Q Fever a Global Zoonosis

Lambs are always crowd-pullers. However, sheep infected with Coxiella burnetii can cause Q fever in the human population during lambing season.

1. Description

Q fever, also called coxiellosis in veterinary medicine, is an infectious disease caused by the bacterium Coxiella (C.) burnetii. As C. burnetii infects humans as well as animals and can be transferred from animals to humans, Q fever is a classical zoonosis.¹

2. History

Q fever was first described in 1937 by the Australian scientist Edward Derrick who observed the disease among abattoir workers in Australia.² As it was not possible for him to assign symptoms to a known disease the illness was called Q fever ("Q" stands for "query"). Both the Australian physician Frank Macfarlane Burnet and the American bacteriologist Herald Rea Cox were successful in researching and isolating the causative agent independently of each other.^3,4 In honour of both scientists the pathogen was named later Coxiella burnetii.

3. Pathogen profile

C. burnetii is an obligate intracellular, immobile, Gram-negative bacterium and is classified taxonomically to the class of gammaproteobacteria, the order Legionellales, the family Coxiellaceae and the genus Coxiella according to Bergey's Manual of Systematic Bacteriology.⁵ The original classification of Coxiella into the family Rickettsiaceae was revised due to 16S-RNA as well as whole genome analyses. These analyses showed that C. burnetii is phylogenetically closely related to Legionella pneumophila, the causative agent of Legionnaire's disease.^6,7

C. burnetii can exist in two antigenic forms: phase I and phase II. This so-called phase variance is comparable with the phase variance of Enterobacteriaceae (e. g. Salmonella) and is based on changes of the lipopolysaccharide structure (LPS) of the outer cell membrane, which are, however, caused by a deletion in the genome of bacteria and are irreversible. Bacteria with complete long chained LPS are designated phase I and are virulent. Phase II bacteria have an extremely shortened LPS and are largely avirulent.^8–10

Coxiella can infect monocytes, dendritic cells and macrophages and proliferate in the acidic environment of the phagolysosome.^11–13 Morphologically, two developmental stages are differentiated namely the small cell variant (SCV) and large cell variant (LCV). SCV is the extracellular, environmental resistant form being able to persist for example in dust over months and remain infectious. LCV is considered the metabolically active, intracellular form capable of reproduction.¹⁴

With the exception of Antarctica and New Zealand C. burnetii has a worldwide geographical distribution.¹ The pathogen is classified as risk group 3 and is considered a potential bioterrorist agent due to its low infectious dose (minimal aerogenic infectious dose less than 10 agents (LD50)), environmental stability and transmissibility through air.^15–17

4. Affected species and reservoir

Many different species ranging from arthropods to mammals can be infected with C. burnetii. Infected ruminants (sheep, goats and cattle) shed the pathogen in large quantities together with birth fluids and the afterbirth, especially when giving birth or during abortion. In addition, there is shedding via milk, urine and faeces. An infection with C. burnetii can be completely asymptomatic especially in sheep. Thus, potential shedding of the pathogen is not noticed unless samples are examined regularly. Nevertheless, abortions, still births and births of weak newborns as well as the retarded expulsion of the afterbirth in ruminants should be taken seriously as a possible sign for Q fever.

As well as other mammals, such as for example cats and dogs, arthropods, such as for example ticks, are also capable of shedding the pathogen. However, it is presumed these species do not present a relevant infectious reservoir for humans.^18–22 The transmission to humans by tick bites has not been understood well. However, tick faeces are supposed to play an essential role in spreading C. burnetii. Infected ticks shed Coxiella together with their faeces, as the pathogen can proliferate in the intestinal cells of the ticks and can be shed in large quantities.^23–25 This could pose a risk when sheep are sheared. Sheep infested with ticks can carry considerable amounts of tick faeces in their wool. When shearing, tick faeces potentially containing Coxiella are whirled up. Therefore, rising contaminated dust particles can be a risk for everybody involved in sheep-shearing.²⁶

5. Transmission and risk groups

Humans get infected mainly by inhaling dust or droplets containing bacteria. There is a particular risk for people being close to ruminants (sheep, goats and cattle). In addition, the pathogen can be disseminated by spreading manure, which hasn’t been stored long enough for inactivation as well as during sheep-shearing by raising dust.²⁷ As the pathogen can be spread easily by the wind there is a high risk for aerogenous infections in the population within a radius of 5 km in case of a Q fever outbreak. For this reason, humans can get infected by C. burnetii, although they were not in direct contact with ruminants.^28–31 Infections caused by consumption of raw milk and raw milk products are extremely rare and the risk for an alimentary infection in humans is considered very low according to the Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung (BfR)).³² Nevertheless, it is recommended to pasteurize raw milk, in order to inactivate the pathogen in milk.^33–35

In particular people who are in contact with sheep, goats or cattle as part of their jobs such as for example animal owners, shepherds, shearers, veterinarians and their employees, laboratory staff as well as abattoir workers have an increased risk for a C. burnetii infection.²⁷

6. Disease symptoms in humans
6.1. Acute Q fever

After an incubation period of 1 – 3 weeks about 40 % of infected people show clinical symptoms, with the infection being asymptomatic in all other cases. Clinical symptoms can be flu-like symptoms like heavy retroorbital headache, fever, weariness, aching limbs and chills. Atypical pneumonia (inflammation of lungs) or hepatitis (inflammation of liver) – which is probably in most cases an accompanying hepatitis due to the infection – can be observed in 10 – 20 % of symptomatic cases. Histologically, granulomatous changes could be detected in the liver parenchyma. The infection very rarely results in a myocarditis (inflammation of the heart muscle), pericarditis (inflammation of the pericard) or meningoencephalitis (inflammation of the brain).^11,36–38

6.2. Infection during pregnancy

An acute infection and chronic Q fever can increase the risk of still birth (mostly when there is an initial infection in the first trimester of pregnancy), a premature birth, placentitis (which can subsequently lead to still birth or low birth weight). A transmission of the pathogen to the foetus in the womb resulting in long term effects for the child has not been described, as yet.^36,39–42Women suffering from acute Q fever are recommended not to breast-feed their child, no matter whether they were treated with antibiotics or not, as the Q fever pathogen can be passed through breast milk and it is possible that the administration of antibiotics cannot completely prevent the bacteria from being shed into the breast milk.³⁶

6.3. Long-term effects
6.3.1. Chronic Q fever

An acute C. burnetii infection leads to chronical Q fever in 1 % of cases i.e. a chronification (after more than 6 months of persistent infection), and frequently manifests clinically in the form of an endocarditis⁴³. Less often, e.g. granulomatous hepatitis or osteomyelitis occurs. Chronic disease requires extended therapy (several years) and mortality is associated with a high complication rate of up to 40 % when not treated.^44,45Patients with existing cardiovascular diseases or severe immunosuppression show a significantly increased risk for a transition to chronic Q fever.⁴⁶ Thus, according to a study from the Netherlands cases with aortic/illiacal changes and other vascular endothelium changes in combination with acute Q fever show a 30% risk of developing chronical Q fever.⁴⁷

6.3.2. Post Q Fever Fatigue Syndrome (QFS)

About 6 months after a C. burnetii infection Post Q Fever Fatigue Syndrome (QFS) can occur. This clinical entity was described by Marmion et al.⁴⁸ in 1996 and has been reported largely in Australian studies/cases. The pathology of QFS attracted or has attracted more attention as part of the follow-up studies of Q fever cases from the outbreaks between 2007 and 2010 in the Netherlands. It was shown that 20 – 30 % of the Q fever patients were not able achieve their previous level of performance and working after one year.^49,50 The most frequent QFS symptoms are: fatigue (tiredness/exhaustion), restrictions in carrying out everyday activities of daily living, lack of concentration, muscle aches and night sweats.⁵¹

7. Disease symptoms in animals

Manifestation of symptoms can be very different in animals. In particular sheep can experience an infection with C. burnetii without any clinical signs of disease. Goats often give birth to weak kids and abortions occur. The clinical picture ranges from asymptomatic to prolonged calving intervals and post-natal complications and even abortion. In general, the following symptoms can be assigned to Q fever in ruminants: fertility problems, abortion, still birth, birth of weak lambs/kids/calves, retarded expulsion of the afterbirth.^52–54

8. Diagnostics
8.1. Detection in humans

Serological detection of specific antibodies against both phase variants of C. burnetii in immunofluorescence test (IFT) is the gold standard in humans. All Ig subclasses are detected with IFT. However, the use of ELISA test methods has proved especially useful for seroepidemiological studies or when there is an outbreak. An acute infection can be distinguished from a chronic one due to the height of antibody titre (IgG and IgM, phase I and II). It should be kept in mind that after an acute infection in some cases it takes a few months until the respective Ig classes decrease and they also can be detected up to several years after infection. This means that evaluation and chronical classification of an infection can be become more complex – especially when there might be the issue of a chronical course of the disease. In addition, PCR should be performed to detect specific Coxiella DNA. PCR has proved effective, as specific antibodies can’t be detected when there is an acute infection, especially in the early phase of the disease, and the infection could be undetected or is not diagnosed before a second serum is tested. PCR is also reasonable in order to assess the chronic phase of the disease with regard to therapy requirements and success of therapy. .^17,55,56 Recent test developments to evaluate the humoral or cellular immunity such as e.g. Western Blot or γ-interferon test⁵⁷ have not been validated or tested sufficiently and therefore have not found their application in routine diagnostics.

8.2. Detection in animals

The most sensitive and meaningful test for verifying a C. burnetii infection is the molecular biological analysis (PCR) of afterbirth material, dead lambs/kids/calves, milk as well as vaginal swabs for detecting gene material (DNA) of the pathogen. If required, preputial swabs can also be used. Using this analysis, a current shedding of C. burnetii can be detected.^53,58 Detection by means of culture is carried out in rare cases, as large quantities of pathogenic material are required and this analysis can only be performed in specialist laboratories under increased security.⁵⁹ Blood analysis of antibodies does not reliably detect an acute infection, however, can reveal a recent infection. This analysis is performed by means of a commercial ELISA on the basis of a mixture of phase I and phase II antigens.⁵⁸

With this analysis the vaccination status of the animals has to be taken into consideration as well, as there is no DIVA (Differentiation of Infected and Vaccinated Animals) vaccine available for C. burnetii. Up to now, there has been no gold standard for serological detection of a C. burnetii infection in veterinary medicine.⁶⁰ Further test methods for detecting humoral and cellular immunity (neutralization assay, γ-interferon assay) are still experimental.^61,62

9. Typing methods

The so-called Multiple Loci Variable Number of Tandem Repeats (VNTR) Analysis (MLVA) allows the typing of whole genome sequences with high discriminatory power.^63,64 In addition, the SNP based Multispacer-Sequence-Typing (MST) method is used, by which, however, only a rough resolution as to regional distribution can be attained.^65,66 Even though these methods don’t play a role in acute diagnostics they can be of importance when there is a Q fever outbreak. For example, the VNTR/MLVA method has proved sufficiently appropriate when clarifying chains of infection. This kind of typing was even possible directly from clinical samples when the wold’s largest Q fever outbreak in the Netherlands (2007 – 2010) occurred.⁶⁷ However, due to insufficient standardization these methods are currently applied in specialized scientific institutions only.⁶⁸

10. Therapy
10.1. Treatment of patients

The treatment of acute Q fever is carried out with antibiotics with first line medication being doxycycline (Dosage: 2 x 100 mg/day, 14 days, in consultation with your medical practitioner). Alternative antibiotics: macrolides (azithromycin, clarithromycin) or fluoroquinolones.^36,69 When using fluoroquinolones, restrictions in use due to potential side effects should be observed. Thus, a diagnostic evaluation against the side-effect profile is very important.
See also risk information/pharmacovigilance of the German Federal Institute for Drugs and Medical Devices (BfArM).⁷⁰

Children under 8 years and pregnant women have to be treated to some extent with antibiotics from other drug classes (e.g. macrolides).⁷¹ In the case of children it is important that dosage has to be adapted to the child’s weight. If there are signs of acute Q fever during pregnancy, antibiotics from another drug class (e.g. cotrimoxazole 800 mg/160 mg; twice daily, in consultation one’s medical practitioner) have to be administered, too. CAVE: Administration of cotrimoxazole is advised only until 32^nd week of pregnancy. When treating pregnant women with cotrimoxazole (contains folic acid antagonists) the increased requirement of folic acid caused by pregnancy must be adapted by substituting with folinic acid (not folic acid!).^36,39 Also, please ensure that when ACE inhibitors or angiotensin II receptor blockers are taken simultaneously a clinically relevant hypercalcemia may be the result, which increases the risk of a sudden cardiac death.⁷²

After acute Q fever it is recommended that a 12-months antibiotic prophylaxis with doxycycline in combination with hydroxychloroquine is prescribed aimed at treating patients with risk factors for chronification (e.g. pre-existing cardiovascular diseases or severe immune suppression), to prevent a possible chonification from developing. Regular (at least annual) follow-ups in patients of risk groups with high phase I specific IgG antibodies are recommended.

When chronification has already occurred (chronic Q fever) a 24-months combined therapy with e.g. doxycycline and hydroxychloroquine is carried out. Alternative antibiotic regimens are possible and have to be adapted individually. In this case regular follow-ups are also required in order to be able to evaluate the success of therapy and the continuation of the antibiotic therapy, if neccessary.⁶⁹

If exposure to C. burnetii can’t be excluded a postexposure prophylaxis is recommended by U. S. Army Medical Research Institute of Infectious Diseases (USAMRIID). Administration of doxycycline (100 mg per os, every 12 hours) for 5 to 7 days should be started from day 8 to day 12 after exposure.⁷³

10.2. Prophylaxis and treatment of animals

The treatment of an acute Q fever event with a huge amount of pathogen shedding in a farm with ruminants is still a big challenge. The treatment with antibiotics especially when using the agent oxytetracycline does not lead to a significant reduction in pathogen shedding.^74,75 However, antibiotic treatment can be reasonable in the case of mixed infections such as e.g. chlamydia, in order to reduce abortion rate.⁷⁶ Other drug classes such as e.g. macrolides have not been tested, yet. Vaccination against C. burnetii purely reduces the shedding of the pathogen in infected animals in the long term. Therefore, ruminants should be vaccinated prophylactically.^27,53,77 The primary immunisation of cattle, goats and sheep should be completed four weeks before the animals undergo mating/insemination. Then a booster vaccination should be carried out annually.⁷⁸ The costs for the vaccine and vaccination by the veterinarian are partly or even completely met by the Animal Diseases Funds (Tierseuchenkassen) of the individual Federal States of Germany. The requirements for assumption of costs should be settled with the individual The Animal Diseases Funds (Tierseuchenkassen) in advance.

11. Vaccine

There is no approved vaccine for humans in Germany. A vaccine is available only in Australia which was approved there exclusively.⁷⁹Since 2010 a vaccine for cattle and goats has been approved in Germany, which can be repurposed for sheep (Coxevac^®, Ceva Santé Animale, Libourne, France).⁸⁰ It is an inactivated phase I vaccine, which is more effective than phase II vaccines.⁸¹ This vaccine reduces pathogen shedding in the long run, however, it can’t prevent it completely.^{77,78,82–84} The costs for the vaccine and vaccination by the veterinarian are partly or even completely met by the Animal Diseases Funds (Tierseuchenkassen) of the individual Federal States of Germany. The requirements for assumption of costs should be settled with the individual The Animal Diseases Funds (Tierseuchenkassen) in advance.

12. Reporting requirements in human medicine

Acute Q fever in humans is a notifiable disease according to the German Infection Protection Act (Infektionsschutzgesetz (IfSG)). When there is an indication of an acute infection the direct or indirect detection of C. burnetii is reported by name to the health authorities according to § 7 section 1 IfSG.⁸⁵

13. Q fever in Animal Health Law

Q fever is a notifiable disease of Category E subject to surveillance according to Annex II of the Implementing Regulation (EU) 2018/1882 and according to Regulation (EU) 2016/429 within the EU.^86,87 Regulations for prevention and control measures of animal diseases listed in the table of the Implementing Regulation should only be applied for in the species stated. In the case of Q fever these are Bison (Bison), Bos (cattle), Bubalus (buffalo), Ovis (sheep) and Capra (goat). Vectors are not given.⁸⁷

The occurrence of the disease should be reported to the responsible authorities by the entrepreneurs and all other natural and legal entities as soon as possible by providing the names of the livestock affected, the date of verification of the species affected, the district or administratively independent city. The authorities forward every report via a disease communication system (Tierseuchen-Nachrichtensystem (TSN)) to the German Federal Ministry for Food and Agriculture (Bundesministerium für Ernährung und Landwirtschaft (BMEL)).⁸⁸ The BMEL reports to the European Commission and the rest of the member states in case of a disease outbreak.⁸⁹ An outbreak has to be reported immediately in order for risk management measures to be implemented in time. The notification does not necessarily result in control measures according to the Regulation on Notifiable Animal Diseases (Verordnung über meldepflichtige Tierkrankheiten (TKrMeldpflV)) in positive livestock.⁸⁸ In order to improve the protection of the population the introduction of an active surveillance and control system would be reasonable.^53,90 National control measures are possible if there aren’t any impediments to intra-European Community movements.

14. Prophylaxis and control strategies against Q fever

A prerequisite for the measures to prevent and control this disease in humans is the identification of the infections in animals, as transmission from human to human is extremely rare. Avoiding contact with pathogen shedding animals is the most important preventive measure. When Q fever infections occur in the human population or in animals a close collaboration of public health authorities and veterinary authorities is required. The objective should be to track down the source of infection and therefore to prevent further cases of Q fever in the population.⁹¹A central control strategy includes the adherence to protection and hygiene measures when giving birth assistance to ruminants and when shearing sheep. Passenger and animal transport should be restricted. Pregnant animals as well as previously lambed sheep/goats with potentially strong shedding of pathogens should be transported to remote stables or locations with low public attendance. Afterbirth material and aborted animals should be stored in a closed container until they are disposed of by rendering plants.^91–93 Manure should be stored under foil as well and away from the population.⁹⁴ When the pathogen was detected, the disinfection of stables, working material and working clothes is essential.⁹⁵ In addition, raw milk or raw milk products should not be sold or offered to consumers.⁹² Pasteurizing reliably inactivates C. burnetii.^92,96 Vaccination of sheep, goat and cattle is recommended.⁹²

Special thanks for proof reading to Elisabeth Noakes.

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Q Fever a Global Zoonosis

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