Culture-negative Prosthetic Joint Arthritis Related to Coxiella burnetii

Accepted Manuscript Culture-Negative Prosthetic Joint Arthritis related to Coxiella burnetii Matthieu Million, MD, PhD Lucile Bellevegue, MD Anne-Sophie Labussiere, MD Michal Dekel, MD Tristan Ferry, MD, PhD Philippe Deroche, MD Cristina Socolovschi, MD, PhD Serge Camillerri, MD, PhD Didier Raoult, MD, PhD PII:

S0002-9343(14)00267-8

DOI:

10.1016/j.amjmed.2014.03.013

Reference:

AJM 12451

To appear in:

The American Journal of Medicine

Received Date: 24 January 2014 Revised Date:

10 March 2014

Accepted Date: 11 March 2014

Please cite this article as: Million M, Bellevegue L, Labussiere AS, Dekel M, Ferry T, Deroche P, Socolovschi C, Camillerri S, Raoult D, Culture-Negative Prosthetic Joint Arthritis related to Coxiella burnetii, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.03.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Culture-Negative Prosthetic Joint Arthritis related to Coxiella burnetii

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Matthieu MILLION, MD, PhD1, Lucile BELLEVEGUE, MD1, Anne-Sophie LABUSSIERE,

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MD2, Michal DEKEL, MD3, Tristan FERRY, MD, PhD4, Philippe DEROCHE, MD5, Cristina

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SOCOLOVSCHI, MD, PhD1, Serge CAMILLERRI, MD, PhD6, Didier RAOULT, MD,

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PhD1#

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1. Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et

Tropicales Emergentes, UM63, CNRS 7278, IRD 198, INSERM 1095, Marseille,

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France

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2. Service de Maladies Infectieuses, Centre Hospitalier Jacques Coeur, Bourges, France 3. Infectious Diseases unit, Tel Aviv Sourasky Medical Center, affiliated with Sackler

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Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel 4. Service de Maladies Infectieuses et Tropicales, Hospices Civils de Lyon, France; Centre Interrégional de Référence Rhône-Alpes Auvergne des Infections Ostéo-

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articulaires complexes; Université Claude Bernard Lyon 1, France; Centre

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International de Recherche en Infectiologie, CIRI, Inserm U1111, CNRS UMR5308,

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ENS de Lyon, UCBL1, Lyon, France

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5. Centre Orthopédique Médico-chirurgical, Dracy le Fort, France

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6. Département de Médecine Nucléaire, Hôpital de La Timone, APHM, Université d’Aix-Marseille, Marseille, France

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Corresponding author: [email protected]

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Alternate corresponding author: [email protected]

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Telephone: (33) 491 38 55 17

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Fax: (33) 491 83 03 90

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Funding source: French National Referral Center for Q Fever

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ACCEPTED MANUSCRIPT Conflict of interest statement: All authors (MM, LB, ASL, MD, TF, PD, CS, SC, DR) have

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no conflict of interest to declare.

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All authors had access to the data and a role in writing the manuscript;

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Article type: Brief observation

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Keywords: Culture negative prosthetic joint arthritis, Q fever, Coxiella burnetii

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Running head: Q fever prosthetic joint arthritis

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Abstract word count: 138

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Body text word count: 1576

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ACCEPTED MANUSCRIPT ABSTRACT

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Background: The number of hip and knee arthroplasty procedures is steadily increasing as

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life expectancy increases. Coxiella burnetii may be responsible for culture-negative prosthetic

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joint arthritis and is associated with antibiotic failure and repeated surgeries. We report here

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the first case series of Coxiella burnetii-related culture-negative prosthetic joint arthritis.

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Methods: Cases were retrieved from the French National Referral center for Q fever.

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Diagnosis was based on 18fluorodeoxyglucose positron emission tomography, serology,

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broad-range polymerase chain reaction and Coxiella burnetii-specific polymerase chain

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reaction.

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Results: Four cases of Coxiella burnetii-related culture-negative prosthetic joint arthritis were

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found. Standard bacteriological procedures would have missed the diagnosis in all cases.

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Etiological diagnosis improved the outcome in all but one case.

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Conclusions and Relevance: A systematic, comprehensive diagnostic strategy should be

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used in culture-negative prosthetic joint arthritis, including testing for Coxiella burnetii in

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endemic areas.

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Prosthetic-joint arthritis, defined as an inflammation of the periprosthetic tissues, has a significant impact on the quality of life. Prosthetic-joint arthritis affects approximately 2% of

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individuals with primary arthroplasty and up to 20% of revision procedures. Prosthetic-joint

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arthritis represents a major public health issue. Approximately 800,000 Americans have a hip

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or knee replaced each year and this number is steadily increasing as life expectancy increases.

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Late prosthetic-joint arthritis is distinguished from early postoperative prosthetic-joint

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arthritis, which is represented mainly by infections acquired during surgery. In our

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experience, late prosthetic-joint arthritis occurs in conditions strikingly similar to late

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endocarditis: both may be linked to a hematogenous infection or to non-infectious diseases

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(gout, aseptic loosening or crystal-induced joint disease for prosthetic-joint arthritis; auto-

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immunity, pork allergy or paraneoplastic disease have been reported for endocarditis)1, 2.

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Both culture-negative prosthetic-joint arthritis and blood culture negative endocarditis have been associated with treatment failure despite multiple antibiotic regimens and

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surgeries1, 3, 4. Indeed, fastidious or zoonotic bacteria and fungi are responsible for infections

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with negative standard bacteriological culture and are usually not eradicated by the antibiotics

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prescribed empirically in culture negative prosthetic-joint arthritis or blood culture-negative

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endocarditis, such as vancomycin. We (DR) previously collaborated with the first Coxiella

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burnetii prosthetic-joint arthritis report3, and we report here four additional cases from the

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French national referral center for Q fever. The diagnosis dramatically improved the outcome

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in all cases but one and led us to propose a comprehensive diagnostic strategy in this context,

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including new criteria to define C. burnetii-related prosthetic joint arthritis (Table 1).

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A 60-year-old woman was admitted on June 2012 for left hip pain. Her medical

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history included a left total hip arthroplasty in 2007. Clinical examination revealed a low-

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grade fever. A pseudo-tumor was observed by magnetic resonance imaging around the

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prosthesis. A one-stage hip revision with resection of the pseudotumor and change of the

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ACCEPTED MANUSCRIPT prosthesis was performed in October 2012. Standard bacteriological cultures of intraoperative

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samples yielded small, curved, Gram-negative bacilli (consistent with C. burnetii) with no

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growth. C. burnetii was identified on the periprosthetic material using 16S rRNA

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amplification and specific quantitative polymerase chain reaction analysis (IS30 and IS1111

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genes). Histopathology confirmed an inflammatory pseudotumor, previously described with Q

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fever. Serological results were phase I IgG, IgM and IgA at 800, 0, and 0, and phase II at

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1600, 0, and 0, respectively, suggesting a persistent infection. This case was considered as a

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definite Q fever prosthetic-joint arthritis based on the proposed criteria (A1B1C3).

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Disappearance of fever and pain and good serological outcome at 12 months while on

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doxycycline and hydroxychloroquine also support the diagnosis.

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In October 2012, an 82-year-old man presented with a new C. burnetii serological increase 3 years after acute Q fever without any symptoms. His past medical history included

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a total hip arthroplasty in 1992 with a revision in 2001. An 18fluorodeoxyglucose positron

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emission tomography showed right hip prosthetic joint hypermetabolism (Figure 1). Standard

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aerobic and anaerobic cultures of joint fluid aspirate were negative. A C. burnetii-specific

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quantitative polymerase chain reaction analysis was positive in two different joint aspirate

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samples and for two different genes (IS30 and IS1111). This case was considered as a definite

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Q fever prosthetic joint arthritis (A1B1C3), although the patient was asymptomatic and had

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no joint pain at the Q fever prosthetic joint arthritis diagnosis. A good serological outcome

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while on doxycycline and hydroxychloroquine also supports the diagnosis.

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In November 2012, an 84-year-old man was admitted complaining of fever and right

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hip pain. The patient’s medical history included a right total hip arthroplasty 27 years before.

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Physical examination revealed right hip pain with irradiation to the knee. Transthoracic

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echocardiography was normal. Blood cultures were negative. C. burnetii serology results

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were phase I IgG, IgM and IgA at 1600, 0 and 0, and phase II IgG, IgM and IgA at 3200, 0

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ACCEPTED MANUSCRIPT and 0, respectively. Phase I IgG rapidly increased to 6400, suggesting a persistent and active

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infection. A positron emission tomography found an uptake at the bone-prosthesis interface

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with exclusion of the head and the tip associated with hypermetabolism of the right iliac

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lymph nodes. No surgery or joint aspiration could be performed because of surgical contra-

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indication due to the condition of the patient and in the absence of collection at the computed

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tomography scan. This case was considered a definite Q fever prosthetic-joint arthritis

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(A0B2C3). Disappearance of pain and positron emission tomography scan anomalies while

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on doxycycline and hydroxychloroquine also support the diagnosis.

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In summer 2013, a 63-year-old woman was admitted for progressive left hip pain without fever. She had a history of left total hip arthroplasty in 1992, revised in 2002, and

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rheumatoid arthritis treated with methotrexate and adalimumab. Symptoms appeared three

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weeks after contact with sheep in Morocco. A periprosthetic collection was identified by a

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computed tomography scan. Liquid joint analysis revealed pus without bacterial growth,

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whereas the patient did not receive antibiotics. C. burnetii was identified using 16S rRNA

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amplification. Serology found phase I IgG at 800 increasing to 1600 two months later,

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without IgM or IgA. The joint prosthesis was removed and replaced by a cement spacer.

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Bacterial cultures remained negative, and histopathology revealed non-specific bone and

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synovial inflammation. C. burnetii was identified on the periprosthetic material using 16S

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rRNA amplification and specific quantitative PCR analysis (IS30 and IS1111 genes) on four

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different periprosthetic samples. This case was considered definite Q fever prosthetic-joint

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arthritis (A1B1C3). Despite prolonged long-term doxycycline and hydroxychloroquine

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therapy, the outcome was unfavorable, and spacer explantation was required with positive

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polymerase chain reaction on spacer at 4 months of treatment. No other infection was

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diagnosed.

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The 4 cases of prosthetic joint arthritis described here were related to C. burnetii because the bacterium was identified by detecting two or three different genes in different

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samples and the serology suggested a persistent C. burnetii infection in all cases. Standard

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cultures of joint samples were negative in the 3 patients in whom it was performed, although

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direct examination was positive and consistent with C. burnetii in one case. The new increase

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of phase I IgG 3 years after primary infection in one case and the rapid serological increase in

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another case also suggest an active infection. The 4 cases were associated with radiological or

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positron emission tomography scan anomalies. In two cases, the positron emission

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tomography scan identified an uptake at the bone-prosthesis interface, which is the best

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criterion for infection. The association with a hypermetabolism of iliac lymph nodes in one

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case also suggests an active infection. In one case, joint aspiration guided by computed

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tomography scan could not be achieved due to the absence of collection. Indeed, absence of

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inflammatory exudate is a classical feature of C. burnetii. An inflammatory pseudotumor is

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characteristic of Q fever and has been previously described in the lung and spleen. The good

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clinical, serological and positron emission tomography scan outcome after specific treatment

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in 3 out of 4 cases also suggests that C. burnetii was the bacteria responsible for the infection.

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Therapeutic failure in the last case remained unexplained and may be linked to a resistant

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strain, previously reported only once in endocarditis, or to the underlying disease (rheumatoid

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arthritis with immunosuppressive treatment).

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Culture-negative prosthetic joint arthritis accounts for 10% of prosthetic joint arthritis,

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whereas blood culture-negative endocarditis accounts for 20% of endocarditis. Of the culture

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negative-prosthetic joint arthritis cases, half are related to the administration of antibiotics

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before the microbiological analysis. Biofilm bacteria on the surface of the removed implants

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are best identified after prosthesis sonication, and recent molecular studies also suggested that

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non-cultivable microorganisms could play a role5. We found 301 documented cases of culture

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ACCEPTED MANUSCRIPT negative prosthetic joint arthritis in the literature, with 98% related to hip or knee articulations

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(hand 3, shoulder 2 and elbow 1 case each). Of these documented cases, 46% were related to

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fungi, 43% to mycobacteria and 11% to bacteria. Excluding 2 cases related to antibiotics, we

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found 31 culture-negative prosthetic arthritis related to bacteria, including Brucella (11 cases),

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C. burnetii3 (5 cases, including the 4 cases reported here and 1 previously reported3),

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Streptococcus (3), Tropheryma whipplei4 (2), Staphylococcus (2), Propionibacterium acnes

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(2) and Listeria monocytogenes (1). Surprisingly, this etiological spectrum is similar to that of

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blood culture negative endocarditis1, except that Bartonella and Chlamydia prosthetic joint

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infections were not present. In addition, the different regional prevalence of zoonotic agents

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must be taken into account. Human cases of Q fever are ubiquitous around the world outside

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of New Zealand but prevalence is particularly increased close to rural areas. In comparison,

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brucellosis is uncommon or absent in most European countries and Australia.

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All patients with suspected prosthetic joint arthritis should have synovial fluid and/or periprosthetic tissue sent for standard microbiological culture and analysis for uric acid

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crystals. If the prosthesis is removed, ultrasonication to dislodge adherent bacteria followed

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by aerobic and anaerobic microbiological culture should be performed. If the microbiological

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standard culture is negative, the patient should undergo a systematic diagnostic procedure for

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culture-negative prosthetic joint arthritis, including C. burnetii and Brucella serology.

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Mycobacterial direct examination and culture as well as conventional broad-range polymerase

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chain reaction5 and fungal-specific polymerase chain reaction should be performed on the

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joint sample.

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Here, we report 4 new cases of prosthetic joint arthritis related to C. burnetii with a

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negative standard bacteriological culture in all 3 cases in which it was performed. As in blood

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culture-negative endocarditis, a systematic comprehensive diagnostic strategy should be

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applied in culture-negative prosthetic joint arthritis, including Coxiella burnetii testing in

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endemic areas.

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ACCEPTED MANUSCRIPT Signed patient consent forms have been obtained for all patients.

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Acknowledgements: We thank all patients for agreeing to the publication of their cases.

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Funding: This work was supported by the French National Referral Center for Q Fever.

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Conflict of interest: All the authors (MM, LB, ASL, MD, TF, PD, CS, SC, DR) declare that

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they have no conflicts of interest.

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ACCEPTED MANUSCRIPT References

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(1)

Fournier PE, Thuny F, Richet H et al. Comprehensive diagnostic strategy for

blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis

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2010;51(2):131-140.

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(2)

Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J

Med 2004;351(16):1645-1654. (3)

Tande AJ, Cunningham SA, Raoult D, Sim FH, Berbari EF, Patel R. A case of

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Q fever prosthetic joint infection and description of an assay for detection of Coxiella

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burnetii. J Clin Microbiol 2013;51(1):66-69.

196 197 198 199 200

(4)

Cremniter J, Bauer T, Lortat-Jacob A et al. Prosthetic hip infection caused by

Tropheryma whipplei. J Clin Microbiol 2008;46(4):1556-1557. (5)

Levy PY, Fournier PE, Fenollar F, Raoult D. Systematic PCR Detection in

Culture-negative Osteoarticular Infections. Am J Med 2013;126(12):1143-33. (6)

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Raoult D. Chronic Q fever: expert opinion versus literature analysis and

consensus. J Infect 2012;65(2):102-108.

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ACCEPTED MANUSCRIPT Figure legends

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Figure 1. PET scan of a case of Q fever Prosthetic Joint Arthritis

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A F18 fluorodeoxyglucose positron emission tomography / computed tomography scan reveals

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an increased radiotracer accumulation in the right hip prosthesis (patient 2). The uptake at the

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bone-prosthesis interface with exclusion of the head and tip, as found in this patient, is

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considered the best criterion for infection, with 92% sensitivity and 97% specificity. This

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patient had an acute episode of Q fever 3 years previously with a new recent serological

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increase (phase I IgG increasing from 800 to 3200 and phase I IgA increasing from 50 to 100

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without IgM). C. burnetii-specific quantitative polymerase chain reaction analysis was

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positive on two different joint aspirate samples and for two different genes (IS30 and IS1111),

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confirming the diagnosis.

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ACCEPTED MANUSCRIPT Table 1. Definition of Coxiella burnetii-related Prosthetic Joint Arthritis (adapted from Raoult et al1). A. Definite criterion Positive culture, polymerase chain reaction, or immunochemistry of a periprosthetic

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biopsy or joint aspirate. B. Major criteria Microbiology:

Positive culture or polymerase chain reaction of the blood

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Positive Coxiella burnetii serology with IgGI antibodies ≥ 6400

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Evidence of prosthetic involvement:

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Computerized tomography scan or magnetic resonance imaging positive for prosthetic infection: collection or pseudotumor of the prosthesis Positron emission tomography scan or indium leucoscan showing a specific

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prosthetic hyperfixation consistent with infection1 C. Minor criteria

Presence of a joint prosthesis (indispensable criteria)

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Joint pain

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Fever, temperature > 38° C

Serological evidence: Positive Coxiella burnetii serology with IgGI antibodies ≥ 800 and < 6400

Diagnosis definite 1) 1A criterion 2) 2B criteria

3) 1B criterion and 3C criteria (including 1 microbiology evidence, and presence of a joint prosthesis)

ACCEPTED MANUSCRIPT Diagnosis possible 1) 1B criterion, 2C criteria (including 1 microbiology evidence and presence of a joint prosthesis)

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2) 3C criteria (including positive serology and presence of a joint prosthesis)

For the F18 fluorodeoxyglucose positron emission tomography scan, the uptake at the bone-

prosthesis interface with exclusion of the head and tip is considered the best criterion for

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infection, with 92% sensitivity and 97% specificity.

ACCEPTED MANUSCRIPT Reference (1) Raoult D. Chronic Q fever: expert opinion versus literature analysis and consensus. J

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Infect 2012;65(2):102-108.

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ACCEPTED MANUSCRIPT Clinical significance Word count: 67 •

Prosthetic joint arthritis involves 2% of individuals with a joint prosthesis, is associated with significant morbidity and will represent a major public health issue in the coming decades Coxiella burnetii may be responsible for culture-negative prosthetic joint arthritis and is

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associated with antibiotic failure and repeated surgeries when undiagnosed

Prosthetic joint infection related to Coxiella burnetii will remain undiagnosed if not suspected

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systematically particularly in endemic areas

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