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Am. J. Trop. Med. Hyg., 79(3), 2008, pp. 441-446
Copyright © 2008 by The American Society of Tropical Medicine and Hygiene

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Clinical Characteristics of Acute Q Fever, Scrub Typhus, and Murine Typhus with Delayed Defervescence Despite Doxycycline Treatment

Chung-Hsu Lai, Chun-Kai Huang, Hui-Ching Weng, Hsing-Chun Chung, Shiou-Haur Liang, Jiun-Nong Lin, Chih-Wen Lin, Chuan-Yuan Hsu, AND Hsi-Hsun Lin*
Section of Infectious Diseases, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaoshiung County, Taiwan, Republic of China; Department of Health Management, I-Shou University, Kaohsiung County, Taiwan, Republic of China; Section of Gastroenterology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaoshiung County, Taiwan, Republic of China


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Doxycycline is the recommended antibiotic for acute Q fever, scrub typhus, and murine typhus and defervescence often occurs within 3 days of treatment. Patients with delayed defervescence (> 3 days) are troublesome for clinicians. To investigate the characteristics of such patients, 18 and 88 cases with and without delayed defervescence, respectively, were studied. By univariate analysis, absence of headache (P = 0.004), jaundice (P = 0.030), icteric sclera (P = 0.030), relative bradycardia (P = 0.003), and pulmonary involvement on chest x-ray (P = 0.028) were significant findings in patients with delayed defervescence. By multivariate analysis, absence of headache (odds ratio [OR] = 8.310; 95% confidence interval [CI] = 1.990–34.706, P = 0.004), jaundice (OR = 6.242; 95% CI = 1.374–28.365, P = 0.018), and relative bradycardia (OR = 10.449; 95% CI = 2.137–51.088, P = 0.004) were the independent characteristics of patients with delayed defervescence. In treating acute Q fever, scrub typhus, and murine typhus with doxycycline, clinicians should be aware that delayed defervescence may occur in patients presenting with jaundice, relative bradycardia, and absence of headache.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rickettsioses are a group of diseases that conventionally include rickettsial diseases, ehrlichiosis, analplasmosis, scrub typhus (caused by Orientia tsutsugamushi), and Q fever (caused by Coxiella burnetii), although the genera Ehrlichia, Anaplasma, Orientia, and Coxiella have been removed from the genus Rickettsia.1 They are common zoonoses in humans that may be the cause of fever of unknown origin in many clinical settings.2 Definitive diagnosis is made through the isolation or detection of the causative pathogens from specimens of the infected hosts, but these methods are laborious and isolating organisms from clinical specimen is difficult.3,4 Because of these disadvantages, serologic assessments that detect the specific antibodies against the organisms in sera have become the universally approved diagnostic methods for rickettsioses. However, serologic assessments are only available in research laboratories, not universally in general hospitals, and require paired serum to confirm the diagnosis, which often takes more than two weeks after the disease onset. Thus, clinicians often empirically administer antibiotics that are effective against rickettsioses, especially tetracyclines, before the final results of confirmatory tests are available.

In Taiwan, acute Q fever, scrub typhus, and murine typhus are the most common rickettsioses.5–9 Although the pathogens, vectors, and transmission routes of the three diseases are different, it is difficult to differentiate from each other by clinical manifestations and doxycycline is the recommended antibiotic for them. Clinicians often empirically prescribe doxycycline as preemptive treatment of patients who are highly suspected of acute Q fever, scrub typhus, or murine typhus, and defervescence is often achieved within 3 days. Because the response to doxycycline is so dramatic, it would make the diagnosis of these diseases unlikely if fever persisted for more than 3 days after treatment. Thus, the emergence of cases with delayed defervescence (fever > 3 days) after treatment with doxycycline will distract clinicians, including infectious disease specialists. This study was conducted to identify the clinical characteristics of acute Q fever, scrub typhus, and murine typhus with delayed defervescence despite doxycycline treatment.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Identification of cases of acute Q fever, scrub typhus, and murine typhus. Patients clinically suspected as cases of rickettsioses were initially reported to the department of infection control of E-Da Hospital by the clinicians. Because acute Q fever, scrub typhus, and murine typhus were the most common rickettsioses in Taiwan, and they were often difficult to be distinguished from each other in clinical, all three diseases were prospectively reported to and paired sera (acute and convalescent phase) were collected and sent to the Centers for Disease Control, Taipei, Taiwan (Taiwan CDC) simultaneously for confirming the diagnoses regardless of which disease was suspected. Serologic assessments for the presence of specific antibodies to C. burnetii, O. tsutsugamushi, and Rickettsia typhi were performed using an indirect immunofluorescence antibody assay (IFA) as previously described.6,8,9

Acute Q fever was diagnosed by either a titer of anti-phase II antigen IgG > 1:200 and anti-phase II antigen IgM > 1:80 in a single serum, or a 4-fold or greater rise of anti-phase II antigen IgG in paired sera. Scrub typhus was diagnosed by either an antibody titer of IgM > 1:80 for Karp, Kato, and Gilliam strains of O. tsutsugamushi, or a 4-fold or greater rise of total antibody titer in paired sera. Murine typhus was diagnosed by either a single IgM titer against R. typhi > 1:80 or a 4-fold or greater rise of IgG titers in paired sera.

Identification of studied cases. The charts of the serologically confirmed cases of acute Q fever, scrub typhus, and murine typhus were reviewed and the demographic data, clinical manifestations, results of laboratory and imaging studies, administration of antibiotics, and highest daily body temperature were recorded for analysis. The dosage of doxycycline was 200 mg orally per day divided into two doses. For clinical practice, ear temperature was used to measure body temperature. The date of defervescence was defined as the first day of the highest body temperature lower than 37.5°C for more than 3 consecutive days. Antipyretics were used only when the body temperature was greater than 38.5°C. Delayed defervescence was defined as the number of days from the administration of doxycycline to defervescence > 3 days.

Patients with the following criteria were excluded from the study: 1) patients who had spontaneous remission defined as defervescence achieved without or before doxycycline treatment; 2) patients without delayed defervescence who received fluoroquinolone treatment within 3 days before the date of defervescence; 3) patients without available daily body temperatures resulting from treatment at the out-patient or emergency departments.

The patients were divided into two groups based on responses to doxycycline treatment: the delayed defervescence group and the group without delayed defervescence.

Confirming tests for hepatitis virus B (HBV) or C (HCV) infection. Because elevated liver enzymes were found in a majority of cases of acute Q fever, scrub typhus, murine typhus, and HBV and HCV infections were endemic in Taiwan; confirming tests for HBV and HCV infection were performed. HBV infection was defined as the presence of hepatitis B surface antigen in serum detected by IMx HBsAg (V2) assay (Abbott IMx system). HCV infection was defined as the presence of antibody to hepatitis C virus in serum detected by IMx HCV version 3.0 (Abbott IMx system).

Statistical analysis. Categorical variables were analyzed using {chi}2 or Fisher’s exact test where appropriate. Continuous variables were analyzed using the Student’s t test, whereas multivariate analysis was performed using logistic regression. All P values were two-tailed and a value < 0.05 was considered statistically significant. The results were analyzed using a commercially available software package (SPSS, version 12.0, Chicago, IL).


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
From April 2004 to December 2007, a total of 130 cases (80 acute Q fever, 40 scrub typhus, and 10 murine typhus) were confirmed by serologic tests at the E-Da Hospital. Among them, 24 (18.5%) were excluded, including 7 (5.4%) cases of spontaneous remission, 3 (2.3%) who received fluoroquinolones treatment within 3 days before defervescence, and 14 (10.8%) unavailable daily body temperatures. A total of 106 cases (61 acute Q fever, 38 scrub typhus, and 7 murine typhus) were included for analysis. Among them, 18 (17.0%) cases (9 acute Q fever, 7 scrub typhus, and 2 murine typhus) had delayed defervescence and 88 (83.0%) cases (52 acute Q fever, 31 scrub typhus, and 5 murine typhus) did not have delayed defervescence. The percentage of each disease in the two groups is not statistically different (Table 1Go). The percentage of fever in patients with and without delayed defervescence after doxycycline treatment is shown in Figure 1Go. The 33.3% (6/18) and 20.5% (18/88) patients with and without delayed defervescence, respectively, had combined other antibiotics (P = 0.233) (data not shown). Except for two patients with delayed defervescence who received additional fluoquinolones on the 5th and 7th day after doxycycline treatment, most of the combined antibiotics were beta-lactams and aminoglycosides, which were not effective for Q fever, scrub typhus, and murine typhus. Furthermore, steroid was administered in two patients with delayed defervescence on the 5th and 7th day after doxycycline treatment.


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TABLE 1
Demographic data, symptoms and signs of acute Q fever, scrub typhus, and murine typhus cases with and without delayed defervescence after doxycycline treatment
 

Figure 1
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  		FIGURE 1. Percentage of fever in patients with and without delayed defervescence after doxycycline treatment.

 
The demographic data and clinical symptoms and signs of cases are listed in Table 1Go. By univariate analysis, absence of headache (38.9% versus 9.1%, P = 0.004), jaundice (27.8% versus 8.0%, P = 0.030), icteric sclera (27.8% versus 8.0%, P = 0.030), and relative bradycardia (83.3% versus 44.3%, P = 0.003) were the predominant characteristics of those with delayed defervescence. Table 2Go shows the results of laboratory examinations and image findings of cases. Only pulmonary involvement on chest x-ray (CXR) (55.6% versus 28.7%, P = 0.028) was predominant for cases with delayed defervescence. The duration from disease onset to doxycycline treatment is shown in Table 3Go and no difference between the two groups was found.


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TABLE 2
Laboratory examinations and image findings of acute Q fever, scrub typhus, and murine typhus cases with and without delayed defervescence after doxycycline treatment
 

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TABLE 3
Duration from disease onset to doxycycline treatment of acute Q fever, scrub typhus, and murine typhus cases with and without delayed defervescence after treatment
 
Among the significant characteristics identified by univariate analysis, absence of headache (odds ratio [OR] = 8.310; 95% confidence interval [CI] = 1.990–34.706, P = 0.004), jaundice (OR = 6.242; 95% CI = 1.374–28.365, P = 0.018), and relative bradycardia (OR = 10.449; 95% CI = 2.137–51.088, P = 0.004) were the independent characteristics of patients with delayed defervescence by multivariate analysis (Table 4Go).


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TABLE 4
Multivariate analysis of characteristics of acute Q fever, scrub typhus, and murine typhus cases with delayed defervescence after doxycycline treatment
 

DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Acute Q fever, scrub typhus, and murine typhus are the most common rickettsioses in Taiwan.5–9 Because the methods for definitive diagnosis of them are either laborious tasks or time-consuming and are available only in research laboratories, clinicians often empirically prescribe doxycycline as preemptive treatment of suspected patients. Thus, cases with delayed defervescence would be troublesome for clinicians. The results of this study suggested that in treating acute Q fever, scrub typhus, and murine typhus with doxycycline, clinicians should be aware that delayed defervescence may occur in patients presenting with jaundice, relative bradycardia, and absence of headache. Administration of appropriate antibiotics (keep doxycycline or use alternative antibiotics, which are also effective for these diseases) should not be influenced by the response to treatment in such patients.

Poor response to doxycycline may be resulting from infections of doxycycline-resistant or particularly virulent strains of the organisms, inadequate doxycycline concentrations in infection sites, more severe diseases, and factors of infected hosts. For scrub typhus, poor response to doxycycline treatment resulting from infections with doxycycline-resistant strains of O. tsutsugamushi has been reported in northern Thailand.10 For acute Q fever, the slow regression of symptoms despite appropriate antibiotic treatment has been mentioned, especially in patients with an erythrocyte sedimentation rate (ESR) of > 100/h, a high level of autoantibodies, and hepatitis.4,11 For such patients, a combination of steroids with appropriate antibiotic therapy has been suggested.4,11 Furthermore, doxycycline-resistant strains of C. burnetii may be one of the possible causes of poor clinical response.12,13 For murine typhus, doxycycline-resistant strains or those with poor response to doxycycline have not been reported in literature. In this study, two cases of murine typhus had delayed defervescence occurring on the 4th and 6th day of doxycycline treatment, respectively. However, the ESR level and autoantibodies are not routine examinations and could not be evaluated in this study. The identification of drug-resistant strains of these organisms can be performed only in highly technical research laboratories and measurement of doxycycline concentrations is not available in general hospitals. Both of them are not applicable in clinical practice.

Relative bradycardia (OR = 10.449; 95% CI = 2.137–51.088, P = 0.004), jaundice (OR = 6.242; 95% CI = 1.374–28.365, P = 0.018), and absence of headache (OR = 8.310; 95% CI = 1.990–34.706, P = 0.004) are the independent characteristics of patients with delayed defervescence in this study (Table 4Go). The exact mechanism of relative bradycardia is not well understood. The mechanism of febrile response during infection is a complex process that includes interactions between exogenous pyogenes, such as exotoxin and endotoxins released from pathogens, and endogenous pyogenes, such as cytokines, tumor necrosis factors-{alpha}(TNF-{alpha}), interleukin-1 (IL-1), interleukin-6 (IL-6), and interferons released from cells of infected hosts.14 In addition to the induction of fever, TNF-{alpha}, IL-1, and IL-6 are inversely associated with vagal activity.15,16 Vagal stimulation can significantly attenuate the release of TNF-{alpha}, IL-1, and IL-6.17 Thus, the possible mechanism for the relative bradycardia may be as follows: infection causes the release of cytokines (TNF-{alpha}, IL-1, and IL-6) that induce fever at the level of the thermoregulation center, whereas the activated vagal response to modulate the release of cytokines also affects cardiac rhythm simultaneously. To the best of our knowledge, the association between relative bradycardia and protracted pyrexia in infectious diseases had never been reported. We hypothesize that patients with delayed defervescence to doxycycline treatment may have higher vagal response to modulate the released cytokines because of individual host factors that results in the significantly higher percentage of relative bradycardia in them. However, the clear mechanism of relative bradycardia and our hypothesis demand further investigation.

Liver involvement in acute Q fever, scrub typhus, and murine typhus is not uncommon, and the clinical manifestations include elevation of liver enzymes (hepatitis), hepatomegaly, and jaundice. For acute Q fever, pneumonia and hepatitis are the two major clinical presentations,4 and the latter is predominant in Taiwan.5,6,18,19 About 23–50% patients of acute Q fever have hepatomegaly.5,6,20–23 For scrub typhus, abnormal liver function is rarely mentioned in Western literature, but it is common in reports from Vietnam,24 Japan,25 and Taiwan26,27 and about 30% of patients have an enlarged spleen and liver.28 For murine typhus, 65–90% of patients have elevated liver enzymes29–31 and hepatomegaly is found in 24% of patients in one study from Thailand.31 Jaundice is found in 4.5–20%,4–6 1–44.7%,6,24,26,27 and 3–11%30,31 of cases of acute Q fever, scrub typhus, and murine typhus, respectively. However, only jaundice was significantly predominant in patients with delayed defervescence both by univariate and multivariate analysis (Tables 1Go and 4Go). The lack of significant difference in serum total bilirubin level > 1.5 mg/dL between the two groups might be resulting from the small numbers of tested cases (59/108, 55.7%), because most clinicians would not examine serum bilirubin levels if jaundice was not clinically obvious. Other hepatic organic abnormalities that may cause hyperbilirubinemia, such as biliary tract obstruction or hepatic lesion, were not found in our cases. Furthermore, the percentage of underlying hepatitis virus infections or cirrhosis was not different between the two groups (Table 1Go). Thus, the presence of jaundice rather than levels of elevated liver enzymes or hepatomegaly may represent a more severe liver involvement in acute Q fever, scrub typhus, and murine typhus and results in delayed defervescence despite doxycycline treatment.

Although headache is a common symptom in rickettsioses and suggests central nervous system (CNS) involvement,32 whether its presence or not is associated with delayed defervescence despite adequate antibiotic treatment has never been reported. CNS involvement with the presentations of meningitis and meningoencephalitis has been reported in Q fever,33,34 scrub typhus,35,36 and murine typhus.36,37 The exact mechanism of CNS involvement in acute Q fever, scrub typhus, and murine typhus has not been well established. Vasculitis presenting as inflammatory cell infiltration over the peri-vascular spaces of CNS capillaries have been found in scrub typhus and murine typhus.35–37 In contrast, in one necropsy findings of a patient who died of Q fever, no peri-vascular infiltration was found despite the existence of capillary endothelial swelling and organisms found inside and outside the endothelial and neuroglial cells.38 It can be expected that patients with CNS involvement represents a more severe disease and results in poorer response to treatment. However, absence of headache is predominant in patients with delayed defervescence both by univariate and multivariate analysis in our study (Tables 1Go and 4Go). It is possible that patients without headache have delayed diagnosis and treatment compared with those with headache, thereby resulting in poorer response to doxycycline treatment. However, the mean days from disease onset to hospital visit and days from disease onset to doxycycline treatment were not different between the two groups (P > 0.05; Tables 1Go–3GoGo). No deterioration of consciousness or focal neurologic signs was found in our patients. However, the headache was severe enough to prompt lumbar puncture in four patients (1 Q fever, 2 scrub typhus, and 1 murine typhus) to rule out meningitis, and they were all cases without delayed defervescence after doxycycline treatment. Thus, the association of absence of headache with delayed defervescence despite doxycycline treatment in acute Q fever, scrub typhus, and murine typhus demands further investigation.

In addition to the clinical characteristics, the possible influence of differences in duration from disease onset to hospital visit, to various examinations, and to initiation of doxycycline treatment between the two groups were excluded in our study because the differences were not statistically significant (P > 0.05; Tables 1Go–3GoGo).

Although the characteristics of acute Q fever, scrub typhus, and murine typhus with delayed defervescence after treatment of doxycycline are identified in our study, they should be applied carefully in clinical. The possibility of misdiagnosis should be kept in mind and further investigation of infections caused by other pathogens should be considered.

Our study has certain limitations. This is a hospital-based retrospective study and the potential bias of including more severe cases may exist. The number of studied cases is small (18 cases with delayed defervescence and 88 cases without delayed defervescence), which may limit the interpretative power of the results. The mechanisms of delayed defervescence despite doxycycline in acute Q fever, scrub typhus, and murine typhus might be different, and it could not be uncovered in this study because the three diseases are included in one study group. Whether infection of doxycycline-resistant strains or failure to reach a minimal inhibitory concentration (MIC) level of doxycycline in serum is one of the causes of delayed defervescence demands further investigation.

In summary, acute Q fever, scrub typhus, and murine typhus with delayed defervescence despite doxycycline treatment are troublesome for clinicians to diagnose and treat. Absence of headache, relative bradycardia, and jaundice are independent characteristics for a patient with delayed defervescence. In addition to infections from doxycycline-resistant or particularly virulent strains of the organisms and more severe diseases, other causes that may produce a poor response to doxycycline treatment, such as factors of infected hosts, require further investigation.

Received April 13, 2008. Accepted for publication June 11, 2008.

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

Disclaimer: All authors have no conflict of interest.

* Address correspondence to Hsi-Hsun Lin, Section 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. E-mail: ed100233{at}yahoo.com.tw Back

Authors’ addresses: Chung-Hsu Lai, Section of Infectious Disease, 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, Tel: 886-7-615-0011-5558, Fax: 886-7-615-0960, E-mail: laich6363{at}yahoo.com.tw. Chun-Kai Huang, Section of Infectious Disease, 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, Tel: 886-7-615-0011-5555, Fax: 886-7-615-0960, E-mail: ed103536{at}edah.org.tw. Hui-Ching Weng, Department of Health Management, I-Shou University, 8 E-Da Road, Jiau-Shu Tsuen, Yan-Chau Shiang, Kaohsiung County, 824 Taiwan Kaohsiung County, Taiwan, Republic of China, Tel: 886-7-615-1100-7420, Fax: 886-7-615-0960, E-mail: weng{at}mail.isu.edu.tw. Hsing-Chun Chung, Section of Infectious Disease, 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, Tel: 886-7-615-0011-5556, Fax: 886-7-615-0960, E-mail: ed102749{at}edah.org.tw. Shiou-Haur Liang, Section of Infectious Disease, 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, Tel: 886-7-615-0011-5554, Fax: 886-7-615-0960, E-mail: ed103519{at}edah.org.tw. Jiun-Nong Lin, Section of Infectious Disease, 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, Tel: 886-7-615-0011-5557, Fax: 886-7-615-0960, E-mail: ed103623{at}edah.org.tw. Chih-Wen Lin and Chuan-Yuan Hsu, Section of Gastroenterology, 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, Tel: 886-7-615-0011, Fax: 886-7-615-0960, E-mails: ed101968{at}edah.org.tw and ed101800{at}edah.org.tw. Hsi-Hsun Lin, Department of Infectious Disease, E-Da Hospital/I-Shou University, 1 E-Da Road, Jiau-Shu Tsuen, Yan-Chau Shiang, Kaohsiung County, 824 Taiwan, Republic of China, Tel: 886-7-615-0011-5550, Fax: 886-7-615-0960, E-mail: ed100233{at}yahoo.org.tw.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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