THE TUBERCULIN SKIN TEST IN CHILDREN WITH TUBERCULOSIS IN THE STATE OF QATAR

Al Marri S.A., Al Taweel A.A. and Elgar F.
Hamad Medical Corporation, Doha, Qatar

Abstract:

To correlate standard tuberculin skin test (TST) results in children diagnosed with active tuberculosis (TB), data was collected retrospectively from the tuberculosis treatment unit, State of Qatar, during the period 1992 to 1996. Sixty-six patients with confirmed tuberculosis included 42 (64%) with pulmonary TB, 24 (36%) with extra-pulmonary TB, 34 Qatar nationals (52%) and 36 females (55%). Mean TST was 13.5 mm ± 9.8mm. TST was negative in 18 (27%), 5-10 mm in three (5%), 10-15 mm in eight (12%) and 15mm or more in 37 (56%) patients. Lower false negative (reaction less than 10mm) was found in five (18%) of the older children (10 to 14 years).

It is concluded that, since one-third of the children with confirmed active tuberculosis had a false negative TST, clinical judgement remains the essential determinant. However, TST remains a potent aide for epidemiological and diagnostic purposes and periodic assessment of this is highly recommended.

Key words: TST, Tuberculosis, children and Qatar.

Introduction:

Robert Koch’s old tuberculin (OT) was further purified by Florence Seibert as “purified protein derivative” (TST)(1,2) and subsequently standardized by Seibert and Glenn (TST-S) to form the basis of an intradermal skin test in humans and as variants in several other species.

Early studies in tuberculosis sanitoria demonstrated the high sensitivity to graduated skin testing with tuberculin and a negative result was used to rule out tuberculosis (TB). However, negative tuberculin reactions have been reported since in 4-5.6% of patients with confirmed pulmonary tuberculosis(3, 4) and there has been considerable controversy about the role of tuberculin testing for diagnosis and prevalence surveys, the potency of tuberculin tests, tuberculin products and method of delivery eg. Mantoux vs multiple punctures(2,5-10).

In most children tuberculin reactivity appears three to six weeks after primary infection although it might be delayed for as long as three months. Once present it remains life-long even after preventive chemotherapy(11). A “booster” phenomenon increases in children previously vaccinated with BCG or in geographic areas endemic with Mycobacterium other than tuberculosis

This is the first paper to examine the reaction and/or potency of TST in Qatari children with tuberculosis. It provides a reference for any future survey and might also provide a reflection of the current status in the area of the Gulf Cooperation Council (GCC).

Methods:

During the five years from January 1992 data was collected retrospectively from the Tuberculosis Treatment Unit (the only registry for the whole of Qatar) from the files of children up to 14 years of age with confirmed tuberculosis (0-14 years being officially the childhood / pediatric age).

Tuberculosis was considered confirmed if Mycobacterium tuberculosis was isolated from any site or if the clinical or radiographic findings were consistent with TB. When the diagnosis was based on clinical and/or radiographic findings, at least two of the following criteria were also required:

a. Close contact with an adult source (open) case.
b. Positive TST 15mm or more for young children and 5mm or more for infants with history of contact with an open case.
c. Exclusion of other clinical entities with an adequate response to anti-TB medication.

In the State of Qatar since 1970 BCG vaccination has been given at birth to all healthy children with a compliance of almost 95%. Boosters were given to children less than five years of age on screening of a close contact, if repeat purified protein derivatives (TST) was negative eight weeks later and active TB could be ruled out.

The Mantoux skin test was done by the nurses at the TB treatment unit using 0.1cc of 5 ITU of purified protein derivative (PPD) CT68 manufactured by the Connaught Laboratories Limited, Toronto, Ontario, Canada, and distributed by Pasteur Merieux Connaught (Rhône-Poulenc group, Pennsylvania, USA). The PPD was injected intradermally in the forearm of the patient, was read by the nurses and confirmed by a doctor.

The size of the reaction (induration) was measured after 48 and 72 hours. An area of 10 mm or more of induration was considered to be a positive reaction. Areas of 5 to 9 mm were classified as weak or doubtful reaction and 0 to 4 mm were considered to be negative. Analysis and significance testing by Fishers Exact and by the x2 testing when appropriate with 95% confidence intervals (Cis) were performed, using EpiInfor version 6 and SPSS version 7.5.

Results:

The mean TST was 13.5mm with a standard deviation of 9.8mm in the 66 children with confirmed tuberculosis. Twenty-one (32%) of them were falsely negative (less than 10mm), of whom 18 (87%) were negative (< 5mm) and three (13%) were doubtful (5-10mm). Eight (12%) patients had 10-15 mm skin reactivity to tuberculin. Thirty-seven (56%) patients had 15mm or more skin reactivity to TST, of which 73% were 20mm or less and 27% were more than 20mm. (Figure 1) ]

The mean age of the children was eight years with a standard deviation of 4.5 (range 1 to 14 years). Twenty-eight (42%) of the children were in the 10 to 14 year age group, which had a significantly lower false negative TST (TST less than 10mm) with p value of 0.038. However “10”of them (67%) were culture positive (Table 1). Although there was no sex disparity (55% females and 45% males), the females had a higher mean (14.6mm ± 10.8 vs 12.2mm ± 8.5). This was not statistically significant (p= 0.81) and the rates of false negative TST’s were 31% for females and 33% for males.

There were 34 (52%) Qatari nationals with TST of 15 ± 10.6 and 32 non-Qataris with TST of 11mm ± 8.8. Skin reactions of less than 10 mm were 29%, 34% for Qatar and non-Qatar nationals respectively. This difference was not statistically significant (p= 0.67).

TST reactivities of less than 10 mm were obtained in 33% and 29% respectively of the 14 pulmonary and seven extra-pulmonary cases (p= 0.73); in four (24%) and ten (43%) of culture positive and culture negative cases respectively (p=0.2); in none, eleven (38%), and two (50%) of cavitary, non-cavitary infiltrate cases, and other chest radiographic findings (such as old change, pleural involvement and normal chest radiographic) respectively (p= 0.10); and in fifteen (34%) and two (22%) of symptomatic and asymptomatic cases respectively (p=0.39). None of these results were statistically significant.

Skin testing repeated eight weeks later in the 21 cases previously with negative TST (less than 10 mm) was positive in ten (15% of the total 66 cases tested)) and persistently negative in eleven (17%). The demographic data of those with persistently negative TST is shown in Table 2.

Discussion:

Two factors contribute to false-negative tuberculin skin tests in patients with confirmed tuberculosis. First is the “host factor”, which includes acute or overwhelming tuberculosis, HIV infection, immunosuppressive diseases (e.g.lymphoma, etc.), viral infections (measles, mumps, varicella), live virus vaccination, renal failure and malnutrition. The second factor relates to faults in the testing procedure; improper storage of TST, improper dilution, delayed injection after filling the syringe, subcutaneous injection, lack of experience in interpretation and /or bias in interpretation(2).

All the children in this survey were well nourished and had no overwhelming disease or clinical evidence of immunological deficiency. The anergic (less than 5 mm TST) patients were not significantly different from those with positive skin tests in respect of age, gender, place of birth, symptoms, or socio-economic status. It is highly unlikely that the results were due improper techniques or faulty test materials as all tests were performed by trained nurses in the tuberculosis treatment unit and reviewed by a TB consultant.

Twenty seven per cent of our patients were anergic to tuberculin, which is similar to several adult studies(5,6,7,8) but higher than the 4% to 5.6% reported in other adult studies(3,4) and the 14% (18.5% including reactions 5-10mm) noted in a previous study of 200 children with culture-proven M. tuberculosis infection in USA(12). In that last study 5.5% of the children had persistently negative tuberculin reactions after therapy compared to 16% in our study after eight weeks of therapy. The presence of anergy did not correlate with a poor prognosis in our patients or another study(12).

There were 14 (33%) pulmonary cases with negative TST, which was similar to a previous study(13) but the four cases (24%) of negative TST in culture-proven M. tuberculosis was higher than previously reported(13). There was a small but consistent decrease in the rate of false negative (low or absent) reactions to TST from nine cases (43%) less than five years of age to five cases (18%) in children 10 to 14 years of age. This was statistically significant, probably due to the high number of older children with positive culture.

There was no significant difference between the ten Qatar nationals (29%) with false negative results and the eleven non-Qataris (34%). This would seem to exclude any effect of racial differences(13). There was no significant difference in false negative TST and chest radiography. Also the reading of the ize of the TST showed a bias, especially in those above 20 mm because of reading the size using the plastic drawing circle ready made. In conclusion, the tuberculin skin test should be regarded solely as an important aid for epidemiological and diagnostic purposes but clinical judgement remains the essential determinant of tuberculosis.

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