Q J Med 2002; 95: 126-128
© 2002 Association of Physicians
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Acute respiratory distress syndrome in scrub typhus
Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
Sir,
Scrub typhus, caused by Orientia tsutsugamushi, is transmitted to humans by the bite of the larval stage of thromboculid mites or chiggers. It is distributed widely in the Asia-Pacific region and is common in some parts of Taiwan. It is an acute febrile illness characterized by a typical primary lesion (eschar), generalized lymphadenopathy, rash, and non-specific symptoms such as fever, chills, cough, abdominal pain and myalgia. Clinically, the manifestations and complications of scrub typhus are protean. Serious complications are not uncommon and may be fatal if diagnosis is delayed. Complications include myocarditis, meningitis, acute renal failure and interstitial pneumonia.1,3–5 Acute respiratory distress syndrome (ARDS) is a rarely reported but serious complication of scrub typhus. It is important to know that ARDS may develop in scrub typhus and the possible risk factors, because it is treatable if considered and diagnosed early.
From June 1993 to July 1997, among 33 hospitalized patients with scrub typhus, five fulfilled the criteria of ARDS. Scrub typhus was confirmed by either a four-fold or greater rise of IgG+IgA+IgM titre, for Karp, Kato and Gilliam strains of O. tsutsugamushi, to at least 1:320 in indirect immunofluorescent antibody (IFA) in paired sera; or a single IgG+IgA+IgM titre 
1:320 and IgM 1:160 in acute and convalescent sera; these IFA assays were performed in the laboratory of the National Institute of Preventive Medicine, Department of Health, Executive Yuan, Taiwan. The criteria for ARDS were defined as an acute onset of severe hypoxaemia with a ratio of arterial pO2 to inspired oxygen fraction (PaO2/FiO2) of >200 mmHg and bilateral diffuse infiltrates on a frontal chest radiograph when left atrial or pulmonary capillary hypertension (PCWP >18 mmHg) had been excluded. Thrombocytopenia was defined as platelet count <130000/mm3 at presentation. Early pneumonitis was defined as evidence of infiltrates on chest radiograph at least 2 days before the development of ARDS. Patients were divided into two groups, scrub typhus with ARDS (n=5) and scrub typhus without ARDS (n=28). The demographic, clinical and laboratory characteristics of the two groups were compared. Statistical analyses included the 
2 test, Fisher's exact test and Student's t test as appropriate. Mantel-Haenszel 2 test was used to adjust the confounding influence of age. A p value of <0.05 was considered statistically significant.
Patients with ARDS were older than patients without ARDS (39±22 vs. 23±9 years, p=0.009). Thrombocytopenia (100% vs. 50%, p=0.049) and early pneumonitis (100% vs. 25%, p=0.003) were more frequently noted in patients with ARDS than patients without ARDS. Otherwise, there were no significant differences between the two groups in the frequency of fever, headache, cough, abdominal pain, eschar, skin rash, lymphadenopathy, and the values of blood white cell counts, alanine aminotransferase, aspartate aminotransferase (AST), and creatinine. When the patients were stratified into 
20/>20 and 30/>30 years age groups, early pneumonitis was a significant risk factor for ARDS (p=0.009), but thrombocytopenia was insignificant (p=0.09).
In our 4-year experience, 36% (12/33) of scrub typhus patients developed pneumonitis. Notably, 42% (5/12) of the patients with pneumonitis progressed to ARDS. Previous reports also showed 55% (39/71) of scrub typhus patients as having interstitial pneumonitis of varying severity.2 Scrub typhus is suggested as a more common cause of pneumonitis in an endemic area than previously realized. Therefore, the pulmonary manifestations of scrub typhus ranged from bronchitis, interstitial pneumonitis to ARDS.
An additional four patients with ARDS in scrub typhus were identified from English-language articles since 1966.3–5 One patient died of multiple organ failure after delay in diagnosis.4 One patient presented with meningo-encephalitis and pneumonitis. Although serious complications usually occurred during the second and third week in the pre-antibiotic era,1,2 44% (4/9) of patients developed ARDS within 4–7 days of onset in this review (Table 1).
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Their ages ranged from 21 to 65 years (mean 43 years) (Table 1). There were five males and four females. Two had diabetes, with good metabolic control. Others had good health before the illness. Duration of symptoms before effective antibiotics ranged from 4 to 19 days (median, 9 days). Days of hospitalization before effective antibiotics ranged from 1 to 9 days (median, 1 day). Non-specific symptoms such as fever, cough, shortness of breath, right upper quadrant abdominal pain, and general malaise were common. Forty-four percent (4/9) of patients had an eschar; 33% (3/9) had a maculopapular skin rash; 56% (5/9) had hepatosplenomegaly. Only one patient had lymphadenopathy. Seventy-eight percent (7/9) of patients had a normal WBC count. Two patients had a mildly elevated WBC count. All of the patients (8/8) with available data had thrombocytopenia, which ranged from 32800/mm3 to 125000/mm3. All had elevation of AST.
In the pre-antibiotic era, the mortality in scrub typhus with extensive pneumonitis and cyanosis unrelieved by oxygen, was 100%.1 Mortality was 22% (2/9) in this review. The major cause of mortality was delay in diagnosis. This could be reflected by a long period of symptoms before antibiotics started (range: 4 to 19 days, median: 9 days). From our experiences, despite the occurrence of serious complications, good response to antibiotic therapy was obtained and the average duration of defervescence was 2 days. All but one received endotracheal intubation with ventilator support. Seventy-seven percent (7/9) of patients recovered without serious sequela after appropriate antimicrobial therapy and intensive care.
In conclusion, older age, thrombocytopenia, and presence of early pneumonitis were identified as risk factors for ARDS in patients with scrub typhus. Scrub typhus should be in the list of differential diagnoses in ARDS patients in endemic areas. Early appropriate antimicrobial therapy and intensive care are crucial for the recovery of ARDS complicating scrub typhus.
References
1. Sayen JJ, Pond HS, Forrester JS, Wood FC. Scrub typhus in Assam and Burma. Medicine1946; 25:155–214.
2. Allen AC, Spitz S. A comparative study of the pathology of scrub typhus (tsutsugamushi disease) and other rickettsial disease. Am J Pathol1945; 21:602–81.
3. Fang CT, Fergn WF, Hwang JJ, Yu CJ, Chen YC, Wang MH, Chang SC, Hsieh WC. Life-threatening scrub typhus with meningoencephalitis and acute respiratory distress syndrome. J Formos Med Assoc1997; 96:213–16.[Medline]
4. Lee WS, Wang FD, Wang LS, Wong WW, Young D, Fung CP, Liu Y. Scrub typhus complicating acute respiratory distress syndrome: A report of two cases. Chin Med J (Taipei)1995; 56:205–10.
5. Chi WC, Huang JJ, Sung JM, Lan RR, Ko WC, Chen FF. Scrub typhus associated with multi-organ failure: a case report. Scand J Infect Dis1997; 29:634–5.[Medline]
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