Multi-organ Dysfunction Caused by Scrub Typhus Initially Misinterpreted as Acute Tonsillitis

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1 Scrub typhus 161 Multi-organ Dysfunction Caused by Scrub Typhus Initially Misinterpreted as Acute Tonsillitis Chun-Chih Chen, Chun-Jung Juan 2,3, Chi-Wen Juan, Xian-Chih Zeng, Mei Huang 1 Scrub typhus is an acute febrile infectious disease caused by Orientia tsutsugamushi. Although not uncommonly seen in northern, eastern and southern Taiwan and the offshore islands, an imported case from the offshore islands might be misdiagnosed in western Taiwan hospitals. Herein, we presented an initially unrecognized case of scrub typhus in a 21 year-old man who was a soldier in Ma-Tzu. He developed nonspecific symptoms including general malaise, muscle pain and fever and was diagnosed with acute tonsillitis at a district hospital in Chang-Hua County. The clinical condition did not respond to penicillin and was complicated by multi-organ dysfunction. After being transferred to our department of emergency medicine, a clinical diagnosis of scrub typhus was made on the basis of chest wall eschar and axillary lymphadenopathy. Although the fever subsided quickly after the administration of tetracycline (100mg, intravenous, every 12 hours), cardiac ischemia, pericardial effusion and acute pulmonary edema together with bone marrow suppression occurred in addition to liver and kidney dysfunction. After one week of above antibiotic control and other supportive treatment, the patient recovered gradually and was discharged uneventfully. Coping with fever of unknown origin in the emergency department remains challenging. Early recognition of eschar, which is rarely seen in other insect-bite diseases, helps differentiate scrub typhus from other infectious diseases and guides the clinician to the proper antibiotics. Diagnosis of scrub typhus depends on a high index of clinical suspicion, detailed travel history and complete physical examination. Serum tests play a limited role in the acute stage but help in eventual confirmation of the clinical diagnosis. Key words: multi-organ dysfunction, orientia tsutsugamushi, scrub typhus, eschar Introduction Scrub typhus may not be recognized, especially in non-endemic area such as western Taiwan. Delayed diagnosis and treatment may lead to severe complications such as multi-organ dysfunction and failure (1) with a high mortality rate (2,3). Serological analysis might be negative in the first two weeks of the disease. Early diagnosis relies on a high index of suspicion, a detailed travel history and familiarity with the typical primary skin lesion in a febrile patient. Herein we report a case of scrub typhus imported from Ma-Tzu. It was initially diagnosed as acute tonsillitis, leading to delayed treatment and multi-organ dysfunction. Received: November 14, 2006 Accepted for publication: February 1, 2007 From the Department of Emergency Medicine, 1 Division of Infectious Disease, Department of Internal Medicine, Show Chwan Memorial Hospital 2 Department of Radiology, Tri-Service General Hospital and National Defense Medial Center 3 Department of Electrical Engineering, National Taiwan University Address for reprints: Dr. Chi-Wen Juan, Department of Emergency Medicine, Show Chwan Memorial Hospital 542, Section 1, Chungshan Road, Changhua City 500, Taiwan (R.O.C.) Tel: (04) ext Fax: (04) juanchiwen@yahoo.com.tw

2 162 J Emerg Crit Care Med. Vol. 18, No. 4, 2007 Case Report A 21-year-old Taiwanese man who served as a soldier with the army in Ma-Tzu developed general malaise, muscle pain and fever in 2006 when he was on leave in Taiwan. These symptoms were followed by a headache and sore throat. Because of persistent symptoms, he visited a district hospital in Chang-Hua county, where he was admitted under the impression of acute tonsillitis and acute hepatitis. Physical examination showed enlarged palatine tonsils and a general skin rash. Laboratory examination showed leukocytosis with neutrophils predominant, thrombocytopenia, and elevated glutamic oxaloacetic transminase (GOT 204 U/L) and glutamic pyruvic transminase (GPT 225U/L). The results of anti-mycoplasma pneumoniae immunoglobulin G (IgG) and immunoglobulin M (IgM) tests were negative. Chest radiographic and sonographic findings were unremarkable. On the fourth day of hospitalization, following the development of a general maculopapular skin rash, an eschar on his left anterior chest wall developed but was ignored. In spite of treatment with aqueous penicillin-g (3 million units, intravenous, every 6 hours), the fever, leukocytosis, and thrombocytopenia worsened, the liver function impairment persisted, and the patient developed shortness of breath, jaundice, and oliguria. On his sixth day of hospitalization, he was transferred to our hospital due to the uncertain diagnosis and uncontrolled complications. In the emergency room, the patient appeared acutely ill-looking, was alert (glascow coma scale: E4M6V5), and had a pupil size of 3 mm with normal light reflexes bilaterally. His blood pressure was 100/70 mmhg, pulse rate 110/min, respiratory rate 30/min, and body temperature Physical examination revealed icteric sclera bilaterally with subconjunctival hemorrhage (Fig. 1A), a 1.5 cm eschar on his left chest wall (Fig. 1B), tenderness and enlargement of the left axillary lymph nodes with limitation in lifting his left arm due to pain, and rhonchi with basal rales bilaterally. Laboratory data revealed acute inflammation with a high C-reactive protein level (CRP 20.5 mg/ dl), leukocytosis, thrombocytopenia, elevation of GOT, GPT, direct (6.9 mg/dl) and total bilirubin (7.9 mg/dl), blood urea nitrogen (BUN 65 mg/dl), creatinine (2.2 mg/dl), and alkaline phosphatase (Alk-p 644U/L), hypoalbuminemia (1.9 mg/dl), proteinuria, and hyperbilirubinuria. Arterial blood gas analysis showed the PO 2 was 59.8 mmhg, - PCO mmhg, HCO mmol/l and SaO % with a ph of Chest radiography showed cardiomegaly and increased interstitial infiltrations in the bilateral lower lobes (Fig. 2). Abdominal sonography revealed hepatomegaly and splenomegaly with coarsening of the hepatic echo pattern and a minimal amount of pleural effusion bilaterally. Scrub typhus with multi-organ dysfunction was diagnosed clinically by a senior physician who had experience in military service in Kin-Men island, one of the endemic areas for scrub typhus. Gram stain and bacterial culture were negative for both aerobic and anaerobic bacteria. The titers of HBsAg and Anti-HCV antibodies were within the normal ranges. Serum titers of S. typh-o and S. typh-h were negative. Tetracycline (Minocycline HCL, 100 mg, every 12 hours) was administered intravenously and the fever subsided from the second day of medication. The white blood cell count (WBC 29190/μL-11100/μL) decreased and the platelet count ( /μl / μl) rose gradually. However, anemia with a gradual decrease in the red blood cell (RBC) count and hemoglobin level (14.7 g/dl-11.9 g/dl) occurred. We reported the case to the Center for Disease Control and asked for confirmation of the diagnosis. A series of chest radiographs showed persistent

3 Scrub typhus 163 (A) (B) Fig. 1 (A) Photographs show subconjunctival hemorrhage (B) and a 1.5 cm eschar on the left anterior chest wall demonstrating erythematous plaque with central erosion Fig. 2 Chest radiography shows cardiomegaly and acute pulmonary edema

4 164 J Emerg Crit Care Med. Vol. 18, No. 4, 2007 cardiomegaly with acute pulmonary edema and pleural effusion. An electrocardiogram showed sinus tachycardia with an elevated ST segment on lead I, V2 and V3, suggestive of cardiomyopathy. Echocardiography disclosed impaired motion of the anteroseptal and apical areas of the left ventricle, dilatation of the left atrium, and a small amount of pericardial effusion. The laboratory data on the third and sixth days of hospitalization showed a trend toward recovery, including a lower WBC count and CRP level, elevated platelet count, lower direct and indirection bilirubin, and lower GOP and GPT (although still abnormal). The serum albumin, BUN, creatinine and potassium returned to the normal level. He was discharged after eight days in the hospital with improvement in cardiac, hepatic and renal function. Results of serum indirect immunofluorescent staining analysis from a blood sample taken on the fifth hospital day showed positive results for both IgG (>1:640) and IgM (>1:160), confirming the clinical diagnosis of scrub typhus. Discussion Scrub typhus, an acute febrile disease caused by infection with Orientia tsutsugamushi transmitted by the bite of larval trombiculid mites (chiggers), is a self-limited or curable disease most of the time. However, it can be a life-threatening disease that can cause multi-organ dysfunction or failure when it is not diagnosed and treated properly (1). Mortality rates of 0% to 30% have been reported (2-3). It is well characterized by a typical primary lesion (eschar), lymphadenopathy, skin rash and some other nonspecific symptoms such as fever, headache, general malase, cough, and sore throat (4). Epidemiologically, scrub typhus commonly occurs in the Asian countries bounded by Pakistan, Afghanistan, Japan and Australia. This is the socalled tsutsugamushi triangle where the disease is endemic (5-6). In Taiwan, it occurs most commonly in northern Taiwan, such as on Yang-Ming Mountain, in eastern Taiwan, such as in Taitung and Hualien, in southern Taiwan, such as in Chiayi, Tainan, Kaohsiung, and Pingtung, and on offshore islands including the Pescadores, Kin-Men, and Ma-Tzu. (4-5). Although sporadic cases have been reported in nearly all counties, physicians on the west coast of Taiwan might be unfamiliar with scrub typhus, leading to delayed diagnosis, as was encountered in our case. Our patient was bitten while in Ma-Tzu, and developed a typical eschar on his chest wall after the fever. This important sign, however, was ignored in his first hospitalization. Humans are accidental hosts in this zoonotic disease and acquire the disease when an infected chigger, the larval stage of the trombiculid mite, bites them while feeding and inoculates Orientia tsutsugamushi pathogens (7). The bacteria multiply at the inoculation site with the formation of a papule that ulcerates and becomes necrotic, evolving into an eschar. However, an eschar is not specific to scrub typhus. Other possible causes include warfarin necrosis, cutaneous anthrax, aspergillous, ecthyma gangrenosum and plague (8). In our patient, the cause of the eschar lesion was more likely to be scrub typhus rather than other diseases, judging from the history and clinical course. Orientia tsutsugamushi is an obligate intracellular gramnegative bacterium that invades the endothelium of affected organs when patients are rickettsemic (9). Perivasculitis of the small blood vessels occurs and results in multi-organ impairment. This explains the multi-organ dysfunction which occurred in our patient (10). Without proper treatment, scrub typhus may lead to severe complications such as multiorgan dysfunction or failure (10), including myocarditis, cardiomegaly and cardiac dysfunction, hypoalbuminemia, interstitial pneumonitis, acute pulmonary edema, acute hepatic and renal failure and bone marrow suppression, shown as

5 Scrub typhus 165 thrombocytopenia, disseminated intravascular coagulation, and anemia (1). Although scrub typhus can be diagnosed based on serological tests such as enzyme immunoassay, enzyme-linked immunosorbent assay, the Weil- Felix test, polymerase chain reaction, and indirect immunofluorescent antibody assay (8-11), our patient initially showed negative serological results sampled within two weeks after infection. The definite diagnosis was made on the 26 th day of disease, an unacceptably long time in the critical treatment of scrub typhus. Our experience highlights the paramount importance of a high index of suspicion for scrub typhus when there are symptoms such as the typical primary skin lesion, eschar, lymphadenopathy, fever and a detailed travel history showing the patient has been in an endemic area, not only for the correct diagnosis but also for timely treatment of this curable disease and prevention of severe complications. In summary, we reported a case of initially unrecognized scrub typhus with multi-organ dysfunction. The patient recovered well with administration of tetracycline under a correct clinical and serological diagnosis (12). Physicians should be aware of scrub typhus in treating patients with fever, rash, eschar and systemic organ dysfunction. References 1. Yen TH, Chang CT, Lin JL, Jiang JR, Lee KF. Scrub typhus: a frequently overlooked cause of acute renal failure. Ren Fail 2003;25: Varghese GM, Abraham OC, Mathai D, et al. Scrub typhus among hospitalised patients with febrile illness in South India: magnitude and clinical predictors. J Infect 2006;52: Kumar K, Saxena VK, Thomas TG, Lal S. Outbreak investigation of scrub Typhus in Himachal Pradesh (India). J Commun Dis 2004;36: L e e H C, K o W C, L e e H L, C h e n H Y. Clinical manifestations and complications of rickettsiosis in southern Taiwan. J Formos Med Assoc 2002;101: Lee YS, Wang PH, Tseng SJ, Ko CF, Teng HJ. Epidemiology of scrub typhus in eastern Taiwan, Jpn J Infect Dis 2006;59: Wa t t G, P a r o l a P. S c r u b t y p h u s a n d tropical rickettsioses. Curr Opin Infect Dis 2003;16: Chanta C, Chanta S. Clinical study of 20 children with scrub typhus at Chiang Rai Regional Hospital. J Med Assoc Thai 2005;88: Kovacova E, Kazar J. Rickettsial diseases and their serological diagnosis. Clin Lab 2000;46: Tamura A. Invasion and intracellular growth of Rickettsia tsutsugamushi. Microbiol Sci 1988;5: Cracco C, Delafosse C, Baril L, et al. Multiple organ failure complicating probable scrub typhus. Clin Infect Dis 2000;31: Sugita Y, Nagatani T, Okuda K, et al. Diagnosis of typhus infection with Rickettsia tsutsugamushi by polymerase chain reaction. J Med Microbiol 1992;37: Panpanich R, Garner P. Antibiotics for treating scrub typhus. Cochrane Database Syst Rev 2000; CD

6 166 J Emerg Crit Care Med. Vol. 18, No. 4, ,3 1 30% 1.5 (eschar) (04) (04) juanchiwen@yahoo.com.tw

WFSICCM SEOUL Managing Scrub Typhus in ICU

WFSICCM SEOUL Managing Scrub Typhus in ICU WFSICCM SEOUL 2015 Managing Scrub Typhus in ICU Dr. Shivakumar Iyer Professor & Head Dept of Critical Care Medicine Bharati Vidyapeeth University Medical College, Pune President Indian Society of Critical