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Global Journal of Health Science; Vol. 9, No. 4; 2017
ISSN 1916-9736 E-ISSN 1916-9744
Published by Canadian Center of Science and Education
A Survey of Acute Q Fever among Patients with Brucellosis-Like and
Atypical Pneumonia Symptoms Who Are Referred to Qaemshahr Razi
Hospital in Northern Iran (2014-2015)
Roya ghasemian1, Ehsan Mostafavi2,3, Saber Esmaeili3,4, Narges Najafi1 & Sara Arabsheybani5
1
Antimicrobial Resistance Research Center, Department of Infectious Diseases, Mazandaran University of
Medical Sciences, Sari, Iran
2
Department of Epidemiology, Pasteur Institute of Iran, Tehran, Iran
3
National Reference Laboratory of Plague, Tularemia and Q Fever, Pasteur Institute of Iran, Tehran, Iran
4
Department of Medical Bacteriology, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran
5
Student Research Committee, Antimicrobial Resistance Research Center, Mazandaran University of Medical
Sciences, Sari, Iran
Correspondence: Sara Arabsheybani, Antimicrobial Resistance Research Center, Department of Infectious
Diseases, Mazandaran University of Medical Sciences, Sari, Iran. Tel/fax: 98-114-231-6319,
[email protected]
Received: June 7, 2016
Accepted: August 1, 2016
doi:10.5539/gjhs.v9n4p225
Online Published: August 25, 2016
URL: http://dx.doi.org/10.5539/gjhs.v9n4p225
Abstract
Introduction: Coxiella burnetii is the etiologic agent of the zoonotic disease of Q fever which causes lots of
morbidities and mortalities every year. The main route of human infection is inhalation of contaminated aerosols;
however, consumption of contaminated dairy products is the second cause. Mazandaran province is one of the
main livestock centers of the country and consumption of raw dairy in the region is quite common. There isn’t any
data about Q fever incidence in this region. It seems that most cases are undiagnosed. Our main target is to prove
existence of Q fever human cases in Mazandaran province. We evaluated suspect Q fever cases to demonstrate its
incidence and identify the risk factors.
Material and Methods: In this cross-sectional study, 56 Patients including 36 patients with brucellosis-like
systemic symptoms identified by negative Wright, Coomb's Wright and 2-mercaptoethanol tests as well as 20
patients with symptoms of atypical pneumonia who did not respond to conventional therapy were enrolled. At the
beginning of hospitalization and 3-4 weeks later, 10cc blood was obtained from each of 56 patients who referred
for a second blood sampling. Demographic, epidemiological, and clinical manifestations of Q fever and clinical
changes were completed for each patient. The samples were evaluated quantitatively in terms of the presence of
phase II IgG antibodies against Coxiella burnetii by ELISA method. Acute Q fever was confirmed by line-sero
conversion (change of antibody from negative to positive) or fourfold antibody rising titer in each patient. The
presence of primary and secondary seropositive samples and absence of line-sero conversion (change of antibody
from negative to positive) or fourfold increase in antibody titer was considered as previous infection.
Results: The prevalence rate of acute Q fever in 56 patients with 2nd blood sample was 5.3%. There was no
history of tick bite, while in 100% of cases there were risk factors such as a history of residence near animal care
centers as well as a history of consumption of raw dairy products (P = 0/001). 23.2% had a previous history of Q
fever infection, out of which 25.8% lived in rural areas. Among people with risk factors of keeping domestic
animals, living close to animal care centers and animal abortion, the prevalence rate of previous infection was
higher compared to those who did not have these risk factors.
Conclusion: Since most of the patients with acute Q fever have no specific symptom, health care providers do not
suspect acute Q fever disease. In this study, it was demonstrated that infection is either directly or indirectly
associated with increase in environmental risk factors including contact with livestock and its products. Our study
proved that Q fever is endemic in Mazandaran province. In order to have an accurate diagnosis and proper
management, clinicians should be aware of existence of this disease in the region. Because of the climate of
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northern Iran and easy transportation of contaminated particles, appropriate measures should be taken to control
and prevent this disease.
Keywords: acute Q fever, livestock, zoonotic, Coxiella burnetii, Iran
1. Introduction
Q fever is a bacterial disease which is caused by Coxiella burnetii. C.burnetii can be resistant to physical and
chemical factors such as heat, dryness and most disinfectants. So it can survive for days and weeks in milk, cream,
butter and cheese. A zoonotic disease that abruptly begins mainly with flu-like symptoms such as high fever,
headaches, muscle aches, chills, sweating and anorexia and chronic form is considered to lead to endocarditis,
pneumonia, hepatitis, myocarditis and finally death (Masala et al., 2004; Seshadri et al., 2003; Williams, 1991).
Because of the ability to transfer via inhalation and being used in sprays, it can be utilized as a bioterrorist device as
well. Q fever disease was first seen among workers in a slaughterhouse in 1935 in Australia and in the same year it
was isolated from Dermacentor mites in the United States(Williams, 1991).
The most common animal reservoir of acute Q fever includes cattle, sheep and goats. The disease often causes an
asymptomatic infection in the animal, although it sometimes causes abortions, stillbirth and infertility in livestock
flocks. Moreover, it is occasionally associated with pneumonia and bronchitis in animals. Shedding of large
numbers of bacteria through placenta, births fluids and other animal wastes as well as survival in the environment
may lead to transmission of infection to other animals and humans through inhalation. Most individuals are
oversensitive to disease and low numbers of bacteria entering the body through inhalation of contaminated
particles cause the disease (Masala et al., 2004; Rodolakis, 2009). 30 to 50% of patients with symptomatic
infection will develop pneumonia. Chronic form of Q fever is known as an infection that survives for 6 months;
this is an unusual but extremely serious form of the disease. Patients with acute form of the disease may develop
the chronic form. The chronic form continues 1-20 years after the initial infection. Endocarditis is the serious
chronic complication of Q fever. Over 65% of patients with chronic disease may eventually die (Howe et al., 2009;
Ledina et al., 2007; Metanat et al., 2014).
Q fever has been reported in all countries around the world. The first acute Q fever in Iran was reported in 1947;
Later, cases of human infection and seroprevalence of Q fever in human populations has been reported from
different regions of the country. The last acute Q fever case in Iran goes back to 1968 and since then, no clinical
case of Q fever has been reported in Iran until 2010. In this year, Q fever antibodies in febrile patients were
reported in southeastern Iran (Caughey, Galoostian, Haroutunian, & Ehsani, 1971; Caughey & Harootunian, 1976;
Eghtedari, Kohout, & Path, 1970; M. Khalili, 2010; Mostafavi, Rastad, & Khalili, 2012).
Few studies have been done in this field in Iran. Older and recent reports about an outbreak of Q fever among
domestic and wild animals in Iran corroborates the notion that this is an endemic disease in Iran, but there is lack of
diagnostic facilities and the health system is barely aware of this disease. As a result, few patients with Q fever,
particularly with chronic form, have been reported (Esmaeili et al., 2016; Esmaeili, Pourhossein, Gouya, Bagheri,
& Mostafavi, 2014; Metanat et al., 2014; Mostafavi et al., 2012; Yaghmaie, Esmaeili, Francis, & Mostafavi, 2015).
Mazandaran province is one of the livestock centers of the country and consumption of raw dairy in this area is
highly frequent. Few reports are published about the prevalence of Q fever in humans and animals in this region. In
a study conducted on sheep in this province, 23.7 % of cases were seropositive for Q fever (Esmaeili, Bagheri, &
Mostafavi, 2014). Hence, it seems that due to the presence of animal antibodies in livestock animals, there may be
human cases of Q fever which are not recorded so far. Since identifying risk factors, early diagnosis and
appropriate treatment can prevent complications and chronicity of the disease, this study was designed to
investigate the prevalence of disease among suspected patients.
2. Material and Methods
2.1 Sampling
This cross-sectional study was conducted to evaluate the prevalence of acute Q fever in patients referring to
Qaemshahr Razi Hospital during 2014 and 2015. In this study, 56 Patients including 36 patients with
brucellosis-like systemic symptoms identified by negative Wright, Coomb's Wright and 2-mercaptoethanol tests as
well as 20 patients with symptoms of atypical pneumonia who did not respond to conventional therapy were
enrolled. After obtaining the informed consent of the participants, a questionnaire consisting of demographic,
epidemiologic and clinical demonstrations of Q fever and Q fever risk factors was filled out for each person.
Required information included age, gender, location, occupational risk, exposure to livestock and livestock
products (veterinarians, farmers, butchers and lab workers), clinical manifestations, laboratory findings, living in
areas close to animal shelters such as livestock, keeping domestic animals during past two months, an acute
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respiratory infection (fever above 38˚C with at least two other symptoms such as chills, headaches, atypical
pneumonia including non-productive or reproductive cough and shortness of breath) and changes in CXR. Cardiac
evaluation and echocardiography were done by a cardiologist and CXR images were applied and interpreted by the
radiologist at Razi hospital. Two blood samples (10 ml) from each patient were obtained at the beginning of
hospitalization and 3-4 weeks later. Blood samples were centrifuged for 10 min at 3000 rpm and were kept at
-20 °C after extracting their sera. Sera samples were transferred to the National Reference Laboratory for Plague,
Tularemia and Q fever (Research Centre for Emerging and Reemerging Infectious Diseases, Pasteur Institute of
Iran).
2.2 Ethical Considerations
The proposal of this study was accepted by the ethics committee of the Mazandaran University of Medical
Sciences.
2.3 Serology
IgG phase II antibodies against C. burnetii were detected using a commercial quantitative enzyme-linked
immunosorbent assay (ELISA) kit (Serion ELISA classic, Institute Virion/Serion GmbH, Würzburg, Germany)
according to the manufacturer's instructions. Paired sera samples of each patient were tested simultaneously.
Dilution protocols were used according to the manufacturer's instructions; thus, a 1:500 dilution for the IgG phase
II assay was used. The plates were read at 405 nm using a microplate reader (ELx808, BioTek Instruments Inc.,
USA). Obtained ODs were analyzed according to the Virion/Serion protocol and IgG phase II was quantitatively
reported. IgG phase II extinctions were expressed in U/ml titer using a logistic-log-model calculation and were
defined as positive when the titer was >30 U/ml, as borderline when the titer was 20-30 U/ml and as negative when
the titer was < 20 U/ml. The laboratory diagnosis of acute infection by C. burnetii was made on the basis of any of
the following serological criteria: (1) seroconversion, defined as the appearance of specific antibodies against
phase II antigen of C. burnetii at a titer of at least 30 U/ml in the convalescent phase (whereas the serum antibody
titer was negative at the initial acute phase), (2) a fourfold increase in serum antibody titer between the acute phase
and the convalescent phase (in two blood samples obtained every 4 weeks). If the primary and secondary serum
titers were positive and if fourfold rise in antibody titers was not observed, it was considered as a previous history
of exposure to Q fever (past infection).
2.4 Statistical Analysis
Statistical analysis was performed using the SPSS software version 16. Descriptive data of variables was
considered as numbers (percentage). Chi-square test was used to compare the variables during analysis. P-value
less than 0.05 were considered statistically significant.
3. Result
In this study, 56 patients were enrolled with suspected Q fever. Among 56 patients with second blood sample, the
prevalence of acute Q fever was 5.3% (3 patients). Most prevalent clinical cases of acute Q fever were observed
among women (2 out of 3 patients with acute Q fever). The effect of age on the distribution of disease outbreaks
was not statistically significant (P = 0.13) and was mostly observed among the patients older than 60. In general,
55.3% of the participants lived in rural areas. Regarding effect of sex and place of residence on prevalence of Q
fever, no significant difference was observed (P = 0.18). There was no history of tick bite in any of cases, but in all
cases, exposure to risk factors including a history of residence near animal care centers and a history of consuming
raw milk or dairy products was observed but there was not a significant difference in patients with acute Q fever
infection (p=1 & p= 0.66 respectively). Out of 56 participants, 23.2% (n = 13) had a history of infection with Q
fever, 9 participants (69.2%) were male, 23% older than 60, and 61.5% lived in rural areas. Additionally, there was
no significant difference between the participants with exposure to risk factors and those who had no risk factor in
terms of acute Q fever infection. (Table 1)
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Table 1. Frequency (percent) of risk factors in patients with acute infection and a history of infection with Q fever
Total(percent)
Variable
N=56
Patients
with
infection(percent)
acute
Those with history of previous
infection (percent)
N=3
N=13
female
23(41%)
2(66.6%)
4(30.7%)
male
33(58.9%)
1(33.3%)
9(69. 2%)
Below 20
3(5.3%)
0
1(7.6%)
20-40
21(37.5%)
1(33.3%)
3(23%)
40-60
21(37.5%)
0
6(46.1%)
60-80
9(16%)
1(33.3%)
3(23%)
Above 80
2(3.5%)
1(33.3%)
0
village
31(55.3%)
2(66.6%)
8(61.5%)
city
25(44.6%)
1(33.3%)
5(38.4%)
farmer
7(12.5%)
0
3(23%)
rancher
10(17.9%)
0
3(23%)
veterinarian
0
0
0
Exposure to dairy
products
0
0
0
Housewife
19(34%)
2(66.6%)
3(23%)
others
20(35.7%)
1(33.3%)
4(30.7%)
Contact with the cattle
43(77%)
3(100%)
10(76.9%)
Living near the cattle
37(66%)
2(66.6%)
8(61.5%)
Keeping domestic animals
27(48.2%)
2(66.6%)
8(61.5%)
Tick bite
3(5.3%)
0
3(23%)
Contact with newborn animal or animal
abortion
8(14.3%)
0
3(23%)
Consumption of raw milk or dairy products in
the last two months
54(96.5%)
3(100%)
13(100%)
Gender
Age(years old)
Location of
residence
Occupation
The clinical characteristics and prevalence rate of patients with clinical symptoms of acute respiratory infection
(headache in the past two weeks, cough, fatigue and malaise, diarrhea, acute infection of the lower respiratory tract,
muscle pain, joint pain, shortness of breath and hepatitis) have been reported as data indicate in Table 2. There is no
statistically significant difference between patients with acute Q fever infection and those without it (P = 0.23).
Table 2. Prevalence (%) and clinical characteristics of patients with acute infection and a history of infection
with Q fever in the last two weeks
Clinical manifestation
Total (percent)
With acute infection(percent)
N=56
N=3
Fever
56(100%)
3(100%)
Malaise
53(94.6%)
3(100%)
Muscle pain
51(91%)
2(66.6%)
Chills
43(76.8%)
2(66.6%)
Headache
40(71.5%)
2(66.6%)
Arthralgia
36(64.3%)
3(100%)
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Cough
22(39.3%)
0
Atypical pneumonia
20(35.7%)
0
Chest pain
16(28.6%)
0
Dyspnea
7(12.5%)
0
Diarrhea
6(10.7%)
1(33.3%)
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The levels of phase II IgG antibody in patients with acute Q fever are shown in Tables 3.
Table 3. Phase II IgG antibody titers in patients with acute Q fever infection
Patient
Concentration of phase II IgG (U/ml)in 1st sample
Concentration of phase II IgG (U/ml)in 2nd sample
1
11
95
2
52
212
3
<5
55
Paraclinical changes in patients with acute Q fever are shown in Table 4. Laboratory test results vary in patients.
Out of 3 patients, 1 patient had abnormal lung imaging.
Table 4. Changes in clinical results of patients with acute Q fever infection
Lab tests
With acute infection
N=3
changes
lower
upper
normal
WBC
-
1
2
HB
2
-
1
PLT
2
-
1
ESR
-
1
2
Liver enzymes
-
1
2
-
1
2
CBC
changes
abnormal
normal
CXR
1
2
echocardiography
-
3
In patients who had a history of Q fever infection, but had not fourfold increase in antibody titers in the 2nd sample,
no significant difference was found compared with healthy subjects in terms of exposure to risk factors such as
domestic animals, living near animal care centers and dairy products.
4. Discussion
This is the first study in northern Iran that shows seroprevalence of Q fever among the patients with acute
respiratory infection or brucellosis-like symptoms and its relationship with host factors. We didn’t exclude other
differential diagnosis such as Leptospirosis and Psittacosis in this study, because their serologic tests didn’t
routinely perform in our hospital. The results of our study demonstrated that the incidence of acute Q fever in
suspected people is 5.3% and 23.2% of participants have serological evidences of previous infection to Q fever.
Coxiella burnetii infection may have acute or chronic clinical manifestations; however, almost 60% of cases of Q
fever are asymptomatic. Among 40% of symptomatic patients, 38% of them experience mild illness without
hospitalization (Masala et al., 2004), Q fever prevalence varies in different regions of the country and the world
and various factors affect this prevalence. For example, in a study in the city of Zahedan (southeastern Iran) in
2011, out of the 105 suspected febrile patients, 35.2% were diagnosed as acute Q fever cases (Metanat et al., 2014).
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This rate is much higher than our study (5.3%). Furthermore, in another study in Iran on febrile patients suspected
to brucellosis in Kerman (southeastern Iran), 36% of people had Q fever with IgG antibodies phase II (M. Khalili,
2010; M. Khalili, Shahabi-nejad, & Aflatoonian, 2011).In a similar study in Mali, out of 165 febrile patients, 3.85%
of cases were diagnosed as acute Q fever cases (Steinmann et al., 2005). In Croatia, a study on 552 patients with
fever showed that 5.8% had acute Q fever (Vilibic-Cavlek et al., 2012). In another study in Denmark, 2.29% of
1613 suspected patients had acute Q fever (Bacci et al., 2012). In a study conducted between 1985 and 2009 in
France, out of 179,794 patients with suspected Q fever, 3723 patients (2.07%) were diagnosed as acute Q fever
cases and over the years, the number of patients with Q fever has increased. This could be due to the improvement
and development of diagnostic tests of Q fever as well as more attention from doctors and health care systems in
France (Frankel, Richet, Renvoisé, & Raoult, 2011). In a study in 2005 on samples taken from 1,600 soldiers in
Iraq, the prevalence was 23%, showing over-expected exposure to Coxiella (Hartzell, Peng, Wood-Morris, &
Sarmiento, 2007). In a study on 438 pregnant women in the UK, the prevalence of Q fever was 4.6%. In this study,
acute Q fever was observed more frequently in rural areas and in older ages. There was no statistically significant
association between risk factors such as age, gender, location, history of tick bites and the risk of acute Q fever
infection. The study of Metanat et al. in Iran demonstrated that gender and age are not significant risk factors for
the development of acute Q fever (Metanat et al., 2014), but reports from other parts of the world were in contrast
with our results. For instance, a study in Australia demonstrated that age, sex and location are risk factors for
acute Q fever infection (Karki, Gidding, Newall, McIntyre, & Liu, 2015). Another study in France demonstrated
that age and sex are important factors for acute Q fever (Frankel et al., 2011). Other risk factors such as occupation,
history of keeping or contact with domestic animals, raw milk and dairy products were observed in patients with
acute Q fever (M. Khalili, Sakhaee, Aflatoonian, & Shahabi-Nejad, 2011). However, since prevalence of these
factors is almost equal in all groups, they were not significantly associated with acute Q fever. Metanat et al.
reported that contact with domestic animals and consumption of raw dairy products are important risk factors for Q
fever (Metanat et al., 2014). In other studies, only gender, location of residence, consumption of raw dairy products
and contact with animal newborn (presence during childbirth) were significant (Steinmann et al., 2005;
Vilibic-Cavlek et al., 2012). Among the clinical manifestations recorded in this study, the most common clinical
symptoms in patients with suspected infection were fever (100%), malaise (94.6%), chills (76.8%), headache
(71.5%), and joint pain (64.3%). Most studies conducted in Iran and other countries were almost identical in this
aspect. 23.2% of patients showed evidence of previous infection history. While the studies conducted in Zahedan
(34.3%) and Kerman (36%) showed more prevalence. In other studies conducted in the country, the seroprevalence
of Q fever in the province of Kurdistan (western Iran) in patients with high-risk jobs such as butchers, abattoir
workers, hunters, health personnel and lab workers was 27.8% (Esmaeili, Mostafavi, Shahdordizadeh, &
Mahmoudi, 2013). The prevalence of Q fever in the province of Kerman was reported 68% among slaughterhouse
workers. In Mali, the prevalence of infection was 35.54%, which had a higher prevalence than ours (Steinmann et
al., 2005). However, in studies in Croatia (21.74%) Denmark (8.68%), Northern Ireland (12.8%) and the United
States (3.1%) the prevalence of people with a previous history of infection were lower than our study (Bacci et
al., 2012; Frankel et al., 2011; Karki et al., 2015; Vilibic-Cavlek et al., 2012)
Studies show that Q fever in Iran is probably an endemic disease and its effect on animal and human health is
underestimated because of the high prevalence of subclinical cases and not being differentiated from clinical cases
of diseases such as brucellosis and influenza (Mostafavi et al., 2012). For instance, the seroprevalence of phase I
and II antibodies of Q fever in individuals with fever (measured by ELISA method) in Bardsir region of Kerrman
in 2010 were 24 and 36%, respectively (Mohammad Khalili, Shahabi-Nejad, & Golchin, 2010). Since most people
with acute Q fever have no specific symptoms, health care providers do not suspect acute Q fever disease.
Although the laboratory diagnosis of acute Q fever can be done on the basis of experimental results, but the exact
diagnosis needs a four-fold increase in phase II IgG antibodies between acute and recovering phases of the disease.
5. Conclusion
Overall, this study was done on patients with suspected acute Q fever symptoms or symptoms similar to atypical
pneumonia or brucellosis. Acute Q fever patients were diagnosed among the suspected febrile patients in Iran
north. The evidences from this study and previous studies conducted in different regions of Iran supports this fact
that Q fever is one of the important endemic zoonotic diseases in Iran and needs more attention by physicians and
health care system.
Acknowledgements
This article is result of Dr. Sara Arabsheybani thesis for specialty of infectious diseases and was supported by the
Vice-Chancellor for Research at Mazandaran University of Medical Sciences (Grant Number: 1028).
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Competing Interests Statement
The authors declare that there is no conflict of interests regarding the publication of this paper.
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