Delayed isolation of smear-positive pulmonary tuberculosis patients in a Japanese acute care hospital

Delayed isolation of smear-positive pulmonary tuberculosis patients in a Japanese acute care... Background: Active pulmonary tuberculosis (TB) is associated with intra-hospital spread of the disease. Expeditious diagnosis and isolation are critical for infection control. However, factors that lead to delayed isolation of smear- positive pulmonary TB patients, especially among the elderly, have not been reported. The purpose of this study is to investigate factors associated with delay in the isolation of smear-positive TB patients. Methods: All patients with smear-positive pulmonary TB admitted between January 2008 and December 2016 were included. The setting was a Japanese acute care teaching hospital. Following univariate analysis, significant factors in the model were analyzed using the multivariate Cox proportional hazard model. Results: Sixty-nine patients with mean age of 81 years were included. The median day to the isolation of pulmonary TB was 1 day with interquartile range, 1–4 days. On univariate analysis, the time to isolation was significantly delayed in male patients (p = 0.009), in patient who had prior treatment with newer quinolone antibiotics (p = 0.027), in patients who did not have chronic cough (p = 0.023), in patients who did not have appetite loss (p = 0.037), and in patients with non-cavitary lesion (p = 0.005), lesion located other than in the upper zone (p = 0.015), and non-disseminated lesion on the chest radiograph (p = 0.028). On multivariate analysis, the time to isolation was significantly delayed in male patients (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.25 to 0. 89; P = 0.02), in patients who did not have chronic chough (HR, 0.52; 95% CI, 0.28 to 0.95; P = 0.033), and in patients with non-cavitary lesion on the chest radiograph (HR, 0.46; 95% CI, 0.23 to 0.92; P = 0.028). Conclusions: In acute care hospitals of an aging society, prompt diagnosis and isolation of TB patients are important for the protection of other patients and healthcare providers. Delay in isolation is associated with male gender, absence of chronic cough, and presence of non-cavitary lesions on the chest radiograph. Keywords: Pulmonary tuberculosis, Delay, Isolation, Diagnosis, Smear-positive Background Although theprevalenceofTBhad reduced to 16.7 Tuberculosis (TB) control is of worldwide interest, espe- per 100,000 among Japanese population in 2012, this cially among patients with active pulmonary TB who are figure remains 3–4 times higher than in Europe and smear-positive for acid-fast bacilli [1]. TB control requires North America [5, 6]. One reason for the relatively early diagnosis and immediate initiation of treatment [2]. high prevalence of TB in Japan is an aging population Delay in diagnosis adversely affects clinical outcome; be- with previous TB infection [7]. In the World Health sides, it increases transmission within the community and Organization 2017 global report, Japanese patients leads to higher transmission rates in an epidemic [3, 4]. with smear-positive pulmonary TB were older and had a higher mortality than in other countries [8, 9]. Given the high rates of hospital admission among eld- * Correspondence: sanazen@hotmail.co.jp Department of General Internal Medicine, Shonan Kamakura General erly patients in developed countries, any delay in Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, Japan diagnosis and isolation of pulmonary TB can cause Department of Internal Medicine, Hayama Heart Center, Hayama, Kanagawa, spread of infection [10]. Therefore, in aging societies Japan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 2 of 7 including Japan, it is important to seek reasons for gastric resection, human immunodeficiency virus infec- delay in the isolation of pulmonary TB patients. tion, preceding treatment with newer quinolone antibi- In previous studies, factors leading to delayed diagnosis otics, steroid use, chronic cough, loss of appetite, body of pulmonary TB have been well reported worldwide [2, mass index, body temperature on arrival, systolic blood 11–14]. These reports focused on ‘patient delay’ and pressure, oxygen requirement, hemoglobin level, serum ‘health care system delay’ [14–16]. Delayed diagnosis has albumin level, C-reactive protein level, presence of a been associated with human immunodeficiency virus in- cavitary, upper zone or disseminated lesion on the chest fection, chronic cough, and presence of incidental lung radiograph, and the raw score. The raw score is a vali- disease [2]. Geographical and socio-psychological barriers dated prognostic score for patients with smear-positive include rural residence and poor access to healthcare [2, pulmonary TB [8]. 11, 12]. Other factors that may delay diagnosis include old We also collected data on the following “facility and age, female gender, alcoholism and substance abuse, initial physician-related factors”: year of hospital visit, time of visitation at a low-level government healthcare facility, pri- arrival (day or night), weekday or weekend arrival, the vate practitioner, or traditional healer [2, 11, 12, 14]. His- attending ER physician, medical care provided by the tory of immigration, poor education status, low awareness resident on arrival, medical care provided by male phys- of TB, irrational beliefs, self-treatment, the associated ician on arrival, and whether transferred to the hospital stigma, consultation at a public hospital, and prior treat- by ambulance. ment with fluoroquinolones may also delay the diagnosis of active pulmonary TB [2, 11–14]. Statistical analysis To the best of our knowledge, factors associated with We aimed to evaluate factors associated with delayed delay in isolation of pulmonary TB patients have not been isolation of smear-positive pulmonary TB patients. The reported. In the clinical setting, any delay in isolation is primary outcome measure was the duration day from critical to control of infection within hospitals. Therefore, hospital visit to the isolation of the patient with TB. we conducted this study to clarify factors associated with Day-to-isolation analysis, based on the Cox proportional delayed isolation of active pulmonary TB patients. hazard model, was used to analyze factors associated with delay to the isolation of pulmonary TB patients. In Methods a univariate model, the “patient-related factors” and Patients and setting “medical facility and physician-related factors” were eval- We conducted a retrospective study on patients who were uated as possible reasons for the delayed isolation of ac- diagnosed with smear-positive pulmonary TB in an urban tive pulmonary TB, based on log-rank test or univariate teaching hospital between January 2008 and December Cox hazard test, as appropriate. Significant factors in the 2016. The hospital provides primary through tertiary care univariate model were analyzed using the multivariate in Kanagawa Prefecture, Japan, with a population of about Cox proportional hazard model. A two-tailed p-value < nine million people. The hospital has no specific wards for 0.05 was considered statistically significant. All data ana- patients with treatment of active pulmonary TB. Those lyses were undertaken using the SPSS Statistics version who are suspected to have active pulmonary TB disease 21 J (IBM, Tokyo, Japan). This study was approved by are immediately isolated in single rooms with negative air the Institutional Review Board of the hospital (No. pressure for definite sputum smear diagnosis, particularly TGE00667-024). with three consecutive sputum or gastric aspiration ana- lysis. After the diagnosis of smear-positive pulmonary TB Results is established, the patients are then transferred to another Sixty-nine patients with smear-positive pulmonary TB hospital that has special wards for the treatment of were enrolled. Base-line characteristics and univariate smear-positive pulmonary TB. Therefore, a delay in isola- analysis were included in Table 1. The mean age of pa- tion on admission may spread the TB infection tients was 81 years, with 18 (26.1%) female patients. All in-hospital. We studied 69 consecutive patients who were patients were hospitalized and isolated for infection con- diagnosed with smear-positive pulmonary TB by examin- trol. Two patients were discharged home, 55 were trans- ation of the sputum or gastric specimen. ferred to other hospitals for the treatment of TB, and 12 died in our hospital. The median length of hospital stay Data collection was 7 days with interquartile range (IQR), 5–18 days. Data collection for each patient, collectively referred to The median day to the isolation of pulmonary TB pa- as “patient-related factors”: age, gender, history of smok- tients was 1 day with IQR, 1–4 days. Figure 1 showed ing or alcoholism, welfare recipient or not, activities of that over 60% patients isolated within 1 day. However, daily living, past history of TB, contact with TB patients, approximately 10% patients isolated over 10 days (Fig. 1). diabetes mellitus, other lung disease, surgical history of On univariate analysis, male gender (p = 0.009), prior Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 3 of 7 Table 1 Clinical characteristics and day-to-isolation univariate analysis (N = 69) Characteristic No.(%) or mean ± SD Day-to-isolation p-value (95% CI) Patient factor Age (years) 81.1 ± 10.0 0.827 Male gender-no.(%) 51 (73.9) 8.2 (3.90–12.41) 0.009* Female gender-no.(%) 18 (26.1) 1.8 (0.70–2.86) Smoking-no.(%) 40 (58.0) 6.6 (3.16–10.09) 0.585 Non-smoking-no.(%) 29 (42.0) 6.3 (0.24–12.38) Alcoholism-no.(%) 4 (5.8) 1.5 (0.52–2.48) 0.217 Non-alcoholism-no.(%) 65 (94.2) 6.8 (3.40–10.21) Welfare recipient-no.(%) 4 (5.8) 1.3 (0.76–1.74) 0.172 Non-welfare recipient-no.(%) 65 (94.2) 6.8 (3.41–10.22) Dependent ADL-no.(%) 12 (17.4) 11.5 (2.67–20.33) 0.129 Partially dependent ADL-no.(%) 20 (29.0) 8.7 (0.08–17.22) Independent ADL-no.(%) 37 (53.6) 3.7 (1.28–6.13) Past history of tuberculosis-no.(%) 28 (40.6) 3.0 (1.44–4.49) 0.073 Non-past history of tuberculosis-no.(%) 41 (59.4) 8.9 (3.69–14.12) Contact with tuberculosis patients-no.(%) 7 (10.1) 3.3 (0.01–6.56) 0.519 Non-contact with tuberculosis patients-no.(%) 62 (89.9) 6.9 (3.30–10.41) Diabetes mellitus-no.(%) 25 (37.3) 3.8 (1.19–6.49) 0.248 Non-diabetes mellitus-no.(%) 42 (60.9) 8.3 (3.31–13.31) Other lung disease-no.(%) 18 (26.1) 5.3 (0.73–9.83) 0.864 Non-other lung disease-no.(%) 51 (73.9) 6.9 (2.86–10.99) Gastric resection-no.(%) 8 (11.6) 4.8 (0.00–11.02) 0.593 Non-gastric resection-no.(%) 61 (88.4) 6.7 (3.16–10.28) Human immunodificiency virus infection -no.(%) 1 (1.4) 1.0 (1.00–1.00) 0.366 Non-human immunodificiency virus infection-no.(%) 68 (98.6) 6.6 (3.31–9.84) Preceding newer quinolone antibiotics-no.(%) 6 (8.7) 23.0 (0.00–51.14) 0.027* Non-preceding newer quinolone antibiotics-no.(%) 63 (91.3) 4.9 (2.77–7.07) Steroid use-no.(%) 15 (21.7) 6.5 (0.38–12.55) 0.923 Non-steriod use-no.(%) 54 (78.3) 6.5 (2.72–10.28) Chronic cough-no.(%) 19 (27.5) 2.3 (0.81–3.82) 0.023* Absence of chronic cough-no.(%) 50 (72.5) 8.1 (3.74–12.42) Appetite loss-no.(%) 48 (70.6) 8.5 (3.96–13.00) 0.037* Absence of appetite loss-no.(%) 20 (29.0) 2.0 (1.36–2.64) BMI (kg/m ) 19.0 ± 3.3 0.213 BT on arrival (°C) 37.2 ± 1.8 0.335 sBP on arrical (mmHg) 123.5 ± 30.3 0.768 Oxygen requirement-no.(%) 25 (36.2) 8.2 (0.89–15.51) 0.555 Non-oxygen requirement-no.(%) 44 (63.8) 5.5 (2.60–8.44) Haemoglobin level (g/dL) 11.9 ± 1.9 0.783 Serum albumin level (g/dL) 2.9 ± 0.6 0.348 CRP level (mg/dL) 9.3 ± 5.6 0.748 Cavitary lesion on the chest radiograph-no.(%) 15 (21.7) 1.3 (1.04–1.50) 0.005* Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 4 of 7 Table 1 Clinical characteristics and day-to-isolation univariate analysis (N = 69) (Continued) Characteristic No.(%) or mean ± SD Day-to-isolation p-value (95% CI) Non-cavitary lesion on the chest radiograph-no.(%) 54 (78.3) 7.9 (3.91–11.98) Upper zone lesion on the chest radiograph-no.(%) 36 (52.2) 3.3 (1.33–5.17) 0.015* Lesion located other than in the upper zone on the chest radiograph-no.(%) 33 (47.8) 10.0 (3.80–16.26) Disseminated lesion on the chest radiograph-no.(%) 32 (46.4) 3.3 (0.72–5.91) 0.028* Non-disseminated lesion on the chest radiograph-no.(%) 37 (53.6) 9.2 (3.79–14.70) Raw score (from −30 points to 60 points) 29.2 ± 18.0 0.973 Medical facility and doctor factor Year of hospital visit (from 2008 to 2016) 2012.4 ± 2.6 0.151 Night-time arrival-no.(%) 27 (39.1) 8.7 (1.87–15.47) 0.248 Day-time arrival-no.(%) 42 (60.9) 5.1 (2.11–8.08) Weekend arrival-no.(%) 13 (18.8) 3.8 (1.06–6.48) 0.517 Weekday arrival-no.(%) 56 (81.2) 7.1 (3.22–11.03) Medical care provided by resident-no.(%) 27 (39.1) 7.1 (0.72–13.58) 0.844 Medical care provided by non-resident-no.(%) 42 (60.9) 6.1 (2.71–9.44) Medical care provided by male doctor-no.(%) 60 (87.0) 5.9 (2.64–9.20) 0.407 Medical care provided by female doctor-no.(%) 9 (13.0) 10.3 (0.00–22.07) Transferred to the hospital by ambulance-no.(%) 39 (56.5) 7.9 (2.74–13.16) 0.523 Transferred to the hospital by non-ambulance-no.(%) 30 (43.5) 4.6 (1.63–7.57) Attending ER physician-no.(%) 55 (79.7) 6.3 (2.53–10.05) 0.580 Attending non-ER physician-no.(%) 14 (20.3) 7.3 (1.27–13.30) Raw score is tuberculosis prognostic score, which is calculated as follows: age(years) + (oxygen requirement, 10 points) − 20 × albumin (g/dl) + (ADL: independent, 0 point; semi-dependent, 5 points; totally dependent, 10 points) Resident indicate physician who was graduated within two years Based on logrank test or cox hazard crude model, where appropriate, *p < 0.05 CI confidence interval, SD = standard deviation, ADL activities of daily living, BMI body mass index, BT body temperature, sBP systolic blood pressure, CRP C- reactive protein, ER emergency room Fig. 1 Kaplan-Meier curve of the time from admission to isolation of pulmonary TB patients. The median time to the isolation of pulmonary TB patients was 1 day with interquartile range, 1–4 days Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 5 of 7 treatment with newer quinolone antibiotics (p = 0.027), shown to be a risk factor for delayed diagnosis of pul- absence of chronic cough (p = 0.023), appetite loss (p = monary TB [11, 12]; there are no previous reports of 0.037), non-cavitary lesion on the chest radiograph (p = male gender being associated with delay in isolation of 0.005), lesion located other than in the upper zone on pulmonary TB patients. the chest radiograph (p = 0.015), and non-disseminated We speculate that the delay in isolation associated lesion on the chest radiograph (p = 0.028) were signifi- with male gender, absence of chronic cough and cant factors associated with a delayed isolation of pul- non-cavitary lesion on the chest radiograph, may be re- monary TB patients (Table 1). lated to the advanced age of our patients (mean age: On multivariate analysis using Cox hazard model, 81.1 years). Younger patients with smear-positive TB male gender (hazard ratio [HR], 0.47; 95% confidence were referred to other hospitals with special wards, interval [CI], 0.25 to 0.89; P = 0.02), absence of chronic resulting in an increase in elderly patients with TB in cough (HR, 0.52; 95% CI, 0.28 to 0.95; P = 0.033), and our hospital. Elderly patients with TB can manifest with non-cavitary lesion on the chest radiograph (HR, 0.46; unusual features that may be confused with aspiration 95% CI, 0.23 to 0.92; P = 0.028) were significantly associ- pneumonia [17], commonly observed in this population ated with delayed isolation of TB patients (Table 2). [18]. The typical symptoms of aspiration pneumonia are Figure 2 showed intergroup comparisons of fever, cough with sputum, and dyspnea; however, day-to-isolation among significant factors associated non-specific symptoms including loss of consciousness with delayed isolation of pulmonary TB patients in the and appetite loss are also important. Thus, the symp- multivariate analysis. toms of pulmonary TB and aspiration pneumonia are similar. Moreover, aspiration pneumonia, a common dis- Discussion ease in an aging society, can co-exist in patients with ac- Our study revealed that male gender, absence of chronic tive pulmonary TB and has drawn increasing attention cough, and non-cavitary lesion on the chest radiograph recently [19]. Although the incidence of active pulmon- were associated with delayed isolation of active pulmon- ary TB has decreased, the number of elderly patients has ary TB patients. increased in Japan [20]. There may be a lack of wide- A non-cavitary lesion on the chest radiograph and ab- spread awareness among healthcare workers, including sence of chronic cough are factors consistent with previ- physicians, of this development. This may have led to ous reports of diagnostic delay in cases of pulmonary failure to consider pulmonary TB in elderly patients. Be- TB; our findings of association of male gender with diag- sides, the symptoms of pulmonary TB can mimic aspir- nostic delay is contrary to the findings of previous stud- ation pneumonia in the elderly. ies. Chronic cough is an important symptom for the Although previous studies have described factors asso- clinician to consider the diagnosis of pulmonary TB ciated with delayed diagnosis of pulmonary TB [11–13, from the clinical history. Moreover, a previous report of 15, 21–27], we focused on factors that delayed isolation, in-hospital diagnostic delay from Southern Taiwan re- especially among elderly patients admitted to hospital. vealed non-cavitary lesion on the chest radiograph as an To the best of our knowledge, ours is the first study that independent risk factor [14], similar to our finding. A deals with delayed isolation of pulmonary TB patients in chest radiograph is commonly employed and easy to an aging society [28, 29]. According to nation-wide Japa- perform; presence of a cavitary lesion is critical in the nese data, the number of patients over 70 years with early detection of pulmonary TB. In previous systematic smear-positive pulmonary TB has increased by 2.5 times reviews and meta-analyses, female gender has been from 1980 to 2000 [20, 30]. In an aging society, the Table 2 Associated factors with delayed isolation among patients with smear positive tuberculosis Variable Adjusted HR 95% CI for HR P value Male gender 0.47 (0.249 to 0.888) 0.020* Appetite loss 0.63 (0.351 to 1.133) 0.123 Absence of chronic cough 0.52 (0.279 to 0.948) 0.033* Preceding newer quinolone antibiotics 0.50 (0.190 to 1.290) 0.150 Non-cavitary lesion on the chest radiograph 0.46 (0.233 to 0.922) 0.028* Non-upper zone lesion on the chest radiograph 0.64 (0.367 to 1.124) 0.120 Non-disseminated lesion on the chest radiograph 0.82 (0.479 to 1.404) 0.470 Multivariable Cox proportional hazards model including all factors p < 0.05 in univariate analysis HR hazard ratio, CI confidence interval, CRP C-reactive protein *p < 0.05 Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 6 of 7 Fig. 2 Grouped bar graphs indicating day-to-isolation of significant factors associated with delayed isolation of pulmonary TB patients number of older patients with smear-positive pulmonary Conclusion TB may have increased in community-based acute care Isolation of active pulmonary TB patients was delayed in hospitals. However, there are few reports of elderly pa- male patients, patients without chronic cough, and pa- tients with pulmonary TB. Thus, our results may be of tients with non-cavitary lesions on the chest radiograph. relevance in an aging society. Elderly TB patients can present with atypical manifesta- There are several limitations to our study. First, ours was tions that mimic other diseases. Thus, physicians need based on a single center cohort study with a small sample to have a heightened awareness of active pulmonary TB, size. The clinical ability of our residents was variable, de- especially among elderly patients; this may prevent pending on their level of training and experience, which spread of infection within the hospital. mayhaveled to bias.Inour studymodel,a p <0.05 was Abbreviations used as the cutoff level. This strict criteria though can pre- CI: Confidence interval; ER: Emergency room; HR: Hazard ratio; maturely exclude relevant variables, which may lead to se- IQR: Interquartile range; TB: Tuberculosis lection bias. Second, we are unable to establish a causal Availability of data and materials relationship in this retrospective observational study. Fur- The datasets generated and/or analyzed during the current study are not ther prospective studies are required to confirm such an as- publicly available but are available from the corresponding author on reasonable request. sociation. Third, as it was a hospital-based study, we could not analyze factors involving delay from symptoms onset to Authors’ contributions hospital visit, reported as “patient delay” in a previous study NS and TS conceived the idea of the work and collected data. NS performed the analysis. NS and TY interpreted the results, KI supervised throughout the [16]. Fourth, the present study may not include all project. All authors read and approved the final manuscript. in-hospital patients with smear-positive pulmonary TB, be- cause there can be presence of the patients who discharged Ethics approval and consent to participate The study was approved by the Institutional Review Board of Shonan or died before the investigation of sputum or gastric smear. Kamakura General Hospital (No. TGE00667-024). For the retrospective study, Future research needs to be directed to understanding we announced officially by the hospital web-site and the signboard in factors associated with a delayed diagnosis of active pul- hospital. All participants didn’t reject the consent for our study. monary TB; this information may help with earlier isola- Competing interests tion of TB patients, improve infection control, and The authors declare that they have no competing interests. reduce adverse outcomes. Therefore, multi-center, pro- spective studies are required, across different population Publisher’sNote groups, in countries with aging populations, to corrobor- Springer Nature remains neutral with regard to jurisdictional claims in ate our results. published maps and institutional affiliations. Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 7 of 7 Author details 20. Ohmori M, Ishikawa N, Yoshiyama T, Uchimura K, Aoki M, Mori T. 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Occurrence and clinical characteristics of tuberculosis among home medical care patients. Kekkaku. 2014;89(7):649–54. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Pulmonary Medicine Springer Journals

Delayed isolation of smear-positive pulmonary tuberculosis patients in a Japanese acute care hospital

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Abstract

Background: Active pulmonary tuberculosis (TB) is associated with intra-hospital spread of the disease. Expeditious diagnosis and isolation are critical for infection control. However, factors that lead to delayed isolation of smear- positive pulmonary TB patients, especially among the elderly, have not been reported. The purpose of this study is to investigate factors associated with delay in the isolation of smear-positive TB patients. Methods: All patients with smear-positive pulmonary TB admitted between January 2008 and December 2016 were included. The setting was a Japanese acute care teaching hospital. Following univariate analysis, significant factors in the model were analyzed using the multivariate Cox proportional hazard model. Results: Sixty-nine patients with mean age of 81 years were included. The median day to the isolation of pulmonary TB was 1 day with interquartile range, 1–4 days. On univariate analysis, the time to isolation was significantly delayed in male patients (p = 0.009), in patient who had prior treatment with newer quinolone antibiotics (p = 0.027), in patients who did not have chronic cough (p = 0.023), in patients who did not have appetite loss (p = 0.037), and in patients with non-cavitary lesion (p = 0.005), lesion located other than in the upper zone (p = 0.015), and non-disseminated lesion on the chest radiograph (p = 0.028). On multivariate analysis, the time to isolation was significantly delayed in male patients (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.25 to 0. 89; P = 0.02), in patients who did not have chronic chough (HR, 0.52; 95% CI, 0.28 to 0.95; P = 0.033), and in patients with non-cavitary lesion on the chest radiograph (HR, 0.46; 95% CI, 0.23 to 0.92; P = 0.028). Conclusions: In acute care hospitals of an aging society, prompt diagnosis and isolation of TB patients are important for the protection of other patients and healthcare providers. Delay in isolation is associated with male gender, absence of chronic cough, and presence of non-cavitary lesions on the chest radiograph. Keywords: Pulmonary tuberculosis, Delay, Isolation, Diagnosis, Smear-positive Background Although theprevalenceofTBhad reduced to 16.7 Tuberculosis (TB) control is of worldwide interest, espe- per 100,000 among Japanese population in 2012, this cially among patients with active pulmonary TB who are figure remains 3–4 times higher than in Europe and smear-positive for acid-fast bacilli [1]. TB control requires North America [5, 6]. One reason for the relatively early diagnosis and immediate initiation of treatment [2]. high prevalence of TB in Japan is an aging population Delay in diagnosis adversely affects clinical outcome; be- with previous TB infection [7]. In the World Health sides, it increases transmission within the community and Organization 2017 global report, Japanese patients leads to higher transmission rates in an epidemic [3, 4]. with smear-positive pulmonary TB were older and had a higher mortality than in other countries [8, 9]. Given the high rates of hospital admission among eld- * Correspondence: sanazen@hotmail.co.jp Department of General Internal Medicine, Shonan Kamakura General erly patients in developed countries, any delay in Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, Japan diagnosis and isolation of pulmonary TB can cause Department of Internal Medicine, Hayama Heart Center, Hayama, Kanagawa, spread of infection [10]. Therefore, in aging societies Japan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 2 of 7 including Japan, it is important to seek reasons for gastric resection, human immunodeficiency virus infec- delay in the isolation of pulmonary TB patients. tion, preceding treatment with newer quinolone antibi- In previous studies, factors leading to delayed diagnosis otics, steroid use, chronic cough, loss of appetite, body of pulmonary TB have been well reported worldwide [2, mass index, body temperature on arrival, systolic blood 11–14]. These reports focused on ‘patient delay’ and pressure, oxygen requirement, hemoglobin level, serum ‘health care system delay’ [14–16]. Delayed diagnosis has albumin level, C-reactive protein level, presence of a been associated with human immunodeficiency virus in- cavitary, upper zone or disseminated lesion on the chest fection, chronic cough, and presence of incidental lung radiograph, and the raw score. The raw score is a vali- disease [2]. Geographical and socio-psychological barriers dated prognostic score for patients with smear-positive include rural residence and poor access to healthcare [2, pulmonary TB [8]. 11, 12]. Other factors that may delay diagnosis include old We also collected data on the following “facility and age, female gender, alcoholism and substance abuse, initial physician-related factors”: year of hospital visit, time of visitation at a low-level government healthcare facility, pri- arrival (day or night), weekday or weekend arrival, the vate practitioner, or traditional healer [2, 11, 12, 14]. His- attending ER physician, medical care provided by the tory of immigration, poor education status, low awareness resident on arrival, medical care provided by male phys- of TB, irrational beliefs, self-treatment, the associated ician on arrival, and whether transferred to the hospital stigma, consultation at a public hospital, and prior treat- by ambulance. ment with fluoroquinolones may also delay the diagnosis of active pulmonary TB [2, 11–14]. Statistical analysis To the best of our knowledge, factors associated with We aimed to evaluate factors associated with delayed delay in isolation of pulmonary TB patients have not been isolation of smear-positive pulmonary TB patients. The reported. In the clinical setting, any delay in isolation is primary outcome measure was the duration day from critical to control of infection within hospitals. Therefore, hospital visit to the isolation of the patient with TB. we conducted this study to clarify factors associated with Day-to-isolation analysis, based on the Cox proportional delayed isolation of active pulmonary TB patients. hazard model, was used to analyze factors associated with delay to the isolation of pulmonary TB patients. In Methods a univariate model, the “patient-related factors” and Patients and setting “medical facility and physician-related factors” were eval- We conducted a retrospective study on patients who were uated as possible reasons for the delayed isolation of ac- diagnosed with smear-positive pulmonary TB in an urban tive pulmonary TB, based on log-rank test or univariate teaching hospital between January 2008 and December Cox hazard test, as appropriate. Significant factors in the 2016. The hospital provides primary through tertiary care univariate model were analyzed using the multivariate in Kanagawa Prefecture, Japan, with a population of about Cox proportional hazard model. A two-tailed p-value < nine million people. The hospital has no specific wards for 0.05 was considered statistically significant. All data ana- patients with treatment of active pulmonary TB. Those lyses were undertaken using the SPSS Statistics version who are suspected to have active pulmonary TB disease 21 J (IBM, Tokyo, Japan). This study was approved by are immediately isolated in single rooms with negative air the Institutional Review Board of the hospital (No. pressure for definite sputum smear diagnosis, particularly TGE00667-024). with three consecutive sputum or gastric aspiration ana- lysis. After the diagnosis of smear-positive pulmonary TB Results is established, the patients are then transferred to another Sixty-nine patients with smear-positive pulmonary TB hospital that has special wards for the treatment of were enrolled. Base-line characteristics and univariate smear-positive pulmonary TB. Therefore, a delay in isola- analysis were included in Table 1. The mean age of pa- tion on admission may spread the TB infection tients was 81 years, with 18 (26.1%) female patients. All in-hospital. We studied 69 consecutive patients who were patients were hospitalized and isolated for infection con- diagnosed with smear-positive pulmonary TB by examin- trol. Two patients were discharged home, 55 were trans- ation of the sputum or gastric specimen. ferred to other hospitals for the treatment of TB, and 12 died in our hospital. The median length of hospital stay Data collection was 7 days with interquartile range (IQR), 5–18 days. Data collection for each patient, collectively referred to The median day to the isolation of pulmonary TB pa- as “patient-related factors”: age, gender, history of smok- tients was 1 day with IQR, 1–4 days. Figure 1 showed ing or alcoholism, welfare recipient or not, activities of that over 60% patients isolated within 1 day. However, daily living, past history of TB, contact with TB patients, approximately 10% patients isolated over 10 days (Fig. 1). diabetes mellitus, other lung disease, surgical history of On univariate analysis, male gender (p = 0.009), prior Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 3 of 7 Table 1 Clinical characteristics and day-to-isolation univariate analysis (N = 69) Characteristic No.(%) or mean ± SD Day-to-isolation p-value (95% CI) Patient factor Age (years) 81.1 ± 10.0 0.827 Male gender-no.(%) 51 (73.9) 8.2 (3.90–12.41) 0.009* Female gender-no.(%) 18 (26.1) 1.8 (0.70–2.86) Smoking-no.(%) 40 (58.0) 6.6 (3.16–10.09) 0.585 Non-smoking-no.(%) 29 (42.0) 6.3 (0.24–12.38) Alcoholism-no.(%) 4 (5.8) 1.5 (0.52–2.48) 0.217 Non-alcoholism-no.(%) 65 (94.2) 6.8 (3.40–10.21) Welfare recipient-no.(%) 4 (5.8) 1.3 (0.76–1.74) 0.172 Non-welfare recipient-no.(%) 65 (94.2) 6.8 (3.41–10.22) Dependent ADL-no.(%) 12 (17.4) 11.5 (2.67–20.33) 0.129 Partially dependent ADL-no.(%) 20 (29.0) 8.7 (0.08–17.22) Independent ADL-no.(%) 37 (53.6) 3.7 (1.28–6.13) Past history of tuberculosis-no.(%) 28 (40.6) 3.0 (1.44–4.49) 0.073 Non-past history of tuberculosis-no.(%) 41 (59.4) 8.9 (3.69–14.12) Contact with tuberculosis patients-no.(%) 7 (10.1) 3.3 (0.01–6.56) 0.519 Non-contact with tuberculosis patients-no.(%) 62 (89.9) 6.9 (3.30–10.41) Diabetes mellitus-no.(%) 25 (37.3) 3.8 (1.19–6.49) 0.248 Non-diabetes mellitus-no.(%) 42 (60.9) 8.3 (3.31–13.31) Other lung disease-no.(%) 18 (26.1) 5.3 (0.73–9.83) 0.864 Non-other lung disease-no.(%) 51 (73.9) 6.9 (2.86–10.99) Gastric resection-no.(%) 8 (11.6) 4.8 (0.00–11.02) 0.593 Non-gastric resection-no.(%) 61 (88.4) 6.7 (3.16–10.28) Human immunodificiency virus infection -no.(%) 1 (1.4) 1.0 (1.00–1.00) 0.366 Non-human immunodificiency virus infection-no.(%) 68 (98.6) 6.6 (3.31–9.84) Preceding newer quinolone antibiotics-no.(%) 6 (8.7) 23.0 (0.00–51.14) 0.027* Non-preceding newer quinolone antibiotics-no.(%) 63 (91.3) 4.9 (2.77–7.07) Steroid use-no.(%) 15 (21.7) 6.5 (0.38–12.55) 0.923 Non-steriod use-no.(%) 54 (78.3) 6.5 (2.72–10.28) Chronic cough-no.(%) 19 (27.5) 2.3 (0.81–3.82) 0.023* Absence of chronic cough-no.(%) 50 (72.5) 8.1 (3.74–12.42) Appetite loss-no.(%) 48 (70.6) 8.5 (3.96–13.00) 0.037* Absence of appetite loss-no.(%) 20 (29.0) 2.0 (1.36–2.64) BMI (kg/m ) 19.0 ± 3.3 0.213 BT on arrival (°C) 37.2 ± 1.8 0.335 sBP on arrical (mmHg) 123.5 ± 30.3 0.768 Oxygen requirement-no.(%) 25 (36.2) 8.2 (0.89–15.51) 0.555 Non-oxygen requirement-no.(%) 44 (63.8) 5.5 (2.60–8.44) Haemoglobin level (g/dL) 11.9 ± 1.9 0.783 Serum albumin level (g/dL) 2.9 ± 0.6 0.348 CRP level (mg/dL) 9.3 ± 5.6 0.748 Cavitary lesion on the chest radiograph-no.(%) 15 (21.7) 1.3 (1.04–1.50) 0.005* Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 4 of 7 Table 1 Clinical characteristics and day-to-isolation univariate analysis (N = 69) (Continued) Characteristic No.(%) or mean ± SD Day-to-isolation p-value (95% CI) Non-cavitary lesion on the chest radiograph-no.(%) 54 (78.3) 7.9 (3.91–11.98) Upper zone lesion on the chest radiograph-no.(%) 36 (52.2) 3.3 (1.33–5.17) 0.015* Lesion located other than in the upper zone on the chest radiograph-no.(%) 33 (47.8) 10.0 (3.80–16.26) Disseminated lesion on the chest radiograph-no.(%) 32 (46.4) 3.3 (0.72–5.91) 0.028* Non-disseminated lesion on the chest radiograph-no.(%) 37 (53.6) 9.2 (3.79–14.70) Raw score (from −30 points to 60 points) 29.2 ± 18.0 0.973 Medical facility and doctor factor Year of hospital visit (from 2008 to 2016) 2012.4 ± 2.6 0.151 Night-time arrival-no.(%) 27 (39.1) 8.7 (1.87–15.47) 0.248 Day-time arrival-no.(%) 42 (60.9) 5.1 (2.11–8.08) Weekend arrival-no.(%) 13 (18.8) 3.8 (1.06–6.48) 0.517 Weekday arrival-no.(%) 56 (81.2) 7.1 (3.22–11.03) Medical care provided by resident-no.(%) 27 (39.1) 7.1 (0.72–13.58) 0.844 Medical care provided by non-resident-no.(%) 42 (60.9) 6.1 (2.71–9.44) Medical care provided by male doctor-no.(%) 60 (87.0) 5.9 (2.64–9.20) 0.407 Medical care provided by female doctor-no.(%) 9 (13.0) 10.3 (0.00–22.07) Transferred to the hospital by ambulance-no.(%) 39 (56.5) 7.9 (2.74–13.16) 0.523 Transferred to the hospital by non-ambulance-no.(%) 30 (43.5) 4.6 (1.63–7.57) Attending ER physician-no.(%) 55 (79.7) 6.3 (2.53–10.05) 0.580 Attending non-ER physician-no.(%) 14 (20.3) 7.3 (1.27–13.30) Raw score is tuberculosis prognostic score, which is calculated as follows: age(years) + (oxygen requirement, 10 points) − 20 × albumin (g/dl) + (ADL: independent, 0 point; semi-dependent, 5 points; totally dependent, 10 points) Resident indicate physician who was graduated within two years Based on logrank test or cox hazard crude model, where appropriate, *p < 0.05 CI confidence interval, SD = standard deviation, ADL activities of daily living, BMI body mass index, BT body temperature, sBP systolic blood pressure, CRP C- reactive protein, ER emergency room Fig. 1 Kaplan-Meier curve of the time from admission to isolation of pulmonary TB patients. The median time to the isolation of pulmonary TB patients was 1 day with interquartile range, 1–4 days Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 5 of 7 treatment with newer quinolone antibiotics (p = 0.027), shown to be a risk factor for delayed diagnosis of pul- absence of chronic cough (p = 0.023), appetite loss (p = monary TB [11, 12]; there are no previous reports of 0.037), non-cavitary lesion on the chest radiograph (p = male gender being associated with delay in isolation of 0.005), lesion located other than in the upper zone on pulmonary TB patients. the chest radiograph (p = 0.015), and non-disseminated We speculate that the delay in isolation associated lesion on the chest radiograph (p = 0.028) were signifi- with male gender, absence of chronic cough and cant factors associated with a delayed isolation of pul- non-cavitary lesion on the chest radiograph, may be re- monary TB patients (Table 1). lated to the advanced age of our patients (mean age: On multivariate analysis using Cox hazard model, 81.1 years). Younger patients with smear-positive TB male gender (hazard ratio [HR], 0.47; 95% confidence were referred to other hospitals with special wards, interval [CI], 0.25 to 0.89; P = 0.02), absence of chronic resulting in an increase in elderly patients with TB in cough (HR, 0.52; 95% CI, 0.28 to 0.95; P = 0.033), and our hospital. Elderly patients with TB can manifest with non-cavitary lesion on the chest radiograph (HR, 0.46; unusual features that may be confused with aspiration 95% CI, 0.23 to 0.92; P = 0.028) were significantly associ- pneumonia [17], commonly observed in this population ated with delayed isolation of TB patients (Table 2). [18]. The typical symptoms of aspiration pneumonia are Figure 2 showed intergroup comparisons of fever, cough with sputum, and dyspnea; however, day-to-isolation among significant factors associated non-specific symptoms including loss of consciousness with delayed isolation of pulmonary TB patients in the and appetite loss are also important. Thus, the symp- multivariate analysis. toms of pulmonary TB and aspiration pneumonia are similar. Moreover, aspiration pneumonia, a common dis- Discussion ease in an aging society, can co-exist in patients with ac- Our study revealed that male gender, absence of chronic tive pulmonary TB and has drawn increasing attention cough, and non-cavitary lesion on the chest radiograph recently [19]. Although the incidence of active pulmon- were associated with delayed isolation of active pulmon- ary TB has decreased, the number of elderly patients has ary TB patients. increased in Japan [20]. There may be a lack of wide- A non-cavitary lesion on the chest radiograph and ab- spread awareness among healthcare workers, including sence of chronic cough are factors consistent with previ- physicians, of this development. This may have led to ous reports of diagnostic delay in cases of pulmonary failure to consider pulmonary TB in elderly patients. Be- TB; our findings of association of male gender with diag- sides, the symptoms of pulmonary TB can mimic aspir- nostic delay is contrary to the findings of previous stud- ation pneumonia in the elderly. ies. Chronic cough is an important symptom for the Although previous studies have described factors asso- clinician to consider the diagnosis of pulmonary TB ciated with delayed diagnosis of pulmonary TB [11–13, from the clinical history. Moreover, a previous report of 15, 21–27], we focused on factors that delayed isolation, in-hospital diagnostic delay from Southern Taiwan re- especially among elderly patients admitted to hospital. vealed non-cavitary lesion on the chest radiograph as an To the best of our knowledge, ours is the first study that independent risk factor [14], similar to our finding. A deals with delayed isolation of pulmonary TB patients in chest radiograph is commonly employed and easy to an aging society [28, 29]. According to nation-wide Japa- perform; presence of a cavitary lesion is critical in the nese data, the number of patients over 70 years with early detection of pulmonary TB. In previous systematic smear-positive pulmonary TB has increased by 2.5 times reviews and meta-analyses, female gender has been from 1980 to 2000 [20, 30]. In an aging society, the Table 2 Associated factors with delayed isolation among patients with smear positive tuberculosis Variable Adjusted HR 95% CI for HR P value Male gender 0.47 (0.249 to 0.888) 0.020* Appetite loss 0.63 (0.351 to 1.133) 0.123 Absence of chronic cough 0.52 (0.279 to 0.948) 0.033* Preceding newer quinolone antibiotics 0.50 (0.190 to 1.290) 0.150 Non-cavitary lesion on the chest radiograph 0.46 (0.233 to 0.922) 0.028* Non-upper zone lesion on the chest radiograph 0.64 (0.367 to 1.124) 0.120 Non-disseminated lesion on the chest radiograph 0.82 (0.479 to 1.404) 0.470 Multivariable Cox proportional hazards model including all factors p < 0.05 in univariate analysis HR hazard ratio, CI confidence interval, CRP C-reactive protein *p < 0.05 Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 6 of 7 Fig. 2 Grouped bar graphs indicating day-to-isolation of significant factors associated with delayed isolation of pulmonary TB patients number of older patients with smear-positive pulmonary Conclusion TB may have increased in community-based acute care Isolation of active pulmonary TB patients was delayed in hospitals. However, there are few reports of elderly pa- male patients, patients without chronic cough, and pa- tients with pulmonary TB. Thus, our results may be of tients with non-cavitary lesions on the chest radiograph. relevance in an aging society. Elderly TB patients can present with atypical manifesta- There are several limitations to our study. First, ours was tions that mimic other diseases. Thus, physicians need based on a single center cohort study with a small sample to have a heightened awareness of active pulmonary TB, size. The clinical ability of our residents was variable, de- especially among elderly patients; this may prevent pending on their level of training and experience, which spread of infection within the hospital. mayhaveled to bias.Inour studymodel,a p <0.05 was Abbreviations used as the cutoff level. This strict criteria though can pre- CI: Confidence interval; ER: Emergency room; HR: Hazard ratio; maturely exclude relevant variables, which may lead to se- IQR: Interquartile range; TB: Tuberculosis lection bias. Second, we are unable to establish a causal Availability of data and materials relationship in this retrospective observational study. Fur- The datasets generated and/or analyzed during the current study are not ther prospective studies are required to confirm such an as- publicly available but are available from the corresponding author on reasonable request. sociation. Third, as it was a hospital-based study, we could not analyze factors involving delay from symptoms onset to Authors’ contributions hospital visit, reported as “patient delay” in a previous study NS and TS conceived the idea of the work and collected data. NS performed the analysis. NS and TY interpreted the results, KI supervised throughout the [16]. Fourth, the present study may not include all project. All authors read and approved the final manuscript. in-hospital patients with smear-positive pulmonary TB, be- cause there can be presence of the patients who discharged Ethics approval and consent to participate The study was approved by the Institutional Review Board of Shonan or died before the investigation of sputum or gastric smear. Kamakura General Hospital (No. TGE00667-024). For the retrospective study, Future research needs to be directed to understanding we announced officially by the hospital web-site and the signboard in factors associated with a delayed diagnosis of active pul- hospital. All participants didn’t reject the consent for our study. monary TB; this information may help with earlier isola- Competing interests tion of TB patients, improve infection control, and The authors declare that they have no competing interests. reduce adverse outcomes. Therefore, multi-center, pro- spective studies are required, across different population Publisher’sNote groups, in countries with aging populations, to corrobor- Springer Nature remains neutral with regard to jurisdictional claims in ate our results. published maps and institutional affiliations. Nishiguchi et al. BMC Pulmonary Medicine (2018) 18:94 Page 7 of 7 Author details 20. Ohmori M, Ishikawa N, Yoshiyama T, Uchimura K, Aoki M, Mori T. 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BMC Pulmonary MedicineSpringer Journals

Published: May 31, 2018

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