The difference in clinical characteristics between acute Q fever and scrub typhus in southern Taiwan

Article Outline

• Summary
• Introduction
• Materials and methods
  • Study institution
  • Diagnosis of acute Q fever and scrub typhus
  • Collection of clinical data
  • Detection of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection
  • Statistical analysis
• Results
• Discussion
• Acknowledgments
• References
• Copyright

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) >88U/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.

Keywords: Acute Q fever, Coxiella burnetii, Scrub typhus, Orientia tsutsugamushi, Clinical characteristics, Taiwan

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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, ⁶, ⁷, 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, ¹², 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, ⁶, ⁷, 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.

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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 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°C 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 IMx^® HBsAg (V2) assay (Abbott IMx^® System), while HCV infection was defined as the presence of antibody to hepatitis C virus (anti-HCV) in serum detected by IMx^® HCV version 3.0 (Abbott IMx^® 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).

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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.

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• 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).

Table 1. Differences in characteristics between cases of acute Q fever and scrub typhus.

	Acute Q fever (N=80) n (%)	Scrub typhus (N=40) n (%)	pa
Demographic characteristics
Mean days from disease onset to hospital visitb	6.1±3.3	5.7±3.8	0.605
Male gender	74 (92.5)	26 (65)	<0.001
Age (years)b	44.3±12.1	42.9±15.3	0.581
Alcoholism	5 (6.3)	2 (5)	0.999
Hepatitis B or C virus infectionc	23/78 (29.5)	7/39 (17.9)	0.178
Hepatitis B virus	16/78 (20.5)	5/39 (12.8)	0.444
Hepatitis C virus	7/78 (9.0)	2/39 (5.1)	0.462
Liver cirrhosisd	1/75 (1.3)	2/35 (5.7)	0.237
Hypertension	9 (11.3)	5 (12.5)	0.999
Diabetes mellitus	5 (6.3)	2 (5)	0.999
Congestive heart failure	1 (1.3)	0 (0)	0.999
Chronic obstructive pulmonary disease	1 (1.3)	1 (2.5)	0.999
Malignancy	1 (1.3)	0 (0)	0.999
Animal contact	24 (30)	10 (25)	0.567
Residence or travel in mountainous regions or offshore islands	11 (13.8)	27 (67.5)	<0.001
Residence in mountainous regions	5 (6.3)	16 (40)	<0.001
History of travel in mountainous regions or offshore islands	7 (8.8)	20 (50)	<0.001
Symptoms
Fever	79 (98.8)	40 (100)	0.999
Chills	66 (82.5)	32 (80)	0.804
Headache	63 (78.8)	32 (80)	0.874
Sore throat	8 (10)	2 (5)	0.493
Cough	26 (32.5)	16 (40)	0.417
Jaundice	7 (8.8)	5 (12.5)	0.531
Diarrhea	7 (8.8)	4 (10)	0.999
Abdominal pain/discomfort	10 (12.5)	6 (15)	0.704
Nausea/vomiting	5 (6.3)	4 (10)	0.479
Arthralgia	2 (2.5)	4 (10)	0.095
Myalgia	24 (30)	13 (32.5)	0.780
General weakness	7 (8.8)	5 (12.5)	0.531
Signs
Skin rash	5 (6.3)	12 (30)	<0.001
Eschar	0 (0)	9 (22.5)	<0.001
Icteric sclera	7 (8.8)	5 (12.5)	0.531
Lymphadenopathy	2 (2.5)	5 (12.5)	0.040
Hepatomegaly	2 (2.5)	0 (0)	0.552
Splenomegaly	0 (0)	1 (2.5)	0.333
Relative bradycardiae	33 (41.3)	21 (52.5)	0.243

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).

Table 2. Differences in laboratory results and imaging findings between cases of acute Q fever and scrub typhus.

	Acute Q fever (N=80) n (%)	Scrub typhus (N=40) n (%)	pa
Blood cell examination
Days from disease onset to examinationb	5.6±3.3	5.8±3.7	0.707
Leukocytosis	1 (1.3)	7 (17.5)	0.002
Monocytosis	6 (7.5)	3 (7.5)	0.999
Anemia	0 (0)	2 (5)	0.109
Platelet count <150×109/l	59 (73.8)	28 (70)	0.665
Platelet count <100×109/l	17 (21.3)	7 (17.5)	0.628
Biochemical examination
Days from disease onset to examinationb	6.0±3.3	5.9±3.6	0.970
Creatinine >2.0mg/dl	1/73 (1.4)	2/39 (5.1)	0.277
ALT >88U/l	53/79 (67.1)	17/39 (43.6)	0.015
AST >76U/l	61 (76.3)	24 (60)	0.065
Total bilirubin >1.5mg/dl	14/39 (35.9)	6/21 (28.6)	0.566
Chest X-ray (CXR)	76 (95)	40 (100)	0.300
Days from disease onset to CXRb	6.0±3.4	5.9±3.7	0.858
Pulmonary involvement on CXR	16/76 (21.1)	19 (47.5)	0.003
Unilateral infiltration	8/76 (10.5)	6 (15)	0.553
Bilateral infiltration	8/76 (10.5)	13 (32.5)	0.003
Consolidation	0 (0)	0 (0)	NC
Abdominal ultrasonography or computerized tomography (CT)	75 (93.8)	35 (87.5)	0.298
Days from disease onset to abdominal ultrasonography or CTb	7.4±4.1	7.5±4.6	0.897
Cholecystitic change	20/75 (26.7)	6/35 (17.1)	0.273
Gallbladder wall thickening	18/75 (24)	4/35 (11.4)	0.125
Gallbladder distention	3/75 (4)	2/35 (5.7)	0.652
Hepatomegaly or splenomegaly	30/75 (40)	12/35 (34.3)	0.566
Hepatomegaly	19/75 (25.3)	6/35 (17.1)	0.340
Splenomegaly	20/75 (26.7)	9/35 (25.7)	0.916
Fatty liver	38/75 (50.7)	20/35 (57.1)	0.526
Cirrhotic change	1/75 (1.3)	2/35 (5.7)	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 <10g/dl.

Table 3. Response to doxycycline treatment in cases of acute Q fever and scrub typhus^a.

	Acute Q fever (61 cases) n (%)	Scrub typhus (38 cases) n (%)	pb
Days from disease onset to doxycycline treatmentc	6.5±3.3	6.8±3.9	0.617
Days from doxycycline treatment to defervescencec	2.2±2.1	2.7±3.5	0.403
Duration from doxycycline treatment to defervescence
>3 days	9 (14.8)	7 (18.4)	0.630
>5 days	6 (9.8)	3 (7.9)	0.999
>7 days	4 (6.6)	2 (5.3)	0.999

Among the significant characteristics identified by univariate analysis, male gender (odds ratio (OR) 10.883, 95% 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).

Table 4. Multivariate analysis of characteristics of cases of acute Q fever vs. scrub typhus.

OR, odds ratio; CI, confidence interval.

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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, ¹⁷, ¹⁸, 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; Table 1, Table 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. 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 (Table 1, Table 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

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, ⁶, ⁷, 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.

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Acknowledgments 

This study was supported in part by a research grant from E-Da Hospital (EDAH-D-97(P)007A).

Conflict of interest: No conflict of interest to declare.

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