Diagnosis of Tuberculosis (TB) Infection
The tuberculin skin test is used principally to identify individuals infected with M. tuberculosis who are at high risk for developing the disease and who may benefit from treatment of latent tuberculosis infection. Previously, ''preventive therapy'' or ''chemoprophylaxis'' was used to describe a simple drug regimen (e.g., isoniazid monotherapy) used to prevent the development of active tuberculosis disease in individuals known or likely to be infected with M. tuberculosis. However, since use of such a regimen rarely results in true primary prevention (i.e., prevention of infection in individuals exposed to infectious tuberculosis), the American Thoracic Society (ATS) and US Centers for Disease Control and Prevention (CDC) currently state that ''treatment of latent tuberculosis infection'' rather than ''preventive therapy'' more accurately describes the intended intervention and potentially will result in greater understanding and more widespread implementation of this tuberculosis control strategy. (For current recommendations on therapy for latent tuberculosis infection, .) The tuberculin skin test also is used in individuals suspected of having clinical tuberculosis to aid in the diagnosis of the disease; a positive (i.e., significant) reaction to the tuberculin skin test
(see Interpretation)does not necessarily signify the presence of disease. While a significant reaction generally indicates that tuberculin sensitivity has developed as a result of infection with M. tuberculosis and supports a diagnosis of tuberculosis, further diagnostic evaluation (e.g., medical history, physical, radiographic, bacteriologic, and/or histologic examinations) usually is necessary to establish whether the infection has progressed to clinical tuberculosis.
The Advisory Council for the Elimination of Tuberculosis (ACET) of the US Public Health Service states that tuberculin skin testing is the standard method for identifying individuals infected with M. tuberculosis. However, the ACET states that screening for disease (e.g., using chest radiography) rather than infection (i.e., via tuberculin skin testing) may be more appropriate in some circumstances (e.g., when results of skin testing may be unreliable or the individual has a severe immediate hypersensitivity reaction to the tuberculin test, when it is impractical to administer and interpret test results or conduct follow-up of infected individuals, when the risk for disease is high, when the consequences of an undiagnosed case may be severe). Although screening high-risk populations for tuberculosis infection and providing therapy for latent tuberculosis infection are crucial to achieving the national goal of eliminating tuberculosis, the ACET states that screening programs should not be undertaken unless necessary facilities for patient evaluation and treatment are identified and made available and unless patients found to be infected are likely to complete therapy for latent tuberculosis infection. In establishing priorities for basic strategies to prevent and control tuberculosis, the first priority should be identifying and completely treating all individuals who have active tuberculosis, the second priority should be contact investigation (i.e., finding and evaluating individuals who had contact with tuberculosis patients, determining if they have infection or disease, and treating them appropriately), and the third priority should be screening populations at high risk for tuberculosis to identify infected individuals and then providing complete, appropriate therapy to prevent the infection from progressing to active, contagious disease.
Individuals at risk for developing tuberculosis include those who have been recently infected with M. tuberculosis and those who have clinical conditions that increase the risk of latent tuberculosis infection progressing to active disease. The likelihood that a positive tuberculin test represents a true infection with M. tuberculosis (positive predictive value) is influenced by the prevalence of infection in the population being tested.
(See Tuberculosis under Interpretation: Mantoux Method.)To prioritize the use of resources for identifying those at risk for developing tuberculosis and minimize the incidence of false-positive tuberculin test results, the ATS and CDC currently recommend that tuberculin testing be targeted toward groups at high risk and discouraged in those at low risk.
The ACET, ATS, and CDC currently recommend that the following individuals or groups with clinical risk factors be targeted for tuberculin testing and, if appropriate, treated for latent tuberculosis infection following exclusion of active tuberculosis disease:
Individuals who are close contacts (i.e., those sharing the same household or other closed environment) of known cases of clinical tuberculosis or individuals suspected of having tuberculosis HIV-infected individuals Other individuals with medical conditions that increase the risk of progressing from latent tuberculosis infection to active tuberculosis if infection were to occur. Medical conditions associated with such increased risk include diabetes mellitus, those requiring prolonged high-dose corticosteroid therapy or other immunosuppressive therapy (including bone marrow and organ transplantation), chronic renal failure, certain hematologic or reticuloendothelial disorders (e.g., leukemias, lymphomas), certain other malignancies (e.g., head and neck or lung cancer), weight loss that is 10% or more below ideal body weight, silicosis, gastrectomy, and jejunoileal bypass. (See Pharmacology: Factors Affecting Tuberculin Sensitivity.) Individuals who inject illicit drugs and other locally identified high-risk substance users (e.g., crack cocaine users) Residents and employees of high-risk congregate settings (e.g., correctional facilities, nursing homes, mental institutions, other long-term residential facilities, homeless shelters) Health-care workers serving high-risk clients Foreign-born individuals, including children who recently arrived (within 5 years) from countries having a high tuberculosis incidence or prevalence and those who are adopted from outside the US. Certain medically underserved, low-income populations Individuals with pulmonary fibrotic lesions on chest radiographs (assumed to be from prior untreated tuberculosis) Children younger than 4 years of age or infants, children, and adolescents exposed to adults in high-risk categories
The American Academy of Pediatrics (AAP) currently recommends that tuberculin skin tests be given immediately to children at high risk of acquiring latent tuberculosis infection and tuberculosis disease, including children who are contacts of individuals with confirmed or suspected contagious tuberculosis; children with radiographic or clinical findings suggestive of tuberculosis; children immigrating from countries where tuberculosis is endemic (e.g., Asia, Middle East, Africa, South America); and children with a history of travel to endemic countries and/or substantial contact with individuals indigenous to such countries. AAP states that annual tuberculin testing (initially at the time of diagnosis or circumstance, beginning at 3 months of age) is indicated for children with HIV infection and for incarcerated adolescents. In addition, the AAP states that some experts recommend tuberculin skin testing every 2-3 years for children with ongoing exposure to the following individuals: HIV-infected individuals, homeless individuals, residents of nursing homes, institutionalized adolescents or adults, users of illicit drugs, incarcerated adolescents or adults, or migrant farm workers. Routine tuberculin tests are not indicated in children at low risk of tuberculosis, including those from areas with a low prevalence of the disease. However, the AAP states that tuberculin skin tests should be considered at 4-6 and 11-16 years of age in children who have no risk factors for tuberculosis but whose parents have emigrated (with unknown tuberculin test status) from high-prevalence regions and in children who have continued potential exposure because of travel to endemic areas and/or household contact with individuals (with unknown tuberculin test status) from those endemic areas.
The AAP states that children with certain other medical conditions, such as diabetes mellitus, chronic renal failure, malnutrition, or congenital or acquired immunodeficiencies, are not at increased risk of acquiring tuberculosis infection unless they have been recently exposed. However, underlying immune deficiencies in such children theoretically would increase the risk for progression of latent tuberculosis infection to severe disease. Therefore, the AAP states that initial histories of potential exposure should be obtained for these patients and, if the history or local epidemiologic factors suggest the possibility of exposure, immediate and periodic tuberculin skin testing should be considered. An initial tuberculin skin test should be performed prior to initiation of immunosuppressive therapy, including prolonged corticosteroid therapy, in any child who has an underlying condition requiring such therapy.
Flexibility is required in defining high-priority groups for screening since the changing epidemiology of tuberculosis indicates that the risk among groups currently considered high priority may decrease over time, and groups currently not identified as at risk subsequently may be considered high priority. Therefore, local public health officials should assess the prevalence, incidence, and sociodemographic characteristics of tuberculosis cases and infected individuals in their community and, based on these data, initiate tuberculin screening programs specifically targeting the high-risk groups.
Federal regulations require that a tuberculin skin test be performed at the initial medical evaluation of patients seeking enrollment in methadone detoxification or maintenance treatment programs; the Mantoux method or, when available, a procedure with equal or better sensitivity should be used. Although not required, detoxification and maintenance treatment programs are encouraged to retest those patients with initially insignificant reactions to tuberculin skin tests, to test program employees at the start of employment, and to periodically retest all employees with initially insignificant reactions. Programs are encouraged to maintain records on patient and staff tuberculin skin test results.
(See Interpretation: Mantoux Method.)A patient or employee with a significant Mantoux skin test reaction or clinical evidence of possible tuberculosis disease should receive prompt medical evaluation and treatment; those who have tuberculosis should be reported to state and local health departments.
Individuals with or at Risk for HIV Infection
Because of the complications associated with active tuberculosis in individuals with HIV infection, such individuals must be screened for latent tuberculosis infection and receive complete treatment of such infection if indicated. Because patients with HIV infection are at high risk of developing mycobacterial infections (e.g., tuberculosis) and the reliability of the tuberculin skin test decreases as the CD4 T-cell count declines, the ATS, the CDC, the ACET, the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA), and others currently recommend that all individuals known to be seropositive for HIV receive a Mantoux skin test as soon as possible after diagnosis of HIV infection. In addition, the ACET states that groups with a substantially higher prevalence of HIV infection than the general population (e.g., drug abusers, inmates of correctional institutions or homeless shelters) should routinely receive a tuberculin skin test, even if counseling and HIV-antibody tests are not routinely offered or are refused. Particular efforts at identifying IV drug abusers with a significant Mantoux skin test reaction should be made since the association between tuberculosis and the acquired immunodeficiency syndrome (AIDS) is most evident in this group. Although the reliability of the tuberculin skin test might diminish as the CD4 T-cell count declines, the USPHS/IDSA states that consideration should be given to repeating tuberculin skin tests annually in HIV-infected individuals who have insignificant reactions to the initial test if such individuals belong to populations in which there is a substantial risk for exposure to M. tuberculosis. If the skin test reaction is significant in a HIV-infected patient, a chest radiograph should be performed and, if abnormalities are noted, additional diagnostic procedures for tuberculosis should be undertaken. In addition to confirming tuberculosis infection, tuberculin skin test conversion in an HIV-infected individual should alert health-care providers to the possibility of recent M. tuberculosis transmission and should prompt notification of public health officials to investigate a possible source case.
HIV-infected individuals who have symptoms suggestive of tuberculosis should receive a chest radiograph and clinical evaluation regardless of the skin test reaction since falsely insignificant reactions to the tuberculin test may occur as a result of immunosuppression associated with the HIV infection. In addition, current evidence suggests that the frequency of falsely insignificant reactions may be higher than previously suspected in asymptomatic HIV-infected patients. Although evaluation of all HIV-infected individuals, whether symptomatic or asymptomatic, for cell-mediated (delayed-type hypersensitivity) anergy at the time of tuberculin skin testing previously was recommended to aid in interpretation of test results, the ATS and CDC state that the usefulness of anergy testing in identifying tuberculin-negative, HIV-infected individuals who might benefit from treatment of latent tuberculosis infection has not been demonstrated, and such testing currently is not recommended by ATS and CDC for use in identifying tuberculosis infection, including in HIV-infected individuals or those who are otherwise immunocompromised. However, the ATS and CDC state that anergy testing may assist in guiding individual treatment decisions in selected situations.
(See Tuberculosis: Anergic Individuals at Risk of Tuberculosis, in Uses).
The USPHS/IDSA and other clinicians have suggested that repeat tuberculin skin testing be performed in HIV-infected patients previously identified as tuberculin-negative if there is evidence suggesting restoration of immune function following effective antiretroviral therapy in such patients (i.e., those whose CD4 T-cell count has increased to greater than 200/ mm).
The CDC recommends that all patients with tuberculosis routinely be counseled and tested for HIV antibody since such patients are at high risk for severe clinical tuberculosis or associated mycobacterial disease (e.g., Mycobacterium avium complex [MAC] infection), which has substantial implications for treatment. Particular suspicion for coexisting HIV infection is warranted in patients with tuberculosis who are in a high-risk group for HIV infection and in patients whose tuberculosis or associated mycobacterial disease is disseminated or characterized by severe or unusual manifestations.
Anergic Individuals at Risk of Tuberculosis
While it generally is recognized that patients with symptomatic HIV infection frequently are anergic and a substantial proportion of those with tuberculosis will have falsely insignificant reactions to tuberculin when tuberculosis occurs concurrently with other HIV-related opportunistic infections, current evidence suggests that HIV infection can depress tuberculin reactions before manifestations (e.g., opportunistic infections) of HIV infection are apparent. Therefore, such concerns have been heightened because the frequency of falsely insignificant reactions may be higher in asymptomatic HIV-infected patients than previously suspected.
Previous CDC guidelines for anergy testing and management of anergic individuals at risk of tuberculosis (e.g., patients with HIV infection) were developed in response to concerns about transient or continuing suppression of cellular hypersensitivity mediated by T cells that may be associated with many diseases and infections, including cancer and certain viral infections (especially HIV infection), or with certain immunosuppressive therapies. Although it had been recommended that all individuals who were HIV seropositive be evaluated for cell-mediated immunity (delayed-type hypersensitivity) using at least two other antigens (i.e., mumps skin test antigen, candida, tetanus toxoid) at the time tuberculin skin testing was performed, the ATS and CDC no longer recommend anergy testing for use in identifying tuberculosis infection in individuals with or without HIV infection because of current information on variability and lack of reproducibility of anergy test methods, variation in the absolute risk of tuberculosis among different anergic groups, and the lack of demonstrated efficacy of therapy for latent tuberculosis infection in anergic individuals. However, the ATS, CDC, and some experts state that there may be selected situations in which evaluation of anergy may assist in guiding individual decisions about therapy for latent tuberculosis infection (e.g., in individuals with insignificant reactions to tuberculin from populations at high risk for Mycobacterium tuberculosis infection).
The ATS and CDC state that valid interpretation of the results of anergy skin testing may be compromised by several factors. A positive response to anergy skin testing in conjunction with an insignificant tuberculin reaction has been interpreted as evidence that the insignificant tuberculin reaction is a true negative and that the individual is not infected with M. tuberculosis. However, selective nonreactivity to tuberculin has been documented in some patients with active, culture-positive tuberculosis. Reactivity to mumps skin test antigen may remain following loss of tuberculin reactivity, and the finding that boosting of the tuberculin response can occur in individuals who have an initial positive response to control antigens suggests that a cell-mediated immune response to other antigens may be preserved after loss of tuberculin reactivity. Therefore, a positive response to control skin-test antigens does not ensure that an insignificant reaction to a tuberculin test applied at the same time indicates absence of infection with M. tuberculosis. In addition, lack of a response to anergy skin testing, in conjunction with an insignificant tuberculin reaction, has been interpreted as evidence that an individual is unable to mount a positive (i.e., significant) response to tuberculin even when infected with M. tuberculosis. However, in populations in which the prevalence of tuberculin reactivity is high, the percentage of individuals who react to tuberculin may exceed the percentage who respond to several other antigens. Even in populations in which the prevalence of tuberculin reactivity is low, some individuals may respond to tuberculin testing despite lack of a response to a companion antigen (e.g., mumps). Therefore, a valid demonstration of anergy does not predict infection with M. tuberculosis but indicates that, for the anergic individual, the results of tuberculin testing may not be useful in judging the likelihood of latent infection with M. tuberculosis and the need for therapy for such infection.
The CDC states that lack of standardization and lack of outcome data based on uniform antigens and tests are among the greatest obstacles to evaluating the effectiveness of anergy testing and making decisions concerning preventive therapy for tuberculosis. Studies have been conducted using a variety of control antigen preparations and methods for reading test results. Current evidence indicates that several antigens may be necessary to maximize the likelihood of accurately identifying individuals who are able to respond to tests of cell-mediated immunity. Responses to tests of cell-mediated immunity may vary in different populations of immunocompetent individuals; for example, reactions of less than 5 mm induration (an induration diameter of at least 5 mm is designated as the cut-off measurement for interpreting a Mantoux-method skin test result as positive) have been reported in young children, who may not have fully developed cellular immunity. Although children with HIV infection have had positive responses to tests of cellular immunity and lack of response has been associated with the stage of HIV-related disease, the applicability and utility of skin-testing methods in the evaluation of tuberculosis in children has not been established. Serial anergy testing of HIV-infected individuals has shown unpredictable differences over time, which may result from changes in host immune competence or characteristics of the tests themselves. The choice and number of companion antigens and the criteria used for the interpretation of results of anergy testing also may lead to erroneous classification of individuals with intact cell-mediated immunity as anergic, or anergic individuals as nonanergic.
Studies conducted to date have not established a definite association between anergy and the risk for active tuberculosis in HIV-infected individuals; the magnitude of the risk is variable and the reason for the variation uncertain. The risk for active tuberculosis in anergic HIV-infected individuals may be associated with ongoing risk for M. tuberculosis transmission (i.e., residence in areas of high tuberculosis case rates) rather than a high probability of latent M. tuberculosis infection alone. Therefore, any effect of therapy for latent tuberculosis infection might be attributable not only to prevention of reactivation of such infection but also (or instead) to primary prophylaxis against new acquisition of infection.
While treatment with isoniazid or short-course (e.g., 2-month), 2-drug regimens (e.g., rifampin-pyrazinamide) is effective in reducing the incidence of active tuberculosis among individuals who have HIV infection and latent tuberculosis infection, placebo-controlled studies in HIV-positive anergic patients, who are assumed to be at high risk for active tuberculosis, have not demonstrated the effectiveness of such regimens to treat latent infection. In 2 controlled studies in anergic patients with HIV infection, 6 months of isoniazid therapy did not significantly reduce the incidence of tuberculosis compared with placebo despite a 56% reduction in the case rate of tuberculosis (from 0.9 to 0.4 cases per 100 patient-years) in one study. The lack of statistically significant benefit with isoniazid treatment in this study has been attributed to the lower-than-expected rate of tuberculosis in the placebo group (0.4 cases per 100 patient-years); based on this low incidence of tuberculosis in untreated patients, therapy for latent tuberculosis infection would have had minimal impact in reducing the number of cases of tuberculosis but would have resulted in a substantial number of uninfected individuals being treated with isoniazid.
For individuals who are known or suspected to be anergic or who exhibit an insignificant reaction to tuberculin, the most important factors in determining whether to administer therapy for latent tuberculosis infection are the likelihood of exposure to transmissible active tuberculosis and the likelihood of such latent infection. While treatment of latent tuberculosis infection has not been shown to be effective in tuberculin-negative, HIV-infected individuals, the ATS and CDC state that most of these individuals who are contacts of patients with active tuberculosis should receive treatment for presumed latent tuberculosis infection even when repeated testing after contact has ended does not indicate latent infection. For additional recommendations regarding the use of therapy for latent tuberculosis infection in HIV-infected individuals, . Some clinicians recommend that tuberculin skin testing be performed in HIV-infected patients previously classified as anergic if there is evidence that a patient's immune function has been restored following effective antiretroviral therapy. Anergic individuals who are at increased risk of tuberculosis but elect not to undergo therapy for latent tuberculosis infection should be educated carefully about the manifestations of tuberculosis in HIV infection and instructed to promptly seek medical attention if any sign or symptom develops.
The incidence of tuberculosis is much higher in many countries than it is in the US, and it is an increasingly serious public health problem. The CDC recommends that travelers who anticipate possible prolonged exposure to tuberculosis (e.g., those who could be expected to routinely come in contact with hospital, prison, or homeless shelter populations) should have a tuberculin skin test prior to leaving the US. If the test is negative, a repeat test should be done after returning to the US. Travelers with HIV infection should be advised to inform their clinicians about their HIV status since these individuals are more likely to have an impaired response to the tuberculin skin test. Except for those with impaired immunity (e.g., HIV-infected individuals), travelers who already have significant reactions to tuberculin are unlikely to be reinfected.
Although there have been several reports of transmission of tuberculosis to individuals traveling on commercial airplanes, the risk of tuberculosis transmission during airplane travel does not appear to be greater than that associated with any other enclosed spaces. The CDC and state and local health departments have investigated 6 instances of possible transmission of tuberculosis during air travel that involved a passenger or flight crew member who traveled while infectious with tuberculosis and, in 2 of these cases, the CDC concluded that tuberculosis probably was transmitted during the flight. The risk of tuberculosis transmission from an infectious individual to another airplane passenger or crew member was greater on long flights (8 hours or longer) and the risk of exposure was higher for those sitting or working near the infectious individual. To prevent possible exposure to tuberculosis on commercial airplanes, the CDC and World Health Organization (WHO) recommend that, if individuals with infectious tuberculosis must travel, these individuals should travel by private transportation and not by commercial carriers. Individuals who are concerned about possible tuberculosis exposure during travel should see their primary health-care provider for a tuberculin skin test.
The CDC states that travelers should be advised to avoid exposure to known tuberculosis-infected patients in crowded settings (e.g., hospitals, prisons, homeless shelters) and travelers who anticipate contact with such patients while working in hospitals or other health-care settings should obtain properly fitted personal respiratory protective devices (i.e., N-95 respirators) from infection control or occupational health experts. In addition, tuberculosis-infected patients should be instructed to cover coughs and sneezes with their hands or tissues.
Internationally Adopted Children and Other Immigrants
To complete an international adoption and bring an infant or a child to the US, prospective parents must fulfill requirements of the Bureau of Citizenship and Immigration Services (BICS), the foreign country in which the infant or child resides, and, possibly, the state of residence of the adoptive parents. All immigrants, including infants and children adopted overseas by US citizens, and refugees coming to the US must be examined in their country of origin by a designated clinician. The main purpose of an overseas medical examination is to detect certain serious contagious diseases that may be the basis for visa ineligibility. Such examinations generally consist of a brief physical exam, medical history evaluation, and chest radiograph to screen for tuberculosis. Immigrants older than 15 years of age also are required to have serologic tests for syphilis and HIV; those younger than 15 years of age require such tests only if there is a clinical suspicion of these diseases. Individuals seeking an immigrant visa for permanent US residency must also provide proof of age-appropriate vaccination according to the current US Recommended Childhood and Adolescent Immunization Schedule or the US Recommended Adult Immunization Schedule ). Although this recently implemented vaccination requirement applies to all immigrant infants and children entering the US, internationally adopted children younger than 11 years of age are exempt from the overseas vaccination requirements; however, adoptive parents are required to sign a waiver indicating their intention to comply with the vaccination requirements within 30 days of the child's arrival in the US.
Internationally adopted infants or children should undergo a follow-up medical examination within 2 weeks of arrival in the US; however, adoptees with an acute illness or a chronic condition should receive immediate medical attention. Medical evaluation of internationally adopted infants and children is a complex and important task because of varied geographic origins, unknown backgrounds before adoption (e.g., parental history, living circumstances), and the inadequacy of health care in many resource-poor countries. All internationally adopted infants and children should have a complete physical examination, review of any available medical records, and age-appropriate screening tests, including evaluation for possible anemia, vision and hearing impairments, assessment of growth and development, and dental evaluation (children older than 18 months of age).
Screening for infectious disease is important for the health of the adopted infant or child and their adoptive family. Infectious disease (often asymptomatic) has been reported in up to 60% of internationally adopted children and varies according to country of origin. The AAP recommends that all internationally adopted children undergo the following screening tests: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, HIV serology, syphilis serology, Mantoux intradermal tuberculin skin test, stool examination for ova and parasites, and complete blood count with red blood cell indices. Additional screening tests may be recommended based on country of origin, risk factors, symptoms, or clinical findings. Laboratory reports from the country of origin should not be considered reliable.
The CDC and AAP recommend Mantoux tuberculin testing for internationally adopted children because the rates of tuberculosis infection are several times higher in such children than in children born in the US. Children with a positive skin test (e.g., 10 mm of induration for children born in regions of the world with a high tuberculosis prevalence) should have a chest radiograph to evaluate for active tuberculosis. If active tuberculosis is evident, efforts should be made to isolate M. tuberculosis for in vitro susceptibility testing since drug resistance is common in many countries outside the US, including countries in Eastern Europe, the former Soviet Union, and Asia.
Mantoux tuberculin testing is not contraindicated in children who have received BCG vaccine. However, when a positive tuberculin skin test result occurs in children vaccinated with BCG, it may be difficult to discern M. tuberculosis infection from a reaction caused by the BCG vaccine. Infection with M. tuberculosis should be strongly suspected in any asymptomatic child with a positive tuberculin skin test, regardless of history of BCG vaccination. The probability that a positive tuberculin skin test is secondary to M. tuberculosis infection is increased if the child has been in contact with an individual with active tuberculosis, immigrated from a country with high prevalence of tuberculosis, or has not received BCG vaccine recently. Because BCG vaccine is not fully protective and because of the high risk for exposure that exists in most countries where the vaccine is given, the AAP recommends that children with a positive tuberculin skin test receive treatment.
Tuberculin Skin Test Methods
Tuberculin skin testing currently is carried out using the Mantoux method. Multiple-puncture devices also have been used for tuberculin skin testing; however, these devices are no longer available in the US.
Although 3 strengths of PPD formerly were available for administration by the Mantoux method (for a description of this method,
see Dosage and Administration: Mantoux Method), only solutions of PPD containing 5 TU/0.1 mL (formerly called intermediate strength PPD) currently are commercially available in the US. When properly administered, a standard Mantoux test (0.1 mL of a 5 TU/0.1 mL solution of PPD) is an accurate and reliable tuberculin skin test and is the tuberculin test recommended by the ATS, CDC, and AAP. Since the dose of tuberculin introduced into the skin with multiple-puncture devices (no longer commercially available in the US) cannot be precisely controlled, the ATS, CDC, and the AAP state that a standard Mantoux test (not a multiple-puncture test) should be used for periodic surveillance of individuals likely to be exposed to clinical tuberculosis or to evaluate individuals who are suspected of having tuberculosis or are contacts of persons with clinical tuberculosis.
The ATS and CDC state that other doses of tuberculin, such as the 1 or 250 TU/0.1 mL solution (no longer commercially available in the US), are remnants of the old graduated system of tuberculin administration and have not been adequately standardized by bioassay; therefore, reactions to these solutions cannot be accurately interpreted. Because of its potency, the 250 TU/0.1 mL solution (no longer commercially available in the US) frequently elicits nonspecific reactions as the result of cross-reactivity with other mycobacteria and may elicit a severe necrotic reaction in some tuberculin-sensitive individuals. Although some patients with clinical tuberculosis may react to the 250 TU/0.1 mL solution of PPD (no longer commercially available in the US) but not to the 5 TU/0.1 mL solution, the more potent solution will not necessarily elicit a reaction in anergic patients with bacteriologically confirmed tuberculosis.
Because the dose of tuberculin introduced into the skin with multiple-puncture devices (no longer commercially available in the US) cannot be precisely controlled, the Advisory Council for the Elimination of Tuberculosis (ACET) recommends that these devices not be used for the periodic surveillance of individuals likely to be exposed to clinical tuberculosis (e.g., personnel and long-term residents in hospitals, nursing homes, mental institutions, prisons) or to evaluate individuals who are suspected of having tuberculosis or are contacts of persons with clinical tuberculosis.
Although several controlled studies have been published that compare the sensitivity and specificity of various multiple-puncture devices (no longer commercially available in the US) with each other and with the Mantoux test, results of these studies are probably equivocal since the potency of tuberculin used on these multiple-puncture devices was not standardized in humans and because the PPD solution used in some of these studies has subsequently been found to be superpotent and may have elicited an unusually high number of falsely positive (falsely significant) reactions. All multiple-puncture devices appear to have the same disadvantage, which is based on their inability to precisely control the dose of tuberculin introduced into the skin.
Tuberculin is used in conjunction with other antigens (e.g., candida, coccidioidin, histoplasmin, mumps skin test antigen, trichophyton) to assess the status of cell-mediated immunity, especially in malnourished patients, surgical patients, or patients with cancer. Because the cell-mediated response to these antigens depends on previous exposure to or infection with them, only those antigens to which the patient has probably been exposed in the past should be used. These antigens are used as screening tests and can only indicate the presence or absence of cell-mediated immunity. In vitro tests (e.g., lymphocyte stimulation, assays for T and B cells) are necessary to diagnose specific immunologic disorders.
When tuberculin is used to assess cell-mediated immunity, a standard Mantoux test (0.1 mL of a 5 TU/0.1 mL solution of PPD) is generally given with a battery of at least 4 other antigens.