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Having previously shown that soluble E-cadherin (sE-cad) is found in sera of Q fever patients and that infection of BeWo cells by C. burnetii leads to modulation of the E-cad/β-cat pathway, our purpose was to identify which sheddase(s) might catalyze the cleavage of E-cad. Here, we searched for a direct mechanism of cleavage initiated by the bacterium itself, assuming the possible synthesis of a sheddase encoded in the genome of C. burnetii or an indirect mechanism based on the activation of a human sheddase. Using a straightforward bioinformatics approach to scan the complete genomes of four laboratory strains of C. burnetii , we demonstrate that C. burnetii encodes a 451 amino acid sheddase (CbHtrA) belonging to the HtrA family that is differently expressed according to the bacterial virulence. An artificial CbHtrA gene (CoxbHtrA) was expressed, and the CoxbHtrA recombinant protein was found to have sheddase activity. We also found evidence that the C. burnetii infection triggers an over-induction of the human HuHtrA gene expression. Finally, we demonstrate that cleavage of E-cad by CoxbHtrA on macrophages-THP-1 cells leads to an M2 polarization of the target cells and the induction of their secretion of IL-10, which "disarms" the target cells and improves C. burnetii replication. Taken together, these results demonstrate that the genome of C . burnetii encodes a functional HtrA sheddase and establishes a link between the HtrA sheddase-induced cleavage of E-cad, the M2 polarization of the target cells and their secretion of IL-10, and the intracellular replication of C. burnetii .

Coxiella burnetii infection is not known to involve directly the kidneys. Kidney injury associated with Q fever usually manifests in the setting of chronic infection or endocarditis with development of immune complex deposition. Acute kidney injury (AKI) in the context of acute Q fever infection may be more pathologically heterogeneous. We describe two cases of severe AKI secondary to acute Q fever infection, each with marked differences in pathological characteristics, and clinical course., (© 2019 Royal Australasian College of Physicians.)

Background: From 2007 through 2010, a large epidemic of acute Q fever occurred in the Netherlands. Patients with cardiac valvulopathy are at high risk to develop chronic Q fever after an acute infection. This patient group was not routinely screened, so it is unknown whether all their chronic infections were diagnosed. This study aims to investigate how many chronic Q fever patients can be identified by routinely screening patients with valvulopathy and to establish whether the policy of not screening should be changed., Methods: In a cross-sectional study (2016-2017) in a hospital at the epicentre of the Q fever epidemic, a blood sample was taken from patients 18 years and older who presented with cardiac valvulopathy. The sample was tested for IgG antibodies against phase I and II of Coxiella burnetii using an immunofluorescence assay. An IgG phase II titre of ≥1:64 was considered serological evidence of a previous Q fever infection. An IgG phase I titre of ≥1:512 was considered suspicious for a chronic infection, and these patients were referred for medical examination., Results: Of the 904 included patients, 133 (15%) had evidence of a previous C. burnetii infection, of whom 6 (5%) had a chronic infection on medical examination., Conclusions: In a group of high-risk patients with a heart valve defect, we diagnosed new chronic Q fever infections seven years after the epidemic, emphasizing the need for screening of this group to prevent complications in those not yet diagnosed in epidemic areas., Competing Interests: The authors have declared that no competing interests exist.

Human Q fever is caused by the intracellular bacterial pathogen Coxiella burnetii Q fever presents with acute flu-like and pulmonary symptoms or can progress to chronic, severe endocarditis. After human inhalation, C. burnetii is engulfed by alveolar macrophages and transits through the phagolysosomal maturation pathway, resisting the acidic pH of lysosomes to form a parasitophorous vacuole (PV) in which to replicate. Previous studies showed that C. burnetii replicates efficiently in primary human alveolar macrophages (hAMs) in ex vivo human lung tissue. Although C. burnetii replicates in most cell types in vitro , the pathogen does not grow in non-hAM cells of human lung tissue. In this study, we investigated the interaction between C. burnetii and other pulmonary cell types apart from the lung environment. C. burnetii formed a prototypical PV and replicated efficiently in human pulmonary fibroblasts and in airway, but not alveolar, epithelial cells. Atypical PV expansion in alveolar epithelial cells was attributed in part to defective recruitment of autophagy-related proteins. Further assessment of the C. burnetii growth niche showed that macrophages mounted a robust interleukin 8 (IL-8), neutrophil-attracting response to C. burnetii and ultimately shifted to an M2-polarized phenotype characteristic of anti-inflammatory macrophages. Considering our findings together, this study provides further clarity on the unique C. burnetii -lung dynamic during early stages of human acute Q fever., (Copyright © 2019 American Society for Microbiology.)

Coxiella burnetii is a multi-host bacterium that causes Q fever in humans, a zoonosis that is emerging worldwide. The ecology of C. burnetii in wildlife is still poorly understood and the influence of host, environmental and pathogen factors is almost unknown. This study gathers current published information on different aspects of C. burnetii infection in wildlife, even in species with high reservoir potential and a high rate of interaction with livestock and humans, in order to partially fill the existing gap and highlight future needs. Exposure and/or infection by C. burnetii has, to date, been reported in 109 wild mammal species. The limited sample size of most of the existing studies could suggest an undervalued prevalence of C. burnetii infection. Knowledge on the clinical outcome of C. burnetii infection in wildlife is also very limited, but currently includes reproductive failure in waterbuck (Kobus ellipsiprymnus), roan antelope (Hippotragus niger), dama gazelle (Nanger dama) and water buffalo (Bubalus bubalis) and placentitis in the Pacific harbor seal (Phoca vitulina richardsi), Steller sea lion (Eumetopias jubatus) and red deer (Cervus elaphus). The currently available serological tests need to be optimised and validated for each wildlife species. Finally, there is a huge gap in the research on C. burnetii control in wildlife, despite of the increasing evidence that wildlife is a source of C. burnetii for both livestock and humans., (© 2018 Blackwell Verlag GmbH.)

Background/purpose: The clinical manifestations of scrub typhus, murine typhus and acute Q fever in the elderly are not clear., Methods: We conducted a retrospective study to identify the characteristics of the elderly aged ≥65 years with a comparison group aged 18-64 years among patients with scrub typhus, murine typhus, or acute Q fever who were serologically confirmed at three hospitals in Taiwan during 2002-2011., Results: Among 441 cases, including 187 cases of scrub typhus, 166 acute Q fever, and 88 murine typhus, 68 (15.4%) cases were elderly patients. The elderly had a higher severe complication rate (10.3% vs. 3.5%, p = 0.022), but did not have a significantly higher mortality rate (1.47% vs. 0.54%, p = 0.396). Compared with those without severe complications, we found the elderly (p = 0.022), dyspnea (p = 0.006), less relative bradycardia (p = 0.004), less febrile illness (p = 0.004), prolonged prothrombin time (PT) (p = 0.002), higher levels of initial C-reactive protein (p = 0.039), blood leukocyte counts (p = 0.01), and lower platelet counts (p = 0.012) are significantly associated with severe complications. Only prolonged prothrombin time was associated with severe complications in multivariate analysis (p = 0.018, CI 95% 0.01-0.66). Among clinical symptoms and laboratory data, multivariate analysis revealed chills was less frequently occurred in the elderly (p = 0.012, 95% confidence interval [CI]: 1.33-9.99)., Conclusion: The elderly cases with scrub typhus, murine typhus, or acute Q fever would be more likely to have severe complications, for which prothrombin time prolongation is an important predictor for severe complications., (Copyright © 2017. Published by Elsevier B.V.)

Q fever is a zoonosis that is broadly distributed worldwide, despite few reports associated with its occurrence in Brazil. Coxiella burnetii, namely the causative agent of Q fever is a gram-negative coccobacillus and an obligate intracellular bacterial parasite of the order of Legionellales. The microorganism is generally present in the urine and feces of infected animals and can be found in large quantities in placental membranes of at-term or aborted animals. The inhalation of particles suspended in the air or contaminated aerosols is the most common form of bacterial contact. Q Fever is a self-limited disease, and often progresses in a benign way. In cases where the disease progresses to the chronic form, endocarditis is the most prevalent manifestation. Clinical diagnosis is difficult since the symptoms are similar to many other diseases. In confirmed cases, antibiotic therapy is the treatment indicated. Given the lack of knowledge about the disease and the difficulty of diagnosis, it is believed that Q fever is more common than generally believed in Brazil.

Background: Q fever often presents as an undifferentiated febrile illness. Cases occur throughout Australia, with higher rates occurring in northern New South Wales and southern Queensland., Objective: This article aims to provide clinicians with an overview of Q fever, and covers epidemiology, clinical features, laboratory diagnosis, sequelae, management and prevention., Discussion: In Australia, Q fever is the most commonly reported zoonotic disease. Presentation includes fever, rigors, chills, headache, extreme fatigue, drenching sweats, weight loss, arthralgia and myalgia, often in conjunction with abnormal liver function tests. These features make it indistinguishable from many other febrile illnesses. Exposure occurs through contact with livestock and other animals. Coxiella bacteria can survive in dust, where infection may result from inhalation. Laboratory diagnosis is made by serology or polymerase chain reaction. An effective vaccine is available for adults (aged >15 years), but can only be administered after a rigorous pre-vaccination assessment to exclude prior exposure to Coxiella burnetii, requiring a detailed medical history, skin test and serology.

Objective: To describe a rare case of acute Q fever with tache noire., Clinical Presentation and Intervention: A 51-year-old man experienced acute Q fever showing tache noire, generally considered a pathognomonic sign of Mediterranean spotted fever (MSF) and MSF-like illness, but not a clinical feature of Q fever. The patient was treated with doxycycline 100 mg every 12 h., Conclusion: In the Mediterranean area, tache noire should be considered pathognomonic of MSF but it should not rule out Q fever. Clinical diagnosis should be supported by accurate laboratory diagnostic tests to guide proper management., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Objectives: Chronic Q fever is a persistent infection with the intracellular Gram-negative bacterium Coxiella burnetii, which can lead to complications of infected aneurysms. Matrix metalloproteinases (MMPs) cleave extracellular matrix and are involved in infections as well as aneurysms. We aimed to study the role of MMPs in the pathogenesis of chronic Q fever., Methods: We investigated gene expression of MMPs through microarray analysis and MMP production with ELISA in C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of patients with chronic Q fever and healthy controls. Twenty single nucleotide polymorphisms (SNPs) of MMP and tissue inhibitor of MMP genes were genotyped in 139 patients with chronic Q fever and 220 controls with similar cardiovascular co-morbidity. Additionally, circulating MMPs levels in patients with chronic Q fever were compared with those in cardiovascular controls with and without a history of past Q fever., Results: In healthy controls, the MMP pathway involving four genes (MMP1, MMP7, MMP10, MMP19) was significantly up-regulated in C. burnetii-stimulated but not in Escherichia coli lipopolysaccharide -stimulated PBMCs. Coxiella burnetii induced MMP-1 and MMP-9 production in PBMCs of healthy individuals (both p<0.001), individuals with past Q fever (p<0.05, p<0.01, respectively) and of patients with chronic Q fever (both p<0.001). SNPs in MMP7 (rs11568810) (p<0.05) and MMP9 (rs17576) (p<0.05) were more common in patients with chronic Q fever. Circulating MMP-7 serum levels were higher in patients with chronic Q fever (median 33.5 ng/mL, interquartile range 22.3-45.7 ng/mL) than controls (20.6 ng/mL, 15.9-33.8 ng/mL)., Conclusion: Coxiella burnetii-induced MMP production may contribute to the development of chronic Q fever., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Long-term fatigue with detrimental effects on daily functioning often occurs following acute Q-fever. Following the 2007-2010 Q-fever outbreak in the Netherlands with over 4000 notified cases, the emphasis on long-term consequences of Q-fever increased. The aim of this study was to provide an overview of all relevant available literature, and to identify knowledge gaps regarding the definition, diagnosis, background, description, aetiology, prevention, therapy, and prognosis, of fatigue following acute Q-fever., Design: A systematic review was conducted through searching Pubmed, Embase, and PsycInfo for relevant literature up to 26th May 2015. References of included articles were hand searched for additional documents, and included articles were quality assessed., Results: Fifty-seven articles were included and four documents classified as grey literature. The quality of most studies was low. The studies suggest that although most patients recover from fatigue within 6-12 months after acute Q-fever, approximately 20% remain chronically fatigued. Several names are used indicating fatigue following acute Q-fever, of which Q-fever fatigue syndrome (QFS) is most customary. Although QFS is described to occur frequently in many countries, a uniform definition is lacking. The studies report major health and work-related consequences, and is frequently accompanied by nonspecific complaints. There is no consensus with regard to aetiology, prevention, treatment, and prognosis., Conclusions: Long-term fatigue following acute Q-fever, generally referred to as QFS, has major health-related consequences. However, information on aetiology, prevention, treatment, and prognosis of QFS is underrepresented in the international literature. In order to facilitate comparison of findings, and as platform for future studies, a uniform definition and diagnostic work-up and uniform measurement tools for QFS are proposed.

Coxiella burnetii is the etiological agent of Q fever, a worldwide zoonosis that can result in large outbreaks. The birth of genomics and sequencing of C. burnetii strains has revolutionized many fields of study of this infection. Accurate genotyping methods and comparative genomic analysis have enabled description of the diversity of strains around the world and their link with pathogenicity. Genomics has also permitted the development of qPCR tools and axenic culture medium, facilitating the diagnosis of Q fever. Moreover, several pathophysiological mechanisms can now be predicted and therapeutic strategies can be determined thanks to in silico genome analysis. An extensive pan-genomic analysis will allow for a comprehensive view of the clonal diversity of C. burnetii and its link with virulence.

Objectives: During the largest Q-fever outbreak ever reported, a cohort study was established to assess the health status of Q-fever patients over a 24-month period and to identify factors associated with health status., Methods: Laboratory-confirmed Q-fever patients participated at six time points after onset of illness. Scores on twelve subdomains from two health status instruments were calculated for each time point to determine progression and compare to reference groups., Results: The study included 336 Q-fever patients. There is a significant linear improvement over time in nine of the twelve health status subdomains. For example, the proportion of patients with severe fatigue improved from 73.0% at three months to 60.0% at twelve months and 37.0% at twenty-four months, but this was still high compared to a healthy reference group (2.5%). For the three most severely affected subdomains -'Fatigue', 'General Quality of Life' and 'Role Physical'- the baseline characteristics significantly associated with a long-term reduced health status were being female, being a young adult and having pre-existing health problems., Conclusions: Despite a significant linear improvement over time in nine of the twelve health status subdomains, more than one out of three patients still suffered from a reduced health status at 24 months., (Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

The paper considers a rare clinical case of severe Q fever in a young man with no compromised premorbid background. It describes and analyzes clinical manifestations and laboratory findings with consideration for the current data available in the literature. The issues of the differential diagnosis, laboratory diagnosis, and treatment of Q fever are discussed.

Background and Aim of the Study: Q fever is a worldwide zoonosis caused by a fastidious bacterium, Coxiella burnetii. A recent major outbreak of which in the Netherlands will most likely lead to the emergence of hundreds of cases of C. burnetii endocarditis during the next decade. Patients undergoing cardiac valve surgery may carry undiagnosed Q fever endocarditis with possible disastrous outcomes, and hence may benefit from a screening strategy. The study aim was to evaluate the frequency of unsuspected latent Q fever endocarditis in patients undergoing routine valve surgery., Methods: At the present authors' institution, all resected cardiac valves/prostheses are examined routinely histologically, microbiologically and on a molecular biological basis, in addition to serological testing for fastidious microorganisms. A retrospective review was conducted of data relating to all patients who had unsuspected Q fever endocarditis that had been diagnosed after routine valve/prosthesis replacement/repair between 2000 and 2013 at the authors' institution., Results: Among 6,401 patients undergoing valve surgery, postoperative examinations of the explanted valves/prostheses led to an unexpected diagnosis of Q fever endocarditis in 14 cases (0.2%), who subsequently underwent appropriate medical treatments. Only two of the patients (14%) had intraoperative findings suggestive of endocarditis. On serological analysis of the blood samples, 11 patients (79%) presented an evocative Phase I IgG antibody titer > or =800. Valvular tissue-sample analyses yielded positive cultures and PCR in the same 13 patients (93%), whereas pathological and immunohistochemical examinations alone were suggestive of endocarditis in only seven Cases (50%)., Conclusion: This screening strategy led to an unexpected diagnosis of Q fever endocarditis in 0.2% of patients undergoing routine valve surgery, who received subsequent appropriate antibiotic therapy. Systematic serological analysis should be mandatory before performing heart valve surgery in countries where C. burnetii is endemic. A positive serology should lead to appropriate valve-specimen analyses, including microbiological, molecular biological and histological evaluations.

The intracellular bacterial pathogen Coxiella burnetii is a category B select agent that causes human Q fever. In vivo, C. burnetii targets alveolar macrophages wherein the pathogen replicates in a lysosome-like parasitophorous vacuole (PV). In vitro, C. burnetii infects a variety of cultured cell lines that have collectively been used to model the pathogen's infectious cycle. However, differences in the cellular response to infection have been observed, and virulent C. burnetii isolate infection of host cells has not been well defined. Because alveolar macrophages are routinely implicated in disease, we established primary human alveolar macrophages (hAMs) as an in vitro model of C. burnetii-host cell interactions. C. burnetii pathotypes, including acute disease and endocarditis isolates, replicated in hAMs, albeit with unique PV properties. Each isolate replicated in large, typical PV and small, non-fused vacuoles, and lipid droplets were present in avirulent C. burnetii PV. Interestingly, a subset of small vacuoles harboured single organisms undergoing degradation. Prototypical PV formation and bacterial growth in hAMs required a functional type IV secretion system, indicating C. burnetii secretes effector proteins that control macrophage functions. Avirulent C. burnetii promoted sustained activation of Akt and Erk1/2 pro-survival kinases and short-termphosphorylation of stress-related p38. Avirulent organisms also triggered a robust, early pro-inflammatory response characterized by increased secretion of TNF-α and IL-6, while virulent isolates elicited substantially reduced secretion of these cytokines. A corresponding increase in pro- and mature IL-1β occurred in hAMs infected with avirulent C. burnetii, while little accumulation was observed following infection with virulent isolates. Finally, treatment of hAMs with IFN-γ controlled intracellular replication, supporting a role for this antibacterial insult in the host response to C. burnetii. Collectively, the current results demonstrate the hAM model is a human disease-relevant platform for defining novel innate immune responses to C. burnetii., (© 2012 John Wiley & Sons Ltd.)

Q fever, caused by the pathogen Coxiella burnetii, is an acute disease that can progress to become a serious chronic illness. The organism leads an obligate, intracellular lifecycle, during which it multiplies in the phagolytic compartments of the phagocytic cells of the immune system of its hosts. This characteristic makes study of the organism particularly difficult and is perhaps one of the reasons why, more than 70 y after its discovery, much remains unknown about the organism and its pathogenesis. A variety of animal species have been used to study both the acute and chronic forms of the disease. Although none of the models perfectly mimics the disease process in humans, each opens a window onto an important aspect of the pathology of the disease. We have learned that immunosuppression, overexpression of IL10, or physical damage to the heart muscle in mice and guinea pigs can induce disease that is similar to the chronic disease seen in humans, suggesting that this aspect of disease may eventually be fully understood. Models using species from mice to nonhuman primates have been used to evaluate and characterize vaccines to protect against the disease and may ultimately yield safer, less expensive vaccines.

Background: Community-acquired pneumonia (CAP) is the major manifestation of Q fever, an emerging disease in French Guiana. Consequently, the empirical antibiotherapy used for the treatment of CAP combines doxycycline and the recommended amoxicillin. Our objectives were to estimate the prevalence of Q fever pneumonia and to build a prediction rule to identify patients with Q fever pneumonia for empirical antibiotic guidance., Methods: A retrospective case-control study was conducted on inpatients admitted with CAP in the Department of Infectious Diseases of Cayenne Hospital from 2004 to 2007. Serodiagnosis for Coxiella burnetii was performed for all patients. Risk factor analysis was performed using multivariate logistic regression, and a prognostic score was computed using bootstrap procedures. The score performance characteristics were used to choose the best prediction rule to identify patients with Q fever pneumonia., Results: One hundred thirty-one patients with CAP were included and the Q fever pneumonia prevalence was 24.4% (95% confidence interval [CI], 17.1-31.9). In multivariate analysis, male sex, middle age (age, 30-60 years), headache, leukocyte count <10 × 10(9)/L and C-reactive protein level >185 mg/L were independently associated with Q fever pneumonia. Patients with a predictive score ≤3 had a low risk of Q fever pneumonia with a negative predictive value of 0.97 (95% CI, .90-1) and a sensitivity of 0.97 (95% CI, .89-1)., Conclusions: The prediction rule described here accurately identifies patients with low risk of Q fever pneumonia and may help physicians to make more rational decisions about the empirical use of antibiotherapy. Further prospective studies should be performed to validate this score.

The acute sickness response to infection is a conserved set of changes in physiology and behaviour, featuring fever, fatigue, musculo-skeletal pain, disturbed mood, and cognitive difficulties. The manifestations differ somewhat between individuals, including those infected with pathogens which do not have genetic variability--suggesting host determinants. Principal components analysis (PCA) was applied to acute phase, self-report symptom data from subjects in the Dubbo Infection Outcomes Study (n=296) to empirically derive indices of fatigue, pain, neurocognitive difficulties, and mood disturbance, as well as overall illness severity. Associations were sought with functional single nucleotide polymorphisms (SNPs) in the cytokine genes, interleukin (IL)-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-10. The summed individual symptom indices correlated with overall severity and also with functional status. The relative contribution of individual symptom domains to the overall illness was stable over time within subjects, but varied between subjects with the same infection. The T allele of the IFN-γ +874 T/A SNP was associated with increased fatigue (p=0.0003; OR: 3.3). The C allele of the IL-10 -592 C/A SNP exerted a protective effect on neurocognitive difficulties (p=0.017; OR: 0.52); while the A allele for the IL-10 -592 SNP was associated with increased mood disturbance (p=0.044; OR: 1.83), as was the G allele of the IL-6 -174 G/C SNP (p=0.051; OR: 1.83). The acute sickness response has discrete symptom domains including fatigue, which have unique genetic associations. These data provide novel insights into the pathophysiology of fatigue states., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: To ascertain the role of platelets in pathogenesis of clinical symptoms in patients with Q-fever., Material and Methods: We studied hemostasis with estimation of functional platelet activity in 49 patients with Q-fever., Results: Hemorrhagic syndrome (HS) occurred in 34.4% patients with Q-fever (QF) during seasonal rise of morbidity. HS manifested with petechiae (12%), hematomas (32%), nasal bleeding (17%), stomatorrhagia (9%), melena (12%). Characteristics and duration of such symptoms as weakness (100%), myalgia (72%), arthralgia (52.9%) suggested hemocoagulatory disorders as a cause of the symptoms appearance. At the height of the disease thrombocytopenia was accompanied with inhibition of platelet aggregation activity, but regression of the clinical symptoms was associated with an increase in platelet count and platelet hyperaggregation. Fibrinogen content was elevated during hospitalization in 50% patients., Conclusion: Clinical manifestations of HS are typical for Q-fever prevalent in the Astrakhan Region. Hemostatic disorders because of altered functional activity of platelets were registered in all the cases and evidence for pathogenetic unbalance of homeostasis in Q-fever patients.

Background: Q fever is a zoonosis caused by the obligate intracellular bacterium Coxiella burnetii. The two long-term complications, after primary infection, are chronic Q fever in ∼1% of patients, and a chronic fatigue syndrome in 10-20%. However, the existence of a protracted decreased health status after Q fever remains controversial., Aim: To determine the health status of the patients of the Q fever outbreak in The Netherlands in 2007, 1 year after primary infection., Design: Cross-sectional case-control study., Methods: Health status of the patients from the 2007 Dutch Q fever outbreak was compared to age-, sex- and geographically matched and Q fever seronegative controls. Health status of both patients and controls was assessed with the Nijmegen Clinical Screening Instrument (NCSI)., Results: Fifty-four Q fever patients provided 34 years of age- and sex-matched controls from the same neighbourhood. Eleven controls had positive Q fever serology and were excluded. Q fever patients had significantly more problems on the subdomains of symptoms and functional impairment. Overall quality of life was decreased in both patients and controls, 59% vs. 39%, respectively, ns). Severe fatigue levels were present in 52% of patients vs. 26% in controls (P < 0.05)., Conclusion: These data support a sustained decrease in many aspects of health status in Q fever patients in The Netherlands, 1 year after primary infection.

Background: Q fever, a zoonosis due to Coxiella burnetii infection, exhibits sexual dimorphism; men are affected more frequently and severely than women for a given exposure. Here we explore whether the severity of C. burnetii infection in mice is related to differences in male and female gene expression profiles., Methodology/principal Findings: Mice were infected with C. burnetii for 24 hours, and gene expression was measured in liver cells using microarrays. Multiclass analysis identified 2,777 probes for which expression was specifically modulated by C. burnetti infection. Only 14% of the modulated genes were sex-independent, and the remaining 86% were differentially expressed in males and females. Castration of males and females showed that sex hormones were responsible for more than 60% of the observed gene modulation, and this reduction was most pronounced in males. Using functional annotation of modulated genes, we identified four clusters enriched in males that were related to cell-cell adhesion, signal transduction, defensins and cytokine/Jak-Stat pathways. Up-regulation of the IL-10 and Stat-3 genes may account for the high susceptibility of men with Q fever to C. burnetii infection and autoantibody production. Two clusters were identified in females, including the circadian rhythm pathway, which consists of positive (Clock, Arntl) and negative (Per) limbs of a feedback loop. We found that Clock and Arntl were down-modulated whereas Per was up-regulated; these changes may be associated with efficient bacterial elimination in females but not in males, in which an exacerbated host response would be prominent., Conclusion: This large-scale study revealed for the first time that circadian rhythm plays a major role in the anti-infectious response of mice, and it provides a new basis for elucidating the role of sexual dimorphism in human infections.

Public awareness and advances in the diagnostic approach to Q fever have provided important information on epidemiological and clinical aspects of this zoonosis. Coxiella burnetii infection exhibits various acute or chronic clinical forms, and infection during pregnancy may jeopardize the integrity of the fetus. The presentation of infection is often nonspecific and this hinders prompt diagnosis. Therapeutic regimens vary, and treating Q fever during pregnancy and childhood is often challenging. Increasing clinical experience with C. burnetii infections has helped create treatment protocols and follow-up algorithms that have considerably improved management and prognosis. Vaccines are available, although their use is still limited.

We conducted a longitudinal observational study of 533 patients presenting to two hospitals in the Ecuadorean Amazon basin with acute undifferentiated febrile illness (AUFI) from 2001 through 2004. Viral isolation, reverse transcription-polymerase chain reaction (RT-PCR), IgM seroconversion, and malaria smears identified pathogens responsible for fever in 122 (40.1%) of 304 patients who provided both acute and convalescent blood samples. Leptospirosis was found in 40 (13.2%), malaria in 38 (12.5%), rickettsioses in 18 (5.9%), dengue fever in 16 (5.3%), Q fever in 15 (4.9%), brucellosis in 4 (1.3%), Ilhéus infection in 3 (1.0%), and Venezuelan equine encephalitis (VEE), Oropouche, and St. Louis encephalitis virus infections in less than 1% of these patients. Viral isolation and RT-PCR on another 229 participants who provided only acute samples identified 3 cases of dengue fever, 2 of VEE, and 1 of Ilhéus. None of these pathogens, except for malaria, had previously been detected in the study area.

Q fever is a worldwide zoonosis caused by Coxiella burnetii. Q fever may be present as an acute or a chronic infection and can be reactivated during subsequent pregnancies. Although its exact prevalence remains unknown, it is likely that the number of cases of Q fever in pregnant women is underestimated. During pregnancy, the illness is likely to be asymptomatic, and diagnosis is based on serology. Acute infection results in appearance of IgM and IgG antibodies mainly directed against the avirulent form of C. burnetii (phase II). Chronic Q fever results in particularly high level of IgG and IgA antibodies directed against both virulent (phase I) and avirulent (phase II) forms of the bacterium. Q fever may result in adverse pregnancy outcome, including spontaneous abortion, intrauterine growth retardation, oligoamnios, intrauterine fetal death (IUFD), and premature delivery. Obstetric complications occur significantly more often as C. burnetii infects the patient at an early stage of her pregnancy. Occurrence of IUFD is correlated with the presence of placental infection by C. burnetii and might be the consequence of direct infection of the fetus. The mother is exposed to the risk of chronic Q fever and endocarditis with potential fatal evolution. Long-term cotrimoxazole therapy prevents from placental infection, IUFD, and maternal chronic Q fever. Such treatment should be used to treat pregnant women with Q fever. Women with previous history of Q fever should have a regular serological follow up. Obstetricians' knowledge about Q fever must be improved.

A mononuclear phagocyte derived from B1b cells (B1CDP) has been described. As these cells migrate from the peritoneal cavity to non-specific inflammatory lesion sites and are highly phagocytic via Fc and mannose receptors, their microbicidal ability of these cells was investigated using the Coxiella burnetii cell infection model in vitro. In this report, the pattern of infection and C. burnetii phase II survival in B1CDP phagosomes was compared with the pattern of infection of peritoneal macrophages from Xid mice (PMphi) and bone marrow derived macrophages (BMMphi). Infection was assessed by determining the large parasitophorous vacuole formation, the relative focus forming units and the quantification of DAPI (4',6-diamino-2-phenylindole) fluorescence images acquired by confocal microscopy. When compared to macrophages, B1CDP are more permissive to the bacterial infection and less effective to kill them. Further, results suggest that IL-10 secreted by B1 cells are involved in their susceptibility to infection by C. burnetti, since B1CDP from IL-10 KO mice are more competent to control C. burnetii infection than cells from wild type mice. These data contribute further to characterize B1CDP as a novel mononuclear phagocyte.

Background: Functional polymorphisms in immune response genes are increasingly recognized as important contributors to the marked individual differences in susceptibility to and outcomes of infectious disease. The acute sickness response is a stereotypical set of illness manifestations mediated by the proinflammatory cytokines induced by many different pathogens. The genetic determinants of severity of the acute sickness response have not previously been explored., Methods: We examined the impact of functional polymorphisms in cytokine genes with critical roles in the early immune response (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and interferon-gamma) on the severity and duration of illness following acute infection with Epstein-Barr virus, Coxiella burnetii (the causative agent of Q fever), or Ross River virus., Results: We found that the interferon-gamma +874T/A and the interleukin-10 -592C/A polymorphisms significantly affected illness severity, cytokine protein levels, and the duration of illness. These cytokine genotypes acted in synergy to potentiate their influence on disease outcomes., Conclusions: These findings suggest that genetically determined variations in the intensity of the inflammatory response underpin the severity of the acute sickness response and predict the recovery time across varied infections.

We determined the epidemiological features of three zoonoses in hospitalized patients in southern Croatia. Patients were diagnosed by serological testing. Clinical and epidemiological data were also collected. Between 1982 and 2002, Mediterranean spotted fever (MSF) was diagnosed in 126 (incidence rate 1.27/100,000 per year), murine typhus (MT), in 57 (incidence rate 0.57/100,000 per year), and Q fever in 170 (incidence rate 1.7/100,000 per year) patients. MSF and Q fever were characterized by a marked seasonality. Incidences of Q fever and of MSF were higher for males than for females (P<0.0001 and P=0.0024, respectively). The most frequent of the three zoonoses in children was MSF. Q fever and MT cases were mostly seen in the 21-50 years age group. We found no statistically significant differences between season- and gender-specific incidence rates of MT. Whereas infections due to rickettsiae decreased, the incidence of Q fever increased over the last 12 years of the study.

An outbreak of Q fever occurred in 22 (58%) of 38 Marines deployed to Iraq in 2005. Fever (in 100% of patients), respiratory symptoms (76%), and gastrointestinal symptoms (53%) were common. Possible risk factors included dust and exposure to animals and ticks.

The clinical information of acute Q fever in Taiwan was limited. A clinical study of 109 adults with serologically documented acute Q fever in the past decade (1994-2005) at 3 referral hospitals in southern Taiwan was reported. Their clinical manifestations, laboratory findings, and clinical outcomes were analyzed. Males predominated (98, 90%). There is a significant correlation between monthly average temperature and case numbers of acute Q fever (r = 0.74, P = 0.006). Fever (99%), chills (69%), and headache (45%) were the common symptoms, and relative bradycardia (44/60, 73 %) was often noted. Acute hepatitis, defined as either serum aspartate aminotransferase >or=60 IU/L or alanine aminotransferase >or=78 IU/L, was found in 88 (85%) cases, and more than one-third (31/87, 36%) had hyperbilirubinemia (serum total bilirubin >or=1.4 mg/dL) at initial presentation. The intervals between initiation of appropriate therapy to defervescence were longer in patients with hyperbilirubinemia than those without hyperbilirubinemia, irrespective of tetracycline or fluoroquinolone therapy. Of note, 8 (7.3%) cases experienced a prolonged period of fever (>28 days). In southern Taiwan, the predominant presentation of acute Q fever is acute febrile illness with hepatitis with or without jaundice. Acute Q fever should be added to the list of differential diagnoses of patients with fever, headache, relative bradycardia, elevated serum aminotransferase levels, or prolongation of activated partial thromboplastin time, irrespective of jaundice.

Acute Q fever is a worldwide zoonosis caused by Coxiella burnetii infection. In Taiwan, cases of acute Q fever increased during 3 y of observation, especially at Kaohsiung County and City in southern Taiwan. From 15 April 2004 to 15 April 2007, a total of 67 cases of acute Q fever were identified at E-Da hospital located at Kaohsiung County. 19 (28.4%) patients had a history of travel in rural areas and only 1 had been outside southern Taiwan. 21 (31.3%) patients had a history of animal contact. 20 (30.8%) of the 65 examined patients had underlying chronic hepatitis B or hepatitis C virus infection. Fever (98.5%), chills (79.1%), headache (79.1%), relative bradycardia (44.8%), elevated aminotransferases (100%), and thrombocytopenia (74.6%) were common manifestations. 12 (19.0%) cases had abnormal findings on chest X-ray. Fatty liver (50.0%) and hepatomegaly and/or splenomegaly (41.9%) were found by abdominal image examinations. 42 (76.4%) of 55 cases had defervescence within 3 d after treatment, whereas 4 (7.3%) had spontaneous remission. Acute Q fever is an endemic infectious disease with hepatitis rather than pneumonia as the major presentation in southern Taiwan and the emergence of Q fever is due to increased alertness for the disease by physicians.

We describe the cases of three children with encephalitis associated with Coxiella burnetii infection. Neurologic features ranged from status epilepticus and coma to headache and pseudotumor cerebri syndrome. Patients had good response to antibiotic treatment with doxycycline and recovered fully. Q fever should be included in the differential diagnosis of children with encephalitis, and routine serological testing should be considered, especially in endemic areas.

Background: Although hepatitis is one of the major presentations of acute Q fever, the possible influence of viral hepatitis in Q fever has, to our knowledge, never been investigated. It is an important issue in regions where Q fever hepatitis and viral hepatitis are prevalent, such as Taiwan. We conducted a study to investigate the possible influence of viral hepatitis in cases of acute Q fever hepatitis., Methods: Cases of acute Q fever confirmed by serologic examination were included in the study. All patients who were found to be positive for Q fever were tested for hepatitis B surface antigen and antibody to hepatitis C virus, and those with positive results had their viral loads determined. Demographic data, clinical manifestations, results of laboratory and imaging examinations, and responses to treatment were recorded retrospectively from charts., Results: A total of 58 patients with acute Q fever hepatitis were studied, of whom 16 (27.6%) had viral hepatitis (hepatitis B virus infection in 12 and hepatitis C virus infection in 4). Patients with and patients without viral hepatitis did not differ with regard to clinical manifestations and responses to treatment, except that chills (100% vs. 73.8%; P=.02) and nausea and/or vomiting (18.8% vs. 2.4%; P=.03) were significantly more common among patients with viral hepatitis. The change in hepatitis B and C virus loads between the acute and convalescent phase was <1.0 log(10)., Conclusions: The clinical manifestations of acute Q fever hepatitis differ little in patients with and patients without underlying viral hepatitis, and replication of hepatitis virus is not influenced by acute Q fever hepatitis.

Q fever is a zoonosis with many manifestations. The most common clinical presentation is an influenza-like illness with varying degrees of pneumonia and hepatitis. Although acute disease is usually self-limiting, people do occasionally die from this condition. Endocarditis is the most frequent chronic presentation. Although Q fever is widespread, practitioner awareness and clinical manifestations vary from region to region. Geographically limited studies suggest that chronic fatigue syndrome and cardiovascular disease are long-term sequelae. An effective whole-cell vaccine is licensed in Australia. Live and acellular vaccines have also been studied, but are not currently licensed.

Background: The clinical manifestations of Q fever endocarditis are protean in nature. Mixed cryoglobulinemia type II is rarely a facet of the presenting clinical manifestations of Q fever endocarditis., Case Presentation: We report a case of a 65-year-old pensioner with such an association and review the literature. As transesophageal echocardiograms are usually normal and blood cultures are usually negative in Q fever endocarditis, many of the manifestations (fever, rash, glomerulonephritis/evidence of renal disease, low serum C4 complement component, presence of mixed type II cryoglobulin, constitutional symptoms as arthralgias and fatigue) can be attributed to Mixed cryoglobulinemia type II per se. The use of Classic Duke Endocarditis Service criteria does not always suffice for the diagnosis of Q fever., Conclusion: The application of the modified criteria proposed by Fournier et al for the improvement of the diagnosis of Q fever endocarditis will help to reach the diagnosis earlier and thus reduce the high mortality of the disease. We would like to stress the importance of ruling out the diagnosis of Q fever endocarditis in cases of mixed type II cryoglobulinemia.

Coxiella burnetii, the etiological agent of Q fever, is a class B biodefense agent. We are continuing the momentum of discovery generated by the first Coxiella genome sequences by extending the breadth of genomics to include four additional heterogeneous C. burnetii strains. We are also sequencing the genome of Rickettsiella grylli, an intracellular parasite of grasshoppers and the closest known phylogenetic relative to the Coxiella group. These data will enable the investigation of fundamental questions about Coxiella pathogenicity and virulence as well as broader evolutionary questions about the transition to obligate intracellular life. Specifically, sequence comparisons will permit examination of genetic differences, allowing us to address key questions: What core genes are necessary for an obligate intracellular lifestyle and developmental cycle of the genus? What specific genetic determinants can be linked to virulence properties such as host preference, disease severity, and pathology (i.e., acute vs. chronic disease)? What are the frequencies of mutation and intragenomic recombination, and levels of genome reduction? What specific factors are relevant to colonization and virulence in human hosts (based on comparisons with R. grylli)? From a public health and biodefense perspective, exposure to different strains, either natural or due to illegitimate release, may have different outcomes. With extensive genomic-level information from diverse strains, investigators can determine effective drug and vaccine targets and design methods to accurately type Coxiella based on a subset of genes, opening the way for cost-effective targeted PCR- or antibody-based tests.

Previous attempts to develop Q fever vaccines were less successful in that the vaccines caused unacceptable side effects or failed to be protective. In this study, we tested the efficacy of a mixture of eight recombinant Coxiella burnetii (C. b.) proteins in sublethal challenge infections with mice. Eight potential C. b. virulence genes (Omp, Pmm, HspB, Fbp, Orf410, Crc, CbMip, and MucZ) were overexpressed in E. coli as his-tagged fusion proteins and partially purified. All recombinant proteins but rPmm proved to be antigenic in BALB/c mice when administered as protein mixtures. For efficacy testing, mice were immunized with an adjuvanted mixture of the eight recombinant proteins and subsequently challenged intraperitoneally with the C. b. isolate Nine Mile RSA493 (1.8 x 10(8) C. b.). Only animals vaccinated with the licensed Q fever vaccine Q-Vax (vaccination control) exhibited milder symptoms and minor gain of spleen and liver weights. In summary, clinical examinations and dissection of mice immunized with the eight recombinant C. b. proteins did not indicate a protective immune response after test infection.

The clinical features in patients with acute Q fever are variable. We present a patient with fever, abdominal distension, pericardial effusion, and diffuse gallium uptake in the abdominal cavity, mimicking peritonitis or peritoneum carcinomatosis. Serologic surveys revealed acute infection by Coxiella burnetii. The patient responded poorly to doxycycline and improved with oral levofloxacin. During the afebrile period, gallium inflammatory scan showed resolution of previous diffuse uptake in the abdomen, and cardiac echo resolution of pericardial effusion, which was suggestive of peritoneal inflammation related to acute C. burnetii infection. Therefore, clinicians in Taiwan should be alert to the possibility of acute Q fever in patients with fever of unknown cause, especially with clinical evidence of peritoneal and/or pericardial inflammation.

Q fever is a zoonosis caused by Coxiella burnetii. Infection with C burnetii can be acute or chronic, and exhibits a wide spectrum of clinical manifestations. The extreme infectivity of the bacterium results in large outbreaks and makes it a potential bioweapon. In the past decade, the complete genome sequencing of C burnetii, the exploration of bacterial interactions with the host, and the description of the natural history of the disease in human beings and in experimental models have all added to our knowledge about this fascinating disease. Advances in understanding the pathophysiology and natural history of Q fever are reviewed.