ABSTRACT
This review aims to provide current information about Q fever, elucidating the etiological, epidemiological, pathogenic, clinical, diagnostic, therapeutic, and prophylactic aspects of the disease for the medical community. We discuss the main forms of presentation of the agent, its ability to persist in the body, the infinite possibilities of susceptible hosts, the main known forms of transmission, its importance in populations at occupational risk, and the role of arthropods in the natural history of the disease. Focusing on Brazil, we present the cases already described and studies developed since its first report, and how there is still much to unravel. We are aware of the possibilities of the persistence of the agent and the development of severe clinical pictures and the specific treatments currently instituted. We also wish to raise awareness about the future, the new genotypes that are emerging, the need to study the effects of vaccines, and the impact of Q fever on the population. Q fever is a poorly understood disease in Latin America, and recent studies, especially in Brazil, have revealed the importance of developing new studies.
Q fever; Coxiella burnetii; Zoonosis; Emerging diseases
INTRODUCTION
Q fever is a human disease caused by the bacterium Coxiella burnetii. This pathogen can infect vertebrate and invertebrate animals and cause a disease termed coxiellosis11. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518-53.. The use of a different nomenclature for the disease in animals and humans is due to the difference in the most common clinical presentation, with reproductive disorders being the most common clinical presentation in animals and a febrile disease with nonspecific symptoms in humans11. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518-53..
Increased knowledge about the disease in recent decades has led to the identification of outbreaks worldwide, suggesting that the bacterium is dispersed across all continents22. Enserink M. Questions abound in Q-fever explosion in the Netherlands. Science. 2010;327:266-7.,33. Beare PA, Sandoz KM, Omsland A, Rockey DD, Heinzen RA, Heinzen RA, et al. Advances in genetic manipulation of obligate intracellular bacterial pathogens. Front Microbiol. 2011:2:97.. Since the first serological evidence of C. burnetii presence in Brazil by Brandao et al.44. Brandão H, Vale LA, Christovão, DA. Investigações sobre a febre Q em São Paulo: estudo sorológico em operários de um frigorífico. Arq Fac Hig Saude Publica Univ Sao Paulo. 1953;7:127-31. in the 1950s, few studies have been published in the country, keeping the disease in the shadows.
C. burnetii is a highly transmissible zoonotic agent that infects a wide range of animal species through different routes of transmission55. Pexara A, Solomakos N, Govaris A. Q fever and prevalence of Coxiella burnetii in milk. Trends Food Sci Technol. 2018;71:65-72.. As in Australia, Q fever is widely studied in various European countries, and several outbreaks in animals and humans have been documented22. Enserink M. Questions abound in Q-fever explosion in the Netherlands. Science. 2010;327:266-7.. In Brazil, the disease is still widely underestimated, not well known by doctors and veterinarians, and depends on more clinical and epidemiological studies to raise awareness of the situation within the country and to enable efficient control and preventive measures66. Damasceno IA, Guerra RC. Coxiella burnetii e a febre Q no Brasil, uma questão de saúde pública. Cien Saude Colet. 2018;23:4231-9..
Etiology
C. burnetii is a gram-negative, pleomorphic, and obligate intracellular bacterium11. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518-53.. Due to its ability to enter cells and replicate, it was taxonomically classified in past decades within the Rickettsiae group due to the impossibility of its isolation in an axenic medium and its ability to infect arthropods. Although there are some similarities with Rickettsiae, current knowledge confirms that C. burnetii does not belong to the group, mainly due to its placement in phylogenetic inferences using sequences of the 16S rRNA gene where Coxiella showed a close relationship to the order Legionallales, distancing it from the Rickettsiales11. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518-53.. In addition, several factors, including metabolism, infectivity, morphological variations during infection, and the ability to form spores, also support the reclassification into the Coxiellaceae family77. Beare PA, Unsworth N, Andoh M, Voth DE, Omsland A, Gilk SD, et al. Comparative genomics reveal extensive transposon-mediated genomic plasticity and diversity among potential effector proteins within the Genus Coxiella. Infect Immun. 2009;77:642-56..
Inside infected cells, C. burnetii can present as a large-cell variant (LCV), which is metabolically active, and as a small-cell variant (SCV), which is a spore-like structure that confers extracellular survival and high environmental resistance88. Voth DE, Heinzen RA. Coxiella type IV secretion and cellular microbiology. Curr Opin Microbiol. 2009;12:74-80.. SCVs differentiate from LCVs only in the intracellular environment after infecting the host, becoming metabolically active and virulent during the stationary phase of the C. burnetii growth cycle, involving changes to the cell surface of the bacteria99. Waag DM. Coxiella burnetii: host and bacterial responses to infection. Vaccine. 2007;25:7288-95.. Due to stress resistance, when excreted by the host organism, SCV can remain for months in the environment, soil, and animal products, even at high temperatures1010. Madariaga MG, Rezai K, Trenholme GM, Weinstein RA. Q fever: a biological weapon in your backyard. Lancet Infect Dis. 2003;3:709-21.,1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14..
The LPS of C. burnetii is a critical virulence factor of the bacterium, a structurally and antigenically distinct protein present in different types1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. There is a configuration of LPS named Phase I LPS, which is related to the complete epitope with the presence of the O-chain; this structure is observed in wild-type C. burnetii and confers virulence1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. There is another configuration of LPS, named Phase II LPS, which is only observed after several passages in the laboratory using cell culture and is characterized as the result of the loss of the O chain of Phase I LPS, related to the deletion of a gene during laboratory manipulation1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. C. burnetii expressing Phase II antigens are avirulent and cannot be found in nature. There are other intermediate forms of LPS, but for diagnosis and treatment purposes, these two configurations are more important1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30..
The LPS layer of C. burnetii has a different relationship with the immune system. In primo-infection, patients presenting acute Q fever initially elicit an Anti-Phase II immune response1414. Hackstadt T, Peacock MG, Hitchcock PJ, Cole RL. Lipopolysaccharide variation in Coxiella burnetti: intrastrain heterogeneity in structure and antigenicity. Infect Immun. 1985;48:359-65.. The rise of Anti-Phase II antibodies can be observed between 7 to 15 days after the onset of the disease1515. Erridge C, Bennett-Guerrero E, Poxton IR. Structure and function of lipopolysaccharides. Microbes Infect. 2002;4:837-51.. With the infection progression, Anti-Phase I antibodies increase and can become prevalent in the serum, with Anti-Phase II antibodies declining between 3 and 6 months post-infection1414. Hackstadt T, Peacock MG, Hitchcock PJ, Cole RL. Lipopolysaccharide variation in Coxiella burnetti: intrastrain heterogeneity in structure and antigenicity. Infect Immun. 1985;48:359-65.. The acute immune response of Q fever is initially related to the presence of Anti-Phase II antibodies, whereas persistent Q fever is linked to high titers of Anti-Phase I antibodies1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.,1515. Erridge C, Bennett-Guerrero E, Poxton IR. Structure and function of lipopolysaccharides. Microbes Infect. 2002;4:837-51.. These data are important for a better understanding of Q fever prevalence studies and can be best checked in Table 1.
An infectious dose of < 10 C. burnetii cells inoculated via the respiratory route is sufficient to generate the disease and for that reason it is placed in category B by the Centers for Disease Control and Prevention (CDC) as a potential risk to human health and the second highest priority for countering bioterrorism1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30..
Epidemiology
In Brazil, although Q fever was introduced as a compulsory notification disease in 2014 (Ordinance 1.271 of June 6, 2014, of the Ministry of Health), the reported cases are counted with other Rickettsioses, which does not allow us to count the actual cases of Q fever, generating confusion about its status as a compulsory notification disease.
In most serological surveys conducted since 1953, people and animals sensitized by the bacterial species were studied, confirming its circulation in some states of the country, such as Rio de Janeiro, Sao Paulo, Minas Gerais, Ceara, Alagoas, Goias, Rio Grande do Sul, Mato Grosso do Sul, Pernambuco, Santa Catarina and Piaui1616. Mioni MS, Costa FB, Ribeiro BL, Teixeira WS, Pelicia VC, Labruna MB, et al. Coxiella burnetii in slaughterhouses in Brazil: a public health concern. PLoS One. 2020;15:e0241246.
17. Ferreira MS, Guterres A, Rozental T, Novaes RL, Vilar EM, Oliveira RC, et al. Coxiella and Bartonella spp. in bats (Chiroptera) captured in the Brazilian Atlantic Forest biome. BMC Vet Res. 2018;14:279.
18. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392.
19. Guimarães MF, Araujo AC, Freire DP, Machado DM, Martins NN, Moraes-Filho J, et al. Investigação sorológica de Rickettsia rickettsii e Coxiella burnetii em caprinos e ovinos no entorno do Parque Nacional da Serra das Confusões, Piauí. Pesqui Vet Bras. 2017;37:555-60.
20. Lemos ER, Rozental T, Siqueira BN, Pessoa Júnior AA, Joaquim TE, Silva RG, et al. Q fever in military firefighters during cadet training in Brazil. Am J Trop Med Hyg. 2018;99:303-5.
21. Mares-Guia MA, Rozental T, Guterres A, Ferreira MS, Botticini RG, Terra AK, et al. Molecular identification of Q fever in patients with a suspected diagnosis of dengue in Brazil in 2013-2014. Am J Trop Med Hyg. 2016;94:1090-4.
22. Meurer IR, Silva MR, Silva MV, Duré AI, Adelino TE, Costa AV, et al. Soroprevalência de anticorpos anti-Coxiella burnetii em pacientes com suspeita de dengue no Estado de Minas Gerais, Brasil. Braz J Infect Dis, 2021;25 Suppl 1:169-70.
23. Mioni MR, Ribeiro BL, Peres MG, Teixeira WS, Pelícia VC, Motta RG, et al. Real-time quantitative PCR-based detection of Coxiella burnetii in unpasteurized cow’s milk sold for human consumption. Zoonoses Public Health. 2019;66:695-700.
24. Mioni MS, Sidi-Boumedine K, Dalanezi FM, Joaquim SF, Denadai R, Teixeira WS, et al. New genotypes of Coxiella burnetii circulating in Brazil and Argentina. Pathogens. 2019;9:30.
25. Rozental T, Ferreira MS, Guterres A, Mares-Guia MA, Teixeira BR, Gonçalves J, et al. Zoonotic pathogens in Atlantic Forest wild rodents in Brazil: Bartonella and Coxiella infections. Acta Trop. 2017;168:64-73.-2626. Souza EA, Castro EM, Oliveira GM, Azevedo SS, Peixoto RM, Labruna MB, et al. Serological diagnosis and risk factors for Coxiella burnetii in goats and sheep in a semiarid region of Northeastern Brazil. Braz J Vet Parasitol. 2018;27:514-20.. Q fever has an occupational character, with many of its articles demonstrating the occurrence of this disease in butchers, veterinarians, farmers, and other professionals who have contact with farm animals44. Brandão H, Vale LA, Christovão, DA. Investigações sobre a febre Q em São Paulo: estudo sorológico em operários de um frigorífico. Arq Fac Hig Saude Publica Univ Sao Paulo. 1953;7:127-31.,1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30.,2020. Lemos ER, Rozental T, Siqueira BN, Pessoa Júnior AA, Joaquim TE, Silva RG, et al. Q fever in military firefighters during cadet training in Brazil. Am J Trop Med Hyg. 2018;99:303-5.,2727. Borges DR. Evidência sorológica de febre Q em carneiros do Brasil. Rev Paul Med. 1962;60:424-32.
28. Ribeiro-Netto A, Nikitin T, Ribeiro IF. Estudo sôbre febre Q em São Paulo: III. Prevalência em ordenhadores e tratadores de bovinos. Rev Inst Med Trop Sao Paulo. 1964;6:255-7.
29. Riemann HP, Brant PC, Behymer DE, Franti CE. Toxoplasma gondii and Coxiella burneti antibodies among Brazilian slaughterhouse employees. Am J Epidemiol. 1975;102:386-93.
30. Travassos J, Ubatuba A, Silva NP, Mello MT. Febre Q no Rio de Janeiro. Cien Cult. 1954;6:199-200.-3131. Valle LA, Brandão H, Christóvão DA, D’Apice M. Investigações sobre a febre Q em São Paulo: II - Estudo em tratadores de gado e em bovinos. Arq Fac Hig Saude Publica Univ Sao Paulo. 1955;9:167-80..
C. burnetii is an opportunistic bacterium that can infect many animal species, such as cattle, sheep, goats, dogs, cats, birds, small rodents, and arthropods11. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518-53.. Although C. burnetii infects a variety of animals, small ruminants are known to be the major disposers of the bacteria in the environment through abortions and parturition and are thus the main hosts of the agent1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30.. Goats and sheep are responsible for disease outbreaks, setting them alongside cattle as the primary sources of infection for humans and the animal species of greatest importance in the chain of transmission of Q fever3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309..
Airborne route: infected mammalian females are very important for the chain of transmission because the microorganism has tropism for the placenta, and at the time of delivery, there is aerosolization, which often results in outbreaks on the property3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. The bacterium is capable of traveling up to 30 km with the wind through aerosolization1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14.. This is the main transmission route of C. burnetii and may be one of the hypotheses for the occurrence of Q fever cases in urban populations with no history of travel to rural areas, who do not consume raw milk or have no contact with infected animals, abortion remains or fecal material (which would be the other possible transmission routes)1818. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392..
Arthropods: arthropods are of little epidemiological importance to humans, as they have a small potential of transmitting the bacteria11. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518-53.. Transmission to humans would only be possible with very young, small ticks that are practically imperceptible to the human eye and are and can attach to the surface of an individual for a prolonged period3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. However, they are relevant amplifiers of bacteria for animal infection due to factors such as attack rate, host preference and contact time3333. Duron O, Sidi-Boumedine K, Rousset E, Moutailler S, Jourdain E. The importance of ticks in Q fever transmission: what has (and has not) been demonstrated? Trends Parasitol. 2015;31:536-52.. In Brazil, Amblyomma cajennense, Rhipicephalus sanguineus and Dermacentor nitens are the most important, present in all regions of Brazil, both in rural and urban areas, and can affect ruminants and companion animals11. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518-53.,3333. Duron O, Sidi-Boumedine K, Rousset E, Moutailler S, Jourdain E. The importance of ticks in Q fever transmission: what has (and has not) been demonstrated? Trends Parasitol. 2015;31:536-52..
Ruminants: contact with ruminants is a significant risk factor associated with C. burnetii infections, especially close to birth or during miscarriage, when a large amount of bacteria is released into the environment and the possibility of infective aerosol generation is increased, which may affect the rural workers, residents, and other animals that come into contact with placental remains1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14.. Moreover, the spore-like forms from infected animals are released into the environment and persist in wool, feeders, water troughs, stables, utensils, equipment, pasture, and feces, resulting in the biological contamination of the environment with significant risk to human health3434. Eldin C, Mélenotte C, Mediannikov O, Ghigo E, Million M, Edouard S, et al. From Q fever to Coxiella burnetii infection: a paradigm change. Clin Microbiol Rev. 2017;30:115-90..
Products of animal origin: due to the tropism of the bacteria by the mammary gland, the consumption of raw unpasteurized milk and its derivatives, which is common in Brazil, appears to be a possible transmission route of the agent3535. Astobiza I, Barandika JF, Hurtado A, Juste RA, García-Pérez AL. Kinetics of Coxiella burnetii excretion in a commercial dairy sheep flock after treatment with oxytetracycline. Vet J. 2010;184:172–5..
Wild animals: except for people who are used to ecotourism or populations that live in forest areas, such as indigenous populations, C. burnetii infection does not present a risk to humans3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. Nevertheless, one should consider the epidemiological possibilities with the advent of today’s environmental conflicts and the importance of wild animals in keeping the agents in circulation and serving as a source of infection for farm animals3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. Furthermore, depending on the epidemiological scenario, wild animals can serve as reservoirs for human disease and represent a public health risk. In Brazil, C. burnetii has been detected in bats, rodents and cervids1717. Ferreira MS, Guterres A, Rozental T, Novaes RL, Vilar EM, Oliveira RC, et al. Coxiella and Bartonella spp. in bats (Chiroptera) captured in the Brazilian Atlantic Forest biome. BMC Vet Res. 2018;14:279.,2525. Rozental T, Ferreira MS, Guterres A, Mares-Guia MA, Teixeira BR, Gonçalves J, et al. Zoonotic pathogens in Atlantic Forest wild rodents in Brazil: Bartonella and Coxiella infections. Acta Trop. 2017;168:64-73..
Person-to-person transmission: although rare, cases have been reported in hospital-acquired infections, congenital infections, blood transfusions, sexual intercourse, and contact with an infected woman in labor3636. Miceli MH, Veryser AK, Anderson AD, Hofinger D, Lee SA, Tancik C. A case of person-to-person transmission of Q fever from an active duty serviceman to his spouse. Vector Borne Zoonotic Dis. 2010;10:539-41.,3737. Milazzo A, Hall R, Storm PA, Harris RJ, Winslow W, Marmion BP. Sexually transmitted Q fever. Clin Infect Dis. 2001;33:399-402..
Brazil’s current situation
There is a lack of information regarding the disease’s epidemiology in Brazil, with only a few focal prevalence studies and case reports that do not represent the actual situation in the country1818. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392..
Animal models
A study conducted in 2018, in Sao Paulo State, identified a prevalence of 23.8% of infected bovine slaughterhouse animals1616. Mioni MS, Costa FB, Ribeiro BL, Teixeira WS, Pelicia VC, Labruna MB, et al. Coxiella burnetii in slaughterhouses in Brazil: a public health concern. PLoS One. 2020;15:e0241246.. The samples were tested by indirect immunofluorescence (IFA), and those that reached titers equal to or greater than 64 were considered positive. The antigen used for the technique was from an Argentinean At12 strain isolated from Amblyomma tigrinum. This work highlights the risk to public and animal health due to the possibility of dissemination of the agent in the environment that can lead to outbreaks of abortions in production animals and human illness among producers and rural workers, as well as for final consumers of animal products1616. Mioni MS, Costa FB, Ribeiro BL, Teixeira WS, Pelicia VC, Labruna MB, et al. Coxiella burnetii in slaughterhouses in Brazil: a public health concern. PLoS One. 2020;15:e0241246.. In addition, the same authors obtained genotyping results that point to the presence of diverse strains already reported in the world literature, further highlighting the need for molecular epidemiology studies and virulence studies of the national strains2424. Mioni MS, Sidi-Boumedine K, Dalanezi FM, Joaquim SF, Denadai R, Teixeira WS, et al. New genotypes of Coxiella burnetii circulating in Brazil and Argentina. Pathogens. 2019;9:30.. The report of a unique genotype in Argentina further highlights the presence of regional strains of the bacterium in Latin America2424. Mioni MS, Sidi-Boumedine K, Dalanezi FM, Joaquim SF, Denadai R, Teixeira WS, et al. New genotypes of Coxiella burnetii circulating in Brazil and Argentina. Pathogens. 2019;9:30..
A study conducted in 2018, in Pernambuco State, found seroprevalences of 2.1% and 2.2% in goats and sheep, respectively. The prevalence of this study was determined by indirect immunofluorescence (IFA) using the same At12 strain described above and considering the animals with titers equal to or greater than 64 as positive3131. Valle LA, Brandão H, Christóvão DA, D’Apice M. Investigações sobre a febre Q em São Paulo: II - Estudo em tratadores de gado e em bovinos. Arq Fac Hig Saude Publica Univ Sao Paulo. 1955;9:167-80.. By molecular methods, C. burnetii was found in raw milk and artisan cheeses commercialized in Goias State and Minas Gerais State, highlighting the public health risk of consuming dairy products2323. Mioni MR, Ribeiro BL, Peres MG, Teixeira WS, Pelícia VC, Motta RG, et al. Real-time quantitative PCR-based detection of Coxiella burnetii in unpasteurized cow’s milk sold for human consumption. Zoonoses Public Health. 2019;66:695-700.,3838. Rozental T, Faria LS, Forneas D, Guterres A, Ribeiro JB, Araújo FR, et al. First molecular detection of Coxiella burnetii in Brazilian artisanal cheese: a neglected food safety hazard in ready-to-eat raw-milk product. Braz J Infect Dis. 2020;24:208-12..
In addition to ruminants, studies have indicated the possibility of the disease occurring in wild reservoirs. In 2016, the etiologic agent was detected among military firefighters of Ribeirao das Lajes city, Rio de Janeiro State, who had contact with goats and capybaras2020. Lemos ER, Rozental T, Siqueira BN, Pessoa Júnior AA, Joaquim TE, Silva RG, et al. Q fever in military firefighters during cadet training in Brazil. Am J Trop Med Hyg. 2018;99:303-5.. In 2018, the same group confirmed the presence of C. burnetii in bats and wild rodents in Brazil’s Southern states, demonstrating the variety of reservoir possibilities and the need for epidemiological surveys to better characterize the primary reservoirs for human diseases and subsequent implementation of control measures1717. Ferreira MS, Guterres A, Rozental T, Novaes RL, Vilar EM, Oliveira RC, et al. Coxiella and Bartonella spp. in bats (Chiroptera) captured in the Brazilian Atlantic Forest biome. BMC Vet Res. 2018;14:279.,2525. Rozental T, Ferreira MS, Guterres A, Mares-Guia MA, Teixeira BR, Gonçalves J, et al. Zoonotic pathogens in Atlantic Forest wild rodents in Brazil: Bartonella and Coxiella infections. Acta Trop. 2017;168:64-73..
Human models
Prevalence studies of human Q fever in Brazil have only been conducted in the Southeastern states, with prevalence ranging from 1.63% to 62.5%, and high rates observed in occupational groups such as slaughterhouse workers and veterinary students. In Sao Paulo city, two surveys from the 1950s investigated C. burnetii in asymptomatic dairy farm workers on dairy farms and slaughterhouse workers, revealing positivity rates of 7% and 1.63%, respectively, using the complement fixation test as the serological method44. Brandão H, Vale LA, Christovão, DA. Investigações sobre a febre Q em São Paulo: estudo sorológico em operários de um frigorífico. Arq Fac Hig Saude Publica Univ Sao Paulo. 1953;7:127-31.,3131. Valle LA, Brandão H, Christóvão DA, D’Apice M. Investigações sobre a febre Q em São Paulo: II - Estudo em tratadores de gado e em bovinos. Arq Fac Hig Saude Publica Univ Sao Paulo. 1955;9:167-80..
Over time, other studies with small sample sizes and diagnostic techniques still under evaluation were performed, such as a study carried out in the Vale do Paraiba region with dairy farm workers and another one carried out in Belo Horizonte city with slaughterhouse workers whose main focus was the study of toxoplasmosis, which showed, for the first time, a high prevalence among the human population tested in the country2828. Ribeiro-Netto A, Nikitin T, Ribeiro IF. Estudo sôbre febre Q em São Paulo: III. Prevalência em ordenhadores e tratadores de bovinos. Rev Inst Med Trop Sao Paulo. 1964;6:255-7.,2929. Riemann HP, Brant PC, Behymer DE, Franti CE. Toxoplasma gondii and Coxiella burneti antibodies among Brazilian slaughterhouse employees. Am J Epidemiol. 1975;102:386-93..
Over the years, and with the improvement of serological diagnosis techniques, between 2005 and 2009, a group of researchers from Juiz de Fora city and Sao Paulo city investigated the occurrence of Q fever among healthy and unhealthy individuals, with the highest seropositivity ever found of 62.5% in febrile patients with signs of pneumonia attended in health care units in Minas Gerais State, and the first diagnosis of endocarditis by C. burnetii was described3939. Costa PS, Brigatte ME, Greco DB. Antibodies to Rickettsia rickettsii, Rickettsia typhi, Coxiella burnetii, Bartonella henselae, Bartonella quintana and Ehrlichia chaffeensis among healthy population in Minas Gerais, Brazil. Mem Inst Oswaldo Cruz. 2005;100:853-9.
40. Costa PS, Brigatte ME, Greco DB. Questing one Brazilian query: reporting 16 cases of Q fever from Minas Gerais, Brazil. Rev Inst Med Trop Sao Paulo. 2006;48:5-9.-4141. Siciliano RF, Strabelli TM, Zeigler R, Rodrigues C, Castelli JB, Grinberg M, et al. Infective endocarditis due to Bartonella spp. and Coxiella burnetii: experience at a cardiology hospital in Sao Paulo, Brazil. Ann N Y Acad Sci. 2006;1078:215-22.. In 2008, C. burnetii endocarditis was described for the second time in Brazil, this time in Sao Felipe municipality, Bahia State, being the only case of the disease described in the state4242. Siciliano RF, Ribeiro HB, Furtado RH, Castelli JB, Sampaio RO, Santos FC, et al. Endocardite por Coxiella burnetii (febre Q): doença rara ou pouco diagnosticada? Relato de caso. Rev Soc Bras Med Trop. 2008;41:409-12.. Additionally, in 2009, a study group from Rio de Janeiro city conducted an important and unprecedented prevalence study in the HIV-positive population in the country, starting a series of investigations in the state4343. Lamas CC, Rozental T, Bóia MN, Favacho AR, Kirsten AH, Silva AP, et al. Seroprevalence of Coxiella burnetii antibodies in human immunodeficiency virus-positive patients in Jacarepaguá, Rio de Janeiro, Brazil. Clin Microbiol Infect. 2009;15 Suppl 2:140-1..
In recent years, some studies have been conducted with symptomatic populations. These populations had clinical signs of dengue, and without laboratory test confirmation, they were diagnosed with Q fever. Mares-Guia et al.2121. Mares-Guia MA, Rozental T, Guterres A, Ferreira MS, Botticini RG, Terra AK, et al. Molecular identification of Q fever in patients with a suspected diagnosis of dengue in Brazil in 2013-2014. Am J Trop Med Hyg. 2016;94:1090-4. confirmed the presence of 10% seropositive individuals in Itaborai municipality, Rio de Janeiro State. Meurer et al.2222. Meurer IR, Silva MR, Silva MV, Duré AI, Adelino TE, Costa AV, et al. Soroprevalência de anticorpos anti-Coxiella burnetii em pacientes com suspeita de dengue no Estado de Minas Gerais, Brasil. Braz J Infect Dis, 2021;25 Suppl 1:169-70. confirmed the presence of 5.3% seropositivity in Minas Gerais State. França et al.1818. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392. confirmed the presence of 21.4% seropositive patients in Sao Paulo State. These studies corroborate the need for more studies in the Southeastern region and at a national level and the possibility of Q fever as a differential diagnosis for dengue. The study carried out in Sao Paulo State, the most populous state in the country, evaluated a very expressive sample of febrile patients and made it possible to analyze not only the prevalence of the disease, but also the profile of these positive-testing patients concerning age, duration of symptoms, place of residence, antibody titers and gender1818. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392..
In addition to the serological investigations, a study from 2015 revealed the agent’s presence by molecular methods in heart valves from endocardial patients with negative cultures4444. Siciliano RF, Castelli JB, Mansur AJ, Santos, FP, Colombo S, Nascimento EM, et al. Bartonella spp. and Coxiella burnetii associated with community acquired, culture-negative endocarditis, Brazil. Emerg Infect Dis. 2015;21:1429-32.. These data point to the importance of Q fever in persistent infection episodes and the possibility of cardiac patients without a proper diagnosis in the national territory4444. Siciliano RF, Castelli JB, Mansur AJ, Santos, FP, Colombo S, Nascimento EM, et al. Bartonella spp. and Coxiella burnetii associated with community acquired, culture-negative endocarditis, Brazil. Emerg Infect Dis. 2015;21:1429-32.. This study, and others, can be seen in Table 2, as well as some of their details.
Due to the asymptomatic character at the onset of infection and symptoms similar to those of common influenza, it is estimated that the prevalence is much higher in Brazil, a tropical and developing country with several wild and farm animal species that act as reservoirs for C. burnetii1818. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392.. Q fever is underdiagnosed and not well known among doctors and veterinarians, with a small number of centers for laboratory diagnosis and few studies concerning the identification and characterization of C. burnetii in humans, animals and the environment1818. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392.. To date, 15 studies have reported direct or indirect evidence of Q fever cases in humans (Figure 1).
Pathogeny
As Toman et al.1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012. described, C. burnetii has particular mechanisms that give it versatility and the ability to survive and replicate in different hosts. These mechanisms are modulated by effector proteins released by a type IVB secretion system with unique functions and features to evade the immune system1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. Among these mechanisms, we can highlight:
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Action against the activation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), the main mechanisms of innate immunity capable of fighting intracellular C. burnetii;
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Growth restricted to a low oxygen environment;
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Release of cations and DNA repair enzymes, allowing the genome to be as small as possible to survive in the environment;
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Bacterial LPS can antagonize TLR4 receptors and limit immune activity in several ways, including penetrating cells through the interaction between the O-chain and lipid rafts;
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Manipulation of signaling mechanisms of infected host cell, preventing its action against C. burnetii;
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Use of cellular kinases and cytoplasmic lipids for the biogenesis of the parasitophorous vacuole (PV) for replication. C. burnetii resists the degradative functions of the vacuole and exploits the acidic pH for metabolic activities;
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Anti-apoptosis activity with the secretion of Bcl-2 protein;
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Autophagic cell recycling activity by the secretion of the Beclin-1 protein;
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Tropism by adipose and placental tissues, strategic for escaping immune surveillance and establishing replicative activity.
It is suggested that inhaled bacteria tend to generate pulmonary complications, while ingestion of contaminated raw milk tends to generate hepatopathies; however, this may also be related to the strain involved99. Waag DM. Coxiella burnetii: host and bacterial responses to infection. Vaccine. 2007;25:7288-95.. The acute disease occurs as a consequence of the genotype involved, while the bacterial persistence is linked to predisposing factors of the individual99. Waag DM. Coxiella burnetii: host and bacterial responses to infection. Vaccine. 2007;25:7288-95..
Clinical signs
C. burnetii is a highly infectious bacterium, and its virulence will depend on the genetic variant99. Waag DM. Coxiella burnetii: host and bacterial responses to infection. Vaccine. 2007;25:7288-95.. In 60% of cases, it is usually asymptomatic in humans, which makes it difficult to control the disease, removing with time the epidemiological link for association4545. Bossi P, van Loock F, Tegnell A, Gouvras G. Bichat clinical guidelines for bioterrorist agents. Euro Surveill. 2004;9:19-20..
Acute Q fever
Regarding symptoms, acute cases occur more frequently (35% to 39%), especially in situations of immunosuppression, although immunocompetent patients may express clinical signs of the disease4646. Harris RJ, Storm PA, Lloyd A, Arens M, Marmion BP. Long-term persistence of Coxiella burnetii in the host after primary Q fever. Epidemiol Infect. 2000;124:543-9.. The acute disease, in most cases, is similar to common cold, accompanied by fever, headache, myalgia and a cough, with some cases developing into pneumonia and hepatitis4646. Harris RJ, Storm PA, Lloyd A, Arens M, Marmion BP. Long-term persistence of Coxiella burnetii in the host after primary Q fever. Epidemiol Infect. 2000;124:543-9.. Complications during the acute phase can occur, with massive replication of C. burnetii in specific regions of the body and the development of atypical pneumonia, arthralgia, muscle lesions, encephalitis, lymphadenomegaly, hepatomegaly and splenomegaly4747. Fenollar F, Fournier PE, Carrieri MP, Habib G, Messana T, Raoult D. Risks factors and prevention of Q fever endocarditis. Clin Infect Dis. 2001;33:312-6..
Persistent Q fever
Innate immunity is extremely limited for combating Q fever, and the outcome of the infection depends on cellular immunity and its efficiency in stopping C. burnetii replication1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. Persistent infections, therefore, are more frequent in immunocompromised patients, pregnant women, or patients with preexisting diseases in the target organs of the bacteria, such as heart valve disease patients4848. Raoult D, Marrie T, Mege J. Natural history and pathophysiology of Q fever. Lancet Infect Dis. 2005;5:219-26.. Persistent infections are less frequent (1% to 5%) but can be detected for months to years. It is possible to notice this with the emergence of studies and reports involving endocarditis patients with anti-C. burnetii antibodies and negative cultures for other common bacteria1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14..
Endocarditis is the main chronic condition evident in patients who develop persistent Q fever1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14.. One patient in every hundred usually develops endocarditis 6 to 18 months after infection. The most affected group is people over 50 years of age1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14.,4444. Siciliano RF, Castelli JB, Mansur AJ, Santos, FP, Colombo S, Nascimento EM, et al. Bartonella spp. and Coxiella burnetii associated with community acquired, culture-negative endocarditis, Brazil. Emerg Infect Dis. 2015;21:1429-32.. Most of these patients already have a previous valvular disease, and this is therefore a factor that should always be considered when treating a patient suspected of having Q fever1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14.. It is worth emphasizing the importance of serologic follow-up of infected patients every 3 to 6 months, considering that endocarditis has been documented in infected patients for 20 years4444. Siciliano RF, Castelli JB, Mansur AJ, Santos, FP, Colombo S, Nascimento EM, et al. Bartonella spp. and Coxiella burnetii associated with community acquired, culture-negative endocarditis, Brazil. Emerg Infect Dis. 2015;21:1429-32.. Echocardiography is used for the diagnosis of infective endocarditis and is associated with high titers of Phase I antibodies (equal to or greater than 800), suggesting that its cause is C. burnetii11. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12:518-53.. Confirmation is only possible from the patient’s valve PCR after surgical procedure or death1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14.. Although there is no confirmation in the diagnostic routine, treatment should be instituted in the same way1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14..
Diagnosis
Diagnosis is based on established clinical-epidemiological and laboratory criteria. Laboratory diagnosis involves direct and indirect methods, depending on the sample type, the period in which it was collected, and the species of origin.
Direct diagnostic methods
Microbiological diagnosis:
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Bacterial isolation in cell culture: The material of choice for isolation will also depend on the clinical presentation of the patient; however, blood, plasma, cerebrospinal fluid, bone marrow, heart valves, aneurysms, vascular prostheses, liver biopsies, and placenta are usually suitable materials1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. Embryonic lung fibroblasts are most often used for culture because they are more susceptible to infection1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. Isolation of C. burnetii should only be performed in a biosafety level 3 laboratory because of its extreme infectivity1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012..
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Bacterial isolation by axenic media (ACCM2): The material of choice will depend on the patient’s clinical presentation, and this is a recent method under evaluation4949. Omsland A, Cockrell DC, Howe D, Fischer ER, Virtaneva K, Sturdevant DE, et al. Host cell-free growth of the Q fever bacterium Coxiella burnetii. Proc Natl Acad Sci U S A. 2009;106:4430-4.. It is a semisolid medium that supports robust growth of C. burnetii via colony formation on agarose plates4949. Omsland A, Cockrell DC, Howe D, Fischer ER, Virtaneva K, Sturdevant DE, et al. Host cell-free growth of the Q fever bacterium Coxiella burnetii. Proc Natl Acad Sci U S A. 2009;106:4430-4.. It has the advantage of overcoming the need for purification required for further molecular analysis of isolates and reducing animal use for isolating the bacteria1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. However, it has been reported that some genotypes (ST1–7/30, ST8, and ST9–10/27–28/30 groups) do not grow in this medium. All these strains have a QpRS plasmid. Hence, its use for primo isolation from clinical samples may not be indicated4949. Omsland A, Cockrell DC, Howe D, Fischer ER, Virtaneva K, Sturdevant DE, et al. Host cell-free growth of the Q fever bacterium Coxiella burnetii. Proc Natl Acad Sci U S A. 2009;106:4430-4..
Molecular diagnosis: the primary technique used by specialized laboratories, both for the acute and persistent phases, is real-time polymerase chain reaction (qPCR), where the target of the reaction is usually the IS1111 gene due to its high diagnostic sensitivity2323. Mioni MR, Ribeiro BL, Peres MG, Teixeira WS, Pelícia VC, Motta RG, et al. Real-time quantitative PCR-based detection of Coxiella burnetii in unpasteurized cow’s milk sold for human consumption. Zoonoses Public Health. 2019;66:695-700.. This method allows detection of the agent from serum, blood, cerebrospinal fluid, tissue and milk samples1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012.. Molecular diagnosis is the most sensitive method for detecting recent infections when serology cannot be used due to the absence of antibodies. However, after 17 days of infection, the DNA of C. burnetii becomes undetectable by the technique because as antibodies are produced, the bacteria stop circulating, limiting molecular diagnosis1212. Toman R, Heinzen RA, Samuel JE, Mege JL, editors. Coxiella burnetii: recent advances and new perspectives in research of the Q fever bacterium. Dordrecht: Springer; 2012..
Indirect diagnostic methods
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Serological diagnosis: laboratory confirmation of acute Q fever is defined by the presence of Anti-Phase II antibodies approximately 7 to 21 days post-infection when seroconversion occurs with IgG titers equal to or greater than 200 and IgM titers equal to or greater than 503232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. Persistent Q fever (formerly known as chronic Q fever) is defined by the presence of Anti-Phase I antibodies with IgG titers equal to or greater than 800, and when lower, this titer is considered the result of residual antibodies and not of a properly active infection3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309. (Table 1).
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Indirect Immunofluorescence Reaction (RIFI): the gold standard for diagnosing the disease in humans. Phase I and II strains of C. burnetii are used to perform the technique. The technique presents superior sensitivity and specificity compared to ELISA for IgM and IgG1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30.. Paired sample collections are preferred, with 2 to 3 weeks between collections, to establish a more effective diagnosis by comparing the increase of titers over a period of time. In summary, it is the method of choice for the clinical monitoring of infected patients1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30..
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Indirect Enzyme Immunoassay (i-ELISA): the gold standard for diagnosing the disease in animals has also been widely used to diagnose the disease in humans1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30.. Some commercial kits detect the different immunoglobulins produced against Phase I and Phase II1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30..
The serological method is the method of choice for analyzing human samples because it is sensitive, specific, inexpensive, fast, safe, and easy to perform3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. However, cross-reactions can occur with species of the genera Bartonella and Legionella, especially in persistent infections with the differential diagnosis of endocarditis and pneumonia1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30.. qPCR is essential for the early diagnosis of acute Q fever in serum samples, considering that when immune defenses are built up, the bacteria become undetectable. In Brazil, qPCR and RIFI are the methods used by national surveillance laboratories1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30.,3434. Eldin C, Mélenotte C, Mediannikov O, Ghigo E, Million M, Edouard S, et al. From Q fever to Coxiella burnetii infection: a paradigm change. Clin Microbiol Rev. 2017;30:115-90..
Treatment
Acute Q fever
Although most acute infections resolve spontaneously, antibiotic therapy significantly reduces the duration of symptomatic illness and the likelihood of persistent infection and should therefore be performed3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. Antibiotic therapy for Q fever treatment usually takes approximately 14 days, and patients should be monitored by laboratory tests to evaluate their recovery3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. The recommended drug for acute cases is doxycycline, 100 mg daily. The efficacy of other antimicrobials is still uncertain and requires further study1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30..
Persistent Q fever
The treatment for persistent Q fever requires a higher pharmacological dosage and a longer treatment regimen of doxycycline and hydroxychloroquine for 18 months3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. In this case, the association with hydroxychloroquine is essential because it can alkalinize C. burnetii VP and potentiate doxycycline’s activity3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. Although there is this indication, and studies show trials for this application, a recently published study does not recommend the use of hydroxychloroquine for the treatment of Q fever, stating that this is not an evidence-based clinical recommendation5050. Stahl JP, Varon E, Bru JP. Treatment of Coxiella burnetii endocarditis with hydroxychloroquine: is it evidence-based? Clinic Microbiol Infect. 2022;28:637-9.. To date, there are no published randomized trials evaluating the best protocol, and no ongoing trials are currently registered5050. Stahl JP, Varon E, Bru JP. Treatment of Coxiella burnetii endocarditis with hydroxychloroquine: is it evidence-based? Clinic Microbiol Infect. 2022;28:637-9..
In persistent infections, specific cases of focal lesions are observed, and the treatment should be better directed to address these situations4747. Fenollar F, Fournier PE, Carrieri MP, Habib G, Messana T, Raoult D. Risks factors and prevention of Q fever endocarditis. Clin Infect Dis. 2001;33:312-6.. Patients with endocarditis, for example, require surgical intervention as an adjunct4747. Fenollar F, Fournier PE, Carrieri MP, Habib G, Messana T, Raoult D. Risks factors and prevention of Q fever endocarditis. Clin Infect Dis. 2001;33:312-6.. Acknowledging the time it takes for seroconversion and the difficulty of a complementary diagnosis in the health care system, treatment should be instituted as soon as Q fever suspicion is assumed, and laboratory monitoring should be performed to confirm it1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30.. In contrast, persistent infections should not be treated without a definite diagnosis due to the complexity of the therapy1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30..
Specific treatments
Children and those allergic to doxycycline: rifampicin and cotrimoxazole are alternatives for those under eight years old or allergic to doxycycline3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309..
Endocarditis: the treatment of acute infection is very important to prevent the development of endovascular disease, even in patients with previous cardiac disease1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14.. As mentioned previously, there is a discussion about the association of hydroxychloroquine and doxycycline for the treatment of persistent Q fever, however, only treating with doxycycline, 200 mg daily, depending on the specificity of the patient, is currently the safest alternative for this condition1111. Tissot-DuPont H, Raoult D. Q fever. Infect Dis Clin North Am. 2008;22:505-14.. Associated with antibiotic therapy, the surgical procedure directed to the affected valves is necessary4747. Fenollar F, Fournier PE, Carrieri MP, Habib G, Messana T, Raoult D. Risks factors and prevention of Q fever endocarditis. Clin Infect Dis. 2001;33:312-6..
Nervous system infection: due to their ability to cross the blood-brain barrier, fluoroquinolones are recommended for patients with neurological signs3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309..
Pregnant women: pregnant women should undergo combination therapy with trimethoprim and sulfamethoxazole as soon as possible3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309.. In addition, a study confirmed that prolonged treatment of these women for more than five months could prevent complications during pregnancy3232. Angelakis E, Raoult D. Q fever. Vet Microbiol, 2010;140:297-309..
Prevention and control
There is a vaccine tested and licensed to protect workers at occupational risk in Australia, although there are still adverse reactions and an improvement project has been proposed5151. Long CM. Q fever vaccine development: current strategies and future considerations. Pathogens. 2021;10:1223.. However, in Brazil and the rest of the world, vaccinating humans has not yet been approved and requires further studies regarding its impact on these workers and a measure by national health agencies5252. Centers for Disease Control and Prevention. Q fever. [cited 2023 Apr 25]. Available from: http://www.cdc.gov/qfever/
http://www.cdc.gov/qfever/...
.
The control of the disease in humans is directly linked to the control of the disease in animals; therefore, the health evaluation and diagnosis of livestock through the surveillance of abortions, animal transit under intense sanitary control, and combating the consumption of uninspected food of animal origin are the main strategies to prevent and control the transmission of the disease1313. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, et al. Diagnosis and management of Q Fever - United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013;62:1-30.. Furthermore, for those at occupational risk, it is essential to use personal protective equipment when handling animals, especially abortion and birth products, take proper care to sanitize the animal facilities, and vaccination, which is not available in Brazil, before primary infection, which, although it does not protect against infection itself, can reduce the excretion of C. burnetii66. Damasceno IA, Guerra RC. Coxiella burnetii e a febre Q no Brasil, uma questão de saúde pública. Cien Saude Colet. 2018;23:4231-9..
Q fever surveillance covers the concept of One Health1818. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392.. It involves the protection of the general population, investigating and mapping the incidence of the disease, always associating outbreaks in animals with the possibility of outbreaks in humans, and identifying the possible environmental source of infection due to high environmental resistance1818. França DA, Mioni MS, Fornazari F, Duré AI, Silva MV, Possebon FS, et al. Seropositivity for Coxiella burnetii in suspected patients with dengue in São Paulo state, Brazil. PLoS Negl Trop Dis. 2022;16:e0010392..
CONCLUSION
The need to consider Q fever as an important airborne and foodborne disease in Brazil can ensure greater safety of milk and meat handling in dairy farms and slaughterhouses nationwide and expand surveillance of disease outbreaks on farms in affected states. Furthermore, with the recent findings of high prevalence in farm animals and humans, the zoonotic potential of C. burnetii needs to be considered, especially for those implementing measures to prevent and control Q fever outbreaks. Clinical and molecular studies involving the occurrence of Q fever in human patients with pneumonia (acute disease) and endocarditis (persistent disease) are needed to discover the impact that this infection has on populations in Brazil beyond fever and animal abortions. We strongly recommend the development of clinical studies in Brazil to observe how patients respond to the different proposed treatments and the real efficiency of hydroxychloroquine for the treatment of endocarditis. Comprehensive studies are also needed from the One Health perspective, verifying the presence of the bacteria in farm animals, people in contact with these animals, and the environment in which both are located, to have a greater perspective on the epidemiology of this disease and how it truly affects populations.
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» http://www.cdc.gov/qfever/
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FUNDING: DAF received financial support from National Council for Scientific and Technological Development (CNPq), grant Nº 155904/2019-1.
Publication Dates
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Publication in this collection
26 June 2023 -
Date of issue
2023
History
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Received
16 Jan 2023 -
Accepted
25 Apr 2023