Severe Localized Q Fever, a Diagnostic Challenge: Report of Two Cases and Review of the Literature

Abstract

Coxiella burnetii (C. burnetii) can cause asymptomatic infections and acute, chronic, or localized manifestations affecting multiple organs. Doxycycline is the most effective treatment for Q fever. We report two cases of localized C. burnetii infections with no evident epidemiological link. Case reports: We present the case of a 51-year-old male patient admitted for low fever, dry cough, and malaise. The physical examination was unremarkable except for painful hepatomegaly. He was diagnosed with a liver abscess based on inflammatory markers, positive serology for C. burnetii, and abdominal computed tomography (CT) showing a large lesion (112/86/93 mm) within the right liver lobe. Blood cultures and the fluid obtained by percutaneous catheter drainage were negative. After 28 days of treatment with doxycycline, he was discharged well. At the three-month reevaluation, blood tests were normal, and a CT scan showed a minimal residual lesion. The second case was an 81-year-old female with many comorbidities, almost simultaneous acute ischemic stroke, and double-valve (native and prosthetic) infective endocarditis (IE). C. burnetii infection was confirmed by high titers of antibodies (phase I and II IgG), most probably the direct cause of both manifestations. These two cases presented with very rare manifestations of C. burnetii infections, highlighting its diagnostic difficulties. Conclusions: A clear distinction between acute and chronic Q fever is difficult in rare localized infections, as are organ abscesses. Coxiella burnetii may cause stroke and infective endocarditis, especially in the elderly. Even in the absence of epidemiological clues, in patients with localized infections, the C. burnetii etiology should be considered.

1. Introduction

Q fever is a worldwide zoonosis caused by C. burnetii, a Gram-negative coccobacillus, an obligate intracellular bacterium living primarily in macrophages inside acidic lysosomes. Coxiella burnetii is a highly virulent, environmentally stable bacterium, ensuring infection at a very low infective dose (<10 bacteria) [1,2,3]. The majority of infections occur after inhaling contaminated aerosols through direct exposure to infected animals or from contaminated soil aerosols conveyed by the wind up to >30 km [4,5]. The digestive route through dairy products (unpasteurized milk) and tick exposure plays a role in transmission [4]. Animal species other than farmed ruminants (such as pets or wild animals) may be considered potential reservoirs [5]. The clinical manifestations occur in less than 50% of infections, mainly in cattle and small ruminants (sheep and goats) and are represented by infertility, stillbirth, abortion, endometriosis, and mastitis [4]. As for 2022, Romania reported 46 cases, with a rate of 0.25 cases per 100,000 population, a decrease compared to 2019 (1.4 cases per 100,000 population) but higher than the EU rate (0.17 cases per 100,000). This might be explained by the mandatory reporting requirement, while not all European countries have the same regulation, and probably because there is no planned surveillance in cattle and small ruminants, though only a few countries (Belgium, The Netherlands) implemented regular PCR tests on bulk milk from dairy sheep and goats [6].

Coxiella burnetii can cause asymptomatic infections (~50–60%) and acute or chronic/persistent manifestations affecting various organs.

Direct diagnosis through culture isolation of C. burnetii is not possible in clinical laboratories; hence, specific diagnostic techniques are commonly used, with the indirect immunofluorescence assay (IFA) being the reference method, while the immunoenzymatic assay (EIA) is a rapid and reliable testing method. Anti-phase II antibodies are detectable 7 to 15 days after onset; 90% of patients develop antibodies by the third week, followed by a decrease within 3 to 6 months [2,5].

Long-lasting phase I antibodies, identified through the EIA technique and IFA, confirm persistent infections at the time of diagnosis. Serum polymerase chain reaction (PCR) assays from whole blood or serum detect C. burnetii in the patients’ sera within the first 2 weeks of infection, but false-negative results are common [4,5].

Classification into acute and chronic C. burnetii infections has raised controversies, while the definitions proposed by Eldin et al. for acute and persistent focalized C. burnetii infections, including endocarditic, vascular, and osteoarticular infections, and persistent lymphadenitis, might be taken into account [4]. Doxycycline is the most effective treatment for acute Q fever, and chronic C. burnetii infections require long-term combination therapy with doxycycline and hydroxychloroquine [2,3]. C. burnetii thrives in the acidic cell phagolysosome, yet at pH ≥ 6, the bacterium does not grow but remains viable. The lack of a bactericidal effect of antibiotics, such as doxycycline or fluoroquinolones, was explained through antibiotic inactivation by the acidic pH of the phagolysosomes [7]. Increasing the pH in phagolysosomes boosts the efficacy of doxycycline, notwithstanding some concerns regarding possible hydroxychloroquine toxicity [7,8,9,10]. Earlier follow-up studies conducted in France [11,12] demonstrated that the accepted protocol with hydroxychloroquine 200 mg three times daily and doxycycline 100 mg twice daily did not show increased toxicity. Moreover, patients with a >12-month delay in starting hydroxychloroquine had a five-fold increased risk of treatment failure and a poor serological outcome [10,11,12]. Nevertheless, cautious monitoring of the therapeutic levels is required, with 0.8–1.2 mg/L of hydroxychloroquine and 4.5–8 mg/L of doxycycline being the suggested amounts [11].

We present two cases of C. burnetii infections with no evident epidemiological link, since both patients lived in a city, none of them were close to animals (including pets) or had tick exposures, and both of them developed very rare manifestations, namely double-valve infective endocarditis and a liver abscess.

2. Case Presentations

2.1. Case 1

A 51-year-old man presented to the Teaching Hospital of Infectious Diseases, Cluj-Napoca, on 21 August 2023, with six days of malaise, a low fever, a dry cough, chills, myalgia, and a decreased appetite. He was treated from adolescence for schizophrenia, being stable in the last years under monthly treatment with extended-release paliperidone injections. No other medical history was revealed except for grade I obesity. He lived in the city, did not have any contact with poultry or animals, and denied any consumption of unpasteurized milk or dairy products of uncertified origin.

On physical examination, he was febrile (37.8 °C), eupneic, without jaundice, mildly dehydrated, his blood pressure was 116/83 mmHg, his heart sounds were normal (heart rate was 103/min), pulmonary auscultation revealed normal breath sounds, his abdominal palpation was minimally painful, especially in the right upper quadrant, and he had hepatomegaly (4 cm below the costal margin). No adenopathies were found.

Blood tests showed a white cell count of 13.1 × 10⁹/L, platelets of 181 × 10⁹/L, C reactive protein (CRP) of 28.08 mg/dL [upper limit of the normal (ULN), 1 mg/dL], procalcitonin of 0.64 ng/mL, sodium of 138 mmol/L, aspartate aminotransferase (AST) of 89 U/L (ULN 45 U/L), alanine transaminase (ALT) of 181 U/L (ULN 45 U/L), γ-glutamyltransferase (γGT) of 242 U/L (ULN 60 U/L), alkaline phosphatase (AP) of 184 U/L (ULN 130 U/L), total bilirubin of 0.62 mg/dL, serum and urine amylases within the normal range, blood cultures, which were harvested in due time and repeatedly, all negative, and echocardiography unremarkable.

A chest X-ray revealed diffuse fine reticulation and veiling of the costodiaphragmatic sinus on the right side. Abdominal ultrasonography showed an image compatible with a liver abscess, immediately followed by an abdominal pelvic computed tomography with contrast protocol, which showed minimal right pleural effusion and in the right liver lobe (segments VII, VI), a large multilocular lesion, circumscribed, polylobate, with an irregular wall (4 mm), pluriseptated, and multiple non-capturing internal areas (liquid and non-liquid densities). The size of the lesion was 112/86/93 mm., and minimal edema in the adjacent liver parenchyma was found (Figure 1).

Viral and bacterial serologies, along with antigenic tests were performed, highlighting positive results for C. burnetii as the following: phase II IgG—reactive, phase II IgM—non-reactive (Vircell EIA, produced in Spain; sensitivity 95% and specificity 97%), and phase I IgG—reactive (Serion EIA, produced in Germany; sensitivity 94% and specificity 96%). Confirmation by IFA was not performed, as it was unavailable in the hospital laboratory. Other possible etiologies were tested, and all turned out to be negative: IgM Chlamydia pneumoniae, IgM Mycoplasma pneumoniae, urinary antigens for Legionella pneumophila and Streptococcus pneumoniae, and all serological markers for hepatitis A, B, C, and E (IgM hepatitis A and E, HBsAg, IgM-HBc, HCVAb). Percutaneous catheter drainage of the liver abscess was repeatedly performed; Gram stains and cultures were negative for aerobic and anaerobic bacteria, and blood cultures were negative (C. burnetii harvesting is not possible in clinical laboratories). A 7-day initial treatment with meropenem and vancomycin was added to doxycycline. After 21 days of treatment only with doxycycline, he was discharged well, with normal routine laboratory tests. He was reassessed monthly, and no additional treatment measures were required. After three months, the patient was in good health with no complaints; hematological and hepatic laboratory tests were normal, and the IFA test (Vircell IFA, produced in Spain; sensitivity phase II IgG 97.7%, phase I IgG 87.2%, and specificity phase II IgM 66.7%, phase I IgM 60.0%) performed in an external laboratory showed C. burnetii phase II IgG: 1/256, phase I IgG: 1/64, phase II IgM: <1/16, phase I IgM: <1/16. According to the CDC case definition, the confirmation of acute Q fever was based on the convalescent phase II IgG antibody titer by the IFA of ≥1/128 [2]. Since we did not find any pathogen, either in the liver abscess or in the blood cultures, the confirmatory serological testing, and the excellent evolution under doxycycline treatment, we concluded that the etiology of the abscess was C. burnetii. The IFA testing was delayed due to the patient’s refusal of an external test, but ultimately, he accepted it at the last check-up. The CT scan showed a residual lesion; no further action was considered (Figure 1). He was scheduled for a reevaluation at 6 months.

2.2. Case 2

An 81-year-old female patient with a clinical history of an aortic valve replacement with a biological prosthesis (2017), insulin-dependent type II diabetes mellitus, asthma, acute ischemic stroke with thrombolysis (8 August 2023), hypertension, diabetic nephropathy (stage 4), Parkinson’s disease, Hashimoto thyroiditis, and overweight was admitted on 15 August 2023, to the Cardiology Department “Niculae Stancioiu” Heart Institute, Cluj-Napoca. The onset was two weeks before, with fever accompanied by chills, night sweats, and shortness of breath. Late aortic prosthetic valve infective endocarditis (IE) was suspected, and transthoracic, transesophageal echocardiography and computed tomography angiography (CT) were performed. The transthoracic ultrasonography revealed a hypoechogenic mass prolapsing in the left ventricular outflow tract (LVOT) and a para-prosthetic leak. The cranial CT revealed a subacute/late ischemic lesion in the territory of the left cerebral posterior artery; the pulmonary and cardiac CT showed minimal bilateral pleural effusions and interstitial edema; small volume mediastinal lymphadenopathy; a minimal thickening of the aortic prosthetic valve; a floating vegetation (12/9 mm) in LVOT; possible aortic thickening; coarse calcification of the mitral ring; dilated heart cavities (mainly the atrial; no thrombus inside); and the abdominal CT revealed recent splenic infarcts (Figure 2).

A diagnosis of definite late aortic PVE was confirmed based on the definitions of the 2023 European Society of Cardiology (ESC)’s modified diagnostic criteria for IE [7].

Since surgery was not recommended by the cardiac surgical team, she was transferred to the Teaching Hospital of Infectious Diseases, Cluj-Napoca, with the diagnosis of culture-negative prosthetic aortic valve endocarditis and splenic embolism after 18 days of empirical treatment with ampicillin 12 g/day, oxacillin 12 g/day, and two weeks of gentamycin, 160 mg/day.

The patient lived in an urban residency and did not have any direct contact with animals or pets. Also, she denied any consumption of unpasteurized dairy products, but she had short stays in her family country house.

Once in our hospital, blood tests showed the following: an erythrocytic sedimentation rate of 62 mm/h, a white cell count of 6.58 × 10⁹/L, hemoglobin of 8.2 g/dL, platelets of 288 × 10⁹/L, fibrinogen of 523 (ULN 400 mg/dL), C reactive protein (CRP) of 10.1 mg/dL, creatinine of 2.28 mg/dL (ULN 1.2 mg/dL), blood urea nitrogen of 50 mg/dL, rheumatoid factor of 64 U/mL (ULN 14 U/mL), an abnormal glycemic profile, normal liver enzymes, and negative blood cultures.

Chest X-rays showed fine to coarse basal reticulation, segmental opacification, and minimal bilateral pleural effusion. On the third day of hospitalization, a possible diagnosis of C. burnetii IE was considered based on phase I IgG—reactive, phase II IgG—non-reactive, and phase II IgM—non-reactive (Serion and Vircell EIA tests). Another transthoracic echocardiography performed after 5 days of hospitalization showed a dilated left atrium and impaired contractility of the left ventricle with an ejection fraction estimated at 45–50%. A mobile vegetation was observed on the ventricular surface of the aortic prosthetic valve, causing moderate aortic regurgitation and stenosis (peak systolic velocity of 3.2 m/s). Two hyperechogenic, calcific masses with diameters of 1.6 cm and 1.2 cm, respectively, were observed on the mitral valve, one of which had a mobile segment attached to the posterior leaflet with severe mitral regurgitation. The right cardiac chambers were also dilated, the tricuspid valve suffered of a moderate insufficiency, and the inferior vena cava was characterized by a decreased inspiratory collapse. All of the above were secondary to significant pulmonary arterial hypertension, estimated at a peak systolic value of 50–60 mmHg. There was no pericardial effusion.

We continued the treatment with ceftriaxone and vancomycin until discharge, and we introduced doxycycline on the 5th day of hospitalization based on the highly probable diagnosis of late aortic prosthetic and native mitral valve C. burnetii IE with unfavorable evolution under empirical treatment for culture-negative IE and a positive serological EIA test (phase I IgG reactive).

After 10 days, a confirmatory IFA detected high titers of C. burnetii phase I IgM (1/258), phase II IgM (1/128), phase I IgG (>1/4096), and phase II IgG (>1/4096). According to 2023 ESC Guidelines for the management of C. burnetii IE, we added hydroxychloroquine at the lowest dose of 200 mg/day (because of age and multiple comorbidities) [7]. Interestingly, during the previous hospitalization and the first days in our hospital, she developed episodes of acute respiratory failure interpreted as asthma attacks, despite the usual inhaled corticosteroid treatment. After the initiation of doxycycline treatment, the evolution was rapidly favorable, with normalization of the respiratory rate and no need for supplemental oxygen.

Echocardiography performed after 20 days of hospitalization showed a mild reduction in the aortic transvalvular peak velocity from 3.2 to 2.8 m/s without any other notable changes regarding the aortic and mitral valves or the size and contractility of the cardiac chambers (Figure 3).

She was discharged stable after 24 days in our hospital (a total of 39 days of treatment) and an estimated >18-month regimen of doxycycline and hydroxychloroquine.

In mid-January 2024, at more than three months after discharge, she was found stable, with mild anemia (Hb—9.2 g/dL), creatinine 1.78 mg/dL, CRP < 1 mg/dL, and rheumatoid factor 62.78 IU/mL. We found lower titers of C. burnetii anti-phase I IgM (1/128), and anti-phase II IgM (1/64), but higher anti-phase I IgG (>1/16,000) and anti-phase II IgG (>1/8192); hence, the successful serological outcome was not achieved [13]. We increased the hydroxychloroquine dose to 600 mg/day, despite the known risks of hypoglycemia and retinopathy. The transthoracic echocardiography showed aortic biological prosthesis, an undilated right ventricle, moderate mitral regurgitation, and vegetation was not observed, if present, due to a coarsely calcified mitral valve. The ejection fraction was estimated at >50% (Figure 2).

We notified the Public Health Authority in Romania following the rule of mandatory reporting of any case of Q fever.

3. Discussions

Coxiella burnetii can cause acute infections, the most frequent being pneumonia, hepatitis, myocarditis, pericarditis, and persistent localized infections, including endocarditis, vascular and osteoarticular infections, and rare syndromes (stroke, lymphoma, and chronic fatigue syndrome) [4,14].

We assume that the first case was a focalized infection with pneumonia and hepatitis based on the flu-like syndrome, reticular pneumonia with minimal pleural effusion, elevated liver tests, and an extremely rare manifestation of C. burnetii infection, a liver abscess.

In liver abscess etiology, polymicrobial involvement is common; K. pneumoniae, E. coli, Enterococcus faecalis, Staphylococcus aureus, and Streptococcus haemolyticus are the most frequently isolated pathogens [15]. In Romanian hospitals, the etiology of liver abscesses is dominated by Gram-negatives, mainly hypervirulent Klebsiella pneumoniae [16].

In a systematic review published in 2020 (including all studies in English on chronic Q fever with no time limits) on the health outcomes associated with non-endocarditis manifestations of Q fever, Manchal et al. found that vascular infections and osteomyelitis were the most common and were associated with pain and non-specific symptoms [17]. Only 60 cases of non-cardiac abscesses were found, the majority of which (45) came from the Netherlands (18% of 249 cases), and there were 15 cases of psoas abscesses associated with vascular infections. Contiguous spread from infected abdominal aortic aneurysms, grafts, or other vascular anomalies was more often the cause of abscesses [18,19,20]. Abscesses of the liver, spleen, or brain were even less common. We found four other case reports (

Table 1. Reports of localized non-cardiac C. burnetii abscesses [17,18,19,20,21,22,23,24].

Study	Cases	Country	Diagnosis
van Roeden et al. [23]	45	Netherlands	Non-cardiac abscesses
Galy et al. [19]	14	France	Psoas abscesses
Barten et al. [20]	1	Netherlands	Psoas abscesses
Gomes et al. [21]	2	Portugal	Liver and spleen abscesses/cerebral abscess
Cathébras et al. [22]	1	France	Spleen abscess
Ziogas et al. [24]	1	Greece	Cerebral abscess

) [19,20,21,22,23,24].

In our patient, negative blood cultures and negative abscess fluid cultures, in the presence of reactive EIA tests for phase II IgG and phase I IgG, entitled us to confirm the diagnosis. Abscess drainage and 28-day treatment with doxycycline cured the patient, as demonstrated by his health status, liver imaging, and laboratory tests in dynamics. The IFA tests performed at 3 months showed elevated phase II IgG, (1/256) which is considered confirmatory for recent acute infection according to the CDC recommendations (>1/128) [2].

Gomez et al. [21] found positive serologies at titers of 1/400 phase II IgG and 1/50 phase II IgM in a patient with C. burnetii liver and splenic abscesses. Compared with C. burnetii IE, in abscesses, the IFA titers were not studied, and no appropriate confirmatory values were established [21]. Had there not been a clinical picture of pneumonia and hepatitis, maybe the diagnosis of C. burnetii liver abscesses would have been missed, and therefore, the patient might have been considered cured after percutaneous drainage and empirical treatment with antibiotics. The 28-day doxycycline regimen most probably prevented other foci of persistent infection. In C. burnetii IE, the treatment duration is well documented, while in non-cardiac abscesses, the regimen is not well asserted. We considered a short duration of treatment (28 days) since repeated and thorough percutaneous drainage overcame the possible residual bacterial inoculum, and the outcome was favorable.

The second case was C. burnetii infective endocarditis, which is the most common clinical presentation of chronic or localized persistent infection following hematogenous spread from the lungs and is found in 37–48% of culture-negative IE [3,5,13]. The risk factors are well known, and except for a certain exposure, age and pre-existing valve defects or prostheses, especially of the aortic valve, account for 60–70% of all cases of chronic Q fever [4,5,13].

According to ESC 2023, elevated phase I IgG titers (>1/800) are a major criterion for C. burnetii IE, and high phase I IgG titers correlate with a higher positive predictive value for the diagnosis of C. burnetii endocarditis, as in our patient [4,13]. In a case series of 35 patients with C. burnetii IE, Lepidi et al. found on their pathological examination that cardiac valves may reveal fibrosis and calcification, slight inflammation and vascularization, and small or absent vegetation [25]. Coarse calcification of the mitral valve was found in our case and may be considered the hallmark of this etiology.

Based on some studies, a serology compatible with persistent or chronic Q fever may be associated with acute ischemic stroke in elderly patients [4,26,27]. We assumed that C. burnetii was the cause of both outcomes based on the sequence of acute stroke with total recovery after thrombolysis and the typical C. burnetii IE presentation in a high-risk patient. However, embolization phenomena can occur in up to 25.3% of patients, and stroke is one of the possible findings [13].

According to the CDC case definition, in acute infection, an antibody response to C. burnetii phase II antigen is predominant and higher than in phase I antigen; conversely, in chronic infection, phase I IgG titers may be higher than phase II IgG. In our case of IE, both phases of IgG antibodies were equally highly elevated, while phase I and II IgM levels were moderately increased [2,4]. Coxiella burnetii IE should always be considered in a negative blood culture IE and in the presence of host factors such as age and prosthetic valves. Hence, the diagnosis was delayed but not missed, and the outcome was fairly good, at least until now.

Since 2018, Romania has reported to the EFSA and ECDC, a few annual human C. burnetii cases, except for in 2019 (109 cases) [6]. No lambing seasons are organized, and urban people rarely consume food items directly from farms; hence, foodborne transmission is improbable [3,4,23]. In fact, we can assume that our cases were related to distant airborne transmission during the spring and summer [3,4].

In each case, follow-up is recommended according to the management algorithm [2], but we have to acknowledge that the reason we presented the first patient was the extremely rare occurrence of a C. burnetii liver abscess, and the good outcome under short-term antibiotic treatment, in the absence of specific guidelines. In the case of IE, we highlighted the patient’s survival and reasonably good quality of life despite her advanced age, many comorbidities, and unsatisfactory serological outcome. Also, acute stroke and double-valve IE might have been caused almost simultaneously by C. burnetii, underlying the debate about localized versus chronic C. burnetii infections.

4. Conclusions

The aim of these case presentations was to highlight the importance of C. burnetii infection in the differential diagnosis of abscesses and culture-negative infective endocarditis, which should be recognized even in the absence of an epidemiological context and in the presence of host risk factors. Notification to public health authorities is recommended, and it is essential to investigate the source of C. burnetii and the persistence of environmental contamination with the aim of limiting human exposure.