The lower Saint Lawrence River region of Quebec, a hot spot for sheepfold-associated Q fever in Canada: Review of 258 cases

Abstract

Background:

The lower Saint Lawrence river region (LSLRR), in Quebec, has a 10-fold higher incidence of Q fever compared to the provincial rate. This study aimed to review clinical cases and the Q fever risk exposure in this region.

Methods:

Data were retrieved from microbiology laboratory, medical records from Rimouski Regional Hospital and Public Health reports between 1991 and 2018. They were analyzed with Epi Info 7.2.2.6. Patients with confirmed acute, probable acute, and chronic Q fever were classified using standard case definitions and mapped according to the postal code, to assess the correlation between cases and sheep distribution.

Results:

Out of 295 cases, 258 were included (241 confirmed acute, seven probable acute, 10 chronic). Median age was 49 years, 76% were male. For acute cases, the prominent symptoms were fever (99%), headache (83%), chills (80%), sweating (72%), myalgia (69%), and fatigue (67%). Clinical presentation was mostly febrile syndrome with mild hepatitis (84%). A seasonal peak was observed from May to July (56% of acute cases). Most cases (56%) occurred within the two counties where sheep production was highest. Exposure to sheep was prominent 93%, including 64% direct contact (15% shepherds, 49% sheepfold visitors), 14% indirect contact, and 15% sheepfold neighbors.

Conclusions:

To our knowledge, this is one of the largest retrospective studies of Q fever cases reported in Canada. Q fever in Quebec LSLRR is associated mainly with sheep exposure. Fever and hepatitis were the most common manifestations. Preventive measures should be considered in this region to protect sheepfold workers, visitors, and their neighbors.

Introduction

Q fever, a zoonotic infection caused by Coxiella burnetii, is a reportable disease in Canada and in the province of Quebec (1). The causative bacterium is an intracellular pathogen replicating in eukaryotic cells which mostly infects ruminants such as sheep, cattle, goats, and cats (2–4). Infected animals spread the bacteria in the environment mainly by releasing contaminated body fluids, such as parturition products, feces, and urine (2,4–6). Transmission to humans occurs primarily via inhalation of aerosols produced by infected animals and the disease causes a broad clinical spectrum, from asymptomatic to acute or chronic infection (2,4). Proximity with contagious livestock has frequently been associated with human acquisition of Q fever, making regions with a high rate of animal production more prone to infection (7,8).

Many studies have shown the importance of sheep as a reservoir for C. burnetii (2,3,5). In Germany, 40 outbreaks of human Q fever were documented from 1947 to 1999 where more than half were caused by sheep exposure (9). In 1983, a major outbreak of Q fever in humans was also reported in Switzerland, involving 415 confirmed cases after sheep gathered in flocks went down from the alpine pastures to a valley near an inhabited town (10). In addition, a study by Lang et al (11) demonstrated that infection in sheep with C. burnetii is highly common in Ontario, Canada. The seroprevalence of the bacteria was measured in 103 sheep flocks and of these herds, 31 had infected animals, assigning this ruminant as the main reservoir for the pathogen in this region. In 2005, our group assessed the seroprevalence of C. burnetii in shepherds and sheepfolds from the lower Saint Lawrence River region (LSLRR) in the province of Quebec, Canada. It was reported that Q fever seroprevalence was 89% for the sheep flocks, and 28% for the shepherds (5).

The incidence of Q fever is considered as highly endemic in Quebec’s LSLRR. From 1990 to 1998, more than a third of the Q fever cases reported in the province were from the LSLRR, although it only represents 5% of Quebec’s population, giving to this area the province’s highest incidence rate. Clinical cases were mainly linked with exposure inside the sheepfold or sheep and goat production in the neighborhood (5,12). Our study aimed at reviewing cases of Q fever in the LSLRR to assess clinical presentation and epidemiological factors associated with the disease.

Methods

Study design

The Centre Hospitalier Régional de Rimouski (CHRR) is a 230-acute care beds facility, located in a rural community, namely LSLRR. A retrospective study was conducted to review all cases of Q fever evaluated in the LSLRR from 1991 to 2018, including inpatients or outpatients. Patient data were retrieved from medical and microbiology logs at CHRR and from Public Health reportable diseases investigation records.

A questionnaire was created and analyzed with Epi Info version 7.2.2.6. software (Centers for Disease Control and Prevention, USA). Data collection included parameters such as demographic data, clinical presentation, epidemiological factors, investigation, and treatment. Patients with confirmed or suspected Q fever were classified according to serological and clinical criteria using case definitions. Confirmed acute cases included: seroconversion (four-fold rise in titers between acute and convalescent 2–6 weeks apart) by complement fixation test (CFT), seroconversion with IgG phase II antigens by indirect immunofluorescence assay (IFA), or a positive PCR on serum or tissue, with or without seroconversion. Probable acute cases included patients with a single titer >1/40 by CFT or >1/128 IgG phase II by IFA, with suspected Q fever presentation. Chronic cases included patients with persistent antibody titers >1/320 by CFT or >1/1,024 IgG phase I by IFA, with or without a positive PCR on serum or tissue. A past infection was determined when a patient had multiple sera 2–6 weeks apart, without seroconversion and without levels featured in the chronic cases definition above. Past infections were excluded from this study.

When available, exposure factors were classified using different contact definitions. A direct contact was defined as a patient who had been in close contact with targeted animals most frequently associated with Q fever (cattle, goats, sheep, and cats), their feces, their amniotic fluid, and their placenta. An indirect contact was identified as a patient being in contact with someone who met the definition of direct contact. A proximity contact targeted patients, without direct or indirect contact, who lived or has been near (<5 km) a farm with cattle, goats, or sheep. No data collection was made for the other infrequent modes of transmission, such as tick bites, human to human, ingestion of unpasteurized milk, or dairy products.

Serological analysis

The complement fixation tests were performed between 1991 and 2000 at the Laboratoire régional de virologie de l’Université Laval (Quebec City, Canada) using a classical CFT with a phase II C. burnetii antigen where the sera were tested with two-fold serial dilution starting at 1/10. The indirect immunofluorescence assays (IFA) used a standard IFA phase I and phase II C. burnetii antigen obtained from the Nine Mile strain, with two-fold serial dilution starting at 1/32. This method has been described elsewhere (5). The IFA were conducted, between 1991 and 2010, at the Laboratory Center for Disease Control (Zoonotic Diseases, National Laboratory for Special Pathogens, Ottawa, Canada), and at the Centre Hospitalier Universitaire de Sherbrooke (Sherbrooke, Quebec, Canada) between 2010 and 2018.

Geographic data

The LSLRR is divided into eight regional counties, namely Kamouraska, Témiscouata, Rivière-du-Loup, Les Basques, Rimouski-Neigette, Mitis, Matapédia, and Matane. According to their address and postal code, each patient with confirmed or probable Q fever was associated with their respective county, to create a cluster map.

To evaluate the relationship between geographical dispersal of Q fever cases and sheep distribution within RCMs, a map on small ruminant density (goats and sheep) was obtained from the Ministère de l’Agriculture, des Pêcheries et de l’Alimentation du Québec (MAPAQ) for the year 2014.

Statistics

The data were analyzed using Epi Info software 7.2.2.6 and R programming. Categorical data comparisons were performed with the Cochran–Mantel–Haenszel chi-square test and Fisher exact test at the 95% confidence interval as the limit. This study was approved by the Ethics Committee of our institution.

Results

Out of the 295 cases identified, 37 were excluded from the study: 17 had a past infection and 20 had no serologic evidence Q fever. A total of 258 cases (252 patients) met our criteria for confirmed and probable Q fever. Six patients suffered from acute Q fever that evolved into a chronic disease. Of the 258 cases, the distribution was: 241 confirmed acute, 7 probable acute, and 10 chronic.

According to Public Heath records, the incidence of Q fever was 10-fold higher in the LSLRR than in the rest of Quebec during the studied period, with a total of 242 reported cases, for a mean incidence rate of Q fever of 4.3/100,000 inhabitants per year, which was significantly higher than the incidence rate of Quebec province (0.41/100,000 inhabitants) (p < .001) (Figure 1). Our study included 258 cases: all 242 public health cases, 12 cases that have not been reported (nine confirmed acute, one acute probable, two chronic) and four cases living outside of LSLRR, since they were evaluated by infectious diseases physicians in our institution.

Figure 1:

Incidence rate of Q fever in Quebec LSLRR, 1991–2018 (n = 242)

We observed an initial rise in reported cases between 1991 and 1994 with the highest number of Q fever cases observed in 2000 and in 2004. In 2004, the peak was related to an outbreak of nine sheepfold-associated cases in Saint-Medard, a rural city near Rimouski (personal communication). All cases were onsite witnesses of truck disembarkation of a new acquired sheep herd, which was proved to be infected, from subsequent public health and MAPAQ investigation. Over the course of our study, we also observed a sharp decrease in hospitalization rate from 66% (24/34 inpatient cases) in 1991–1997 period, to 31% (55/180 inpatient cases) in 1998–2018 (p < 0.001).

The median age of Q fever cases was 49 years (range of 3–84 years). The male:female ratio among patients was 3:1 (195 men, 63 women), significantly greater than that in the province of Quebec in terms of population (0.98) (p < 0.001). Patients aged between 30 and 69 years represented 86% of our cases, with comorbidities more common in chronic patients. The most frequent clinical manifestations were hepatitis (84%) in acute cases, and cardiovascular infections (80%) in chronic cases (Table 1). Acute hepatitis was associated with low level increased in alanine aminotransferase (ALT) levels (50–200 UI/L) in 70% of cases, and only 6% had ALT levels above 200 IU/L (Table 2).

Table 1:

Clinical presentation and comorbidities among acute and chronic Q fever cases

Clinical presentation	Acute, no./n (%); n = 248	Chronic, no./n (%); n = 10	p-value
Clinical manifestations
Hepatitis*	168/201 (84)	1/10 (10)	<0.001
Endocarditis/myopericarditis	11/222 (5)	3/10 (30)	0.02
Pneumonia	9/211 (4)	0
Meningoencephalitis	3/191 (2)	0
Vascular aneurysms/infections	0	5/10 (50)
Comorbidities
COPD	7/216 (3)	2/7 (29)	0.03
Coronary artery disease	11/216 (5)	5/8 (63)	<0.001
Diabetes	4/217 (2)	2/7 (29)	0.01
Immunosuppression	19/216 (9)	3/8 (38)	0.03
Valvular heart disease	9/218 (4)	3/7 (43)	0.003
Prosthetic valve	3/217 (1)	1/7 (14)	NS

^* Hepatitis defined by alanine aminotransferase (ALT) above the upper limit normal (≥ 33 UI/L). Granulomateous hepatitis confirmed in six cases through a biopsy.

COPD = Chronic obstructive pulmonary disease; NS = Not significant

Table 2:

Hepatic abnormalities in acute Q fever cases in the Lower Saint Lawrence River Region (n = 183)

Alanine aminotransferase,UI/L	No. (%)
<33	15 (8)
33–49	29 (16)
50–100	79 (43)
101–200	49 (27)
>201	11 (6)

Patients with acute Q fever had mainly a clinical presentation compatible with a nonspecific febrile illness (Table 3). Prolonged fever was present in 99% of cases, with a median duration of 11 days. Headache occurred in 83%, mostly with mild intensity and diarrhea was infrequent (19%). Doxycycline was used in 93% of acute cases, for a median of 14 days. A seasonal peak in infections was found from May to July, representing 56% of our acute cases (Figure 2), which is also synchronous with the peak of sheep parturition period.

Table 3:

Symptoms at clinical presentation of acute Q fever

Clinical findings	No. (%)
Fever*	234/235 (99)
Headaches	185/224 (83)
Chills	175/225 (79)
Loss of appetite	157/219 (72)
Sweats	159/221 (72)
Myalgia	151/221 (68)
Fatigue	110/167 (66)
Diarrhea	41/179 (23)

^* Mean and median temperatures: 39.4°C, range: 37.8–41°C, n = 133; Mean duration: 13 days, median: 11 days, range: 1–32 days, n = 170

Figure 2:

Monthly distribution of acute Q fever cases (n = 248)

Sheep was the most frequent animal contact reported all Q fever cases (p < 0.001) (Figure 3). Among the 238 cases where data were available, sheep exposition was present in 93% (64% direct contact, 14% indirect contact, 15% sheepfold proximity within 5 km) (Figure 4). Among the 139 cases with direct contact, 35 (25%) were shepherds and 75% were visitors.

Figure 3:

Animal exposure among all Q fever cases (n = 238)

Figure 4:

Level of sheep exposure among Q fever cases (n = 218)

Geolocation of cases showed an excellent correlation with small ruminants (sheep and goats) density production in LSLRR, as >95% of these animals were sheep (Figure 5). Interestingly, most cases (62%) occurred within the two counties where ovine production is the highest.

Figure 5:

(a) Small ruminents (sheep and goats) density. (b) Correlation between geographic distribution of Q fever cases and sheep production in LSLRR (n = 254)

Discussion

Incidence rate

During the 27-year period of our study, we could observe a clear rise of the incidence rate in the LSLRR. However, it is difficult to assess if this trend really reveals an increase of affected patients or is just due to further testing, more sensitive assays, or an improved awareness of the disease by clinicians, in particular for patients with sheep contact. Indeed, depending on the method used as serological tests, results may greatly vary (13). A retrospective study in France from 1985 to 2009 demonstrated that the test-positive proportion changed from 1% in 1989 to 4% in 2009, which could be from commercial tests becoming more and more sensitive (14). For example, a review including 92 cases of chronic Q fever in France showed that the diagnosis delay in Marseille, where the disease is better known by physicians, was much shorter than in other parts of the country. The increase of cases diagnosed from 1982 to 1990 could also be due to a better understanding of the disease rather than having its actual incidence changed (15). In the United States, Q fever became a reportable disease in 1999 and the number of cases increased by 250% between 2000 and 2004, which also suggested an improved recognition of this infection (16). In this study, we observed a significant reduction of hospitalization rate between 1991 and 2018. Also, during that period, the infectious diseases and the public health doctors provided with many training and tutorials about Q fever not only to the clinicians, but also to the ruminant’s producers, which also contributed to better knowledge and prompted its management. Thus, we cannot exclude the possibility that the higher incidence rate in the LSLRR could be due to greater awareness of the infection, thereby leading to a detection bias. In France, such premise was raised since the highest incidence of Q fever is in Bouches-du-Rhône, where the national reference centre is located (14).

We cannot exclude the possibility that a real increase in the burden of the disease could be in play. Most reports of Q fever outbreaks are associated with farm animals (17). Interestingly, we noted new developments in agritourism which could contribute to the increased incidence rate that we observed in the Quebec Province (18). Agritourism offers new strategies for income growth from agricultural businesses. Multiple agricultural exhibitions occur annually in the region, where livestock competitions are common, attracting a lot of visitors. This is associated with moving of potentially infected animals and subsequent contamination of exposed livestock and humans. From 2005 to 2012, the number of farms offering agritourism activities tripled in Quebec, with more than half (55%) of them providing guided tours and about 10% in the sheep and goat sector.

The emergence of strains that are more contagious or virulent may also be at stake, but such evaluation was not performed in our study. Indeed, an important genetic variation exists between genomic groups of C. burnetii and there is evidence supporting their dissemination across continents (19,20).

Patients

Our study revealed that Q fever mainly affects men, which agrees with literature (21–24). A vast majority of our cases (86%) were in the age groups between 30 and 69 years. In a retrospective study by Raoult et al (21), these equivalent age groups were significantly more likely to be at risk. In the United States, the highest number of cases was in ages 60–64 (2). Brouqui et al (15) estimate the risk of having Q fever is five times higher in the 60–69 age group. The severity of the illness also seems to be greater in older patients (25). Acute Q fever cases were usually adult men with a history of sheep contact, whereas most of chronic cases were elderly with comorbidities.

Symptoms

Studies in which all individuals exposed to an outbreak are tested suggest a high proportion of Q fever have self-limited asymptomatic infection. For example, only 50% of seropositive patients exhibited symptoms during an outbreak in Switzerland (10). In an outbreak in Israel, 34% of confirmed infections were asymptomatic, but it was mentioned that this proportion is probably underestimate, since symptomatic individuals are more likely to be tested (26).

Q fever can develop into acute or chronic forms and their clinical presentations are distinct. The acute disease is an influenza-like illness, with fever, pneumonia, and hepatitis being the most common manifestations (17,24). Interestingly, among cases presented in our study, whether they were acute and chronic, nearly all had fever except one patient. Presentation of the disease also varies with the geographic location of patients. For example, pneumonia is the most frequent manifestation in Nova Scotia patients whereas in France it is granulomatous hepatitis (27). Variations can occur within much smaller territories, like in Spain where the most commonly encountered clinical presentation is hepatitis in Catalonia (24), but pneumonia in the Basque Country (28,29). Also, several papers in North America revealed a high proportion of patients with pneumonia (30–33), as in Trois-Rivières, another region of Quebec (34). In our region, hepatitis was the most frequent manifestation. Further strain characterization of C. burnetii would have been of interest, to understand fully the predominant strain in our community and its associated tropism.

Our study included only 10 cases of chronic Q fever with predominance of cardiovascular disease (80%), which is concordant with literature (60%–70%) (17,22,23). Similarly, underlying heart disease and immunodeficiency were common among these patients (15).

Exposure

The proportion of individuals having Q fever antibodies, which suggest a prior contact with the bacterium, is higher in Quebec (5%) (35) than in the Western provinces (about 1%) (36). Q fever outbreaks are mostly associated with animal contact, and the disease often affects workers like veterinarians, farmers, livestock carriers, slaughterhouse employees, etc. (2,15,37). For example, the first Q fever epidemic cases in Canada originated from an abattoir in Princeville (36). The prevalence of C. burnetii is the highest in sheep flocks compared to other animals (38), estimated at 70.8% in Quebec (39). Quebec is the second-largest ovine producer in Canada and 25% of the province’s sheep and goat farms are in the LSLRR (40), where Q fever incidence rate is at the top. The higher incidence of the disease in that region could be explained by the importance of sheep farming and a higher prevalence of C. burnetii in sheep flocks, estimated at 89% (5). Such correlation was also described in France (14,23), Australia (41), and the Netherlands (42–44).

Contact with sheep was highly preponderant in 93% of our cases, and it underlines the importance of proper epidemiologic questionnaire to search for such direct or indirect exposition. Many studies outlined the difficulties of recognition of indirect contacts associated with winds dispersing infectious particles from farms toward surrounding areas. Such transmission generated an epidemic in Hungary, where fecal contamination and maternal fluids were carried by the wind, infecting nearby residents (45). Also, an outbreak near a slaughterhouse in France, caused 29 cases of acute Q fever, where sheep waste was left uncovered (46). Evidence supports that contaminated straw (10,47–52), feces (53–55), and mainly parturition products (53,56–59), play a major role in wind transmission of C. burnetii (41). Sheepfold and its associated airborne particles can remain contaminated several weeks after delivery (7,55,57,60), which plays an important role in the wind dissemination of the disease (23,50,61–63). Contaminated aerosols can be found up to 30 km away from the infected animals (61), allowing transmission between farms (64). It is interesting to note that the annual average wind speed is much more in the LSLRR (14.2 km/h) than in the whole province (11 km/h) (65), but it is difficult to assess the role of this factor.

Seasonal peak

In agreement with previous studies (4,14,25), we noted a seasonal peak in Q fever cases from the May to July. These months do not correspond to stronger winds, which are in January (65). Sheep have a natural breeding during spring season, which could explain the concomitant peak observed for Q fever which also includes the early summertime (5,66). Spring is also the period of manure spreading and stable cleaning (67,9,68) and summer is the busiest season in terms of sheep production and agritourism (18). Another explanation could be an increase in lambs slaughtered around Easter, as proposed by Tissot-Dupont et al (23). Also, the higher summer temperatures could cause the soil to dry out, which is more prone to erosion and dispersion of the dust by wind (6,63).

Vaccination and prevention

Sheepfold workers should wear appropriate personal protective equipment, particularly when assisting parturition, such as gloves, mask, jumpsuit, dedicated footwear, which should be washed or decontaminated, if reused. Goggles and N95 respirators should be worn during aerosol-generating procedures. Stables and other areas should be frequently cleaned and disinfected according to contemporary recommendations. Potentially contaminated birthing products such as placenta, aborted fetuses, biological waste should be removed quickly and disposed appropriately to reduce aerosols dispersion (69). For farms that have diversified productions, sheep and goats should be kept separate to limit cross-contamination. Surveillance testing of animal samples by PCR can also be done for early detection and prevention of environmental contamination. Furthermore, raising awareness among at-risk employees could contribute to enforcement of better preventive practices (70,71).

Preventive antibiotic treatment for ruminants is not recommended and this could lead to antimicrobial resistance (72). Following a large outbreak of 3,500 human cases over 3 years, the Netherlands implemented a Q fever immunization program for goats and sheep (73) with subsequent reduction of environment contamination and human infections. Australia introduced in 2002 a national Q fever vaccination program for farmers, veterinarians, and abattoir workers (74–81), with 94% vaccine efficacy. No immunisation program for Q fever is in place in Canada. Our paper outlines the need for further public health evaluation regarding Q fever vaccination strategy for targeted humans and/or animals in Canada.

Conclusions

To our knowledge, this one the largest retrospective study on Q fever clinical cases in Canada. Q fever in Quebec LSLRR is highly prevalent and is associated with sheep exposure. Fever with hepatitis were the most common manifestations. Additional preventive measures, such as immunization, should be considered to protect the workers of ovine industry and their neighbors.

Funding Statement

Funding: No funding was received for this work.

Contributors:

Conceptualization, P Dolcé, P Jutras, J Aubé-Maurice; Methodology, P Dolcé, P Jutras, A de Beaumont-Dupont, MA Rosca, J Aubé-Maurice; Validation, P Dolcé, P Jutras, A de Beaumont-Dupont, F Mailhot-Léonard, J Aubé-Maurice; Formal Analysis, P Dolcé, P Jutras, A de Beaumont-Dupont, F Mailhot-Léonard; Investigation, P Dolcé, P Jutras, A de Beaumont-Dupont, MA Rosca; Resources, P Dolcé, A de Beaumont-Dupont, J Aubé-Maurice; Software, P Dolcé, A de Beaumont-Dupont, MA Rosca; Supervision, P Dolcé, P Jutras, A de Beaumont-Dupont, J Aubé-Maurice; Data Curation, P Dolcé, P Jutras, A de Beaumont-Dupont, MA Rosca; Writing – Original Draft, P Dolcé, A de Beaumont-Dupont, F Mailhot-Léonard; Writing – Review & Editing, P Dolcé, P Jutras, F Mailhot-Léonard; Visualization, P Dolcé, P Jutras, J Aubé-Maurice; Project Administration, P Dolcé, P Jutras, A de Beaumont-Dupont, F Mailhot-Léonard.

Ethics Approval:

All research meets the ethical guidelines, including adherence to the legal requirements of the study country.

Informed Consent:

N/A

Registry and the Registration No. of the Study/Trial:

CISSS du Bas-Saint-Laurent, CISSSBSL-2018-03, 4 May 2018.

Data Accessibility:

All data will not be made publicly available. Researchers who require access to the study data can contact the corresponding author for further information.

Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A