made to obtain cultures from the child. Unfortunately, this is not easy. The most reliable source for cultures from the lungs in young children is the gastric aspirate. The aspiration must be performed early in the morning, as the child is first awakening, before the stomach empties of the overnight accumulations of swallowed respiratory secretions. This necessitates keeping the child overnight in the hospital or an emergency department. Usually three gastric aspirates are recommended. The yield in positive cultures ranges from 40% to 60%. Sputum may be obtained from an older child. Cerebrospinal fluid from children who have tuberculous meningitis will yield positive cultures less than 50% of the time. Pleural or joint fluid usually has a low yield of positive cultures. Any biopsy or resected lymph node should be cultured.Newer culture methods are now available. The BACTEC radiometric system, now widely used in myco-bacterial reference laboratories,can grow mycobacteria from sputum specimens in 7 to 10 days. Unfortunately,most specimens from children have few organisms, and cultures sometimes take 4 to 6 weeks to grow. Identification of the organism as M tuberculosis, M avium complex, or M kansasii with a DNA probe of the BACTEC culture can be accomplished in 12 hours. Standard mycobacterial identification also should be undertaken. Drug susceptibility testing by a BACTEC method requires 7 days after full growth has been obtained.Recently, the usefulness of the polymerase chain reaction (PCR) was evaluated in a variety of specimens from 35 children who had tuberculosis and 28 controls. The 40% sensitivity was comparable to that seen with cultures, but the specificity was only 80%. Thus, although PCR was very rapid, it was not sufficiently reliable to diagnose tuberculosis among children.Routine complete blood counts and white blood cell differentials rarely aid in the diagnosis of tuberculosis. Liver function abnormalities suggest disseminated disease. Analysis of body fluids (cerebrospinal, pleural, or joint) that reveals lymphocytes, elevated protein levels, and decreased glucose levels suggests tuberculosis.Evaluation for tuberculosis is carried out on most children after they are identified as PPD reactors during contact investigation of active cases of the disease. A smaller group of children is evaluated because signs or symptoms suggest that they may have the disease. These children need to have the Mantoux skin test applied and a careful inquiry made about possible exposure to an adult who has contagious pulmonary tuberculosis. Both groups require PA and lateral view chest radiographs and appropriate laboratory tests and cultures. Even if cultures are positive, the information comes too late; treatment must be instituted on the basis of clinical and laboratory information that is quickly available. Families of children diagnosed because of clinical symptoms need to be referred to the local public health facility for evaluation of household contacts for evidence of disease or skin test reactivity.The microbiologic basis for treatment of tuberculosis is the characteristics of the tubercle bacillus as a slowly growing and frequently dormant organism that has a small subpopulation of naturally drug-resistant mutants. In large bacterial populations, as in cavitary disease, many mutants will be present, but treatment is successful if at least two drugs to which the population is sensitive are used. Formerly, treatment took as long as 18 months. After the discovery of RIF, it was found that if two bactericidal drugs (INH and RIF) were used, treatment could be shortened to less than 1 year, and much of it could be given twice weekly. This made directly observed therapy (DOT) feasible.If, due to patient or physician error, only a single drug is taken to which the organisms are sensitive, relapse will occur with organisms resistant to that drug. The use of tablets containing two or three medications would decrease this problem. Unfortunately, many patients have been found recently whose cultures contain bacilli resistant to both INH and RIF. A child can be infected with such organisms from his or her source case.The most effective way to prevent the emergence of drug resistance is to provide universal DOT. Communities that have used DOT for all their patients have demonstrated a decline in drug resistance in organisms cultured.INH is the agent used most widely. It is bactericidal, relatively nontoxic,and inexpensive. The major toxicity is hepatitis, which is rare in children, but may be more common in disseminated disease and in adolescents. Toxicity can be monitored by clinical symptoms and liver function tests taken only if symptoms develop. Pyridoxine metabolism may be affected, but in children,supplemental pyridoxine is needed only in those who have diabetes,uremia, malnutrition, or a seizure disorder or who are pregnant. Toxic serum levels of phenytoin may develop in the presence of INH. The syrup form of INH sometimes is absorbed poorly, can cause diarrhea,and in large doses (3 or 4 tsp a day)can be difficult to sustain for long periods. Placing crushed tablets in a bite of food or jam is a preferable method of administration.RIF is bactericidal and relatively nontoxic. It can cause gastrointestinal symptoms and hepatitis. A flu-like syndrome or thrombocytopenia are rare complications. The drug is excreted in urine, tears, sweat, and other body fluids, turning them orange, and can stain soft contact lenses. RIF induces hepatic microsomal enzymes, thereby accelerating the clearance of drugs such as glucocorticoids, theophylline,anticonvulsants, ketoconazole, and estrogens. The latter effect may render oral contraceptives ineffective. RIF is available in 150- and 300-mg capsules, which are suitable for the full dose range of 10 to 20 mg/kg. There is no commercial liquid preparation, and formulated syrups are not reliable.Streptomycin (SM) is available for the treatment of tuberculosis only through the CDC. It is given intramuscularly. Ototoxicity is its primary side effect, usually causing vertigo, but hearing loss can occur with prolonged use. Thus, hearing should be monitored. Occasionally,nephrotoxicity is seen.Pyrazinamide (PZA), an old drug newly rediscovered, was found to be so effective during the first 2 months of treatment that the overall treatment regimen could be reduced to 6 months. It is hepatotoxic and may cause hyperuricemia; in children, the latter rarely causes arthralgias.INH and PZA penetrate the cerebrospinal fluid readily. RIF and SM primarily penetrate inflamed meninges.Ethambutol (EMB) is used primarily when the likelihood of resistance to other drugs is high. At doses of 15 mg/kg, its effect is bacteriostatic, but it may be bactericidal at daily doses of 25 mg/kg. Because reversible retrobulbar neuritis causing red-green color blindness and loss of visual acuity may occur,vision should be screened monthly. A preliminary evaluation by an ophthalmologist is advisable if the higher dose (25 mg/kg) is used. Younger children, whose vision cannot be screened, should be given ethambutol only under the care of a tuberculosis specialist.The standard recommended treatment for tuberculosis in all forms and for all ages is a 6-month regimen consisting of INH, RIF, and PZA daily for 2 months followed by INH and RIF either daily or twice weekly for 4 additional months. If there is a good possibility of drug resistance, EMB or SM should be added until cultures and drug susceptibility studies become available. Children are at risk for being infected with drug-resistant organisms if exposed to a case caused by drug-resistant organisms. Other high-risk contacts include anyone who has had treatment with antituberculosis drugs or is from a foreign country or American community that has a high prevalence of drug resistance. The four-drug, 6-month regimen is effective even if the organism is INH-resistant.All treatment must be monitored closely. If there is any hint of noncompliance, DOT must be started. Treatment should not be extended on the basis of the chest radiograph findings; hilar adenopathy may persist for 1 to 3 years and large pulmonary infiltrates nearly as long. If the organism is resistant to INH and RIF, consultation should be obtained from a tuberculosis specialist.The official recommendation is that children who have miliary disease, bone and joint tuberculosis, or tuberculous meningitis receive a total of 12 months of treatment, with 10 months of INH and RIF following the initial 2 months of daily multi-drug treatment. No doubt experience soon will show that the shorter course is effective for these patients as well because all have a relatively small number of infecting organisms. A recent study on tuberculous meningitis from Thailand showed that a 6-month PZA-containing regimen was more efficacious than longer regimens without PZA.Prophylaxis is considered primary if the initial infection with M tuberculosis is prevented. The most effective method of prophylaxis is prompt diagnosis and appropriate treatment of all contagious active cases of tuberculosis in the community. The diagnosis of tuberculosis in pregnant women and appropriate treatment of their disease will prevent congenital or neonatally acquired disease in their infants. The placement of ultraviolet light fixtures 12 to 18 inches beneath the ceiling can decrease greatly contamination of room air by tubercle bacilli from an infectious case. Appropriate ventilation of indoor spaces from the outside also is helpful. Finally, INH can be given to tuberculin nonreactors who are in close contact with someone who has an infectious case of tuberculosis. The efficacy of this was proven in 1952 in South Africa where neonates, given INH from birth,never became infected from their tuberculous mothers.Vaccination with BCG does not prevent infection but does decrease the incidence of serious disease. A recent meta-analysis of the efficacy of BCG from the Harvard School of Public Health concluded that BCG vaccination in infancy decreases the risk for serious tuberculous disease by 50%. Although certainly not ideal, this vaccination is being considered for use in the United States for people who are nontuberculin reactors entering homeless shelters, health care workers exposed frequently to tuberculosis, and individuals exposed to multidrug-resistant tuberculosis. Indications for BCG vaccination of children in the United States are extremely limited. Any physician considering it should consult with the director of the local tuberculosis control program.Chemoprophylaxis with INH for tuberculin skin test-positive individuals—that is, secondary prevention—effectively prevents disease. It originally was given for 1 year, but recent studies from eastern Europe have shown that a 6-month regimen is almost as good and more cost-effective than a 12-month regimen. However, fewer than 6 months clearly is inferior. The AAP recommends a 9-month course. Much experience but no controlled trials suggest that INH given at the standard twice-weekly dose is as effective as daily dosing. If the source case is known to have INH-resistant organisms, RIF in a dose of 15 mg/kg may be given for 6 to 9 months. All PPD-positive children should receive chemoprophylaxis. This treatment should be monitored carefully because drug toxicity can occur.Ideally, a local public health facility and its related state organization should be able to diagnose and treat active tuberculosis and provide radiographs, cultures, free medication,and supervision by clinicians who are experts in the treatment of the disease. The public health nurses should be able to evaluate contacts fully on all new cases and supervise treatment, including DOT, when ordered. However, not all public health services provide all these services. It is the pediatrician’s responsibility to determine what the local health unit can do and encourage them to upgrade and improve their capabilities." @default.
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W2075887079 title "Tuberculosis: An Update" @default.
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