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Risks Factors and Prevention of Q Fever Endocarditis

  1. Florence Fenollar1,
  2. Pierre-Edouard Fournier1,
  3. M. Patrizia Carrieri2,
  4. Gilbert Habib3,
  5. Thierry Messana4, and
  6. Didier Raoult1
  1. 1 Unité des Rickettsies, Centre Nationale de Recherche Scientifique: Unité Mixte de Recherche 6020, Faculté de Médecine, Université de la Méditerranée, Marseille, France
  2. 2 Institut Nationale de Santé et de Recherche Médicale Unité 379, Marseille, France
  3. 3 Service de Cardiologie, Hôpital de La Timone, Marseille, France
  4. 4 Service de Chirurgie Cardiaque, Hôpital de La Timone, Marseille, France
  1. Reprints or correspondence: Dr. Didier Raoult, Unité des Rickettsies, CNRS:UPRESA 6020, Faculté de Médecine, Université de la Méditerranée, 27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France (Raoult{at}univ.mrs.fr).
 
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Abstract

Coxiella burnetii causes acute and chronic Q fever. To evaluate the risk factors of development of chronic endocarditis following Q fever and to assess the best preventive therapy, a retrospective study of patients diagnosed as having Q fever during 1985–2000 was conducted. Twelve patients with acute Q fever who developed endocarditis and 102 patients with Q fever endocarditis were included in the study. When compared to 200 control patients with acute Q fever, preexisting valvular disease (P < 10−7), especially a prosthetic valve (P = .01), were encountered more often among patients with endocarditis. Among patients with valvular defects, we estimate the risk of developing endocarditis to be 39%. A combination of doxycycline plus hydroxychloroquine was better at preventing the development of endocarditis than doxycycline alone (P = .009). Our results should encourage physicians to detect valvular lesions in patients with acute Q fever and to search for acute Q fever in patients with a valvulopathy and unexplained fever. A proper treatment for such patients and a scheduled follow-up should reduce the risk of developing endocarditis.

Coxiella burnetii is a zoonotic agent that may be acquired by the respiratory or digestive route, mostly after contact with newborn and/or pregnant mammals [1]. The diagnosis of Q fever relies mainly on serological examination. Q fever is divided into acute and chronic infections characterized by different evolution, serological profiles, and treatments [1]. Acute Q fever is asymptomatic in 50% of cases [1]. In symptomatic patients, the clinical presentation is usually polymorphic and lacks specificity [1]. The major recognized forms of acute Q fever are febrile illness, atypical pneumonia, and hepatitis. In patients with chronic Q fever, the heart is the most frequently involved organ [2]. Q fever represents 3%–5% of all cases of endocarditis [3, 4]. Endocarditis usually occurs in patients with previous valvular damage or those who are immunocompromised [2, 5–8]. Because symptoms of Q fever endocarditis are not specific, diagnosis is often delayed, which results in an increased mortality rate. Although chronic Q fever is likely to develop after an acute episode—due to the multiplication of C. burnetii inside the macrophage [9], which results in a permanent bacteremia with no possibility of spontaneous cure [10], and high titer levels of persistent antibodies to phase I [11]—documented cases of such a transformation have not been frequently reported. As a result of 16 years of active surveillance, we observed the transformation from acute disease to endocarditis during clinical and serological follow-up of 12 patients from a large series of patients with Q fever. In this study, we evaluate the risk of valvulopathy in patients with acute infection, the probability of developing chronic Q fever for patients with valvular defect, the best therapy for prevention and the best follow-up in these patients.

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Patients and Methods

Patients. As a reference center for the diagnosis and study of rickettsial diseases, our laboratory receives serum samples from throughout France and abroad for Q fever diagnosis. For each patient, a standardized questionnaire, including epidemiological and clinical features, is completed by the physician in charge and logged into a database. Sex, age, address, and occupation are required. The presence of immunosuppression or valvular disease is also recorded. Patients with Q fever endocarditis are also asked questions that include those used in the diagnostic score of the Duke Endocarditis Service (Durham, NC) [12]. Finally, evolution and prognosis were categorized as full recovery, evolution to a chronic disease, or death.

In order to determine whether specific factors are associated with the development of chronic Q fever, we instigated a retrospective analysis of patients drawn from those diagnosed in our laboratory from 1985 through June 2000. Among the 1569 patients who had acute Q fever diagnosed, 12 patients who had subsequently developed endocarditis were investigated.

In order to estimate the influence of a preexisting cardiovascular disease or an immunocompromising condition in the development of C. burnetii endocarditis, we also studied the medical records of 102 patients with Q fever endocarditis and compared them with those of 200 patients with acute Q fever who were randomly selected from our database and who did not develop chronic Q fever. The 102 patients with C. burnetii endocarditis had been completely followed-up since 1983 and had been prescribed therapy by a member of our team (D.R.).

Moreover, in order to estimate the incidence of chronic manifestations, we also prospectively studied the medical records of 97 patients living in the Marseille area who presented with acute Q fever and whose medical supervision was overseen by one of us (D.R.). Of the patients, 21 (21.6%) who had a valvulopathy were proposed treatments that included either doxycycline or a combination of doxycycline and hydroxychloroquine. The incidence of endocarditis was compared in these 21 patients with valvulopathies and the 76 patients with no valvulopathy. With the same objective, to these 21 patients, we added a 10 more patients from our series who presented acute Q fever and valvulopathies.

Diagnostic criteria. The antigenic variation of C. burnetii is useful in differentiating acute and chronic illness [13]. During the course of acute Q fever, antibodies to phase II antigens predominate and their titer is greater than that of phase I antibodies. In chronic forms, however, elevated anti-phase I antibodies are uniformly detected. As cutoff values in the immunofluorescence assay, Tissot-Dupont et al. [13] recommended titers of anti-phase II IgG of ⩾200 and titers of anti-phase II IgM ⩾50, for the diagnosis of acute Q fever, and titers of anti-phase I IgG ⩾800, for the diagnosis of chronic Q fever. In our study, a serum sample with IgG titer of anti-phase I of ⩾800 was classified as “acute” or “chronic infection” according to clinical findings. Endocarditis was defined according to the modified Duke criteria [4].

Statistical methods. The proportion of preexisting valvulopathy or immunodepression among patients who developed chronic Q fever after documented acute Q fever and patients in an acute Q fever control group were compared using Fisher's exact test. We also compared the rates of response depending on the antibiotic therapy regimen that had been prescribed during the acute phase of illness. P < .05 was considered statistically significant. In order to assess the strength of association between the factors examined and the occurrence of endocarditis, ORs or RRs and their 95% CIs were calculated. When necessary, maximum likelihood methods for the relative risk estimation and 95% CIs were also calculated.

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Results

Cases that evolved from acute Q fever to endocarditis. From January 1984 through June 2000, 1569 patients had acute Q fever diagnosed; of these patients, 12 (0.76%) subsequently developed endocarditis. Four of these patients were female and 8 were male. Their mean age was 59.6 years (range, 45–74 years). Chronic infection occurred after a median of 6 months (range, 1–18 months) from the onset of acute Q fever. All patients had known preexisting valvular disease, which consisted of both a mitral and aortic insufficiency (3 patients), a mitral insufficiency (4), an aortic insufficiency (1), a mitral prosthesis (3), and a mitral and aortic prosthesis (1). Clinical symptoms of acute Q fever were pneumonia (1 patient), hepatitis (4), and flulike syndromes (6). One patient presented with asymptomatic acute Q fever and developed a pulmonary embolism due to a phlebitis of his left leg during the convalescent phase. For 10 of the patients, chronic Q fever manifestations included prolonged fever (8 patients), a new heart murmur (2), and purpuric eruption (1). The eleventh patient developed endocarditis due to Streptococcus bovis on a native mitral valve ∼4 months after he had acute Q fever, for which he underwent valvular surgery. At this stage, his anti-phase I and anti-phase II titers were low, but the results of a C. burnetii-specific PCR analysis of the vegetation were positive. Seven months after this case of endocarditis, an increase in serological titers, especially anti-phase I IgG and IgA associated with an increase of erythrocyte sedimentation rate and the detection of rheumatoid factor, were evidence that Q fever endocarditis was progressing. For the last patient, aggravation of a cardiac insufficiency required aortic valve removal. The results of a C. burnetii-specific PCR analysis of the valve was positive, and subsequently an isolate of C. burnetii was obtained from this material. Echocardiography revealed vegetations in 3 of the 12 patients.

Comparison of patients who had endocarditis with controls who had acute Q fever. The comparison of risk factors of 102 patients who developed C. burnetii endocarditis and 200 patients with acute Q fever are summarized in table 1. Among the 102 patients with Q fever endocarditis, the existence of previous valvulopathies was reported by 95 patients (93%), none of whom reported a mitral prolapse. Of the 7 patients without any previous valvulopathies, 3 had an active lymphoma and 2 had an active cancer when the diagnosis was made. Only 2 patients had no recognized predisposing factor. Among the 200 randomly selected control patients with acute Q fever, 6 had a previously known valvular disease. None had a known cancer in evolution at the time of diagnosis. In comparison with the patients with endocarditis, patients in the control group had a significantly lower prevalence of cancer (P = .004) and a significantly lower prevalence of a preexisting valvulopathy (P < .0001).

Table 1
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Table 1

Retrospective comparison of risk factors of 102 patients who developed Coxiella burnetii endocarditis and 200 patients with acute Q fever.

Role of valvulopathies in the development of endocarditis. We studied 21 patients with valvulopathies among 97 patients who presented with acute Q fever who were followed by 1 of the authors (D.R.). The development of endocarditis was observed in 7 patients (33.3%) who had had previous valvulopathies but in none of the 76 patients without a preexisting valvulopathy (P = .0002). In order to improve the study of the role of specific cardiac conditions and the type of treatment on the incidence of endocarditis, we added to the 21 patients a set of 10 patients from our series who presented acute Q fever and valvulopathies, 5 of whom had cases that evolved to endocarditis (n = 31). A total of 12 (38.7%) of 31 patients with acute Q fever and a valvulopathy developed endocarditis; however, the type of preexisting valvular disease (table 2) appeared not to influence a progression to endocarditis (P = .14). Nonetheless, patients with a prosthesis did appear to be at greater risk of developing endocarditis (P = .01).

Table 2
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Table 2

Comparison of type of preexisting valvular disease and treatment of 12 patients who developed Coxiella burnetii endocarditis following acute Q fever and 19 who did not have cardiac infection.

The antibiotic regimen was only known for 30 of the 31 patients and is summarized in table 2. When we compared these regimens, we found that 6 (75%) of 8 patients who did not receive treatment developed a chronic infection, 5 of 10 developed a chronic infection when receiving doxycycline from 2 weeks to 6 months, and none of the 12 who received doxycycline and hydroxychloroquine for 1 month to 15 months developed chronic infection. Of these 12 patients, 3 received treatment for 1 month, 3 for 6 months, 2 for 8 months, 1 for 9 months, 2 for 12 months, and 1 for 15 months. The regimen containing hydroxychloroquine was found to be significantly superior in preventing Q fever when compared with doxycycline alone (P = .009). No significant differences were found between treatment with doxycycline alone and no treatment.

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Discussion

Of the 1569 patients with acute Q fever in our series, 12 (7.6%) developed endocarditis. This study helped to confirm some characteristics of the disease that, so far, have only been suggested by anecdotal case reports or experimental models. During the past 20 years, the respective roles of strain specificity and host factors in the presentation of Q fever have been discussed [6, 14–18]. C. burnetii is able to survive in host macrophages after they develop acute Q fever despite apparent cure [9, 19] and can, therefore, relapse [20, 21]. Although several authors have proposed that different C. burnetii strains are associated with different clinical presentations, experimental and clinical data support the fact that host factors, such as immunosuppression or valvular damage, are the main factors that influence the clinical course of Q fever [1, 6, 7, 14, 16, 18, 22–29]. La Scola et al. [24] demonstrated that 50% of guinea pigs with electrocoagulated aortic valves developed infective endocarditis versus none of those that had normal valves and that were inoculated intraperitoneally with C. burnetii.

In the present study, the data show that patients with valvular diseases who experience acute Q fever may remain asymptomatically infected. Moreover, all patients who developed endocarditis after an identified acute Q fever had a previously known valvulopathy. Because patients with valvular defects have a higher risk of developing chronic Q fever [30], they should be treated immediately and monitored for at least 2 years to reduce the risk of chronic infection. The incidence of endocarditis among patients with acute Q fever and valvular abnormality was estimated to be 39% (12 of 31 patients) but was even higher (6 [75%] of 8) among untreated patients. Both incidence estimations are consistent with those reported in the guinea pig experimental model [24]. By extrapolating the estimated prevalence rate of valvulopathies among patients with acute Q fever to the series of 1569 patients, 47 patients have been expected to have valvular defects. Of these 47 patients, 18 (38.7%) are predicted to develop endocarditis, and currently this number is close to the number of endocarditis cases with valvular defects diagnosed in this study (12). We found that patients with a prosthetic valve were at high risk, but only 4 patients had such a factor. These data are in accordance with those of published studies of Q fever endocarditis that most frequently involves prosthetic valves [30] and less frequently the aortic valve than other causes of endocarditis [2, 31]. Because the relative risk of developing endocarditis is high, we believe that all patients who have acute Q fever diagnosed should be screened for a clinical history of valvulopathy. Indeed, the occurrence of valvulopathy appears to be relatively common. For example, a recent study, which was based on a review of the medical records of patients in Rochester, Minnesota, estimated the prevalence of mitral valve disease (excluding mitral valve prolapse) to be 1.2% in patients ⩾35 years of age [32]. Another study found a prevalence of aortic valve or mitral valve insufficiency of 1.3% among a control group of obese patients who did not use appetite suppressants [33]. Conversely, because acute Q fever often presents in a nonspecific manner, patients with valvulopathy and fever should be tested for C. burnetii infection. Contrary to our findings, an early study [34] concluded that the risk of endocarditis was not increased among patients who had been acutely infected with C. burnetii when compared with those who had not been acutely infected; however, follow-up was available for only 411 patients who had presented with acute Q fever. If we extrapolate data from our 1569 patients, we would estimate that the earlier survey would have diagnosed only 3 cases of endocarditis, and this figure may have been further decreased if the prevalence of valvular diseases in the population that was studied was lower than that in ours. Furthermore, because the methods for diagnosing Q fever were not disclosed in this earlier work, it is impossible to assess whether the best strategies for achieving this aim were being employed.

Usually, a regimen of doxycycline, 200 mg per day for 3 weeks, is recommended for patients with acute Q fever. Presently, this treatment of patients with acute Q fever is not sufficient to prevent the development of chronic Q fever. Five of our patients developed chronic Q fever despite having completed a regimen of doxycycline, 200 mg per day for between 2 weeks and 6 months. We have now observed that the combination of doxycycline plus hydroxychloroquine had a significant effect in stopping patients from developing chronic disease. In a previous study [35], we demonstrated that the treatment of patients with chronic Q fever with a combination of doxycycline plus hydroxychloroquine was more efficient and had a shorter duration than did any other antibiotic regimen [19]. We suggest that, in patients with acute Q fever and with cardiovascular defects should be treated with doxycycline plus hydroxychloroquine for 12 months. In addition, there should be a serological follow-up every 3 months for ⩾2 years. It must also be emphasized that some cases of endocarditis have been documented as occurring as long as 20 years after infection [36]. Systematic vaccination in patients who risk having chronic Q fever should also be proposed in areas where the disease is recognized [37]. Investigations into the prophylactic effectiveness and safety of a Q fever vaccine in exposed individuals with valve risk factors are lacking, however, and should be performed. In conclusion, we confirm the predisposing role of previous cardiac damage in the development of endocarditis and evaluate the incidence in this population to be 1 in 3. The next challenge will be to better define the management of acute Q fever in patients with cardiovascular defects and the diagnosis of valvular lesions in patients with acute Q fever. Improvement in the diagnosis and management of the acute episode is essential, as is improving the follow-up; however, our preliminary data show that a specific antibiotic regimen can avoid a deleterious evolution.

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Acknowledgments

We acknowledge Emma Birtles, Richard Birtles, and Lesley Sakyi, for reviewing this manuscript.

  • Received July 28, 2000.
  • Revision received November 29, 2000.
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  1. Clin Infect Dis. (2001) 33 (3): 312-316. doi: 10.1086/321889
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