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* From the Division of Tuberculosis Control (Drs. Marciniuk, McNab, and Hoeppner) and Department of Microbiology (Dr. Martin), The Research Center for the Elimination of Tuberculosis, Royal University Hospital, University of Saskatchewan, Saskatoon, Canada.
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Abstract |
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Setting: Centralized, provincial TB control program.
Subjects: Twenty-five patients with culture-positive pulmonary TB and a normal CXR were identified from a review of 518 consecutive patients with culture-positive pulmonary TB in the province of Saskatchewan from January 1, 1988 to March 31, 1997. Patients with abnormal CXRs at the time of diagnosis were excluded from the analysis.
Results: Twenty-three of the 25 patients (92%) were symptomatic at the time of diagnosis, with cough/sputum (76%) being reported most commonly. Eleven patients were identified because of contact tracing from cases of infectious pulmonary TB, while the other 14 patients were identified because of an investigation of symptoms. Twenty-four patients (96%) exhibited one or more symptoms of cough for > 1 month, fever for > 1 week, or skin-test conversion after contact with infectious TB. The sputum smear of only one patient was positive. Two patients were pregnant at the time of diagnosis, one patient was HIV-positive, and one patient demonstrated isoniazid-resistant organisms on sensitivity testing. Five patients were diagnosed as having primary TB associated with Mantoux skin-test conversion. The incidence of culture-positive pulmonary TB with a normal chest radiograph was < 1% in the period from 1988 to 1989 and steadily increased to 10% in the period from 1996 to 1997.
Conclusions: Culture-positive pulmonary TB with a normal CXR is not uncommon, and the incidence of this presentation is increasing. Patients with this presentation of TB are typically symptomatic and/or are detected by contact tracing to infectious cases of pulmonary TB. The results suggest that patients presenting with a cough for > 1 month, with a fever for > 1 week, or with documented skin-test conversion < 2 years after known exposure to infectious TB should have sputum submitted for a Mycobacterium tuberculosis smear and culture despite a normal CXR.
Key Words: chest radiograph • cough • diagnosis • symptoms • TB
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We, therefore, undertook this study in view of these clinical impressions suggesting an increasing incidence and the lack of objective data describing pulmonary TB with a normal CXR. We were interested in documenting and closely examining the clinical features and presentation of pulmonary TB with a normal CXR and also in establishing whether the incidence of this presentation was indeed increasing. Finally, if we were able to document an increased incidence, we examined the reasons for it, with the intention of gaining insight into this increasingly frequent presentation of TB.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five hundred eighteen consecutive patients with culture-positive pulmonary TB were identified during the time period. Arthropometric data, symptoms (cough, sputum production, hemoptysis, fever, weight loss, night sweats, and anorexia), previous antibiotic therapy, method of detection (symptoms, contact trace, physician referral, etc), cultures (site, dates, results, and sensitivity), Mantoux skin tests (dates and results), and other associated medical conditions were collected as recorded by the TB consultant in the standardized case and computer database for each identified patient.
CXR Interpretations
In each identified case, CXR interpretations by both the TB
consultant and a board-certified radiologist were reviewed. CXRs were
recorded as normal only if both the attending TB consultant and the
radiologist (who was blinded to the interpretation by the TB consultant
and was not employed by the Saskatchewan Tuberculosis Control
Program) gave written interpretations concluding that the films
were normal. If more than one CXR was performed for any patient, he or
she was not included in this review, and patients were excluded from
analysis if any of the CXRs showed abnormalities (ie, all
radiographs had to be normal).
Mycobacteria Cultures
All specimens for mycobacterial culture were processed at one of
two centralized reference laboratories. In the laboratory, sputa were
transferred into a 50-mL centrifuge tube. An equal volume of 4% NaOH
and 0.5 g N-acetyl-L-cysteine (giving a final concentration of
2% NaOH and 0.25% N-acetyl-L-cysteine) was then added before
vortexing to facilitate liquefaction of the specimen. The treated
specimen was then kept at room temperature for 15 min. A buffer
solution (pH 6.8) was added to bring the volume to the 40-mL mark of
the centrifuge tube, and the specimen was centrifuged for 20 min at
4,000 rpm in a refrigerated centrifuge (RC-3B; Sorvall; Newton,
CT). After decanting the supernatant, the sediment was then resuspended
in 1.5 mL of sterile distilled water. This concentrate was used to
prepare smears and inoculate cultures.
Smears for fluorochrome staining for acid-fast bacilli were heat-fixed at 65°C for 1 h. The slides then were flooded with auramine O stain and kept at room temperature for 15 to 20 min, washed with distilled water, drained, and decolorized with acid alcohol for 2 min. Potassium permanganate solution was applied as a background stain. The slides again were drained and air dried before microscopic examination.
Cultures were performed by pipetting 0.1 mL of suspension into Lowenstein-Jensen medium and incubating the medium in 7% CO2 at 37°C. In addition, 0.6 mL of the concentrate was injected into a vial of medium (Bactec 12B medium; Becton Dickinson; Cockeysville, MD) and incubated at 37°C. If growth was detected in or on either medium, smears were prepared from the cultures and were stained by Kinyoun's method to confirm the presence of acid-fast bacilli. Growth was identified as Mycobacterium tuberculosis complex by using a DNA probe (Accuprobe; Gen-Probe; San Diego, CA). At a later date, biochemical tests (niacin, nitrate reduction, and 68°C catalase) were also performed.
Antimicrobial susceptibility testing was performed on all isolates of Mycobacterium tuberculosis complex against isoniazid, rifampin, ethambutol, and streptomycin.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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10 years old at the
time of diagnosis. Seventeen patients were female, and 8 patients were
male. Twenty-two positive cultures were from sputum samples (1 was
smear-positive; the remaining 21 cultures were smear-negative), and 3
positive cultures were from gastric washings (all from patients 10
years old). Fifty-two percent of the patients were status Indian
(persons registered as Indian under the Federal Indian Act), 24% were
nonstatus Indian, 16% were foreign born, and 8% of the patients were
nonaboriginal Canadian born compared to 54%, 27%, 6%, and 14%,
respectively, in all culture-positive pulmonary TB patients diagnosed
during the same time period in Saskatchewan.
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A Mantoux skin test was recorded in 23 patients (92%) and was not performed in 2 patients. Of the 23 patients, 5 patients were previously known to have an induration size of > 10 mm, as revealed in a Mantoux skin text at least 2 years before the diagnosis of pulmonary TB, and, therefore, the test was not repeated at the time of diagnosis. Five patients were skin-test converters with an induration size of 0 mm3, as determined by a previous Mantoux skin test, having been recorded within 2 years of a later significant skin test. In all patients, the mean size of induration was 19 mm, although four patients (16%) had an induration size of 0 mm. A skin test repeated 1 and 3 months after the initial skin test, respectively, in two of these patients also revealed an induration size of 0 mm, although a test was not repeated in the remaining two patients (one of these latter patients was HIV-positive). For comparison, 5% of all patients with culture-positive TB and an abnormal CXR (n = 493) during the study period had an induration size of 0 mm, as determined by a Mantoux skin test.
All 25 patients had a CXR at the time of diagnosis that was interpreted as normal by both the radiologist and the TB consultant. For additional confirmation, 24 patients (96%) had a second normal CXR (mean [± SD] time interval after the first radiograph, 1.8 ± 2.3 months), and 16 patients (63%) had a third normal CXR (mean [± SD] time interval after the first radiograph, 5.1 ± 3.7 months). Repeat CXRs (after the initial normal CXR) were not obtained for the remaining patient.
Table 2 outlines the clinical characteristics of the patients with normal CXRs and culture-positive pulmonary TB. Eight patients had multiple cultures positive for M tuberculosis. Although 2 patients were asymptomatic, in the remaining 23 patients, clinical symptoms consistent with TB responded to the initiation of anti-TB chemotherapy. Two patients were pregnant at the time of the diagnosis of TB and one patient was HIV-positive. One patient had disseminated TB, as evidenced by sputum cultures, and an enlarged lymph node that was positive for M tuberculosis. One patient also was found to have erythema nodosum at the time of diagnosis.
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Discussion |
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This study confirms our clinical impressions that the incidence of pulmonary TB presenting in this fashion has increased in the past 10 years. The incidence of culture-positive pulmonary TB was 0.7% (1988 to 1989) and 3.5% (1990 to 1991); however, more recently, the incidence of culture-positive pulmonary TB with a normal CXR has increased to 10% (1996 to 1997) (see Fig 1 ).
There are many possible reasons for this increasing occurrence. Although the incidence of HIV infection/AIDS has also increased during this period, and the interaction of TB and HIV infection has been well documented,8 ,9 it is unlikely that the increased incidence can be attributed to known HIV infection/AIDS, because this association was present in only one patient in our series. However, while counseled regarding HIV infection, the other twenty- four patients did not undergo testing. Nonetheless, although it appears that HIV infection/AIDS may be a significant factor contributing to the incidence of pulmonary TB with a normal CXR (see the following), our study findings suggest that other factors exist in our series.
A likely explanation for this increasing incidence may be improved detection of early disease. In this regard, it is possible that case detection bias may contribute to these findings, and the increased incidence of pulmonary TB with a normal CXR in patients with HIV infection/AIDS would support this assertion. The index of suspicion for infectious diseases is very high in patients with HIV infection/AIDS, and thus TB may be diagnosed at an early stage when the CXR is still normal. Similarly, the index of suspicion for TB in Saskatchewan has also been heightened recently. Through the combined efforts of both federal and provincial government agencies, the Saskatchewan Tuberculosis Control Program has undergone several significant enhancements in the past 10 years. Most notable is the universal provision and funding of directly observed therapy, although this would not impact the results of this study. Nonetheless, resources for the program have been enhanced in such a way that screening efforts have also been greatly reinforced. In addition, procedures and resources directed at appropriate and timely contact tracing have been strengthened. For example, as mentioned in the Introduction, and in view of our clinical impression that this mode of TB was occurring with increasing frequency, we began to obtain sputum cultures more often from our patients, even if the CXR was normal. Therefore, it is likely that these combined efforts contributed to the findings in this study.
The issue of case-detection bias probably explains the finding of a higher incidence of culture-positive pulmonary TB with a normal CXR in the foreign-born patient, and a lower incidence in the Canadian-born patient. Similar to the situation in the HIV/AIDS patient described above, the index of suspicion for TB is very high in recent immigrants to Canada,5 and thus it is not surprising that TB may be diagnosed at an earlier stage in these patients.
Another contributing factor may be that within the last 10 to 12 years, two laboratory techniques have improved the sensitivity of mycobacterial cultures, facilitating the detection and isolation of smaller numbers of tubercle bacilli. First, high-speed refrigerated centrifugation of processed specimens has improved the concentration of tubercle bacilli before culture.10 Second, the introduction of the Bactec 460 TB System (Becton Dickinson), using a broth medium and carbon-14 growth detection system, has improved sensitivity for the isolation of M tuberculosis.11 ,12 The former improvement was introduced in one of our laboratories in 1986, the latter system in 1988.
It is possible that some of the results may have been due to false-positive cultures for M tuberculosis, although we do not think that this factor alone is a significant contributor to our findings. Although the incidence of false-positive cultures has been estimated to be approximately 1.1 to 3.6% in some laboratories,6 and contamination has been documented even in reference laboratories using strict and appropriate techniques (similar to ours),6 ,13 in these instances, the patients with false-positive isolates did not have a clinical syndrome compatible with active TB, and the diagnosis of TB was unlikely on clinical grounds.6 This is vastly different than our study population, because after applying the criteria outlined by Burman et al,6 23 of our 25 patients (92%) would fulfill the "true-positive" criterion (see Table 5 ). Furthermore, the remaining two patients (who were asymptomatic) were documented skin-test converters found when contact tracing for infectious pulmonary TB was performed. As outlined in Table 2 , the clinical features in our series of patients with normal CXRs and positive cultures for M tuberculosis are suggestive of and compatible with the diagnosis of TB.
There were several important precautions taken by our laboratories to reduce the rate of false-positive smears and cultures for M tuberculosis, including:
1. Staff experience and awareness of the potential for false-positive cultures is crucial. For example, the collective experience dedicated to mycobacteriology for the three full-time equivalents in one of the two provincial laboratories exceeds 60 years.
2. Ongoing and open communication between the TB clinicians and the TB laboratory staff is also essential for the early detection of false-positive smears and cultures. To maintain this necessary communication, regular weekly rounds are held that TB clinical and laboratory personnel attend and in which they participate. Interaction of the TB laboratory with clinicians receiving doubtful results and clinicians being critical of these results is of the utmost importance.14
3. Phosphate buffer reagent is transferred from stock bottles to a sterile beaker before use. Any unused buffer in the beaker is discarded. The top of the centrifuge tube is not touched during the transfer process. Stock bottles of buffer are used completely within 2 to 3 days.
4. Bactec needles are changed routinely twice a week.
5. Smears are spaced with a blank between the positive control smear and smears from clinical specimens on the staining rack. Any positive smears that occur on adjacent slides are immediately investigated and repeated.
6. Safety checks on biohazard hoods are performed every 6 months. In addition, daily checks of the airflow gauge are performed.
Although these precautions diminish the probability, the possibility of false-positive cultures for M tuberculosis can never be overemphasized.
We documented a 4.8% incidence of culture-positive TB with normal CXR in our patients. This frequency agrees with other reports, although differences do exist. Fitzgerald et al9 reported a 10% incidence in their series of 218 patients, Long et al15 noted a 7% incidence (67 patients), and Greenberg et al1 reported a 14% incidence (133 patients). However, it must be emphasized that these studies were only in patients with documented HIV infection/AIDS, a patient population in which TB is routinely suspected. In patients with TB who were being admitted to a hospital, a normal CXR was reported in 12% of HIV-infected individuals, whereas none of the HIV-negative patients with TB had a normal CXR in their series.7 In patients without documented HIV infection/AIDS, Miller and MacGregor16 noted a 3% incidence, Barnes et al4 reported a 1% incidence, and Gatner and Burkhardt17 documented a 1.4% incidence. Unfortunately, in some of these studies, serial CXRs were not obtained. In other reports,18 the findings are difficult to interpret because CXR findings and terms such as "pleural effusion," "old healed scars," and "rapid resolution" are reported as negative for TB, even though it appears that they were not "normal." In this study, only CXRs that were normal were included in the analysis, and serial CXRs were obtained in 96% of the study population.
Although the Mantoux skin test generally was positive (mean induration, 19 mm), in four patients the skin test showed an induration size of 0 mm. These four patients were all symptomatic, with cough for > 1 month (3/4), fever for > 1 week (3/4), or weight loss (2/4). These data serve to emphasize that a diagnosis of TB can be established in the presence of a "negative" Mantoux skin test,19 regardless of whether the CXR is abnormal or normal.
As stated earlier, all the patients in our series were detected either because of symptoms or because of contact tracing. Schmidek and Hardy2 reported eight cases of pulmonary TB with a normal CXR aboard a large navy heavy cruiser: six patients were asymptomatic; one patient had weight loss, and one patient had hemoptysis. All patients had documented tuberculin skin-test conversion had been in contact with infectious TB. Unfortunately, there is no mention of either cough or sputum in the article. In our study, 24 of the 25 patients (96%) would have been identified using the criteria of a cough for > 1 month, a fever for > 1 week, or skin-test conversion after contact with infectious TB. Our findings suggest that sputum for M tuberculosis smear and culture should be obtained in these patients regardless of the CXR findings (typical, atypical, or normal).
Characteristically in pulmonary TB, there is the almost imperceptible onset of cough.20 This slowly progresses over weeks or months to become more frequent and is often associated with sputum production.20 The presence of a cough for > 1 month was a very common symptom in our patients, and our findings agree with the hypothesis of a previous study that used the presence of cough to screen for TB in an outpatient setting in Kenya.21 In patients with TB, cough has been reported previously to be present in approximately 69%,5 although in this latter study, 79% of patients were sputum smear-positive for acid-fast bacillus, indicating further advanced disease. In another series of patients who died with pulmonary TB, only 41% of patients had cough on admission to the hospital, and 44% had CXR abnormalities reported as atypical for pulmonary TB.22 However, in contrast, only one patient had a positive sputum smear for acid-fast bacillus in our study, and we reported no deaths among our patients, although 76% of those with pulmonary TB and negative CXRs reported coughing.
Establishing a diagnosis of TB at an early stage is, of course, desirable.19 First, there are fewer public health concerns when cases are not smear positive, and only one case in our study was smear positive and considered potentially infectious. Second, the patient benefits from early diagnosis and treatment in terms of outcome and complications, and from less time and money lost from employment. Finally, the clinician avoids the serious consequences of delayed diagnosis or drug resistance by offering single-drug chemoprophylaxis to a patient with current pulmonary TB.
At its commencement, TB is difficult to understand but easy to cure. When the disease has neither been discovered in time nor treated with a proper regimen, it becomes easy to understand but difficult to cure.23 Therefore, it is critical to obtain a culture specimen from patients being investigated for possible TB,17 ,21 because CXRs alone cannot be relied on to discover all cases of pulmonary TB.16 ,18 Our results reveal that culture-positive pulmonary TB in the presence of a normal CXR is not uncommon, that the incidence appears to be increasing, and that patients with this presentation are typically symptomatic and/or are detected by contact tracing. The results also suggest that patients presenting with a cough for > 1 month, a fever for > 1 week, or with a documented skin-test conversion < 2 years after known exposure to infectious TB should have sputum submitted for an M tuberculosis smear and culture and should be investigated further for pulmonary TB, despite a normal CXR.
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Footnotes |
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Abbreviations: CXR = chest radiograph; TB = tuberculosis
Received for publication February 18, 1998. Accepted for publication August 18, 1998.
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This article has been cited by other articles:
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  E Hernandez-Garduno, V Cook, D Kunimoto, R K Elwood, W A Black, and J M FitzGerald Transmission of tuberculosis from smear negative patients: a molecular epidemiology study Thorax, April 1, 2004; 59(4): 286 - 290. [Abstract] [Full Text] [PDF]
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 T. F. JONES and W. SCHAFFNER Miniature Chest Radiograph Screening for Tuberculosis in Jails . A Cost-effectiveness Analysis Am. J. Respir. Crit. Care Med., July 1, 2001; 164(1): 77 - 81. [Abstract] [Full Text] [PDF]
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B. D. McNAB, D. D. MARCINIUK, R. A. ALVI, L. TAN, and V. H. HOEPPNER Twice Weekly Isoniazid and Rifampin Treatment of Latent Tuberculosis Infection in Canadian Plains Aborigines Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 989 - 993. [Abstract] [Full Text]
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 J. M. FitzGerald, L. Wang, and R. K. Elwood Tuberculosis: 13. Control of the disease among aboriginal people in Canada Can. Med. Assoc. J., February 1, 2000; 162(3): 351 - 355. [Abstract] [Full Text] [PDF]
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