- Research article
- Open Access
- Open Peer Review
Clinical significance of hypoalbuminemia in outcome of patients with scrub typhus
© Lee et al; licensee BioMed Central Ltd. 2010
- Received: 5 March 2010
- Accepted: 21 July 2010
- Published: 21 July 2010
This study was designed to investigate the clinical significance of hypoalbuminemia as a marker of severity and mortality in patients with Scrub typhus.
The patients with scrub typhus were divided into two groups based on the serum albumin levels; Group I (serum albumin <3.0 g/dL) and Group II (serum albumin ≥3.0 g/dL). The outcome of patients with hypoalbuminemia was compared with that of normoalbuminemia.
Of the total 246 patients who underwent the study, 84 patients (34.1%) were categorized as Group I and 162 patients were (65.9%) as Group II. Group I showed significantly higher incidence of confusion (24.6% vs. 5.3%, p < 0.001), pulmonary edema (15.8% vs. 3.2%, p = 0.002), pleural effusion (22.8% vs. 11.1%, p = 0.03), arrhythmia (12.3% vs. 2.6%, p = 0.008) and non-oliguric acute renal failure (40.4% vs. 11.1%, p < 0.001) compared to group II. Hypoalbuminemic group had a higher APACHE II score (11.37 ± 5.0 vs. 6.94 ± 4.2, p < 0.001), longer hospital stay (19.9 ± 42.1 days vs 7.5 ± 13.8 days, p = 0.012), and higher hospital cost compared to Group II.
This study showed hypoalbuminemia in scrub typhus was closely related to the frequency of various complication, longer hospital stay, consequently the higher medical cost, necessitating more efficient management of patients, including medical resources.
- Chronic Obstructive Pulmonary Disease
- Acute Renal Failure
- Pulmonary Edema
- Aplastic Anemia
- Serum Albumin Level
Scrub typhus is an acute febrile illness with the characteristic findings of high fever, eschar, maculopapular rash, lymphadenopathy, headache, and myalgia [1–3]. Scrub typhus caused by infection with Orientia tsutsugamushi occurs over a wide area of Eastern Asia and the Western Pacific region . Usually, the symptoms of this disease are mild and its clinical course is uneventful. However, some patients experience severe or fatal events such as acute renal failure, respiratory distress or multiorgan dysfunctions [1, 4, 5].
Generally, hypoalbuminemia is known to be associated with complications and mortality in patients with acute infectious disease . In scrub typhus, about 25%~69.2% of patients presented hypoalbuminemia [7, 8]. For the mechanism of hypoalbuminemia, decreased synthesis of albumin due to hepatic dysfunction, increased catabolism of protein, albuminuria, decreased intestinal absorption of protein due to poor oral intake, and extensive vascular leakage of serum protein due to increased capillary permeability have been postulated .
Despite the common occurrence of hypoalbuminemia in patients with scrub typhus, there has been limited information about the relationship between the hypoalbuminemia and the severity of disease. To confirm the significance of hypoalbuminemia on the outcome of patients with scrub typhus, the clinical records of 299 patients with Scrub typhus were reviewed retrospectively.
Study population and design
Diagnosis of scrub typhus
The diagnosis of scrub typhus was made on clinical manifestations and passive hemagglutination assay (PHA) against O. tsutsugamushi. A definite case of scrub typhus was defined by an increased titer of Passive Hemagglutination Assay (PHA) against O. tsutsugamushi (≥1:80) in a single serum sample or by a 4-fold or greater increase of titer in the follow-up [9–11]. PHA was performed at the NeoDIN Medical Institute in Seoul, Korea using Genedia Tsutsu PHA II test kits. Genedia Tsutsu PHA II is a test kit for the qualitative and quantitative detection of antibodies against O. tsutsugamushi in human serum based on the PHA. In the kit, we used sheep erythrocytes sensitized by Karp and Gilliam strains, including the Boryong strain found in Korea [12, 13].
Hypoalbuminemia was defined as a first serum albumin of less than 3.0 g/dL on their initial visit [6, 8]. Central nervous system (CNS) involvement was defined by the presence of CNS related symptoms such as confusion, seizure or coma. Involvement of respiratory system (RS) was defined by the presence of symptoms, signs and investigation results supporting evidence of pulmonary edema, interstitial pneumonia, pleural effusion or the need for mechanical ventilation. Cardiovascular system (CS) involvement was defined by the presence of symptoms, signs and investigation results supporting pericardial effusion, new onset of atrial fibrillation and ischemic heart disease. New onset of atrial fibrillation was defined as such when the symptoms improved with clinical recovery of scrub typhus. Gastrointestinal system (GS) involvement was defined by the presence of symptoms, signs and investigation results supporting gastric ulcer, pancreatitis, and upper gastrointestinal bleeding. Acute renal failure (ARF) was defined as such when at least 50% reduction was seen in glomerular filtration rate (GFR) using the abbreviated modified diet in renal disease (MDRD) equation, namely: GFR(mL/min/1.73 m2) = 186 Pcr -1.154 × age-0.203 × (1.212 if black) × (0.742 if female) . An "ST interval" was defined as an interval from the day when clinical symptoms began (prior to the admission) and to the day when appropriate treatment with antibiotics (Doxycycline or azithromycin) begun. An "AT interval" was defined as an interval from the day of admission to the day when appropriate treatment started.
All costs were expressed in US dollars. The currency rate was 1,300 Korean Won per 1 United States Dollar. We estimated only the direct medical cost, which included treatment (oral and/or intravenous administration), examination (laboratory and imaging studies), surgical and nonsurgical procedures, physical therapies, and room and board.
The results were analyzed using SPSS v 15.0 (SPSS, Inc., Chicago, IL, USA). Categorical variables were compared by Fisher's exact test or chi-square test and continuous variables were compared by the ANCOVA. All tests of significance were two-tailed; p values ≤ 0.05 were considered to be significant.
Since the age in Group I was significantly older than Group II (p < 0.001), we adjusted all variables for age to avoid biased outcome due to this demographic difference. Meanwhile, there were no statistical differences in gender and underlying diseases such as diabetes mellitus, hypertension, chronic hepatitis B and chronic hepatitis C.
Demographic and Clinical Characteristics of 246 Study Patients
Age, mean ± SD, years
71.4 ± 10.6
60.7 ± 12.2
Chronic hepatitis B
Chronic hepatitis C
Complications of the Patients in the study
Central Nervous System
Ischemic heart disease
Upper gastrointestinal bleeding
Admission Laboratory Findings of the study Patients*
10.79 ± 4.04
8.57 ± 4.10
30.87 ± 10.98
31.86 ± 12.03
11.63 ± 1.92
12.38 ± 1.60
115.11 ± 69.07
161.28 ± 90.92
121.60 ± 85.95
106.87 ± 99.44
107.35 ± 168.92
97.15 ± 103.94
1.417 ± 1.33
0.84 ± 0.59
2.69 ± 0.22
3.56 ± 0.35
32.94 ± 17.05
19.50 ± 14.11
61.64 ± 37.37
79.51 ± 33.16
134.18 ± 6.11
135.19 ± 11.14
3.70 ± 0.70
3.88 ± 0.71
The Comparison of ST, AT interval, APACHE II score, Intensive Care Unit Admission, Septic Shock, and Mortality of the Patients*
ST interval, mean ± SD
6.84 ± 4.14
7.44 ± 4.12
AT interval, mean ± SD
0.98 ± 1.89
0.87 ± 2.34
APACHE II Score, mean ± SD
11.37 ± 5.1
6.94 ± 4.2
Intensive Care Unit Admission
Comparison of Length of hospital Stay, and the Cost Between the Two Groups*
Duration of hospital Stay, mean ± SD
11.46 ± 8.9
5.93 ± 5.9
2357.83 ± 2284.15
1135.97 ± 1668.62
In this study, scrub typhus patients with hypoalbuminemia had a higher APACHE II score, longer hospital stay, and higher medical cost compared to the patients without hypoalbuminemia. And in the hypoalbuminemic group, thrombocytopenia and leukocytosis, which were known to be clinical parameters representing disease severity , were more severe. In addition, the hypoalbuminemic group showed a higher rate of complication in CNS, RS, GS, and non-oliguric ARF.
Generally, the mechanism of hypoalbuminemia in acute infectious disease is known to be related with poor oral intake of protein, decreased synthesis of protein from the liver, increased catabolism of protein, and increased metabolism of albumin due to the vascular leakage of serum protein due to increased vascular permeability . A major and serious pathologic change of scrub typhus is a focal or disseminated vasculitis due to the destruction of endothelial cell lining of the small vessels, which is manifested as perivascular infiltration of leukocytes [17–19], an increased vascular permeability with extravascular protein loss, and consequently the hypoalbuminemia.
The widespread vasculitis or perivasuculitis in scrub typhus may involve the lung, cardiovascular system, brain, kidney, gastrointestinal tract, liver, and lymph nodes [4, 17–21]. Song et al  showed that interstitial pneumonia, pleural effusion, and pulmonary edema were more frequently reported in scrub typhus patients with hypoalbuminemia than in patients without hypoalbuminemia. In this study, dyspnea and pulmonary edema occurred more frequently in the group with hypoalbuminemia than in the patients without hypoalbuminemia. This finding concurred with that of Song et al .
Previous reports showed that septic shock  and hepatic dysfunction  were frequently reported in patients with scrub typhus with hypoalbuminemia. They suggested that these complications were closely associated with the disease severity of scrub typhus. In this study, the level of AST and total bilirubin were higher in the hypoalbuminemia group than in the group without hypoalbuminemia.
Acute renal failure can occur due to acute tubular necrosis caused by direct invasion of Oriential tsutsugamushi . Renal complications may prolong its morbidity and even lead to death. In this study, renal failure was more frequently reported in the group with hypoalbuminema. We suggest that the hypoalbuminemia has close association with acute renal failure. The absolute WBC counts varied but had a significantly higher mean value in the hypoalbuminemia group. This suggests that patients with hypoalbuminemia might have been more seriously ill.
Though hypoalbuminemia is a powerful predictor of mortality in patients with various illnesses [25–27], this study did not show significantly higher mortality in patients with hypoalbuminemia than the nonhypoalbuminemic patients. Incidence of severe scrub typhus is actually low, and an active treatment with antibiotics will suffice for managing the case. Therefore, the hypoalbuminemia itself may be insignificant in predicting poor clinical courses in scrub typhus. This suggestion can be supported by lower APACHE II score in hypoalbuminemic scrub typhus patients compared to other severe septic conditions.
The length of hospital stay in the hypoalbuminemic group was significantly longer than that of group without hypoalbuminemia, raising the cost of their hospital stay significantly higher for more tests and treatments. It is suggested that scrub typhus patients with hypoalbuminemia had more complications than the patients without hypoalbuminemia, although their mortality rate remained low.
Our study has some limitations. Firstly, our study is retrospective, which has obvious limitations. Secondly, we classified the level of albumin into two groups. Therefore, the clinical impact of hypoalbuminemia on patients with scrub typhus could not be evaluated. Thirdly, outcomes of albumin administration had not been evaluated.
As the annual incidence of scrub typhus in Korea has been increasing steadily with its reported cases sharply rose to 6057 in 2008 , the financial burden of caring for scrub typhus is becoming an emerging problem. This study was done in search of more effective measures for improving patient care in scrub typhus. The hypoalbuminemia as a criterion is an important marker on the clinical outcome of patients with scrub typhus.
- Saah A: Orientia tsutsugamushi (scrub typhus). Principles and practice of infectious disease. Edited by: Mandell GL, Bennett JE, Dolin R. 2000, Philadelphia: Churchill Livingstone, 2: 2056-2057. 5Google Scholar
- Watt G, Parola P: Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. 2003, 16: 429-436. 10.1097/00001432-200310000-00009.View ArticlePubMedGoogle Scholar
- Tsay RW, Chang FY: Serious complications in scrub typhus. J Microbiol Immunol Infect. 1998, 31: 240-244.PubMedGoogle Scholar
- Chi WC, Huang JJ, Sung JM, Lan RR, Ko WC, Chen FF: Scrub typhus associated with multiorgan failure: A case report. Scand J Infect Dis. 1997, 29: 634-635. 10.3109/00365549709035911.View ArticlePubMedGoogle Scholar
- Hsu GJ, Young T, Peng MY, Chang FY, Chou MY, Sheu LF: Acute renal failure associated with scrub typhus: Report of a case. J Formos Med Assoc. 1993, 92: 475-477.PubMedGoogle Scholar
- Carratala J, Roson B, Fernandez-Sabe N, Shaw E, del Rio O, Rivera A: Factors associated with complications and mortality in adult patients hospitalized for infectious cellulitis. Eur J Clin Microbiol Infect Dis. 2003, 22: 151-157.PubMedGoogle Scholar
- Jang KM, Kang MH, Yang YS, Hwang HG, Lee KP, Lee JS: The twenty cases of serologically confirmed tsutsugamushi disease. J Korean Med Assoc. 1987, 30: 638-646.Google Scholar
- Song SW, Kim KT, Ku YM, Park SH, Kim YS, Lee DG, Yoon SA, Kim YO: Clinical role of interstitial pneumonia in patients with scrub typhus: A possible marker of disease severity. J Korean Med Sci. 2004, 19: 668-673. 10.3346/jkms.2004.19.5.668.View ArticlePubMedPubMed CentralGoogle Scholar
- Kim DM, Yun NR, Yang TY, Lee JH, Yang JT, Shim SK, Choi EN, Park MY, Lee SH: Usefulness of nested PCR for the diagnosis of scrub typhus in clinical practice: A prospective study. Am J Trop Med Hyg. 2006, 75: 542-545.PubMedGoogle Scholar
- Kim IS, Seong SY, Woo SG, Choi MS, Kang JS, Chang WH: Rapid diagnosis of scrub typhus by a passive hemagglutination assay using recombinant 56-kilodalton polypeptides. J Clin Microbiol. 1993, 31: 2057-2060.PubMedPubMed CentralGoogle Scholar
- Song HJ, Seong SY, Huh MS, Park SG, Jang WJ, Kee SH, Kim KH, Kim SC, Choi MS, Kim IS, Chang WH: Molecular and serologic survey of orientia tsutsugamushi infection among field rodents in southern cholla province, korea. Am J Trop Med Hyg. 1998, 58: 513-518.PubMedGoogle Scholar
- Kim YS, Yun HJ, Shim SK, Koo SH, Kim SY, Kim S: A comparative trial of a single dose of azithromycin versus doxycycline for the treatment of mild scrub typhus. Clin Infect Dis. 2004, 39: 1329-1335. 10.1086/425008.View ArticlePubMedGoogle Scholar
- Chang WH, Kang JS, Lee WK, Choi MS, Lee JH: Serological classification by monoclonal antibodies of rickettsia tsutsugamushi isolated in korea. J Clin Microbiol. 1990, 28: 685-688.PubMedPubMed CentralGoogle Scholar
- Manjunath G, Sarnak MJ, Levey AS: Prediction equations to estimate glomerular filtration rate: An update. Curr Opin Nephrol Hypertens. 2001, 10: 785-792. 10.1097/00041552-200111000-00009.View ArticlePubMedGoogle Scholar
- Wang CC, Liu SF, Liu JW, Chung YH, Su MC, Lin MC: Acute respiratory distress syndrome in scrub typhus. Am J Trop Med Hyg. 2007, 76: 1148-1152.PubMedGoogle Scholar
- Kim YO, Yoon SA, Ku YM, Yang CW, Kim YS, Kim SY, Choi EJ, Chang YS, Bang BK: Serum albumin level correlates with disease severity in patients with hemorrhagic fever with renal syndrome. J Korean Med Sci. 2003, 18: 696-700. 10.3346/jkms.2003.18.4.483.View ArticlePubMedPubMed CentralGoogle Scholar
- Strickman D, Smith CD, Corcoran KD, Ngampochjana M, Watcharapichat P, Phulsuksombati D, Tanskul P, Dasch GA, Kelly DJ: Pathology of rickettsia tsutsugamushi infection in bandicota savilei, a natural host in thailand. Am J Trop Med Hyg. 1994, 51: 416-423.PubMedGoogle Scholar
- Kim SJ, Chung IK, Chung IS, Song DH, Park SH, Kim HS, Lee MH: The clinical significance of upper gastrointestinal endoscopy in gastrointestinal vasculitis related to scrub typhus. Endoscopy. 2000, 32: 950-955. 10.1055/s-2000-9621.View ArticlePubMedGoogle Scholar
- Seong SY, Choi MS, Kim IS: Orientia tsutsugamushi infection: Overview and immune responses. Microbes Infect. 2001, 3: 11-21. 10.1016/S1286-4579(00)01352-6.View ArticlePubMedGoogle Scholar
- Hwang TS, Chu YC, Kim YB, Lim BU, Kang JS: Pathologic study of mice infected with rickettsia tsutsugamushi r19 strain. J Korean Med Sci. 1993, 8: 437-445.View ArticlePubMedPubMed CentralGoogle Scholar
- Sirisanthana V, Puthanakit T, Sirisanthana T: Epidemiologic, clinical and laboratory features of scrub typhus in thirty thai children. Pediatr Infect Dis J. 2003, 22: 341-345.PubMedGoogle Scholar
- Thap LC, Supanaranond W, Treeprasertsuk S, Kitvatanachai S, Chinprasatsak S, Phonrat B: Septic shock secondary to scrub typhus: Characteristics and complications. Southeast Asian J Trop Med Public Health. 2002, 33: 780-786.PubMedGoogle Scholar
- Chanta C, Triratanapa K, Ratanasirichup P, Mahaprom W: Hepatic dysfunction in pediatric scrub typhus: Role of liver function test in diagnosis and marker of disease severity. J Med Assoc Thai. 2007, 90: 2366-2369.PubMedGoogle Scholar
- Kim DM, Kang DW, Kim JO, Chung JH, Kim HL, Park CY, Lim SC: Acute renal failure due to acute tubular necrosis caused by direct invasion of Oriential tsutsugamushi. J Clin Microbiol. 2008, 46: 1548-1550. 10.1128/JCM.01040-07.View ArticlePubMedGoogle Scholar
- Zisman DA, Kawut SM, Lederer DJ, Belperio JA, Lynch JP, Schwarz MI, Tayek JA, Reuben DB, Karlamangla AS: Serum albumin concentration and waiting list mortality in idiopathic interstitial pneumonia. Chest. 2009, 135: 929-935. 10.1378/chest.08-0754.View ArticlePubMedGoogle Scholar
- Boonpipattanapong T, Chewatanakornkul S: Preoperative carcinoembryonic antigen and albumin in predicting survival in patients with colon and rectal carcinomas. J Clin Gastroenterol. 2006, 40: 592-595. 10.1097/00004836-200608000-00006.View ArticlePubMedGoogle Scholar
- Franch-Arcas G: The meaning of hypoalbuminaemia in clinical practice. Clin Nutr. 2001, 20: 265-269. 10.1054/clnu.2001.0438.View ArticlePubMedGoogle Scholar
- Korea Center for Disease Control and Prevention: Disease web statistics system. Accessed 11 July 2010, [http://stat.cdc.go.kr/]
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/10/216/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.