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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]
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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.
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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).
Table 1.
Characteristics and clinical courses of eleven scrub typhus patients with acute respiratory distress syndrome
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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.
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% |
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.
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