• 1

    Tamura A, Ohashi N, Urakami H, Miyamura S, 1995. Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen nov., as Orientia tsutusgamushi comb. Nov.Int J Syst Bacteriol 45 :589–591.

    • Search Google Scholar
    • Export Citation
  • 2

    Strickman D, Tanskul P, Eamsila C, Kelly DJ, 1994. Prevalence of antibodies to rickettsiae in the human population of suburban Bangkok. Am J Trop Med Hyg 51 :149–153.

    • Search Google Scholar
    • Export Citation
  • 3

    Fan MY, Walker DH, Yu SR, Liu QH, 1987. Epidemiology and ecology of rickettsial diseases in the People’s Republic of China. Rev Infect Dis 9 :823–840.

    • Search Google Scholar
    • Export Citation
  • 4

    Horinouchi H, Murai K, Okayama A, Nagatomo Y, Tachibana N, Tsubouchi H, 1997. Prevalence of genotypes of Orientia tsutsugamushi in patients with scrub typhus in Miyazaki Prefecture. Microbiol Immunol 41 :503–507.

    • Search Google Scholar
    • Export Citation
  • 5

    Fang CT, Ferng WF, Hwang JJ, Yu CJ, Chen YC, Wang MH, Chang SC, Hsieh WC, 1997. Life-threatening scrub typhus with meningoencephalitis and acute respiratory distress syndrome. J Formos Med Assoc 96 :213–216.

    • Search Google Scholar
    • Export Citation
  • 6

    Yi KS, Chong Y, Covington SC, Donahue BJ, Rothen RL, Rodriguez J, Arthur JD, 1993. Scrub typhus in Korea: Importance of early clinical diagnosis in this newly recognized endemic area. Mil Med 158 :269–273.

    • Search Google Scholar
    • Export Citation
  • 7

    Currie B, O’Connor L, Dwyer B, 1993. A new focus of scrub typhus in tropical Australia. Am J Trop Med Hyg 49 :425–429.

  • 8

    Tsay RW, Chang FY, 1998. Serious complications in scrub typhus. J Microbiol Immunol Infect 31 :240–244.

  • 9

    Aronoff DM, Watt G, 2003. Prevalence of relative bradycardia in Orientia tsutsugamushi infection. Am J Trop Med Hyg 68 :477– 479.

  • 10

    Silpapojakul K, Ukkachoke C, Krisanapan S, Silpapojakul K, 1991. Rickettsial meningitis and encephalitis. Arch Intern Med 151 :1753–1757.

    • Search Google Scholar
    • Export Citation
  • 11

    Premaratna R, Chandrasena TG, Dassayake AS, Loftis AD, Dasch GA, de Silva HJ, 2006. Acute hearing loss due to scrub typhus: a forgotten complication of a reemerging disease. Clin Infect Dis 42 :e6–e8.

    • Search Google Scholar
    • Export Citation
  • 12

    Chang JH, Ju MS, Chang JE, Park YS, Han WS, Kim IS, Chang WH, 2000. Pericarditis due to Tsutsugamushi disease. Scand J Infect Dis 32 :101–102.

    • Search Google Scholar
    • Export Citation
  • 13

    Hu ML, Liu JW, Wu KL, Lu SN, Chiou SS, Kuo CH, Chuah SK, Wang JH, Hu TH, Chiu KW, Lee CM, Changchien CS, 2005. Short report: Abnormal liver function in scrub typhus. Am J Trop Med Hyg 73 :667–668.

    • Search Google Scholar
    • Export Citation
  • 14

    Ichimura K, Uchida Y, Arai K, Nakazawa K, Sasaki J, Kobayashi K, Iwai K, Kubo N, 2002. Afebrile scrub typhus (Tsutsugamushi disease) with acute respiratory distress syndrome. Intern Med 41 :667–670.

    • Search Google Scholar
    • Export Citation
  • 15

    Tsay RW, Chang FY, 2002. Acute respiratory distress syndrome in scrub typhus. QJM 95: 126–128.

  • 16

    Chi WC, Huang JJ, Sung JM, Lan RR, Ko WC, Chen FF, 1997. Scrub typhus associated with multiorgan failure: a case report. Scand J Infect Dis 29 :634–635.

    • Search Google Scholar
    • Export Citation
  • 17

    Lee WS, Wang FD, Wang LS, Wong WW, Young D, Fung CP, Liu CY, 1995. Scrub typhus complicating acute respiratory distress syndrome: a report of two cases. Zhonghua Yi Xue Za Zhi (Taipei) 56 :205–210.

    • Search Google Scholar
    • Export Citation
  • 18

    Park JS, Jee YK, Lee KY, Kim KY, Myong NH, Seo PW, 2000. Acute respiratory distress syndrome associated with scrub typhus: diffuse alveolar damage without pulmonary vasculitis. J Korean Med Sci 15 :343–345.

    • Search Google Scholar
    • Export Citation
  • 19

    Wang CC, Lai YF, Wong SL, 1999. Adult respiratory distress syndrome (ARDS) caused by scrub typhus—a case report. Thorac Med 14 :89–93.

    • Search Google Scholar
    • Export Citation
  • 20

    Ho M, 1998. Current outlook of infectious diseases in Taiwan. J Microbiol Immunol Infect 31 :73–83.

  • 21

    Gale JL, Irving GS, Wang HC, Lien JC, Chen WF, Cross JH, 1974. Scrub typhus in eastern Taiwan, 1970. Am J Trop Med Hyg 23 :679–684.

  • 22

    Furuya Y, Yoshida Y, Katayama T, Yamamoto S, Kawamura A, 1993. Serotype-specific amplification of Rickettsia tsutusgamushi DNA by nested polymerase chain reaction. J Clin Microbiol 31 :1637–1643.

    • Search Google Scholar
    • Export Citation
  • 23

    Robinson DM, Brown G, Gan E, Huxsoll DL, 1976. Adaptation of microimmunofluorescence test to the study of human Rickettsia tsutsugamushi antibody. Am J Trop Med Hyg 25 :900– 905.

    • Search Google Scholar
    • Export Citation
  • 24

    Jiang J, Marienau KJ, May LA, Beecham HJ 3rd, Wilkinson R, Ching WM, Richards AL, 2003. 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 69 :60–66.

    • Search Google Scholar
    • Export Citation
  • 25

    Chen HL, Shieh GJ, Chen HY, Horng CB, 1995. Isolation of Rickettsia tsutsugamushi from the blood samples of patients in Taiwan. J Formos Med Assoc 94 :S112–S119.

    • Search Google Scholar
    • Export Citation
  • 26

    Centers for Disease Control, Republic of China (Taiwan). Available from http://www.cdc.gov.tw

  • 27

    Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R, 1994. The American-European consensus conference on ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149 :818–824.

    • Search Google Scholar
    • Export Citation
  • 28

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

  • 29

    Berman SJ, Kundin WD, 1973. Scrub typhus in South Vietnam. A study of 87 cases. Ann Intern Med 79 :26–30.

  • 30

    Sheehy TW, Hazlett D, Turk RE, 1973. Scrub typhus. A comparison of chloramphenicol and tetracycline in its treatment. Arch Intern Med 132 :77–80.

    • Search Google Scholar
    • Export Citation
  • 31

    Song JH, Lee C, Chang WH, Choi SW, Choi JE, Kim YS, Cho SR, Ryu J, Pai CH, 1995. Short-course doxycycline treatment versus conventional tetracycline therapy for scrub typhus: a multicenter randomized trial. Clin Infect Dis 21 :506–510.

    • Search Google Scholar
    • Export Citation
  • 32

    Milberg JA, Davis DR, Steinberg KP, Hudson LD, 1995. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 273: 306–309.

    • Search Google Scholar
    • Export Citation
  • 33

    Stapleton RD, Wang BM, Hudson LD, Rubenfeld GD, Caldwell ES, Steinberg KP, 2005. Causes and timing of death in patients with ARDS. Chest 128 :525–532.

    • Search Google Scholar
    • Export Citation
  • 34

    Abel SJ, Finney SJ, Brett SJ, Keogh BF, Morgan CJ, Evans TW, 1998. Reduced mortality in association with the acute respiratory distress syndrome (ARDS). Thorax 53 :292–294.

    • Search Google Scholar
    • Export Citation
  • 35

    Luhr OR, Antonsen K, Karlsson M, Aardal S, Thorsteinsson A, Frostell CG, Bonde J, 1999. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. Am J Respir Crit Care Med 159 :1849–1861.

    • Search Google Scholar
    • Export Citation

 

 

 

 

 

ACUTE RESPIRATORY DISTRESS SYNDROME IN SCRUB TYPHUS

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  • 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China

Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi. Acute respiratory distress syndrome (ARDS) is a serious complication of scrub typhus. This study retrospectively reviewed the medical records of 72 patients diagnosed with scrub typhus from January 1998 to August 2006 in Kaohsiung Chang Gung Memorial Hospital in Taiwan. Eight of 72 scrub typhus patients with ARDS were included in the study; the other patients without ARDS were used as controls. The mortality rate for the scrub typhus patients with ARDS was 25%. The eight patients seldom had underlying diseases. Initial presentations of dyspnea and cough, white blood cell count, hematocrit, total bilirubin, and delayed used of appropriate antibiotics use were significant predictors of ARDS. Multivariate analysis showed that albumin, prothrombin time, and delayed use of appropriate antibiotics were independent predictors of ARDS. Identification of these relative risk factors may help clinicians evaluate clinical cases of scrub typhus with ARDS.

INTRODUCTION

Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi (previously known as Rickettsia tsutsugamushi).1 The disease is distributed throughout the Asia Pacific rim and is endemic in South Korea, China, Taiwan, Japan, Pakistan, India, Thailand, Malaysia, and northern Australia.27 Scrub typhus is an acute febrile disease characterized by a typical primary necrotic lesion (eschar), generalized lymphadenopathy, rash, and non-specific symptoms such as fever, headache, myalgia and cough. Severe complications include prominent encephalitis, interstitial pneumonia, acute respiratory distress, myocarditis and pericarditis, cardiac arrhythmia, acute renal failure, acute hepatic failure, and acute hearing loss.813 Acute respiratory distress syndrome (ARDS) is a serious complication of scrub typhus. However, few case reports of scrub typhus and no cohort studies of scrub typhus complicated by ARDS have been reported.5,8,1418

Taiwan has been endemic for scrub typhus for many decades.1921 In southern Taiwan, many scrub typhus patients are admitted to Kaohsiung Chang Gung Memorial Hospital, a 2,500-bed hospital that is the largest tertiary medical center in southern Taiwan. This study retrospectively analyzed the medical records of scrub typhus patients admitted to Kaohsiung Chang Gung Memorial Hospital. The goal of the present study was to investigate the clinical course and outcome of scrub typhus patients with ARDS and to identify the relative risk factors for acquiring ARDS in scrub typhus patients. Identification of relative risk factors may help clinicians evaluate the clinical course of scrub typhus complicated by ARDS.

MATERIALS AND METHODS

The study protocol was reviewed and approved by the Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital. This study retrospectively reviewed the medical records of 72 patients diagnosed with scrub typhus between January 1998, and August 2006, in Kaohsiung Chang Gung Memorial Hospital. Quality assurance procedures for diagnostic tests for the 72 scrub typhus patients were conducted by the Center for Disease Control (Taipei, Taiwan) based on a polymerase chain reaction (PCR) or serologic analysis for indirect microimmunofluorescent antibody (IFA) for O. tsutsugamushi. Diagnostic IFA results were positive for O. tsutsugamushi if the total antibody titer for the Karp, Kato, and Gilliam strains of O. tsutsugamushi showed a ≥ 4-fold increase in paired positive serum samples or the antibody titer for IgM was ≥ 1:80.22,2426 A diagnosis of ARDS was based on the criteria for ARDS of the American-European Consensus Committee: 1) acute onset timing; 2) chest radiograph showing bilateral lung infiltrates; 3) severe hypoxia with a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) ≤ 200 mm of Hg, regardless of the level of positive end-expiratory pressure; and 4) no clinical evidence of increased left atrial pressure with a pulmonary arterial wedge pressure ≤ 18 mm of Hg.27

Patients with scrub typhus complicated by ARDS (n = 8) comprised the ARDS group. Scrub typhus patients with no ARDS complications were grouped as controls (n = 64). Demographic characteristics and clinical manifestations were recorded. Laboratory data recorded upon admission of each patient, which included white blood cell (WBC) count, hematocrit (Hct), hemoglobin (Hb) level, platelet counts, prothrombin time (PT), activated partial thromboplastin time (APTT), and blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and albumin (ALB) levels, were obtained from medical records. Data regarding microorganisms identified by blood culture and antibiotics administered were also obtained from medical records.

An antibiotic day (A day) was defined as the day when appropriate treatment with antibiotics (tetracyclines or chloramphenicol) was begun for patients with scrub typhus complicated by ARDS after illness onset (defined as the time the fever began). An intubation day (I day) was defined as the day when the scrub typhus patient with ARDS was intubated after illness onset (beginning of fever). Acute renal failure was defined as oliguria with marked increase in BUN and creatinine. Acute hepatic failure was defined as encephalopathy or jaundice with a marked increase in liver enzyme levels (AST and ALT). Upper gastrointestinal bleeding was defined as hematemesis or tarry stool passage that was confirmed by panendoscopy.

Statistical analysis.

Data were collected and analyzed with SPSS for Windows version 13.0 (SPSS Inc., Chicago, IL). Quantitative variables are presented as means ± SD. Statistical significance of univariate analysis was determined by an independent-sample t-test or a Mann-Whitney U test for continuous variables. A chi-square test was used to determine dichromatic variables. Differences were considered statistically significant when P was < 0.05.

RESULTS

Eight of 72 (11.1%) scrub typhus patients had ARDS. Sixty-four scrub typhus patients without ARDS were used as controls. Table 1 summarizes the characteristics and clinical course of the eight (three males and five females ) scrub typhus patients with ARDS. The mean ± SD age of the eight patients was 55.38 ± 21.51 years (range = 24–75 years). The mortality rate for the subjects was 25% (2 of 8). Three patients had no underlying diseases, three had chronic obstructive pulmonary disease (COPD), one had diabetes mellitus, one had hypertension, one had gout, and one was thirty-one weeks pregnant. The two most common complications in the study population were acute hepatic failure (6 of 8, 75%) and upper gastrointestinal bleeding (5 of 8, 62.5%). Two subjects had acute renal failure (25%), two had pneumonia (25%), two had urinary tract infection (25%), one had a central venous pressure line infection (12.5%), one had pre-eclampsia (12.5%), and one had a seizure (12.5%). None of the scrub typhus patients with ARDS were initially treated with tetracyclines or chloramphenicol. The mean ± SD A day was day 8.25 ± 5.05 (range = days 2–16). The mean ± SD I day was day 6.88 ± 3.64 (range = days 4–14). The mean ± SD duration of ventilation support was 14.75 ± 10.40 days (range = 7–35 days).

Table 2 shows a presents a comparison of sex, age, and underlying diseases between subjects with ARDS and subjects without ARDS. Underlying diseases were seldom noted in subjects with or without ARDS. Other than COPD (37.5%), the percentage of all underlying diseases was less than 15%. Furthermore, the ARDS group and the control group did not significantly differ in sex, age, or underlying disease.

Table 3 summarizes the clinical presentations of scrub typhus patients with ARDS and those without ARDS. In addition to fever, the most common clinical presentations for scrub typhus patients with ARDS were cough (100%) and dyspnea (87.5%); there were significant differences in cough (P < 0.001) or dyspnea (P < 0.001) between the ARDS group and the control group.

Table 4 shows a summary of initial laboratory findings for subjects with and without ARDS and compares characteristics and initial laboratory findings between the ARDS group and the control group. The ARDS group did not significantly differ from the control group in platelet count, Hb level, PT, APTT, and BUN, creatinine, AST, ALT, ALP, or albumin levels. However, the ARDS group differed significantly from the control group in WBC count (P = 0.018), Hct (P = 0.047), and total bilirubin level (P = 0.050).

Table 5 compares appropriate antibiotics course (tetracyclines or chloramphenicol) in scrub typhus patients with ARDS and without ARDS. The mean ± SD A day for the ARDS group was day 8.25 ± 5.01, which was later than that of the control group (day 5.05 ± 2.79) (P = 0.059). The mean ± SD duration of antibiotics use in the ARDS group was 13.88 ± 4.19 days, which was longer than that of the control group (9.25 ± 3.35 days) (P = 0.002).

Multivariate analysis showed that a low level of ALB, prolonged PT, and delayed treatment with antibiotics were independent predictive variables associated with ARDS complications in scrub typhus patients (Table 6).

DISCUSSION

This retrospective study showed that 11.1% of the 72 scrub typhus patients had ARDS complications. The mortality rate for the eight scrub typhus patients with ARDS was 25% (2 of 8). Whether this mortality rate for patients with scrub typhus complicated by ARDS assessed at a medical center reflect rates for the general population remains uncertain. Because patients were admitted to a tertiary medical center, the study population was likely biased by patient selection and referral patterns. Scrub typhus complicated by ARDS has seldom been discussed; few case reports and only one short communication report have been published.1418 Additional clinical studies are needed to increase awareness of ARDS in scrub typhus patients. Consequently, clinicians are likely not aware of the potential for ADRS when treating scrub typhus patients at high risk for ARDS.

The pulmonary manifestations of scrub typhus are varying grades of bronchitis and interstitial pneumonitis progressing to ARDS.28 Acute respiratory distress syndrome is defined as an acute and persistent lung inflammation with increased vascular permeability and is most often associated with sepsis syndrome, aspiration, primary pneumonia, or multiple traumas.27

The pathologic progression of ARDS reflects the sequentially occurring exudative, organizing (fibroproliferative) and fibrotic stages. Park and others reported diffuse alveolar damage in the organizing stage without evidence of vasculitis.18 Immunologic response of the lung to previous O. tsutsugamushi infection, without direct invasion of the organism, might have been involved in the pathogenesis.

Other than COPD (37.5%) in the ARDS group, the incidence of other underlying diseases was low (less than 20%) in the current study; furthermore, no history of stroke was noted in either group of scrub typhus patients. One possible reason is that scrub typhus is a mite-borne infectious disease caused by O. tsutsugamushi. Almost all subjects had a history of traveling to areas endemic for scrub typhus, which indicates that most patients with scrub typhus have the resilience to survive extensive travel.

Scrub typhus may begin insidiously with headache, anorexia, or malaise. In some cases, scrub typhus appears abruptly with chills and fever; rash and eschar may also be present.29,30 Respiratory problems are often present; 45% of the patients in one study had a cough.29 In the control group of the current study, fever, cough, rash, and eschar were observed in 96.9%, 39.1%, 37.5% and 65.6% of the study population, respectively. These findings are consistent with findings of previous reports. However, some clinical manifestations in the 64 control patients differed from those reported elsewhere: incidence of myalgia (7.8%) and headache (40.6%) were lower than those previously reported.29 Clinical presentations of respiratory system (cough and dyspnea) were the most significant differences between the ARDS group and the control group in the current study. A reasonable conclusion is that scrub typhus patients should be carefully evaluated for potential progression to ARDS if they initially have respiratory symptoms.

The WBC counts of the ARDS group were significantly higher than those of the control group, which indicated that the ARDS group was more seriously infected than the control group. Hematocrit in the ARDS group was significantly lower than that of the control group, which suggested that the ARDS group was more anemic than the control group. Although all liver enzyme levels (AST, ALT, ALP, and total bilirubin) were increased in both the ARDS and control groups, only the total bilirubin level was significantly higher in the ARDS group than in the control group. A scrub typhus patient with severe infection, anemia, and jaundice may be considered to be at high risk for developing ARDS.

Treatment with doxycycline or chloramphenicol usually lowers fever within 24 hours. Doxycycline may be more effective for rapidly ameliorating symptoms. In the current study, one patient was treated with oxytetracycline and seven were treated with doxycycline in the ARDS group. In the control group, five patients were treated with oxytetracycline, fifty-four were treated with doxycycline, and two were treated with chloramphenicol. Three patients in the control group were not treated with doxycycline or chloramphenicol.

The optimal duration of therapy is uncertain. In a study with three days of therapy, short courses of doxycycline or chloramphenicol are associated with an increased risk of relapse.30 However, a study of a larger population reported short-course therapy to be effective; in this multicenter trial, patients with scrub typhus randomly received seven days of treatment with tetracycline or three days of treatment with of doxycycline.31 Scrub typhus lasts for 14–21 days without treatment. Serious complications of scrub typhus generally occur in the second week of an untreated illness.8,28,29 In contrast, scrub typhus patients treated with appropriate antibiotics (tetracyclines or chloramphenicol) typically become afebrile within 48 hours of starting therapy.30 In the present study, the mean ± SD day of appropriate antibiotics treatment in the ARDS group was day 8.25 ± 5.01, which was significantly later than that in the control group (day 5.05 ± 2.79) (P = 0.059). The mean ± SD I day (day 6.88 ± 3.64, range = days 4–14) was earlier than the mean ± SD A day (day 8.25 ± 5.01, range = days 2–16) (Table 1). The mean ± SD duration of appropriate antibiotics in the ARDS group (13.88 ± 4.19 days) was significantly longer than that in the control group (9.25 ± 3.35 days). It may be concluded that scrub typhus patients are at high risk for developing ARDS if appropriate antibiotics treatment is delayed, and scrub typhus patients with ARDS need a longer course of antibiotics than those without ARDS. Therefore, early use of appropriate antibiotics is vital.

Survival of ARDS patients improved over time. Mortality of these patients is currently estimated to be approximately 35–40%.3235 Respiratory failure is unusual as a direct cause of death. In one study of 47 patients, death during the first 3 days usually resulted from an underlying cause of ARDS, not respiratory failure.33 In the same study, nosocomial infections and sepsis accounted for most deaths. In the present study, the mortality rate of scrub typhus patients with ARDS was 25% (2 of 8), which was lower than the mortality rate for ARDS caused by other microorganisms. The two deaths in our study may have been caused by a delay in appropriate treatment (day 9 and day 16) and multiple organ failure (Table 1).

In the current study, multivariate analysis showed that an ALB level, a prolonged PT and delayed treatment with antibiotics were independently predictive variables. Because of the limitation of the statistical software (SPSS for Windows version 13.0), only variables regarding age, sex, A day, and initial laboratory data were used in the multivariate analysis.

This retrospective study had several limitations. First, this study was conducted at one medical center, and the patient population may be biased by patient selection and referral pattern. Second, this study was a retrospective survey, which not only resulted in incomplete data for some patients, but also did not control for laboratory examinations and clinical courses of all scrub typhus patients. Additional prospective investigations should be conducted. Despite these limitations, this study provides relatively rare data regarding a series of scrub typhus patients with ARDS.

In conclusion, scrub typhus, a mite-borne infectious disease caused by O. tsutsugamushi, is distributed throughout the Asia Pacific rim and can appear in a wide range of clinical manifestations, ranging from a mild febrile illness to life-threatening complications. In scrub typhus patients, ARDS is one of the most serious complications. This study analyzed scrub typhus patients with ARDS. Univariate analysis showed that initial symptoms of dyspnea and cough, higher WBC counts, lower hematocrits, higher total bilirubin counts, and delayed treatment with appropriate antibiotics were significantly predictive variables associated with scrub typhus patients with ARDS. Multivariate analysis showed that low ALB levels, prolonged PT, and delayed treatment with appropriate antibiotics were independent predictive variables associated with scrub typhus complicated by ARDS.

Table 1

Characteristics and clinical course of eight scrub typhus patients with ARDS*

No.Age (years), SexUnderlying diseasesComplicationsAntibiotics courseA dayI dayDuration of ventilationOutcome
* ARDS = acute respiratory distress syndrome; A day = the day when antibiotic use was started. I day = the day when the patient was intubated after the onset of illness; HTN = hypertension; UGI = upper gastrointestinal; COPD = chronic obstructive pulmonary disease; CVP = central venous pressure; DM = diabetes mellitus.
166, FNoneAcute hepatic failure
 Acute renal failure
 Urinary tract infectionPenicillin plus ceftriaxone, doxycyclineDay 14Day 97 daysSurvived
270, FHTNUGI bleeding
 Pneumonia (Pseudomonas Aeruginosa)Cefamazin plus gentamicin, OxytetracyclineDay 9Day 49 daysSurvived
371, MCOPDAcute hepatic failure
 UGI bleeding
 Urinary tract infectionPiperacillin plus amikacin, doxycyclineDay 2Day 313 daysSurvived
444, FNoneAcute hepatic failure
 UGI bleeding
 CVP line infectionPenicillin plus ceftriaxone, doxycycline, ClindamycinDay 7Day 827 daysSurvived
524, FPregnancy (31 weeks)Pre-eclampsiaPenicillin plus ceftriaxone, oxytetracyclineDay 2Day 510 daysSurvived
624, FNoneAcute hepatic failureLevofloxacin, DoxycyclineDay 7Day 88 daysSurvived
775, MDM
 COPDAcute hepatic failure
 Seizure
 UGI bleeding
 Pneumonia (Acinetobacter baumannii) (Conynebacterium)Ceftriaxone plus Amikacin, Doxycycline, TeicoplaninDay 9Day 435 daysDied
869, MCOPD
 GoutyAcute hepatic failure
 Acute renal failure
 UGI bleedingPenicillin plus Ceftriaxone, Doxycycline, CeftizoximeDay 16Day 149 daysDied
Table 2

Comparisons of underlying diseases in scrub typhus patients with ARDS (ARDS group) and without ARDS (control group)*

ARDS group (n = 8)Control group (n = 64)P
* ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease.
Sex (M/F ratio)3/540/240.254
Mean ± SD age, years55.38 ± 21.5146.72 ± 17.450.113
Diabetes mellitus (%)1 (12.5)3 (4.7)0.382
Hypertension (%)1 (12.5)7 (10.9)1.000
COPD (%)3 (37.5)9 (14.1)0.123
Stroke (%)0 (0.0)0 (0.0)
Malignancy (%)0 (0.0)2 (3.1)1.000
Table 3

Comparison of symptoms/signs in scrub typhus patients with ARDS (ARDS group) and without ARDS (control group)*

Symptom/signARDS group n = 8 (%)Control group n = 64 (%)P
* An individual patient might have more than one symptom and/or sign; ARDS = acute respiratory distress syndrome.
Fever8 (100)62 (96.9)1.000
Rash3 (37.5)24 (37.5)1.000
Bone pain0 (0.0)9 (14.1)0.584
Myalgia0 (0.0)5 (7.8)1.000
Dyspnea7 (87.5)9 (14.1)< 0.001
Cough8 (100)25 (39.1)0.001
Chest pain2 (25.0)7 (10.9)0.260
Abdominal pain3 (37.5)28 (43.8)1.000
Headache2 (25.0)26 (40.6)0.471
Fatigue1 (12.5)19 (29.7)0.429
Vomitting1 (12.5)12 (18.6)1.000
Tarry stool2 (25.0)5 (7.8)0.171
Conscious drowsy1 (12.5)3 (4.7)0.382
Eschar5 (62.5)42 (65.6)1.000
Table 4

Comparisons of initial laboratory findings in scrub typhus patients with ARDS (ARDS group) and without ARDS (control group)*

ARDS group (n = sample size)Control group (n = sample size)P
* Values are the mean ± SD. ARDS = acute respiratory distress syndrome; WBC = white blood cell; Hct = hematocrit; Hb = hemoglobin; PT = prothrombin time; APTT = activated partial thromboplastin time; BUN = blood urea nitrogen; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; BIL = total bilirubin; ALB = albumin.
WBC (×103/μL)11.33 ± 4.66 (n = 8)8.38 ± 3.06 (n = 64)0.018
Hct (%)32.23 ± 5.49 (n = 8)36.92 ± 5.14 (n = 63)0.018
Hb (g/dL)11.29 ± 1.98 (n = 8)15.02 ± 19.03 (n = 63)0.072
Platelet (×104/μL)10.09 ± 9.49 (n = 8)12.03 ± 5.70 (n = 63)0.087
PT (sec)11.38 ± 2.62 (n = 4)10.86 ± 0.98 (n = 18)0.831
APTT (sec)38.10 ± 4.01 (n = 4)38.38 ± 3.68 (n = 15)0.726
BUN (mg/dL)18.75 ± 10.32 (n = 8)21.88 ± 32.65(n = 43)0.392
Creatinine (mg/dL)0.98 ± 0.36 (n = 8)1.32 ± 1.28 (n = 58)0.490
AST (U/L)148.25 ± 81.77 (n = 8)155.87 ± 192.33 (n = 63)0.373
ALT (U/L)133.71 ± 78.04 (n = 7)134.23 ± 125.16 (n = 48)0.528
ALP (U/L)175.63 ± 102.51 (n = 8)183.58 ± 128.18 (n = 40)0.978
BIL (mg/dL)3.51 ± 3.44 (n = 8)1.76 ± 2.08 (n = 39)0.050
ALB (g/dL)2.24 ± 0.42 (n = 7)2.81 ± 0.77 (n = 19)0.081
Table 5

Comparisons of appropriate antibiotics course (tetracyclines or chloramphenicol) in scrub typhus patients with ARDS (ARDS group) and without ARDS (control group)*

ARDS group (n = 8)Control group (n = 61)P
* ARDS = acute respiratory distress syndrome. A day = the day when antibiotic use (tetracyclines or chloramphenicol) was started after illness onset (fever onset). Duration of antibiotics = duartion (in days) of antibiotics (tetracyclines or chloramphenicol) used.
A day ± SD8.25 ± 5.015.05 ± 2.790.059
Mean ± SD duration of antibiotics13.88 ± 4.199.25 ± 3.350.002
Table 6

Multivariable analysis of associated risk factors for scrub typhus patients with complicated ARDS*

POdds ratio95% CI for odds ratio
* ARDS = acute respiratory distress syndrome; CI = confidence interval; ALB = albumin; PT = prothrombin time; A day = the day when antibiotic use (tetracyclines or chloramphenicol) was started after illness onset (fever onset).
ALB (g/dL)0.0060.0140.001–0.304
PT (sec)0.0282.6061.110–6.119
A day (days)0.0131.4151.075–1.863

*

Address correspondence to Meng-Chih Lin, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, 123 Dabi Road, Niaosung, Shiang, Kaohsiung, Taiwan, Republic of China. E-mail: mengchih@adm.cgmh.org.tw

Authors’ addresses: Chin-Chou Wang, Shih-Feng Liu, Yu-Hsiu Chung, and Mao-Chang Su, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China. Jien-Wei Liu, Division of Infectious Disease, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China. Meng-Chih Lin, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center; Department of Respiratory Care, Chang Gung Institute of Technology, Chiayi, Taiwan, Republic of China.

REFERENCES

  • 1

    Tamura A, Ohashi N, Urakami H, Miyamura S, 1995. Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen nov., as Orientia tsutusgamushi comb. Nov.Int J Syst Bacteriol 45 :589–591.

    • Search Google Scholar
    • Export Citation
  • 2

    Strickman D, Tanskul P, Eamsila C, Kelly DJ, 1994. Prevalence of antibodies to rickettsiae in the human population of suburban Bangkok. Am J Trop Med Hyg 51 :149–153.

    • Search Google Scholar
    • Export Citation
  • 3

    Fan MY, Walker DH, Yu SR, Liu QH, 1987. Epidemiology and ecology of rickettsial diseases in the People’s Republic of China. Rev Infect Dis 9 :823–840.

    • Search Google Scholar
    • Export Citation
  • 4

    Horinouchi H, Murai K, Okayama A, Nagatomo Y, Tachibana N, Tsubouchi H, 1997. Prevalence of genotypes of Orientia tsutsugamushi in patients with scrub typhus in Miyazaki Prefecture. Microbiol Immunol 41 :503–507.

    • Search Google Scholar
    • Export Citation
  • 5

    Fang CT, Ferng WF, Hwang JJ, Yu CJ, Chen YC, Wang MH, Chang SC, Hsieh WC, 1997. Life-threatening scrub typhus with meningoencephalitis and acute respiratory distress syndrome. J Formos Med Assoc 96 :213–216.

    • Search Google Scholar
    • Export Citation
  • 6

    Yi KS, Chong Y, Covington SC, Donahue BJ, Rothen RL, Rodriguez J, Arthur JD, 1993. Scrub typhus in Korea: Importance of early clinical diagnosis in this newly recognized endemic area. Mil Med 158 :269–273.

    • Search Google Scholar
    • Export Citation
  • 7

    Currie B, O’Connor L, Dwyer B, 1993. A new focus of scrub typhus in tropical Australia. Am J Trop Med Hyg 49 :425–429.

  • 8

    Tsay RW, Chang FY, 1998. Serious complications in scrub typhus. J Microbiol Immunol Infect 31 :240–244.

  • 9

    Aronoff DM, Watt G, 2003. Prevalence of relative bradycardia in Orientia tsutsugamushi infection. Am J Trop Med Hyg 68 :477– 479.

  • 10

    Silpapojakul K, Ukkachoke C, Krisanapan S, Silpapojakul K, 1991. Rickettsial meningitis and encephalitis. Arch Intern Med 151 :1753–1757.

    • Search Google Scholar
    • Export Citation
  • 11

    Premaratna R, Chandrasena TG, Dassayake AS, Loftis AD, Dasch GA, de Silva HJ, 2006. Acute hearing loss due to scrub typhus: a forgotten complication of a reemerging disease. Clin Infect Dis 42 :e6–e8.

    • Search Google Scholar
    • Export Citation
  • 12

    Chang JH, Ju MS, Chang JE, Park YS, Han WS, Kim IS, Chang WH, 2000. Pericarditis due to Tsutsugamushi disease. Scand J Infect Dis 32 :101–102.

    • Search Google Scholar
    • Export Citation
  • 13

    Hu ML, Liu JW, Wu KL, Lu SN, Chiou SS, Kuo CH, Chuah SK, Wang JH, Hu TH, Chiu KW, Lee CM, Changchien CS, 2005. Short report: Abnormal liver function in scrub typhus. Am J Trop Med Hyg 73 :667–668.

    • Search Google Scholar
    • Export Citation
  • 14

    Ichimura K, Uchida Y, Arai K, Nakazawa K, Sasaki J, Kobayashi K, Iwai K, Kubo N, 2002. Afebrile scrub typhus (Tsutsugamushi disease) with acute respiratory distress syndrome. Intern Med 41 :667–670.

    • Search Google Scholar
    • Export Citation
  • 15

    Tsay RW, Chang FY, 2002. Acute respiratory distress syndrome in scrub typhus. QJM 95: 126–128.

  • 16

    Chi WC, Huang JJ, Sung JM, Lan RR, Ko WC, Chen FF, 1997. Scrub typhus associated with multiorgan failure: a case report. Scand J Infect Dis 29 :634–635.

    • Search Google Scholar
    • Export Citation
  • 17

    Lee WS, Wang FD, Wang LS, Wong WW, Young D, Fung CP, Liu CY, 1995. Scrub typhus complicating acute respiratory distress syndrome: a report of two cases. Zhonghua Yi Xue Za Zhi (Taipei) 56 :205–210.

    • Search Google Scholar
    • Export Citation
  • 18

    Park JS, Jee YK, Lee KY, Kim KY, Myong NH, Seo PW, 2000. Acute respiratory distress syndrome associated with scrub typhus: diffuse alveolar damage without pulmonary vasculitis. J Korean Med Sci 15 :343–345.

    • Search Google Scholar
    • Export Citation
  • 19

    Wang CC, Lai YF, Wong SL, 1999. Adult respiratory distress syndrome (ARDS) caused by scrub typhus—a case report. Thorac Med 14 :89–93.

    • Search Google Scholar
    • Export Citation
  • 20

    Ho M, 1998. Current outlook of infectious diseases in Taiwan. J Microbiol Immunol Infect 31 :73–83.

  • 21

    Gale JL, Irving GS, Wang HC, Lien JC, Chen WF, Cross JH, 1974. Scrub typhus in eastern Taiwan, 1970. Am J Trop Med Hyg 23 :679–684.

  • 22

    Furuya Y, Yoshida Y, Katayama T, Yamamoto S, Kawamura A, 1993. Serotype-specific amplification of Rickettsia tsutusgamushi DNA by nested polymerase chain reaction. J Clin Microbiol 31 :1637–1643.

    • Search Google Scholar
    • Export Citation
  • 23

    Robinson DM, Brown G, Gan E, Huxsoll DL, 1976. Adaptation of microimmunofluorescence test to the study of human Rickettsia tsutsugamushi antibody. Am J Trop Med Hyg 25 :900– 905.

    • Search Google Scholar
    • Export Citation
  • 24

    Jiang J, Marienau KJ, May LA, Beecham HJ 3rd, Wilkinson R, Ching WM, Richards AL, 2003. 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 69 :60–66.

    • Search Google Scholar
    • Export Citation
  • 25

    Chen HL, Shieh GJ, Chen HY, Horng CB, 1995. Isolation of Rickettsia tsutsugamushi from the blood samples of patients in Taiwan. J Formos Med Assoc 94 :S112–S119.

    • Search Google Scholar
    • Export Citation
  • 26

    Centers for Disease Control, Republic of China (Taiwan). Available from http://www.cdc.gov.tw

  • 27

    Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R, 1994. The American-European consensus conference on ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149 :818–824.

    • Search Google Scholar
    • Export Citation
  • 28

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

  • 29

    Berman SJ, Kundin WD, 1973. Scrub typhus in South Vietnam. A study of 87 cases. Ann Intern Med 79 :26–30.

  • 30

    Sheehy TW, Hazlett D, Turk RE, 1973. Scrub typhus. A comparison of chloramphenicol and tetracycline in its treatment. Arch Intern Med 132 :77–80.

    • Search Google Scholar
    • Export Citation
  • 31

    Song JH, Lee C, Chang WH, Choi SW, Choi JE, Kim YS, Cho SR, Ryu J, Pai CH, 1995. Short-course doxycycline treatment versus conventional tetracycline therapy for scrub typhus: a multicenter randomized trial. Clin Infect Dis 21 :506–510.

    • Search Google Scholar
    • Export Citation
  • 32

    Milberg JA, Davis DR, Steinberg KP, Hudson LD, 1995. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 273: 306–309.

    • Search Google Scholar
    • Export Citation
  • 33

    Stapleton RD, Wang BM, Hudson LD, Rubenfeld GD, Caldwell ES, Steinberg KP, 2005. Causes and timing of death in patients with ARDS. Chest 128 :525–532.

    • Search Google Scholar
    • Export Citation
  • 34

    Abel SJ, Finney SJ, Brett SJ, Keogh BF, Morgan CJ, Evans TW, 1998. Reduced mortality in association with the acute respiratory distress syndrome (ARDS). Thorax 53 :292–294.

    • Search Google Scholar
    • Export Citation
  • 35

    Luhr OR, Antonsen K, Karlsson M, Aardal S, Thorsteinsson A, Frostell CG, Bonde J, 1999. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. Am J Respir Crit Care Med 159 :1849–1861.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Meng-Chih Lin, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Department of Respiratory Care, Chang Gung Institute of Technology, 123 Dabi Road, Niaosung Shiang, Kaohsiung, Taiwan, Chiayi, Taiwan, Republic of China, Telephone: 886-7-731-7123 extension 8199, Fax: 886-7-732-2402, E-mail: mengchih@adm.cgmh.org.tw.
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