Figure 1. Tuberculosis death rates for selected years, 1932-72. (Adapted from Edwards.
Figure 2. Tuberculosis case rates for selected years, 1932-72. (Adapted from Edwards.4)
Tuberculosis, the "white plague" of the past, has shown a sharp decline in Western countries during the past 40 years, and there is real hope that it will be completely eradicated in the not too distant future.
The revolutionary advances in control of the disease have followed the discovery of its cause, development of BCG (bacille CalmetteGuérin) vaccine, major advances in chemotherapy, and the implementation of better health and socioeconomic conditions in many countries.
While active cases of tuberculosis have disappeared in most communities, tuberculosis is still a major health problem in the ghetto areas of large cities and throughout many countries of Asia, Africa, and Central and South America. The World Health Organization estimates that more than 15 million persons now have active tuberculosis.1
The progress of control measures can be seen in a comparison of the statistics. In the United States, early in the 19th century, there were 400 deaths from tuberculosis annually per 100,000 people. By 1932, as the BCG vaccine became widely used, the death rate had dropped to 63 per 100,000. In the 1950s, with the development of chemotherapy, the death rate dropped precipitously - from 16 per 100,000 in 1952 to 5 per 100,000 in 1962, to 1.8 per 100,000 in 1974,2 and to 1.5 in 19763 (Figure 1).
Figure 3. New active tuberculosis case rates by county. Averages for 1973 through 1975. Courtesy oí the Center for Disease Control, Tuberculosis Control Division. (The 1974-76 chart is now being prepared.)
Figure 4. Tuberculosis infection by age group. (Adapted from Tuberculosis Program Reports.1)
The development of chemotherapy, of course, meant a sharp drop not only in the death rate but also in the incidence. In 1932, new active cases of tuberculosis totaled 76.7 per 100,000 in the United States. The rate had fallen to 55.4 per 100,000 in 1952 and to 16.1 per 100,000 by 19724 (Figure 2). Last year there were 32,105 active cases of tuberculosis in the United States, a case rate of 15 per 100,000,5 or 1.5 cases for every 10,000 people (Figure 3).
The epidemiology of tuberculosis has changed; it is no longer a disease of the general population. Today tuberculosis is seldom seen in children, and it has become a disease of older people; 85 per cent of the cases develop in persons more than 25 years of age (Figure 4).
While the overall incidence is low in children, it is relatively high in children living in the ghetto areas of some cities. For example, we carried out several studies of the incidence of tuberculosis in the ghettos of Puerto Rico from 1955 to 1957* Eighty-one per cent of the tuberculous children hospitalized in the Alejandro Ruiz Solder Sanatorium came from the slum of La Perla; that is, four out of every five cases of active tuberculosis that had brought about hospitalization were traceable to just one slum area.
In this study, more than 500 children living in a slum were skin-tested in house-to-house visits. The Vollmer patch method was used initially, and positive reactors were confirmed by the standard 5-tuberculin-unit purifiedprotein-derivative Mantoux test. We found 10.4 per cent of the babies under one year of age to be positive reactors, but the percentage rose dramatically with age until, by the time they were five, 88.9 per cent of the children were positive reactors.* Children living outside the slum areas fared quite differently; there were 2 per cent positive reactors among those less than one year of age, with the percentages ranging upward to 18 per cent for the five-year-olds.
Following this study, the U.S. Public Health Service funded similar studies in ghetto areas of Philadelphia, Savannah, New Orleans, and Houston. Working with local agencies in each city, we tested between 1,000 and 1,500 preschool children ranging in age from under one year to six. We found that the percentage of positive reactions did not exceed 3.5 per cent, indicating that there is a definite correlation between higher living standards and a low incidence of infection.7
M. tuberculosis. Since the discovery of the acid-fast bacillus Mycobacterium tuberculosis by Koch in 1882, the human tubercle bacillus has remained the primary pathogenic organism causing tuberculous infections in human beings. Five strains of M. tuberculosis have been identified - human, bovine, avian, murine, and piscine - but only the human and bovine strains are pathogenic to man. The bovine tubercle bacillus, once a major cause of infections, has almost been eradicated in the United States. It remains a major pathogen in many countries where tuberculosis of cattle still exists.
Atypical mycobacteria. In recent years more knowledge has been obtained about another group of mycobacteria, known as unclassified or atypical mycobacteria.8 These bacteria not only resemble M. tuberculosis in appearance but also may cause similar lesions. They are indistinguishable on smear tests from M. tuberculosis but can be identified by culture and also by niacin test. The latter is positive for M. tuberculosis but negative for unclassified mycobacteria.
Atypical mycobacteria can be found in soil (which is believed to be the principal source of infection), water, saliva, sputum, and the infected lymph nodes of both human beings and animals. In contrast to M. tuberculosis, atypical mycobacteria cannot be transmitted from one person to another or by animal contact.
Infections with atypical mycobacteria have been found most frequently in the central, Southwestern, and Southeastern states. They have also been found in many other parts of the world.
CLASSIFICATION OF ATYPICAL MYCOBACTERIA
More than 20 species of atypical mycobacteria have been identified. They have been classified by Runyon9 into the groups listed in Table 1.
While the lung is the main focus of infection in adults, in children the presence of these organisms is most often characterized by infections of the lymph glands - particularly the cervical, submandibular, and preauricular nodes. There are also occasional cases of skin infection from swimming pools where M. balnei is present. It is important to keep in mind that even though large numbers of positive reactors to the atypical mycobacteria will be found, few of the children will develop disease.
Purified protein derivatives (PPD) have been prepared from these organisms. They are labeled PPD-B for the Battey antigen, PPD-G for the Cause, and PPD-Y for the M. kansasii bacillus (yellow). Skin testing is performed by the Mantoux method. Cross- reaction s occur between the antigen of PPD-S and the atypical antigens. A person with a doubtful or weak reaction to PPD-S (e.g., 5-9 mm.) may produce a larger reaction to the atypical antigens, or vice versa. Unfortunately, the unclassified mycobacteria are resistant to an t ituberculous medication. Although responses to rifampin for the treatment of certain strains causing lymph-node disease in children have been reported, surgery remains the treatment of choice for certain patients with cavitary pulmonary disease and lymph-node infection that fails to respond to chemotherapy.
Tuberculosis has not yet disappeared. New cases are still reported yearly. The main route of spread is the inhalation of tubercle bacilli.
Wells first introduced the concept of the "droplet nucleus."10 Particles may be expelled from a person with active pulmonary tuberculosis by coughing, sneezing, and talking. These particles gradually evaporate, leaving a nucleus that can be as small as 1-10 mg. - small enough to remain airborne around the room for several hours. These small droplets may be inhaled down to the alveoli and may produce a tuberculous infection.11 Fortunately, larger particles carrying large numbers of tubercle bacilli are heavy enough to fall to the floor. When inhaled, they settle on the upper airways or trachea and can be removed easily by expectoration or swallowing, without producing infection. An ordinary cough may produce up to 3,500 droplets, while sneezing may expel up to a million droplet nuclei.
The main source of infection for children is an adult or adolescent with active pulmonary disease. Among infants or young children, the source is usually a member of the immediate family.12 Among children of school age, a teacher or an older student with active disease may be the source of infection. Occasionally, the source is a maid, baby-sitter, or caretaker. Children with primary pulmonary tuberculosis are generally considered noninfectious and are usually placed in general wards unless a cavitary complication is present. Most children with primary lesions are asymptomatic except for fever, cough less than adults, and have a small amount of sputum and few if any colonies on culture. Adults usually become noninfectious, and isolation may be discontinued after two weeks of therapy.13
There are many factors that may predispose a child to a tuberculous infection.14 So far, however, there is no proof of a genetic factor.
Age is an important factor for prognosis. Owing to the lack of resistance, the younger the child (especially an infant), the higher the risk.
Race has been considered to play a role, since higher infection and death rates are seen in various racial groups. As was mentioned previously, the rate of new active cases for the U.S. population has dropped to 10 per 100,000; but the rate among the nonwhite population, especially among those in large urban centers, has been estimated to be as high as 50 to 100 cases per 100,000 people. A recent study among black children in Philadelphia showed that the new case rate for tuberculosis was as high as 177/100,000/ year.15 High rates are also seen among American Indians and Eskimos, whose lower socioeconomic levels are linked to poorer environmental conditions and inadequate nutrition.
Sex plays a role. Preadolescent and adolescent girls have a higher mortality and are more apt to develop reinfection tuberculosis.
Other factors that may have an effect on tuberculosis, by lowering the resistance and reactivating an old tuberculous lesion, include acute or chronic infectious diseases. Measles and pertussis are well known for their effect. Unusual physical or mental stresses and steroids have also been described as factors that lower resistance to tuberculosis.16
The lung is the main portal of entry. Bacilli carried by droplet nuclei enter the respiratory track, are lodged in the alveoli, invade the tissues, and start to multiply. If the person has been previously infected by tubercle bacilli, the tissues have been already sensitized and the body attempts to localize the infection. In an uninfected person, however, these multiplying tubercle bacilli find an exit through the lymphatics and infect the regional lymphatic glands. They multiply, invade the bloodstream, and are carried throughout the body. This is the usual course of the primary infection in children.
The lower lobes of the lung are most often involved. The so-called primary tuberculous complex is produced by three components - the primary focus, where the tubercle bacilli initially settle; the lymphatics that carry them; and the regional glands, which also become infected.
An immune response - manifested by a positive tuberculin test - usually develops within two to eight weeks after the initial infection. When this happens, a perifocal reaction occurs around the primary focus and is associated with enlargement of the regional glands. A chest x-ray may reveal the primary lesion and the enlarged regional hilar or paratracheal nodes.14
The progress of these primary lesions is benign in most cases. Many of the bacilli are destroyed, and healing occurs mainly through calcification. Healing both of the primary focus and of the lymphatic glands is usually completed within a year.
Some infected patients, however, may develop clinical tuberculosis, particularly when there has been hematogenous dissemination of tubercle bacilli during the postprimary period (i.e., before immunity has developed) to other tissues and organs. About 3 per cent of recent tuberculin converters may thus develop the disease within the first year after infection. The five-year infection rate ranges from 5 to 15 per cent; thereafter, the infection rate drops to within 3 to 5 per cent for the rest of one's life.17
Certain parts of the body are particularly vulnerable to postprimary bloodstream settings: the upper lobes of the lungs, the epiphyseal lines of the bones, the kidneys, the cerebral cortex, and the meninges. Bacteria may die at these new foci or may produce disease soon after invasion; or they may remain quiescent for many years, only to become reactivated in old age.
Progressive primary tuberculosis is another condition that is occasionally seen in children. This occurs when a primary focus, instead of healing, progresses by becoming larger and caseous. The caseous material liquefies and is evacuated into the bronchi, allowing the infection to spread to other parts of the lungs and producing a tuberculous pneumonia. X-ray may indicate a cavity. The reasons for this severe complication are not yet fully known.
Tuberculous endobronchitis is another common manifestation of an early stage of tuberculosis in children. This occurs when there has been an extension of the disease to the bronchial wall from the surrounding tuberculous lymph nodes. As a result, the involved mucosa of the bronchus become swollen and granulomatous, ulcerative lesions develop. Occasionally there is a polyp formation. This causes narrowing and sometimes complete obstruction of the bronchus, producing hyperaeration or atelectasis of the involved segment or lobe. Diagnosis is clarified by chest x-ray, bronchogram, and especially bronchoscopy. Bronchiectasis may develop in some patients.
Undoubtedly, the child's immunologie response to infection with either M. tuberculosis or atypical mycobacteria is important in the pathogenesis of the disease. Despite many decades of study, the relationship between hyper sensitivity (as manifested by the tuberculin test) and acquired resistance to tuberculosis remains unclear.
The immunologie process in tuberculin reactions is cell-mediated immunity or delayed-type hypersensitivity.* The classic method of demonstrating cell-mediated immunity is to inject an antigen intradermally. A sensitized person will have an inflammatory reaction in the form of a wheal at the injection site, which reaches its peak within 24 to 48 hours.
The T cells - lymphocytes derived from the thymus - are the mediators of cellmediated immunity in human beings. These cells secrete various lymphokines, which act against foreign "invaders"; they are, for example, the killer cells of graft rejection. They are cytotoxic. The T cells, responsible for immunologie memory, attract the macrophages and polymorphonuclear phagocytes that form the first line of defense against an invading antigen.
Communication between lymphocytes takes place via a "transfer factor," and it is in this way that specific sensitivity to tuberculin can be transferred from one lymphocyte to another.
The tuberculin-sensitized lymphocyte responds to the antigen by growing into a large blastlike cell that rapidly divides. It thus gives rise to many other cells sensitized to tuberculin. A migration-inhibitory factor is also produced, and this keeps the macrophages clustered around the M. tuberculosis organisms. Lymphokines are then released to slowly destroy the mycobacterium.
As all pediatricians know, tuberculin sensitivity correlates poorly with immunity to M. tuberculosis. That is, while tuberculin skin testing is useful for case finding, it may or may not reflect immunity.18 The discrepancy is thought to reflect variations in the immuneresponse genes in different individuals. M. tuberculosis probably has several antigens, each with different genetic control. P antigens are proteins that stimulate B and T cells and produce both tuberculin hyper sensitivity and protection. The C antigen of the mycobacterium is a carbohydrate - an antigen controlled by genes different from those controlling P antigens. " Non resp onde rs" do not respond to C antigen. "Responders" have increased susceptibility to tuberculosis, owing to the presence of im mune- response genes controlling the response to C antigen by the formation of an anti-C antibody; this interferes with the defense against this organism by inhibiting the activation of macrophages by lymphocytes and by coating the bacilli preventing phagocytosis by macrophages. Note that the anti-C antibody interferes with development of an immune response to tuberculin; it has nothing to do with delayed-type hypersensitivity. Thus, when BCG vaccine - an altered organism containing no C antigen at all - is injected intra dermalry, it will be effective in protecting both "responders" and "nonresponders" to C antigen.19
Early detection of tuberculosis forms the basis for both effective treatment of the patient and prevention of the spread of the disease. There are many ways to discover the disease. Tuberculin testing remains the primary tool of detection even though its efficacy has been questioned. (Proven tuberculous patients have at times been found to have a negative tuberculin test,20 but this has usually been due to using material of low potency.21 Additional possible causes are discussed below.)
As we have seen, the tuberculin test demonstrates a delayed-type hypersensitivity produced by cell-mediated immune response. The tests in common use a few years ago - the old tuberculin, the patch, and the Heaf tests -have all been replaced by the tine test and the Mantoux test. The tine test is a quick screening method that is less painful than earlier ones; its results can be verified by the intracutaneous Mantoux test using PPD. Polysorbate 80 (T ween® 80) is added to the PPD solution to produce a "stabilized" tuberculin solution.22
Because biologic activity of PPD varies from batch to batch, it has been biologically standardized for potency in terms of international tuberculin units (TU). For mass screening purposes, intermediate strength, or 5 TU of PPD, gives the best results. On rare occasions, what is known as "first strength" solution (1 TU of PPD) is used; this is the weakest solution. The strongest solution, known as "second strength," is 250 TU of PPD; it is likely to cause severe necrotic reactions at the injection site of tuberculin-positive subjects. The 1-TU solution is sometimes used in testing highly allergic persons, even though there is a possibility of a number of false- negatives. The 250-TU solution is useful when it is necessary to completely exclude a diagnosis of tuberculosis after a negative test has resulted from 5-TU PPD.
The tine test, less specific than an intradermal test, has the advantage of requiring less skill in administration and is used extensively in clinics and physicians* offices. The fourpronged "needle" used in the test is disposable, and the test is quick and less painful than the screening methods it has displaced. The test is considered positive if one or more of the four punctures develops a papule of at least 2 mm. of induration within 72 hours.
To confirm a tine test as positive, the Mantoux test is used. An intradermal injection of 0.1 ml. of tuberculin (5 TU of PPD) is made in the flexor or extensor surface of the forearm. The Mantoux test is read 48 to 72 hours after injection. A reaction of 10 mm. or more of induration is a definite positive reaction; one of 5-9 mm. is considered doubtful, and the test is repeated. When the test is repeated, it is worthwhile to skin-test the person with specific unclassified antigens at the same time. A larger reaction to the latter (i.e., more than 10 mm. of induration) will help in the differential diagnosis.
Occasionally, even after a second test, the reaction will be doubtful (and may well be due to cross- react ion with atypical mycobacteria). In these cases, the patient should be considered infected if (1) there is x-ray evidence, (2) the person has had definite contact with an active case of tuberculosis, or (3) he lives in an area where atypical reactions are not usual.23
A reaction is negative if the induration is smaller than 4 mm. As noted above in the discussion of the immunology of tuberculosis, the size of the person's positive reaction has no relation to the activity or duration of the disease. Rather, it is a reflection of the individual's sensitivity to the tuberculin. However, some studies have indicated that the size of the reaction may have some prognostic value.
Sometimes a patient who is infected with M. tuberculosis will produce a negative tuberculin reaction. The cause of such a falsenegative may be technical, due to poor testing materials or techniques (i.e., subcutaneous injection). Patients who are severely ill may give a negative tuberculin result. A false- negati ve may also come from children recently vaccinated for measles or rubella or who have an intercurrent infection of either. Patients receiving corticosteroids or immunosuppressive drugs and patients with such diseases as sarcoidosis or Hodgkin's disease will have a depressed tuberculin reaction. It should also be borne in mind that skin testing during the incubation period of active tuberculosis - two to eight weeks after the initial infection - will also give a negative result.
Infants and children should be tested for tuberculosis routinely, beginning between nine and 12 months of age and continuing annually thereafter. Testing should be more frequent if the child is in contact with someone who has an active case of tuberculosis. A tuberculin test should be withheld for six weeks if the child has recently been vaccinated against measles, mumps, rubella, polio, smallpox, or influenza.
Once a person tests positive to the tuberculin test, he will remain positive for years -possibly for life. Thus, periodic retesting is not indicated. A few of these patients, however, may develop a negative reaction later in life, regardless of whether or not they have received antituberculosis medications. This reversion to negative is more likely to be seen in patients who initially had a positive tuberculin reaction without developing any x-ray evidence or other signs of a tuberculous lesion.
As with some other DTH reactions, delayed hypersensitivity to tuberculin may wane in some patients as they grow older. In these cases, what would otherwise be a positive reaction will become doubtful or even negative. In some of these patients, the stimulation caused by repeated tuberculin testing may "boost" the size of the reaction. Obviously, when such repeated testing is done, care will have to be taken in interpreting the results.
Figure 5. Primary tuberculosis with enlarged hilar nodes, right.
Confirmation of tuberculosis is made by a positive culture for M. tuberculosis. Sputum and gastric and other secretions should be collected and tested before initiation of chemotherapy. Because children produce very little sputum or swallow it, the contents of a gastric lavage done early in the morning are used for culture. Recently, electronic nebulizers - e.g., Mistogen®* - for sputum induction have been used in clinics and offices. These machines can easily be used by children, who breathe cold mist directly from a nozzle attached to the nebulizer transducer. Secretions are collected into a sputum container when patients attempt to clear their throats or expectorate deep mucus.
A positive smear of sputum or other secretions is only presumptive evidence of tuberculosis, since unclassified mycobacteria give similar results. Sensitivity studies should be done on every positive culture. At times, guinea-pig inoculations can be utilized for detection of tuberculosis.
Once a positive tuberculin test has been obtained, x-ray follow-up is important. (Mass x-ray screening, so helpful in the past, has been discontinued. The yield had become too low to make it justifiable,24 the cost was relatively high, and it had the added disadvantage of exposing large numbers of people to radiation unnecessarily.)
Histologie and culture evaluation of materials obtained by biopsy and surgical resection can be another aid in the diagnosis of tuberculosis. Obscure disease has been clarified by histopathologic detection of the characteristic lesions of tuberculosis.
Tuberculosis in children may be present in any form and may affect almost any part of the body. The manifestations, complications, diagnosis, and treatment vary with respect to different age groups.
A brief discussion of the various forms of tuberculosis follows.14
Figure 6. Primary tuberculosis with bilateral hilar enlargement.
Over 90 per cent of primary tuberculosis affects the lungs. A primary focus of the intestines, with a primary complex involving the mesenteric glands, is rarely seen today, owing to the elimination of tuberculous disease of cattle. A primary infection of the skin, with involvement of the regional lymphatic glands, is still seen occasionally.
As was described earlier, the tubercle bacilli, which settle in the lung, start to multiply and spread through the lymphatics to the regional tracheobronchial glands. After an incubation period ranging from two to eight weeks, the tuberculin test becomes positive. Generally, a child with primary tuberculosis is asymptomatic. Occasionally, symptoms and signs resembling an infection of the upper respiratory tract - with slight cough, fever, and fatigability - may be present. Physical examination gives essentially negative results. However, in case of progressive primary tuberculosis with cavitation, spread, and development of tuberculous pneumonia, the child appears acutely ill, with high fever, frequent cough, respiratory distress, and at times apathy. On physical examination, dullness to percussion and moist rales can be elicited. Children with endobronchial involvement produce a harsh, brassy cough, at times resembling croup.
The diagnosis of primary tuberculosis is based mainly on a positive tuberculin reaction and x-ray picture of the lungs. The primary focus is usually invisible, but if visualized, it may look like a round density 1-2 cm. in diameter. The tracheobronchial glands are generally enlarged in children, either on one side or bilaterally (Figures 5 and 6). When healing takes place, a calcine density may be visualized on the site of the primary focus; more likely, one or more irregular densities will be seen in the hilar or paratracheal areas (Figure 7). Clouding due to obstruction of one or more segments or lobes may be present on x-ray film for months - or, sometimes, for more than a year - with generally slow resolution until re-aeration takes place. At times, however, the obstructed area shrinks and may end in development of bronchiectasis. Bronchoscopy may help in the diagnosis of the endobronchial lesions, and bronchograms may detect bronchiectasis. The roentgenogram of a child with a progressive primary disease initially demonstrates a cavitary lesion and later, if it is not treated, mottlings and bronchopneumonic lesions in the same lung or in both lungs.
Figure 7. Primary tuberculosis, calcified (primary focus and hilar nodes).
Figure 6. Miliary tuberculosis.
Figura 8. Chronic pulmonary tuberculosis in an adolescent.
Hematogenous spread. As was mentioned in the section on pathogenesis, there are postprimary seedings through the lymphatic system and the bloodstream to various parts of the body. Clinically, most of these seedings may remain asymptomatic and quiescent. At times, however - depending on the frequency of the spread, the number of tubercle bacilli involved, and their toxicity - they may produce various clinical manifestations, ranging from mild illness with lymph-node, spleen, and liver enlargement and low-grade fever to the severe illness seen with miliary tuberculosis and meningitis.
Acute miliary tuberculosis, which is usually seen in infants, is an early complication of tuberculosis. It is produced by a massive invasion of the bloodstream by tubercle bacilli. They disseminate in every organ of the body and become lodged in the capillaries, forming tubercles with caseation. Clinically, the child appears acutely ill with high fever, resembling sepsis, and has enlargement of spleen, liver, and lymph nodes and choroid tubercle formations. As the disease progresses, the child may become dyspneic, and fine crepitant rales may be heard in both lungs. On x-ray, the lungs show fine mot t lings, bilaterally, of less than 2 mm. (Figure 8). If not treated, the child usually dies within three months.
Chronic Pulmonary Tuberculosis
Chronic pulmonary tuberculosis is seen primarily in adolescents and adults, so it is often described as "reinfection" or "adult tuberculosis." Most cases are endogenous, rather than being caused by an exogenous reinfection. Studies have shown that 90 per cent of the cases of chronic pulmonary tuberculosis occur in patients who have been infected with tuberculosis in the past.17,25
When chronic pulmonary tuberculosis develops in a person, bacteria that have settled in the apices of the lungs during the postprimary seeding start to reactivate after a period of quiescence. Tuberculous bronchopneumonia develops and spreads through the bronchi to other parts of the lungs. Usually there is no lymphatic or hematogenous spread, since the tissues have already been sensitized to tuberculin. The infection, consequently, is localized.
Clinical symptoms can vary, depending on whether the disease is minimal or advanced. In a minimal case, the only symptoms may be low-grade fever, slight cough, and anorexia. In advanced stages of the disease, however, the patient will have lost a considerable amount of weight, coughs frequently (at times with hemoptysis), has a high fever, and produces large amounts of sputum in which many tubercle bacilli can be easily found. Roentgenographic lesions may vary from small homogeneous or linear densities or mottlings to larger areas of clouding with cavity formations (Figure 9).
This condition is unusual in young children. It almost always involves one side and most of the time originates from extension of the lung lesion to the pleura; occasionally, it may be caused by hematogenous spread. The symptoms may vary from chest pain with breathing to signs of respiratory distress, when considerable pleural fluid has accumulated; fever may also be present. There is dullness on percussion and decrease or absence of breath sounds on auscultation. On x-ray there is a homogeneous clouding covering part or all of the lung, depending on the amount of fluid. The fluid is usually absorbed within three weeks, and the only evidence remaining is a thickened pleura.26 Aspiration of fluid is made only for diagnostic purposes; if dyspnea occurs, as much fluid as possible should be removed to permit re-expansion of the lung.
Tuberculous meningitis is an early complication of primary tuberculosis, commonly seen in infancy.27 Before the advent of chemotherapy, death usually occurred within three weeks of onset. The meninges are involved by the spread of tubercle bacilli into the subarachnoid space from caseous foci in the cerebral cortex, by tuberculoma, or by direct extension from lesions of the vertebrae or mastoids. Hematogenous infection of the meninges may also occur. Tubercles and exudate over the brain, especially at the base of the brain and the brain stem, may involve various cranial nerves; hydrocephalus may also be caused by obstruction of the basal cisterns.
The symptoms vary according to the stage of the disease, each lasting about one week. In the initial stage the symptoms are vague, with slight fever and irritability; this is followed by the second stage of neurologic manifestation, with signs of meningeal irritation, drowsiness, convulsions, and encephalitis. By the third stage the child will have proceeded to coma and rigidity, with opisthotonos and cranial nerve palsies.
Diagnosis is based on the history, the positive tuberculin, the above-mentioned symptoms and signs, and, mainly, the findings in the cerebrospinal fluid - increased CSF pressure, increased WBC (predominantly lymphocytes), increased protein, and decreased sugar. The fluid is clear but easily forms a pellicle, which may reveal tubercle bacilli by smear or culture.
Before chemotherapy, tuberculous meningitis was 100 per cent fatal. Today complete recovery is obtained, especially if treatment is started early. However, certain patients may have residua with palsies and mental retardation.
Tuberculosis of the Superficial Lymph Nodes
Involvement of the superficial lymph glands is commonly seen in children with primary tuberculosis. Most often the invasion is part of the postprimary seeding. It may also be seen as part of a primary tuberculous infection, with the primary focus in the skin. Cervical nodes are the ones most commonly involved - either by the primary lesion, which is located in the mouth or tonsils, or from infections originating from the upper mediastinal nodes or apices of the lungs.
All tuberculous nodes do not react in the same way. Most of them will remain unnoticeable, and others will progress to caseation and breakdown. Initially the nodes are small, firm, discrete, movable, and not tender and produce no constitutional symptoms. They may remain in this stage for years or may heal completely, leaving a calcific density after healing. Others may progress, become caseous, and, by erosion of their capsule, become matted together. This mass becomes attached to the surrounding structures and to the overlying skin. By liquefaction of the caseous mass, rupture may occur - with perforation taking any direction, usually to the overlying skin. The discharge of this caseous material through one or more sinuses may continue for months or years, until the involved lymphatic tissue is broken down and evacuated. When healing takes place, it usually leaves permanent and ugly scars.28 The diagnosis will be confirmed by the finding of the tubercle bacilli on culture. Positive smears may also be produced by the unclassified mycobacteria.
Tuberculosis of the Bones and Joints
Tuberculosis of the bones and joints is ordinarily a late clinical complication. It usually results by hematogenous spread from a focus elsewhere in the body. Occasionally, involvement of the spine may occur from contiguous caseous lymph nodes.
Tuberculosis may affect any bone or joint. However, the most common sites are the spine, hip, knee, ankle, and, in infants, the bones of the hands, producing tuberculous dactylitis29 (Figure 10). In children the initial involvement of the bone is at the metaphysis. The necrosis caused by granulation tissue and caseation obliterates the vascular supply to the area, involves the cortex, and forms the so-called cold abscess. The lesions may extend further to the epiphysis and to the joint space with the formation of abscesses and draining sinuses. Healing takes place by formation of fibrous tissue. In the vertebra the lesion develops in the vertebral body, with progressive destruction and collapse.30
The diagnosis in a tuberculous patient is made primarily by roentgenogram. The initial change seen is a localized osteoporosis in the metaphysis, with areas of bone destruction, followed by areas of cortical erosion and cartilaginous destruction. In the vertebra the initial change is a slight narrowing of the intravertebral space; local osteoporosis may be seen. Further destruction of the adjacent vertebral bodies will lead to vertebral collapse with the formation of kyphosis or scoliosis (Figure 11).
Figure 10. Tuberculous dactylitis.
Clinically, pain is a more common symptom; swelling and stiffness of the affected joint are also present. Tubercle bacilli may be demonstrated in the aspirated fluid. Biopsy of the synovial membrane may also confirm the diagnosis. Chemotherapy has greatly improved the prognosis of this complication, and surgery is indicated less often today than it once was.
Intestinal tuberculosis has decreased since the eradication of the bovine tuberculosis. Tuberculosis enteritis, as a primary infection, was a common manifestation years ago because of bovine tubercle bacilli. More commonly, it occurs secondary to swallowed sputum, usually in adolescents and adults with advanced pulmonary disease. Ulcers may be seen in the ileum and cecum. Signs and symptoms of ileocolitis - with abdominal pain, diarrhea, hemorrhage, and anemia - are common. The mesenteric glands are involved, either as part of the primary complex or secondarily by bloodsteam invasion (Figure 12). The infected nodes can adhere to the peritoneum or the intestines, causing colicky pains and, at times, intestinal obstruction. Abdominal tuberculosis thus often simulates appendicitis. (In fact, tuberculosis of the appendix is not unknown.)
Tuberculous peritonitis is usually a result of extension from caseous mesenteric nodes or part of hematogenous spread, as in miliary tuberculosis. The types most often seen are the plastic form, with local adhesions, and the ascitic, with effusion.
Tuberculosis of the Genitourinary System
This complication is usually part of the hematogenous spread and is not uncommon. Tuberculous epididymitis in boys and tuberculosis of the fallopian tubes in girls are the most common manifestations encountered.31
Tuberculosis of the urinary tract is the result of the hematogenous seeding to the cortex of the kidney. It may remain quiescent for many years before producing renal tuberculosis with erosion and cavitation. The infection may advance to the renal pelvis and by the ureter to the bladder. Examination of the urine may reveal chronic pyuria, red cells, proteinuria, and acid-fast bacteria on culture. The destructive changes may well be seen on an intravenous pyelogram or cystoscopy.
As was mentioned initially, tuberculosis may involve any organ in the body - tonsils, larynx,32 middle ear, mastoids, eyes, pericardium, salivary and lacrimal glands, mammary glands, and, more rarely, endocrine glands. The skin is involved as a primary infection or secondarily to hematogenous dissemination.33
Congenital tuberculosis is a very rare disease.34"35 Only about 150 cases have been reported in the world literature. The intrauterine infection is transmitted by ingestion or aspiration of the amniotic fluid by the fetus or by hematogenous spread by the infected placenta. Such newborns are premature and usually produce symptoms within two to four weeks after birth, sometimes even earlier. They may have prolonged fever, failure to thrive, lymphadenopathy, splenomegaly, and calcification of liver and spleen. The tuberculin test may be negative even though gastric cultures may grow tubercle bacilli. Before chemotherapy, all these newborns died. Since chemotherapy, scattered reports have shown that some of the survivors have developed mental and motor retardation.
The treatment of tuberculosis is chemotherapy (Table 2). It entails a prolonged period of therapy, ranging from 12 to 24 months, and controls the disease in almost all cases - assuming that one is dealing with susceptible organisms.14,36 Early diagnosis and early treatment of the disease are very important. Education of the patient is paramount. Tuberculosis is an infectious disease that can be transmitted to others. However, the present antituberculous drugs have proved very effective. They control the infection promptly by preventing the multiplication of the tubercle bacilli, and long isolation of the patient in a sanatorium or hospital is no longer warranted.37 Studies have shown, for example, that only one case in 1,400 is as infectious after a month of chemotherapy as it is before treatment has been initiated.38 Most children, especially those with asymptomatic primary tuberculosis, do not require hospitalization and should be allowed to continue attendance at school. Hospitalizaron may be necessary, of course, when the child is sick enough to require such care or needs additional studies or surgery.
Figure 11. Tuberculosis of vertebrae.
Figure 12. Intra-abdominal tuberculosis (calcified mesenterio nodes).
Obviously, all children with active disease anywhere in the body should be treated.39 Dosages for treatment of pulmonary and extrapulmonary tuberculosis are shown in Table 2. In addition, the following patients should receive chemotherapy 10 mg. of
CHEMOTHERAPY FOR TUBERCULOSIS
CHEMOTHERAPY FOR TUBERCULOSIS
isoniazid daily per kilogram of body weight, for at least a year):
1. Persons of any age who are recent tuberculin converters.
2. All children under the age of four who have a positive tuberculin reaction.
3. Older children with a positive reaction who have x-ray evidence of primary tuberculosis, even though it appears to be inactive, and who have not previously received antitube rculo sis treatment. Preventive treatment is, however, highly recommended for positive reactors up to the age of 35 years.
4. Any child who has recently been in contact with "open" tuberculosis, especially when it has been a household contact. Whether or not he is a positive or negative reactor, this child is considered at high risk and should be treated. When such a child has a "doubtful reaction" (5-9 mm. of induration), it is likely to be evidence of exposure to tuberculosis - rather than a cross- reaction to unclassified mycobacteria, as would be the case in other children. Treatment may be discontinued if the child remains negative after three months of preventive therapy, provided exposure has ended. Periodic skin testing should be continued, however, as a follow-up precaution.
Prophylactic treatment should also be given to children who are at increased risk of developing tuberculosis. This would include (!) all children with positive tuberculin who have been placed on long-term corticosteroid treatment and immun osuppressi ve drugs and (2) all children with positive tuberculin who have been infected with measles or had a Uve measles vaccine. Treatment should continue for six weeks.
Isoniazid is tolerated by children better than by adults, so larger amounts can be given without much toxicity. The question whether to use a single agent or at least two drugs has to be considered with each case, depending on the extent of the disease and the severity of the complication. Isoniazid alone (10 mg. per kilogram of body weight per day, up to 300 mg. a day) has been shown to be very effective in prevention of tuberculosis.40 The question is also raised whether a period of six months may be as effective.
When choosing a regimen for treatment, one hopes that he will be able to eradicate the bacilli rapidly, prevent the emergence of drug- resistant organisms, and prevent relapses. Isoniazid alone has been very effective for infections involving a small number of organisms. When a large population of bacilli is present, however, combined therapy is more effective.41 It has been shown that isoniazidresistant bacilli occur at the rate of about one in 100,000, while the figure for streptomycin is one in a million; therefore, only one of 100 billion bacilli will be resistant to both drugs.42
The drugs used are generally more effective against rapidly multiplying organisms. Therefore, in areas of caseous and necrotic tissue, the bacteria remain dormant, nonmeta bolizing, and obviously unaffected by treatment. Chemotherapy is effective by acting on the metabolic processes of the organism. The site of action of isoniazid is on the DNA synthesis, while of rifampin and ethambutol it is on the RNA synthesis and of streptomycin it is on protein synthesis. Most of the dormant bacilli will metabolize within two years; therefore, treatment of 18 to 24 months' duration is effective enough to reduce the relapse rate to less than 2 per cent.43 Since there is such great variation in the response from person to person, however, it is obvious that the immunedefense system of the host plays a great role. Recent studies have shown that rifampin is capable of killing even dormant bacilli, and successful six-month regimens have been reported.44
Of the commonly used drugs for the treatment of tuberculosis, isoniazid, rifampin, streptomycin, and ethionamide are bactericidal drugs and obviously more effective; ethambutol and para-aminosalicylic acid (PAS) are bacteriostatic. The combination of isoniazid and rifampin is very effective but is not used extensively; there is higher toxidty when both drugs are combined, and the treatment is more expensive because of the high cost of rifampin. Isoniazid and ethambutol are more commonly used in the initial treatment of adults. Since rifampin is so highly effective, however, it may soon replace streptomycin for the severe complications of primary tuberculosis in children.
A two-phase chemotherapy regimen has been used in adults to treat severe cases of far-advanced cavitary disease. It consists of an initial period of intensive drug therapy (isoniazid, ethambutol, and streptomycin daily, for eight to 12 weeks) when the population of the bacilli is large, followed by less intensive treatment (isoniazid and ethambutol alone, given daily) when the number of bacilli is smaller.45 Some investigators have substituted rifampin for streptomycin with equally good results. Recently, PAS has been replaced almost completely by ethambutol, which has proved effective in preventing the emergence of organisms resistant to isoniazid.
Intermittent chemotherapy has also been tried in adults, especially when dealing with unreliable patients. Isoniazid and ethambutol or, preferably, isoniazid and streptomycin are administered twice a week in doses two to three times larger than those employed when the agents are given daily.46 Most investigators, however, have used an initial period of daily chemotherapy lasting for four to 12 weeks.47 The results have proved as effective as routine daily use of the drugs, with negligible toxicity. The recommended twiceweekly dosage is: isoniazid, 15 mg./kg., given orally; streptomycin, 25-30 mg./kg., given intramascularly; and ethambutol, 50 mg./kg., given orally. It is suggested that this therapy be maintained for 18 months. It is evident, by the experience gained so far, that intermittent chemotherapy may be considered an alternative method for the initial treatment of pulmonary tuberculosis.48
Short-course chemotherapy is the latest approach in the pharmacologie treatment of tuberculosis.44 Trials lasting only six months are being carried out with various combinations of drugs. From results to date, it appears that this briefer therapy may be adequate; if so, it will reduce or eliminate problems caused by the longer courses.49
The benefits of short-course therapy, if it proves to be efficacious, are obvious: it will reduce the likelihood of drug toxicity, lower medication costs, and make it more likely that an "unreliable patient" will complete his full course of treatment. And all these benefits are particularly valuable in the underdeveloped countries, where the incidence of tuberculosis is highest.50
Drugs Employed in Treatment
Isoniazid (INH) is the most important single drug used in the treatment of tuberculosis, and it is included in any regimen for treating children and adults. It is bactericidal and highly effective, has low toxicity, and costs little. It penetrates tissues well, including the spinal fluid; even in sputum, it has a concentration similar to that in blood.51 It is metabolized in the liver and excreted mainly by the kidneys. The recommended dose for children is 10-20 mg./kg./day, not exceeding 400 mg. daily. The daily dose may be given in a single dose or divided into two parts; it is supplied in 50-, 100-, and 300-mg. tablets.
Drug toxicity is rare in infants and children but may be significant in adults. Toxicity usually manifests itself early in therapy. Hepatitis, which is one of the major complications, is evidenced by elevated levels of SGOT and bilirubin.
Some liver damage is probably produced by the metabolic products of isoniazid.52,53 Although the elevated levels of the enzymes usually return to normal despite continuance of the patient on medication, it is probably wise to discontinue isoniazid once enzyme levels (transaminases) exceed the 250-unit level.
Pyridoxine is not given to children, since they do not develop peripheral neuritis.54 However, when isoniazid is given to adolescents, a daily dose of 50-100 mg. of pyridoxine is recommended.
Convulsions, toxic encephalopathy, optic neuritis and atrophy, and toxic psychosis have also been reported. Because of the possibility of complications - particularly liver damage - preventive treatment is not recommended for positive reactors over 35 years of age.
Rifampin (RMP) has recently been introduced for the chemotherapy of tuberculosis. It is bactericidal and is considered as effective as isoniazid. It is also effective against most of the unclassified mycobacteria and, apparently, against bacilli during the dormant stage. Rifampin is supplied in capsules of 300 mg. and is given after meals, in a single dose of 10-20 mg./kgJday, not to exceed 600 mg, per patient per day.
At present, use of rifampin is limited in infants and children; the dosage given above is that recommended for adults. The drug is well absorbed by the intestinal tract and is excreted by the bile and urine.
Rifampin is somewhat more toxic than isoniazid. The most common adverse reactions are due to liver dysfunction and include increased transaminase and bilirubin levels, hypersensitivity, itching, and rash. Significant toxic manifestations have been observed - both abdominal (pain, vomiting, diarrhea, gas, cramps) and respiratory (dyspnea, wheezing). Thrombocytopenia has occurred when rifampin and ethambutol were administered together in an intermittent twice-a-week, high-dose schedule.55
Immunosuppressive properties have also been described.56 Use of rifampin is limited today, not so much because of its toxicity as because of its relatively high cost. The possible teratogenic potential should be kept in mind by pediatricians who are counseling mothers at risk or with active tuberculosis.
Ethambutol (EMB) is the most common companion of isoniazid for the initial treatment of tuberculosis, and it is the drug of choice.57 It has largely replaced PAS. As pediatricians know, many children did not like PAS, and the dosages required were high (200 mg./kg./day). Ethambutol is probably slightly less effective than PAS, but it is a bacteriostatic drug that produces no gastrointestinal problems. It is given orally in dosages of 15 mg./kgJday. An initial treatment of 25 mg./ kgJday for a two-month period is acceptable.) It is supplied in tablets of 100 and 400 mg. Ethambutol is excreted in the urine.
Ethambutol is not recommended for use in children under the age of 13, since safe conditions for use have not been established. Among adults, about 3 per cent of the patients show manifestations of ocular toxicity when the daily dosage exceeds the 25-mg. level; the condition is reversible within a few weeks when the drug is discontinued.58 No such complications have been reported with the smaller (15 mg./kg.) dosage. Retrobulbar neuritis is not a serious problem in adults if they are seen monthly, ophthalmosopic examination is done, and visual acuity testing is done. Monthly visual testing is not required if the 15-mg./kg./day dosage is not exceeded and patients are educated on the importance of reporting any visual symptoms.
Streptomycin (SM) was the first really effective antimicrobial agent used against tuberculosis. With the development of the newer agents it is seldom used anymore, since the route of administration is intramuscular and deafness has resulted in a disturbing percentage of children following its use. Streptomycin is toxic to the vestibular and cochlear division of the eighth nerve if the drug is continued beyond the initial symptoms; labyrinthine complications are more common than loss of hearing. The usual form of therapy is streptomycin (0.5-1 gm. per day for children in a single dose), PAS, and isoniazid. Ultimately, the streptomycin therapy should be discontinued or reduced in dosage to two or three times weekly.
Para-aminosalicylic acid (PAS), as noted above, has been replaced by ethambutol. PAS is a bacterio st a ti e drug and was given in dosages of 200-300 mg./kg./day, divided in four doses. The high dosages caused many adverse reactions due to gastric irritation and hypersensitivity to the drug.
Ethionamide is a bactericidal agent that may also be used with isoniazid instead of PAS or ethambutol. While optimum dosage for children has not been established, it may be given in divided doses (three per day) totaling 20-30 mg./kg./day, administered orally. The main toxic reactions are gastrointestinal and hepatic.
Other drugs. Other antituberculous medications are seldom used unless the patient is being admitted for retreatment. Drugs that may then be useful include cycloserine, pyrazinamide, kanamycin, viomycin, and capreomycin. Fortunately relapses among children are rare,59 so this group of drugs are rarely administered to the pediatrie age group.
Corticosteroide are occasionally used in the treatment of tuberculosis to reduce the inflammation caused by some lesions - for example, in the early stages of tuberculous endobronchial disease,60 tuberculous meningitis, and pleurisy.61 They must always be given under the coverage of other antituberculous drugs. Prednisone is given in a dose of 1-2 mg./kg./day and is withdrawn gradually as the condition improves. As the manufacturer of one corticosteroid preparation indicates, tuberculosis - "whether active, suspected or questionably healed" - is usually an absolute contraindication to the administration of corticosteroids. If they are given to a patient with this condition, "the benefits of therapy must be weighed against possible deleterious effects."62
We are still far from our final goal of complete eradication of tuberculosis. Even though tuberculous cases and deaths have been on the decline, there are still new cases reported every year. And last year, 32,105 new active cases were reported in the United States5 - a marked increase overfthe 30,210 active cases reported just two years earlier.2 The inability to find every case and treat it effectively is one of the major problems that must be resolved before the disease can be completely conquered.
It is possible to prevent the spread of tuberculosis; if every person with active disease is identified and treated, the disease could disappear. Strong efforts must be continued, particularly among high-risk groups in which contact with persons with active tuberculosis cannot be avoided. BCG vaccination, coupled with isoniazid chemoprophylaxis, is a documented approach to control of the disease.63'*4
BCG vaccination is a live attenuated strain of M. bovis that was first used in human beings in 1921. In most areas of the United States, the risk of exposure to tuberculosis has reached a sufficiently low level that "expending time and money on BCG programs is not considered to be as effective as expending the same amount of time and money on testing, x-ray screening of special groups, thorough treatment of patients with known cases and thorough investigation of contacts of those with open cases and new tuberculin reactions."65 However, it may still be indicated in certain pediatric-age patients in high-risk situations - for example, children living in parts of New York City or Philadelphia.66
BCG is a safe vaccine with few complications, and it affords protection for many years. The tuberculin test will become positive within six weeks to three months after vaccination; if the test is negative, vaccination should be repeated.
In this country, BCG should be considered for children in high-risk environments and for those whose parents are unlikely to follow a tuberculosis treatment schedule that requires many visits. Newborns of tuberculous mothers are included in the latter group, especially if the organism is resistant to isoniazid.67 There has been a suggestion that some unclassified mycobacteria produce subclinical infection affording patients some protection similar to that offered by BCG.68
BCG should not be given to those with leukemia, malignancies, or immune deficiencies. The most common adverse reaction is an ulceration at the site of the vaccination, which at times may be severe. Occasionally there may be lymphadenitis with abscesses and disseminated BCG infection. The biggest disadvantage of BCG is the loss of usefulness of the tuberculin test, the most powerful tool in detecting new infection.
Chemoprophylaxis for tuberculosis was unheard of until the introduction of isoniazid in 1952. Then the possibility of using this oral, safe, inexpensive agent - not only for treatment but also for the prevention of disease - stimulated the minds of many investigators. Lincoln noticed that the children treated for miliary tuberculosis at Bellevue Hospital in New York did not develop meningitis. This observation stimulated the United States Public Health Service to organize the Tuberculous Meningitis Prophylaxis Study.69
In this study of 2,750 children with asymptomatic primary tuberculosis - made with the cooperation of 32 centers in the United States, Mexico, and Canada - half of the children were treated with isoniazid for one year and half with a placebo. In the 10-year follow-up, there was a rate of 30.2 cases of tuberculosis per 1,000 children in the placebo group, compared with 3.6 per 1,000 in the isoniazid group. Of the 41 complications that developed among the 1,375 children receiving the placebo, there were six cases of meningitis and one of miliary tuberculosis. There were no cases of meningitis or miliary tuberculosis in the isoniazid group.
These children, originally interviewed in 1955, have been followed through puberty and adolescence. By 1970 two cases of chronic pulmonary tuberculosis had developed in the placebo group, none in the isoniazid group.40
As reviewed by Ferebee, many other controlled trials have been carried out with similar results.40 Even though there are reports of tuberculin reversion to negative after isoniazid treatment,70 most investigators today believe that isoniazid has only a modest effect on established tuberculin allergy. It does appear that a tuberculin reaction may remain positive in the absence of living bacilli and that complete eradication of tubercle bacilli is not necessary to prevent tuberculosis.
A wealth of documentation makes it evident that isoniazid chemotherapy is effective for both primary prophylaxis and secondary prophylaxis - that is, both for the prevention of infection in the individual and for the prevention of the disease in the community. The effectiveness of chemoprophylaxis can be seen by the fact that nine out of 10 new cases of tuberculosis in the United States today come from the breakdown of previous infections. Thus, treatment of the infected person, who can derive no benefit from BCG vaccination and who is at the greatest risk of developing the disease, will definitely reduce the incidence of tuberculosis.45
I woutd like to thank Drs. Samuel Stone and Herbert I. Cohen for their advice and comments in the preparation of this article.
1. Freedman, S. O. Tuberculin testing and screening: A critical evaluation. Hosp. Practice 7 (May, 1972), 63.
2. Tuberculous Program Reports - 1973-December, 1974. Washington, D.C.: U.S. Department of Health. Educalion, and Welfare, Public Health Service, 1974.
3. Monthly Vital Statistics Report 26:1 (April 1, 1977). Rockville, Md.: U.S. Department of Health, Education, and Welfare.
4. Edwards, P. Q. Is tuberculosis still a problem? Health Serv. Rep. 80(1973). 483.
5. 1976 Tuberculosis Statistics, States and Cities. Atlanta, Ga,: U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, 1977.
6. Sitantes. J. E.. and Anastasiades, A. A. Primary tuberculosis in infants and young children: Survey of a slum area in Puerto Rico. Am. Rev. Tubero. 76 (1957), 388.
7. Anastasiades, A. A. Unpublished data.
8. Lincoln, E. M., and Gilbert, L. A. Disease in children due to mycobacteria other than Mycobacterium tuberculosis. Am. Rev. Respir.Dis. 105 (1972), 683.
9. Runyon, E. H. Pathogenic mycobacteria. Adv. Tuberc. Res. 14 (1965). 235.
10. Wells, W. F. On air-borne infection. II: Droplets and droplet nuclei. Am. J. Hygiene 20 (1 934). 61 1 .
11. Riley, R. L., and O'Grady. F. Airborne Infection: Transmission and Control. New York: The Macmillan Company. 1961, p. 1T?.
12. Furcotow. M. L.. et al. Tuberculosis casefinding by tuberculin testing among various age children. Crtesf 59 (1971), 618.
13. Tuberculosis Program, 1972. U.S. Department of Health. Education and Welfare. Public Health Service, DHEW Publication No. (CDC) 74-8189, November, 1973, p. 1.
14. Lincoln, E. M.. and Sewell, E. M. Tuberculosis in Children. New York: McGraw-Hill Book Company, 1963.
15. Lee, M. W.. and Adebonop, F. O. Tuberculosis among urban black children. CHn. Pediatr. 15 (1976). 1055.
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1 7. Sbarbaro, J. A. Tuberculosis: The new challenge to the practicing clinician. Chest 68 Suppl., 1975), 436.
18. Collins, F. M., and Mackaness, G. B. The relationship o! delayed hypersensitivity to acquired antitubercubus immunity. CeW. Immunol. 1 (1970), 253.
19. Freedman, S. 0., and Kongsharn, P. L. Immunology of tuberculin hypersensitivity. Chest 68 (1975). 470.
20. Kent. D. C.. and Schwarte, R. Active pulmonary tuberculosis with negative tuberculin skin reactions. Am. Rev. Respir. Dis. 95 (1967). 411.
21 . Holden, M., et at. Frequency of negative intermediate-strength tuberculin sensitivity in patients with active tuberculosis. N. Engl. J. Med. 285 (1975). 1506.
22. Landi. S.. Held. H. R., and Tseng, M. C. Disparity of potency between stabilized and nonstabilized dilute tuberculin solutions. Am. Rev. fiespir. Dis. 104 (1971). 385.
23. Hyde, L. Clinical significance of the tuberculin skin test. Am. Rev. Respir. Dis. 105 (1972). 453.
24. Polk, L. D. No more mass x-ray screening for tuberculosis. Clin. Pediatr. 15 (1976), 983.
25. Horwitz, O., Edwards. P. Q.. and Lowell, A. M. National tuberculosis control program in Denmark and the United States. Health Sen. Rep. 88 (1973), 493.
26. Lincoln, E. M., Davies, P. A., and Bovornkrtti. S. Tuberculous pleurisy with effusion in children: A study of 202 children with particular reference to prognosis. Am. Rev. Tubare. 77 (1958). 271.
27. Lincoln, E. M., Sordilto, V. R., and Davies, P. A. Tuberculous meningitis in children: A review of 167 untreated and 74 treated patients with special reference to early diagnosis. J. Pediatr. 57 (1960), 807.
28. Anastasiades. A. A., Tsikoudas. E. C.. Lincoln, E. M., and DaIy. J. F. Tuberculosis of the superficial lymph nodes in children: A review with a report of experience of enzymatic debridement. Am. Rev. Tubero. 76 (1957). 588.
29. Sitantes, J. E., and Díaz de Garare, P. Skeletal tuberculosis in infants and children. BoV. Asoc. Med. P.R. 57 (1965). 392.
30. Statement of the Subcommittee on Surgery and the Committee on Therapy. American Thoracic Society. The present status of skeletal tuberculosis. Am. Rev. Respir. Dis. 88 (1963), 272.
31. Ehrlich, R. M.. and Lattjmer, J K. Urogenital tuberculosis in Children. J. Urol. 105 (1971), 461.
32. Rohwedder, J. J. Upper respiratory tract tuberculosis. Ann. Intem. Med. 80(1974), 708.
33. Miller, F. J. W. Recognition of primary tuberculous infection of skin and mucosa Lancet 1 (1953), 5.
34. Davis,S. F., et al. Congenital tuberculosis. J. Pediatr. 57(1960). 221.
35. Reisinger. K. S., et al. Congenital tuberculosis: Report of a case. Pediatrics 54 (?974), 74.
36. Lincoln, E. M.. Sewell. E. M.. and Anastasiades. A. A The treatment of primary tuberculosis in children. Postgrad. Med. 16 (1954). 422
37. Guidelines for the general hospital m the admission and care of tuberculous patients. National Tuberculosis Association. Ad Hoc Committee on the Treatment of Tuberculous Patients in General Hospitals. Am. Rev. Respir. Dis. 99 (1 969), 631
38. Loudon, R. G., and Spohn, S. K. Cough frequency and infectivity in patients with pulmonary tuberculosis. Am. Rev. Respir Dis. 99 (1969). 109.
39. High, R H. Tuberculosis. In Vaughan. V. C.. and McKay. R. J. (eds.). Nefcon Textbook of Pe&airics IOthEditon. Philadelphia: W. B. Saunders Company. 1975.
40. Ferebee, S. H. Controlled chemoprophylaxis trials in tuberculosis: A general review. AoV. Tubero. Res. 17 (1970), 28.
41. Russell, W. F.. and Middlebrook. G. Chemotherapy of Tuberculosis. Springfield. III.: Charles C Thomas. Publisher, 1961.
42. Barlow, P, B. Treatment of tuberculosis. Am. Thoracic Soc. Basics R.D. 5 (September, 1976). 1.
43. Report to the Medical Research Council by the Tuberculosis Chemotherapy Trials Committee. Tubercle 43 (1962), 201.
44. Short-course chemotherapy in pulmonary tuberculosis: A controlled trial by the British Thoracic and Tuberculosis Association. Lancet 1 (1975), 119.
45. Johnston, R. E.. and Wildrick, K. H. The impact of chemotherapy on the care of patients with tuberculosis. Am. Rev. Respir. Dis. 109 (1974), 636.
46. Official Statement of the American Thoracic Society. Intermittent chemotherapy for adults with tuberculosis. Am. Rev. Respir. Dis. ITO (1974), 374.
47. Hudson. L. D., and Sbarbaro. J. A. Twice weekly tuberculosis chemotherapy. J.A.M.A. 233 (1973), 139.
48. Ramakrishnan, C. V., étal. A four-year follow-up of patients with quiescent pulmonary tuberculosis at the end of a year of chemotherapy with twice-weekly isoniazid plus streptomycin or daily isoniazid plus PAS. Tubercle 50 (1969). 115.
49. Fox. W., and Mitchison. D. A. Short-course chemotherapy for pulmonary tuberculosis. Am. Rev. Respir. Dis. 111 (1975), 845.
50. East African/British Medical Research Councils. Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet I (1973), 1331.
51. Sultan. L. V., et al. Tuberculosis disseminators: A study of the variability of aerial infectivity of tuberculosis patients. Am. Rev. Respir. 0/5.82(1960), 358.
52. Garibaldi, R. A., et al. Isoniazid-associated hepatitis. Am. Rev. Respir. Dis. 106 (1972), 357.
53. Ad Hoc Committee on Isoniazid and Liver Disease, Center for Disease Control, Department of Health, Education, and Welfare. Isoniazid and liver disease. Am. Rev. Respir. Dis. 104 (1971), 454.
54. Morales. S. M., and Lincoln, E. M. The effect of isoniazid therapy on pyridoxine metabolism in children. Am. Rev. Tubero. 75 (1957), 594.
55. Aquinas, S. M., et al. Adverse reactions to daily and intermittent rifampin regimens for pulmonary tuberculosis in Hong Kong. Br. Med. J. 1 (1972). 765.
56. Nilsson, B. S. Rifampin: an immunosuppresant? Lancei 2 (1971). 374.
57. Dosten. B., et al. Ethambutol in the initial treatment of pulmonary tuberculosis. Am. Rev. Respir. Dis. 107 (1973), 177.
58. Leiboid, J. E. The ocular toxicity of ethambutol and its relation to dose. Ann. N.Y. Acad. Sc/. Í35 (1966). 904.
59. Edsall. J., and Collins, G. Routine follow-up of inactive tuberculosis: A practice to be abandoned. Am. Rev. Respir. Dis. 107 (1973). 851.
60. Nemir. R. L., et al. Prednisone therapy as an adjunct in the treatment of lymph node-bronchial tuberculosis in childhood. Am. Rev. Respir. Dis. 88 (1963), 189.
61. Filler, J., and Porter, M. Physiologic studies of the sequelae of tuberculous pleural effusion in children treated with antimicrobial drugs and prednisone. Am. Rev. Respir. Dis. 88 (1963), 181.
62. Physicians' Desk Reference. Oradeil, N.J.: Medical Economics Company. 1977. p. 1226.
63. Smith, D. T. Isoniazid prophylaxis and BCG vaccination in the control of tuberculosis. A/cft. Environ. Health 23 (1971). 235.
64. Barlow, P. B., et al. Preventive therapy of tuberculous infection. (Official Statement of the American Thoracic Society May 12, 1974.) Am. Rev. Respir. Dis. 110 (1974). 371.
65. Micheil, R. S. Contrai of tuberculosis. N Engl. J. Med 276 (1967), 842
66. Smith. M. H. D. Tuberculose in adolescents: Characteristics. recognition, management Clin. Pediatr. 6 (1967), 9.
67. Kendig, E. L, Jr. The place of BCG vaccine in the management of infants bom of tuberculous mothers. N. Engl. J. Med. 281 (1969). 520
68. Palmer. C. E., and Long. M. W. Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis. Am Rev. Respir. Dis. 94 (1966). 553
69 Ferebee. S. H.. Mount, F. W., and Anastasiades, A. A. Prophylactc effects of isoniazid on primary tuberculose in children: A preliminary report Am. Rev. Tubero 76 (1957), 942.
70. Houk. V. N-. et al The eradicaton of tuberculosis infection by isoniazid chemoprophylaxe. Arch. Environ. Health 16 (1968), 46.
CLASSIFICATION OF ATYPICAL MYCOBACTERIA
CHEMOTHERAPY FOR TUBERCULOSIS
CHEMOTHERAPY FOR TUBERCULOSIS