# Polymicrobial Infections Among Patients with Vascular Q Fever, France, 2004–2020

Mathilde Puges, Xavier Bérard, Caroline Caradu, Maïlys Ducours, Carole Eldin, Mathilde Carrer, Noémie Sauvage, Marc-Olivier Vareil, Laure Alleman, Fatima M'zali, et al.

<figure><img src="image_1.png" /></figure>

To cite this version:

Mathilde Puges, Xavier Bérard, Caroline Caradu, Maïlys Ducours, Carole Eldin, et al. Polymicrobial Infections Among Patients with Vascular Q Fever, France, 2004–2020. Emerging Infectious Diseases, 2021, 27 (7), pp.1961-1963. 10.3201/eid2707.210282. hal-03334371

HAL Id: hal-03334371

https://amu.hal.science/hal-03334371

Submitted on 6 Sep 2021

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Polymicrobial Infections Among Patients with Vascular Q Fever, France, 2004–2020

Mathilde Puges, Xavier Bérard, Caroline Caradu, Maïlys Ducours, Carole Eldin, Mathilde Carrer, Noémie Sauvage, Marc-Olivier Vareil, Laure Alleman, Fatima M'Zali, Sabine Pereyre, Charles Cazanave

We report 5 cases of vascular Q fever complicated by polymicrobial superinfection in patients who had no risk factors for acute Q fever. Q fever was diagnosed by serologic and molecular assays for *Coxiella burnetii*. We confirmed additional infections using conventional graft cultures.

Vascular Q fever, which is caused by *Coxiella burnetii*, is well-described disease; recent publications on the topic include large studies in France and the Netherlands (1-3). Unlike other vascular graft and endograft infections, especially of aortic and aortoenteric fistulas, vascular Q fever is usually caused by a single microorganism. However, when clinical samples (e.g., blood, vascular graft tissue) test positive for bacterial infection, no recommendation exists for screening for additional microorganisms. Researchers have documented ≥5 cases of vascular Q fever complicated by polymicrobial superinfection, all involving a single co-infecting species: *Bacteroides fragilis*, *Streptococcus* spp., *S. anginosus*, *Yersinia enterocolitica*, or *Klebsiella pneumoniae* (4-6). Researchers also have documented several cases of Q fever endocarditis complicated by an additional microorganism: *Enterococcus faecalis*, *S. viridans*, *S. mitis*, *S. gallolyticus*, *S. salivarius*, *S. crispatus*, *S. gordonii*, or *Staphylococcus aureus* (7-10). We describe 5 cases of vascular Q fever complicated by polymicrobial superinfection.

Author affiliations: Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France (M. Puges, X. Bérard, C. Caradu, M. Ducours, M. Carrer, N. Sauvage, S. Pereyre, C. Cazanave); IHU-Méditerranée Infection, Marseille, France (C. Eldin); Aix Marseille University, IRD, AP-HM, SSA, VITROME, Marseille (C. Eldin); Centre Hospitalier de la Côte Basque, Bayonne, France (M.-O. Vareil, L. Alleman); University of Bordeaux, Bordeaux (F. M'Zali, S. Pereyre, C. Cazanave)

DOI: https://doi.org/10.3201/eid2707.210282

## The Study

We retrospectively screened the Bordeaux University Hospital Vascular Infections database for patients with chronic Q fever treated at Bordeaux University Hospital (BUH; Bordeaux, France) or Bayonne District Hospital (Bayonne, France) during January 2004–June 2020. To be included in the study, patients had to have a *C. burnetii* phase I IgG titer >6,400 or molecular detection in blood or infected tissues, as well as clinical signs of a vascular infection or evidence from computed tomography or nuclear imaging scans (6). We conducted an immunofluorescence assay for *C. burnetii* at BUH and Bayonne Hospital, then sent the samples to the French National Reference Center (Marseille, France) for species confirmation (6). When patients had borderline or positive *C. burnetii* serologic results (phase I IgG titer ≥100), we also conducted PCR on an arterial biopsy or vascular graft sample. PCR also was conducted at the French National Reference Center as previously described (6). In accordance with national legislation, surviving patients did not object to the analysis of their data for research purposes.

Of 425 patients with vascular infections during January 2004–June 2020, 16 had Q fever, including 7 since 2019, when BUH and Bayonne Hospital began conducting systematic Q fever serologic assays for all patients with vascular infections. In total, 5 patients (1 with aortitis and 4 with vascular graft and endograft infections) had vascular Q fever complicated by polymicrobial superinfection in the abdominal aorta (Table 1, https://wwwnc.cdc.gov/EID/article/27/7/21-0282-T1.htm). Of the 5 cases, 4 had occurred since 2015. All 5 patients had undergone surgery; 4 had an aortoduodenal fistula, and the remainder had intimate contact between the aortic graft and the duodenum.

In total, 4 patients had *C. burnetii* phase I IgG titer ≥100 and <6,400. Patient 3 had a borderline result; therefore, that patient's sample was not sent to
the French National Reference Center for species con-
firmation (Tables 1, 2). Four patients tested positive
by PCR on vascular or graft samples, whereas patient
5 tested positive by PCR on a vertebral biopsy (Ta-
ble 1). We conducted PCR on serum samples from 2
patients; the samples tested negative for C. burnetii.
None of the patients had risk factors for acute Q fe-
ver, such as contact with animals, consumption of
raw milk, or tick bites. Three of the patients lived in
the countryside of the Nouvelle-Aquitaine region. We
isolated 2–10 additional microorganisms using con-
ventional graft cultures, identifying concurrent bacte-
remia in 3 patients (patients 2, 3, and 4) (Table 1). All
isolated microorganisms were common commensals
of the oral or gut microflora. Only patient 3 had a fun-
gal co-infection (Candida albicans).

Patients 3 and 5 had been treated for previous
episodes of vascular Q fever; their infections relapsed
after the end of treatment. Patient 3 had been treated
with hydroxychloroquine and doxycycline for 2 years
for a Q fever aortic graft infection. The infected graft
was not removed, and the infection relapsed 2 months
after the end of treatment. Patient 5 had Q fever aor-
titis and spondylodiscitis 4 years before this episode.
He had been treated with hydroxychloroquine and
doxycycline for 18 months and had received an aortic
graft implantation. However, the infection in the aor-
tic graft relapsed 2 years after the end of treatment.

In total, 3 patients died of vascular graft and en-
dograft infections; another died of a different cause.
Patients 1, 3, and 4 were treated with hydroxychlo-
roquine and doxycycline. Only patients 1 and 3 com-
pleted the 18-month therapy; the other patients died
before or during treatment (Table 1). All patients also
had a 6-week course of antimicrobial therapy for the
other identified microorganisms.

Conclusions

We identified 5 cases of vascular Q fever complicated by polymicrobial superinfection in patients with no documented risk factors for acute Q fever. Q fever was diagnosed by serologic and molecular assays. We isolated additional microorganisms from clinical samples from 5 of 16 patients with vascular fever, suggesting that co-infections might be more common than previously thought. Furthermore, 4 of the cases complicated by polymicrobial superinfection were diagnosed during the past 5 years, suggesting that this condition might be emergent.

All patients had an aortoduodenal fistula or intimate contact between the aortic graft and the duodenum. The role of C. burnetii in vascular fistulas is well-described, especially in aortoenteric fistulas but also in aortobronchial, aortocaval, and arteriocutaneous fistulas (2,11–13). Death rates among patients with chronic Q fever complicated by arterial fistula are higher than among those without fistulas (2). Aortoenteric fistulas arise from infection and inflammation of the aortic wall or the perigraft tissues created by C. burnetii infection, which erodes the adjacent digestive tract. Diagnostic delays might contribute to fistula development; therefore, earlier detection of vascular Q fever might reduce the incidence of these complications.

We found that 31% of patients with vascular Q
fever in this study also had an aortoenteric fistula, a
concurrent condition that might have contributed to
superinfection. This rate is higher than that suggested
by previously published studies on vascular Q fever
and aortoenteric fistulas (2). We might have found a
higher rate because we have conducted systematic Q
fever screening in every patient with vascular infec-
tion since 2019.

<table><caption>**Table 2.** Serologic assay results of patients with vascular Q fever complicated by polymicrobial infections, France, 2014–2020*</caption>
  <thead>
    <tr>
      <th rowspan="2">Serologic results, time of assay†</th>
      <th colspan="5">Patient (month of Q fever diagnosis)</th>
    </tr>
    <tr>
      <th>1 (2015 Apr)</th>
      <th>2 (2020 Jun)</th>
      <th>3 (2015 Jul)</th>
      <th>4 (2019 Sep)</th>
      <th>5 (2020 Dec)</th>
    </tr>
  </thead>
  <tbody>
    <tr>
      <td>Before Q fever diagnosis</td>
      <td>NA</td>
      <td>NA</td>
      <td>NA</td>
      <td>NA</td>
      <td>2007 Aug 9: 1,600/0/0–3,200/0/0; 2007 Aug 29: 1,600/0/0–3,200/0/0; 2007 Nov: 1,600/0/0–3,200/0/0; 2008 May: 800/0/0–1,600/0/0</td>
    </tr>
    <tr>
      <td>At Q fever diagnosis</td>
      <td>2015 Apr: 800/0/200–100/0/0</td>
      <td>2020 Jun 15: 100/0/0–100/0/0; 2020 Jun 17: 100/0/0–100/0/0</td>
      <td>Borderline</td>
      <td>2019 Sep: 1,600/0/800–1,600/0/800</td>
      <td>2010 Dec: 400/0/100–800/0/200</td>
    </tr>
    <tr>
      <td>After Q fever diagnosis</td>
      <td>2015 Jul: 800/0/200–400/0/0; 2016 Aug: 800/0/400–200/0/0; 2017 Dec: 400/0/200–200/0/100</td>
      <td>NA‡</td>
      <td>NA</td>
      <td>NA‡</td>
      <td>NA‡</td>
    </tr>
  </tbody>
</table>

<footnote>*NA, not available.</footnote>

<footnote>†Values are titers against C. burnetti phase I–phase II (IgG/IgM/IgA).</footnote>

<footnote>‡Values NA because of patient death: patient 2 died on day 37, patient 4 died on day 27, and patient 5 died on day 12.</footnote>
In conclusion, we report a small case series of vascular Q fever complicated by polymicrobial superinfection. Our findings support systematic screening for C. burnetii in patients with vascular infections, especially when an arterial fistula is suspected or confirmed. We believe these screenings should be conducted even when more common microorganisms are isolated by culture. The screening should not be limited to patients with risk factors for acute Q fever. The patients in this study had low C. burnetti phase I IgG titers (none >6,400) and all had vascular Q fever confirmed by molecular diagnosis. Low phase I IgG titers have been described in acute Q fever endocarditis (10,14), suggesting that some of our patients might have had acute rather than chronic vascular Q fever. Therefore, physicians should conduct PCR selective for C. burnetii on vascular grafts or arterial biopsies when patients with a vascular infection have a phase I IgG titer ≥100. However, this low cutoff might impair specificity and positive predictive value (15) and should be further investigated. We highlight that vascular Q fever requires a specific and prolonged therapy, including surgery, to prevent relapse and other complications. We emphasize the need for systematic C. burnetii screening in patients with vascular infections, even when cultures test positive for other microbes.

## About the Author

Dr. Puges is an infectious diseases physician at Bordeaux University Hospital in Bordeaux, France. Her primary research interests include vascular infections and implant-related infections.

## References

1. Broos PPHL, Hagenaars JCJP, Kampschreur LM, Wever PC, Bleeker-Rovers CP, Koning OHJ, et al. Vascular complications and surgical interventions after world's largest Q fever outbreak. J Vasc Surg. 2015;62:1273-80. https://doi.org/10.1016/j.jvs.2015.06.217

2. Karhof S, van Roeden SE, Oosterheert JJ, Bleeker-Rovers CP, Renders NHM, de Borst GJ, et al. Primary and secondary arterial fistulas during chronic Q fever. J Vasc Surg. 2018;68:1906-1913.e1. https://doi.org/10.1016/j.jvs.2018.01.044

3. Botelho-Nevers E, Fournier P-E, Richet H, Fenollar F, Lepidi H, Foucault C, et al. Coxiella burnetii infection of aortic aneurysms or vascular grafts: report of 30 new cases

and evaluation of outcome. Eur J Clin Microbiol Infect Dis. 2007;26:635-40. https://doi.org/10.1007/s10096-007-0357-6

4. Dvorak S, Bizzini A. Streptococcus anginosus and Coxiella burnetii vascular graft co-infection. IDCases. 2020;19:e00697. https://doi.org/10.1016/j.idcr.2020.e00697

5. Bisharat N, Minuhin I. Prosthetic vascular graft infections between blood and concordance of graft culture pathogen. Am J Med Sci. 2012;344:431-5. https://doi.org/10.1097/MAJ.0b013e3182442eb3

6. Eldin C, Mélenotte C, Mediannikov O, Ghigo E, Million M, Edouard S, et al. From Q fever to Coxiella burnetii infection: a paradigm change. Clin Microbiol Rev. 2017;30:115-90. https://doi.org/10.1128/CMR.00045-16

7. 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. https://doi.org/10.1016/S1473-3099(10)70135-3

8. Recovery C, Granel B, Casalta J-P, Lepidi H, Habib G, Raoult D. Coinfection with Coxiella burnetii in infectious endocarditis. Clin Microbiol Infect. 2009;15:190-1. https://doi.org/10.1111/j.1469-0691.2008.02221.x

9. Kampschreur LM, Oosterheert JJ, de Vries Feyens CA, Delsing CE, Hermans MHA, van Sluisveld ILL, et al. Chronic Q fever-related dual-pathogen endocarditis: case series of three patients. J Clin Microbiol. 2011;49:1692-4. https://doi.org/10.1128/JCM.02596-10

10. Younis S, Stein M, Reisfeld S. Screening for Q fever during other bacterial endocarditis in endemic areas: our experience with three patients. Case Rep Infect Dis. 2019;2019:9890659.

11. Prinsen J-HS, Boersma D, van Loenhout R, van Schaik PM, Verhoeven BA. Persistent endoleak after endovascular aneurysm repair for acute Q-fever-infected aortocaval fistula. Vascular. 2015;23:645-7. https://doi.org/10.1177/1708538114562658

12. Sigterman TA, Bendermacher BLW, Welten RJTJ, Krasznai A, Bouwman LH. Primary aortoduodenal fistula and Q-fever. Vasc Med. 2013;18:347-9. https://doi.org/10.1177/1358863X13508337

13. Mejia A, Toursarkissian B, Hagino RT, Myers JG, Sykes MT. Primary aortoduodenal fistula and Q fever: an underrecognized association? Ann Vasc Surg. 2000;14:271-3. https://doi.org/10.1007/s100169910046

14. Melenotte C, Epelboin L, Million M, Hubert S, Monsec T, Djossou F, et al. Acute Q fever endocarditis: a paradigm shift following the systematic use of transthoracic echocardiography during acute Q fever. Clin Infect Dis. 2019;69:1987-95.

15. Kampschreur LM, Oosterheert JJ, Koop AMC, Wegdam-Blans MCA, Delsing CE, Bleeker-Rovers CP, et al. Microbiological challenges in the diagnosis of chronic Q fever. Clin Vaccine Immunol. 2012;19:787-90. https://doi.org/10.1128/CVI.05724-11

Address for correspondence: Mathilde Puges, Service des Maladies Infectieuses et Tropicales, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, F-33076, France; email: mathilde.puges@chu-bordeaux.fr