Cholecystitis associated with Q fever: case report and systematic review.

84% of patients underwent an abdominal ultrasound and 40% had a CT scan (Table  1 ). Fifteen patients (55%) only underwent ultrasounds whereas four patients (15%) only underwent a CT scan. The diagnosis of cholecystitis was established with imaging data showing distension of the gallbladder in 18 patients (67%) or a thickening of the vesicle wall in 16 patients (59%). Furthermore, the CT scan or the ultrasound showed hepatic steatosis in six cases (22%), and hepatomegaly in eight cases (30%). It should be noted that only three patients (11%) showed the presence of gallstones on imaging, including one case of micro-lithiasis and one case with a single gallstone. All diagnoses were established with clinical and imaging data.

This study was conducted after gaining the approval of a patient ethics and data protection board (PADS VDLX5Z, Ethic committee: CSE24-51). The described patient, treated in Martigues in collaboration with the NRC, gave his written consent for use of his medical data. The web search engines used included Cochrane, PubMed, and Web of Knowledge, with the queries “ Coxiella burnetii cholecystitis” and “Q fever cholecystitis”, encompassing all published cases, in any language, up to 31 August 2024 (Fig.  1 ). Articles not in French or English were translated using the free online software Reverso. Only cases described with a diagnosis of cholecystitis concurrent with a Q fever diagnosis were included. The inclusion criterion “having cholecystitis” was based on the 2020 recommendations of the International Society of Emergency Surgeons [ 11 ], specifically a combination of clinical, biological, and imaging signs consistent with gallbladder inflammation. At the NRC, phase II IgM threshold of > 1/50 during the acute phase is used for the diagnosis of acute Q fever. An phase I or phase II IgG threshold > 1/800 suggests a persistent focal Q fever. Data were collected and consolidated into a pre-established digital questionnaire, which was modified if new relevant information was identified. Fig. 1 Study flowchart Study flowchart

The patient was a 48-year-old male living in Martigues, France, which is an endemic area, and who had been in contact with horses. He had a history of smoking, hypothyroidism, and pericarditis following tonsillitis. He was hospitalised on 13 October 2023, for abdominal pain and a flu-like syndrome (headache, arthralgia, myalgia, and fever) that had persisted for ten days. Biologically, hepatic cytolysis was observed, with AST and ALT levels of 410 IU/L and 414 IU/L, respectively. Other results included levels of GGT of 540 IU/L, alkaline phosphatase of 502 IU/L, LDH of 488 IU/L, elevated lipase of 323 IU/L, total bilirubin of 18 µmol/L, conjugated bilirubin of 6.9 µmol/L, and free bilirubin of 11.1 µmol/L. CRP was elevated (197 mg/L). The platelet count was 159 G/L and the leukocyte count was 6.4 G/L (neutrophils 4.99 G/L, lymphocytes 0.96 G/L, monocytes 0.33 G/L, eosinophils 0.08 G/L, basophils 0.02 G/L). Activated partial thromboplastin time was 1.23. Detection of anticoagulant antibody was positive. The abdominal ultrasound revealed a non-dysmorphic liver and a thickened gallbladder wall at 7 mm with Doppler hyperaemia. Echo-endoscopy showed lithiasic cholecystitis without complications, and the patient underwent cholecystectomy. As the patient resides in Châteauneuf-les-Martigues, near the Étang de Berre, a geographical area known to be frequently affected by Q fever due to its proximity to the Crau Valley (a region with a high density of sheep associated with the mistral wind) [ 12 ]. In addition, as initial clinical presentation was atypical (no clear abdominal pain, but rather fever and diffuse myalgia), the emergency physicians contacted the hospital’s infectious disease specialist (MH), who recommended testing for Q fever. C. burnetii serology, was positive (levels of IgM to phases 1 and 2 of 1/100, without any IgA or IgG) using indirect immunofluorescent assay. Two weeks later, follow-up serology showed IgM to phases 1 and 2 levels of 1/200, IgG to phases 1 and 2 of 1/400, and IgA to phases 1 and 2 of 1/50. C. burnetii PCR assays (targeting the IS1111 and IS30A repeat elements) were positive on the gallbladder biopsy and blood sample at 31 Ct and 36 Ct values, respectively. Histological examination revealed chronic cholecystitis. The patient was treated from 25 October with doxycycline alone (200 mg/day) then from 6 December in association with hydroxychloroquine (600 mg/day), until anticoagulant antibodies were negative. Regular serological monitoring showed a concurrent rise of IgM (up to 1/3200) and IgG (up to 1/1600) titers, followed by a steady decrease over time. After nine months, IgM titers were negative, and IgG to phases 1 and 2 were 1/400. During the acute phase, a transient prolongation of activated partial thromboplastin time was noted, which normalised under antibiotic treatment. Endocarditis was ruled out by a normal transthoracic ultrasound. A positron emission tomography scan (PET scan) was performed on 15 December which found an adenopathy in the cervical area, which was not persistent in the imaging control conducted on March, 14, 2024.

The most frequent clinical signs (Table  1 ) were fever (96%), abdominal pain (88%) particularly localised in the right upper quadrant (70%), hepatomegaly (52%), and headache (51%). Other notable symptoms included asthenia (22%) and gastrointestinal manifestations such as diarrhoea (19%) and vomiting (26%). Additionally, 22% of the patients presented with jaundice. Biological analyses (Table  1 ) revealed liver cytolysis in 88% of cases. The mean level of aspartate aminotransferase (ASAT) was 225 UI/L (range: <40 to 993 UI/L). On average, alanine aminotransferase (ALAT) level was 234 UI/L (< 40 to 824 UI/L), and gamma-glutamyl transferase (GGT) was 216 UI/L (< 40 to 844 UI/L). The average CRP level was 144 mg/L (standard deviation of 67 mg/L). The mean platelet count was 169 G/L (range: 32 to 609 G/L). Thrombocytopaenia was observed in 14 patients (58%), while one (8%) had thrombocytosis. Of the four patients tested, 100% had positive antiphospholipid antibodies, with IgM and IgG anticardiolipin antibodies found in 3/4 (75%); ¼ (25%) had positive anti-β2GP1 antibodies; and one patient had positive antiphospholipid antibodies that were not detailed.

One case [ 13 ] was excluded from this systematic review because the diagnosis of cholecystitis was not established according to the international recommendations of the Society of Emergency Surgeons [ 11 ]. A total of 27 patients (Table  1 ) were included in the study. Median age was 40 years (range: 8 to 74 years; interquartile range: 28–54 years). Of them, three (11%) were children under the age of ten [ 14 , 15 ]. The male-to-female ratio was 8:1, with 89% of the patients being male. 59% of the patients reported contact with animals: five with sheep, four with cattle, two with goats, two with pigs. Data were not available for ten patients. Table 1 Demographic, clinical, biology and imaging data n  = 27 † Age (median [1IQ-3IQ]) 40 (28–54)  Min age; max age 8; 74  number of children (< 10 years old) 3 (11%) Sexe ratio M/F (%) 24 M / 3 F (89%) Contact with animals (%) 10/17 (59%) Clinical signs (%)  Fever 26 (96%)  Headache 14 (51%)  Abdominal pain 24 (88%)  right hypochondrium pain 17 (63%)  epigastric pain 4 (15%)  Cough 4 (15%)  Arthromyalgia 7 (26%)  Asthenia 6 (22%)  Hepatomegaly 13 (48%)  Jaundice 6 (22%)  Diarrhea 5 (19%)  Vomiting 7 (26%) Biological data  Cytolysis 23/26 (88%)  Mean ASAT level (UI/L) [range] 225 [< 40; 993]  Mean ALAT level (UI/L) [range] 234 [< 40; 824]  Mean GGT level (UI/L) [range] 216 [ 450 G/L) 2/24 (8%)  Thombocytopenia (< 150G/L) 14/24 (58%)  Antiphospholipid antibodies 5/5 (100%)  IgM anticardiolipin antibodies 3/4 (75%)  IgG anticardiolipin antibodies 2/4 (50%)  β2GP1 antibodies 1/4 (25%) Described radiographic abnormality  Gallbladder distension 18 (67%)  Steaohepatitis 6 (22%)  Hepatomegaly 8 (30%)  Thickening of the gallbladder wall 16 (59%)  Presence of gallstone 3 (11%)  Effusion in the peritoneum 6 (22%) † : Data from references [ 9 , 10 , 13 – 16 , 20 – 30 ] Demographic, clinical, biology and imaging data † : Data from references [ 9 , 10 , 13 – 16 , 20 – 30 ]

This study highlights the fact that Q fever cholecystitis is a challenging diagnosis to consider but can be straightforward to confirm. Early serum PCR and Serology, as well as imaging and PCR from gallbladder tissue, are essential tools for diagnosis. Thrombocytopaenia can guide the diagnosis, as can the absence of gallbladder stones on imaging. The origin of the inflammatory mechanism is uncertain, but it appears likely to be autoimmune in nature. As the patient’s number who underwent PCR on gallbladder is small, new studies systematically testing PCR on gallbladder in endemic areas, and specifically patients with Q fever, are needed. These findings underscore the necessity for early diagnosis and appropriate management of this disease to prevent chronic complications of Q fever. The need to perform C. burnetii serum PCR and serology in children with acalculous cholecystitis may be evaluated in future prospective studies. In addition, future research may focus on the mechanisms of biliary stasis in cholecystitis associated with Q fever.

This study aimed to characterize cholecystitis associated with Q fever, a rare but emerging clinical entity. Our findings provide important insights for understanding and managing this rare condition. First and a main issue for Q fever diagnosis, the question is when to suspect it and perform PCR and serology? The diagnosis of C. burnetii cholecystitis should be systematically suspected in two different situations. In patients with acalculous cholecystitis, specific serum PCR and serology should be performed, particularly if the patient is a child living in a rural area and the clinical picture include flu-like symptoms, thrombocytopaenia, and/or anticoagulant antibodies (anticardiolipin antibodies, prolonged thromboplastin time and/or lupus anticoagulant). On the other hand, in a patient with acute Q fever and abdominal pain, an abdominal ultrasound is necessary to rule out Q fever-related cholecystitis. For our patient, the geographical location and the atypical clinical presentation (persistent fever despite cholecystectomy and adequate antibiotics) motivated the infectious diseases specialist to test it allowing us to report such an atypical case. Q fever outbreaks have generally been associated with contact with sheep and goats, more often than with cattle [ 17 ]. Our patient was in contact with horses. Coxiella burnetii infection has been reported in horses [ 18 ] and several cases have been confirmed by serological testing. However, the epidemiological importance of horses as a reservoir for human infection has not been definitively confirmed [ 18 ]. In our case, the equestrian center refused any veterinary investigation. The present case could also have been contaminated by sheep and goats, as epidemiological studies have shown that the bacterium can be carried by the wind over distances of up to 18 km from the source of infection, particularly during lambing, when large quantities of bacteria can be released into the environment [ 17 ]. The transmission distance varies depending on environmental conditions such as wind speed, topography, and vegetation. Châteauneuf-les-Martigues, where the patient lives, has already been reported as an endemic area, particularly after a period of wind [ 12 ]. This town is located near the Crau plain, where hundreds of sheep are raised. Our analysis demonstrated that Q fever cholecystitis presents as an acute infection. In opposition, one case underwent cholecystectomy after 510 days. It questions the possibility of chronic form of cholecystitis associated with Coxiella burnetii . Serologically, elevated IgM to phase 2 C. burnetii are mainly observed, which aligns with the natural history of acute Q fever [ 5 ]. The 100% positivity of PCR on resected gallbladders suggests the effectiveness of this diagnostic tool. However, the small number of tested patients does not allow definitive conclusions to be drawn. In most cases, no gallbladder stones were found, which differs from most classic cholecystitis cases related to stone migration [ 1 ]. The number of patients with gallbladder distension suggests an obstruction of the cystic duct. Two different hypotheses may be implicated. One is an autoimmune mechanism, supported by the detection of anti-phospholipid antibodies and the negativity of the immunohistochemistry. This association has heretofore been described ( OR 6.9 (0.7–62.8) p  = 0.09) [ 19 ]. Furthermore, the ROC analysis of IgG anticardiolipin antibodies and acute Q fever complications demonstrated a correlative association ( p  = 0.05) [ 19 ]. The other mechanism could be a direct bacterial action, supported by the positivity of PCR from gallbladder biopsies and blood. Positive PCR from blood was associated with a higher risk of developing a chronic infection in a previous study [ 20 ]. A bacterial culture or specific immunohistochemistry of the bile and/or resected gallbladder could answer this question. We were unable to perform these assays due to the lack of specimens. Pathological data show the presence of hepatitis with characteristic granulomas in most cases. Furthermore, 10% of patients were children under the age of ten. In this population, where 2/3 of cholecystitis cases are acalculous [ 2 ], the prevalence of C. burnetii involvement is likely to be underestimated. Further studies are needed to investigate this possibility. The treatment of Q fever cholecystitis depends on its severity. At the NRC, we use doxycycline, 2 × 100 mg/d for 14 to 21 days. In children, 2 mg/kg every 12 h (4 mg/kg/day– max. 200 mg/day) for 7 days may be used. In adults with antiphospholipid marker, doxycycline and hydroxychloroquine may be continued until negativation of all antiphospholipid markers (IgG anticardiolipin antibody and/or prolonged thromboplastin time and/or lupus anticoagulant). Surgery does not appear to be necessary in patients with mild evolution but may be discussed in case of severe forms. Because Q fever cholecystitis is an acute event, at the NRC we perform serological follow-up 15 days, three months, and six months after disease onset. Systematic echocardiography should be performed to ensure the absence of valvular defect which, if present may justify specific endocarditis prophylaxis. Our study ( n  = 27) represents the largest database describing Q fever cholecystitis since 2003 ( n  = 9) [ 9 ]. It highlights the necessity of a prospective study of Coxiella burnetii -related cholecystitis, especially in paediatric cases, and the value and potential of PCR following gallbladder resection in cases of acute acalculous cholecystitis. Moreover, it undelights important data about the clinical, biological, and biomolecular characteristics of cholecystitis associated with Q fever. Our study has certain limitations. It is a small sample study, and PCR testing on gallbladder was available for only 2 patients. This emphasizes the rarity, but also the potential underdiagnosis of this condition, particularly in paediatric and rural populations. Our data collected retrospectively are subject to memory bias and lack a comparative approach. Additionally, the diversity of demographic characteristics may introduce biases in interpreting clinical and biological data. Finally, the limited availability of biological samples prevented us from comparing samples. In this context, we propose a call for prospective surveillance.

Cholecystitis, an acute inflammation of the gallbladder, is associated with bacterial infections such as those caused by Escherichia coli and Salmonella sp. It most often complicates a biliary obstruction by a gallstone [ 1 ]. In other cases, cholecystitis is acalculous, complicating surgery, or linked to infection. For instance, 50–70% of cholecystitis cases in children are acalculous [ 2 ]. Among cases of acalculous cholecystitis cases, antiphospholipid syndrome is recognized as an etiological condition [ 3 , 4 ]. Q fever is a less frequently considered cause of cholecystitis. Coxiella burnetii is an obligate intracellular pathogen that causes a variety of symptoms ranging from mild fever to serious complications such as endocarditis or vascular infections [ 5 ]. Its ability to persist in various environments and cause persistent infections makes its identification challenging [ 6 , 7 ]. Manifestations of Q fever, including cholecystitis, are often associated with contact with infected animals, notably cattle, sheep, and goats, through zoonotic transmission [ 8 ]. Diagnostic challenges are compounded by the nonspecific clinical presentation and the absence of specific laboratory and imaging findings, which often delays diagnosis. Coxiella burnetii infections can progress to serious complications if not treated effectively. The most recent literature review on C. burnetii -associated cholecystitis was published in 2003 ( n  = 9) [ 9 ]. Of all cases described to date, only one was diagnosed by PCR (polymerase chain reaction) on surgical specimens [ 10 ]. Since 2003, no new literature reviews on this topic have been performed, highlighting the need to update knowledge in this area. This review aims to discuss cases of cholecystitis associated with C. burnetii reported in the literature. We also report a case documented by PCR and recently treated (2024) in Martigues, France, in collaboration with our center, the National Reference Centre for Q fever (NRC). We particularly emphasized the clinical, diagnostic, and therapeutic characteristics of Q fever-associated cholecystitis as a new and emerging clinical entity.

Gallbladder pathological analysis was available for 10 cases and revealed signs of acute non-specific inflammation in four cases (40%) and chronic non-specific inflammation in five cases (50%). In addition, seven patients of the 8 patients (88%) who underwent liver biopsy had typical evidence of Q fever such as granulomas with central vacuoles and neutrophils [ 9 ]. Immunohistochemistry was performed for 6 cases and was always negative. Regarding serologies (Table  1 ), data were available for 25 of the 27 patients at diagnosis. A total of 22 patients had a positive Q fever serology at diagnosis. Fourteen patients had both initial and follow-up serological results. Of them, five showed seroconversion. The median antibody titres were calculated only from cases referred to the NRC, as the various titration methods used in the literature did not allow for standardisation of results. Thus, the median levels of immunoglobulin M, G, and A to phase 1 were 1/50, 1/50 and 0 at diagnosis, and 1/200, 1/100 and 0 on follow-up, while the median IgM, G, and A levels to phase 2 were 1/400, 1/50 and 0 at diagnosis and 1/800, 1/200 and 0 on follow-up. All available serological data of the included patients is provided in the Supplementary data. In total, of the eight patients for whom serological data were available at the NRC ( n  = 8), only one patient had IgG levels to phases 1 or 2 > 1/800 at diagnosis. In contrast, all patients showed a significant increase in IgM > 1/50, or positivity for IgM, within the two weeks following diagnosis. The results of this study suggest that C. burnetii cholecystitis mainly occurs during the acute phase of the disease. PCR assays (Table  2 ) were conducted on blood samples from three patients. One patient was tested for the IS1111 and Com1 targets sequences [ 16 ]. Another patient was tested for the IS1111 and IS30A repeat elements. The PCR targets used for the third patient were not described [ 10 ]. Two out of two (100%) patients tested positive for the IS1111 target, one out of one was positive for Com1 targets, and one out of one was positive for IS30A. In total, 100% (three out of three) of the tested patients exhibited a positive PCR result in the blood at diagnosis. Samples from two patients were subjected to PCR for C. burnetii from resected gallbladder tissue [ 10 ], both had positive IS1111 PCRs sequences, one had a positive IS30A result, and one had a positive Com1 result. Table 2 Microbiological data n  = 3 PCR from blood at diagnosis 3 (100%)  IS1111 repeat 2/2 (100%)  IS30A repeat 1/1 (100%)   Com1 gene 1/1(100%) PCR from removed gallbladder ( n  = 2)  IS1111 repeat 2/2 (100%)  IS30A repeat 1/1 (100%)   Com1 gene 1/1 (100%) Microbiological data Eleven patients underwent cholecystectomy on average 2.2 days after the onset of symptoms. It is noteworthy that one additional patient, not included in this average, was surgically treated 510 days after the onset of symptoms due to recurrent pancreatitis [ 9 ]. A liver biopsy was performed in eight patients (30%). Nineteen patients (64%) were treated with oral doxycycline, 12 of whom were given it as first-line antibiotic therapy and seven as second-line therapy. The other first-line antibiotics administered prior to the diagnosis of Q fever cholecystitis included a beta-lactam combined with metronidazole, an aminoglycoside, and a fluoroquinolone. Two patients received no antibiotic treatment (Fu et al., 2022; Rolain et al., 2003). All patients (100%) had a favourable outcome. All patients experienced rapid improvement (< one week) of their symptoms after the initiation of antibiotics and/or cholecystectomy. However, one patient developed Guillain-Barré syndrome [ 16 ]. Three paediatric cases have been published in the literature: two brothers aged eight and nine who were exposed to cows and goats [ 14 ], and one nine-year-old child living in a rural area [ 15 ]. Clinically, the presentation was similar to that of adults, except that all three cases exhibited hepatomegaly. In our analysis, thrombocytopenia in paediatric cases was more severe than in adults, with a mean platelet count of 46 G/L (standard deviation (SD) = 12.5), along with a leucopoenia averaging at 2.7 G/L (SD = 0.1). Imaging results were consistent across the three paediatric cases: distended gallbladder with thickened walls, acalculous, along with hepatomegaly without described steatosis. The evolution was favourable under doxycycline, similar to the outcomes observed in adults.

Below is the link to the electronic supplementary material. Supplementary Material 1 Supplementary Material 1