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The difference in clinical characteristics between acute Q fever and scrub typhus in southern Taiwan
International Journal of Infectious Diseases (2009) 13, 387—393
http://intl.elsevierhealth.com/journals/ijid
The difference in clinical characteristics between acute Q fever and scrub typhus in southern Taiwan Chung-Hsu Lai a,b, Chun-Kai Huang a, Hui-Ching Weng c, Hsing-Chun Chung a, Shiou-Haur Liang a, Jiun-Nong Lin a,b, Chih-Wen Lin d, Chuan-Yuan Hsu d, Hsi-Hsun Lin a,* a
Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital/I-Shou University, 1 E-Da Road, Jiau-Shu Tsuen, Yan-Chau Shiang, Kaohsiung County, 824 Taiwan, Republic of China b Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung County, Taiwan, Republic of China c Department of Health Management, I-Shou University, Kaohsiung County, Taiwan, Republic of China d Section of Gastroenterology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung County, Taiwan, Republic of China Received 14 April 2008; received in revised form 17 July 2008; accepted 29 July 2008 Corresponding Editor: Craig Lee, Ottawa, Canada
KEYWORDS Acute Q fever; Coxiella burnetii; Scrub typhus; Orientia tsutsugamushi; Clinical characteristics; Taiwan
Summary Objective: To identify the differences in clinical characteristics between acute Q fever and scrub typhus in southern Taiwan. Methods: A prospective observational study was conducted in which serological tests for acute Q fever and scrub typhus were performed simultaneously regardless of which disease was suspected clinically. From April 2004 to December 2007, 80 and 40 cases of serologically confirmed acute Q fever and scrub typhus, respectively, were identified and included in the study for comparison. Results: By univariate analysis, being male ( p < 0.001) and having an alanine aminotransferase (ALT) >88 U/l ( p = 0.015) were more common in acute Q fever, whereas residence or travel in a mountainous region or offshore island of Taiwan ( p < 0.001), skin rash ( p < 0.001), eschar ( p < 0.001), lymphadenopathy ( p = 0.04), leukocytosis ( p = 0.002), and pulmonary involvement on chest X-ray ( p = 0.003) were more common in scrub typhus. In the multivariate analysis, being male (odds ratio (OR) 10.883, 95% confidence interval (CI) 2.079—56.441, p = 0.005) was an independent characteristic of acute Q fever, while residence or travel in a mountainous region or offshore island (OR 0.073, 95% CI 0.019—0.275, p < 0.001) and skin rash (OR 0.152, 95% CI 0.024— 0.945, p = 0.043) were independent characteristics of scrub typhus. The response to doxycycline treatment was not different. Conclusions: In southern Taiwan, sex, area of residence, travel history, and physical examination are important in the differentiation of acute Q fever from scrub typhus. # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +886 7 615 0011 ext. 5550; fax: +886 7 615 0960. E-mail address: [email protected] (H.-H. Lin). 1201-9712/$36.00 # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2008.07.020
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Introduction Q fever and scrub typhus are common zoonotic diseases in humans. Q fever, caused by Coxiella burnetii infection, is distributed worldwide. Its major clinical presentation is fever with varying degrees of pneumonia and hepatitis.1 Scrub typhus, caused by Orientia tsutsugamushi infection, is endemic to East Asia and the Western Pacific region. Its major clinical manifestation is abrupt fever with the characteristic skin lesion of eschar found at the inoculation site of the chigger bite.2 Other non-specific symptoms such as headache, chills, cough, myalgia, arthralgia, and skin rash are found in both diseases.1,2 However, the distinctive eschar of scrub typhus is not always found, with about 90% in reports from Japan3 and Korea,4 but only about 23—67% from Taiwan.5—8 Without this distinctive lesion, it is difficult to differentiate scrub typhus from acute Q fever in clinical practice. In febrile patients, in addition to the presence of eschar, a history of foreign travel in areas endemic for scrub typhus, such as Southeast Asia, is a useful clue for clinicians in Western countries in the diagnosis of scrub typhus.9,10 In Taiwan, however, acute Q fever8,11—13 and scrub typhus5,14 are both endemic diseases and the rate of presence of scrub typhus eschar is relatively lower than in other countries.5—8 Thus, clinically differentiating acute Q fever from scrub typhus in Taiwan is difficult. This study was conducted to further identify the differences between acute Q fever and scrub typhus.
Materials and methods Study institution E-Da Hospital is a regional hospital with 1100 beds that opened in Kaohsiung County in southern Taiwan in April 2004. Since then, sera from patients suspected of having acute Q fever or scrub typhus have been referred to the Center for Disease Control, Taipei, Taiwan (Taiwan CDC) for simultaneous testing of both diseases regardless of which was suspected clinically.
Diagnosis of acute Q fever and scrub typhus Serologic assessments using indirect immunofluorescence antibody assay (IFA) were performed in the contract laboratory of Taiwan CDC to confirm the diagnosis of acute Q fever and scrub typhus as previously described.8,12,14 Acute Q fever was diagnosed by either an anti-phase II antigen IgG titer of 1:320 and anti-phase II antigen IgM titer of 1:80 in a single serum, or a four-fold or greater increase of anti-phase II antigen IgG titer in paired sera. Scrub typhus was diagnosed by either an antibody titer of IgM 1:80 or a four-fold or greater rise of total antibody (IgG + IgA + IgM) titer in paired sera for Karp, Kato, and Gilliam strains of O. tsutsugamushi.
Collection of clinical data The charts of serologically confirmed cases of acute Q fever and scrub typhus were reviewed and the demographic data, clinical manifestations, results of laboratory and image
C.-H. Lai et al. examinations, administration of antimicrobial agents, and highest daily body temperature (ear temperature) were recorded for analysis. The results of chest X-ray (CXR) and abdominal computed tomography (CT) were recorded according to the formal reports made by radiologists. The results of abdominal ultrasonography were recorded according to the formal reports made by gastroenterologists. The date of defervescence was defined as the first day of the highest body temperature lower than 37.5 8C for more than three consecutive days.
Detection of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection Because elevated liver enzymes are found in the majority of cases of acute Q fever and scrub typhus and HBV and HCV infections are endemic in Taiwan, confirming tests for HBV and HCV infection were performed. HBV infection was defined as the presence of hepatitis B surface antigen (HBsAg) in serum detected by IMx1 HBsAg (V2) assay (Abbott IMx1 System), while HCV infection was defined as the presence of antibody to hepatitis C virus (anti-HCV) in serum detected by IMx1 HCV version 3.0 (Abbott IMx1 System).
Statistical analysis Categorical variables were analyzed using the Chi-square or Fisher’s exact test where appropriate. Continuous variables were analyzed using the Student’s t-test, while multivariate analysis was performed using logistic regression. All p values were two-tailed and a p value <0.05 was considered statistically significant. All statistical analyses were done using a commercially available software package (SPSS, version 12.0, SPSS Inc., Chicago, IL, USA).
Results From April 2004 to December 2007, 80 cases of acute Q fever and 40 cases of scrub typhus were identified in E-Da hospital. Figure 1 shows the distribution of the cases by area of residence. The percentage of patients who lived in a mountainous region was significantly higher in scrub typhus than in acute Q fever (40% vs. 6.3%, p < 0.001). The demographic data and clinical symptoms and signs of the patients with acute Q fever and scrub typhus are listed in Table 1. Male gender was more common in cases of acute Q fever (92.5% vs. 65%, p < 0.001), while residence or travel in a mountainous region or offshore island of Taiwan (67.5% vs. 13.8%, p < 0.001), skin rash (30% vs. 6.3%, p < 0.001), eschar (22.5% vs. 0%, p < 0.001), and lymphadenopathy (12.5% vs. 2.5%, p = 0.04) were more common in scrub typhus. Table 2 shows the laboratory examinations and image findings. Elevated alanine aminotransferase (ALT) >88 U/l was more common in acute Q fever (67.1% vs. 43.6%, p = 0.015), whereas leukocytosis (17.5% vs. 1.3%, p = 0.002) and pulmonary involvement on CXR were more common in scrub typhus (47.5% vs. 21.1%, p = 0.003). There was no difference between acute Q fever and scrub typhus in terms of response to doxycycline treatment (Table 3). Among the significant characteristics identified by univariate analysis, male gender (odds ratio (OR) 10.883, 95%
Acute Q fever and scrub typhus in Taiwan
389
Figure 1 Distribution of acute Q fever and scrub typhus cases in southern Taiwan. Cases of acute Q fever (left) are mainly distributed in the plains regions (white-colored areas) with only five of 80 cases (6.3%) from the mountainous regions (gray-colored areas). In contrast, 16 of 40 cases (40%) of scrub typhus (right) are distributed in the mountainous regions. By univariate analysis, residence in a mountainous region was significantly different between Q fever and scrub typhus ( p < 0.001).
confidence interval (CI) 2.079—56.441, p = 0.005) was an independent characteristic of Q fever. Residence or travel in a mountainous region or offshore island (OR 0.073, 95% CI 0.019—0.275, p < 0.001) and skin rash (OR 0.152, 95% CI 0.024—0.945, p = 0.043) were the independent characteristics of scrub typhus by multivariate analysis (Table 4).
Discussion Although the major clinical manifestations of Q fever1 and scrub typhus15 have been described and reviewed, to the best of our knowledge, this is the first study conducted to identify the different characteristics between acute Q fever and scrub typhus. These findings are important for clinicians to preemptively differentiate the two diseases and to order appropriate confirmatory tests, particularly in regions where Q fever and scrub typhus are endemic and diagnostic tools are not sufficient to examine both diseases. In addition, this study re-emphasizes the importance of history-taking and physical examinations in differentiating the two diseases clinically. Nonetheless, further epidemiologic investigations for these diseases are required. Males account for about 70—90% of acute Q fever cases13,16—19 and 50—63% of scrub typhus cases.3,5,20 In Taiwan, as in many other countries, men are the major workers and participants in field activities, which increases their risk of acquiring Q fever and scrub typhus. However, the percentage of males was found to be significantly higher in acute Q fever than in scrub typhus by both univariate analysis (92.5% vs. 65%, p < 0.001) and multivariate analysis (OR 10.883, 95% CI 2.079—56.441, p = 0.005) in our study. Tissot-Dupont et al.
found a male to female ratio of 2.3:1 for Q fever, but an equal ratio by seroprevalence.19 This indicates that males and females are equally at risk for Q fever, but that the symptoms may be more severe in men so that more of them consult a physician and are diagnosed. In addition, the protective effect of female hormones in C. burnetii infection found in animal studies provides a partial explanation for the sexual discrepancy in Q fever.21 Accordingly, male gender is a characteristic for acute Q fever compared with scrub typhus. Because Q fever is a worldwide zoonosis with natural animal reservoirs, including cattle, sheep, goats, and cats, a history of animal contact or occupational exposure in febrile patients should lead clinicians to suspect Q fever.22 However, only 30% of cases in our study had a history of animal contact, and this rate was not significantly different from cases of scrub typhus (25%, p = 0.567). In fact, there are dairies located in the plains area, which includes northern Kaohsiung City and western Kaohsiung County, and this area includes many of the cases of acute Q fever (Figure 1). In contrast to a history of animal contact, the rate of residence or travel in a mountainous region or offshore island was significantly higher in scrub typhus than in acute Q fever (67.5% vs. 13.8%, p < 0.001) (Figure 1; Tables 1 and 4). In Taiwan, scrub typhus is mostly distributed across eastern Taiwan (Taitung and Hualien counties, a mountainous region) and the offshore islands (Penghu and Kinmen counties).5,14 Similarly, nearly half of the scrub typhus cases in our study were resident over eastern Kaohsiung County, a mountainous region close to Taitung and Hualien counties (Figure 1). So in southern Taiwan a history of exposure to mountainous regions and offshore islands is more useful than a history of animal contact in differentiating scrub typhus from acute Q fever.
390 Table 1
C.-H. Lai et al. Differences in characteristics between cases of acute Q fever and scrub typhus.
Demographic characteristics Mean days from disease onset to hospital visit b Male gender Age (years) b Alcoholism Hepatitis B or C virus infection c Hepatitis B virus Hepatitis C virus Liver cirrhosis d Hypertension Diabetes mellitus Congestive heart failure Chronic obstructive pulmonary disease Malignancy Animal contact Residence or travel in mountainous regions or offshore islands Residence in mountainous regions History of travel in mountainous regions or offshore islands
Acute Q fever (N = 80) n (%)
Scrub typhus (N = 40) n (%)
pa
6.1 3.3 74 (92.5) 44.3 12.1 5 (6.3) 23/78 (29.5) 16/78 (20.5) 7/78 (9.0) 1/75 (1.3) 9 (11.3) 5 (6.3) 1 (1.3) 1 (1.3) 1 (1.3) 24 (30) 11 (13.8)
5.7 3.8 26 (65) 42.9 15.3 2 (5) 7/39 (17.9) 5/39 (12.8) 2/39 (5.1) 2/35 (5.7) 5 (12.5) 2 (5) 0 (0) 1 (2.5) 0 (0) 10 (25) 27 (67.5)
0.605 <0.001 0.581 0.999 0.178 0.444 0.462 0.237 0.999 0.999 0.999 0.999 0.999 0.567 <0.001
16 (40) 20 (50)
<0.001 <0.001
5 (6.3) 7 (8.8)
Symptoms Fever Chills Headache Sore throat Cough Jaundice Diarrhea Abdominal pain/discomfort Nausea/vomiting Arthralgia Myalgia General weakness
79 66 63 8 26 7 7 10 5 2 24 7
(98.8) (82.5) (78.8) (10) (32.5) (8.8) (8.8) (12.5) (6.3) (2.5) (30) (8.8)
40 32 32 2 16 5 4 6 4 4 13 5
(100) (80) (80) (5) (40) (12.5) (10) (15) (10) (10) (32.5) (12.5)
0.999 0.804 0.874 0.493 0.417 0.531 0.999 0.704 0.479 0.095 0.780 0.531
Signs Skin rash Eschar Icteric sclera Lymphadenopathy Hepatomegaly Splenomegaly Relative bradycardia e
5 0 7 2 2 0 33
(6.3) (0) (8.8) (2.5) (2.5) (0) (41.3)
12 9 5 5 0 1 21
(30) (22.5) (12.5) (12.5) (0) (2.5) (52.5)
<0.001 <0.001 0.531 0.040 0.552 0.333 0.243
a
Categorical variables were analyzed using the Chi-square or Fisher’s exact test as appropriate. Continuous variables were analyzed using the Student’s t-test. b Presented as mean value standard deviation. c Confirmed by examinations of HBsAg and anti-HCV. d Confirmed by abdominal ultrasonography or computed tomography. e Body temperature 38.9 8C and heart rate <110/min without medication with calcium blockers, beta-blockers, or anti-arrhythmic agents.
Mountainous regions and offshore islands are environments that harbor chiggers, the vector of scrub typhus. Although only 30% of scrub typhus cases had a skin rash, this was significantly higher than in acute Q fever (6.3%) by both univariate and multivariate analysis (Tables 1 and 4). This may be due to the different pathogenesis of the two diseases. The endothelial cells are the target cells of O.
tsutsugamushi, which causes vasculitis in involved organs; skin rash can be the presentation of vasculitis in the cutaneous tissue.23 In contrast, C. burnetii targets monocytes/ macrophages, not endothelial cells, and induces the formation of doughnut-like granulomatous lesions in the involved organs.1 In a recent review of Q fever, skin rash was found to occur in 5—20% of patients.22
Acute Q fever and scrub typhus in Taiwan Table 2
391
Differences in laboratory results and imaging findings between cases of acute Q fever and scrub typhus.
Blood cell examination Days from disease onset to examination b Leukocytosis Monocytosis Anemia Platelet count <150 109/l Platelet count <100 109/l Biochemical examination Days from disease onset to examination b Creatinine >2.0 mg/dl ALT >88 U/l AST >76 U/l Total bilirubin >1.5 mg/dl Chest X-ray (CXR) Days from disease onset to CXR b Pulmonary involvement on CXR Unilateral infiltration Bilateral infiltration Consolidation Abdominal ultrasonography or computerized tomography (CT) Days from disease onset to abdominal ultrasonography or CTb Cholecystitic change Gallbladder wall thickening Gallbladder distention Hepatomegaly or splenomegaly Hepatomegaly Splenomegaly Fatty liver Cirrhotic change
Acute Q fever (N = 80) n (%)
Scrub typhus (N = 40) n (%)
5.6 3.3 1 (1.3) 6 (7.5) 0 (0) 59 (73.8) 17 (21.3)
5.8 3.7 7 (17.5) 3 (7.5) 2 (5) 28 (70) 7 (17.5)
6.0 3.3 1/73 (1.4) 53/79 (67.1) 61 (76.3) 14/39 (35.9) 76 (95) 6.0 3.4 16/76 (21.1) 8/76 (10.5) 8/76 (10.5) 0 (0) 75 (93.8)
5.9 3.6 2/39 (5.1) 17/39 (43.6) 24 (60) 6/21 (28.6) 40 (100) 5.9 3.7 19 (47.5) 6 (15) 13 (32.5) 0 (0) 35 (87.5)
7.4 4.1
7.5 4.6
20/75 18/75 3/75 30/75 19/75 20/75 38/75 1/75
(26.7) (24) (4) (40) (25.3) (26.7) (50.7) (1.3)
6/35 4/35 2/35 12/35 6/35 9/35 20/35 2/35
(17.1) (11.4) (5.7) (34.3) (17.1) (25.7) (57.1) (5.7)
pa
0.707 0.002 0.999 0.109 0.665 0.628 0.970 0.277 0.015 0.065 0.566 0.300 0.858 0.003 0.553 0.003 NC 0.298 0.897 0.273 0.125 0.652 0.566 0.340 0.916 0.526 0.237
ALT, alanine aminotransferase; AST, aspartate aminotransferase; NC, not calculated. Leukocytosis = white blood cell count >10 109/l; monocytosis = monocyte count >0.8 109/l; anemia = hemoglobin <10 g/dl. a Categorical variables were analyzed using the Chi-square or Fisher’s exact test as appropriate. Continuous variables were analyzed using the Student’s t-test. b Presented as mean value standard deviation.
Table 3
Response to doxycycline treatment in cases of acute Q fever and scrub typhusa.
Days from disease onset to doxycycline treatment c Days from doxycycline treatment to defervescence c Duration from doxycycline treatment to defervescence >3 days >5 days >7 days
Acute Q fever (61 cases) n (%)
Scrub typhus (38 cases) n (%)
pb
6.5 3.3
6.8 3.9
0.617
2.2 2.1
2.7 3.5
0.403
9 (14.8) 6 (9.8) 4 (6.6)
7 (18.4) 3 (7.9) 2 (5.3)
0.630 0.999 0.999
a Patients who were in spontaneous remission, whose daily body temperature was not available, or who were treated with fluoroquinolones were excluded. b Categorical variables were analyzed using the Chi-square or Fisher’s exact test as appropriate. Continuous variables were analyzed using the Student’s t-test. c Presented as mean value standard deviation.
392 Table 4
C.-H. Lai et al. Multivariate analysis of characteristics of cases of acute Q fever vs. scrub typhus.
Characteristics
OR (95% CI)
p
Male gender Residence or travel in mountainous regions or offshore islands Skin rash
10.833 (2.079—56.441) 0.073 (0.019—0.275) 0.152 (0.024—0.945)
0.005 <0.001 0.043
OR, odds ratio; CI, confidence interval.
Eschar, the distinctive characteristic of scrub typhus caused by the chigger bite, is found in about 90% of cases in Japan3 and Korea.4 However, it is found in only about 23— 67% of cases in Taiwan,5—8 and was found in 22.5% of our cases. Despite this low percentage, it was significantly more common in scrub typhus compared to acute Q fever by univariate analysis (22.5% vs. 0%, p < 0.001). As expected, eschars were not found in acute Q fever because its major route of transmission is by inhalation, not direct inoculation by an arthropod bite. The low percentage of eschar found in scrub typhus in this study may have been due to an incomplete physical examination, as clinicians who are not familiar with scrub typhus may fail to search for eschars located in the genital or axillary areas. In addition, in this study, serology for Q fever and scrub typhus were both performed regardless of which was suspected. This may have increased the detection rate of scrub typhus without eschar. In other studies it may have been more likely that serology for scrub typhus was performed when an eschar was found to be present. Although the presence of an eschar was not statistically significant in scrub typhus by multivariate analysis, this does not preclude it as a distinctive characteristic of scrub typhus. It is noteworthy that pulmonary involvement on CXR was significantly more common in scrub typhus than in Q fever by univariate analysis (47.5% vs. 21.1%, p = 0.003), although the difference was not significant by multivariate analysis. Pneumonia is the major presentation of acute Q fever in many areas, but hepatitis rather than pneumonia is the predominant presentation of acute Q fever in southern Taiwan.8,24,25 It is not understood why hepatitis rather than pneumonia is the major presentation of acute Q fever in Taiwan when airborne transmission is the main route of infection.13,25 Pneumonitis is one of the presentations of scrub typhus,26,27 while acute respiratory distress syndrome (ARDS) is its most common serious complication in Taiwan.8,28 Accordingly, in patients suspected of acute Q fever or scrub typhus with pulmonary involvement, the latter rather than the former is favored in southern Taiwan. There are limitations in this study. First, this was a hospital-based study and the potential bias of including more severe cases may exist. Second, the clinical findings were recorded retrospectively by chart review; further study with standard collection tools on patient admission is needed. Third, only 80 cases of acute Q fever and 40 cases of scrub typhus were studied, which may limit the interpretative power of the results. Finally, the application of our results to other regions may be limited because of the existence of geographic differences in clinical manifestations of acute Q fever.1,22 In summary, by comparison of the clinical manifestations of the two diseases, we demonstrate that male gender is an independent characteristic of acute Q fever, while residence
or travel in mountainous regions or offshore islands and skin rash are independent characteristics of scrub typhus. This study re-emphasizes the importance of history-taking and physical examination in differentiating acute Q fever and scrub typhus in clinical practice. Further epidemiologic investigation is needed, particularly in regions endemic for both diseases.
Acknowledgments This study was supported in part by a research grant from EDa Hospital (EDAH-D-97(P)007A). Conflict of interest: No conflict of interest to declare.
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The difference in clinical characteristics between acute Q fever and scrub typhus in southern Taiwan Chung-Hsu Lai a,b, Chun-Kai Huang a, Hui-Ching Weng c, Hsing-Chun Chung a, Shiou-Haur Liang a, Jiun-Nong Lin a,b, Chih-Wen Lin d, Chuan-Yuan Hsu d, Hsi-Hsun Lin a,* a
Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital/I-Shou University, 1 E-Da Road, Jiau-Shu Tsuen, Yan-Chau Shiang, Kaohsiung County, 824 Taiwan, Republic of China b Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung County, Taiwan, Republic of China c Department of Health Management, I-Shou University, Kaohsiung County, Taiwan, Republic of China d Section of Gastroenterology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung County, Taiwan, Republic of China Received 14 April 2008; received in revised form 17 July 2008; accepted 29 July 2008 Corresponding Editor: Craig Lee, Ottawa, Canada
KEYWORDS Acute Q fever; Coxiella burnetii; Scrub typhus; Orientia tsutsugamushi; Clinical characteristics; Taiwan
Summary Objective: To identify the differences in clinical characteristics between acute Q fever and scrub typhus in southern Taiwan. Methods: A prospective observational study was conducted in which serological tests for acute Q fever and scrub typhus were performed simultaneously regardless of which disease was suspected clinically. From April 2004 to December 2007, 80 and 40 cases of serologically confirmed acute Q fever and scrub typhus, respectively, were identified and included in the study for comparison. Results: By univariate analysis, being male ( p < 0.001) and having an alanine aminotransferase (ALT) >88 U/l ( p = 0.015) were more common in acute Q fever, whereas residence or travel in a mountainous region or offshore island of Taiwan ( p < 0.001), skin rash ( p < 0.001), eschar ( p < 0.001), lymphadenopathy ( p = 0.04), leukocytosis ( p = 0.002), and pulmonary involvement on chest X-ray ( p = 0.003) were more common in scrub typhus. In the multivariate analysis, being male (odds ratio (OR) 10.883, 95% confidence interval (CI) 2.079—56.441, p = 0.005) was an independent characteristic of acute Q fever, while residence or travel in a mountainous region or offshore island (OR 0.073, 95% CI 0.019—0.275, p < 0.001) and skin rash (OR 0.152, 95% CI 0.024— 0.945, p = 0.043) were independent characteristics of scrub typhus. The response to doxycycline treatment was not different. Conclusions: In southern Taiwan, sex, area of residence, travel history, and physical examination are important in the differentiation of acute Q fever from scrub typhus. # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +886 7 615 0011 ext. 5550; fax: +886 7 615 0960. E-mail address: [email protected] (H.-H. Lin). 1201-9712/$36.00 # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2008.07.020
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Introduction Q fever and scrub typhus are common zoonotic diseases in humans. Q fever, caused by Coxiella burnetii infection, is distributed worldwide. Its major clinical presentation is fever with varying degrees of pneumonia and hepatitis.1 Scrub typhus, caused by Orientia tsutsugamushi infection, is endemic to East Asia and the Western Pacific region. Its major clinical manifestation is abrupt fever with the characteristic skin lesion of eschar found at the inoculation site of the chigger bite.2 Other non-specific symptoms such as headache, chills, cough, myalgia, arthralgia, and skin rash are found in both diseases.1,2 However, the distinctive eschar of scrub typhus is not always found, with about 90% in reports from Japan3 and Korea,4 but only about 23—67% from Taiwan.5—8 Without this distinctive lesion, it is difficult to differentiate scrub typhus from acute Q fever in clinical practice. In febrile patients, in addition to the presence of eschar, a history of foreign travel in areas endemic for scrub typhus, such as Southeast Asia, is a useful clue for clinicians in Western countries in the diagnosis of scrub typhus.9,10 In Taiwan, however, acute Q fever8,11—13 and scrub typhus5,14 are both endemic diseases and the rate of presence of scrub typhus eschar is relatively lower than in other countries.5—8 Thus, clinically differentiating acute Q fever from scrub typhus in Taiwan is difficult. This study was conducted to further identify the differences between acute Q fever and scrub typhus.
Materials and methods Study institution E-Da Hospital is a regional hospital with 1100 beds that opened in Kaohsiung County in southern Taiwan in April 2004. Since then, sera from patients suspected of having acute Q fever or scrub typhus have been referred to the Center for Disease Control, Taipei, Taiwan (Taiwan CDC) for simultaneous testing of both diseases regardless of which was suspected clinically.
Diagnosis of acute Q fever and scrub typhus Serologic assessments using indirect immunofluorescence antibody assay (IFA) were performed in the contract laboratory of Taiwan CDC to confirm the diagnosis of acute Q fever and scrub typhus as previously described.8,12,14 Acute Q fever was diagnosed by either an anti-phase II antigen IgG titer of 1:320 and anti-phase II antigen IgM titer of 1:80 in a single serum, or a four-fold or greater increase of anti-phase II antigen IgG titer in paired sera. Scrub typhus was diagnosed by either an antibody titer of IgM 1:80 or a four-fold or greater rise of total antibody (IgG + IgA + IgM) titer in paired sera for Karp, Kato, and Gilliam strains of O. tsutsugamushi.
Collection of clinical data The charts of serologically confirmed cases of acute Q fever and scrub typhus were reviewed and the demographic data, clinical manifestations, results of laboratory and image
C.-H. Lai et al. examinations, administration of antimicrobial agents, and highest daily body temperature (ear temperature) were recorded for analysis. The results of chest X-ray (CXR) and abdominal computed tomography (CT) were recorded according to the formal reports made by radiologists. The results of abdominal ultrasonography were recorded according to the formal reports made by gastroenterologists. The date of defervescence was defined as the first day of the highest body temperature lower than 37.5 8C for more than three consecutive days.
Detection of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection Because elevated liver enzymes are found in the majority of cases of acute Q fever and scrub typhus and HBV and HCV infections are endemic in Taiwan, confirming tests for HBV and HCV infection were performed. HBV infection was defined as the presence of hepatitis B surface antigen (HBsAg) in serum detected by IMx1 HBsAg (V2) assay (Abbott IMx1 System), while HCV infection was defined as the presence of antibody to hepatitis C virus (anti-HCV) in serum detected by IMx1 HCV version 3.0 (Abbott IMx1 System).
Statistical analysis Categorical variables were analyzed using the Chi-square or Fisher’s exact test where appropriate. Continuous variables were analyzed using the Student’s t-test, while multivariate analysis was performed using logistic regression. All p values were two-tailed and a p value <0.05 was considered statistically significant. All statistical analyses were done using a commercially available software package (SPSS, version 12.0, SPSS Inc., Chicago, IL, USA).
Results From April 2004 to December 2007, 80 cases of acute Q fever and 40 cases of scrub typhus were identified in E-Da hospital. Figure 1 shows the distribution of the cases by area of residence. The percentage of patients who lived in a mountainous region was significantly higher in scrub typhus than in acute Q fever (40% vs. 6.3%, p < 0.001). The demographic data and clinical symptoms and signs of the patients with acute Q fever and scrub typhus are listed in Table 1. Male gender was more common in cases of acute Q fever (92.5% vs. 65%, p < 0.001), while residence or travel in a mountainous region or offshore island of Taiwan (67.5% vs. 13.8%, p < 0.001), skin rash (30% vs. 6.3%, p < 0.001), eschar (22.5% vs. 0%, p < 0.001), and lymphadenopathy (12.5% vs. 2.5%, p = 0.04) were more common in scrub typhus. Table 2 shows the laboratory examinations and image findings. Elevated alanine aminotransferase (ALT) >88 U/l was more common in acute Q fever (67.1% vs. 43.6%, p = 0.015), whereas leukocytosis (17.5% vs. 1.3%, p = 0.002) and pulmonary involvement on CXR were more common in scrub typhus (47.5% vs. 21.1%, p = 0.003). There was no difference between acute Q fever and scrub typhus in terms of response to doxycycline treatment (Table 3). Among the significant characteristics identified by univariate analysis, male gender (odds ratio (OR) 10.883, 95%
Acute Q fever and scrub typhus in Taiwan
389
Figure 1 Distribution of acute Q fever and scrub typhus cases in southern Taiwan. Cases of acute Q fever (left) are mainly distributed in the plains regions (white-colored areas) with only five of 80 cases (6.3%) from the mountainous regions (gray-colored areas). In contrast, 16 of 40 cases (40%) of scrub typhus (right) are distributed in the mountainous regions. By univariate analysis, residence in a mountainous region was significantly different between Q fever and scrub typhus ( p < 0.001).
confidence interval (CI) 2.079—56.441, p = 0.005) was an independent characteristic of Q fever. Residence or travel in a mountainous region or offshore island (OR 0.073, 95% CI 0.019—0.275, p < 0.001) and skin rash (OR 0.152, 95% CI 0.024—0.945, p = 0.043) were the independent characteristics of scrub typhus by multivariate analysis (Table 4).
Discussion Although the major clinical manifestations of Q fever1 and scrub typhus15 have been described and reviewed, to the best of our knowledge, this is the first study conducted to identify the different characteristics between acute Q fever and scrub typhus. These findings are important for clinicians to preemptively differentiate the two diseases and to order appropriate confirmatory tests, particularly in regions where Q fever and scrub typhus are endemic and diagnostic tools are not sufficient to examine both diseases. In addition, this study re-emphasizes the importance of history-taking and physical examinations in differentiating the two diseases clinically. Nonetheless, further epidemiologic investigations for these diseases are required. Males account for about 70—90% of acute Q fever cases13,16—19 and 50—63% of scrub typhus cases.3,5,20 In Taiwan, as in many other countries, men are the major workers and participants in field activities, which increases their risk of acquiring Q fever and scrub typhus. However, the percentage of males was found to be significantly higher in acute Q fever than in scrub typhus by both univariate analysis (92.5% vs. 65%, p < 0.001) and multivariate analysis (OR 10.883, 95% CI 2.079—56.441, p = 0.005) in our study. Tissot-Dupont et al.
found a male to female ratio of 2.3:1 for Q fever, but an equal ratio by seroprevalence.19 This indicates that males and females are equally at risk for Q fever, but that the symptoms may be more severe in men so that more of them consult a physician and are diagnosed. In addition, the protective effect of female hormones in C. burnetii infection found in animal studies provides a partial explanation for the sexual discrepancy in Q fever.21 Accordingly, male gender is a characteristic for acute Q fever compared with scrub typhus. Because Q fever is a worldwide zoonosis with natural animal reservoirs, including cattle, sheep, goats, and cats, a history of animal contact or occupational exposure in febrile patients should lead clinicians to suspect Q fever.22 However, only 30% of cases in our study had a history of animal contact, and this rate was not significantly different from cases of scrub typhus (25%, p = 0.567). In fact, there are dairies located in the plains area, which includes northern Kaohsiung City and western Kaohsiung County, and this area includes many of the cases of acute Q fever (Figure 1). In contrast to a history of animal contact, the rate of residence or travel in a mountainous region or offshore island was significantly higher in scrub typhus than in acute Q fever (67.5% vs. 13.8%, p < 0.001) (Figure 1; Tables 1 and 4). In Taiwan, scrub typhus is mostly distributed across eastern Taiwan (Taitung and Hualien counties, a mountainous region) and the offshore islands (Penghu and Kinmen counties).5,14 Similarly, nearly half of the scrub typhus cases in our study were resident over eastern Kaohsiung County, a mountainous region close to Taitung and Hualien counties (Figure 1). So in southern Taiwan a history of exposure to mountainous regions and offshore islands is more useful than a history of animal contact in differentiating scrub typhus from acute Q fever.
390 Table 1
C.-H. Lai et al. Differences in characteristics between cases of acute Q fever and scrub typhus.
Demographic characteristics Mean days from disease onset to hospital visit b Male gender Age (years) b Alcoholism Hepatitis B or C virus infection c Hepatitis B virus Hepatitis C virus Liver cirrhosis d Hypertension Diabetes mellitus Congestive heart failure Chronic obstructive pulmonary disease Malignancy Animal contact Residence or travel in mountainous regions or offshore islands Residence in mountainous regions History of travel in mountainous regions or offshore islands
Acute Q fever (N = 80) n (%)
Scrub typhus (N = 40) n (%)
pa
6.1 3.3 74 (92.5) 44.3 12.1 5 (6.3) 23/78 (29.5) 16/78 (20.5) 7/78 (9.0) 1/75 (1.3) 9 (11.3) 5 (6.3) 1 (1.3) 1 (1.3) 1 (1.3) 24 (30) 11 (13.8)
5.7 3.8 26 (65) 42.9 15.3 2 (5) 7/39 (17.9) 5/39 (12.8) 2/39 (5.1) 2/35 (5.7) 5 (12.5) 2 (5) 0 (0) 1 (2.5) 0 (0) 10 (25) 27 (67.5)
0.605 <0.001 0.581 0.999 0.178 0.444 0.462 0.237 0.999 0.999 0.999 0.999 0.999 0.567 <0.001
16 (40) 20 (50)
<0.001 <0.001
5 (6.3) 7 (8.8)
Symptoms Fever Chills Headache Sore throat Cough Jaundice Diarrhea Abdominal pain/discomfort Nausea/vomiting Arthralgia Myalgia General weakness
79 66 63 8 26 7 7 10 5 2 24 7
(98.8) (82.5) (78.8) (10) (32.5) (8.8) (8.8) (12.5) (6.3) (2.5) (30) (8.8)
40 32 32 2 16 5 4 6 4 4 13 5
(100) (80) (80) (5) (40) (12.5) (10) (15) (10) (10) (32.5) (12.5)
0.999 0.804 0.874 0.493 0.417 0.531 0.999 0.704 0.479 0.095 0.780 0.531
Signs Skin rash Eschar Icteric sclera Lymphadenopathy Hepatomegaly Splenomegaly Relative bradycardia e
5 0 7 2 2 0 33
(6.3) (0) (8.8) (2.5) (2.5) (0) (41.3)
12 9 5 5 0 1 21
(30) (22.5) (12.5) (12.5) (0) (2.5) (52.5)
<0.001 <0.001 0.531 0.040 0.552 0.333 0.243
a
Categorical variables were analyzed using the Chi-square or Fisher’s exact test as appropriate. Continuous variables were analyzed using the Student’s t-test. b Presented as mean value standard deviation. c Confirmed by examinations of HBsAg and anti-HCV. d Confirmed by abdominal ultrasonography or computed tomography. e Body temperature 38.9 8C and heart rate <110/min without medication with calcium blockers, beta-blockers, or anti-arrhythmic agents.
Mountainous regions and offshore islands are environments that harbor chiggers, the vector of scrub typhus. Although only 30% of scrub typhus cases had a skin rash, this was significantly higher than in acute Q fever (6.3%) by both univariate and multivariate analysis (Tables 1 and 4). This may be due to the different pathogenesis of the two diseases. The endothelial cells are the target cells of O.
tsutsugamushi, which causes vasculitis in involved organs; skin rash can be the presentation of vasculitis in the cutaneous tissue.23 In contrast, C. burnetii targets monocytes/ macrophages, not endothelial cells, and induces the formation of doughnut-like granulomatous lesions in the involved organs.1 In a recent review of Q fever, skin rash was found to occur in 5—20% of patients.22
Acute Q fever and scrub typhus in Taiwan Table 2
391
Differences in laboratory results and imaging findings between cases of acute Q fever and scrub typhus.
Blood cell examination Days from disease onset to examination b Leukocytosis Monocytosis Anemia Platelet count <150 109/l Platelet count <100 109/l Biochemical examination Days from disease onset to examination b Creatinine >2.0 mg/dl ALT >88 U/l AST >76 U/l Total bilirubin >1.5 mg/dl Chest X-ray (CXR) Days from disease onset to CXR b Pulmonary involvement on CXR Unilateral infiltration Bilateral infiltration Consolidation Abdominal ultrasonography or computerized tomography (CT) Days from disease onset to abdominal ultrasonography or CTb Cholecystitic change Gallbladder wall thickening Gallbladder distention Hepatomegaly or splenomegaly Hepatomegaly Splenomegaly Fatty liver Cirrhotic change
Acute Q fever (N = 80) n (%)
Scrub typhus (N = 40) n (%)
5.6 3.3 1 (1.3) 6 (7.5) 0 (0) 59 (73.8) 17 (21.3)
5.8 3.7 7 (17.5) 3 (7.5) 2 (5) 28 (70) 7 (17.5)
6.0 3.3 1/73 (1.4) 53/79 (67.1) 61 (76.3) 14/39 (35.9) 76 (95) 6.0 3.4 16/76 (21.1) 8/76 (10.5) 8/76 (10.5) 0 (0) 75 (93.8)
5.9 3.6 2/39 (5.1) 17/39 (43.6) 24 (60) 6/21 (28.6) 40 (100) 5.9 3.7 19 (47.5) 6 (15) 13 (32.5) 0 (0) 35 (87.5)
7.4 4.1
7.5 4.6
20/75 18/75 3/75 30/75 19/75 20/75 38/75 1/75
(26.7) (24) (4) (40) (25.3) (26.7) (50.7) (1.3)
6/35 4/35 2/35 12/35 6/35 9/35 20/35 2/35
(17.1) (11.4) (5.7) (34.3) (17.1) (25.7) (57.1) (5.7)
pa
0.707 0.002 0.999 0.109 0.665 0.628 0.970 0.277 0.015 0.065 0.566 0.300 0.858 0.003 0.553 0.003 NC 0.298 0.897 0.273 0.125 0.652 0.566 0.340 0.916 0.526 0.237
ALT, alanine aminotransferase; AST, aspartate aminotransferase; NC, not calculated. Leukocytosis = white blood cell count >10 109/l; monocytosis = monocyte count >0.8 109/l; anemia = hemoglobin <10 g/dl. a Categorical variables were analyzed using the Chi-square or Fisher’s exact test as appropriate. Continuous variables were analyzed using the Student’s t-test. b Presented as mean value standard deviation.
Table 3
Response to doxycycline treatment in cases of acute Q fever and scrub typhusa.
Days from disease onset to doxycycline treatment c Days from doxycycline treatment to defervescence c Duration from doxycycline treatment to defervescence >3 days >5 days >7 days
Acute Q fever (61 cases) n (%)
Scrub typhus (38 cases) n (%)
pb
6.5 3.3
6.8 3.9
0.617
2.2 2.1
2.7 3.5
0.403
9 (14.8) 6 (9.8) 4 (6.6)
7 (18.4) 3 (7.9) 2 (5.3)
0.630 0.999 0.999
a Patients who were in spontaneous remission, whose daily body temperature was not available, or who were treated with fluoroquinolones were excluded. b Categorical variables were analyzed using the Chi-square or Fisher’s exact test as appropriate. Continuous variables were analyzed using the Student’s t-test. c Presented as mean value standard deviation.
392 Table 4
C.-H. Lai et al. Multivariate analysis of characteristics of cases of acute Q fever vs. scrub typhus.
Characteristics
OR (95% CI)
p
Male gender Residence or travel in mountainous regions or offshore islands Skin rash
10.833 (2.079—56.441) 0.073 (0.019—0.275) 0.152 (0.024—0.945)
0.005 <0.001 0.043
OR, odds ratio; CI, confidence interval.
Eschar, the distinctive characteristic of scrub typhus caused by the chigger bite, is found in about 90% of cases in Japan3 and Korea.4 However, it is found in only about 23— 67% of cases in Taiwan,5—8 and was found in 22.5% of our cases. Despite this low percentage, it was significantly more common in scrub typhus compared to acute Q fever by univariate analysis (22.5% vs. 0%, p < 0.001). As expected, eschars were not found in acute Q fever because its major route of transmission is by inhalation, not direct inoculation by an arthropod bite. The low percentage of eschar found in scrub typhus in this study may have been due to an incomplete physical examination, as clinicians who are not familiar with scrub typhus may fail to search for eschars located in the genital or axillary areas. In addition, in this study, serology for Q fever and scrub typhus were both performed regardless of which was suspected. This may have increased the detection rate of scrub typhus without eschar. In other studies it may have been more likely that serology for scrub typhus was performed when an eschar was found to be present. Although the presence of an eschar was not statistically significant in scrub typhus by multivariate analysis, this does not preclude it as a distinctive characteristic of scrub typhus. It is noteworthy that pulmonary involvement on CXR was significantly more common in scrub typhus than in Q fever by univariate analysis (47.5% vs. 21.1%, p = 0.003), although the difference was not significant by multivariate analysis. Pneumonia is the major presentation of acute Q fever in many areas, but hepatitis rather than pneumonia is the predominant presentation of acute Q fever in southern Taiwan.8,24,25 It is not understood why hepatitis rather than pneumonia is the major presentation of acute Q fever in Taiwan when airborne transmission is the main route of infection.13,25 Pneumonitis is one of the presentations of scrub typhus,26,27 while acute respiratory distress syndrome (ARDS) is its most common serious complication in Taiwan.8,28 Accordingly, in patients suspected of acute Q fever or scrub typhus with pulmonary involvement, the latter rather than the former is favored in southern Taiwan. There are limitations in this study. First, this was a hospital-based study and the potential bias of including more severe cases may exist. Second, the clinical findings were recorded retrospectively by chart review; further study with standard collection tools on patient admission is needed. Third, only 80 cases of acute Q fever and 40 cases of scrub typhus were studied, which may limit the interpretative power of the results. Finally, the application of our results to other regions may be limited because of the existence of geographic differences in clinical manifestations of acute Q fever.1,22 In summary, by comparison of the clinical manifestations of the two diseases, we demonstrate that male gender is an independent characteristic of acute Q fever, while residence
or travel in mountainous regions or offshore islands and skin rash are independent characteristics of scrub typhus. This study re-emphasizes the importance of history-taking and physical examination in differentiating acute Q fever and scrub typhus in clinical practice. Further epidemiologic investigation is needed, particularly in regions endemic for both diseases.
Acknowledgments This study was supported in part by a research grant from EDa Hospital (EDAH-D-97(P)007A). Conflict of interest: No conflict of interest to declare.
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