Skip to main content
PLOS Neglected Tropical Diseases logoLink to PLOS Neglected Tropical Diseases
. 2018 Mar 15;12(3):e0006338. doi: 10.1371/journal.pntd.0006338

Q fever in Spain: Description of a new series, and systematic review

Vanesa Alende-Castro 1,#, Cristina Macía-Rodríguez 2,#, Ignacio Novo-Veleiro 1,*,#, Xana García-Fernández 3,, Mercedes Treviño-Castellano 3,, Sergio Rodríguez-Fernández 2,, Arturo González-Quintela 1,
Editor: Didier Raoult4
PMCID: PMC5871012  PMID: 29543806

Abstract

Background

Forms of presentation of Q fever vary widely across Spain, with differences between the north and south. In the absence of reported case series from Galicia (north-west Spain), this study sought to describe a Q-fever case series in this region for the first time, and conduct a systematic review to analyse all available data on the disease in Spain.

Methods

Patients with positive serum antibodies to Coxiella burnetii from a single institution over a 5-year period (January 2011-December 2015) were included. Patients with phase II titres above 1/128 (or documented seroconversion) and compatible clinical criterial were considered as having Q fever. Patients with clinical suspicion of chronic Q-fever and IgG antibodies to phase I-antigen of over 1/1024, or persistently high levels six months after treatment were considered to be cases of probable chronic Q-fever. Systematic review: We conducted a search of the Pubmed/Medline database using the terms: Q Fever OR Coxiella burnetii AND Spain. Our search yielded a total of 318 studies: 244 were excluded because they failed to match the main criteria, and 41 were discarded due to methodological problems, incomplete information or duplication. Finally, 33 studies were included.

Results

A total of 155 patients, all of them from Galicia, with positive serological determination were located during the study period; 116 (75%) were deemed to be serologically positive patients without Q fever and the remaining 39 (25%) were diagnosed with Q fever. A potential exposure risk was found in 2 patients (5%). The most frequent form of presentation was pneumonia (87%), followed by isolated fever (5%), diarrhoea (5%) and endocarditis (3%). The main symptoms were headache (100%), cough (77%) and fever (69%). A trend to a paucisymptomatic illness was observed in women. Hospital admission was required in 37 cases, and 6 patients died while in hospital. Only 2 patients developed chronic Q-fever. Systematic review: Most cases were sporadic, mainly presented during the winter and spring, as pneumonia in 37%, hepatitis in 31% and isolated fever in 29.6% of patients. In the north of Spain, 71% of patients had pneumonia, 13.2% isolated fever and 13% hepatitis. In the central and southern areas, isolated fever was the most frequent form of presentation (40%), followed by hepatitis (38.4%) and pneumonia (17.6%). Only 31.7% of patients reported risk factors, and an urban-environment was the most frequent place of origin. Overall mortality was 0.9%, and the percentage of patients with chronic forms of Q-fever was 2%.

Conclusions

This is the first study to report on a Q-fever case series in Galicia. It shows that in this region, the disease affects the elderly population -even in the absence of risk factors- and is linked to a higher mortality than reported by previous studies. While pneumonia is the most frequent form of presentation in the north of the country, isolated fever and hepatitis tend to be more frequent in the central and southern areas. In Spain, 32% of Q-fever cases do not report contact with traditional risk factors, and around 58% live in urban areas.

Author summary

We present, for the first time, a series which describes clinical and epidemiological characteristics of patients diagnosed with Q fever in our region (Galicia, North-Western Spain). Our results showed that pneumonia is the main form of presentation of Q fever in our area, with headache and cough as the most frequent symptoms. We also found a very low percentage of patients with potential exposure risks (5%), which reinforces the hypothesis of the existence of alternative mechanisms of transmission to animal reservoir contact. Due to the lack of data available, we believe that the present work could be the starting point to improve the knowledge of this disease in our area. We also developed a systematic review of all series published in Spain, which showed a geographycal pattern linked to form of presentation, with pneumonia as the main form in Northern regions and hepatitis and isolated fever in Central and Southern regions.

Introduction

Q fever is a zoonosis with a world-wide distribution, caused by Coxiella burnetii, which can present as sporadic cases or through outbreaks in a specific region. Although ticks can play a role as vectors [1], the usual sources of human infection are cattle, sheep, goats, and wildlife. Since its description, Q fever has been widely studied by many groups, with the 2008 outbreak in the Netherlands increasing interest in the disease in Europe in recent years [2].

The relevance of Q fever in Spain varies widely depending on the region in question, e.g., whereas large series have been reported in the Basque Country, only a few case reports have come from other regions [3,4]. These differences might be due to climatological, social or environmental factors but for the most part, knowledge of the epidemiology of Coxiella burnetii is poor in Spain. To our knowledge there have been no previously reported case series of Q fever in Galicia (north-west Spain), and we only have a limited perspective of the distribution of Coxiella burnetii in animal reservoirs [5], along with reports of a few isolated cases [6]. Although the presence of cattle is frequent in all areas of Galicia, the existence of an additional wildlife reservoir is also plausible, because populations of foxes, wolves, wild boars and other species also exist in the region. While existing data tend to suggest a difference in clinical presentation between the north and south of the country [7,8], there are nevertheless insufficient data to describe this in Galicia and elsewhere for the purpose of giving a complete picture of Q fever in Spain.

Accordingly, the main objectives of this study were: on one hand, to describe a Q-fever case series in Galicia for the first time; and on the other, to conduct a systematic review to clarify and analyse all available data on the disease in Spain.

Results

Case-series report

A total of 155 patients were located with positive serological determination during the study period; of these, 116 (75%) were deemed to be serologically positive patients without Q fever (unrelated to an acute or chronic Coxiella burnetii infection) and the remaining 39 (25%) were diagnosed with Q fever. Regarding the group without Q fever, the indication for serological testing was atypical pneumonia or pneumonia in patients with risk factor for Q fever in 80% of cases, and fever wihtout a clear origin in the remainder. In this second group, main final diagnoses were gastrointenstinal disease, viral infections and neoplasia. All patients included in the group without Q fever had a final diagnosis that excluded Q fever as the cause of their symptoms. Of the Q fever patients, 27 were men (69%), and only 2 (5%) were found to have a potential risk of exposure (contact with cattle), although this data was available only in 50% of patients. A rural environment was the most frequent place of residence (22 patients, 56%). None of the patients had reported a tick bite before the appearance of clinical symptoms. A breakdown of the complete epidemiological profile of the series is shown in Table 1.

Table 1. Clinical and epidemiological characteristics of patients and differences between genders.

Total (n = 39) Men (n = 27) Women (n = 12) P
Age 73 (15) 73 (11) 72 (22) 0.839
Animal exposure 2 (5) 0 (0) 2 (17) -
Rural environment 22 (56) 15 (55.5) 7 (58) 0.872
COPD 9 (23) 9 (33) 0 (0) 0.022
Chronic heart failure 12 (47) 9 (33) 3 (25) 0.450
Chronic liver disease 2 (5) 2 (7) 0 (0) 0.474
Fever 27 (69) 21 (78) 6 (50) 0.089
Headache 39 (100) 27 (100) 12 (100) -
Dyspnea 23 (59) 20 (74) 3 (25) 0.006
Cough 30 (77) 22 (81.5) 8 (67) 0.268
Chest pain 11 (28) 9 (33) 2 (17) 0.253
Abdominal pain 7 (18) 5 (18.5) 2 (17) 0.635
ESR > 35 mm/h 16 (41) 11 (41) 5 (42) 0.614
CRP > 2 mg/dL 16 (41) 9 (33) 7 (58) 0.133
CRP > 10 mg/dL 9 (23) 7 (26) 2 (17) 0.424
Leukocytes > 10000/μL 24 (62) 17 (63) 7 (58) 0.528
Leukocytes < 5000/μL 4 (10) 4 (15) 0 (0) 0.213
Cytolysis (AST/ALT > 45 IU/L) 10 (26) 8 (30) 2 (17) 0.332
Cholestasis (GGT > 55 IU/L or AP > 150 IU/L) 16 (41) 11 (41) 5 (42) 0.893
Anaemia
(Hb < 12 g/dL)
13 (33) 7 (26) 6 (50) 0.135

Data are shown as absolute values (percentage).

COPD: chronic obstructive pulmonary disease. ESR: erythrocyte sedimentation rate. CRP: C reactive protein. AST: aspartate amino-transferase. ALT: alanine amino-transferase. GGT: gamma glutamyl-transferase. AP: alkaline phosphatase. Hb: haemoglobin.

Most cases were diagnosed during 2015 (26 cases, 67%) and 2014 (11 cases, 28%), with all presenting in the period from December to June (winter and spring). In terms of clinical manifestations, the most frequent form of presentation was pneumonia (35 cases, 90%), followed by isolated febrile syndrome (2 cases), diarrhoea (2 cases) and endocarditis (1 case). The main symptom reported by patients was headache (100%), followed by cough (77%) and fever (69%). It is remarkable that a trend to paucisymptomatic illness was observed in women compared with men. All clinical and analytical aspects are shown in Table 1.

Hospital admission in the Internal Medicine or Pneumology departments was required in all but 2 patients, both of whom successfully underwent ambulatory treatment and follow-up. When it came to empirical treatment, the most frequent regimen included a beta-lactam antibiotic (25 patients, 64%), either alone (8 patients) or in combination with a fluoroquinolone (7 patients) or a macrolide (10 patients). After diagnosis of Q fever, 11 patients were switched to doxycycline in monotherapy and another 6 patients to a fluoroquinolone, while the remaining 22 patients completed the initial empirical treatment. There were no differences in patients’ length of hospital stay, duration of symptoms or mortality rates by reference to the treatment received, with the average length of antibiotic therapy being 13 (SD = 6) days.

At the date of diagnosis, 28 patients (72%) had phase II titres of over 1/512. Across follow-up, only 2 patients developed a probable chronic Q fever: one had confirmed endocarditis through transesophageal echocardiogram, and the other had a persistent febrile syndrome which was also judged to be endocarditis, despite it was not possible to perform a complete study due to poor general condition of this patient. Both patients were alive at the end of the study period, and continued undergoing long-term treatment with doxycycline and hydroxychloroquine.

Insofar as mortality was concerned, six patients (15%) died, in all cases due to respiratory complications during hospital stay. No epidemiological, clinical or biochemical variable was found to be linked to mortality in our series.

Systematic review

This review covered 33 case-series reports (excluding ours) spanning a 38-year period (1977–2014) in Spain. Data on a total of 1960 patients (including our study) were analysed. A breakdown of the main data available from the studies is shown in Table 2.

Table 2. Main data obtained from the studies included in the systematic review.

STUDY Location DATE N SERIES CLINICAL PRESENTATION SYMPTOMS ENVIRONMENT RISK FACTORS BIOCHEMICAL DATA EVOLUTION
Hellín et al.[9]
Madrid
Sept 1977—Aug 1980 23 Sporadic Isolated fever: 14 (61)
Pneumonia: 9 (39)
Fever: 23 (100)
Headache: 18 (78)
Myalgia: 14 (61)
Respiratory symptoms: 13 (56)
ND Animal (livestock) or food exposure: 9 (39) Transaminase: 17 (74)
Leukopenia: 10 (43)
Leukocytosis: 2 (9)
Deceased: 0 (0)
Chronic: 0 (0)
Montejo-Baranda et al.[7]
Vizcaya
June 1981- June 1982 11 Sporadic Pneumonia: 10 (91)
Isolated fever: 1 (9)
Fever: 11 (100)
Headache: 11 (11)
Myalgia: 11 (100)
Urban: 6 (54)
Rural: 5 (46)
Non-specific: 4 (36) Transaminase: 7 (64)
Leukopenia: 5 (36)
Deceased: 0 (0)
Chronic: 0 (0)
Aguirre-Errasti et al.[10]
Vizcaya
March—May 1982 42 Epidemic Pneumonia: 28 (67)
Hepatitis: 11 (26)
Fever: 42 (100)
Headache: 42 (100)
Myalgia: 42 (100)
ND ND Transaminase: 16 (38) Chronic: 0 (0)
Deceased: 0 (0)
Menéndez-Caro et al.[11]
Madrid
1982–1983 26 Sporadic Isolated fever: 22 (85)
Pneumonia: 3 (11)
Endocarditis: 1 (4)
Fever: 26 (100)
Headache: 18 (69)
Asthenia: 16 (61)
Chills: 11 (42)
Sweating: 8 (31)
Cough: 7 (27)
ND Food exposure: 4 (15)
Animal exposure (livestock): 2 (8)
Transaminase: 15 (58)
ESR: 8 (31)
Leukocytosis: 7 (27)
Leukopenia: 7 (27)
Deceased: 1 (4)
Chronic: 3 (11)
Fernández-Roblas et al.[12]
Madrid
1982–1984 37 Sporadic Isolated fever: 28 (75)
Pneumonia: 8 (22)
Hepatitis: 1 (3)
Fever: 37 (100)
Headache: 27 (73)
Chills: 20 (54)
Respiratory symptoms: 18 (49)
Arthromyalgia: 14 (38)
ND Non-specific: 12 (32) Transaminase: 21 (57)
Leukopenia: 5 (13.5)
Deceased: 0 (0)
Chronic: 5 (13.5)
Sobradillo et al.[13]
Vizcaya
Jul 1982—Dec 1986 164 Sporadic Pneumonia: 164 (100) Fever: 158 (96)
Headache: 91 (55)
Myalgia: 88 (54)
Cough 88 (54)
Chest pain: 56 (34)
Urban: 89 (54)
Rural: 75 (46)
Animal exposure (ND): 13 (8) Transaminase: 74 (45)
ESR: 71 (43)
Leukocytosis: 22 (13)
Deceased: 0 (0)
Chronic: 0 (0)
De Alarcón et al.[8]
Seville
1983–1999 231 Sporadic Hepatitis: 148 (64)
Isolated fever: 75 (32)
Pneumonia: 3 (1)
Fever: 231 (100)
Chills: 174 (75)
Headache: 172 (74.5)
Myalgia: 158 (68)
Arthralgia: 139 (60)
Cough: 41 (18)
Urban: 123 (53)
Rural: 108 (47)
Animal exposure (ND): 91 (39)
Food exposure: 46 (20)
Rural stay: 19 (15)
Transaminase: 139 (60)
Thrombocytosis: 43 (19)
Thrombopenia: 41 (18)
Leukopenia: 23 (10)
Leukocytosis: 16 (7)
Chronic: 0 (0)
Deceased: 0 (0)
Martínez-Luengas et al.[14]
Seville
Sept 1983—Oct 1984 34 Sporadic Pneumonia: 11 (32)
Isolated fever: 22 (65)
Fever: 34 (100)
Headache: 32 (94)
Arthromyalgia: 31 (91)
ND Non-specific: 20 (59) Transaminase: 17 (50)
ESR: 14 (41)
Leukocytosis: 5 (15)
Chronic: 1 (3)
Deceased: 0 (0)
Merino et al.[15]
Soria
Jan 1984—Dec 1996 13 Sporadic Pneumonia: 10 (77)
Isolated fever: 1 (8)
Hepatitis: 1 (8)
Fever: 13 (100)
Cough: 4 (31)
Headache: 3 (23)
ND Animal exposure (ND): 2 (16) ND Chronic: 1 (8)
Deceased: 0 (0)
Domingo et al.[16]
Barcelona
Jan 1985—Dec 1997 63 Sporadic Hepatitis: 30 (48)
Pneumonia: 26 (41)
Isolated fever: 7 (11)
Fever: 63 (100) Urban: 63 (100) Animal exposure (pets): 30 (48) ND Deceased: 0 (0)
Chronic: 0 (0)
Antón-Aranda et al.[17]
Guipúzcoa
1985–1989 60 Sporadic Pneumonia: 44 (73)
Hepatitis: 17 (28)
Isolated fever: 7 (12)
Fever: 60 (100)
Arthromyalgia: 38 (63)
Cough: 33 (55)
Headache: 32 (53)
ND Animal (livestock) or food exposure: 10 (17) Transaminase: 28 (47)
ESR: 17 (28)
LDH: 11 (18)
Leukocytosis: 11 (18)
Thrombopenia: 11 (18)
Deceased: 0 (0)
Chronic: 1 (2)
Millán-Mon et al.[18]
La Palma
Canary Islands
1986–1988 35 Sporadic Isolated fever: 26 (74)
Hepatitis: 7 (20)
Pneumonia: 2 (6)
Fever: 35 (100)
Headache: 16 (46)
Cough: 9 (26)
Arthromyalgia: 13 (37)
ND Animal exposure (goats): 18 (51) Transaminase: 31 (88)
ESR: 27 (77)
Leukocytosis: 9 (26)
ND
Romero-Jiménez et al.[19]
Huelva
1987–1999 109 Sporadic Hepatitis: 60 (55)
Isolated fever: 47 (43)
Fever: 106 (97)
Headache: 83 (76)
Arthromyalgia: 48 (44)
Urban: 10 (9)
Rural: 99 (91)
Animal exposure (ND): 57 (52) Leukopenia: 36 (33)
Thrombopenia: 28 (26)
ND
Abad et al.[20]
Vizcaya
Jan 1988—Jan 1998 73 Sporadic Pneumonia: 55 (75)
Isolated fever: 18 (25)
Fever: 73 (100)
Headache: 33 (45)
Cough: 30 (41)
ND Non-specific: 11 (15) Transaminase: 33 (45)
Leukocytosis: 5 (7)
Deceased: 0 (0)
Chronic: 0 (0)
Rotaeche del Campo et al.[21]
Guipúzcoa
Feb 1989 5 Epidemic Pneumonia: 3 (60)
Isolated fever: 2 (40)
Fever: 5 (100)
Myalgia: 5 (100)
Headache: 4
Rural: 5 (100) Animal exposure (ND): 5 (100) ESR: 3 (60)
Transaminase: 2 (40)
ND
Bella et al.[22]
Barcelona
1989 17 Sporadic Pneumonia: 4 (23)
Hepatitis: 12 (71)
Isolated fever: 1 (6)
Fever: 17 (100) Urban: 17 (100) ND Transaminase: 14 (82) ND
Sampere et al.[23]
Barcelona
1989–1999 66 Sporadic Pneumonia: 37 (56)
Hepatitis: 22 (33)
Isolated fever: 5 (7.5)
Pleuropericarditis: 1 (1.5)
Bronchitis: 1 (1.5)
Fever: 52 (79)
Headache: 28 (42)
Arthromyalgia: 27 (41)
Urban: 66 (100) Animal exposure (ND): 24 (36)
Rural stay: 8 (12)
Transaminase: 40 (61)
Cholestasis: 29 (44)
Deceased: 0 (0)
Chronic: ND
Martínez-Eizaguirre et al.[24]
Guipúzcoa
April—June 1990 30 Epidemic Isolated fever: 30 (100) Fever: 30 (100)
Sweating: 29 (97)
Headache: 26 (87)
Chills: 25 (83)
Myalgia: 22 (73)
Rural: 30 (100) ND Transaminase: 26 (86)
ESR: 5 (17)
Leukocytosis: 4 (13)
Leukopenia: 4 (13)
Deceased: 0 (0)
Chronic: ND
Pascual-Velasco et al.[25]
Lanzarote
Canary Islands
1991–1992 94 Sporadic Pneumonia: 52 (55)
Isolated fever: 42 (45)
ND ND Animal exposure (goats): 25 (27) ND ND
Muñoz-Sanz et al.[26]
Badajoz
June 1992—May 2005 124 Sporadic Isolated fever: 64 (52)
Hepatitis: 53 (43)
Pneumonia: 14 (11)
Endocarditis: 7 (6)
Fever: 120 (97)
Headache: 40 (32)
Urban: 48 (39)
Rural: 76 (61)
Animal exposure (sheep, goats and cows): 58 (47) ND Deceased: 0 (0)
Chronic: 7 (6)
Espejo et al.[27]
Canary Islands—La Rioja—Catalonia
1995–2009 (Canary Islands 2005–2009) 183 Sporadic Hepatitis: 90 (49)
Isolated fever: 58 (32)
Pneumonia: 35 (19)
Headache: 107 (58.5)
Arthromyalgia: 69 (38)
Nausea/vomiting: 32 (17.5)
Urban: 120 (65.5)
Rural: 63 (34.5)
ND ND Deceased: 2 (1)
Chronic: ND
Nuño-Mateo et al.[28]
Asturias
Feb 1996—May 2001 12 Sporadic Pneumonia: 10 (83)
Isolated fever: 2 (17)
Headache: 12 (100)
Fever: 12 (100)
Cough: 8 (66)
Rural: 3 (25)
Urban: 9 (75)
Animal exposure (sheep and cattle): 5 (42) Transaminase: 11 (90)
ESR: 11 (90)
Deceased: 0 (0)
Chronic: 0 (0)
Lepe et al.[29]
Huelva
1996–1997 21 Sporadic Isolated fever: 19 (90)
Pneumonia: 2 (10)
Fever: 21 (100)
Headache: 21 (100)
Myalgia: 21 (100)
ND Animal exposure (ND): 9 (43) Transaminase: 21 (100) Deceased: 0 (0)
Chronic: 0 (0)
Bartolomé et al.[30]
Albacete
April 1997—Sept 2002 35 Sporadic Hepatitis: 17 (48)
Pneumonia: 9 (26)
Isolated fever: 8 (23)
Myocarditis: 1 (3)
Fever: 34 (95)
Headache: 16 (46)
Arthromyalgia: 13 (37)
Cough: 12 (34)
Urban: 25 (71.5)
Rural: 10 (28.5)
Animal exposure (livestock): 9 (26)
Rural stay: 5 (14)
Transaminase: 26 (74)
ESR: 14 (40)
Deceased: 1 (3)
Chronic: ND
Nebreda et al.[31]
Soria
May 1998 14 Epidemic Pneumonia: 9 (64)
Isolated fever: 5 (36)
Fever: 13 (93)
Headache: 10 (71)
Sweating: 8 (57)
Myalgia: 5 (36)
Rural: 14 (100) Animal exposure (ND): 3 (21)
Food exposure: 1 (7)
Rural stay: 2 (14)
Leukopenia: 2 (14) Chronic: 0 (0)
Deceased: 0 (0)
Bolaños et al.[32]
Gran Canaria
Canary Islands
1998–2000 59 Sporadic Hepatitis: 52 (88)
Pneumonia: 7 (12)
Isolated fever: 3 (5)
Fever: 59 (100)
Urban: 32 (54)
Rural: 27 (46)
Animal exposure (ND): 15 (25) Transaminase: 52 (88)
APTT: 26 (44)
Deceased: 1 (2)
Chronic: 0 (0)
Martín-Aspas et al.[33]
Cádiz
2000–2010 80 Sporadic Hepatitis: 50 (63)
Isolated fever: 16 (20)
Fever: 78 (98) Urban: 69 (86)
Rural: 11 (14)
ND Transaminase: 43 (54)
Thrombocytopenia: 39 (49)
Deceased: ND
Chronic: 16 (20)*
Ramos et al.[4]
Alicante
Jan 2001—Sept 2004 30 Sporadic Hepatitis: 21 (70)
Isolated fever: 5 (17)
Pneumonia: 3 (10)
Meningo-encephalitis: 1 (3)
Fever: 30 (100)
Headache: 29 (97)
Myalgia: 25 (83)
Urban: 20 (67)
Rural: 10 (33)
Animal exposure (ND): 16 (53) CRP: 29 (97)
Transaminase: 20 (67)
ESR: 19 (63)
LDH: 17 (51.5)
APTT: 12 (36)
Deceased: 0 (0)
Chronic: ND
Ruiz-Seco et al.[34]
Madrid
2001–2008 54 Sporadic Pneumonia: 29 (54)
Hepatitis: 13 (24)
Isolated fever: 13 (24)
Fever: 37 (68)
Cough: 25 (47)
Breathless: 13 (25)
Urban: 28 (52)
Rural: 26 (48)
Animal exposure (ND): 32 (59) ESR: 37 (72)
Leukopenia: (60)
Thrombocytosis: (60)
Chronic: 3 (8)
Deceased: 3 (8)
García-Clemente et al.[35]
Asturias
Jan/Feb 2003 60 Epidemic Pneumonia: 60 (100) Fever: 60 (100)
Headache: 48 (80)
Myalgia: 46 (77)
Cough: 42 (70)
Rural: 29 (48)
Urban: 31 (52)
Animal exposure (livestock): 4 (7) Transaminase: 21 (35)
APTT: 14 (24)
Deceased: 0 (0)
Chronic: 0 (0)
Raya-Cruz et al.[36]
Mallorca
Balearic Islands
March 2003—Feb 2011 87 Sporadic Pneumonia: 39 (45)
Isolated fever: 21 (24)
Hepatitis: 19 (22)
Pericarditis: 3 (3.5)
Meningitis: 1 (1)
Meningo-encephalitis: 1 (1)
Fever: 62 (71)
Cough: 32 (37)
Headache: 23 (26)
Breathless: 15 (17)
Urban: 35 (40)
Rural: 39 (45)
Undefined: 13 (15)
Animal exposure (cattle, sheep and goats): 8 (9)
Urban animal exposure (pets): 31 (36)
Food exposure: 1 (1)
Leukocytosis: 27 (31)
Transaminase: 29 (33)
Chronic: 1 (1)
Deceased: 3 (3.4)
De los Ríos-Martín et al.[37]
Madrid
Feb—March 2004 16 Epidemic Isolated fever: 14 (87.5)
Pneumonia: 2 (12.5)
Fever: 16 (100)
Anorexia: 13 (81)
Asthenia: 11 (69)
Cough: 9 (56)
ND Animal exposure (ND): 16 (100) Transaminase: 2 (12.5)
Thrombopenia: 2 (12.5)
ND
Alonso et al.[38]
Vizcaya
Feb—April 2014 50 Epidemic Isolated fever: 14 (28)
Pneumonia: 13 (26)
Fever: 27 (54)
Headache: 22 (44)
Myalgia: 11 (22)
Urban: 44 (88)
Rural: 6 (12)
Animal exposure (livestock): 3 (6) ND Chronic: 0 (0)
Deceased: 0 (0)

Data are shown as absolute values (percentage).

* All patients diagnosed with chronic Q fever on the basis of biochemical criteria alone.

CRP: C reactive protein; ESR: erythrocyte sedimentation rate; LDH: lactate dehydrogenase; APTT: activated partial thromboplastin time; ND: no data.

It was noteworthy that, when the overall data (including those of our series) were analysed, most of the cases were seen to be sporadic, presenting mainly during winter and spring, as pneumonia in 37%, hepatitis in 31% and isolated fever in 29.6% of cases. Furthermore, on pooling the case series from areas located in the northern third of the country and comparing these to the remaining series from central and southern Spain, a significant difference was seen in the form of presentation of Q fever. In the northern areas, 71% of patients had pneumonia, followed by isolated fever (13.2%) and hepatitis (13%), while in the central and southern areas isolated fever was the most frequent form of presentation (40%), followed by hepatitis (38.4%) and pneumonia (17.6%).

With regard to clinical manifestations, fever was the most frequent (94.6%), followed by headache (50.2%), and myalgia or arthromyalgia (33.5%). Mention should be made of the absence of fever in 108 cases (5.4%), despite diagnosis of Q fever. A risk factor, mainly animal exposure (in most of cases livestock, but also pets), was identified in only 31.7% of patients, and urban environment was the most frequent place of origin (833/1469, 58%), though these data were missing in 12 studies.

Overall mortality was 0.9% but the absence of mortality data in 8 studies should be noted. The total percentage of patients with chronic forms of Q fever was 2%, yet it has to be said that no data were reported in 11 studies, and in one study 16 cases were reported as chronic on the basis of serological criteria alone [33].

Discussion

To our knowledge, this is the first Q fever case-series study to have been conducted in Galicia (north-west Spain), an area not previously considered endemic. In this respect, our data show a significant increase in diagnosis of Q fever in recent years, with a peak in 2015. Even so, we observed no evidence of geographical clustering or contact between cases that would justify our series being classified as an outbreak. A high percentage (75%) of patients with positive serological determination were deemed to be serologically positive patients without Q fever, in most cases (80%) due to low titres in the context of a community-acquired pneumonia caused by other bacteria. In respect of these patients, there are two important aspects that could represent potential limitations: on the one hand, there was no serological follow-up in any case to exclude late seroconversion; and on the other, our data did not contain the necessary information on Coxiella burnetii seroprevalence to evaluate these results. Further analysis is thus called for. The main limitation of our series report is the restrospective design, which limitates information about exposures and specific clinical data.

Analysis of the clinical presentation of the cases included shows that the high percentage of pneumonia observed by us is consistent with the findings reported by other studies conducted in the north of Spain [8,17,39] but not with those reported by studies conducted in the south [8,14,19]. The reasons for this difference between northern and southern areas of the country are not completely understood. Recent studies suggest that different Coxiella burnetii genotypes coexist and infect different wildlife species in Spain [40]. Hence, one could hypothesize that different bacterial genotypes might lead to different clinical presentations of Q fever. Further studies are needed to clarify this potential relationship.

Our study observed a difference between men and women in the prevalence of respiratory symptoms and fever, a finding consistent with recent reports [41]. While this difference could be due to a higher prevalence of chronic obstructive pulmonary disease among men, or, by the same token, to a different inflammatory response in women. In this connection, a different prevalence of adverse effects to Coxiella burnetii vaccine in men and women has recently been reported [42].

The presence of some cases without fever which were nonetheless diagnosed as Q fever is clearly striking. In our series, this group accounted for 31% of patients, and while this percentage is similar to that reported by previous studies in Madrid [34], the Balearic Islands [36] and the Basque Country [38], it is not the usual pattern [710,13,14,16,17,20,22,24,26,32]. As the above three were the most recently published case-series studies prior to ours, diagnosis of cases without fever could reflect the greater reliability of new diagnostic methods, or even a higher level of suspicion among physicians vis-à-vis patients who present with symptoms and signs compatible with Q fever, due to better knowledge of this disease and its epidemiology. The absence of fever in a third of the patients in our series could be due to a higher prevalence of pneumonia caused by Coxiella burnetii, which can be suspected and diagnosed without fever [43]. In our series, all patients without fever (12) had pneumonia, which was also the main clinical presentation in the series from Madrid and the Balearic Islands [34,36]. These findings are in line with those reported by studies undertaken elsewhere [44,45] and may reflect the usefulness of performing Q fever serological tests on all patients with community-acquired pneumonia [44].

With regard to risk factors, these were found in only 2 patients (5%). Moreover, nearly half of the cases lived in urban areas, theoretically less exposed to contact with Coxiella burnetii. This lack of association with traditional risk factors for Q fever was confirmed by our systematic review, which showed a higher percentage of patients from urban areas, and the presence of risk factors in only a third of all patients [7,8,13]. This same finding has been observed in studies conducted at different periods in different geographical areas [79,13,19,26,36]. The first explanation to be considered is the high percentage of missing data on risk factors in most of the studies analysed, something that could clearly lead to such factors being underestimated [10,18,24,27]. Other possible explanations are linked to different mechanisms of transmission, such as aerosols in drinking water [46], consumption of unpasteurised milk products [47], or contact with ticks and other vectors [48], which might not have been investigated in all patients. Recent studies also suggest the possibility of long-distance dispersion of Coxiella burnetii by wind [49], transmission through waste manipulation [38], or even human transmission [50] as novel mechanisms that might not have been considered in most series. At all events, in future detailed investigation of potential risk factors should be made standard practice in all patients diagnosed with Q fever, to clarify all possible transmission mechanisms.

In terms of biochemical markers, as in other studies, the most frequent alteration in our series was elevation of the leukocyte count and liver enzyme levels, even in the absence of cases presented as hepatitis [8,20,24].

Only two cases were diagnosed as probable chronic Q fever, one which initially presented as endocarditis and another which presented as a persistent febrile syndrome. Serological follow-up was performed in only a third of patients, something that might represent a potential study limitation. Previous studies reported similar percentages, probably due to the same limitation [13,17,32]. Martín-Aspas et al found a higher proportion of patients who fulfilled the serological criteria for chronic Q fever 3 months after diagnosis, but none of them met the clinical criteria for complete diagnosis of chronic Q fever [33]. This study underscores the vital importance of long-term follow-up in patients diagnosed with Q fever, regardless of the duration or type of treatment received, and puts into question the usefulness of serological monitoring, in which analysis has previously yielded contradictory results [51,52]. A regular, full clinical evaluation thus remains the main tool for diagnosis of chronic forms of Q fever, and the follow-up period should be no less than 6 months [53]. Other diagnostic tests, like Positron Emission Tomography (PET, not available in our series), have showed an increasing utility in the diagnosis of Q fever, particularly in persistent forms [54].

Another remarkable finding was the mortality observed in our series (15%), in that it is the highest Q fever-related mortality rate reported in Spain, according to our systematic review. Possible explanations for this difference might lie in a higher prevalence of comorbidity and an older cohort. In this regard, most studies reported cases in younger adult populations, mean age 30–40 years [810,13,14,1620,22,30,37,38], whereas the age range in our study extended up to 73 years. Furthermore, the prevalence of previous chronic diseases was also higher in our series, in which 20 patients (51%) had at least one chronic disease. In contrast, previous studies reported a comorbidity prevalence of around 20% [32,35,36], which may have contributed to a less severe disease profile and a lower mortality rate. Lastly, our series included patients who required hospitalisation in 95% of cases, which implies a greater severity and a higher risk of complications. Other authors included a variable percentage of outpatients, ranging from 20–40% [20,32] to 80% [10,38], which probably means the presence of less severe forms of Q fever and, by extension, lower mortality. Another plausible explanation could be the existence of a more virulent clone or genotype of Coxiella burnetii in our area, which would require further studies to be demonstrated [41].

Conclusions

To the best of our knowledge, this is the first Q fever case-series study to have been conducted in Galicia (north-west Spain), an area that had not been considered endemic until now. Our study shows that the presence of Q fever in this area is relevant, affects the elderly population even in the absence of risk factors, and is linked to a higher mortality than previous studies have indicated. Our systematic review confirms the different presentation of Q fever in northern areas of Spain, where pneumonia is the most frequent form, compared to central and southern areas, where isolated fever and hepatitis are more frequent. This systematic review also shows that nearly 32% of Q fever cases do not report contact with traditional risk factors, and that around 58% of them reside in urban areas. Better knowledge of seroprevalence in different areas and a higher level of clinical suspicion are therefore needed, in order to improve diagnosis and prevention of this disease in Spain.

Materials and methods

Case-series report

A search of the Microbiology Unit database at the Santiago de Compostela University Teaching Hospital (A Coruña, Galicia, Spain), covering a 4-year period from January 2011 to December 2015, located a total of 155 patients. We reviewed the clinical histories of all patients with positive serological determination. In terms of area of residence, “urban” was defined as any area having a population of over 50000, “suburban” as any area having a population of 5000 to 50000, and “rural” as any area having a population of less than 5000.

IgG antibodies to phase I and phase II Coxiella burnetii antigens were determined by indirect immunofluorescence [55,56], according to the manufacturer's instructions (Vircell, Spain). Assayed dilutions began from 1/64 onwards. Seroconversion was considered in all patients with phase-II titres of over 1/128 who had previously been seronegative, or in those who showed a fourfold or greater rise in IgG antibody titre to Coxiella burnetii phase II antigen (corresponding to 2 dilutions) [57,58]. All titres above 1/128 were deemed to be positive, and we investigated the clinical history of all patients with these serological levels.

Clinical, epidemiological, microbiological, radiological and biochemical variables were collected by reviewing patients’ electronic medical records to check for diagnosis of acute Q fever. Inclusion criteria were defined as: positive serological determination; or alternatively, documented seroconversion and clinical diagnosis of acute Q fever, based on compatible signs and symptoms and exclusion of other causes. Patients with a positive serological test but a confirmed aetiology for clinical manifestations other than Q fever were excluded and classified as serologically positive patients without Q fever. Patients with clinical suspicion of chronic Q fever (cardiac valve disease, prosthetic or bone infection, immunocompromised hosts, or persistent fever of unknown origin) and IgG antibodies to phase-I antigen of over 1/1024, or persistently high levels (over 1/800) six months after treatment were considered to be cases of probable chronic Q fever [59]. Patients with criteria for probable chronic Q fever and vegetations in trasesophageal echocardiogram and/or compatible findings after pathological examination of cardiac valves after surgery were considered as Q fever endocarditis [41].

As regards clinical presentation, patients were classified as having: pneumonia, on presentation of radiological consolidation and fever; hepatitis, on presentation of transaminase elevation more than twofold the upper limit of normal; and fever of unknown origin, if they displayed no other clinical, radiological or biochemical alterations.

Ethics statement

The study protocol was reviewed and approved by the Galician Clinical Research Ethics Committee. All data analyzed were anonymized.

Systematic review

We conducted a systematic review in order to identify observational studies published before December 2015, describing Q fever case series in Spain. To this end, we searched the Pubmed/Medline database using the following terms: Q Fever OR Coxiella burnetii AND Spain. In addition, we retrieved additional series by surveying references cited in other reports and using the MEDLINE option, "Related articles".

These search methods yielded a total of 318 studies; after a critical perusal of titles and abstracts, 244 were excluded for failing to fulfil the main eligibility criteria (series reports with a complete clinical description). A critical, full-text review of the remaining 74 papers led to a further 41 being discarded because of methodological problems, incomplete clinical information or series duplication. Finally, 33 studies were included in the systematic review.

Statistical methods

A descriptive analysis was performed, by calculating qualitative-variable rates along with their mean and standard deviation. We used the Chi-square or Fisher's exact tests, as appropriate (expected frequency value <5), to compare qualitative variables, and the Student's t test for quantitative variables. A P-value <0.05 was regarded as significant. All analyses were performed using the SPSS v. 22.0 computer software package (SPSS Inc., Chicago, IL, USA).

Supporting information

S1 Checklist. STROBE checklist.

(DOC)

S2 Checklist. PRISMA checklist.

(DOC)

S1 Flowchart. PRISMA flowchart.

(DOC)

S1 Database. Cases database.

(XLS)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

References

  • 1.Raoult D, Marrie T. Q fever. Clin Infect Dis Off Publ Infect Dis Soc Am. 1995;20: 489–495; quiz 496. [DOI] [PubMed] [Google Scholar]
  • 2.Schimmer B, Morroy G, Dijkstra F, Schneeberger PM, Weers-Pothoff G, Timen A, et al. Large ongoing Q fever outbreak in the south of The Netherlands, 2008. Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull. 2008;13. [PubMed] [Google Scholar]
  • 3.Montes M, Cilla G, Vicente D, Nieto V, Ercibengoa M, Perez-Trallero E. Gipuzkoa, Basque Country, Spain (1984–2004): a hyperendemic area of Q fever. Ann N Y Acad Sci. 2006;1078: 129–132. doi: 10.1196/annals.1374.020 [DOI] [PubMed] [Google Scholar]
  • 4.Ramosa JM, Masía M, Rodríguez JC, Gutiérrez F. [Acute Q fever in the Valencian autonomous community. A study of 30 cases]. Enfermedades Infecc Microbiol Clínica. 2005;23: 512–513. [DOI] [PubMed] [Google Scholar]
  • 5.Díaz JM, Fernández G, Prieto A, Valverde S, Lago N, Díaz P, et al. Epidemiology of reproductive pathogens in semi-intensive lamb-producing flocks in North-West Spain: a comparative serological study. Vet J Lond Engl 1997. 2014;200: 335–338. doi: 10.1016/j.tvjl.2014.02.022 [DOI] [PubMed] [Google Scholar]
  • 6.Tellez A, Sainz C, Echevarria C, de Carlos S, Fernandez MV, Leon P, et al. Q fever in Spain: acute and chronic cases, 1981–1985. Rev Infect Dis. 1988;10: 198–202. [DOI] [PubMed] [Google Scholar]
  • 7.Montejo Baranda M, Corral Carranceja J, Aguirre Errasti C. Q fever in the Basque Country: 1981–1984. Rev Infect Dis. 1985;7: 700–701. [DOI] [PubMed] [Google Scholar]
  • 8.Alarcón A de, Villanueva JL, Viciana P, López-Cortés L, Torronteras R, Bernabeu M, et al. Q fever: epidemiology, clinical features and prognosis. A study from 1983 to 1999 in the South of Spain. J Infect. 2003;47: 110–116. [DOI] [PubMed] [Google Scholar]
  • 9.Hellín T, Bouza E, Casimir L, Guerrero A, Ferrer M, González-Sainz J, et al. [Acute Q fever: study of 23 patients (author’s transl)]. Med Clin (Barc). 1981;77: 1–7. [PubMed] [Google Scholar]
  • 10.Aguirre Errasti C, Montejo Baranda M, Hernandez Almaraz JL, de la Hoz Torres C, Martinez Gutierrez E, Villate Navarro JL, et al. An outbreak of Q fever in the Basque country. Can Med Assoc J. 1984;131: 48–49. [PMC free article] [PubMed] [Google Scholar]
  • 11.Menéndez Caro JL, Yebra Bango M, Alés Martínez J, Girón González A, Manzano Espinosa L, Daza Pérez R. [Q fever. Report of 26 cases]. An Med Interna Madr Spain 1984. 1986;III: 316–320. [Google Scholar]
  • 12.Fernández Roblas R, Wilhelmi I, Díaz Curiel M, Gómez P, Aguado JM, Fernández Guerrero ML, et al. [Acute and chronic Q fever: clinical aspects, epidemiology, isolation of the agent and serologic data]. Rev Clin Esp. 1985;177: 62–69. [PubMed] [Google Scholar]
  • 13.Sobradillo V, Ansola P, Baranda F, Corral C. Q fever pneumonia: a review of 164 community-acquired cases in the Basque country. Eur Respir J. 1989;2: 263–266. [PubMed] [Google Scholar]
  • 14.Martínez-Luengas F, Borobio MV, Gálvez J, León de Lope M, Corral JL, Mañas R, et al. [Q fever in Seville. Comparison with other entities. Description of 34 cases and review]. Rev Clin Esp. 1985;176: 400–405. [PubMed] [Google Scholar]
  • 15.Merino FJ, Nebreda T, Campos A. Most common clinical presentation of Q fever in a province in the north of Spain. Eur J Epidemiol. 1998;14: 729–730. [DOI] [PubMed] [Google Scholar]
  • 16.Domingo P, Muñoz C, Franquet T, Gurguí M, Sancho F, Vazquez G. Acute Q fever in adult patients: report on 63 sporadic cases in an urban area. Clin Infect Dis Off Publ Infect Dis Soc Am. 1999;29: 874–879. doi: 10.1086/520452 [DOI] [PubMed] [Google Scholar]
  • 17.Antón Aranda E, Altuna Basurto E, García Martín C, Martí Cabane J, Bustillo Gutiérrez JM. [Incidence and characteristics of Q fever in a community habitat]. Enferm Infecc Microbiol Clin. 1990;8: 350–353. [PubMed] [Google Scholar]
  • 18.Millán Mon A, Argany Fajardo A, Febles Bethencourt J, González Caloca C, Vento Remedios TE, Fernández Cabrera M. [Q fever on the island of La Palma. A review of 35 patients]. An Med Interna Madr Spain 1984. 1989;6: 527–530. [PubMed] [Google Scholar]
  • 19.Romero-Jiménez MJ, Suárez-Lozano I, Fajardo JM, Benavente A, Menchero A, de la Iglesia A. [Hepatitis as unique manifestation of Q fever: clinical and epidemiologic characteristics in 109 patients]. Enferm Infecc Microbiol Clin. 2003;21: 193–195. [DOI] [PubMed] [Google Scholar]
  • 20.Abad A, Pardo C, Imaz M. [Q fever: a retrospective study over the last 10 years in the area of the Hospital de Basurto (Bilbao)]. Rev Clin Esp. 1999;199: 618–619. [PubMed] [Google Scholar]
  • 21.Rotaeche del Campo R, Anta Unanue JL. [Q fever. A familial outbreak of 5 cases]. Aten Primaria. 1990;7: 211–212, 214–215. [PubMed] [Google Scholar]
  • 22.Bella F, Espejo E, Mauri M, Alegre MD. Clinical presentation of acute Australian Q fever. Am J Med. 1994;96: 397–398. [DOI] [PubMed] [Google Scholar]
  • 23.Sampere M, Font B, Font J, Sanfeliu I, Segura F. Q fever in adults: review of 66 clinical cases. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2003;22: 108–110. doi: 10.1007/s10096-002-0873-3 [DOI] [PubMed] [Google Scholar]
  • 24.Martínez Eizaguirre JM, Pérez Rizo M, Olivella Pedregal A, García Ventura S, Cancio Fanlo M, Basabe Zapirain M. [Q fever: epidemic outbreak of the pure febrile form]. Aten Primaria. 1992;9: 425–428. [PubMed] [Google Scholar]
  • 25.Pascual Velasco F, Borobio Enciso MV, González Lama Z, Carrascosa Porras M. Clinical presentation of acute Q fever in lanzarote (Canary Islands): a 2-year prospective study. Scand J Infect Dis. 1996;28: 533–534. [DOI] [PubMed] [Google Scholar]
  • 26.Muñoz-Sanz A, Vera A, Rodríguez Vidigal FF. [Q fever in Extremadura: an emerging infection]. Enferm Infecc Microbiol Clin. 2007;25: 230–234. [DOI] [PubMed] [Google Scholar]
  • 27.Espejo E, Gil-Díaz A, Oteo JA, Castillo-Rueda R, García-Alvarez L, Santana-Báez S, et al. Clinical presentation of acute Q fever in Spain: seasonal and geographical differences. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2014;26: 162–164. doi: 10.1016/j.ijid.2014.06.016 [DOI] [PubMed] [Google Scholar]
  • 28.Nuño Mateo FJ, Noval Menéndez J, Campoamor Serrano MT, del Valle Prieto A. [Acute Q fever in Asturias]. Rev Clin Esp. 2002;202: 572–573. [PubMed] [Google Scholar]
  • 29.Lepe JA, Guerrero FJ, Ruiz-Calderón A, del Castillo E, Gómez-Salvago S, Jiménez-Alonso MA, et al. [The epidemiology of Q fever in the northern area of Huelva, Spain]. Enferm Infecc Microbiol Clin. 1999;17: 65–68. [PubMed] [Google Scholar]
  • 30.Bartolomé J, Marín A, Lorente S, Heredero E, Crespo MD. [Acute Q Fever: 35 cases in Castilla-La Mancha]. Enferm Infecc Microbiol Clin. 2004;22: 292–294. [DOI] [PubMed] [Google Scholar]
  • 31.Nebreda T, Contreras E, Jesús Merino F, Dodero E, Campos A. [Outbreak of Q fever and seroprevalence in a rural population from Soria Province]. Enferm Infecc Microbiol Clin. 2001;19: 57–60. [DOI] [PubMed] [Google Scholar]
  • 32.Bolaños M, Santana O-E, Pérez-Arellano JL, Angel-Moreno A, Moreno G, Burgazzoli JL, et al. [Q fever in Gran Canaria: 40 new cases]. Enferm Infecc Microbiol Clin. 2003;21: 20–23. [DOI] [PubMed] [Google Scholar]
  • 33.Martín-Aspas A, Collado-Pérez C, Vela-Manzano L, Fernández-Gutiérrez Del Álamo C, Tinoco-Racero I, Girón-González JA. Acute Q fever and the risk of developing endocarditis. Rev Clin Esp. 2015;215: 265–271. doi: 10.1016/j.rce.2015.01.011 [DOI] [PubMed] [Google Scholar]
  • 34.Ruiz Seco MP, López Rodríguez M, Estébanez Muñoz M, Pagán B, Gómez Cerezo JF, Barbado Hernández FJ. [Q fever: 54 new cases from a tertiary hospital in Madrid]. Rev Clin Esp. 2011;211: 240–244. doi: 10.1016/j.rce.2011.01.003 [DOI] [PubMed] [Google Scholar]
  • 35.García-Clemente M, Seco-García AJ, Gutiérrez-Rodríguez M, Romero-Alvarez P, Fernández-Bustamante J, Rodríguez-Pérez M. [Outbreak of Coxiella burnetii pneumonia]. Enferm Infecc Microbiol Clin. 2007;25: 184–186. [DOI] [PubMed] [Google Scholar]
  • 36.Raya Cruz M, Gállego Lezaún C, García Gasalla M, Cifuentes Luna C, Forteza Forteza T, Fernández-Baca V, et al. [Symptomatic acute Q fever: a series of 87 cases in an area of Mallorca]. Enferm Infecc Microbiol Clin. 2014;32: 213–218. doi: 10.1016/j.eimc.2013.06.004 [DOI] [PubMed] [Google Scholar]
  • 37.De los Ríos-Martín R, Sanz-Moreno JC, Martín-Martínez F, Tébar-Betegón MA, Cortés-García M, Escudero-Nieto R. [Q fever outbreak in an urban area following a school-farm visit]. Med Clin (Barc). 2006;126: 573–575. [DOI] [PubMed] [Google Scholar]
  • 38.Alonso E, Lopez-Etxaniz I, Hurtado A, Liendo P, Urbaneja F, Aspiritxaga I, et al. Q Fever Outbreak among Workers at a Waste-Sorting Plant. PloS One. 2015;10: e0138817 doi: 10.1371/journal.pone.0138817 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Fariñas MTF, Collado CM. [Infection by Coxiella burnetii (Q fever)]. Enferm Infecc Microbiol Clin. 2010;28 Suppl 1: 29–32. doi: 10.1016/S0213-005X(10)70005-7 [DOI] [PubMed] [Google Scholar]
  • 40.González-Barrio D, Hagen F, Tilburg JJHC, Ruiz-Fons F. Coxiella burnetii Genotypes in Iberian Wildlife. Microb Ecol. 2016;72: 890–897. doi: 10.1007/s00248-016-0786-9 [DOI] [PubMed] [Google Scholar]
  • 41.Eldin C, Mélenotte C, Mediannikov O, Ghigo E, Million M, Edouard S, et al. From Q Fever to Coxiella burnetii Infection: a Paradigm Change. Clin Microbiol Rev. 2017;30: 115–190. doi: 10.1128/CMR.00045-16 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Schoffelen T, Wong A, Rümke HC, Netea MG, Timen A, van Deuren M, et al. Adverse events and association with age, sex and immunological parameters of Q fever vaccination in patients at risk for chronic Q fever in the Netherlands 2011. Vaccine. 2014;32: 6622–6630. doi: 10.1016/j.vaccine.2014.09.061 [DOI] [PubMed] [Google Scholar]
  • 43.Marrie TJ. Q fever pneumonia. Infect Dis Clin North Am. 2010;24: 27–41. doi: 10.1016/j.idc.2009.10.004 [DOI] [PubMed] [Google Scholar]
  • 44.Schack M, Sachse S, Rödel J, Frangoulidis D, Pletz MW, Rohde GU, et al. Coxiella burnetii (Q fever) as a cause of community-acquired pneumonia during the warm season in Germany. Epidemiol Infect. 2014;142: 1905–1910. doi: 10.1017/S0950268813002914 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Epelboin L, Chesnais C, Boullé C, Drogoul A-S, Raoult D, Djossou F, et al. Q fever pneumonia in French Guiana: prevalence, risk factors, and prognostic score. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012;55: 67–74. doi: 10.1093/cid/cis288 [DOI] [PubMed] [Google Scholar]
  • 46.Sales-Ortells H, Medema G. Screening-level risk assessment of Coxiella burnetii (Q fever) transmission via aeration of drinking water. Environ Sci Technol. 2012;46: 4125–4133. doi: 10.1021/es203744g [DOI] [PubMed] [Google Scholar]
  • 47.Gale P, Kelly L, Mearns R, Duggan J, Snary EL. Q fever through consumption of unpasteurised milk and milk products—a risk profile and exposure assessment. J Appl Microbiol. 2015;118: 1083–1095. doi: 10.1111/jam.12778 [DOI] [PubMed] [Google Scholar]
  • 48.Duron O, Sidi-Boumedine K, Rousset E, Moutailler S, Jourdain E. The Importance of Ticks in Q Fever Transmission: What Has (and Has Not) Been Demonstrated? Trends Parasitol. 2015;31: 536–552. doi: 10.1016/j.pt.2015.06.014 [DOI] [PubMed] [Google Scholar]
  • 49.O’Connor BA, Tribe IG, Givney R. A windy day in a sheep saleyard: an outbreak of Q fever in rural South Australia. Epidemiol Infect. 2015;143: 391–398. doi: 10.1017/S0950268814001083 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Amit S, Shinar S, Halutz O, Atiya-Nasagi Y, Giladi M. Suspected person-to-person transmission of Q fever among hospitalized pregnant women. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014;58: e146–147. doi: 10.1093/cid/ciu151 [DOI] [PubMed] [Google Scholar]
  • 51.Wielders CCH, Morroy G, Wever PC, Coutinho RA, Schneeberger PM, van der Hoek W. Strategies for early detection of chronic Q-fever: a systematic review. Eur J Clin Invest. 2013;43: 616–639. doi: 10.1111/eci.12073 [DOI] [PubMed] [Google Scholar]
  • 52.Van der Hoek W, Versteeg B, Meekelenkamp JCE, Renders NHM, e ACAP, Weers-Pothoff I, et al. Follow-up of 686 patients with acute Q fever and detection of chronic infection. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011;52: 1431–1436. doi: 10.1093/cid/cir234 [DOI] [PubMed] [Google Scholar]
  • 53.Muniain Ezcurra MA, Gálvez-Acebal J. Q fever and fever of unknown origin. Are the chronic forms of these conditions preventable? Rev Clin Esp. 2015;215: 274–275. doi: 10.1016/j.rce.2015.03.008 [DOI] [PubMed] [Google Scholar]
  • 54.Eldin C, Melenotte C, Million M, Cammilleri S, Sotto A, Elsendoorn A, et al. 18F-FDG PET/CT as a central tool in the shift from chronic Q fever to Coxiella burnetii persistent focalized infection: A consecutive case series. Medicine (Baltimore). 2016;95: e4287 doi: 10.1097/MD.0000000000004287 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Raoult D. Diagnostique biologique de la fièvre Q. Rev Fr Lab. 1991;227: 667–75. [Google Scholar]
  • 56.Nistal de Paz F, Nistal de Paz C. [Q fever]. Med Clínica. 1994;103: 667–675. [PubMed] [Google Scholar]
  • 57.Dupont HT, Thirion X, Raoult D. Q fever serology: cutoff determination for microimmunofluorescence. Clin Diagn Lab Immunol. 1994;1: 189–196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Fournier PE, Marrie TJ, Raoult D. Diagnosis of Q fever. J Clin Microbiol. 1998;36: 1823–1834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Wegdam-Blans MCA, Kampschreur LM, Delsing CE, Bleeker-Rovers CP, Sprong T, van Kasteren MEE, et al. Chronic Q fever: review of the literature and a proposal of new diagnostic criteria. J Infect. 2012;64: 247–259. doi: 10.1016/j.jinf.2011.12.014 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. STROBE checklist.

(DOC)

S2 Checklist. PRISMA checklist.

(DOC)

S1 Flowchart. PRISMA flowchart.

(DOC)

S1 Database. Cases database.

(XLS)

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.


Articles from PLoS Neglected Tropical Diseases are provided here courtesy of PLOS

RESOURCES