Patients with Acute Respiratory Distress Syndrome Caused by Scrub Typhus: Clinical Experiences of Eight Patients

Sun Young Kim; Hang Jea Jang; Hyunkuk Kim; Kyunghwa Shin; Mi-Hyun Kim; Kwangha Lee; Ki Uk Kim; Hye-Kyung Park; Min Ki Lee

doi:10.4266/kjccm.2014.29.3.189

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This article has been corrected. See "Patients with Acute Respiratory Distress Syndrome Caused by Scrub Typhus: Clinical Experiences of Eight Patients" in Volume 29 on page 348.

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Kim, Jang, Kim, Shin, Kim, Lee, Kim, Park, and Lee: Patients with Acute Respiratory Distress Syndrome Caused by Scrub Typhus: Clinical Experiences of Eight Patients

Original Article

The Korean Journal of Critical Care Medicine 2014; 29(3): 189-193.

Published online: 31 August 2014

DOI: https://doi.org/10.4266/kjccm.2014.29.3.189

Patients with Acute Respiratory Distress Syndrome Caused by Scrub Typhus: Clinical Experiences of Eight Patients

Sun Young Kim, M.D., Hang Jea Jang, M.D., Hyunkuk Kim, M.D., Kyunghwa Shin, M.D.^*, Mi-Hyun Kim, M.D.^†, Kwangha Lee, M.D.^†,, Ki Uk Kim, M.D.^†, Hye-Kyung Park, M.D.^†, Min Ki Lee, M.D.^†

Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

^*Department of Internal Medicine, Daedong Hospital, Busan, Korea

^†Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea

Correspondence to: Kwangha Lee, Department of Internal Medicine, Pusan National University Hospital, Pusan National University School, of Medicine, 179 Gudeok-ro, Seo-gu, Busan 602-739, Korea, Tel: +82-51-240-7743, Fax: +82-51-254-3127, E-mail: jubilate@pusan.ac.kr

Received 25 February 2014 Revised 11 May 2014 Accepted 19 May 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The aim of this study is to describe the clinical course and outcome of patients who were diagnosed with acute respiratory distress syndrome (ARDS) caused by scrub typhus and who received ventilator care in the intensive care units (ICU) of two university hospitals.

Methods

We performed a retrospective analysis of all adult ventilated patients who were diagnosed with ARDS caused by scrub typhus.

Results

Eleven (1.7%) of 632 scrub typhus patients were diagnosed with ARDS (median age 72; seven were male). Eight patients had underlying diseases, the most common of which was hypertension (four patients). Eight patients (72.7%) were admitted in November. The most common chief complaints of the patients were fever and rash (63.6%). All patients had skin eschar and rash; seven were treated for shock. On the day of diagnosis with ARDS, the median Acute Physiology and Chronic Health Evaluation score was 20 (range 11–28) and Sequential Organ Failure Assessment score was 7 (range 4–14). All patients had PaO₂/FiO₂ < 200 mmHg, high serum aspartate aminotransferase level (> 40 IU/L), and hypoalbuminemia (< 3.3 g/dl). Nine patients were treated with doxycycline on the day of admission. Their median lengths of stay in the ICU and hospital were 10 (range 4–65) and 14 (4–136) days, respectively. The mortality rate during treatment in the hospital was 36.4%.

Conclusions

In our study, the risk of ARDS among patients diagnosed with scrub typhus was at least 1.7%, with a hospital mortality rate of 36.4%.

Keywords: acute respiratory distress syndrome, intensive care unit, scrub typhus

Introduction

Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi[1] distributed throughout the Asia–Pacific area.[2] Scrub typhus, an acute febrile disease, is characterized by a typical primary necrotic lesion (eschar), generalized lymphadenopathy, rash, and non-specific symptoms such as fever, headache, myalgia and cough. Rarely, severe complications, including prominent encephalitis, interstitial pneumonia, acute respiratory distress syndrome (ARDS), acute renal and hepatic failure, and acute hearing loss, have been reported.[3–8] Serious pulmonary involvement such as ARDS has rarely been seen, likely because of the introduction of specific antibiotic therapy. Although one observational study reported the clinical characteristics of eight patients with ARDS,[9] scrub typhus complicated by ARDS has seldom been discussed; few case reports have been published.[10–13] Moreover, no reports include data on the clinical characteristics of these patients in South Korea.

The aim of this study was to investigate the clinical course and outcome of patients diagnosed with ARDS caused by scrub typhus and received ventilator care in the intensive care units (ICU) of two university hospitals in Busan, South Korea. Also, we examined potential differences from previous reports.[9]

Materials and Methods

1) Study subjects

We performed a retrospective search of all adult patients (age ≥ 17 years) admitted to the ICU who met the criteria for both code A753 (scrub typhus) and J80 (ARDS) according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10). A total of 11 ventilated patients diagnosed with ARDS caused by scrub typhus were enrolled in this study. Of these patients, nine were from Pusan National University Hospital between 1 January 1995 and 31 December 2012 and two were from Haeundae Baik Hospital between 1 January 2010 and 31 December 2012. ARDS patients were managed according to the therapeutic guideline for lung-protective ventilation.[14] Medical records and laboratory and radiographic findings of all patients were collected. Investigators from each center completed a case report form, and data were collected from September to October 2013. Three investigators (SYK, KS and KL) confirmed that the study objectives and procedures were honestly disclosed, and both had full access to all of the data. The protocol for this study was approved by the Institutional Review Boards of the two participating institutions.

2) Data collection

The following data were gathered from the medical records of each patient: age, gender, duration of mechanical ventilation, length of stay in the ICU and in the hospital, hospital mortality, month of admission and chief complaint at admission. Acute Physiology and Chronic Health Evaluation (APACHE) and Sequential Organ Failure Assessment (SOFA) scores were calculated on the day of ARDS diagnosis.[15,16] The Charlson Comorbidity Index was calculated from medical records.[17] The following laboratory data collected on the day of ARDS diagnosis were obtained from medical records: white blood cell count, lowest PaO₂/FiO₂ ratio, C-reactive protein, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and albumin level. In addition, we recorded the occurrence of septic shock at ARDS diagnosis, tracheostomy during hospitalization, and time from admission to the beginning of treatment with doxycycline.

3) Definition

A diagnosis of scrub typhus was based on an indirect microimmunofluorescence antibody (IFA) test for O. tsutsugamushi. Diagnostic IFA results were positive if total antibody titer showed a fourfold increase in paired positive serum samples or the antibody titer was ≥ 1:160.[18,19] The diagnosis of ARDS was based on the consensus criteria of the American-European Consensus Conferences, which was defined as acute onset, PaO₂/FiO₂ ≤ 200 mmHg regardless of positive end-expiratory pressure, bilateral infiltrates seen on frontal chest radiograph, and pulmonary artery wedge ≤ 18 mmHg when measured or no clinical evidence of left atrial hypertension.[20] Sepsis, severe sepsis, and septic shock were defined using criteria from the American College of Chest Physicians/Society of Critical Care Medicine.[21] Acute kidney injury was defined as oliguria and marked increase in BUN and creatinine, and ventilator-associated pneumonia was defined as a modified Clinical Pulmonary Infection Score of 6 or greater.[22] Survivors were defined as patients who survived to discharge from hospital.

4) Statistical analysis

Continuous variables are expressed as medians and ranges and compared using the Mann-Whitney U-test. Categorical variables were compared using chi-square and Fisher’s exact tests. All statistical analyses were performed using the Statistical Package for the Social Sciences (version 18.0, SPSS, Chicago, IL, USA). A two-tailed p < 0.05 was considered to indicate statistical significance.

Results

During enrolled period, a total of 632 patients were diagnosed with scrub typhus. Of these patients, eleven were diagnosed with ARDS. Patients’ characteristics and their clinical courses are summarized in Table 1. The median patient age was 72 (range 29–85) years, and seven (63.6%) patients were male. Eight patients (72.7%) had underlying diseases and most common underlying disease was hypertension (four patients). The median Charlson Comorbidity Score was 1 (range 0–3). Eight patients (72.7%) were admitted in November. The most common chief complaint of the patients was fever and dyspnea (63.6%). All patients had skin rash and eschar; seven were also treated for shock. The median APACHE and SOFA score on the day of diagnosis with ARDS were 20 (range 11–28) and 7 (4–14), respectively. All patients had PaO₂/FiO₂ < 200 mmHg, high serum AST levels (> 40 IU/L), and hypoalbuminemia (< 3.3 g/dl). Seven patients had diagnostic IFA results, which all patients had the antibody titer was ≥ 1:160. Nine patients were treated with doxycycline on the day of admission (range of interval from hospital admission to commencement of antibiotic, 0–5). The two most common complications in the study population were hospital-acquired pneumonia and acute kidney injury (each occurring in 2 of 11 or 18.2% of patients). The median duration of ventilator care was 6 days (range 1–61), and median length of stay in the ICU and hospital were 10 (range 4–65) and 14 (4–136) days, respectively. One patient was received tracheostomy. The hospital mortality rate was 36.4% (4 of 11). However, there were no significant differences regarding the above clinical characteristics and laboratory data between survivors and non-survivors (data not shown).

Discussion

This study investigated the clinical characteristics of patients with ARDS caused by scrub typhus in South Korea. According to the literature, the pulmonary manifestations of scrub typhus are varying grades of bronchitis and interstitial pneumonitis progressing to ARDS.[23] ARDS might arise as a result of the immunological response of the lung to previous O. tsutsugamushi infection without direct invasion of the organism.[9,10] Also, interstitial pneumonia might be associated with disease severity as reported in a previous study.[24]

In the present study, we found that all patients had low comorbidity scores, and most patients were hospitalized in November. These findings suggest that development of ARDS caused by scrub typhus does not correlate with underlying diseases and that November might be a period during which development of ARDS is prevalent.

Also, the five major clinical symptoms are well known to include fever, headache, eschar, rash, and lymphadenopathy; 83% of the cases presented with one to three clinical symptoms and 10% with four to five symptoms.[25] However, in this study, the chief complaint was dyspnea and fever, which was consistent with a previous report;[9] initial respiratory symptoms at the time of diagnosis with scrub typhus might be an indication for careful evaluation for progression to ARDS.

Several published case reports and study described clinical manifestations in patients with ARDS caused by scrub typhus which are summarized in Table 2.[9–13] Compared with these previous reports, all our patients presented with hypoalbuminemia, which was consistent with previous reports.[9,11–13] In the reported data in Taiwan, hypoalbuminemia was an independent predictor for development of ARDS. Though we hypothesized this feature would also indicate prognosis in our patients, the small sample size prevented a clear conclusion.

Treatment with doxycycline usually lowers fever within 24 hours, and severe complications such as sepsis and ARDS are typically the result of delayed diagnosis and treatment. In our study, all patients were treated with doxycycline, and 10 patients (91%) received antibiotics within 2 days after hospitalization. This interval was somewhat shorter than in a previous report[9] (median: 0 vs. 8 days). However, the mortality rate we observed was higher than in that study.[9] This difference may be due to the fact that all patients included in our analysis had low PaO₂/FiO₂, and 63.6% were experiencing shock at ARDS diagnosis. Our results suggest that the mortality rate in patients with ARDS caused by scrub typhus is higher than that for scrub typhus overall, even with prompt treatment using appropriate antibiotics.

There were several limitations to our research because of its retrospective design and the small number of patients. First, we hypothesized that all patients would have serious neurologic complications caused by scrub typhus at admission; because a previous study showed that the presence of pneumonitis was associated with the occurrence of scrub typhus meningitis and meningoencephalitis.[26] However, we could not identify additional complications as shown in Table 1 because the study was retrospective. Second, there would be different serotype of Orientia tsutsugamushi depending on the region, which might be associated with different disease severity and clinical outcome. Therefore, our study reflected the regional characteristics, especially focused on Busan area.

In conclusion, our study found the risk of ARDS among patients diagnosed with scrub typhus was at least 1.7%, and their hospital mortality rate was 36.4%. Further, large-scale studies are needed to identify prognostic indicators for development of ARDS and to establish whether the clinical outcomes of scrub typhus differ according to the respiratory reaction.

Notes

No potential conflict of interest relevant to this article was reported.

References

1). Tamura A, Ohashi N, Urakami H, Miyamura S. Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen. nov., as Orientia tsutsugamushi comb. nov. Int J Syst Bacteriol. 1995; 45:589–91.

2). Rapmund G. Rickettsial diseases of the Far East: new perspectives. J Infect Dis. 1984; 149:330–8.

3). Tsay RW, Chang FY. Serious complications in scrub typhus. J Microbiol Immunol Infect. 1998; 31:240–4.

4). Aronoff DM, Watt G. Prevalence of relative bradycardia in Orientia tsutsugamushi infection. Am J Trop Med Hyg. 2003; 68:477–9.

5). Silpapojakul K, Ukkachoke C, Krisanapan S. Rickettsial meningitis and encephalitis. Arch Intern Med. 1991; 151:1753–7.

6). Premaratna R, Chandrasena TG, Dassayake AS, Loftis AD, Dasch GA, de Silva HJ. Acute hearing loss due to scrub typhus: a forgotten complication of a reemerging disease. Clin Infect Dis. 2006; 42:e6–8.

7). Chang JH, Ju MS, Chang JE, Park YS, Han WS, Kim IS, et al. Pericarditis due to Tsutsugamushi disease. Scand J Infect Dis. 2000; 32:101–2.

8). Hu ML, Liu JW, Wu KL, Lu SN, Chiou SS, Kuo CH, et al. Short report: Abnormal liver function in scrub typhus. Am J Trop Med Hyg. 2005; 73:667–8.

9). Wang CC, Liu SF, Liu JW, Chung YH, Su MC, Lin MC. Acute respiratory distress syndrome in scrub typhus. Am J Trop Med Hyg. 2007; 76:1148–52.

10). Park JS, Jee YK, Lee KY, Kim KY, Myong NH, Seo PW. Acute respiratory distress syndrome associated with scrub typhus: diffuse alveolar damage without pulmonary vasculitis. J Korean Med Sci. 2000; 15:343–5.

11). Kurup A, Issac A, Loh JP, Lee TB, Chua R, Bist P, et al. Scrub typhus with sepsis and acute respiratory distress syndrome. J Clin Microbiol. 2013; 51:2787–90.

12). Tseng CC, Tung HH, Wu SF, Wang TJ. Acute respiratory distress syndrome following scrub typhus: a case report. J Am Acad Nurse Pract. 2012; 24:160–5.

13). Ryu KH, Kim KH, Kim HD, Son JW, Na MJ, Choi E. A case of ARDS overlooked Tsutstugamushi disease that presented as simple cutaneous lesion. Tuberc Respir Dis. 2006; 61:389–93.

14). Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000; 342:1301–8.

15). Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985; 13:818–29.

16). Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996; 22:707–10.

17). Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40:373–83.

18). Amano K, Suzuki N, Fujita M, Nakamura Y, Suto T. Serological reactivity of sera from scrub typhus patients against Weil-Felix test antigens. Microbiol Immunol. 1993; 37:927–33.

19). Jiang J, Marienau KJ, May LA, Beecham HJ 3rd, Wilkinson R, Ching WM, et al. Laboratory diagnosis of two scrub typhus outbreaks at Camp Fuji, Japan in 2000 and 2001 by enzyme-linked immunosorbent assay, rapid flow assay, and Western blot assay using outer membrane 56-kD recombinant proteins. Am J Trop Med Hyg. 2003; 69:60–6.

20). Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994; 149(3 Pt 1):818–24.

21). Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest. 1992; 101:1481–3.

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23). Chayakul P, Panich V, Silpapojakul K. Scrub typhus pneumonitis: an entity which is frequently missed. Q J Med. 1988; 68:595–602.

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25). Lee YS, Wang PH, Tseng SJ, Ko CF, Teng HJ. Epidemiology of scrub typhus in eastern Taiwan, 2000–2004. Jpn J Infect Dis. 2006; 59:235–8.

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Table 1.

Characteristics and clinical courses of eleven scrub typhus patients with acute respiratory distress syndrome

N	Age/Sex	Month of admission	Chief complaint	APACHE II score	SOFA score	CCI	MV LOS	ICU LOS	Hospital LOS	Shock	PaO₂/FiO₂ (mmHg)	Complication during hospital course	Hospital outcome
1	77/M	November	RUQ pain, fever	23	11	2	17	20	26	Yes	66.6	Pneumonia	Survived
2	72/M	December	Dyspnea, fever	15	6	1	6	7	13	Yes	70.5	None	Survived
3	72/M	October	Fever	23	6	3	1	10	19	No	155.2	None	Survived
4	83/F	November	Fever	17	7	0	5	9	18	No	106.6	None	Survived
5	66/M	November	Dyspnea, fever	22	5	0	6	6	13	No	101.8	None	Survived
6	64/M	November	Dyspnea, fever	25	11	1	61	65	136	Yes	107.5	Pneumonia, TEN	Survived
7	85/M	November	Hematochezia	18	10	1	1	14	14	No	73.5	Ischemic colitis	Died
8	67/F	November	Dyspnea, fever	15	9	1	12	12	12	Yes	114.1	None	Died
9	73/M	November	Dyspnea	28	14	1	4	4	4	Yes	41.8	Acute kidney injury, encephalitis	Died
10	66/F	November	Dyspnea	20	4	3	18	19	20	Yes	88.0	Acute kidney injury	Died
11	29/F	October	Dyspnea	11	5	0	5	5	13	Yes	53.0	None	Survived

APACHE: acute physiology and chronic health evaluation; SOFA: sequential organ failure assessment; CCI: charlson comorbidity index; MV: mechanical ventilation; ICU: intensive care unit; LOS: length of stay; RUQ: right upper quadrant; TEN: toxic epidermal necrolysis.

Table 2.

Summary of previous case reports and study of patients with acute respiratory distress syndrome caused by scrub typhus

	Age/Sex	Chief complaint	MV LOS	Hospital LOS	PaO₂/FiO₂ (mmHg)	WBC (/mm³)	CRP (mg/dl)	AST (IU/L)	ALT (IU/L)	Total bilirubin (mg/dl)	Albumin (g/dl)	Creatinine (mg/dl)	Hospital outcome
Park et al.[10] (Korea, case report)	72/F	Dyspnea	10	15	161.2	14,000	0.89	Unknow n	Unknown	Unknow n	Unknow n	Unknow n	Died
Kurup et al.[11] (Singapore, case report)	35/M	Fever	7	11	Unknown	12,300	18.2	113	140	0.22	2.4	1.54	Survived
Tseng et al.[12] (Taiwan, case report)	67/M	Dyspnea	Unknown	Unknown	51.1	10,800	14.0	63	93	0.5	2.3	0.8	Survived
Ryu et al.[13] (Korea, case)	78/M	Decreased mental status	87	Unknown	Unknown	9,450	19.0	57	43	0.85	1.78	1.71	Survived
Wang et al.^*[9] (Taiwan, 8 patients)	Age: 55.3± 21.5 M/F: 3/5	Fever, cough (100%) Dyspnea (87.5%)	14.8 ±10.4	Unknown	Unknown	11,330± 4,660		148.3 ±81.8	133.7 ±78.0	3.5 ± 3.4	2.2 ± 0.4	1.0 ± 0.4	Mortality: 25%
This study^* (Korea, 11 patients)	Age: 68.6± 14.8 M/F:7/4	Fever, dyspnea (63.6%)	12.4 ±17.1	26.2 ±36.9	89.0 ± 32.3	12,022± 4,597	17.3 ±10.0	111.2 ±72.3	66.0 ± 39.7	1.4 ± 1.4	2.1 ± 0.4	1.1 ± 0.5	Mortality: 36%

^* All data are presented as mean ± SD. MV: mechanical ventilation; LOS: length of stay; WBC: white blood cell; CRP: C-reactive protein; AST: aspartate aminotransferase; ALT: alanine aminotransferase.

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