Pulmonary Tuberculosis in Patients with Diabetes mellitus

Clinical Investigations Respiration 2001;68:595–600

Received: November 13, 2000 Accepted after revision: April 24, 2001

Pulmonary Tuberculosis in Patients with Diabetes mellitus Feza Bacakog˘lu Özen Kaçmaz Bas¸og˘lu Gürsel Çok Abdullah Sayıner Mahmut Ates¸ Department of Chest Diseases, Ege University Medical School, Izmir, Turkey

Key Words Tuberculosis W Diabetes mellitus, insulin-dependent W Radiography W Cavity W Bacteriology

Abstract Background: Diabetes mellitus has been reported to modify the presenting features of pulmonary tuberculosis, but there are varying data, particularly regarding the association with lower lung field involvement. Objectives: To determine whether diabetes mellitus alters the clinical and radiographic manifestations of tuberculosis in nonimmunocompromised hosts and to define the determinants of lower lung field involvement. Methods: A retrospective review of the records of all patients with tuberculosis and diabetes mellitus seen during a 14-year period and of an age- and sex-matched nondiabetic control group with tuberculosis was carried out. The duration of symptoms, tuberculin reaction, bacteriologic and radiographic findings of the two groups were compared. Results: The presence of diabetes mellitus was found not to have an effect on patients’ symptomatology, bacteriology results, tuberculin reaction and localization of pulmonary infiltrates. On the other hand, fewer diabetic patients were smear-positive and fewer had reticulonodular opacities compared with the control patients. A higher number of insulin-dependent diabetic patients

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presented with cavitary disease as compared with nondiabetic controls. Lower lung field tuberculosis was significantly associated with female gender and, in patients older than 40 years, was more frequently observed in diabetics. Conclusion: These data show that diabetes does not affect the presenting features of pulmonary tuberculosis to a large extent and is only associated with lower lung field disease in older patients. Copyright © 2001 S. Karger AG, Basel

Introduction

The relationship between diabetes mellitus (DM) and pulmonary tuberculosis has attracted the interest of many clinicians and investigators for a long time. Many studies have shown that the prevalence of tuberculosis among diabetics is 2–5 times higher than in the nondiabetic population [1, 2]. On the other hand, there appears to be little information on whether DM affects the diagnostic findings in tuberculosis. The radiographic manifestations of tuberculosis may differ from the findings in nondiabetic controls as was initially reported by Sosman and Steidl [3], who found a higher rate of lower lung field (LLF) involvement in their diabetic patients. This was followed by other studies which reported rates ranging between 3.4 and 32.2% [4–8].

Dr. Abdullah Sayıner Ege Üniversitesi Tıp Fakültesi Gög˘üs Hastalıkları A.D. TR–35100 Bornova, Izmir (Turkey) Tel. +90 232 388 1423, Fax +90 232 388 7192, E-Mail [email protected]

These were, on the other hand, mainly uncontrolled, descriptive studies and have not been confirmed by more recent reports which included control groups. Instead, some of the latter studies showed higher prevalences of multilobar involvement and of cavitary disease [8–12]. It is as yet difficult to draw definitive conclusions from the literature because of the varying findings in the reported studies done on relatively small populations. There is even less data on clinical and microbiologic findings and on tuberculin reactivity in diabetic patients. The aims of this study were to determine whether DM alters the clinical and radiographic manifestations of tuberculosis in nonimmunocompromised hosts and to define the determinants of LLF involvement. We thus retrospectively reviewed the findings of patients with tuberculosis and diabetes hospitalized in our department during the last 14 years and compared them with those of an age- and sex-matched nondiabetic control group. We also further examined the patients with tuberculosis involving the LLF so as to identify whether there was any difference in these patients’ characteristics, clinical course and other radiographic features.

Material and Methods Study Population A review of the records of all patients admitted to our department, a 105-bed department for chest diseases in a 1,600-bed university hospital, between 1985 and 1998 disclosed 927 cases with culture-positive pulmonary tuberculosis, i.e. ‘definite’ cases, as defined by Rieder et al. [13]. All patients were hospitalized for 1–4 weeks, which is an institutional policy. This period includes educational sessions on the treatment and social aspects of the disease and facilitates early control of compliance with therapy. One hundred and fourteen of the patients (12.3%) were found to have concomitant DM. The files were retrieved from the department archives and 22 patients were excluded because either the radiogram done at the first presentation was missing or there was no clear data on bacteriology and history of DM, as radiographic and bacteriologic findings were the main parameters that this study investigated in patients with and without diabetes. These were, therefore, not examined and 92 cases were finally included as the study group (group 1). Patients were included in the DM group if they had a previous history of DM and had been receiving insulin and/or an oral hypoglycemic agent at the time of hospital admission or were found to have two or more fasting blood glucose levels greater than 140 mg/dl and were thus started on antidiabetic treatment. An age- and sexmatched group of 92 cases, who were hospitalized in the same period and who did not have DM, was chosen as the control group (group 2). None of the patients in the study or control groups was HIV-positive. Patients who had been receiving immunosuppressive treatment or corticosteroids during the 6 months preceding the diagnosis of tuberculosis were excluded from analysis.

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Reviewed Parameters Upon examination of the patients’ files, the following parameters were recorded and comparisons were made between the two groups: symptoms and their duration, smear and culture positivity, resistance to antituberculosis drugs, interval at which the sputum culture became negative, tuberculin skin test reactivity as measured by the Mantoux method [14], radiographic features including localization and characteristics of the infiltrates, presence of pleural involvement, duration of hospitalization and treatment. Radiographic Interpretation The data on radiographic findings were collected using the P-A roentgenograms obtained at the time of diagnosis. The X-rays were read by two of the investigators (G.C., A.S.) who remained blinded to the presence or absence of diabetes. Localizations of the infiltrates were interpreted using two different classifications. First, in compliance with the usual clinical approach, the upper, mid and lower zones were defined to be separated by imaginary horizontal lines passing at the level of the anterior ends of the second and fourth ribs, respectively. The LLF was separately defined as the area below an imaginary line traced across the hila and including the parahilar regions on a standard posteroanterior chest roentgenogram. This was to allow comparisons to be made with previous reports that used the same definition [4, 15]. Treatment of Tuberculosis The usual treatment regimen consisted of an initial phase of isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol given daily for 2 months followed by isoniazid and rifampin for 7 months. This standard regimen was modified or extended depending on the rate of response and the presence of drug resistance. Analysis Student’s t test was used to compare the ages, durations of symptoms and of treatment, and time to sputum conversion. ¯2 test was done to determine the significance of the differences in sex, symptoms, tuberculin positivity, smear positivity, drug resistance and radiographic characteristics. Unless otherwise stated, all data are expressed as mean B SD. A p value of less than 0.05 was considered significant.

Results

The demographic data of the study and control groups (groups 1 and 2, respectively) are presented in table 1. There was no difference between the two groups regarding the prevalence of symptoms. Group 1 had a shorter duration of symptoms, but it was found not to be statistically significant (p = 0.16). History and Treatment of DM By definition, none of the cases in the control group was diagnosed to have DM, nor was hyperglycemia detected in the routine biochemistry workup. Fifty-nine patients (64.1%) in the study group had prior diagnosis of DM of 1–22 years’ duration (mean 6.8

Bacakog˘lu/Bas¸og˘lu/Çok/Sayıner/Ates¸

B 8.9 years). In 33 cases (35.9%), it was diagnosed when they were admitted to hospital for tuberculosis and they continued to receive medication for DM for at least 1 year. Twenty-one cases required insulin treatment for the control of hyperglycemia (type 1, insulin-dependent), whereas the remaining 71 cases were controlled with oral hypoglycemic agents (type 2, non-insulin-dependent). These cases had a diabetes history of 13.0 B 13.6 years (0–15) and 5.0 B 4.2 years (0–22), respectively (p ! 0.01). One patient in group 1 also had lung cancer. In group 2, lung cancer and breast cancer were found in 1 patient each (table 1). Bacteriology By definition, tuberculosis was proven in all cases by positive cultures for Mycobacterium tuberculosis. The smears were positive for acid-fast bacilli in 67 cases (72.8%) and 84 cases (91.3%) in groups 1 and 2, respectively (p ! 0.01). There was no difference between the study and control groups regarding the time taken for the sputum culture to become negative and drug resistance rates (table 2). Tuberculin Test Results Tuberculin skin test was performed on 62 cases (67.4%) in the diabetic group (group 1) and 65 cases (70.7%) in the control group (group 2). It was found to be positive in 48 cases (77.4%) and 50 cases (76.9%) in the two groups, respectively. Radiographic Findings Fewer cases in group 1 (11/92, 12.0%) had upper-zone involvement only compared with group 2 (16/92 cases, 17.4%), but the difference was not statistically significant (p = 0.30). Similarly, there was a higher number of cases in group 1 with only LLF involvement (20/92 cases, 21.7% vs. 13/92 cases, 14.1%), but this again did not reach statistical significance (p = 0.18). There was no difference between the two groups regarding the radiographic involvement of the lung zones. The radiographic features including the prevalences of acinar opacities, cavities and pleural thickening were again similar in the two groups, but significantly fewer patients in the diabetes group presented with reticulonodular opacities (table 3). In the diabetic group, 21 cases (22.8%) were insulindependent (type 1) and 71 cases were non-insulin-dependent (type 2). The clinical features of these two subgroups are presented in table 4 and the radiographic characteris-

Pulmonary Tuberculosis in Patients with Diabetes mellitus

Table 1. Demographic data of the study and control groups

Mean age, years Range Sex (F:M) Duration of DM, years Duration of symptoms, days a Concomitant disease b

Group 1

Group 2

49.1B11.8 24–81 35:57 6.8B8.9 59.3B45.1 1

52.4B8.5 18–76 35:57 – 74.5B56.1 2

a The duration of symptoms was recorded in 47.8 and 92.4% of DM and control group, respectively. b One patient in group 1 had lung cancer. In group 2, lung cancer and breast cancer were found in 1 patient each.

Table 2. Results of bacteriology and tuberculin test in the study and

control groups

Number of smear-positive cases Number of cases with drug resistance Time to conversion of culture, days Tuberculin reactivity Positive:negative a

Group 1

Group 2

67 (72.8)* 18 (19.6) 52.8B31.4 48:14 77.4:22.6

84 (91.3) 22 (23.9) 68.5B51.9 50:15 76.9:23.1

Figures in parentheses represent percentage. * p ! 0.01 vs. control group. a Tuberculin test was performed in 62 and 65 patients in group 1 and 2, respectively.

Table 3. Radiographic findings in the study and control groups

Acinar opacities/consolidation Cavity Reticulonodular opacities Pleural involvement a

Group 1

Group 2

90 (97.8) 54 (58.7) 12 (13.0) 21 (22.8)

87 (94.6) 47 (51.1) 28 (30.4)* 30 (32.6)

Figures in parentheses represent percentage. * p ! 0.01 vs. group 1. a All these cases had pleural thickening adjacent to areas of parenchymal involvement. No pleural fluid was seen in any patient.


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Table 4. Characteristics of cases with DM

Mean age, years Sex (F:M) Number of smear-positive cases Number of cases with drug resistance Time to conversion of culture, days Tuberculin reactivity (positive:negative) Number of cases with LLF involvement only

Type 1 DM (n = 21)

Type 2 DM (n = 71)

47.1B13.8 (18–70) 9:12 (42.9:57.1) 14 (66.7) 6 (29.6) 61.0B66.8 12:2 (85.7:14.3) 5 (23.0)

54.0B9.5 (27–76) 26:45 (36.6:63.4) 53 (74.6) 12 (19.6) 49.7B40.1 36:12 (75.0:25.0) 15 (22.5)

With the exception of age (range) figures in parentheses represent percentage.

Table 5. Radiographic features of patients with DM

Acinar opacities/consolidation Cavity Reticulonodular opacities Pleural involvement

Discussion

Type 1 DM (n = 21)

Type 2 DM (n = 71)

21 (100.0) 16 (76.2) 3 (14.3) 4 (19.0)

69 (97.2) 38 (53.5) 9 (12.7) 17 (23.9)

Figures in parentheses represent percentage.

tics in table 5. No significant difference was found between these two subgroups of diabetic patients. However, when compared with nondiabetic controls, type 1 DM patients presented with cavitary disease significantly more frequently (76.2 vs. 51.1%, respectively, p = 0.037). Characteristics of Patients with LLF Tuberculosis A total of 33 cases (17.9%) had LLF tuberculosis only, i.e. without the involvement of other fields. This was more frequently observed in female patients (p ! 0.001), but was not related to the presence of DM (p = 0.18). However, DM was significantly associated with LLF disease in older patients. Thus, among patients older than 40 years, LLF disease was more frequently observed in diabetics (17/81, 21.0%) as compared to nondiabetics (4/61, 6.6%; p = 0.031). None of the cases presenting with LLF tuberculosis had reticulonodular opacities. The comparisons of the clinical and radiographic findings of these patients with the findings of cases without LLF disease are shown in tables 6 and 7.

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The association of tuberculosis and DM has attracted the attention of clinicians for years. The incidence of diabetes among tuberculosis cases reviewed in this study, 12.3%, is similar to those rates previously reported, 2.1 and 13.2% [16, 17], and is markedly higher than in the general population. With this retrospective review of patients’ records, we aimed to provide information regarding the clinical and radiographic manifestations of this association. This study, which included a matched control group of nondiabetic patients, showed that DM did not alter the symptomatology, tuberculin reactivity, the rate of drug resistance and the response to antituberculosis therapy. It also did not affect the radiographic localization of pulmonary infiltrates, except that LLF involvement was significantly associated with DM in patients older than 40 years and with female gender. The higher prevalence in women has been consistently reported in other studies [4, 16, 18]. Besides, two significant differences were detected between tuberculosis patients with and without DM, i.e. the prevalences of smear-positive cases and of reticulonodular opacities were lower in the former group. Early studies on the radiographic findings of tuberculosis patients with DM reported atypical localization patterns, namely an increased incidence of LLF involvement that ranged between 8.1 and 29% [5, 8, 12]. More recent reports did not confirm these observations [8, 12, 17, 18]; instead, some found higher rates of multilobar involvement [12, 19, 20], which was not confirmed in this study. In the largest series on clinical findings in tuberculosis, Aktog˘u et al. [16] also found a higher rate of LLF tuberculosis among diabetics as compared with nondiabetics (11.0 and 5.3%, respectively). This was a retrospective review of all tuberculosis cases, however, and was not


Table 6. Characteristics of cases with LLF

tuberculosis only

Age, years Sex (F:M) Number of cases with DM Duration of symptoms, days a Number of smear-positive cases Number of cases with drug resistance Tuberculin reactivity (positive:negative)

Cases with LLF involvement only (n = 33)

Cases without LLF involvement (n = 151)

49.9B13.3 (18–70) 24:9 (72.7:27.3)* 20 (60.6) 48.8B26.6 26 (78.8) 8 (24.2) 20:3 (87.0:13.0)

51.1B9.7 (24–81) 46:105 (30.5:69.5) 72 (47.7) 148.3B80.5 125 (82.8) 32 (21.2) 71:20 (78.0:22.0)

With the exception of age (range) figures in parentheses represent percentage. * p ! 0.001 vs. group without LLF involvement. a The duration of symptoms was recorded in 54.5 and 73.5% of the patients with and without LLF involvement, respectively.

designed for this purpose. The two groups were not matched and they possibly included immunocompromised hosts. In our study, although there was a tendency for an increased prevalence of LLF disease in diabetics, this was not statistically significant. However, age was found to be an important determinant of the relationship between DM and LLF disease; LLF involvement was significantly associated with DM only in patients older than 40 years. This is partly in accordance with recent reports on the more frequent occurrence of unusual presentations in older age groups [18, 21]. This effect of age may explain the differences in the results of previous studies which might have included populations with varying ages. A similar controversy exists as regards the prevalence of cavitary disease in diabetics. Studies that reported a higher rate [12, 20, 22] have not been confirmed by others [8, 19]. In the present study, although diabetics and nondiabetics had similar rates of cavitary disease, a significantly higher rate was observed in tuberculosis patients with type 1 DM. Differences in the composition of diabetic patients (type 1 vs. type 2), therefore, may have been the reason for the contradictory results in previous studies. An interesting finding was the presence of increasing cavitation together with decreased smear positivity in the diabetic group. Cavitary disease is expected to be associated with a larger population of bacilli and we speculate that this finding might be related with the muscle weakness caused by uncontrolled glycemia, leading to less effective expectoration.

Table 7. Radiographic features of patients with LLF tuberculosis

Pulmonary Tuberculosis in Patients with Diabetes mellitus


only With LLF Without LLF involvement only involvement (n = 33) (n = 151) Acinar opacities/consolidation Cavity Reticulonodular opacities Pleural involvement

32 (97.0) 14 (42.4) 0* 7 (21.2)

145 (96.0) 87 (57.6) 40 (26.5) 44 (29.1)

Figures in parentheses represent percentage. * p ! 0.01 vs. group without LLF involvement.

Lower rates of reticulonodular opacities were observed in patients with DM and in cases with LLF involvement. This may be evaluated in conjunction with the finding that these patients had somewhat shorter durations of symptoms, although they were not found to be statistically significant. A more acute onset has been observed and reported by others [7] in LLF disease. It may perhaps be speculated that a shorter duration of disease enables earlier diagnosis, leading to a less frequent occurrence of fibronodular opacities and a lower incidence of positive smears in microscopic examination. Whether the type of diabetes influences the clinical and radiographic presentation of tuberculosis is another issue, on which there is little data in the literature. Poorly controlled hyperglycemia is usually considered to be the main factor causing increased susceptibility to infections

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[23] and thus insulin-dependent diabetics are expected to be more frequently or severely affected. One study published in Russian showed that type 1 diabetes has a more acute onset and runs a more symptomatic course compared with type 2 disease [24], but no data can be obtained from the abstract as to the glycemia level, gender, age and immune status of the two groups. The present study documented that similar findings are observed in these two groups of diabetic patients, except for the higher rate of cavitary disease in type 1 disease as compared to nondiabetics.

In conclusion, diabetes does not affect the clinical and radiographic presentation of tuberculosis to a significant extent. However, age appears to be a determinant of the effects of DM on tuberculosis presentation, in that LLF tuberculosis occurs more frequently in patients with DM who are older than 40 years when compared to nondiabetic patients. It is also significantly associated with the female gender.

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