Journal of Infection (2005) 51, e57e60

www.elsevierhealth.com/journals/jinf

CASE REPORT

Typhoid fever complicated by multiple organ involvement: report of two cases

Guan-Cheng Huanga, Chia-Ming Changb, Wen-Chien Kob,c, Yu-Lun Huangd, Yin-Ching Chuangd,*
Department of Internal Medicine, Chi Mei Medical Center, 901 Chung-Hwa Road, Yung-Kang City, Tainan County 710, Taiwan, ROC b Department of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70428, Taiwan, ROC c Department of Medicine, Medical College of National Cheng Kung University, 138, Sheng-Li Road, Tainan 70428, Taiwan, ROC d Departments of Medical Research and Medicine, Chi Mei Medical Center, 901 Chung-Hwa Road, Yung-Kang City, Tainan County 710, Taiwan, ROC
Accepted 7 August 2004 Available online 7 January 2005
a

KEYWORDS
Typhoid fever; Salmonella typhi; Multiple organ failure

Abstract Typhoid fever complicated by multiple organ involvement has been rarely mentioned in the literature. We reported two cases of typhoid fever with several unusual manifestations, including acute renal failure, acute hepatitis, acute pancreatitis, disseminated intravascular coagulation, and lower gastrointestinal bleeding. A renal biopsy in the rst case showed no pathological change. Bone marrow biopsy showed focal necrosis of matrix, which might have been due to severe illness. A liver biopsy in the second case showed a predominantly histiocytic proliferation with occasional neutrophilic inltration in the portal areas and hepatic sinusoids. Focal necrosis, bile duct injury, and multiple eosinophilic bodies were also noted. After appropriate antimicrobial therapy, both patients recovered without any sequelae. The potential of multiple organ involvement is highlighted in typhoid fever, which, on rare occasions, may occur simultaneously in the same patient. Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

Introduction
Despite effective antimicrobial agents, typhoid fever remains an important public health problem

* Corresponding author. Tel.: C886-6-281-2811x2612; fax: C 886-6-251-7849 E-mail address: chuangkenneth@hotmail.com (Y.-C.Chuang).

in developing countries. It is a severe disease with a variety of complications,1 including meningitis,2 psychosis,3 pneumonia,4 myocarditis,5 hepatitis,69 pancreatitis,1013 nephritis,9,14 osteomyelitis,15 and disseminated intravascular coagulation (DIC).9,15 However, multiple organ involvement in the same patient has rarely been reported in the literature. 79,17 In order to alert clinicians to the potential of typhoid fever to cause serious

0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.08.018

e58 complications, we report two cases with the complications of acute renal failure, acute hepatitis, acute pancreatitis, DIC, and lower gastrointestinal bleeding.

G.-C. Huang et al. end of the rst week, massive bloody stool due to active bleeding from the proximal ascending colon was detected by a red blood cell scan. Twelve units of packed blood cells were subsequently transfused. The bleeding stopped 3 days later. Despite of this catastrophe, no haemodynamic change was documented. No haemodialysis was administered, but supportive care was given for acute renal failure. A bone marrow biopsy showed focal necrosis of matrix, which might have been due to severe illness. A renal biopsy, performed on the 13th hospital day, revealed no increase in mesangial cellularity and matrix, with no obsolete glomeruli. Neither focal tubular atrophy nor interstitial brosis was noted. An immunouorescence study demonstrated no deposition of IgA, IgG, IgM, C3, C1q, and C4, and an electromicroscopic study did not show remarkable ndings. The tests for hepatitis B virus, hepatitis C virus, and human immunodeciency virus were negative. By the end of the fourth week, his condition was stable, and liver and renal function had recovered (BUN 15 mg/dl, serum creatinine 1.4 mg/dl, AST 23 U/l, ALT 28 U/l). He was discharged after 4 weeks of hospitalization. The second case, a 35-year-old man with a 6-year history of chronic schizophrenia, had been in a chronic care centre for 6 years because of his psychiatric condition. When referred to our hospital because of diarrhoea, vomiting, abdominal cramping pain, and high fever for 1 week, he was illlooking with icteric conjunctiva and epigastric tenderness. The liver and spleen were not palpable. His temperature was 38.8 8C; pulse, 87 beats/min; respiration, 19/min; and blood pressure, 117/71 mmHg. A hemogram at the time of admission showed a normal leukocyte count of 8300/mm3 and low platelet count of 35 000/mm3. The biochemical data were as follows: AST 306 U/l, ALT 133 U/l, total/direct bilirubin 4.3/3.8 mg/dl, Alk-P 195 U/l, g-GT 295 U/l, LDH 502 U/l, amylase 1761 U/dl, lipase 2294 U/dl, BUN 10 mg/dl, serum creatinine 1.0 mg/dl, CR2 244 mg/l, CPK 974 U/l, and CK-MB 4 U/l. Urinalysis showed mild proteinuria (2C) and hematuria (4C). The DIC prole revealed PT of 10.8 s (control, 12.3 s), APTT of 31.7 s (control, 25.6 s), brinogen at 382 mg/dl, FDPs O40 mg/ml, and D-dimer O1.0 mg/l. Since the two blood cultures grew S. typhi, treatment with cefotaxime was initiated. He became afebrile 4 days later. The urinalysis returned to normal 2 weeks later. A liver biopsy performed on the 17th day of hospitalization showed a predominantly histiocytic proliferation with occasional neutrophilic inltration in the portal areas and hepatic sinusoids. Focal

Case reports
The rst case, a 31-year-old married salesman, presented with a 2-week history of fever and a 1-week history of abdominal distention, constipation, and epigastric pain. He had not travelled abroad. The physical examination revealed tenderness in the right upper quadrant and lower abdomen. The liver and spleen were not palpable. His temperature was 38.6 8C; pulse, 124 beats/min; respiration, 20/min; and blood pressure, 100/65 mmHg. On admission, a hemogram revealed a leukocyte count of 3600/mm3 (normal, 34009100/mm3), platelet count of 18 000/mm3 (normal, 138 100 353 400/mm3), and haemoglobin level of 11.8 g/dl (normal, 13.517 g/dl). Abnormal biochemical values were as follows: blood urea nitrogen (BUN) 74 mg/dl (normal, 721 mg/dl), serum creatinine 6.5 mg/dl (normal, 0.71.5 mg/dl), aspartate aminotransferase (AST) 238 U/l (normal, 540 U/l), alanine aminotransferase (ALT) 218 U/l (normal, 555 U/l), serum total bilirubin 2.1 mg/dl (normal, 0.21.4 mg/dl) with a direct reacting bilirubin 1.6 mg/dl (normal, 00.4 mg/dl), alkaline phosphatase (Alk-P) 413 U/l (normal, 30110 U/l), g-glutamyl transferase (g-GT) 737 U/l (normal, 880 U/l), lactic dehydrogenase (LDH) 1310 U/l (normal, 100 200 U/l), amylase 311 U/dl (normal, 25125 U/l), lipase 1763 U/dl (normal, 23208 U/l), and C-reactive protein (CRP) 185 mg/l (normal, 05 mg/l). A urinalysis showed mild proteinuria (2C) and haematuria (4C). The occult blood test of stool was strongly positive. Additional laboratory data divulged a prothrombin time (PT) of 13.3 s (control, 11.8 s), activated partial thromboplastic time (APTT) of 31.4 s (control, 24.8 s), brinogen level of 171 mg/dl (normal, 216318 mg/dl), brin degeneration products (FDP) of 40 mg/ml (normal, 010 mg/ml), and D-dimer O1.0 mg/l (normal, !0.5 mg/l). On the second day of hospitalization, the patient experienced chest tightness. The serum levels of creatine phosphokinase (CPK) and cardiac isoenzyme were 857 U/l (normal, 50350 U/l) and 18 U/l (normal, 010 U/l), respectively. An electrocardiogram showed non-specic changes in the S-T segment. Blood cultures yielded growth of Salmonella typhi. Therefore, cefotaxime was administered. Fever subsided 7 days later. At the

Typhoid fever with multiple organ involvement necrosis, bile duct injury, and multiple eosinophilic bodies were also noted. The patient was discharged after 3 weeks of hospitalization.

e59 evidence of pancreatitis, 50% of them had elevated serum amylase and lipase. However, the clinical signs of pancreatitis were only observed in 57% of patients with elevated serum amylase and lipase. Our cases had elevation of amylase and lipase levels, but the clinical signs of pancreatitis were minimal. Asymptomatic typhoid pancreatitis is not signicant in the prognosis.1012 The mechanism of asymptomatic pancreatitis was unclear. The bile reux theory suggests that S. typhi invades the bile and is reuxed into the pancreatic duct.11 However, other causes, such as toxins or an immune response to bacteria, should also be considered.12,13 Bulter et al.19 suggested that laboratory abnormalities compatible with DIC were common in patients with typhoid fever. However, there is no correlation between gross intestinal bleeding and the degree of abnormal coagulation tests.19 Such is the case in our report of the rst case that suffered from gross intestinal bleeding on the sixth day of hospitalization when his platelet count was normal. The incidence of intestinal haemorrhage in typhoid fever varies from 1% to 13.8%.20 The most common site of haemorrhage is the small intestine, and massive colonic haemorrhage rarely occurs.21 In current opinion,22 selective angiography with surgical intervention is the rst choice of management. Some patients require only appropriate blood replacement. Hoffman et al.23 reported that 92% of patients had raised LDH, and that 30% of patients had elevated levels of both LDH and CPK. In our two cases, the levels of LDH and CPK increased, but no specic change was found in the electrocardiograms. The raised levels of LDH may be caused by hepatitis, but whether raised CPK is caused by injury to muscle remains for further study.18 In summary, our report highlights the potentially serious complications of multiple organ involvement in typhoid fever. Early recognition, together with supportive and adequate antimicrobial treatment, are mandatory for these patients.

Discussion
The importance in reporting these two cases is to highlight the spectrum of multiple organ involvement in typhoid fever, which, on rare occasions, may occur simultaneously in the same patient. Physicians must be aware of the potential of this disease to cause serious complications. Renal involvement is a rare manifestation of typhoid fever. 9,18 Although previous studies suggested that tubular necrosis9 or immune complex glomerulitis14 was the possible cause, the renal biopsy in our rst case showed no pathological change. The cause of acute renal failure in our rst case may be related to the severe sepsis rather than the bacteria itself. Unlike the previous case report,9 our case did not undergo haemodialysis for acute renal failure, and his renal function recovered completely without any sequelae. The urinalysis in our second case returned to normal 2 weeks later. Eradication of the bacteria may lead to complete resolution of renal function impairment. Khan et al. studied 57 African patients with culture-proven typhoid fever with hepatic dysfunction and found that clinically detectable glomerulonephritis occurred more frequently in icteric patients.8 The reason for the association between glomerulonephritis and hepatic dysfunction with jaundice in typhoid fever remains unclear. Severe sepsis is often associated with multiple organ dysfunctions. However, jaundice may indicate severe hepatic injury, which can lead to glomerulonephritis when defective reticuloendothelial clearance in the liver allows the accumulations of circulating immune complexes.8 Abnormal liver function tests and jaundice were present in our cases. Asymptomatic hepatitis commonly occurs in typhoid fever, with most patients having only minor elevations of AST and ALT, and more than one third with jaundice.8 Typhoid fever-associated hepatitis was manifested in the liver biopsy of case 2, which showed multifocal inammatory inltrations. Cohen et al. reported that 42% of patients with salmonella intra-abdominal infections had underlying anatomical anomalies, including biliary stones, cholestasis, or cirrhosis.1 However, our cases did not have any known preexisting abnormalities. Hermans et al.12 reported a series of patients with typhoid fever that exhibited biochemical

Acknowledgements
We thank Dr Joshua Fierer, the head of the Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California, San Diego, for his critical review of our manuscript and his comments.

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13. Stauffer W, Mantey K, Kamat D. Multiple extraintestinal manifestations of typhoid fever. Infection 2002;30:113. 14. Sitprija V, Pipantanagul V, Boonpucknavig V, Boonpucknavig S. Glomerulitis in typhoid fever. Ann Intern Med 1974;81:2103. 15. Harris NH. Salmonella typhi osteomyelitis. Proc R Soc Med 1966;59:70910. 17. Lambotte O, Debord T, Castagne C, Roue R. Unusual presentation of typhoid fever: cutaneous vasculitis, pancreatitis, and splenic abscess. J Infect 2001;42:1612. 18. Rheingold OJ, Greenwald RA, Hayes PJ, Tedesco FJ. Myoglobinuria and renal failure associated with typhoid fever. JAMA 1977;238:341. 19. Butler T, Bell WR, Levin J, Linh NN, Arnold K. Typhoid fever. Studies of blood coagulation, bacteremia, and endotoxemia. Arch Intern Med 1978;138:40710. 20. Wong SH. The emergency surgical management of massive and persistent intestinal haemorrhage due to typhoid fever: a report of 3 cases. Br J Surg 1978;65:745. 21. Wig JD, Malik AK, Khanna SK, Singh K, Talwar BL, Shukla NK, Sekar N. Massive lower gastrointestinal bleeding in patients with typhoid fever. Am J Gastroenterol 1981;75:4458. 22. Rubin CM, Fairhurst JJ. Life-threatening haemorrhage from typhoid fever. Br J Radiol 1988;61:4156. 23. Hoffman TA, Ruiz CJ, Counts GW, Sachs JM, Nitzkin JL. Waterborne typhoid fever in Dade County, Florida. Clinical and therapeutic evaluation of 105 bacteremic patients. Am J Med 1975;59:4817.

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