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Delayed diagnosis of chronic Q fever and cardiac valve surgery.

Q fever, a zoonosis caused by the intracellular gram-negative bacterium Coxiella burnetii, occurs in outbreaks and is prevalent worldwide. Q fever has acute and chronic stages (1). Acute Q fever is a self-limiting febrile disease occurring in 40%-50% of C. burnetii-infected persons (1). Chronic Q fever can develop years after primary infection and occurs in 1%-5% of C. burnetii-infected persons (1,2). The most critical manifestations of chronic Q fever are endocarditis and infections of vascular prosthesis and aortic aneurysms (3). Persons with pre-existing valvular cardiac disease have a reported 40% risk of Q fever endocarditis when infected with C. burnetii (2,4).

During 2007-2010, an outbreak of >4,000 cases of acute Q fever occurred in the Netherlands (5). To increase understanding of the role of Q fever in valvular cardiac disease, we present 3 cases of chronic Q fever and valvular cardiac disease requiring surgery in patients from the Netherlands. The diagnosis of chronic Q fever was not made until after the patients had elective cardiac valve surgery for progressive valvular dysfunction.

Case 1

In 2004, aortic valve stenosis of a tricuspid valve was diagnosed in a 73-year-old man. Additional medical history included atrial fibrillation and transient ischemic attacks. Because of progressive stenosis, the patient underwent aortic valve replacement with a bioprosthesis in May 2011. The removed valve had no macroscopic signs of endocarditis, so neither microbiological nor pathological examination was requested. Four months later, paravalvular insufficiency of the bioprosthesis developed in the patient, requiring a second valve replacement. Transesophageal echocardiography revealed no vegetations. Macroscopic signs of endocarditis were not observed on the removed valve; further examination was not requested. However, serologic testing for C. burnetii revealed chronic infection (Table).

The patient had not been aware of previous acute Q fever infection and had not experienced fever, night sweats, weight loss, or malaise. Further examination by fluorodeoxyglucose positron emission tomography (FDG PET) combined with low-dose computed tomography (CT) demonstrated no other chronic Q fever focus or vascular abnormalities. The patient started antimicrobial drug therapy (doxycycline and hydroxychloroquine) and was doing well 3 months later. Retrospective microbiological examination of a serum sample obtained at the time of the first valve replacement demonstrated a profile consistent with chronic Q fever (Table).

Case 2

A 78-year-old man had a medical history of aortic valve stenosis of a tricuspid valve, abdominal aortic aneurysm, and endovascular aneurysm repair in 2005. In July 2011, he was screened for chronic Q fever in a program for patients at high risk for development of chronic Q fever (e.g., persons with a vascular prosthesis or aneurysm) (6); the screening revealed that he did have chronic Q fever infection (Table). The patient had not been aware of an acute Q fever episode and did not report night sweats, weight loss, malaise, or fever. Because the he had progressive aortic valve stenosis, the patient was on a waiting list for elective valve replacement at an academic cardiovascular center. This center, located outside the Q fever epidemic area and unaware of the patient's Q fever status, placed a bioprosthesis in the patient in August 2011. The native valve was not further examined because there were no macroscopic signs of endocarditis.

After the surgery, the Q fever screening results were acted upon. FDG PET/CT scan results showed no signs of infection at the abdominal aortic prosthesis or elsewhere. In September 2011, the patient started antimicrobial drug therapy (doxycycline and hydroxychloroquine) and was doing well at a 6-month follow-up visit.

Case 3

A 70-year-old woman had a longstanding history of rheumatoid arthritis that was treated consecutively with infliximab and etanercept plus corticosteroids and azathioprine. In 2009, she was hospitalized because of heart failure caused by mitral valve insufficiency, possibly resulting from chordal rupture, combined with an atrial septal defect and left ventricular systolic dysfunction. In October 2010, mitral valve repair, a coronary bypass, and atrial septal defect closure were performed. The patient was registered for vaccination against C. burnetii, which was offered by the government to persons with aortic (endo) vascular prostheses or cardiac valve abnormalities. In April 2011, prevaccination screening results showed she was positive for chronic Q fever (Table). The patient did not recall a previous acute Q fever episode, and she had not experienced fever, night sweats, malaise, or weight loss. FDG PET/CT scan results showed no FDG uptake in the large vessels.

Transesophageal echocardiography revealed an insufficiency of the mitral valve repair. An echocardiogram was not performed immediately after the valve repair in 2010, so it could not be determined whether this insufficiency was new. No vegetations or signs of endocarditis were seen. Antimicrobial drug treatment (doxycycline and hydroxychloroquine) was started and later switched to moxifloxacin monotherapy because of elevated liver enzyme levels and severe nausea and vomiting, possibly caused by hydroxychloroquine. After 15 months of treatment, the patient still had a high level of C. burnetii antibody.

Conclusions

We reviewed 3 cases of chronic Q fever and valvular cardiac disease requiring surgery. The diagnosis of chronic Q fever was not made until after the elective surgery. Early diagnosis and antimicrobial drug treatment of Q fever endocarditis might have prevented surgery. Symptoms of Q fever endocarditis can be nonspecific, and vegetations are usually absent or small (7). As observed in the cases presented here, C-reactive protein levels can be normal or only mildly elevated (8) (Table). The most frequent signs of Q fever endocarditis are a new valvular insufficiency or worsening of preexisting valvular insufficiency (8-10). C. burnetii-infected cardiac valves can appear normal on visual inspection, as demonstrated in the cases presented here, and on histologic evaluation (11).

Diagnosis of chronic Q fever is challenging. Chronic infection is determined on the basis of serologic testing and PCR of blood samples and, if available, tissue samples. In the absence of acute Q fever, PCR results positive for C. burnetii in blood or tissue prove chronic infection; however, the sensitivity of this test is only 50%-60% in patients with chronic Q fever (12). When cultured in cells, C. burnetii exhibits antigenic variation in which the virulent variant, called phase I, shifts to an avirulent variant, called phase II. During acute infection, antibodies to phase II antigens are detected first; persisting high levels of antibodies to phase II, and especially phase I antigens, are indicative of chronic Q fever (13). A phase I IgG titer >800 or >1,024, depending on the type of immunofluorescence assay used, has been internationally accepted for the serologic diagnosis of chronic Q fever (14,15).

Long-term antimicrobial drug treatment, preferably doxycycline plus hydroxychloroquine, is the treatment of choice for chronic Q fever. Treatment should continue for 18 months for native valves and 24 months for prosthetic valves, until a 4-fold decrease of phase I IgG titers and a complete clearance of phase II IgM are reached. If phase I IgG titers remain high or phase II IgM is detectable, treatment should be extended. The rates of morbidity and mortality among people with chronic Q fever are high, reaching >60% if treatment is delayed or not initiated. With adequate treatment, the mortality rate for Q fever endocarditis has declined to 5%. Chronic Q fever involving prosthetic valves is associated with a higher mortality rate, longer treatment, and elevated chance of complications (9). For the cases reported here, preoperative diagnosis of chronic Q fever might have prevented the second valve replacement in case-patient 1 and the delay in treatment initiation in case-patients 2 and 3. We advise preoperative serologic screening for chronic Q fever in all patients undergoing elective cardiac valve surgery in Q fever epidemic areas. If serologic test results are positive for C. burnetii antibodies, PCR of the excised valve should be performed.

Dr Kampschreur is an infectious disease fellow and PhD student at the Division of Medicine, Department of Internal Medicine and Infectious Diseases of the University Medical Center Utrecht. Her research topic is chronic Q fever in the Netherlands.

References

(1.) Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999; 12:518-53.

(2.) Landais C, Fenollar F, Thuny F, Raoult D. From acute Q fever to endocarditis: serological follow-up strategy. Clin Infect Dis. 2007; 44:1337-40. http://dx.doi.org/10.1086/515401

(3.) Raoult D, Tissot-Dupont H, Foucault C, Gouvernet J, Fournier PE, Bernit E, et al. Q fever 1985-1998. Clinical and epidemiologic features of 1,383 infections. Medicine (Baltimore). 2000; 79:109-23. http://dx.doi.org/10.1097/00005792-200003000-00005

(4.) Tissot-Dupont H, Vaillant V, Rey S, Raoult D. Role of sex, age, previous valve lesion, and pregnancy in the clinical expression and outcome of Q fever after a large outbreak. Clin Infect Dis. 2007; 44:232-7. http://dx.doi.org/10.1086/510389

(5.) van der Hoek W, Dijkstra F, Schimmer B, Schneeberger PM, Vellema P, Wijkmans C et al. Q fever in the Netherlands: an update on the epidemiology and control measures. Euro Surveill. 2010 [cited 2012 Feb 22]. http://www.eurosurveillance.org/ViewArticle. aspx?ArticleId=19520

(6.) Wever PC, Arts CH, Groot CA, Lestrade PJ, Koning OH, Renders NH. Screening for chronic Q fever in symptomatic patients with an aortic aneurysm or prosthesis [in Dutch]. Ned Tijdschr Geneeskd. 2010; 154:A2122.

(7.) Salamand AC, Collart F, Caus T, Casalta JP, Mouly-Bandini A, Monties JR, et al. Q fever endocarditis: over 14 years of surgical experience in a referral center for rickettsioses. J Heart Valve Dis. 2002; 11:84-90.

(8.) Issartel B, Gauduchon V, Chalabreysse L, Celard M, Ninet J, Lepidi H, et al. Clinically and histologically silent Q fever endocarditis accidentally diagnosed by PCR. Clin Microbiol Infect. 2002; 8: 113-4. http://dx.doi.org/10.1046/j.1198-743x.2001.00360.x

(9.) Million M, Thuny F, Richet H, Raoult D. Long-term outcome of Q fever endocarditis: a 26-year personal survey. Lancet Infect Dis. 2010; 10:527-35. http://dx.doi.org/10.1016/S1473-3099(10)70135-3

(10.) Lepidi H, Houpikian P, Liang Z, Raoult D. Cardiac valves in patients with Q fever endocarditis: microbiological, molecular, and histologic studies. J Infect Dis. 2003; 187:1097-106. http://dx.doi. org/10.1086/368219

(11.) Brouqui P, Raoult D. Endocarditis due to rare and fastidious bacteria. Clin Microbiol Rev. 2001; 14:177-207. http://dx.doi.org/10.1128/ CMR.14.1.177-207.2001

(12.) Fenollar F, Fournier PE, Raoult D. Molecular detection of Coxiella burnetii in the sera of patients with Q fever endocarditis or vascular infection. J Clin Microbiol. 2004; 42:4919-24. http://dx.doi. org/10.1128/JCM.42.11.4919-4924.2004

(13.) Raoult D, Marrie T, Mege J. Natural history and pathophysiology of Q fever. Lancet Infect Dis. 2005; 5:219-26. http://dx.doi. org/10.1016/S1473-3099(05)70052-9

(14.) Dupont HT, Thirion X, Raoult D. Q fever serology: cutoff determination for microimmunofluorescence. Clin Diagn Lab Immunol. 1994; 1:189-96.

(15.) van der Hoek W, Versteeg B, Meekelenkamp JC, Renders NH, Leenders AC, Weers-Pothoff I, et al. Follow-up of 686 patients with acute Q fever and detection of chronic infection. Clin Infect Dis. 2011; 52:1431-6. http://dx.doi.org/10.1093/cid/cir234

Author affiliations: University Medical Center Utrecht, Utrecht, the Netherlands (L.M. Kampschreur, J.J. Oosterheert); and Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands (L.M. Kampschreur, E. Hoornenborg, N,H.M. Renders, J.F. Haverman, P. Elsman, P.C. Wever)

DOI: http://dx.doi.org/10.3201/eid1905.120353

Address for correspondence: Linda M. Kampschreur, Division of Medicine, Department of Internal Medicine and Infectious Diseases, Rm F02-107, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands; email: l.m.kampschreur@umcutrecht.nl
Table. Results of Coxiella burnetii and C-reactive protein testing for
3 patients with chronic Q fever and valvular cardiac disease requiring
valve surgery, the Netherlands *

 Results for C. burnetii testing

 IFA ([dagger])

 Phase I Phase II
Case-patient IgG titer IgG titer PCR

1
 Before valve surgery ([dagger]) 32,768 65,536 Negative
 After valve surgery 8,192 8,192 Positive

2
 Before valve surgery 16,384 16,384 Positive
 After valve surgery 16,384 16,384 Positive

3 ([double dagger])
 After valve surgery 8,192 8,192 Positive

Case-patient C-reactive protein, mg/L

1
 Before valve surgery ([dagger]) <6
 After valve surgery 52

2
 Before valve surgery 22
 After valve surgery 26

3 ([double dagger])
 After valve surgery 11

* IFA, immunofluorescence assay.

([dagger]) Q fever serologic testing was perform

([double dagger]) Serologic testing was not available before surgery.
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Article Details
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Title Annotation:DISPATCHES
Author:Kampschreur, Linda M.; Hoornenborg, Elske; Renders, Nicole H.M.; Oosterheert, Jan Jelrik; Haverman,
Publication:Emerging Infectious Diseases
Geographic Code:4EUNE
Date:May 1, 2013
Words:2064
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