Please note: In 2003, the CTF updated its Grades of Recommendations to include an "I Recommendation" for situations where insufficient evidence exists to allow a recommendation to be made. (Formerly, these situations were captured under a "C Recommendation".) This change is not retroactive, and all "C Recommendations" made prior to 2003 have not been reevaluated in light of the new "I" recommendation grade. For a discussion of these recommendation grades, please link to the 2003 article in the Canadian Medical Association Journal here.
Overview
Tuberculosis remains a major worldwide health
problem with at least 10 million new cases and 3 million deaths estimated
to occur annually. In 1979, the Canadian Task Force on the Periodic Health
Exam< 1> recommended Bacille Calmette-GuŽ erin (BCG) immunization
and chemoprophylaxis of unimmunized tuberculin-positive individuals from
high risk-groups (A Recommendation) but not for the general population
(E Recommendation). With the changing epidemiology of tuberculosis in North
America and concerns about the risk of drug-induced hepatitis, the value
of screening for tuberculosis and of isoniazid (INH) chemoprophylactic
therapy as part of the periodic health examination was re-examined. The
Task Force concludes that screening by tuberculin skin testing should be
offered to persons at high risk of infection, but is not recommended for
the general population. INH chemoprophylactic therapy is recommended for
household contacts of active cases of tuberculosis. It is also recommended
for persons with positive tuberculin skin tests who have documented skin
test conversion, radiographic lesions suggestive of inactive but previously
untreated tuberculosis, who are under 35 years of age, or those with an
underlying medical condition which predisposes them to reactivation (especially
HIV infection) regardless of age.
Burden of Suffering
The number of cases of active tuberculosis in
Canada has been decreasing gradually over the past few decades, and in
the past few years has plateaued, with 1,995 cases (7.5 per 100,000) reported
in 1990.<2> For individuals born in Canada, most reported cases occur
in the very young and in those of advancing age. Among the Canadian-born,
rates are ten times higher for the aboriginal group. Proportionally, more
active cases occur in immigrants to Canada, with the highest rates reported
in those immigrating from areas where tuberculosis is endemic, including
Africa, Asia, Central America and certain countries in South America and
the Caribbean.
Death rates from tuberculosis have also declined. In Canada in 1990, 129 persons with tuberculosis died (0.6 per 100,000 population) and in 60 cases, tuberculosis was the cause of, or a significant contributor to death.
Most new cases of tuberculosis are pulmonary. Persons infected with large inocula (i.e. following household exposure to a cavitary case) and those with increased susceptibility to infection (e.g. children less than 5 years) are at higher risk of acquiring infection. In 90% of exposed persons, host defenses contain the primary infection, but the individual develops a positive tuberculin skin test. In the absence of preventive measures 5-15% will develop reactivation tuberculosis during their lifetime, the risk being greatest during the first two years following exposure. From observational studies, certain groups have been identified to be at an increased risk of reactivation, although in many cases the exact level of risk is not well defined. In patients with silicosis, head and neck cancer, jejunoileal bypass or in those who require hemodialysis, the relative risk is reported to be increased 10-30 times over that of the baseline population. The relative risk for patients with low body weight or nutritional deficiency, diabetes mellitus, or gastrectomy is reported to be increased 2-5 times. Persons infected with HIV are now recognized to be at the highest risk of reactivation with rates reported at 8-9% per year in recent studies. Other groups identified to be at increased risk are those with other immunosuppressive disorders (hematologic malignancies), those requiring immunosuppressive therapy for malignant or non-malignant conditions, patients requiring high dosages of corticosteroids over prolonged periods, the urban poor, persons living in shelters, intravenous drug users and alcoholics.
Maneuver
The Mantoux tuberculin skin test is the gold
standard screening test to identify infection with the human tubercle bacillus.
For testing, 0.1 ml of PPD-T (standardized purified protein derivative,
Connaught Laboratories) containing 5 TU (tuberculin units) is injected
intracutaneously into the dorsal (volar) surface of the forearm. The 1
TU and 250 TU tuberculins are not biologically standardized and are not
recommended for routine use. The injection is made intradermally and a
discrete wheal 6-10 mm in diameter should be produced in all cases. Tuberculin
tests should be read at 48-72 hours. The basis of reading is the transverse
diameter in millimetres of the induration (not the erythema) which can
be determined by inspection and palpation or by the ball point pen method.
The cut-off point for the interpretation of a positive test was derived from multiple population surveys comparing the reaction size in patients with or without presumed exposure and development of subsequent active disease. There is no clear point of separation between a positive and a negative test. Defining a positive reaction becomes increasingly difficult as the prevalence of cross-reactions with atypical mycobacteria increases and true infections due to Mycobacterium tuberculosis become less frequent. These observations have led experts to recommend use of different cut-off values for different population groups.<3> For individuals at very high risk of reactivation, including contacts of infectious cases, and persons with HIV infection, the recommended cut point is 5 mm. For persons not likely to be exposed, who reside in geographic areas where infection with atypical mycobacterium is common (i.e. the United States), the cut off is increased to 15 mm. For those with an intermediate risk, such as those living in or immigrating from endemic areas, or those areas where cross reactions with atypical mycobacteria are less common (i.e. Canada) an intermediate level of 10 mm is used. It should be noted that most patients who receive BCG vaccination as children, lose their cutaneous hypersensitivity reaction to tuberculin within 5 years. Therefore, a significant reaction more likely represents true exposure to tuberculosis especially in the setting of a recent exposure.
Another problem with tuberculin skin testing is inter- and intra-observer variation in the interpretation of test results.<4> Agreement is highest when the results are clearly positive (>15 mm) or clearly negative (<5 mm), with more inter-observer variation (mean 6 mm) when more readings are in the 5-14 mm range. This degree of variation can result in incorrect labelling. Some patients with compromised immune systems (especially those infected with HIV who have low CD4 counts) may be anergic. These individuals are unable to mount a skin test response to injected antigens (including tuberculin) despite previous exposure, and may be incorrectly labelled as negative.
The tuberculin skin test is a safe procedure. Purified protein derivative (PPD) does not sensitize nor activate a latent reaction. A few (1-2%) exquisitively sensitive persons with positive tests may respond with a severe local reaction with ulceration or vesiculation, regional adenopathy and fever. These reactions are typically self-limited, but painful, and may be reduced with intralesional steroids. Localized allergic reactions including wheal and flare and localized rash may occur in 2-3% of patients particularly those with a history of atopy. These reactions tend to occur in the first few hours, are self-limited, and do not correlate with the tuberculin response. Anaphylaxis or death have not been reported.
For persons with positive reactions it is imperative to rule out active disease by clinical history, chest radiograph and the appropriate laboratory investigations. Once active infection is ruled out, it is important to explain to the patient that a positive reaction implies a subclinical infection with tuberculosis and the risk for subsequent reactivation to active disease, but that the individual does not have active disease nor are they infectious to others.
Effectiveness of Prevention
The main purpose of chemoprophylaxis is to prevent
reactivation of a latent infection to clinical disease. It is important
prior to the initiation of chemoprophylaxis that active TB is excluded.
The only drug which has been studied extensively for chemoprophylaxis is
Isoniazid (INH). More than 20 clinical trials evaluating the role of chemoprophylaxis
in tuberculosis are reported in the literature. Despite the multitude of
methodological flaws of these early studies, including 1) non-random allocation;
2) inclusion of previously treated cases; 3) use of other therapies in
combination with INH; 4) historical controls; 5) randomization by groups
(families, hospital wards), but analysis by individuals; and 6) the inclusion
of active cases, all but one of these trials has shown a significant benefit
for INH prophylaxis. The best studies demonstrating effectiveness of INH
prophylaxis in different patient groups are outlined below:
Positive Tuberculin Skin Test <35 Years
During a routine skin testing program (1958-1966)
in San Francisco public school students with a large immigrant population,<5>
a non-randomized comparative study evaluated INH prophylaxis. Over a 1-2
year follow up, 1 of 2,910 children in the INH-treated group (0.34 per
1,000) and 25 of 1,192 on no treatment (20.9 per 1,000) developed active
tuberculosis. Although demonstrating a highly statistical and clinical
benefit of INH prophylaxis, there is concern about the comparability of
the two groups, with racial differences noted between the treatment and
control groups. Other reasons for not choosing treatment may also have
been associated with increased risk of tuberculosis in controls. There
is fair evidence to support prophylaxis in this setting, especially for
children.
Positive Tuberculin Skin Test > 35 Years
27,924 patients from 39 U.S. Mental Institutions
were randomly allocated by ward to receive INH or placebo.<6> During
the medication year, 21 of 12,326 (1.7 per 1,000) patients assigned placebo
and 4 of 12,884 (0.3 per 1,000) assigned INH developed active tuberculosis,
with 17 of the 25 patients who developed tuberculosis having had an abnormal
chest x-ray on entry. Although this is a statistically significant reduction
in cases, the clinical significance and generalizability of the results
are uncertain. The crowding and institutionalization would likely have
increased the risk of disease. Other biases in the study weaken the strength
of the observations. The Task Force feels there is insufficient evidence
to recommend routine prophylaxis for all adults >35 years with a positive
tuberculin skin test.
Although no controlled studies have been performed, INH prophylaxis is strongly recommended (by expert opinion) for patients with medical conditions that increase the risk of reactivation of tuberculosis, regardless of age.<16>
HIV Infected Patients
From 1986-89, 118 asymptomatic HIV positive persons
in Haiti were randomized to receive INH prophylaxis with vitamin B6 or
B6 alone for 12 months.<7> Eleven of sixty (18%) patients in the B6
group developed active tuberculosis over the study period in contrast to
four of 62 who received INH and B6, p=0.03. This is consistent with a reduction
from 7.5 to 2.2 cases per 100-person years. There is good evidence to support
the use of INH prophylaxis in patients with HIV infection.
Household Contacts of Active Cases
The Tuberculosis Program of the U.S. Public Health
Service studied INH prophylaxis in household contacts of new active pulmonary
cases in the U.S. and Puerto Rico between 1957 and 1960.<8> The groups
were similar in age and race distribution. Two thirds of all participants
<20 years were randomized to receive INH or placebo for one year. Pulmonary
or extrapulmonary tuberculosis developed in 78 of 12,594 (6.5 per 1,000)
placebo recipients versus 18 of 12,439 (1.5 per 1,000) INH recipients.
A similar household-based study in Japan failed to show a benefit of INH prophylaxis<9> although there was a trend toward decreased tuberculosis in the INH treated group (8 per 1,142) compared to the control group (11 per 1,096). Poor compliance and the small sample size were the most likely reasons for the lack of significant effect.
The Task Force concludes there is good evidence to support the role of INH chemoprophylaxis in household contacts of active cases of tuberculosis.
Tuberculin Skin Test Converters
Recruits of the Royal Netherlands Navy whose
skin tests converted to positive following exposure to an active case of
pulmonary tuberculosis were randomized to receive INH (n=133) or placebo
(n=128) for one year.<10> During the treatment year, 9 cases of tuberculosis
developed in the placebo recipients (70 per 1,000) in contrast to 1 case
in the INH group (7.5 per 1,000), a significant difference.
INH prophylaxis was evaluated in a cohort of nursing home patients with tuberculin skin test conversion.<11> Tuberculosis developed in 1 of 605 converters receiving INH (1.6 per 1,000) and in 45 of 757 (59 per 1,000) receiving no treatment. This was clinically and statistically significant.
The Task Force concludes that there is good evidence to recommend INH prophylaxis in skin test converters regardless of age.
PPD Positive, Old Fibrotic Scar on Chest
Radiograph
The International Union Against Tuberculosis
(IUAT) performed a European multi-center, double-blind, placebo-controlled
trial of INH prophylaxis in patients with a positive PPD and an old fibrotic
scar on chest x-ray.<12> Of the 27,830 patients enrolled (median age
50 years), 6,953 were randomized to receive INH for 12 weeks, 6,965 INH
for 24 weeks, 6,919 INH for 52 weeks and 6,990 patients were randomized
to placebo. Over the 5 year study, active pulmonary tuberculosis developed
in 97 placebo recipients (14.3 per 1,000), 76 patients on INH for 12 weeks
(11.3 per 1,000), 34 patients on 24 weeks of INH (5.0 per 1,000) and 24
patients on 52 weeks of INH (3.6 per 1,000). This represents a 60% reduction
in cases for patients receiving a 6 month course and approximately 90%
reduction for patients receiving a 12 month course of INH. An additional
181 patients were removed from the trial as suspected cases of tuberculosis
(either extra-pulmonary tuberculosis, or pulmonary tuberculosis without
positive culture) but it is not reported how many of these patients received
INH. Based on this study the Task Force feels there is fair evidence to
support the use of INH prophylaxis in this setting.
Duration of Therapy
Most studies evaluating INH chemoprophylaxis
have utilized a one year course of therapy, and this is the duration recommended
by the Task Force. A cost analysis study has suggested that a 24 week regime
was more cost effective.<13>
Alternative Regimes
There have been case reports of failed INH chemoprophylaxis
for patients infected with INH-resistant organisms. There is no study available
to recommend alternative agents in this setting. Expert opinion suggests
that Rifampin and Ethambutol, Rifampin and INH or Pyrazinamide containing
regimes should be considered.
Compliance
Compliance remains an important barrier to effective
chemoprophylaxis. In the clinical trials cited above, compliance ranged
from 50-75% through one year of preventive therapy. In a study involving
Canadian aboriginals, compliance was improved by a program of daily observed
prophylaxis and education but was not sustained after observation was discontinued.<14>
Adverse Events of Screening and Treatment
Prophylaxis with INH has been associated with
many adverse events, including hypersensitivity reactions, INH-induced
lupus-like syndrome, peripheral neuropathy, gastrointestinal distress,
and central nervous system abnormalities ranging from memory loss to psychosis
or seizures. The most significant and potentially dose-limiting side effect
is hepatitis. Fifteen percent of patients will experience a transient asymptomatic
increase in their liver transaminases on treatment. Clinical hepatitis
is much less common and is rarely fatal, particularly when recommendations
for surveillance are followed.
The best prospective study to determine the incidence of INH hepatitis documented 236 suspected cases among 13,838 receiving prophylaxis.<15> Of these cases, 92 were classified as probably INH-related and 82 possibly INH-related by an expert panel. The case rates appeared to increase with age, with rates for probable cases <20 years (0 per 1,000), 20-34 years (3 per 1,000), 35-49 (12 per 1,000), 50-64 years (23 per 1,000) and >64 years (8 per 1,000). The rates also varied with race, with the highest rates occurring in Orientals (18 per 1,000) in contrast to 11.4 per 1,000 in whites and 7.1 per 1,000 for blacks. The rate for those who drank alcohol (14.1 per 1,000) was double that of non-drinkers and the rate for daily drinkers (26.5 per 1,000) was even higher. In the IUAT trial, the risk of INH-related hepatitis was 0.5%, with a mortality rate of 14 per 100,000.<12>
Other disadvantages of chemoprophylaxis include the inconvenience of daily medication over a one year period and the need to attend regular clinic visits. The cost of the program, and demands on staff for screening and follow-up must also be considered.
Recommendations of Others
The American Thoracic Society (ATS) has recently
published new guidelines.<7> They propose the same groups for tuberculin
testing as the Canadian Task Force but use "recent contacts" rather than
"household contacts" of new cases. The high risk group for reactivation
infection, also includes medically underserviced populations, persons resident
in long-term care facilities, nursing homes, mental institutions and correctional
institutions. They do not recommend prophylaxis for patients with positive
tuberculin skin test and fibrotic lesions on chest radiographs, but rather
recommend that these patients be treated with multi-drug regimes as for
active disease. They recommend INH prophylaxis for all patients with known
or suspected HIV infection and a positive PPD.
The Centers For Disease Control in Atlanta also recommend routine skin testing of all persons at high risk, including the homeless.<17>
The Canadian Thoracic Society has also developed new guidelines (personal communication, Dr. M. Fitzgerald). They recommend that given the low frequency of infection with atypical mycobacteria, that the 10 mm cut-off be used for the general Canadian population.
In 1989, the U.S. Preventive Services Task Force recommended skin testing for patients at increased risk for tuberculosis.<18> In addition, they recommend following the ATS guidelines for prophylaxis.
The American Academy of Pediatrics Redbook recommends annual testing of high-risk children, including those who are black, Hispanic, Asian, American Indian, Native Alaskan, the socioeconomically deprived, those living in neighbourhoods where case rates are above the national average, children or their parents who themselves have immigrated from high risk areas of Asia, Africa, the Middle East, Latin America or the Caribbean, households where there have been active cases and those with underlying medical risk factors.<19> Annual testing is not recommended for low-risk groups but skin testing in these low-risk children is recommended at 12-15 months, 4-6 years, and 14-16 years. INH is recommended for all infants, children and young adults up to 35 years of age with positive PPD for 9 months. No justification is given for the duration
Conclusions and Recommendations
Tuberculosis screening should be offered to persons
in Canada at high risk of infection with the tubercle bacillus, including
immigrants from endemic areas, Canadian-born aboriginals, close contacts
of active cases, persons with abnormal chest radiographs consistent with
healed tuberculosis, and persons with underlying medical conditions which
increase their likelihood of reactivation of tuberculosis if infected,
including those with HIV infection, silicosis, hemodialysis patients, those
with immunosuppressive conditions or therapy, intravenous drug users, diabetes,
gastrectomy patients or those with gastrointestinal bypass surgery, and
the nutritionally deficient (A Recommendation). Routine screening is not
recommended for the general population (E Recommendation). INH prophylaxis
for twelve months is recommended for household contacts of active cases
of tuberculosis (A Recommendation) and for persons with positive tuberculin
skin tests who have documented skin test conversion (A Recommendation),
chest radiographic lesions suggestive of inactive tuberculosis (B Recommendation),
HIV infection (A Recommendation) and for patients under 35 years of age
with a positive tuberculin test (B Recommendation). Prophylactic therapy
is not recommended for persons with positive skin tests over the age of
35 years (C Recommendation) unless they have a medical condition associated
with an increased risk of reactivation where prophylaxis is recommended
(A Recommendation).
Unanswered Questions (Research
Agenda)
A number of areas continue to be of concern regarding
the detection of infected persons and the use of prophylaxis. Priorities
that need to be addressed include the development of: 1) more effective,
less toxic, shorter duration preventive treatments; 2) ways to improve
compliance with chemoprophylaxis; 3) effective vaccines; 4) better studies
to determine the true incidence of reactivation tuberculosis in patients
with isolated positive tuberculin skin tests with no other risk factors;
5) the true relative risks for reactivation in those patients with various
underlying medical disorders; and 6) chemoprophylactic measures for patients
infected with INH resistant strains.
Evidence
The literature was identified with a MEDLINE
search with the use of the main MESH heading "tuberculosis" and the subheadings
"tuberculin skin test", "prevention and control" and "isoniazid" for articles
presented from 1966 through 1992. Indices of the American Review of Respiratory
Diseases and Tubercle were screened from 1960-1992 for articles with emphasis
on screening and treatment.
This review was initiated in August 1992 and the recommendations were finalized by the Task Force in January 1994.
Acknowledgements
The Task Force thanks Sam Akor, BSc, MB, ChB,
MCommH, MA, Director/DMOH, Rural Health Training School, Kintempo, Ghana
for his work on the preliminary report. Helen Holden MD, FRCPC, FCCP, Valley
Regional Hospital, Kentville, Nova Scotia, Richard Menzies, MD, MSc, FRCPC,
Assistant Professor, McGill University and Montreal Chest Hospital, Montreal,
Quebec and Mark Fitzgerald, MD, FRCPC, Assistant Professor, University
of British Columbia and Department of Respiratory Medicine, Vancouver General
Hospital, Vancouver, British Columbia are thanked for reviewing the draft
report.
Full Citation
Walmsley SL. Screening and isoniazid prophylactic
therapy for tuberculosis. In: Canadian Task Force on the Periodic Health
Examination. Canadian
Guide to Clinical Preventive Health Care. Ottawa: Health Canada,
1994; 754-65.