Chronic Q fever, including endocarditis

INTRODUCTION — 

Chronic Q fever refers to the chronic clinical syndrome that appears months to years after acquisition of Coxiella burnetii, a gram-negative intracellular bacterium. The most common manifestations of chronic Q fever are endocarditis and vascular infections.

This topic will discuss the epidemiology, risk factors, clinical manifestations, diagnosis, and treatment of chronic Q fever.

Detailed discussions of acute Q fever, Q fever in pregnancy, and the epidemiology of Q fever are found separately. (See "Acute Q fever in nonpregnant patients" and "Q fever in pregnancy", section on 'Duration of therapy' and "Q fever: Epidemiology, microbiology, and diagnostic tests".)

EPIDEMIOLOGY AND RISK FACTORS — 

Chronic Q fever is estimated to occur in approximately 1 to 5 percent of patients following a documented symptomatic episode of acute Q fever [1]. It can also occur in individuals who have no known prior diagnosis of acute Q fever; in these individuals, the initial infection was either asymptomatic or self-limited without a formal diagnosis.

Risk factors for development of chronic Q fever include the following [1-11]:

●Known or suspected valvulopathy or prosthetic heart valve

●Vascular aneurysm or graft

●Pregnancy

●Immunosuppression

●Age >50 years

In addition, the infection is more common in males than females.

CLINICAL SYNDROMES — 

Chronic Q fever has multiple clinical presentations, most commonly infective endocarditis and vascular infection. Concomitant endocarditis and vascular infection has been reported in 7 to 15 percent of cases [4,12].

Many patients with chronic Q fever will have no recollection or documentation of prior acute Q fever or exposure to the pathogen [4,5].

The variability in clinical manifestations is attributed to the host's predisposition (eg, valvular or vascular abnormalities, immune status) and the specific bacterial strain and virulence factors [3].

Culture-negative endocarditis — Endocarditis is the most common manifestation of chronic Q fever in most chronic Q fever studies [1]. In large cohort studies, endocarditis accounted for 76 percent (in France) and 35 percent (in the Netherlands) of cases of chronic Q fever [4,5].

Patients with Q fever endocarditis present with a wide range of symptoms. Some patients present with weeks or months of fever, malaise, anemia, anorexia, progressive weight loss, thrombocytopenia and/or hepatosplenomegaly [6,8,13,14]. In others, the predominant clinical presentation results from valvular damage caused by infection, mainly progressive heart failure [6,8,13]. Less often, the presenting manifestation is due to embolic events, such as stroke [8,13].

Delayed diagnosis is common, primarily due to the disease's nonspecific presentation and lack of awareness of the disease. The median time interval from symptom onset to diagnosis was five months (range 1 to 108 months) in a cohort of 21 patients from Switzerland [15]. In some cases, patients had undergone valve replacement due to presumed mechanical failure but were found to have Q fever once the extracted valve was evaluated [7,16,17].

Among all patients with endocarditis, C. burnetii is an uncommon pathogen [18-22]. In the International Collaborative Endocarditis Prospective Cohort Study, which included 2781 definite endocarditis cases from 25 countries, C. burnetii was the causative agent of 1 percent of cases [18]. In endemic settings, up to 5 percent of endocarditis is due to Q fever [20]. In studies confined to culture-negative endocarditis, rates of Q fever are as high as 30 to 48 percent in endemic settings [21,22].

Vascular infection — Chronic Q fever vascular infection usually involves large vessels, either native or prosthetic. The abdominal aorta is the most common site of infection. Vascular infection is the primary form of disease in 70 percent of patients with chronic Q fever in the Netherlands [12,23]. In France, the routine use of positron emission tomography/computed tomography (PET/CT) has increased the reported rate of vascular infection in patients suspected or confirmed to have chronic Q fever [4,24-26].

Symptoms and signs of Q fever vascular infection include abdominal pain with or without weight loss, fatigue, and elevated inflammatory markers. The presence of fever is variable, reported to be present in 15 to 80 percent of cases [9,24]. Acute vascular complication, such as ruptured aneurysm, may cause internal hemorrhage or ischemia. Patients may present with back pain due to extension of the infection from an adjacent aortic aneurysm or graft to the spine [25,27]. Asymptomatic infection is also common, reported in up to 20 percent of cases in one cohort [9].

Arterial fistula to adjacent organs is a feared complication. Most commonly, a fistula develops between an infected aorta and the intestinal tract. Patients can present with rapid decompensation due to hemorrhage and profuse hematochezia. This complication is associated with high mortality and necessitates urgent surgical intervention. In one report of 167 patients with Q fever vascular infection, 25 patients (15 percent) had arterial fistula; mortality was 60 percent among those with a fistula compared with 21 percent for those without [28].

Bone and joint infection — Bone and joint infections are less common than endocarditis and vascular infection. Most infections are primarily bone or joint infections with no other organ involvement, but a substantial minority (approximately 30 percent) are caused by the spread of infection to bone from a contiguous site of infection (eg, vascular infection) [4,27].

The clinical presentation is similar to other types of osteomyelitis or joint infection, mainly focal pain with or without fever.

In adults, the spine is the most common site of infection, followed by long bones, prosthetic joints, and native joints [4,29].

In children, the lower limbs are the most common site, but cases in the spine and other sites have been reported; in some cases, multiple bones or joints are involved [30,31]. The disease can be prolonged, indolent, and recurrent in children.

Other manifestations — Granulomatous hepatitis, interstitial lung disease, and lymphadenitis are rare manifestations of chronic Q fever [32].

DIAGNOSIS

When to suspect chronic Q fever — We consider the diagnosis of chronic Q fever in individuals who have symptoms and signs of a compatible syndrome (eg, endocarditis, vascular infection) and have risk factors for acquiring Q fever and developing chronic Q fever. (See 'Clinical syndromes' above.)

Risk factors for acquiring infection include exposure to an endemic or epidemic setting or to livestock. Further discussion of these risk factors is found separately. (See "Q fever: Epidemiology, microbiology, and diagnostic tests", section on 'Risk factors'.)

Risk factors for the chronic form of Q fever include cardiac valvular disease and vascular abnormalities, among others. (See 'Epidemiology and risk factors' above.)

Confirming the diagnosis

Approach to diagnosis — The mainstay of diagnosing chronic Q fever is the presence of clinical syndromes compatible with the chronic form of the disease and microbiologic tests confirming or supporting infection with C. burnetii.

Imaging tools (eg, echocardiography, fluorodeoxyglucose positron emission tomography/computed tomography [FDG PET/CT]) play a critical role in localizing the site or sites of infection.

The combination of clinical presentation, microbiologic tests, and imaging findings determine the level of certainty of the diagnosis. Several expert organizations have created definitions and criteria for the diagnosis of chronic Q fever, as described below. (See 'Diagnostic criteria for chronic Q fever' below.)

Diagnostic tests — The main types of tests used to diagnose chronic Q fever are microbiologic tests (serology, polymerase chain reaction [PCR]) and imaging studies, including echocardiography.

Microbiologic tests — Serology and molecular tests are the main laboratory tests used to diagnose chronic Q fever infection. Culture is rarely used in clinical settings because C. burnetii does not grow in routine cultures.

Serology — Serologic diagnosis of chronic infection is based on detection of a high level of immunoglobulin G (IgG) antibodies against phase I C. burnetii.

Phase I IgG antibodies usually coexist with phase II IgG antibodies, which are formed after acute infection and often persist for many years. The threshold of phase I IgG that should be used for diagnosing chronic Q fever is controversial. Different diagnostic criteria have different thresholds, either a threshold of 1:6400 or 1:800; the higher threshold of 1:6400 has lower sensitivity but higher specificity than the threshold of 1:800 [33]. (See 'Diagnostic criteria for chronic Q fever' below.)

It is important to highlight that the presence of phase I IgG, even at high levels, does not necessarily indicate chronic Q fever. Phase I IgG can be detected a few weeks to months after acute infection. Phase I IgG levels then decline but may persist for over a year [34,35].

The presence of immunoglobulin M (IgM) antibodies (either phase I or II) in chronic infection is variable and not particularly helpful for diagnosing or ruling out chronic Q fever.

More in-depth discussion of serology testing for Q fever is found separately. (See "Q fever: Epidemiology, microbiology, and diagnostic tests", section on 'Serology'.)

Polymerase chain reaction — A positive polymerase chain reaction (PCR) test is definitive evidence of infection. The test can be especially useful if the diagnosis is uncertain due to borderline titers of phase I IgG or uncertainty about titer results in the setting of recent acute infection. A negative serum PCR test does not rule out chronic Q fever because PCR sensitivity is suboptimal in patients with chronic Q fever, ranging from 56 to 70 percent [36-38].

More in-depth discussion of serology testing for Q fever is found separately. (See "Q fever: Epidemiology, microbiology, and diagnostic tests", section on 'Polymerase chain reaction'.)

Other tests — Tissue sampling is often necessary to confirm the diagnosis in uncommon presentations of chronic Q fever (eg, osteomyelitis, hepatitis, lymphadenitis), particularly in endemic areas where diagnosis based on serology alone can be misleading [4]. Immunohistochemistry or PCR staining of tissue samples have been used to detect C. burnetii in tissue [3].

Other sophisticated methods with limited availability in clinical use are culture (usually cell line cultures).

Imaging studies

Echocardiography — The role of echocardiography in the diagnosis of endocarditis is well established. (See "Role of echocardiography in infective endocarditis".)

Echocardiography has lower sensitivity and specificity for Q fever endocarditis compared with other forms of infective endocarditis; minor or inconclusive results occur in up to 70 percent of cases [39]. Q fever vegetations are often small or absent, and findings are often most consistent with degenerative valve disease with thickened and/or calcified leaflets [40]. Perivalvular leak is a more common finding than vegetations in some studies [41].

In patients with a negative or nondiagnostic transthoracic echocardiogram (TTE), transesophageal echocardiography (TEE) should be performed if clinical suspicion persists [4]. However, a negative TEE does not rule out Q fever endocarditis; in one study of 19 confirmed cases of chronic endocarditis, only six had conclusive TTE or TEE results [39].

In patients with nondiagnostic echocardiography, FDG PET/CT has been used successfully to diagnose Q fever endocarditis, as discussed below. (See 'FDG PET/CT' below.)

FDG PET/CT — Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is particularly helpful for localizing the infectious process in the diagnosis of chronic Q fever. It is recommended to perform FDG PET/CT upon suspicion or confirmation of any new diagnosis of chronic Q fever. The FDG PET/CT should be done using a protocol appropriate for suppressing physiologic myocardial uptake of FDG, including prolonged fasting before the scan and a carbohydrate-free diet for 24 hours before fasting [42].

FDG PET/CT also allows assessment of response to treatment in patients with chronic Q fever. It is often performed for follow-up and at the end of treatment, the latter serving as the baseline test for comparison in case of suspected relapse of the infection after cessation of treatment. It is important to note that disappearance of the FDG uptake is not a mandatory requirement to stop treatment, particularly in the presence of a vascular graft, where FDG uptake may persist for many years and could represent a noninfectious process [43]. (See 'Monitoring and follow-up' below.)

The role of FDG PET/CT in chronic Q fever was evaluated following a large outbreak in the Netherlands [44]. FDG PET/CT was performed in 273 patients diagnosed with chronic Q fever at baseline and/or during their follow-up. In 20 percent of the patients, the FDG PET/CT results led to treatment modification. Although diffuse myocardial uptake confounded the ability to detect endocarditis in most patients, definite infective endocarditis diagnoses increased from 9 (3.8 percent) to 17 (7.2 percent), including six cases that would have been rejected by Duke criteria without the addition of FDG PET/CT as a major criterion. During follow-up, FDG PET/CT scans resulted in treatment modification in 125 out of 218 scans (57 percent) performed in 143 patients. These modifications included the prolongation of antibiotic treatment because of persistent focal FDG uptake in asymptomatic patients with low serology titer [44]. Whether this modification improved patients' outcomes or resulted in unnecessary treatment is uncertain.

In another retrospective study from France, focal infection was detected by FDG PET/CT in 99 of 167 patients (59 percent) with Q fever who underwent FDG PET/CT [26]. The authors observed 21 valvular foci, 34 vascular foci, and a higher number of osteoarticular localizations than expected (n = 21). Diagnosis was modified following positive FDG PET/CT in 62 out of 99 patients (62 percent). Based on these results, the authors included FDG PET/CT positive findings as a major criterion in the newly proposed diagnostic definitions of the disease [4]. In parallel, the inclusion of FDG PET/CT as a major criterion in endocarditis diagnosis in general has been adopted [45-47]. (See 'Diagnostic criteria for chronic Q fever' below.)

Other imaging studies — Detection of vascular infection can be challenging if FDG/PET is not available. CT angiography or CT scan with contrast can detect focal vascular inflammation in many patients. Ultrasound is less sensitive and specific but can detect aneurysm in some instances. (See "Overview of infected (mycotic) arterial aneurysm", section on 'Vascular imaging'.)

For osteomyelitis, magnetic resonance imaging (MRI) is the test of choice. PET/CT allows detection of asymptomatic or multiple foci, but MRI is highly sensitive for detection of focal osteomyelitis. (See "Imaging studies for osteomyelitis".)

Diagnostic criteria for chronic Q fever — There are several sets of proposed criteria and definitions for the diagnosis of chronic Q fever, each derived from expert consensus. Although similar, differences include the need to prove focal disease and the threshold of phase I IgG required to make the diagnosis [48].

Duke criteria for infective endocarditis — The Duke criteria are used to diagnose infective endocarditis from any cause and have specific criteria for the diagnosis of chronic Q fever endocarditis. A 2023 update to the Duke criteria now includes positive PCR for C. burnetii and specific PET/CT findings as major criteria [45,49]. The threshold for phase I IgG remains >1:800 (table 1 and table 2). (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis", section on '2023 Duke-ISCVID criteria'.)

Dutch Consensus guidelines — These guidelines focus on the diagnosis of specific syndromes caused by chronic Q fever, including endocarditis, vascular infection, osteomyelitis, and chronic hepatitis [38,50]. Cases are categorized into one of three categories: proven, probable, and possible infection. Proven infection requires either a positive PCR or a phase I IgG ≥1:1024 plus Duke criteria for endocarditis or specific imaging findings consistent with a vascular infection.

French NRC criteria — The French National Reference Center (NRC) definition for chronic Q fever provides specific criteria for five different syndromes: endocarditis, vascular infection, prosthetic joint infection, native osteoarticular infection, and lymphadenitis [4]. One major change in this definition is the concept that chronic Q fever infection must be accompanied by a focal infection, which prompted the French authors to propose a new term of "persistent focalized C. burnetii infection" instead of chronic Q fever. Additionally, the new definition sets a higher IgG phase I threshold for confirmed infection, with IgG phase I levels of ≥6400 as a major microbiologic criterion. The old criterion of IgG phase I levels of ≥800 is considered a minor criterion.

CDC surveillance case definition — The United States Centers for Disease Control and Prevention (CDC) definition combines clinical criteria and laboratory tests of varying levels of evidence (table 3) [1]. Clinical criteria focus on endocarditis and vascular infection but also include other less common manifestations such as osteoarticular infection, hepatitis, and unexplained pneumonitis. The laboratory confirmatory diagnostic criteria include positive serology (IgG phase I ≥800) or evidence of the existence of the bacteria (PCR, immunohistochemistry, and culture), with equal weight given to each. In addition, a supportive laboratory result is considered when there is a serology with IgG phase I ≥128 and <800; it is important to note that this cutoff is problematic, especially in endemic areas where titers of this magnitude are common in patients with a past resolved infection. It is also important to emphasize that these criteria are used for epidemiologic surveillance purposes rather than for clinical treatment definitions.

Role of screening asymptomatic patients — In endemic regions or outbreak settings, serologic screening of patients with large vessel vascular disease or who are undergoing routine valve replacement has been suggested to allow early detection and treatment of asymptomatic chronic Q fever.

●Serologic screening of patients with large vessel disease (aortic or iliac disease with or without grafts) has been found to be beneficial in an outbreak setting. In one study during the large Dutch outbreak, 770 patients with aortic/iliac vascular disease were screened by serology for Q fever, leading to the detection of 40 patients (5 percent) with chronic Q fever vascular infection [51]. During serologic follow-up, an additional 5 out of 107 were diagnosed with vascular infection, four within two years and one five years after initial screening [52].

●Serologic screening of 155 patients undergoing routine transcatheter aortic valve implantation in an endemic setting (Israel) identified four patients (2.6 percent) of undiagnosed Q fever endocarditis [53]. These patients were treated after implantation, and no prosthetic valvular dysfunction was detected at a median follow-up of 12 months.

TREATMENT

Antibiotic regimens — Data supporting specific regimens for chronic Q fever are scarce.

Preferred regimen — Our preferred regimen for treatment of chronic Q fever in nonpregnant adults is combination therapy with doxycycline plus hydroxychloroquine. Initial dosing is doxycycline 100 mg orally twice daily plus hydroxychloroquine 200 mg orally every eight hours.

We monitor levels for both doxycycline and hydroxychloroquine during treatment. Doses should be adjusted according to serum drug levels after reaching a steady state. The targeted levels are 5 to 10 micrograms/mL for doxycycline and 0.8 to 1.2 micrograms/mL for hydroxychloroquine. Measurement of doxycycline levels during therapy has been associated with reduced disease-related complications in patients with chronic Q fever [54]. If doxycycline levels are not available, we treat for the entire course with 100 mg orally twice daily.

Hydroxychloroquine can cause retinal toxicity, so experts recommend a baseline ophthalmic examination before treatment and every six months thereafter [1]. It is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency or retinal or visual field deficits [1]. Concerns regarding prolongation of the QT interval due to hydroxychloroquine have been raised. Studies suggested an increased risk for prolonged QTc, particularly when hydroxychloroquine was combined with other drugs known to prolong the QT interval [55,56]. The clinical significance of this potential effect is still controversial; a review showed that hydroxychloroquine was not associated with major adverse cardiac events [57].

Both doxycycline and hydroxychloroquine can cause nausea, vomiting, epigastric pain, photosensitivity, and skin pigmentation (especially on the face, dorsal palms, and calves) (picture 1). Patients should be advised to take precautions with sun exposure, take pills with a sufficient amount of water, and avoid laying down for at least 30 minutes after taking the pills. For more information about these medications, including more side effects, see separate drug-specific topics. (See "Tetracyclines".)

The combination of doxycycline plus hydroxychloroquine is based on a small retrospective study of 35 patients with endocarditis that compared this regimen with doxycycline plus a fluoroquinolone; 17 of 19 patients (89 percent) had serologic-based cure with the doxycycline-based regimen compared with 5 of 13 (38 percent) in the quinolone-based group [58]. In retrospect, defining treatment success based on serology reduction led to debates about the real benefit of this regimen compared with doxycycline and ciprofloxacin. A larger retrospective study of 276 patients from the Netherlands found no difference in mortality, complications, or therapeutic failure in patients treated with doxycycline plus hydroxychloroquine (n = 254) compared with various other regimens; multiple regimens were used during the treatment course in many patients [59]. Finally, although the evidence behind favoring combination treatment of doxycycline and hydroxychloroquine over other regimens is weak and debated, it is the regimen with the most clinical experience [60].

Alternative regimens — For nonpregnant adults unable to take hydroxychloroquine, an alternative treatment regimen is combination therapy with doxycycline plus a fluoroquinolone. Quinolone options include moxifloxacin (400 mg orally once daily) or ofloxacin (200 mg orally twice daily) [59].

Doxycycline-related issues, including drug monitoring, are discussed above and separately (see 'Preferred regimen' above and "Tetracyclines"). Quinolone-related side effects are discussed separately. (See "Fluoroquinolones", section on 'Adverse effects'.)

Children and pregnant patients — Data are scarce for treatment of chronic Q fever in children and pregnant patients [1]. Consultation with an infectious diseases expert is recommended.

●Children – The United States Centers for Disease Control and Prevention (CDC) suggests potential regimens of either a fluoroquinolone (eg, moxifloxacin) plus rifampin, or trimethoprim-sulfamethoxazole plus doxycycline [1].

●Pregnant patients – Experts suggest trimethoprim-sulfamethoxazole plus folic acid supplementation for the entire pregnancy [1,3]. After delivery, standard therapy and duration for nonpregnant patients with doxycycline plus hydroxychloroquine is suggested. While on these medications, breastfeeding is not recommended. Further discussion of chronic Q fever in pregnancy is found separately. (See "Q fever in pregnancy", section on 'Chronic Q fever'.)

Side effects related to these medications are discussed above and in separate drug-specific topics. (See 'Preferred regimen' above and "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Rifampin' and "Trimethoprim-sulfamethoxazole: An overview", section on 'Adverse effects and precautions'.)

Duration of treatment — For patients with an appropriate response to therapy, we treat for 18 months unless the patient has infected prosthetic material, in which case we treat for 24 months [1,3]. For patients who undergo removal of prosthetic material, we treat for 24 months from the date of removal of the prosthetic.

We prolong treatment beyond the above-mentioned duration in certain situations, including the following:

●Complicated infection, such as patients who have undrained fluid collections or who meet criteria for surgery (eg, valve replacement, graft removal) but are unable to undergo surgery

●Increasing titers of phase I IgG during treatment (see 'Monitoring and follow-up' below)

●Evidence of new sites of infection on imaging (eg, positron emission tomography/CT [PET/CT]) while on therapy (see 'FDG PET/CT' above)

In addition to prolonging therapy, we search for additional sites of infection or other complications in compliant patients whose serology or imaging fails to improve. (See 'Monitoring and follow-up' below.)

Surgical intervention

●Endocarditis – Indications for surgery in Q fever endocarditis are similar to those applied in endocarditis caused by other organisms [47,61]. (See "Surgery for left-sided native valve infective endocarditis" and "Prosthetic valve endocarditis: Surgical management".)

It is recommended to discuss these cases with an endocarditis team, weighting risk of intervention against the expected benefits and determining the appropriate time for operation if needed. In carefully selected, very high-risk patients for open heart surgery, percutaneous interventions (repair or valve implantation) may be considered.

In the past, many patients with Q fever endocarditis needed surgery and had high mortality rates [6,62]. Over time, likely related to earlier diagnosis and new combination antibiotic regimens, fewer patients needed surgery. In a French cohort that was followed for 26 years, 46 of 104 patients (45 percent) with Q fever endocarditis underwent surgery, and a marked decrease in surgery occurred over the years (for the five-year interval from diagnosis: 59 percent before 1992 to 15 percent after 2000) [13]. In this cohort, surgery was not associated with improved survival.

●Vascular infection – For vascular infection, surgical intervention is usually urgent in cases presenting with symptomatic aneurysm or pending rupture. Endovascular aortic repair (EVAR) has become common in such cases, as either a bridge to more definitive surgery or as a replacement for surgery. Patients with arterial fistula usually need open surgical intervention for resection of the fistula. Abscess drainage is important for controlling infection and is highly recommended whenever possible. (See "Overview of infected (mycotic) arterial aneurysm", section on 'Management'.)

Case series provide insight into management of vascular infection from Q fever:

•In a retrospective cohort study that included 122 patients with Q fever vascular infection, one-half (n = 61) underwent surgery. Patients with ruptured aneurysm underwent EVAR in most cases (8 out of 9 [91 percent]), while patients with symptomatic aneurysms more often underwent vascular repair by an open surgery (13 out of 18 [72 percent]) [9].

•In a retrospective study from France, which included 100 patients with Q fever vascular infection, surgery was independently associated with improved survival (hazard ratio [HR] 0.17, 95% CI 0.03-0.79) [25].

•In a retrospective study from the Netherlands, 25 out of 169 patients (15 percent) with vascular Q fever were diagnosed with arterial fistula, and 17 of them underwent surgery. Deaths occurred in nine (53 percent) of those who underwent surgery versus six (75 percent) of those who did not [28].

Monitoring and follow-up — Patients should be closely followed during treatment through clinical evaluation, imaging, microbiologic testing, and drug levels for doxycycline and hydroxychloroquine. After stopping treatment, follow-up should continue for at least five years.

During therapy, our general approach to monitoring the response to therapy is as follows [1,3]:

●Clinic visits one month after starting treatment, then every three months to evaluate symptoms, drug compliance, and side effects. Over time, we decrease the frequency of visits if the patient responds to therapy.

●Drug levels for doxycycline and hydroxychloroquine one month after start of treatment until stable in-range levels are achieved.

●Serology every three months for the first year and every six months for years 2 through 5.

●Polymerase chain reaction (PCR) at 3 months, 12 months, and at the end of treatment.

●For patients with endocarditis, echocardiography at three months, six months, and every six months thereafter during therapy. After completion of therapy, the valve function should be assessed regularly (eg, annually).

●Fluorodeoxyglucose (FDG) PET/CT at 12 months, 24 months, and end of treatment.

The United States CDC and French National Reference Center (NRC) team both consider a fourfold decrease in phase I IgG and a negative phase II IgM to meet criteria for stopping therapy (once the minimum duration of therapy has been completed (see 'Duration of treatment' above)) [1,3].

Studies on the use of serology to define treatment response and cure are conflicting. In the largest cohort of endocarditis from the French NRC (n = 104), failure to meet the above criteria for stopping therapy was associated with increased mortality (HR 5.69, 95% CI 1.00-32.22 for the absence of a fourfold decrease of phase I antibody at one year, and HR 12.08, 95% CI 3.11-46.85 for the presence of phase II IgM at one year) [13]. In contrast, data from the Dutch cohort of 337 patients with chronic Q fever (vascular and endocarditis) found no association between serologic results and clinical outcome [12].

These and other studies had limitations [63], and a clear conclusion on the role of serologic follow-up to guide treatment decisions cannot be made [64]. Until more conclusive data are available, we continue to monitor serology response during and after treatment discontinuation. However, we do not use serology as the only criterion for management decisions.

PROGNOSIS — 

Chronic Q fever is associated with a high rate of complications, depending on the site of infection. Common complications include congestive heart failure, cardiac and noncardiac abscesses, stroke, acute aneurysm, and arterial fistula.

In a cohort of 439 patients with chronic Q fever, the overall complication rate was 39 percent, which included acute aneurysms (14 percent), heart failure (13 percent), and noncardiac abscesses (10 percent) [23]. In a different analysis of 337 patients from the Dutch cohort, complications occurred in 190 (56 percent) [12,23].

The reported overall mortality rates vary. For endocarditis, mortality rates have decreased over the years [6,8], ranging from 5 [8,14] to 12 percent [5,23]. In the chronic Q fever Dutch cohort, mortality was highest in patients with combined vascular and endocarditis infection (33 percent), followed by vascular infection (25 percent), and lowest with isolated endocarditis (12 percent) [23].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Q fever".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – Chronic Q fever is estimated to occur in approximately 1 to 5 percent of patients following a documented symptomatic episode of acute Q fever.

Risk factors for development of chronic Q fever include the following:

•Known or suspected valvulopathy or prosthetic heart valve

•Vascular aneurysm or graft

•Pregnancy

•Immunosuppression

•Age >50 years (see 'Epidemiology and risk factors' above)

●Clinical syndromes – Chronic Q fever has multiple clinical presentations (see 'Clinical syndromes' above):

•Culture-negative endocarditis – Symptoms may include weeks to months of fever, malaise, and weight loss; progressive heart failure or valvular disease; or an embolic event (eg, stroke). (See 'Culture-negative endocarditis' above.)

•Vascular infection – Infection of large native or prosthetic blood vessels, especially the aorta, is the most common form of vascular infection.

Symptoms may include abdominal pain, weight loss, and fatigue with or without fever. Patients may present with acute hemorrhage due to ruptured infected aneurysm. (See 'Vascular infection' above.)

•Other syndromes – Bone and joint infections, granulomatous hepatitis, interstitial lung disease, and lymphadenitis have all been reported. (See 'Bone and joint infection' above and 'Other manifestations' above.)

●Diagnosis – In patients with a compatible syndrome, the diagnosis is confirmed by microbiologic tests. Imaging studies localize the site of infection. (See 'Diagnosis' above.)

Several sets of criteria and definitions for the diagnosis of chronic Q fever have been proposed, each derived from expert consensus. (See 'Diagnostic criteria for chronic Q fever' above.)

•Microbiologic tests

-Serology – Detection of a high level of IgG antibodies against phase I Coxiella burnetii can confirm the diagnosis. However, the minimal threshold of phase I IgG that should be used ranges from 1:800 to 1:6400 depending on different expert guidelines. (See 'Serology' above and 'Diagnostic criteria for chronic Q fever' above.)

-PCR – A positive polymerase chain reaction (PCR) test provides definitive evidence of infection, but sensitivity is suboptimal, ranging from 56 to 70 percent. (See 'Polymerase chain reaction' above.)

-Other tests – Tissue samples from biopsies can confirm the diagnosis via histopathologic staining and tissue PCR. (See 'Other tests' above.)

•Imaging studies – (See 'Imaging studies' above.)

-Echocardiography – Echocardiography may detect evidence of endocarditis, but minor or inconclusive results occur in up to 70 percent of cases of chronic Q fever endocarditis. (See 'Echocardiography' above.)

-FDG PET/CT – Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is particularly helpful for localizing the infectious process in the diagnosis of chronic Q fever. (See 'FDG PET/CT' above.)

-Other imaging studies – If FDG/PET is not an option, CT angiography or CT scan with contrast can detect focal vascular inflammation in many patients with vascular infection. Ultrasound is less sensitive and specific but can detect aneurysm in some instances. (See 'Other imaging studies' above.)

•Role of screening asymptomatic patients – In endemic regions or outbreak settings, serologic screening of patients with large vessel vascular disease or who are undergoing routine valve replacement has been suggested to allow early detection and treatment of asymptomatic chronic Q fever. (See 'Role of screening asymptomatic patients' above.)

●Treatment

•Antibiotic regimens – (See 'Antibiotic regimens' above.)

-Preferred regimen for nonpregnant adults – For these patients, we suggest combination therapy with doxycycline plus hydroxychloroquine (Grade 2C). If hydroxychloroquine cannot be used, doxycycline plus either moxifloxacin or ofloxacin are reasonable alternatives. (See 'Preferred regimen' above and 'Alternative regimens' above.)

-Children and pregnant patients – Data are scarce for treatment of chronic Q fever in children and pregnant patients. Consultation with an infectious diseases expert is recommended. (See 'Children and pregnant patients' above and "Q fever in pregnancy", section on 'Chronic Q fever'.)

-Duration of treatment – For patients with appropriate response to therapy, we typically treat for 18 months unless the patient has infected prosthetic material, in which case we treat for 24 months. For patients who undergo removal of prosthetic material, we treat for 24 months from the date of removal of the prosthetic.

•Surgical intervention – For patients with endocarditis, indications for surgery are similar to those applied in endocarditis caused by other organisms. (See 'Surgical intervention' above and "Surgery for left-sided native valve infective endocarditis" and "Prosthetic valve endocarditis: Surgical management".)

For patients with vascular infection, surgery is necessary to cure the infection and is urgent in patients with symptomatic aneurysm or pending rupture. (See 'Surgical intervention' above.)

•Monitoring and follow-up – Patients should be closely followed during treatment by serial clinical evaluation, imaging, microbiologic testing, and drug levels for doxycycline and hydroxychloroquine. After stopping treatment, follow-up should continue for at least five years. (See 'Monitoring and follow-up' above.)

●Prognosis – For endocarditis, mortality rates have decreased, ranging from 5 to 12 percent. Mortality rates of 25 percent have been reported for patients with vascular infection. (See 'Prognosis' above.)