Open Veterinary Journal, (2024), Vol. 14(10): 2509–2524

Review Article

10.5455/OVJ.2024.v14.i10.2

Navigating Q fever: Current perspectives and challenges in outbreak preparedness

Dewa Ketut Meles¹, Aswin Rafif Khairullah², Imam Mustofa^3*, Wurlina Wurlina³, Adeyinka Oye Akintunde⁴, Niluh Suwasanti⁵, Rheza Imawan Mustofa⁶, Satriawan Wedniyanto Putra⁷, Ikechukwu Benjamin Moses⁸, Muhammad Khaliim Jati Kusala², Ricadonna Raissa⁹, Kartika Afrida Fauzia^10,11, Suhita Aryaloka¹², Ima Fauziah², Sheila Marty Yanestria¹³ and Syahputra Wibowo¹⁴

¹Division of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia

²Research Center for Veterinary Science, National Research and Innovation Agency (BRIN), Bogor, Indonesia

³Division of Veterinary Reproduction, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia

⁴Department of Agriculture and Industrial Technology, Babcock University, Ilishan Remo, Nigeria

⁵Department of Clinical Pathology, Faculty of Medicine, Universitas Katolik Widya Mandala Surabaya, Surabaya, Indonesia

⁶Physician in Nayaka Hostpital, Surabaya, Indonesia

⁷Internship Physician in Rumah Sakit Angkatan Udara, Malang, Indonesia

⁸Department of Applied Microbiology, Faculty of Science, Ebonyi State University, Abakaliki, Nigeria

⁹Department of Pharmacology, Faculty of Veterinary Medicine, Universitas Brawijaya, Malang, Indonesia

¹⁰Research Center for Preclinical and Clinical Medicine, National Research and Innovation Agency (BRIN), Bogor, Indonesia

¹¹Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Japan

¹²Master Program of Veterinary Agribusiness, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia

¹³Faculty of Veterinary Medicine, Universitas Wijaya Kusuma Surabaya, Surabaya, Indonesia

¹⁴Eijkman Research Center for Molecular Biology, National Research and Innovation Agency (BRIN), Bogor, Indonesia

*Corresponding Author: Imam Mustofa. Division of Veterinary Reproduction, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia. Email: imam.mustofa [at] fkh.unair.ac.id

Submitted: 26/06/2024 Accepted: 02/09/2024 Published: 31/10/2024

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Abstract

Q fever, also known as query fever, is a zoonotic illness brought on by the Coxiella burnetii bacteria. This disease was first discovered in 1935 in Queensland, Australia. Worldwide, Q fever is a disease that requires notification, and certain nations classify it as a national health concern. A feature of C. burnetii is known as cell wall phase fluctuation. Serological testing is the main method used to diagnose Q fever illnesses. Inhalation is the primary method of C. burnetii transmission in both people and animals, with smaller amounts occurring through milk and milk product ingestion. The bacterial strain that is causing the infection determines how severe it is. Q fever is a significant zoonosis that can be dangerous for personnel working in veterinary laboratories, livestock breeding operations, and slaughterhouses due to its high human contagiousness. Coxiella burnetii is a biological weapon that can be sprayed on food, water, or even mail. It can also be employed as an aerosol. Antibiotics work well against this disease’s acute form, but as the infection develops into a chronic form, treatment becomes more difficult and the illness frequently returns, which can result in a high death rate. Vaccination has been demonstrated to lower the incidence of animal infections, C. burnetii shedding, and abortion. Several hygienic precautions should be put in place during an outbreak to lessen the spread of disease to animals.

Keywords: Aerosol, C. burnetii, Public health, Q fever, Zoonosis.

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Introduction

Q fever, also known as query fever, is a zoonotic illness caused by the Coxiella burnetii bacteria (Ullah et al., 2022). Coxiella burnetii is a Gram-negative γ-proteobacterium that is a member of the Coxiellaceae family and the Legionellales order of bacteria (Ohlopkova et al., 2023). The Q fever disease can infect dogs, cats, birds, fish, reptiles, arthropods, people, ruminants, and rodents (Porter et al., 2011). Domestic ruminants, such as cattle, sheep, and goats, are commonly thought to be the primary reservoir of these infections (Robi et al., 2023). During intraperitoneal infection tests, this disease was found to be extremely infectious in experimental rabbits (Eldin et al., 2017).

Q fever was first reported in Australia in 1935 and then spread throughout the world until now (Celina and Cerný, 2022). The understanding of this illness and C. burnetii, the causal culprit, has advanced dramatically in recent years. In most nations where systematic serology is conducted, C. burnetii is acknowledged as a global cause of endocarditis (Bozza et al., 2023). Q fever may be a widespread cause of fever in intertropical zones, according to research conducted in tropical regions and recent wars in the Middle East (Ahmadinezhad et al., 2022). Since the 2007 outbreak in the Netherlands, where the disease sickened over 4,000 people, Q fever has become more relevant to public health in the past 10 years (Bronner et al., 2020).

Aerosols tainted with bacteria are the most frequent means of Q fever transmission (Miller et al., 2021). The pathogenic bacterium that causes this disease, C. burnetii, is highly contagious and spreads through aerosol, making it potentially employed as a biological weapon (Dragan and Voth, 2020). For this reason, prompt and appropriate treatment is required in the event of an outbreak. Wind can help the bacteria travel away from the main site of infection, putting people who live close to rural regions or have direct contact with domestic ruminants at greater risk of getting this bacterial infection (Clark and Magalhães, 2018). Though it is uncommon, human transmission of C. burnetii infection can occur through ticks’ bites and the consumption of unpasteurized milk or cheese (Abdali et al., 2018).

Human Q fever manifests as an acute fever with symptoms resembling those of influenza, frequently accompanied by lung inflammation or pneumonia (Miller et al., 2021). In contrast, Q fever is frequently subclinical in animals (Ullah et al., 2022). Severe Q fever can cause fatal conditions such as liver failure, brain inflammation, blood vessel abnormalities, inflammation of the bones, and endocarditis, an infection of the heart that frequently results in death. Additionally, severe Q fever is a common cause of abortion and infertility in ruminant animals (Miller et al., 2021). According to recent studies, pulmonary lesions can result from the aerosol transmission of Q fever (Gregory et al., 2019). The development of quick and precise Q fever diagnosis is still ongoing in wealthy nations.

Due to its effects on human health, cattle’s responsiveness to interventions, clinical severity, and emergencies, Q fever has become a serious worry as it has spread around the world, especially in developing countries (Toledo-Perona et al., 2024). Despite being a worldwide health concern, Q fever is underreported, and disease surveillance is frequently disregarded. So the aim of this review article is to explain the etiology, history, epidemiology, pathogenesis, clinical symptoms, diagnosis, transmission, risk factors, public health importance, potential as bioterrorism, treatment, vaccination, and control of Q fever.

Etiology

Coxiella burnetii is a Gram-negative γ-proteobacterium that reproduces only inside cells (Sireci et al., 2021). Prior names for C. burnetii were Rickettsia diaporica and Rickettsia burnetii (Gürtler et al., 2014). The organism’s present name commemorates its discoverer and indicates its minuscule size. Despite having historically been related to Rickettsia, C. burnetii is currently classified by gene sequence analysis in the family Coxiellaceae, order Legionella (Ohlopkova et al., 2023). As a result, Coxiella is distinct from ordinary Rickettsia in a few aspects.

Coxiella burnetii is a 0.3 × 1.0 µm coccobacillus that exhibits significant pleomorphism (Shaw and Voth, 2019). The outer and inner membranes of this organism’s envelope are each 6.5 nm thick. There is a layer of peptidoglycan between the two membranes (Shepherd et al., 2023). Although Coxiella is categorized as Gram-negative, staining might be a Gram variable based on the mutation (Eldin et al., 2017). The fact that this bacteria can cause illness makes it one of the most contagious organisms. These bacteria can also persist in the environment for long periods of time due to their great stability (Anastácio et al., 2022). Coxiella is an intracellular pathogen that survives in phagolysosomes with a pH of 4.8. In these environments, it can survive in infected cells without endangering their viability (Samanta et al., 2019).

The developmental cycle of C. burnetii consists of two stages: transverse binary fission and sporulation (Tagesu, 2019). Because of its spore-like shape, it is resistant to heat and disinfectants and has a very extended environmental life span (Pexara et al., 2018). This spore-like appearance differs from the typical spores found in Gram-positive species. The DNA is filled with a protein that resembles histone Hc1 in the ground body of Chlamydia trachomatis but lacks the cysteine-rich spore coat and dipicolinic acid present in spores of Gram-positive bacteria (He et al., 2024).

The two morphological forms of Coxiella, giant and small, are shown by electron microscopy (Sitdikov et al., 2020). This phenomenon differs from the phenomena of phase variation and an organism’s developmental phases. Host cells consume Coxiella in its tiny variant form. Phagosomes that contain the organism fuse with the main lysosomes (Wallqvist et al., 2017). Because phagolysosomes have an acidic pH, C. burnetii enzymes are activated and big-cell variants are developed. These variants can then form spores that are extremely resistant. There have been descriptions of six different strain types: Dod, Biothere, Hamilton, Bacca, Rasche, and Corazon (Long et al., 2019).

History

In August 1935, the Queensland Department of Health in Brisbane, Australia, ordered Dr. E. H. Derrick, the Director of the Microbiology and Pathology Laboratory, to look into a “fever-like” disease outbreak among its abattoir workers that went untreated (Ullah et al., 2022). The illness he called “Q” for “Query fever”; “Q” for “Queensland”. Derrick injects blood or urine from “Q” fever sufferers into guinea pigs. The guinea pig then developed a fever (Sam et al., 2023). Derrick sent a salt emulsion of diseased guinea pig livers to Macfarlane Burnet in Melbourne after failing to identify the agent causing the sickness. It was possible for Burnet to separate organisms that “seemed to be rickettsial” (Gürtler et al., 2014). Nearly simultaneously, researchers at Rocky Mountain Laboratory in Montana, Drs. Herald Rea Cox and Gordon Davis, are investigating potential hay fever and tularemia vectors found in the Rocky Mountains. Davis fed guinea pigs fleas, which are thought to be the vector, causing the guinea pigs to become ill (Christodoulou et al., 2023).

Dr. Rolla Dyer, the director of the National Institutes of Health, went to see Cox in Montana in May 1938 in order to refute Cox’s claim that he had grown a significant amount of rickettsiae in embryonated eggs. He became unwell 10 days later, experiencing fever, chills, sweats, and retro-orbital pain. Guinea pigs given 5 ml of blood on the sixth day of sickness developed a fever after the injection (Dzul-Rosado et al., 2013). Studies conducted later revealed that this agent was the same as the Nine Mile agent that was separated from ticks (Dragan and Voth, 2020). Burnet delivered Dyer mice’s spleens in April 1938, and Dyer demonstrated that the Q fever agent was the same as the Nine Mile agent (Eldin et al., 2017). To reflect the filterable qualities of the Nine Mile agent, Cox gave it the name Rickettsia diaporica (diaporica means having the property or ability to pass through) (Vellema et al., 2021). Meanwhile, Derrick proposes R. burnetii as the name of the Q fever agent in Australia (Gürtler et al., 2014). Since it seemed that R. burnetii was different from other rickettsiae in 1948, Cornelius B. Philip suggested that this organism be regarded as a solitary species within its own genus (Sam et al., 2023). He recommended Coxiella as a name. The Q fever agent is now known as C. burnetii (Ullah et al., 2022). In 1986, Cox and Burnet passed away.

Epidemiology

Infected ruminants are usually the main source of infection in most Q fever outbreaks, and the number of cases is directly connected to the local livestock population (Celina and Cerný, 2022). Pet animals, particularly dogs and cats that are kept in close proximity to their owners, are recognized to be significant reservoirs of C. burnetii during urban Q fever outbreaks, aside from livestock (Ma et al., 2020). It has been hypothesized that dogs and cats may become infected through tick bites, eating raw meat, drinking milk from infected animals, breathing in aerosolized bacteria from the environment, or preying on contaminated animal species, even though the primary causes of infection in pets are still poorly understood (Cyr et al., 2021).

Although less common than in livestock, C. burnetii infections have been documented in other domestic mammals, such as horses, pigs, camels, rabbits, water buffalo, rats, and mice (Celina and Cerný, 2022). There have been numerous reports of serological evidence of C. burnetii infection in horses thus far (Akter et al., 2020; Khademi et al., 2020). Horses are reservoirs for C. burnetii, although their epidemiological significance has not been sufficiently investigated.

Numerous wild species, both captive and in the wild, are home to C. burnetii, which has been linked to the spread of Q fever. Starting with birds, infections with C. burnetii have been reported in both farm and pet birds (Ebani and Mancianti, 2022). These include barn common quail, swallows, Eclectus parrots, turkeys, pheasants, wood-pigeons, pigeons, Italian sparrows, rooks, Eurasian reed warblers, carrion crows, ravens, house sparrows, white wagtails, redstarts, western yellow wagtails, Japanese quail, black-headed gulls, common terns, hooded crows, common starlings, black kites, magpies, wild ducks, Eurasian griffon vultures, fieldfare, thrush nightingale, willow warblers, common blackbirds, turtle doves, great white pelicans, and wood sandpipers (Celina and Cerný, 2022).

Coxiella burnetii was discovered in several earlier studies on reptiles, where the bacterium was seropositive in snakes and tortoises (Sander et al., 2021; Mendoza-Roldan et al., 2023). Numerous mammal species have been shown to be infected with C. burnetii. Cervids, such as white-tailed deer, California mule deer, black-tailed deer, and Rocky Mountain mule deer in the United States, have been found to harbor C. burnetii (Kirchgessner et al., 2013). Among the European cervids that have been documented to be affected include fallow, red, and roe deer (Ruiz-Fons et al., 2008). Additionally, reports of Sika deer displaying serological indications of infection have been made from Japan (Ejercito et al., 1993).

Moreover, hares, numerous rodent species, and wild boars have all been found to harbor C. burnetii. In the domestic cycle of C. burnetii, rodents are thought to be important reservoirs of infection. Several rodent species have been linked to coxiellosis in livestock (Mangombi-Pambou et al., 2023). Furthermore, C. burnetii has been linked to reproductive losses in exotic ungulates kept in captivity, such as sable antelopes, waterbucks, and numerous gazelles, including dama gazelle, Cuvier’s gazelle, and arbor gazelle (González-Barrio and Ruiz-Fons, 2019).

In addition to land mammals, marine animals such as sea otters, northern fur seals, steller sea lions, and harbor seals have been shown to contain C. burnetii (Minor et al., 2013). Coyotes, wild cats, jaguars, red foxes, western grey kangaroos, common genets, North African hedgehogs, and Amur hedgehogs are among the other mammals that have been found to carry C. burnetii (Celina and Cerný, 2022).

Q fever is a disease that requires worldwide notification (except from New Zealand), and certain nations classify it as a national health concern (Salifu et al., 2019). The prevalence varies significantly across nations as a result of potential subnotification and epidemiological gaps. Q fever occasionally breaks out in endemic areas, usually following the completion of dangerous tasks like employment in slaughterhouses or agriculture (Epelboin et al., 2021). It is believed that ticks or other arthropods carry the disease, with domestic animals serving as a secondary reservoir despite wild animals being the primary reservoir (Eldin et al., 2017). From 2003 to 2017, there were 400–600 cases reported annually in Australia (Miller et al., 2021).

In 1940, 15 people were infected in the United States after the start of the Q fever study at the National Institutes of Health. Then, in 1946, the illness struck 47 individuals in the same area (Dragan and Voth, 2020). Since not all affected individuals work directly with the disease, it is thought that improper handling of the bacteria is what caused the agent to be released into the facility’s air in these cases. Cases in the nation were first reported to the Centers for Disease Control and Prevention in 1999; between 2016 and 2018, there were between 164 and 215 cases reported (Cho et al., 2023).

In 1955, nine nations in Africa reported differing numbers of cases of Q fever, making it the third continent to be documented with the illness (Sadiki et al., 2023). The disease arrived in South America that same year, with the first case being reported in a slaughterhouse in Cayenne, French Guiana (Thill et al., 2022). South America has long experienced sporadic instances; in 2005, there were 150 cases per 100,000 people (Fernandes and de Lemos, 2023).

The Netherlands experienced the greatest Q fever outbreak in history between 2007 and 2010. There have been at least 4,000 acute cases and an estimated 40,000 total illnesses as a result of the seasonal outbreak (van der Hoek et al., 2012). The sick individuals were not all directly involved with animals, but many were situated near dairy farms (Byeon et al., 2022). When public health initiatives were ineffective, it was determined to methodically kill pregnant animals, which resulted in the slaughter of over 50,000 animals (Schneeberger et al., 2014). Animal vaccinations are used to control this disease.

Pathogenesis

A feature of C. burnetii is known as cell wall phase fluctuation (Beare et al., 2018). Phase I bacteria are extremely pathogenic and possess whole lipopolysaccharide (LPS) molecules (Williams-Macdonald et al., 2023). It is possible to separate this lethal strain of the bacteria from infected humans, animals, and fleas. However, Phase I bacteria can be serially passed in chicken embryonates or in cell culture to produce Phase II bacteria, which are avirulent (Sireci et al., 2021). Stage II LPS is abrasive and jagged. The two antigenic variants of C. burnetii have different cell densities, surface charges, and surface protein configurations in addition to LPS (Howe et al., 2010). There are two distinct morphological forms of C. burnetii: the small-cell variant (SCV) and the large-cell variant (LCV) (Sobotta et al., 2017). LCV is larger and has fewer electron-rich centers than SCV, which is a less replicative and metabolically inactive form with a compact rod shape and a dense core region (Claudel et al., 2020). Environmental pollution results from the discharge of this SCV by diseased animals (Gerba, 2015).

Inhalation is the primary method of C. burnetii transmission in both people and animals, with smaller amounts occurring through milk and milk product ingestion (Knobel et al., 2013). Bacteria adhere to the cell membranes of phagocytes (monocytes/macrophages) once they have entered the body. While integrin avb3 and the complement receptor CR3 mediate the attachment of avirulent bacteria to phagocytic cells, integrin avb3 starts the attachment of virulent bacteria to these cells (Walbaum et al., 2021). Phagocytic cells allow phase I bacteria to persist, whereas phase II bacteria are destroyed. Furthermore, host cells phagocytose many fewer Phase I bacteria than Phase II germs (Howe et al., 2010).

Monocytes and macrophages phagocytose SCVs, which then enter the phagolysosome (Szulc-Dąbrowska et al., 2020). Here, the SCV merges with the lysosomal contents, changes into a form that is metabolically active, grows vegetatively, and eventually becomes the LCV. Normally, this phagolysosomal niche contains both antigenic variants of C. burnetii (Sobotta et al., 2016). Nevertheless, Phase II bacteria were promptly eradicated. C. burnetii grows particularly well in the acidic environment of phagolysosomes (Kodori et al., 2023). The organism’s propensity to acquire chronic infections and its capacity for reproduction in acidic phagolysosomes are particularly significant. This acidic niche is where metabolically active Phase I bacteria complete their whole developmental cycle (Shepherd et al., 2023). Because of its acidic pH, C. burnetii can grow and thrive while being shielded from the harmful effects of many antimicrobials (Smith et al., 2019).

The function of host cellular immunity in infected human patients is not well understood. Specific IgG and IgM Phase II antibodies can be detected in goats’ blood 2 weeks after infection, and their titers can stay elevated for up to 13 weeks. This is indicative of the immunological response of goats to C. burnetii infection (Muleme et al., 2017). After 4 weeks of Phase II antibodies, Phase I antibodies appear. The immunological response to C. burnetii can linger anywhere from a few months to several years (Kersh et al., 2013). The primary source of metabolically active LCV is placental trophoblasts (Gauster et al., 2022). During an acute infection, the organism is found in the host’s lungs, liver, spleen, and blood (Anastácio et al., 2022). In non-pregnant animals, the condition is primarily asymptomatic; however, in pregnant animals, the most significant clinical signs are abortion, stillbirth, weak offspring birth, and premature birth (Plummer et al., 2018). Q fever infection may be the cause of respiratory and intestinal issues in otherwise healthy youngsters living in high-risk locations (Ullah et al., 2022). While Q fever rarely results in reproductive problems in domestic animals, it has been known to cause up to 90% more abortions in goats (Agerholm, 2013).

Human infections caused by C. burnetii can manifest as either acute or chronic. Chronic Q fever can be fatal in many cases when combined with chronic endocarditis, while acute infections usually go away on their own with mild flu-like symptoms (Das et al., 2014). The fetus normally appears fresh and normal in abortions caused by C. burnetii infection; however, occasionally the fetus turns necrotic (Álvarez-Alonso et al., 2018). There is macroscopic placental inflammation in the badly damaged intercotyledonous gaps, accompanied by a purulent brownish-yellow exudate (Zarza et al., 2021). Under a microscope, the most impacted trophoblast cells are those found in the intercotyledonary region of the allanto-chorion and at the base of the villi (Roest et al., 2012). This inflammation might present as chronic necrosis with pus-like discharge or as modest mononuclear infiltration. The basophilic intracytoplasmic granulations and foamy vacuolated cytoplasm are frequently observed in the epithelial cells located in the chorionic membrane at the base of the villi (Purnamiharja et al., 2023). Several fetuses had liver inflammation and moderate granulations on the histopathological investigation. Yet, it was discovered that other organs appeared normal (Lee et al., 2012).

Clinical symptoms

Clinical symptoms in humans: Humans infected with C. burnetii can exhibit both acute and persistent clinical symptoms. Nonetheless, some patients develop severe illness, and 60% of infections are asymptomatic (Ghaoui et al., 2023). Depending on the mode of infection, Q fever takes 2 to 3 weeks to incubate (Knobel et al., 2013). Acute Q fever symptoms are nonspecific and differ from patient to patient. The most common clinical presentation is a self-limiting febrile fever with accompanying severe headache, arthralgia, myalgia, and cough (Finn et al., 2021).

A prolonged fever, which can reach 39°C–40°C, typically lasts for 2–4 days before progressively returning to normal over the following 5–14 days (Sam et al., 2023). Atypical pneumonia is yet another typical sign of severe Q fever (Honarmand, 2012). The symptoms of mild pneumonia typically include a dry cough, fever, and little respiratory discomfort (Kelm et al., 2017). Additionally, patients may develop subclinical hepatitis, granulomatous hepatitis with persistent fever, and hepatitis with hepatomegaly but without jaundice (Lee et al., 2012). Hepatitis typically develops in immunocompromised young children, but pneumonia typically affects older patients (Eldin et al., 2017).

Pericarditis may coexist with myocarditis, which affects 2% of individuals with acute illness (Jacobson and Sutthiwan, 2019). Acute Q fever cases have also been linked to skin rashes and neurological conditions such as meningoencephalitis and encephalitis, lymphocytic meningitis, and peripheral neuropathy (Gu et al., 2022). Pregnant-infected women may experience spontaneous abortion, intrauterine fetal death, early birth, or stunted fetal growth (Mboussou et al., 2019). Women who are pregnant have the potential to become chronically infected and lose their babies in later pregnancies. In the acute stage of the illness, death is an uncommon result. However, myocarditis and acute respiratory distress can be fatal (Honarmand, 2012).

Chronic Q fever is characterized as an infection that lasts longer than 6 months after the sickness first appears (Buijs et al., 2021). In less than 5% of cases, this happens. Endocarditis is the primary clinical manifestation of this type of illness (Bozza et al., 2023). In 60%–70% of all chronic cases, this happens. Patients receiving antibiotic treatment have a death rate of less than 10% in cases of Q fever endocarditis (Kampschreur et al., 2012). Usually, the mitral and aortic valves are impacted. Non-specific symptoms could include weakness, exhaustion, anorexia, heart failure, intermittent fever, or weight loss (Ramos et al., 2023). Additional symptoms include clubbing, purpuric rash, hepatomegaly, splenomegaly, osteomyelitis, osteoarthritis, and arterial embolism (Monteiro et al., 2021).

Clinical symptoms in animals: The majority of animal infections have no symptoms. During acute experimental infections, the organism is detected in the blood, lungs, liver, and spleen; however, chronically infected animals continuously excrete the germs on their faces and urine (Porter et al., 2011). The majority of pet infections are still unclear. It is believed that Q fever contributes to pet reproductive issues and abortions (Eldin et al., 2017). Scientific data backs up the theory that C. burnetii can spread epidemics of infertility in sheep and goats but not in cattle (Garcia-Ispierto et al., 2014). Endometritis, metritis, stillbirth, low birth weight, and infertility are examples of reproductive problems in pets (Agerholm, 2013).

Coxiella burnetii antibody levels in bulk tank milk from Danish dairy cows were not linked to stillbirth or prenatal mortality rates in herds (Nielsen et al., 2011). Sheep and goats have comparatively greater abortion rates than cattle (Cantas et al., 2011). Both sheeps and cows typically have abortions at the end of their pregnancies. The aborted fetus seems normal in the majority of abortion instances. Infected placentas may exhibit fibrous thickening of the intracotyl and discolored exudates (Ullah et al., 2022). In goats and cattle, the most commonly reported clinical symptoms are severe myometrial inflammation and metritis (Robi et al., 2023).

Diagnosis

Serological testing is the main method used to diagnose Q fever illnesses. Although there are numerous laboratory studies available, the immunofluorescence test is the most widely used approach for antibody detection because of its high sensitivity and specificity (Gutiérrez-Bautista et al., 2024). The use of polymerase chain reaction (PCR), a promising test that may even be able to identify C. burnetii in the early stages of the illness, is presently restricted to research and reference labs. The molecular detection of C. burnetii in blood and tissue samples using conventional PCR involves targeting and sequencing the transposase gene insertion element, IS1111, of C. burnetii. PCR and sequencing of the IS1111 gene help in achieving a short turn-around time for results, including high specificity (Bae et al., 2019).

Regular Giemsa staining can be used to generate frozen tissue or smears that display C. burnetii (Honarmand, 2012). Though not unique to Q fever, the occurrence of donut granulomas, or fibrin rings, in histopathological specimens is traditionally linked to the illness (Carvalho et al., 2021). There are a number of issues with culture or visualizing the organism, even when isolation of the organism yields a conclusive diagnosis. Since C. burnetii is highly contagious and might be used as a bioterrorism weapon, most clinical laboratories do not culture it due to its technical difficulty and requirement for level 3 biosafety procedures (Francis et al., 2020). Consequently, it is not recommended to isolate the organism in settings without sufficient security.

Serological procedures are the preferred diagnostic procedure since they are safer and simpler than isolation attempts. ELISA methods, one of the serological procedures, are widely recognized and used in the diagnosis of acute and chronic C. burnetii infection (Gutiérrez-Bautista et al., 2024). The ELISA technique has arrays of advantages, such as its ease of execution, objective interpretation, and potential for automation; thus, making it a suitable screening option, especially when analyzing a large number of samples and also for epidemiological studies. However, some inconsistent results have been reported while using different ELISA kits (Horigan et al., 2011; Gutiérrez-Bautista et al., 2024). One option is to use multiple kits to determine the status of a serum. Additionally, available serological methods do not have the capability to distinguish between infected and vaccinated ruminants (Gutiérrez-Bautista et al., 2024). Phase I and II antibody detection are the most often utilized serological tests in clinical settings (Wielders et al., 2012). The US Army employed phase I and II antibody detection, which was initially reported by Bengtson in 1941, to characterize eight outbreaks of Q fever in Allied forces between 1944 and 1945 (Hartzell et al., 2008). For those who are not familiar with Q fever, test results can be misleading because phase I antibodies typically stay high in chronic illness, whereas phase II antibodies are positive in acute illness (Alhetheel et al., 2018). The antibody response is a result of phase shifts in C. burnetii. IgG titers of 200 or higher against phase II antibodies and an IgM of 50 or higher against phase I antibodies indicate a recent Q fever infection; an IgG titer of 800 or higher against phase I antibodies indicates a chronic infection (Bae et al., 2019). These limitations differ throughout laboratories, and particular limitations for every test must be applied.

Most patients have phase II antibodies within 2 weeks of infection, and 90% of patients have them by 3 weeks (Porter et al., 2011). Antibodies absent after 4 weeks point to a different diagnosis. IgG titers may continue to rise, although antibodies often reach their peak in 2 months and then progressively fall (Wielders et al., 2015). If the elevation continues, a chronic illness (endocarditis) should be suspected.

Clinical endocarditis, isolation of C. burnetii, or serological evidence are necessary for the diagnosis of Q fever endocarditis (Cotar et al., 2011). Since Q fever endocarditis is a chronic condition, a single serum specimen suffices for diagnosis; matched sera are not necessary (Psaroulaki et al., 2020). The Duke criteria have been changed to include a phase I IgG titer of 800 or above. An early diagnosis of acute Q fever endocarditis can be made with a positive PCR for C. burnetii when there is a high degree of clinical suspicion and the antibody titers are either low or negative (Bae et al., 2021).

The majority of the current guidelines for people with acute Q fever are derived from clinical experience in an elderly population in a single country (El Zein et al., 2024). It’s unclear if this kind of care is suitable for all patients. Nonetheless, this method is advised for patients with acute Q fever until research in other populations is completed. While other follow-up techniques could make sense, they should always be used in consultation with an infectious disease expert.

Transmission

Coxiella burnetii is an obligatory intracellular bacteria that is highly contagious to both humans and animals. It possesses resilience and stability in the environment (Celina and Cerný, 2022). In actuality, inhaling infected aerosols can only infect and cause disease in 1–10 healthy individuals (Gregory et al., 2019). Ruminants have been identified as the main source of infection for humans, despite the fact that this agent may replicate in a wide range of animal hosts, including birds, arthropods, domestic mammals, and wild mammals (Robi et al., 2023). These animals mostly transmit infectious agents through vaginal fluids, milk, feces, urine, and semen when they are infected (Winter et al., 2021). Furthermore, these organisms may endure for a month in chilled meat, 10 months at 15°C–25°C in sheep wool, and 40 months at ambient temperature in powdered milk (Gürtler et al., 2014). The main way that humans become sick is by breathing in contaminated aerosols (Gregory et al., 2019).

When the bacteria infect placental trophoblast cells in the placentas of ruminants and other mammals, they can grow at extremely high densities (Miller et al., 2021). Abortion is a frequently recognized clinical indication in goats and sheep (Winter and Campe, 2022). Mammals either give birth to healthy or sick children when their gestation period ends. At this point, the placenta and birth fluid allow C. burnetii spores to enter the environment (de Souza et al., 2022). As a result, C. burnetii can pollute the environment and be passed on immediately from birth.

The wind has the ability to spread Q fever up to 18 km from its source (Clark and Magalhães, 2018). The quantity of people afflicted with airborne diseases is also influenced by the intensity of the emission; airborne transmission from source to recipient is contingent upon meteorological conditions, environmental elements, and human exposure (location, duration, and physical activity) (Van Leuken et al., 2016). For instance, the spread of C. burnetii is more common in regions with little vegetation and poor soil moisture (Ahmad et al., 2023).

Rarer means of infection include person-to-person transmission, eating unpasteurized milk or milk products, and flea bites (Gale et al., 2015). On the other hand, research on the significance of consuming tainted milk and milk products in the epidemiology of Q fever is still lacking (Pexara et al., 2018). In contrast to aerosol inhalation, higher dosages are thought to be required for a successful infection; nevertheless, the infective dose required for oral transmission of this agent remains unknown. There has been documented epidemiological evidence linking the eating of unpasteurized dairy products to Q fever outbreaks (Mokarizadeh et al., 2023). Furthermore, because of its great heat tolerance and pathogenicity, C. burnetii has been regarded since 1957 as the primary microbe that should be removed from milk by exposure to high temperatures (Cho et al., 2023).

Risk factors

Agent factors: The bacterial strain that is causing the infection determines how severe it is. Bacteria of phase I are more pathogenic than those of phase II (van Schaik et al., 2013). The genome of C. burnetii type IIII causes acute infections in humans, while types IV and V cause persistent illnesses (Palanisamy et al., 2024). It’s unknown how virulent type VI is.

Host factors: Two risk variables that have been shown to affect the likelihood of Q fever in humans are age and gender (Muema et al., 2022). The most susceptible age range is between 30 and 60 years old, and men are more likely than women to have this clinical illness (Porter et al., 2011). Pregnant women, those with immunosuppressive disorders like AIDS, and those with a history of valvulopathy are the most vulnerable (Robi et al., 2023). Research indicates a comparatively higher incidence in particular occupations, such as veterinary care, laboratory work, slaughterhouse work, and workers with livestock, where there is a higher chance of infection or seropositivity than in other occupations (Cook et al., 2021).

There is a correlation between age and sex and C. burnetii infection in animals, particularly in cattle (Mwololo et al., 2022). Numerous studies have demonstrated that in sheep and cattle, the prevalence of C. burnetii infection rises with increasing age or parity (Ullah et al., 2019; Nejad et al., 2023). Compared to beef cattle, the frequency is higher in dairy cattle. It is reported that among dairy breeds, Holsteins have a higher incidence (Dhaka et al., 2020). Animal density is a possible risk factor for C. burnetii infection because it raises the environmental load of infection (Selim et al., 2023). Numerous studies conducted on cattle indicate that seroprevalence rises as animal size increases (Deressa et al., 2020; Ferrara et al., 2022). Flock size is reported to have a similar effect on sheep (Elsohaby et al., 2021). The seroprevalence of C. burnetii infection in animals can also be attributed to a number of management factors, including housing systems and the isolation of new animals (Sadiki et al., 2023).

Seasonal, environmental, and management factors: There are seasonal differences in the incidence of Q fever in people. However, the geographical location affects this variation. Nonetheless, spring or early summer is when the majority of Q fever cases are documented (Halsby et al., 2017). Human Q fever has been demonstrated to be correlated with rainfall rather than seasonality (Van Leuken et al., 2016). Q fever is more common in areas with a high livestock density or around sick animals (Smit et al., 2012).

Public health importance

Q fever is a significant zoonosis that can be dangerous for personnel working in veterinary laboratories, livestock breeding operations, and slaughterhouses due to its high human contagiousness (Plummer et al., 2018). Numerous livestock workers have antibodies, according to surveys, indicating that they were exposed to the pathogen (Dione et al., 2022). The majority of infections are minor, and less than half of those who are infected get sick. However, those who are afflicted may have a high fever along with headaches, aches in the muscles, a sore throat, nausea, vomiting, and pain in the chest and stomach (Sam et al., 2023).

The fever could result in pneumonia or have an impact on the liver and last for a week or two (Honarmand, 2012). The course of treatment entails continuous antibiotic use. A small number of people develop a severe, incapacitating chronic illness. This potentially catastrophic consequence is more likely to occur in people who already have cardiac valve issues or have weakened immune systems (de Lange et al., 2019). In addition, post-Q fever chronic tiredness syndrome exists (Morroy et al., 2016). The most frequently reported laboratory infection, Q fever, has been known to occur in multiple recorded outbreaks involving 15 or more individuals (Robi et al., 2023).

Initial human exposure to C. burnetii can result in acute or chronic disease, as well as moderate or asymptomatic infections (Bauer et al., 2023). Clinical diagnosis might be exceedingly challenging. Even though risk factors for its severity, such as pregnancy, immunosuppression, cardiac valvulopathy, vascular grafts, and aneurysms, have been identified, the causes of this high degree of clinical polymorphism remain largely unclear (Ali et al., 2022). Even with therapy, the condition can be extremely disabling and cause considerable morbidity, even though it is rarely fatal. The majority of cases involving humans are caused by dust particles inhaled from contaminated animals or animal products (Celina and Cerný, 2022).

Potential as bioterrorism

Coxiella burnetii is a biological weapon that can be sprayed on food, water, or even mail. It can also be employed as an aerosol (Stein et al., 2005). Moderate Coxiella ingestion is unlikely to result in clinical signs. Human subjects who drank milk tainted with C. burnetii experienced seroconversion without experiencing any symptoms of illness (Porter et al., 2011). However, nothing is known about the use of high Coxiella concentrations as a food or water product pollutant.

When Coxiella is released as an aerosol in heavily populated places, the disease will appear suddenly and resemble a naturally occurring illness (Dragan and Voth, 2020). After the pathogen is released, the outbreak will start 14–26 days later. Individuals will arrive with intense headaches, body aches, and a fever (Honarmand, 2012). Even though the cough may be mild or nonexistent, most patients have radiographic signs of pneumonia (von Ranke et al., 2019). Additionally, some people could have hepatitis symptoms (Jama et al., 2023). It can be difficult to clinically differentiate the initial occurrence from naturally occurring influenza epidemics or from other types of atypical pneumonia, such as mycoplasma or viral pneumonia (Keijmel et al., 2015).

The quick onset of febrile illness epidemics in metropolitan areas with peaks in cases, including exposure to a specific source without secondary transmission, is an epidemiological hint to the employment of Q fever as a biological weapon (Kagawa et al., 2003). It is anticipated that 50 kg of C. burnetii would reach an area more than 20 km away and cause around 150 fatalities and 125,000 impairments if it were released 2 km downwind from a population of 500,000 (Stein et al., 2005). In the months that follow, some 9,000 of the acutely afflicted patients might develop endocarditis (Bozza et al., 2023). The amount of acute and long-term mental health injuries brought on by this agent is hard to measure, although anxiety levels may be higher than with other agents because of concern about serious long-term consequences such as endocarditis and chronic fatigue syndrome (Morroy et al., 2011). Bioterrorism can potentially attack animals. Q fever can result in pandemic abortions in cattle, raising worries about the use of meat and the possibility of human transmission (Saegerman et al., 2022).

Treatment

Treatment in humans: Acute and chronic Q fever are the two types that affect people. Antibiotics work well against this disease’s acute form, but as the infection develops into a chronic form, treatment becomes more difficult and the illness frequently returns, which can result in a high death rate (Kersh, 2013). In patients with Q fever, the length of antibiotic treatment was decided by monitoring their serological titers. As soon as a clinical illness appears, antibiotics should be taken because delaying treatment could be counterproductive (Porter et al., 2011). Acute Q fever typically resolves on its own. Nonetheless, prompt diagnosis and treatment with antibiotics can shorten the illness’s duration and lessen its severity. The preferred medications for treating Q fever are hydroxychloroquine and doxycycline (Raoult et al., 1999). Most often, these medications are combined. As an alternative course of treatment, other antibiotics such as erythromycin, rifampicin, clarithromycin, and roxithromycin may be utilized (Gikas et al., 2001). Doxycycline 100 mg twice daily for 2–3 weeks is advised for patients with acute Q fever, especially adult patients and non-pregnant women (Kersh, 2013). It is also possible to combine hydroxychloroquine with doxycycline. Phagolysosome pH is raised by the lysosomotrophic medication hydroxychloroquine (Rolain et al., 2007). Since C. burnetii needs an acidic environment to reproduce, hydroxychloroquine serves as a bacteriostatic by raising the pH of phagolysosomes (Smith et al., 2019). For the treatment of Q fever, cotrimoxazole is safe to use in pregnant women and children under the age of eight (Ford et al., 2014).

In situations of persistent Q fever, antibiotics such as hydroxychloroquine and doxycycline, especially in cases of native and prosthetic valve endocarditis, can be effectively utilized at a dose of 200 mg per day for a lengthy period of 18–24 months (Stahl et al., 2022). When combined with doxycycline, combination therapy is a more effective way to prevent endocarditis than when used alone. Because of their decreased efficacy against C. burnetii infections, rifampicin, macrolides, and quinolones are not typically utilized as alternate treatments for this illness (Fullerton et al., 2021). A crucial steroid alternative, methotrexate, is utilized to control vascular inflammation and preserve the ascending aorta and thorax’s homeostasis (Yang et al., 2021). Following antibiotic therapy, follow-up care is required, such as routine heart rate and eye reflex tests. Following the usage of antibiotics, some individuals may experience photosensitivity (Robi et al., 2023). In the late stages of chronic Q fever, which are marked by severe heart failure or the development of an abscess on the heart valves, the use of antibiotics is not advised (Ullah et al., 2022). Under these circumstances, heart surgery is advised. It has also been demonstrated that interferon and tumor necrosis factor are useful treatments for persistent Q fever (Andoh et al., 2007). Treatment can be discontinued in situations of chronic infection when the Phase I IgG antibody titer drops by at least four times and follow-up serological response is required (Wielders et al., 2015). Q fever infections can result in significant rates of morbidity and mortality if left untreated, so people who are more sensitive to them should receive extra care (Kampschreur et al., 2015).

Treatment in animals: There is not much information about treating coxiellosis in animals. The effectiveness of medicines in decreasing bacterial shedding and reproductive loss in animals infected with C. burnetii requires extensive research. Tetracycline is generally advised for animal therapy; however, because of its decreased bioavailability following oral administration, tetracycline cannot be used in animal feed during pregnancy as a disease control approach at the herd level (Ullah et al., 2022). In order to prevent reproductive injury in animals suffering from chronic coxiellosis, parenteral administration of two injections of long-acting oxytetracycline at a dose of 20 mg/kg 20 days apart may be helpful (Eldin et al., 2017). Nevertheless, oxytetracycline taken orally did not alter the animal’s serological status or lessen the amount of bacteria shed through birth fluids (Astobiza et al., 2013). Tetracycline is an effective way to lower the risk of abortion in ruminant animals caused by other diseases like Chlamydophila abortus (Gisbert et al., 2024a). Tetracycline should be administered to pregnant animals at intervals of 2–3 weeks starting on the 95th day of pregnancy and continuing until the postpartum period.

Vaccination

Vaccination has been demonstrated to lower the incidence of animal infections, C. burnetii shedding, and abortion (Hogerwerf et al., 2011). Those infected groups receive vaccinations due to the outbreak. In addition to offering effective protection against abortion, the inactivated phase I vaccine has been demonstrated to stop germs from shedding into feces, milk, and vaginal mucus (Porter et al., 2011). Animal immunization experiments using inactivated vaccines showed robust and long-lasting antibody responses and showed that vaccination can reduce the organism’s excretion (Sam et al., 2023).

Australian regulators approved a formaldehyde-inactivated vaccine derived from a Phase I strain of C. burnetii in 1989 (Graves et al., 2022). At this point, the Phase II vaccine is 100 times more effective against mouse spleen colonization than the phase I vaccine; therefore, the results are approaching those of the Phase I vaccination (Williams-Macdonald et al., 2023). Nonetheless, it has been demonstrated that vaccination works better in nulliparous animals than in parous animals (Long, 2021). Moreover, vaccinations do not totally remove sickness in goats and animals who have already contracted it. The phase I vaccine is more efficacious; however, those who have had seroconversion or been exposed should not receive the vaccination (Gisbert et al., 2024b). It is advisable to vaccinate young animals for several years after vaccination and to choose sero-negative groups or animals.

Coxevac^®, an inactivated C. burnetii PhI-vaccine, has been used off-label in sheep for a number of years in Europe, but nothing is known about how it affects sheep immunological response and health. Furthermore, there are differing suggestions regarding the dosages of vaccines for sheep (Böttcher et al., 2022). The immunological response and few adverse effects suggest that Coxevac^® is a low-risk, safe vaccination for sheep. It is preferable to have extensive, uniform immunization programs with suitable vaccination schedules within the framework of the One Health philosophy (Winter et al., 2021). Because it costs less to administer a vaccination to sheep (1 ml as opposed to 2 ml for goats and 4 ml for cattle), sheep producers may be more receptive (Bauer et al., 2023).

However, as C. burnetii is present in practically all domestic and wild ruminant populations globally, efforts have been made to determine how well the Coxevac^® (inactivated phase I vaccination) works to suppress infection in endemic circumstances. According to several of these studies, if long-term immunization is carried out, Coxevac^® may be helpful in controlling C. burnetii infection (Astobiza et al., 2011). The field experiment opens a path of inquiry into C. burnetii control in wildlife and shows that Coxevac^® may be useful in lowering the amount of C. burnetii that deer shed over time (González-Barrio et al., 2017).

Control

Several hygienic precautions should be put in place during an outbreak to lessen the spread of disease to animals. Waste management techniques that have changed include covering, naturally composting, or plowing waste; using lime or calcium cyanide in the manure; and discarding animal abortions and birth products (Ayilara et al., 2020). Cleaning of contaminated locations, including walkways and stable settings, as well as monitoring animal reproduction (Winter et al., 2021). However, it’s still unclear whether different control strategies are successful. According to reports, even in the absence of any control measures, the prevalence of C. burnetii in affected herds often declines over time (Robi et al., 2023). This could be because animals are thought to naturally immunize themselves.

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Conclusion

Q fever is a zoonotic disease caused by C. burnetii. The most common route of transmission of Q fever is via aerosols contaminated with bacteria. Treatment of this disease can be done by administering antibiotics. Several hygienic precautions should be put in place during an outbreak to lessen the spread of disease to animals.

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Acknowledgments

The authors thank to Universitas Airlangga and Badan Riset dan Inovasi Nasional.

Conflict of interest

The authors declare that there is no conflict of interest.

Funding

The authors thank Universitas Airlangga for managerial support, Salma Firdausya Qurrotunnada Noor, Eunice Wong Hui Wen, Joo Jia Yin, and Rahma Novhira for technical support. This research was funded by the Directorate of Research and Community Service, Deputy for Strengthening Research and Technology, Ministry of Research and Technology/National Research and Innovation Agency for the 2022 fiscal year, Chancellor’s Decree number: 770/UN3.14/PT/2022.

Author’s contributions

DKM, ARK, IBM, and MKJK drafted the manuscript. WW, IM, AOA, and SMY revise and edits the manuscripts. NS, RIM, SWP, and KAF took part in preparing and critical checking this manuscript. RR, IF, SW, and SA edit the references. All authors read and approved the final manuscript.

Data availability

All references are open access, so data can be obtained from the online web.

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