Summary

Introduction: Q fever is a zoonotic disease with a high seroprevalence in our region and a low awareness in our country. Patients who were diagnosed as having Q fever clinically, serologically, and radiologically during 2017-2020 were evaluated retrospectively and classified according to the organ involvement.
Materials and Methods: The diagnosis was made according to the radiological, clinical and serological findings of the patient. The patients were distinguished as acute, acute/possible, and chronic/persistent according to phase I and phase II antibody titration. Serological studies were carried out via immune fluorescent method. Patients included in the study were evaluated in terms of age, gender, admission date, organ involvement, responses to treatment, and acute phase indicators.
Results: A total of 107 patients were evaluated retrospectively. Sixty three patients (58.9%) were defined as having acute disease, 29 (27.1%) acute/possible disease and 15 (14%) chronic/persistent disease. Patients with acute disease were admitted to the hospital in winter, patients with acute/possible disease were admittedin summer/spring and patients with chronic/persistent disease in summer. Lung involvement was found in 45.8% of patients with positive Q fever serology, kidney involvement in 30.8%, neurological involvement in 29.9%, liver involvement in 22.4%, joint involvement in 18.7%, heart involvement in 5.6%, lymphadenomegaly in 4.7%, and bone involvement in 1.9%. Hepatic involvement was higher in patients with chronic/persistent disease (22.4%), while fever (39.7%) and muscle-joint pain (23.8%) were seen more frequently in patients with acute disease. There were no statistically significant differences in demographical data and levels of acute phase reactants.
Conclusion: Since a non-routine test is used in the diagnosis of the disease, occupational exposure should be evaluated in complaints of unknown origin. The patients having unexplained organ involvement and elevated acute phase reactants should be examined serologically for Q fever, especially in endemic areas.

Keywords:

Q fever, Coxiella burnetii infection, Q fever serology, acute Q fever, chronic Q fever

Introduction

Q fever is a disease caused by Coxiella burnetii, which was previously thought to be from the Rickettsia family and was later identified as a separate group^{[1, 2]}. It was a disease called Q fever in the sense of question/unknown fever, which was first defined as a tick-borne Rickettsia disease by Derrick and Burnet from Australia in 1934^{[3, 4]}. In the following years, it was shown to cause atypical pneumonia first in the USA and then in Germany, Greece and the Balkan countries during the Second World War^{[3, 5-7]}. Q fever is an overlooked and neglected zoonosis that occurs after oral ingestion of unpasteurized milk/milk products of animals with causative pathogenic bacteria, and being exposed to congenital secretions or infected wastes of animals by contact or airborne inhalation. The rate of seropositivity in sheep, goats and cattle is different in the world. It was detected at a rate of 20% in the milk of our country’s animals^{[1, 8]}. The first patients described by Payzın in 1947 in our country were neglected and then reported after 1970^{[9, 10]}. The bacterium is in the form of Gram-negative coccobacillus, and it is found phylogenetically closer to Legionella and Barthonella by using 16S rRNA analysis^[11]. C. burnetii is a microorganism that forms spore-like forms, unlike Rickettsias, with a structure in two phases: a small non-infective form (small dense-phase II) and a large infective form (large dense-phase I). In the definition of the disease, titrations of antibodies formed according to the phase status and clinical complaints should be evaluated together^[12]. The isolation of the bacteria is difficult and it requires special media. While it is not very significant in acute patients, its isolation from the tissue is significant in chronic patients. Diagnosis of the disease is made by immunofluorescence, complement fixation test and ELISA test for specific antibodies, and detection of antigens by polymerase chain reaction (PCR) in tissue and blood. After ingestion of the bacterium, the antibody formed can remain positive at low titration in the blood for life. Clinically, patients are defined as probable or definite, temporally as acute or chronic/persistent^[13]. Phase I antibodies are positive in chronic infection, and phase II antibodies are positive in acute infection^{[7, 14]}. A diagnosis of acute infection is made when the phase II IgG titration is >1/128 and the IgM titration is >1/50 and/or the IgG titration is quadrupled within 2-4 weeks and/ or IgG and IgM are positive together. It is observed that phase II IgG antibodies are positive within 2-3 weeks after exposure to the agent and in the following months^{[13, 15]}. Chronic/persistent disease is defined as the presence of complaints lasting more than six months and the development of phase I antibodies serologically in patients who ingest the bacterium. Especially in persistent patients, phase I IgG or phase II IgG antibodies may remain positive at low titer for a long time.

Q fever is seen at a higher rate in those who are engaged in animal husbandry such as butchers, farmers and veterinarians. It spread all over Europe with an epidemic in the Netherlands in 2007 and its effects lasted for years. It has been reported to lead to serious clinical pictures, especially in immunosuppressive patients and patients with cardiac problems^{[5, 16]}. Although Q fever was a neglected disease, it caused epidemics affecting many countries in Europe in 2007-2014 and caused serious economic losses^{[6, 17]}. In a study published from Spain, it was stated that 4214 patients were seen mostly in March-August, and it was noted that the most common involvement was lung involvement^[18]. In this study, mortality was found to be 2.8% in hospitalized patients with Q fever, and it was reported that it costed 36000 Euros for each patient^[18].

Although it is known clinically that Q fever usually starts with the common cold and continues with pneumonia, hepatitis and neurological findings, a fatal outcome has been reported very rarely^{[1, 19, 20]}. Q fever, a neglected zoonotic disease, can affect many organ systems with its different clinical forms^{[11, 16, 21]}. The aim of this study is to retrospectively examine the patients with positive serology in our clinic in the light of the literature in terms of demographic and seasonal features, and organ involvement, between 2017-2020.

Methods

This study was conducted by retrospectively scanning the files of the patients who were admitted to Bolu Abant İzzet Baysal University, Faculty of Medicine between 2017-2020 and were diagnosed as having Q fever clinically, radiologically and serologically. The study was approved by Bolu Abant İzzet Baysal University Clinical Research Ethics Committee’s decision dated 18.02.2020, numbered 86-2020/18. Q fever serology of all patients was studied with the indirect immunofluorescence method in the Ministry of Health Public Health Microbiology Laboratory. Patients were classified as acute, acute/possible, and chronic/persistent. Acute patients were evaluated as serologically confirmed, acute/possible patients as having clinical complaints suggesting Q fever but positive antibody titration at low titer, and chronic/persistent patients as those whose complaints lasted more than six months and whose serology was positive. Those with positive phase I antibodies in chronic infection and those with positive phase II antibodies in acute infection were included in the study. Evaluation in terms of titration was as follows;

a. Acute patients: IgG >1/128 and IgM>1/50 titration of phase II antibodies and/or IgG+ IgM positivity and/or phase II IgG titration quadrupling within 2-4 weeks.

b. Acute/possible patients: Those whose clinical complaints are compatible with the symptoms of Q fever, whose sedimentation/C-reactive protein (CRP) elevation cannot be attributed to any other cause, and who improve with antibiotic treatment and whose phase II IgG titration is ≥1/256.

c. Chronic/persistent patients: Phase I IgG>1/800 and/or phase I IgG (<1/800) + phase II IgG (<1/256) positivity and complaints due to organ involvement for more than six months.

The patients were classified according to organ involvement based on pathological findings in specific blood biochemistry tests in line with their complaints, high level of acute phase reactants (sedimentation and CRP) that could not be attributed to another cause, and radiological imaging methods. At least two of the following criteria and seropositivity were considered organ involvement;

- Lung involvement: Cough, fever and pathological findings (lobar or lobular consolidation, hilar fullness, nodular involvement) in radiological imaging (X-ray and computed tomography),

- Liver involvement: Jaundice, weakness, elevation in blood liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total/direct bilirubin level, alkaline phosphatase and gamma glutamyl transpeptidase)] and ultrasonography findings,

- Nausea, vomiting, high blood urea and creatinine levels, and proteinuria in the urine in renal involvement,

- Neurological involvement: Headache, fever and unidentified central nervous system complaints, radiological imaging findings (cranial tomography and magnetic resonance imaging if there are findings suggesting encephalitis, meningoencephalitis and meningitis) and elevated protein in the cerebrospinal fluid (CSF),

- Palpitations, echocardiography and electrocardiography changes or underlying cardiac valvulopathy in cardiac involvement,

- Pain, swelling, redness in the joints and increase in the number of cells in the joint fluid and X-ray graphy findings in locomotor and bone involvement.

Since the study was retrospective, the patients who had clinical complaints, organ involvement, other comorbidities during the serological positivity process and did not improve with antibiotic treatment were excluded from the study. Patients with positive organ findings and serology, but whose complaints and laboratory findings did not improve as a result of treatment were not included in the evaluation. The focus of infection was investigated in patients with elevated sedimentation and CRP who were referred to our clinic. Routine Q fever serology was studied in the patients in whom the focus could not be found. Q fever serology was studied again after 2-4 weeks in patients with low titer antibody positivity and those with increased titration were included in the evaluation. Patients with occupational exposure who had low titer antibody positivity and considered clinically positive were evaluated as having probable acute disease.

In all patients, elevated sedimentation and CRP levels due to another cause, malignancy, connective tissue diseases, bacterial, viral, fungal and parasitic diseases were examined by using clinical, serological and radiological differential diagnosis methods, and patients with other causes were excluded from the study. No patient was examined for antibodies to Barthonella and Legionella, but the patients were evaluated for exposure and occupational status. Doxycycline was preferred as the treatment for Q fever, since all patients were followed up by us. Response to treatment, decrease in sedimentation and CRP levels, resolution of complaints and improvement in pathological findings were considered as parameters supporting our diagnostic criteria. The results were evaluated in terms of age, gender, seasonal presentation, organ involvement and clinical complaints. Because our study was retrospective, the patients could not be confirmed by using culture and PCR. Evaluation of all patients only serologically, clinically, radiologically and in terms of response to treatment was among the limitations of our study.

Statistical Analysis

Numerical variables were summarized as mean±standard deviation, and categorical variables were summarized as frequency (percentage). Variables with normal distribution were compared with a one-way ANOVA test. Pearson’s chi-square analysis and Fisher’s Exact test were used in the analysis of categorical variables. Statistical significance level was accepted as p≤0.05 in all tests. Statistical Package for Social Sciences for Windows 25.0 package program was used for statistical analysis of the data.

Results

In the last three years, 45 (42.1%) of the 107 patients that we diagnosed clinically and serologically were female and 62 (57.9%) were male, with a mean age of 57.9±17.4 years. Of these patients, 63 (58.9%) were defined as acute, 29 (27.1%) acute/probable, and 15 (14.0%) chronic/persistent. When these groups were compared according to their demographic characteristics, no difference was found in terms of age and gender.

When the seasons of admission to the hospital were examined, a statistically significant difference was found between the groups (p=0.049) (Table 1). Chronic/persistent patients were mostly admitted to the hospital in summer, acute patients mostly in winter, and acute/possible patients mostly in summer and spring.

Table 1: Demographic analysis of the patients according to their clinical findings

The most common organ involvements in patients were lung, kidney, nervous system, liver, joint (arthritis or atralgia), heart, lymphoid tissues (>0.5-1 cm lymphadenomegaly) and bone (Table 1). Patients with Q fever serology positivity with headache and neurological involvement, and without focal infection focus who were referred by the neurology clinic were evaluated as having neurological involvement. Cranial tomography/magnetic resonance was performed in all of these patients and lumbar puncture was performed in patients with meningeal irritation findings.

The rate of unexplained ALT and AST elevations in liver involvement were significantly different between the diagnostic groups (p<0.050). Liver involvement was higher in chronic/persistent patients than in acute and acute/possible patients (Table 1). There was no statistically significant difference between the groups in terms of other organ involvement.

Elevated sedimentation was detected in 78 (80.4%) and elevated CRP level in 71 (72.4%) of all patients, but there was no statistically significant difference between clinical groups in terms of elevation in sedimentation and CRP. Average sedimentation and CRP levels are shown in Table 1.

The most common complaints in the patients were listed as cough, fever, weakness, muscle/joint pain, shortness of breath, headache, rash, nausea, vomiting and diarrhea (Table 2). There was a statistically significant difference between the rates of fever (p=0.041) and muscle/joint pain (p<0.050) complaints in the diagnostic groups (Table 2). Complaints of fever and muscle/joint pain were observed more frequently among acute patients than in other groups (Figure 1). In chronic/persistent patients, cough and fatigue complaints were more common. However, there was no statistical difference between the groups in terms of these complaints.

Table 2: Distribution of complaints in patients

Figure 1: Distribution of complaints in chronic/persistent, acute and acute/possible patients

Discussion

During windy seasons, bacteria from animal wastes can spread over a wide area^{[1, 5, 16, 17]}. The variation in the disease risk is shown from spring to summer and from winter to spring in Germany^[22]. The seroprevalence of Q fever is high (23.8%) in our region^[23]. In our study, it was observed that hospital admissions due to Q fever were more common in winter-spring months. All of our patients had a relationship with farming and animal husbandry, and all of them were consuming traditional village products in our region.

Acute Q fever is a clinical picture that lasts more than 15 days and presents with complaints of fever, cold, chronic fatigue symptoms, hepatitis, weakness, myalgia, headache, retro-orbital pain and loss of appetite. The complaints and increased seropositivity of our acute and acute/possible patients were evaluated together. Of the patients 39.7% had fever and 23.8% had muscle/joint pain. In our study, elevated sedimentation (80.4%) and CRP (72.4%), which were common acute phase reactants, were found to be an important laboratory finding in patients with Q fever.

In our study, the most common organ involvement was lung with the rate of 45.8%, while renal involvement was the second most common organ involvement with the rate of 30.8%. No other comorbidity was found in the patients with renal involvement. Renal involvement in acute Q fever were reported as case reports^[24]. The third most common involvement was neurological involvement with the rate of 29.9% which was similar to the literature. The fourth most involvement was liver involvement with the rate of 22.4% which was observed in the chronic persistent group and in the summer months. This shows that we should consider Q fever in patients with positive hepatitis markers. In our case series, arthritis was found in 18.7%, lymphadenomegaly in 4.7%, and bone involvement in 1.9%. In our study, culture and blood PCR could not be performed in patients with acute Q fever. Our use of only serology and clinical features in diagnosis is similar to many retrospective studies^[25-27].

Bernit et al.^[19] suggested in their review that recurrent occupational exposure and younger age were associated with neurological findings in particular. Meningitis, meningo-encephalitis and encephalitis are seen in patients with neurological involvement^{[19, 25]}. In a study of 1383 patients, 1% of the patients had meningo-encephalitis^[28], while acute pneumonia was the most common in 121 patients reported from Greece. Confusion was found in 4.1% and meningitis was found in 0.8% and both were described in some patients in that study^[25].

In our study, we found neurologic involvement with a rate of 29.9%. Two of our patients presented with fever and meningo-encephalitis and they died. The serological diagnosis of the fatal patients was delayed and PCR could not be performed. At the same time, postmortem examination of the patients could not be done. In our study, radiological, neurological and CSF findings were evaluated together in the diagnosis of two acute fatal meningo-encephalitis. There was no response to the empirical treatment of ceftriaxone + acyclovir at the dose of meningitis^[29]. The diagnosis of all patients was made serologically. PCR and culture could not be performed due to limited opportunities. Mortality in Q fever is very low, and studies have shown mortality in acute patients, especially in patients with neurological involvement^{[30, 31]}. The mortality rate is less than 2%, and if it is diagnosed and treated in a short time, a rapid recovery is observed^{[19, 31, 32]}. Mortality was observed in two (1.9%) of 107 patients in our series.

In the serological follow-up of patients with suspected Q fever, 46% of those with liver involvement showed chronicity^{[1, 6]}. In our patients, liver involvement was most common in chronic/persisted patients. The reason why we saw it more frequently in the chronic/persistent patient group was that these patients were investigated in different clinics for other diseases and that the cause of elevated liver enzymes could not be found. The Q fever serology positivity of the patients and the response to treatment indicate that this zoonotic disease should be investigated in patients of unexplained hepatitis. It was important for the awareness of Q fever that the patients who presented with elevated liver enzymes and were followed up with prolonged mild hepatitis recovered with treatment.

Cough (n=7, 46.7%) and fatigue (n=6, 40.0%) were more common in chronic/persistent patients. In the follow-up of our patients, clinical and serological findings were consistent with the chronic/persistent infection (Table 1)^{[1, 11]}. Endocarditis is seen in 60-70% of chronic patients and if untreated, mortality is between 25-60%^[33-35]. Although it has been stated in some publications that endocarditis can be seen in 1-6% of the patients with chronic Q fever, this rate may vary in patients with cardiovalvular problems^[33]. In a study on 125 patients with cardiovascular involvement, although the phase I antibody titer was low there were patients in whom the causative pathogen was demonstrated with PCR in valve biopsy^[36]. In our series, cardiac involvement was seen with a rate of 5.6%. Two of our patients had chronic/persistent infection and the other 4 patients were found to have acute Q fever. All patients responded well to doxycycline treatment, and only our chronic/persistent patients received 18 months of treatment. Although chloroquine and doxycycline were recommended in the treatment of Q fever with cardiac involvement, chloroquine could not be used in our patients because it caused bone marrow suppression.

The most important limitation of our study was the retrospective collection of these patients over a three-year period. It was observed that the patients presented sporadically were more common in recent years and only serology was used in the diagnosis.

Conclusion

In conclusion, in this single-center study, we wanted to draw attention to this disease in our country by examining the patients that we found serologically positive considering Q fever. In a total of 107 patients that we encountered in the last three years, it was seen that chronic/persistent patients were admitted mostly in July-August, acute patients in January-February, and acute/possible patients in March-August. This can be interpreted as the fact that acute patients come into contact with animals most frequently during the winter months, and the overlooked symptoms of acute-possible patients are seen in the spring and summer months. Chronic/persistent patients were patients whose complaints were always attributed to another cause, and who were diagnosed when they were admitted to our clinic when no results could be obtained. In our region, where animal husbandry is common, we think that the bacteria are transmitted to humans by inhalation, as animals are kept indoors, especially in winter. Examining the Q fever serology which is not a routine, in unexplained organ involvement and clinical complaints was realized thanks to our past clinical experience. We believe that Q fever serology, which is not routinely performed, should be performed in suspected patients in terms of diagnosis and treatment. Despite the high seroprevalence of Q fever in animals in our country, studies in humans are insufficient and urgent measures are required. We believe that the presence of Q fever in different clinical manifestations and persistent infection should be taken into account by physicians and awareness should be raised in clinical practice.

Ethics

Ethics Committee Approval: The study was approved by Bolu Abant İzzet Baysal University Clinical Research Ethics Committee (decision no: 86-2020/18, date: 18.02.2020).

Informed Consent: Retrospective study.

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions

Concept: F.S., Design: F.S., S.K., Data Collection or Processing: F.S., S.K., P.B., T.D., H.T.G., Analysis or Interpretation: O.K., T.O.Ö., Literature Search: F.S., T.O.Ö., Writing: F.S., P.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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An Overlooked Zoonotic Disease: Retrospective Evaluation of Q Fever Seropositivity with Clinical Findings