Abstract
Introduction
Acute respiratory distress syndrome (ARDS) is considered a poor prognostic factor for miliary tuberculosis (MTB), but little is known about the effectiveness of steroid pulse therapy for MTB complicated by ARDS.
Patients and methods
Medical records were used to retrospectively investigate the prognosis and clinical information of 13 patients diagnosed with MTB complicated by ARDS among 68 patients diagnosed with MTB at our hospital between January 1994 and October 2016. None of the patients had multidrug resistant tuberculosis (TB). MTB was diagnosed by 1 radiologist and 2 respiratory physicians based on the observation of randomly distributed, uniformly sized diffuse bilateral nodules on chest computed tomography and the detection of mycobacterium TB from clinical specimens. ARDS was diagnosed based on the Berlin definition of ARDS. The effect of steroid pulse therapy on death within 3 months of hospitalization was examined using Cox proportional hazards models. Variables were selected by the stepwise method (variable reduction method).
Results
Six of 8 patients with MTB complicated by ARDS were alive 3 months after hospitalization in the steroid pulse therapy group, whereas only 1 of 5 patients was alive in the non-steroid pulse therapy group. Analysis of factors related to the survival of patients with MTB complicated by ARDS revealed that steroid pulse therapy was the strong prognostic factor (hazard ratio = 0.136 (95 % CI: 0.023–0.815)).
Conclusion
Our findings suggest that steroid pulse therapy improves the short-term prognosis of patients with MTB complicated by ARDS.
Abbreviations: Alb, albumin; AFB, acid-fast bacilli; ALT, alanine transaminase; ARDS, acute respiratory distress syndrome; AST, aspartate transaminase; BMI, body mass index; BUN, Blood urea nitrogen; CI, confidence interval; CRP, C-reactive protein; CT, computed tomography; DM, diabetes mellitus; FiO2, inspired oxygen fraction; Hb, hemoglobin; LDH, Lactate dehydrogenase; MGIT, Mycobacteria Growth Indicator Tube; MTB, Miliary tuberculosis; PaO2, partial pressure of arterial oxygen; PCR, polymerase chain reaction; PS, performance status; SOFA, sequential organ failure assessment; TB, tuberculosis; WBC, white blood cell
Keywords: Miliary tuberculosis, ARDS, Steroid pulse therapy
1. Introduction
Miliary tuberculosis (MTB) is a fatal disease caused by the hematogenous dissemination of Mycobacterium tuberculosis infection. It is also a rare cause of acute respiratory distress syndrome (ARDS). In many patients, the prognosis of MTB can be improved by introducing effective anti-TB agents. However, patients with MTB complicated by ARDS have a poor prognosis. Only a few studies to date have reported on MTB complicated by ARDS, with mortality reported to be in the range of 33–100 % [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. Moreover, few studies have described treatments which effectively improved patient outcomes [2], [3], [4], [5], [6], [7], [11], [12]. The aim of the study is to investigate the effect of steroid pulse therapy on the 3 months survival following MTB complicated by ARDS.
2. Patients and methods
2.1. Patients
Over a period of 22 years (January 1, 1994 – October 1, 2016), 2293 patients were hospitalized at the National Hospital Organization Omuta National Hospital with a diagnosis of TB. Of these, 70 were diagnosed with MTB. Two patients who did not undergo chest CT were excluded from the analysis. Of the remaining 68 patients, 13 were complicated by ARDS. Of these, all who died from TB did not survive beyond 3 months after the diagnosis. Therefore, the group of patients who survived ≥3 months after diagnosis was defined as the alive group (n = 7).
The following clinical information at hospitalization was collected from medical records: age, sex, history of smoking, alcohol intake, underlying diseases, symptoms, performance status (PS), microbiological data (including drug sensitivity pattern of M. tuberculosis isolates), partial pressure of arterial oxygen (PaO2)/inspired oxygen fraction (FiO2) ratio, laboratory findings, time from onset to admission, time from admission to anti-TB therapy, time from onset to anti-TB therapy, length of hospital stay, presence or absence of ARDS, and use of mechanical ventilation.
2.2. Diagnosis of MTB
MTB was diagnosed by 1 radiologist and 2 respiratory physicians based on the observation of randomly distributed, uniformly sized diffuse bilateral nodules on chest computed tomography (CT). A definitive diagnosis of TB was made when the following criteria were met: positive acid-fast bacilli (AFB) smear and/or culture for M. tuberculosis from clinical specimens such as sputum, bronchial lavage fluid, pleural fluid, urine, and bone marrow aspirate.
2.3. Diagnosis of ARDS
ARDS was diagnosed according to the Berlin definition of ARDS based on chest X-ray and chest CT findings and the PaO2/FiO2 ratio considered with a Continuous Positive Airway Pressure (CPAP) or positive end-expiratory pressure (PEEP) value of at least 5 cmH2O [13].
2.4. Statistical analysis
We used median (interquartile range) for continuous variables and frequency and percentages for categorical variables.
Survival was estimated with the Kaplan-Meier method to compare between patients who received steroid pulse therapy and those who did not. According to a previous study which examined MTB, old age, onset of ARDS, poor PS, consciousness disorder, liver disease, and high Blood urea nitrogen (BUN) were found to be prognostic factors [14]. As an independent variable, the effect of steroid pulse therapy on death within 3 months of hospitalization was examined using survival analysis. Variable selection was based on the stepwise method; the full model with steroid pulse treatment, age, liver disease, BUN and conscious disturbance was fitted, and the least-significant term with P > 0.2 was removed. STATA v14.2 software (StataCorp, Texas) was used for statistical analyses.
3. Results
3.1. Demographic data and clinical characteristics
Of the 13 patients with MTB complicated by ARDS, 8 received steroid pulse therapy (therapy group) and 5 did not (non-therapy group). The median age of patients with MTB complicated by ARDS was 81.0 years (interquartile range: 78.0–85.0 years). There were no differences between the therapy and non-therapy groups in sex, smoking history, and alcohol consumption, but age was older in the non-therapy group. There were 25 underlying diseases in the 13 patients, with diabetes being more common in the therapy group. There were no differences in symptoms or sequential organ failure assessment (SOFA) score between the two groups (Table 1).
Table 1.
Comparison of Non-steroid pulse therapy group and Steroid pulse therapy group of patients with miliary tuberculosis complicated by acute respiratory distress syndrome (n = 13).
| Total (n = 13) | Non-steroid pulse therapy group (n = 5) |
Steroid pulse therapy group (n = 8) |
||
|---|---|---|---|---|
| Age (years) | 81.0 (78.0∼85.0)* | 85.0 (84.0∼87.0)* | 78.5 (75.8∼80.8)* | |
| Sex (male/female) | 4/9** | 1/4** | 3/5** | |
| Smoking history: presence/absence/unknown |
3/9/1** | 1/4/0** | 2/5/1** | |
| Alcohol: presence/absence/unknown | 3/9/1** | 1/4/0** | 2/5/1** | |
| Underlying disease: | ||||
| Heart disease | 3 (23 %)*** | 1 (20 %)*** | 2 (25 %)*** | |
| Diabetes | 5 (38 %)*** | 0 (0 %)*** | 5 (63 %)*** | |
| Dementia | 7 (54 %)*** | 3 (10 %)*** | 4 (50 %)*** | |
| Malignant disease | 2 (15 %)*** | 0 (0 %)*** | 2 (25 %)*** | |
| Cerebrovascular disorder | 2 (15 %)*** | 0 (0 %)*** | 2 (25 %)*** | |
| Renal disease | 4 (31 %)*** | 2 (40 %)*** | 2 (25 %)*** | |
| Liver disease | 1 (8 %)*** | 0 (0 %)*** | 1 (13 %)*** | |
| Collagen disease (while taking steroids) |
1 (8 %)*** | 0 (0 %)*** | 1 (13 %)*** | |
| Aortic aneurysm | 0 (0 %)*** | 0 (0 %)*** | 0 (0 %)*** | |
| Neuromuscular disease | 0 (0 %)*** | 0 (0 %)*** | 1 (13 %)*** | |
| None | 0 (0 %)*** | 0 (0 %)*** | 0 (0 %)*** | |
| Symptoms | Fever (≥38 °C) | 10 (77 %)*** | 3 (60 %)*** | 7 (54 %)*** |
| Cough | 3 (23 %)*** | 1 (20 %)*** | 2 (25 %)*** | |
| Sputum | 2 (15 %)*** | 1 (20 %)*** | 1 (13 %)*** | |
| Dyspnea | 9 (69 %)*** | 4 (80 %)*** | 5 (63 %)*** | |
| Loss of appetite | 10 (77 %)*** | 3 (60 %)*** | 7 (86 %)*** | |
| General malaise | 10 (77 %)*** | 3 (60 %***) | 7 (86 %)*** | |
| Disturbance of consciousness | 2 (15 %)*** | 0 (0 %)*** | 2 (25 %)*** | |
| Lumbago | 0 (0 %)*** | 0 (0 %)*** | 0 (0 %)*** | |
| PS (median) | 4.0 (4.0∼4.0)* | 4.0 (4.0∼4.0)* | 4.0 (3.0∼4.0)* | |
| AFB in sputum: positive/total (%) | Smear | 12 (92 %)*** | 5 (100 %)*** | 7 (88 %)*** |
| PCR | 10 (77 %)*** | 4 (100 %)*** | 6 (75 %)*** | |
| MGIT | 10 (77 %)*** | 3 (100 %)*** | 7 (100 %)*** | |
| Culture | 13 (100 %)*** | 5 (100 %)*** | 8 (100 %)*** | |
| Culture of AFB in specimens positive/total (%) |
Sputum | 13 (100 %)*** | 5 (100 %)*** | 8 (100 %)*** |
| Urine | 3 (38 %)*** | 1 (33 %)*** | 2 (40 %)*** | |
| Gastric juice | 1 (100 %***) | 1 (100 %)*** | 0 (0 %)*** | |
| Stool | 1 (14 %)*** | 1 (50 %)*** | 0 (0 %)*** | |
| Pleural effusion | 1 (50 %)*** | 0 (0 %)*** | 1 (50 %)*** | |
| Cerebrospinal fluid | 0 (0 %)*** | 0 (0 %)*** | 0 (0 %)*** | |
| Blood | 0 (0 %)*** | 0 (0 %)*** | 0 (0 %)*** | |
| Period from onset to hospital admission (days) | 64.0 (33.0∼87.0)* | 75.0 (64.0∼197.0)* | 39.0 (29.0∼76.5)* | |
| Period from hospital admission to anti-TB treatment (days) | 2.0 (1.8∼2.0)* | 2.0 (1.8∼2.0)* | 2.0 (1.8∼2.0)* | |
| Period from onset to anti-TB treatment (days) | 51.5 (33.8∼73.8)* | 61.5 (50.3∼67.0)* | 43.5 (32.8∼76.8)* | |
| Hospital stay (days) | 96.0 (9.0∼147.0)* | 9.0 (3.0∼18.0)* | 99.0 (96.5∼149.0)* | |
| Ventilator management | 1** | 1** | 0** | |
| CPAP | 0** | 0** | 0** | |
| PaO2/FiO2 ratio | 157.0 (128.0∼235.0)* | 214.3 (128.0∼235.0)* | 139.0 (123.9∼204.0)* | |
| Body mass index (kg/m2) | 20.4 (19.4∼21.6)* | 21.8 (21.4∼22.2)* | 19.7 (18.5∼21.1)* | |
| WBC (/μl) | 5300 (3100∼8300)* | 3800 (2800∼8300)* | 5500 (4075∼8725)* | |
| Neutrophils (/μl) | 4770 (2793∼8134)* | 3572 (2240∼8134)* | 4770 (3150∼8042)* | |
| Lymphocytes (/μl) | 371 (195∼466)* | 245 (83∼420)* | 405.0 (152.0∼475.2)* | |
| Platelets (×104/μl) | 11.7 (10.8∼23.9)* | 10.8 (8.2∼15.7)* | 16.4 (11.0∼25.6)* | |
| CRP (mg/dl) | 9.8 (6.8∼12.8)* | 12.8 (9.1∼16.2)* | 9.5 (5.4∼10.9)* | |
| Total protein (g/dl) | 5.7 (5.3∼6.1)* | 5.4 (4.7∼6.1)* | 5.8 (5.4∼6.1)* | |
| Albumin (g/dl) | 2.2 (2.1∼2.4)* | 2.2 (1.8∼2.4)* | 2.3 (2.2∼2.5)* | |
| AST (IU/L) | 52.5 (43.8∼94.0)* | 81.0 (63.3∼105.5)* | 45.5 (41.8∼57.5)* | |
| ALT (IU/L) | 43.0 (33.8∼47.0)* | 43.0 (42.0∼46.3)* | 38.5 (32.3∼47.3)* | |
| LDH (IU/L) | 399.5 (367.0∼443.8)* | 422.5 (367.0∼540.8)* | 399.5 (346.0∼413.3)* | |
| ALP (U/L) | 490.0 (255.3∼834.5)* | 466 (238.8∼790.3)* | 490 (358.0∼876.3)* | |
| Total bilirubin (mg/dl) | 1.2 (0.6∼1.8)* | 2.7 (1.1∼4.1)* | 0.9 (0.6∼1.4)* | |
| BUN (mg/dl) | 27.0 (22.0∼36.0)* | 36 (32.0∼43.0)* | 25 (19.8∼27.5)* | |
| Cr (mg/dl) | 0.9 (0.7∼1.2)* | 1.1 (0.7∼1.6)* | 0.9 (0.7∼0.9)* | |
| Total cholesterol (mg/dl) | 135.0 (90.8∼200.0)* | 93.0 (53.0∼131.0)* | 137.0 (135.0∼206.0)* | |
| SOFA score | 6 (5∼7)* | 6 (4.5∼7.8)* | 6 (5.3∼7.0)* | |
| Pre-ARDS steroid administration | 5** | 2** | 3** | |
*median (interquartile range).
**number of cases.
***number of cases (percentages).
There was no difference in PS or SOFA scores between the two groups examined in the survivor group and non-survivor group, while steroid pulse therapy was frequently administered in the survival group (Table2).
Table 2.
Comparison of survivor group and non-Survivor group of patients with miliary tuberculosis complicated by acute respiratory distress syndrome (n = 13).
| Total (n = 13) | Survivor group (n = 7) |
Non-Survivor group (n = 6) |
||
|---|---|---|---|---|
| Age (years) | 81.0 (78.0∼85.0)* | 78.0 (75.5∼82.0)* | 83.5 (81.5∼86.3)* | |
| Sex (male/female) | 4/9** | 3/4** | 1/5** | |
| Smoking history: presence/absence/unknown |
3/9/1** | 2/5/0** | 1/4/1** | |
| Alcohol: presence/absence/unknown | 3/9/1** | 2/5/0** | 1/4/1** | |
| Underlying disease: | ||||
| Heart disease | 3 (23%)*** | 2 (29%)*** | 1 (17%)*** | |
| Diabetes | 5 (38%)*** | 4 (57%)*** | 1 (17%)*** | |
| Dementia | 7 (54%)*** | 4 (57%)*** | 3 (50%)*** | |
| Malignant disease | 2 (15%)*** | 1 (14%)*** | 1 (17%)*** | |
| Cerebrovascular disorder | 2 (15%)*** | 2 (29%)*** | 0 (0%)*** | |
| Renal disease | 4 (31%)*** | 2 (29%)*** | 2 (33%)*** | |
| Liver disease | 1 (8%)*** | 1 (14%)*** | 0 (0%)*** | |
| Collagen disease (while taking steroids) |
1 (8%)*** | 1 (14%)*** | 0 (0%)*** | |
| Aortic aneurysm | 0 (0%)*** | 0 (0%)*** | 0 (0%)*** | |
| Neuromuscular disease | 1 (8%)*** | 1 (14%)*** | 0 (0%)*** | |
| None | 0 (0%)*** | 0 (0%)*** | 0 (0%)*** | |
| Symptoms | Fever (≥38 °C) | 10 (77%)*** | 7 (100%)*** | 3 (50%)*** |
| Cough | 3 (23%)*** | 1 (14%)*** | 2 (33%)*** | |
| Sputum | 2 (15%)*** | 0 (0%)*** | 2 (33%)*** | |
| Dyspnea | 9 (69%)*** | 4 (57%)*** | 5 (83%)*** | |
| Loss of appetite | 10 (77%)*** | 6 (86%)*** | 4 (67%)*** | |
| General malaise | 10 (77%)*** | 6 (86%)*** | 4 (67%)*** | |
| Disturbance of consciousness | 2 (15%)*** | 2 (29%)*** | 0 (0%)*** | |
| Lumbago | 0 (0%)*** | 0 (0%)*** | 0 (0%)*** | |
| PS (median) | 4.0 (4.0∼4.0)* | 4.0 (4.0∼4.0)* | 4.0 (3.3∼4.0)* | |
| AFB in sputum: positive/total (%) | Smear | 12 (92%)*** | 7 (100%)*** | 5 (83%)*** |
| PCR | 10 (77%)*** | 6 (86%)*** | 4 (67%)*** | |
| MGIT | 10 (77%)*** | 6 (86%)*** | 4 (67%)*** | |
| Culture | 13 (100%)*** | 7 (100%)*** | 6 (100%)*** | |
| Culture of AFB in specimens: positive/total (%) | Sputum | 13 (100%)*** | 7 (100%)*** | 6 (100%)*** |
| Urine | 3 (38%)*** | 3 (43%)*** | 0 (0%)*** | |
| Gastric juice | 1 (8%)*** | 0 (0%)*** | 1 (17%)*** | |
| Stool | 1 (8%)*** | 1 (14%)*** | 0 (0%)*** | |
| Pleural effusion | 1 (8%)*** | 1 (14%)*** | 0 (0%)*** | |
| Cerebrospinal fluid | 0 (0%)*** | 0 (0%)*** | 0 (0%)*** | |
| Blood | 0 (0%)*** | 0 (0%)*** | 0 (0%)*** | |
| Period from onset to hospital admission (days) | 64.0 (33.0∼87.0)* | 73.0 (27.0∼81.0)* | 52.5 (35.0∼163.8)* | |
| Period from hospital admission to anti-TB treatment (days) | 2.0 (1.8∼2.0)* | 2.0 (1.5∼2.0)* | 2.0 (2.0∼2.0)* | |
| Period from onset to anti-TB treatment (days) | 51.5 (33.8∼73.8)* | 73.0 (28.5∼82.0)* | 44.0 (43.0∼59.0)* | |
| Hospital stay (days) | 96.0 (9.0∼147.0)* | 147.0 (98.0∼159.0)* | 6.5 (3.3∼12.8)* | |
| Ventilator management | 1** | 1** | 0** | |
| CPAP | 0** | 0** | 0** | |
| PaO2/FiO2 ratio | 157.0 (128.0∼235.0)* | 166.4 (136.4∼238.3)* | 142.5 (117.5∼200.0)* | |
| Body mass index (kg/m2) | 20.4 (19.4∼21.6)* | 20.4 (18.8∼21.9)* | 20.4 (19.5∼21.4)* | |
| WBC (/μl) | 5300 (3100∼8300)* | 5300 (3750∼10200)* | 4750 (3050∼7125)* | |
| Neutrophils (/μl) | 4770 (2793∼8134)* | 4770 (3150∼9573)* | 4323 (2573∼6797)* | |
| Lymphocytes (/μl) | 371 (195∼466)* | 371 (217∼453)* | 333 (175∼481)* | |
| Platelets (×104/μl) | 11.7 (10.8∼23.9)* | 11.1 (10.8∼27.4)* | 13.7 (9.1∼19.8)* | |
| CRP (mg/dl) | 9.8 (6.8∼12.8*) | 10.5 (9.5∼12.4)* | 8.0 (2.9∼14.5)* | |
| Total protein (g/dl) | 5.7 (5.3∼6.1)* | 5.7 (5.4∼6.2)* | 5.7 (4.9∼6.1)* | |
| Albumin (g/dl) | 2.2 (2.1∼2.4)* | 2.2 (2.2∼2.4)* | 2.3 (1.9∼3.2)* | |
| AST (IU/L) | 52.5 (43.8∼94.0)* | 44.0 (40.5∼58.0)* | 96.0 (55.0∼134.0)* | |
| ALT (IU/L) | 43.0 (33.8∼47.0)* | 43.0 (32.0∼50.0)* | 43.0 (39.0∼43.0)* | |
| LDH (IU/L) | 399.5 (367.0∼443.8)* | 393.0 (317.0∼406.0)* | 435.0 (375.0∼563.0)* | |
| ALP (U/L) | 490.0 (255.3∼834.5)* | 568.0 (188.0∼704.5)* | 394.0 (257.0∼1136.0)* | |
| Total bilirubin (mg/dl) | 1.2 (0.6∼1.8)* | 0.6 (0.6∼1.3)* | 1.5 (1.3∼4.0)* | |
| BUN (mg/dl) | 27.0 (22.0∼36.0)* | 26.0 (13.5∼28.0)* | 34.0 (26.0∼41.3)* | |
| Cr (mg/dl) | 0.9 (0.7∼1.2)* | 0.9 (0.6∼1.0)* | 1.0 (0.8∼1.5)* | |
| Total cholesterol (mg/dl) | 135.0 (90.8∼200.0)* | 136.5 (132.3∼197.8)* | 113.5 (63.0∼179.0)* | |
| SOFA score | 6 (5∼7)* | 6 (5∼7)* | 6 (5∼7)* | |
| Pre-ARDS steroid administration | 5** | 3** | 2** | |
| Steroid pulse therapy(presence/absence) | 8/5** | 6/1** | 2/4** | |
median (interquartile range).
number of cases.
number of cases (percentages).
3.2. Diagnostic findings
Consistent with diagnostic criteria for ARDS on chest CT, all patients had ground-glass to infiltrative shadows in entire lung fields. Three patients in the therapy group had pleural effusions (Fig. 1).
Fig. 1.
Chest computed tomography showed a pattern of diffuse nodules in a random distribution with ground glass opacities.
A definitive diagnosis of TB was made according to the criteria described above. All patients were ultimately verified to have M. tuberculosis. Of the 13 patients with MTB complicated by ARDS, all 13 patients have positive cultures, respectively, during hospitalization. In 6 patients, M. tuberculosis was detected from extrapulmonary specimens (3 from urine, 1 from pleural effusion, 1 from gastric effusion, and 1 from scrotal pus).
Drug susceptibility testing was performed on 12 isolates of M. tuberculosis. Ten of the isolates (83.3 %) were sensitive to all anti-TB drugs (isoniazid [H], rifampicin [R], ethambutol [E], pyrazinamide [Z], cycloserine, para-aminosalicylic acid [PAS], ethionamide, ofloxacin, streptomycin [S], kanamycin, enviomycin). The remaining 2 isolates (17 %) were resistant to at least one drug (one to H and one to E).
3.3. anti-TB drug treatment and steroid pulse therapy
Anti-TB drugs were prescribed in 12 of 13 patients. One patient was not administered an anti-TB drug because he died on the second day of hospitalization due to his poor condition. Two patients were treated with isoniazid [H], rifampicin [R], ethambutol [E], pyrazinamide [Z] (HREZ), 5 with isoniazid [H], rifampicin [R], ethambutol [E] (HRE), 1 with HREZ + Levofloxaci n(LVFX), 1 with isoniazid [H], streptomycin [S], ethambutol [E] (HSE), 1 with isoniazid [H], rifampicin [R], ethambutol [E], streptomycin [S] (HRES), 1 with isoniazid [H], rifampicin [R] (HR), and 1 with H + ciprofloxacin (CFLX). The median (range) time lag from hospitalization to anti-TB drug administration was 2 days (0–4 days), with no difference between the therapy and non-therapy groups.
Three patients in the therapy group and 2 in the non-therapy group had already received steroids of former, prednisolone (PSL) 8 mg/day, 10 mg/day, 20 mg/day, 20 mg/day, 20 mg/day latter at the onset of ARDS.
In the therapy group, 6 patients received methylprednisolone (mPSL) 1000 mg/day steroid pulse therapy for 3 days and 2 patients received mPSL 500 mg/day for 3 days. Of these 8 patients, 3 received steroid maintenance therapy. Of the 2 patients who died in the therapy group, one was administered mPSL 1000 mg/day for 3 days, and the other was administered mPSL 500 mg/day for 3 days. Steroid pulse therapy was initiated on admission in 3 of 6 patients who had already developed ARDS at admission, and 3 started therapy on the day after admission. Two patients who developed ARDS after hospitalization began therapy on the day of onset.
3.4. Prognostic factors of MTB complicated by ARDS
Six of 13 patients died of TB (mortality rate: 46.2 %). Six of 8 patients survived in the therapy group, whereas 1 of 5 patients survived in the non-therapy group. The effect of steroid pulse therapy on death within 3 months of hospitalization was examined by survival analysis. Only steroid pulse therapy was a factor that was associated with improved prognosis in patients with MTB complicated by ARDS (Fig. 2). High BUN and impaired consciousness were not factors, but tended to increase the risk of death (Table 3).
Fig. 2.
Kaplan-Meier analysis. T The graph shows a comparison between those who received steroid pulse therapy and those who did not.
Table 3.
Relationship between steroid pulse therapy and risk of death within 3 months of hospitalization.
| Survived beyond 3 months |
HR | 95 %C.I. |
||||
|---|---|---|---|---|---|---|
| Yes (7) | No (6) | Lower limit | Upper limit | |||
| Steroid pulse therapy | Yes | 1 | 4 | 0.136 | 0.023 | 0.815 |
| No | 6 | 2 | ||||
| Disturbance of consciousness | No | 5 | 6 | 77.118 | 0.372 | 15984.87 |
| Yes | 2 | 0 | ||||
| BUN (mg/dl) | 7- | 2 | 0 | 10.511 | 0.813 | 135.870 |
| 14- | 1 | 0 | ||||
| 21- | 4 | 6 | ||||
4. Discussion
ARDS is a rare but fatal complication of MTB. To date, studies have shown that the disease-specific mortality rate in patients with MTB complicated by ARDS is high [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. In the present study, fifteen of 68 patients died within three months due to tuberculosis, with a mortality rate of 22.1 %. Of the 15 patients, 6 had ARDS. Compared to the mortality rate within three months of 16 % among patients without ARDS, the mortality rate within three months was 46.2 % among patients who developed ARDS [14]. Therefore, examining potentially effective treatments for patients with MTB complicated by ARDS is highly meaningful, and the present study is the first to demonstrate the effectiveness of steroid pulse therapy in treating these patients.
There are a couple of prior investigations examining the role of adjunct steroid therapy with pulmonary TB complicated by acute respiratory failure. These studies provide mixed results that is some showed decreased TB related mortally with steroid therapy while others did no benefit at all.
Two studies have evaluated mortality factors associated with ARDS-associated MTB [6], [7]. In one study, Lee et al. identified SOFA score as a prognostic factor, with patients in that study having an average SOFA score of 9. In the present study, SOFA score was not a prognostic factor, with patients having a median SOFA score of 9. The difference in outcome may have been due to the lower disease severity of our patients.
In the other study, Deng et al. reported better prognosis among patients who received early anti-TB therapy and mechanical ventilation [7]. Specifically, that study reported that the prognosis of those who received intravenous glucocorticoid therapy (methylprednisolone: 80 mg/day) for a maximum of 5 days with anti-TB therapy was good [7]. However, ventilator management was performed in all patients of that study, and thus the contribution of glucocorticoid therapy itself is unclear. Moreover, none of the patients had received steroid pulse therapy. In the present study, CPAP was used in all patients due to respiratory failure at the time of hospitalization, but consent for continuous use of CPAP could not be obtained except for one patient who was transferred to mechanical ventilation management due to older age. There may have been more severe cases in the nonsteroidal pulse group, including one who died despite receiving mechanical ventilation and one who died before receiving treatment with antituberculous drugs. Background factors including SOFA score, which has been reported to be associated with prognosis, did not differ between the two groups. Ventilator management/CPAP was not performed in 8 patients who underwent steroid pulse therapy, and thus we were able to assess the contribution of steroid pulse therapy alone on short-term prognosis.
The rapid aging of Japan’s population has been remarkable [15]. In the present study, the median age of patients was 81 years. Although the age of the therapy group was younger than that of the non-therapy group, multivariate analysis did not find age to be a prognostic factor.
Early treatment is important for treating MTB complicated by ARDS, but the effectiveness of mechanical ventilation, particularly in elderly patients, requires further study. Barnato et al. reported that dysfunction after ventilator management was much larger than expected, and explained the long-term sequelae, how to spend the rest of life, merits and demerits to the person, and the need to obtain consent [16]. Thus, ventilator management could potentially be problematic for elderly patients with MTB complicated by ARDS. In such patients, steroid pulse therapy is likely to be a viable alternative. Early diagnosis and early intervention are important because it will be difficult to save lives if there is a delay from the onset of ARDS associated with granule tuberculosis to the start of steroid pulse therapy.
This study has some limitations. First, the study was retrospective in design, used data obtained from a single center, and was limited in sample size. Second, we did not investigate long-term prognosis. Third, in this study, there was only one case of mechanical ventilation management, which has been pointed out to be related to the prognosis. Therefore, it is uncertain whether steroid pulse therapy improves prognosis of patients receiving mechanical ventilation. Finally, information on the degree of consciousness disorder was not available.
5. Conclusion
Steroid pulse therapy significantly improved the short-term prognosis of patients with MTB complicated by ARDS.
Author contributions
K. W. assisted with study design and interpretation of the data, had full access to the study data, assumes responsibility for the integrity of the data and the accuracy of the analysis, and drafted the manuscript. N. N., S. H., M. H., K. K., M. H., A. N., N. N., M. O., K. K., T. A., S. M., M. I., M. K., and Y. H. assisted with study design and interpretation of the data and edited the initial draft of the manuscript. I. F. and R. K. contributed to data collection and management. K.W, N.N., H. K. contributed to categorization of patients with miliary tuberculosis complicated by acute respiratory distress syndrome. All authors reviewed and approved the final version of the manuscript.
Availability of data
There are no data other than those included in this article.
Ethical considerations
The present study was approved by the Ethics Committee of the National Hospital Organization at Omuta Hospital (IRB approval number: 29-43).
Funding
The authors declare that they received no funding for this study.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
None.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jctube.2022.100341.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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Data Availability Statement
There are no data other than those included in this article.