Q FEVER. By Theresa Deike. Disease Etiologic Agent. Disease Transmission and Reservoirs

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1 Q FEVER By Theresa Deike Disease Etiologic Agent Q fever is a zoonosis disease caused by the gram-negative bacterium Coxiella burnetii. The causative microbe, C. burnetii, is an obligate parasitic coccobacillus that resides within the phagolysosome of infected eukaryotic cells of both livestock and humans. C. burnetii belongs to the phylum Proteobacteria, class Alphaproteobacteria, order Legionellales, family Coxiellaceae, and genus Coxiella (2.) Unlike other bacteria utilizing tick or mite vectors, C. burnetii is not a member of the family Rickettsiae (3. ) Unlike rickettsial agents, C. burnetii is highly resilient to extremes in conditions and is not transmitted through tick vectors when infecting humans (1,4.) It is this resilience to extremes and unique variants that make the bacterium so virulent (2,3.) These factors combined with the aerosolized spread of the bacterium in humans make this bacterium of great concern to the Pentagon due to the implications for bioterrosim (2,5.) Disease Transmission and Reservoirs While most mammals contract the disease via the bite of an infected tick or mite, humans are unable to be infected through a mite or tick vector (1,5). Instead, human infection occurs primarily through the inhalation of bacterium-containing dust containing particulates from animal feces, urine, and milk products from infected animals5. According to the CDC, the bacterium is highly virulent once inhaledrequiring fewer than ten individual C. burnetii bacterium to cause infection. In rare cases, the infection has been shown to occur through the ingestion of infected unpasteurized milk products and via sexual transmission (6.) The most common animal reservoirs for human infection are animals raised for use in the meat and textile industries such as sheep, cattle, and goats (5.) However, the disease has been known to spread through dust produced from other farm animals and birds as well (3.) As such, persons who work closely with these animals or animal products such as veterinarians, butchers, farmers, and laboratory workers, as well as persons who live in rural areas, are at highest risk of contracting Q Fever (1,3.) Characteristics Unique to C. burnetii is the presence of an endospore like phase that scientists believe may enhance its environmental resilience as compared to its distant relatives the Rickettsiae- the causative agents for Rocky Mountain Spotted Fever and Louse-borne Typhoid Fever (1,3). Research by Sandoz et al., showed that the endospore-like phase, small cell variant (SCV), has a unique cell envelope and a condensed nucleoid. These features were shown experimentally to allow the

2 bacterium to exist in stationary phase stasis for weeks outside of a host (4,7.) The study concluded that this adaptation of C. burnetii allows for the bacterium to efficiently infect hosts weeks after introduction into the air despite requiring host Endothelium cells for survival (4.) Once introduced in aerosol form to the host, the bacterium enters the lungs and infects the phagolysosomes of Kupffer cells and other macrophages (1,4.) Within the acidic environment of the phagolysosome metabolic activity substantially increases as the cell transitions from its SCV to large cell variant (LCV) phase (1,4,7. ) Genes related to cell division and virulence become activated on the bacterium s plasmid, and the cell divides within the phagolysosome spreading through the bloodstream to proliferate in the lungs, liver, bone marrow, and spleen (1,4,3.) As the bacterium causes minimal damage to the host cell, the bacterium is primarily protected from humoral antibodies making it more difficult for the immune system to mount an effective response (4,7.) Host-mediated pathogenic mechanisms are associated with many of the symptoms of Q Fever mainly due to the formation of T-lymphocytemediated granulomas (1,3.) Virulence Factors Despite its worldwide presence and high infectious potential, there is only one currently identified virulence factor. The structurally unique lipopolysaccharide, LPS, is found to differ between the stages of the infection of the bacterium (4,8.) While both the SCV and LCV forms have been found to be equally virulent upon initial infection, LCV after prolonged infection modifies its gene expression to become less virulent (4.) Such as the case with Chronic Q Fever, LCV alters the composition of their LPS by truncating the molecular weight and omitting crucial O- antigen sugars noted to cause increased virulence (4,8.) The high virulence levels associated with the SCV form, due in part to the O-antigen sugars and its environmental resilience make the bacterium of concern to the US Military (3.) As a result of the high virulence of the bacterium in its SCV form and the small number of particles required for infection, the Pentagon has concerns that the bacterium can readily weaponized (2,3.) As such, it is categorized as a Select Agent by the Centers for Disease Control and Prevention (5.) Diagnosis There exist two primary methods of diagnosis for Q fever, serum examination of IgG and IgM specific to C. burnetii, and the genetic analysis of patient samples-primarily lung tissue biopsies and serum (9.) According to Pradeep, Stephen, Ambroise, & Gunasekaran, while the primary standard for the diagnosis of Q Fever is Immunofluorescence Assays, IFA, several new lower cost alternatives have been developed utilizing Polymerase Chain Reaction, PCR. PCR tests for the presence of genetic sequence specific to the bacterium in tissues and serum whereas IFA uses fluorescent markers to test for the presence of antibodies against the bacterium in

3 serum4. While both tests are useful, IFA is considered the Gold Standard as it can detect the presence of the bacterium in the early stages of infection (9.) The use of PCR requires that the patient is in the more acute stages of the infection or a potentially invasive biopsy for proper diagnosis (4,9.) The distinction between infection stages is particularly essential with Q Fever as there exist two distinct infection states. While the infection is typically asymptomatic, when a patient begins to display symptoms they are categorized as one of two categories- Acute and Chronic Q Fever (3.) Acute Q Fever is diagnosed by the development of antibodies against primarily LCV C. burnetii (2.) When in the early stages of the disease, IFA is the only diagnostic tool (4,9.) Chronic Q Fever is primarily diagnosed via IFA with confirmation from PCR on a biopsy (4,9.) When in the advanced form of Chronic Q Fever, PCR from serum samples is sufficient for diagnosis (4,9.) PCR has proven to be one of the best tools for the treatment of Chronic Q Fever, aiding doctors in identifying resistance and susceptibility to available antibiotics to custom tailor the most effective treatment following diagnosis (9.) Signs and Symptoms As discussed in the previous paragraph symptomatic C. burnetii, infection is divided into two categories-chronic and Acute. According to Anderson, Bijlmer, & Fournier of the CDC, Acute Q Fever accounts for over one-half of all Q Fever cases and has an incubation period of only 2-3 weeks before the rapid onset of symptoms. Though symptoms widely vary from patient to patient most cases present with pneumonia, fever, myalgia, fatigue, and cough (2,10.) Commonly headaches and associated photophobia are reported, which may result in an improper diagnosis of the condition in more impoverished regions of the world (3.) While most cases resolve on their own within ten days without antibiotic treatment, complications have been shown to arise in immunocompromised and elderly patients emphasizing the importance of early detection for these populations (3,9.) Chronic Q Fever, though only impacting 5% of those infected with C. burnetii, has been proven to cause severe damage to the heart and lungs resulting in a worse prognosis for patients than patients with Acute Q Fever (1,3.) With an incubation period up to a decade in length, Chronic Q Fever is associated with severely high serum levels of IgM, IgD, and IgA and has been shown to cause endocarditis and aortic aneurysms (9.) Other manifestations include osteomyelitis, pericarditis, Hepatitis, pseudotumors of the lung, chronic pulmonary fibrosis, and musculoskeletal infection (9.) Despite their differences, the two categories of Q Fever are interlinked. Once a patient has had either form of Q Fever they are at an increased risk for reinfection. The report by Anderson, Bijlmer, & Fournier states that 40% of patients with Acute Q Fever and valvulopathy or cardiovascular replacement values or implants develop Chronic Q Fever over their lifetime. Also, patients with Chronic Q Fever are at an

4 increased risk for the reemergence of symptoms following treatment and the increased risk of the development of Acute Q Fever upon reintroduction to the bacterium (3,9.) History and Current Outbreaks The CDC states that Q fever was first documented as a human disease in Australia in 1935 by Frank Macfarlane Burnet and Mavis Freeman who isolated the bacterium from sick meatpackers in Australia. Despite the prevalence of the disease over the past 83 years, experts do not agree on the origins of the Q in Q Fever. According to the CDC, the name stands for query as the cause of the disease was unknown when it was discovered. However, other scientists disagree stating that the Q comes from Queensland, Australia- the location of the meat packing plant where the disease was first identified (6). Since its discovery in the 1930 s Q Fever has been found worldwide in nearly every country except New Zealand (2.) Infection rates for both humans have found to be highest in areas where animal husbandry involving sheep and goats is a primary industry (2,9.) According to Outbreak News today, several outbreaks of Q Fever have been confirmed over the past few months in the Osorno Province of Chile with over 30 confirmed and 167 suspected cases. The CABI Invasive Species Compendium states that the disease is endemic throughout the Middle East and Africa, but poor reporting methods and incorrect diagnosis of humans and livestock makes accurate reporting difficult. Texas A&M Health Science Center reports that the disease has infected several hundred US troops stationed in Iraq and Afghanistan due to the dust produced by helicopters and military operations in areas with animal husbandry. While cases in the US are rare compared to other areas of the world, the CDC reports that the most common states of infection are California, Texas, Colorado, and Illinois. In 2014, the CDC states that there were 0.3 cases per million people in the state of Texas. The CABI Invasive Species Compendium statistics show that on average Texas has 3 to 10 unrelated cases over a calendar year with no major outbreaks in recent years. The last notable outbreak in the US occurred in 2014 in Oregon with four confirmed cases occurring over a 2-week period in a state that on average has 3-5 confirmed cases a year (11.) Treatment and Prevention While most cases of Acute Q Fever resolve without treatment, the current gold standard antibiotic against C. burnetii is doxycycline (4,5.) Doxycycline has proven to be an effective treatment for both Acute and Chronic Q Fever with antibiotic therapy occurring for two weeks for acute infections and combination doxycycline and hydroxychloroquine treatment over the course of several months for chronic infection (2,5.) While a vaccine against whole cell C. burnetii exists, it is not available in the US commercially despite its proven success in Australia and European

5 countries (5,2.) Current preventative measures in the US aim to reduce of environmental contamination to protect at-risk workers including the use of personal protective equipment such as N-95 fit-tested respirators and eye protection as well as the proper disposal of waste products of infected animals (3.) Whereas civilian prevention in the US is aimed at the protection of workers, due to its potential use as a bioweapon the US Military has invested heavily in a vaccination solution to protect US troops (12.) Though the current vaccination has shown to drop infection rates in Australia dramatically, the vaccination is designed to protect against accidental workplace exposure rather than an intentional attack utilizing the bacterium in a concentrated form as a bioweapon (2,12.) The Pentagon is working with Texas A&M to develop a more efficient vaccination with the aim of protecting soldiers against intentional infection (12.) Conclusion The causative microbe of Q Fever, C. burnetii, is a highly virulent gram-negative coccobacillus that resides within the phagolysosome of infected eukaryotic cells. Infecting both humans and animals, the disease has implications for both industries involving animal products and bioterrorism due to the SCV form of the bacterium that is readily aerosolized. While most infections are asymptomatic, the disease is broken into two categories- Acute and Chronic Q Fever. While Acute Q Fever usually resolves without the need for antibiotics, Chronic Q Fever commonly results in devastating consequences such as endocarditis and aortic aneurysms. As such, early diagnosis and proper treatment is key to patient prognosis. End Notes 1. Walker DH. Rickettsiae. In: Baron S, editor. (1996) Medical Microbiology. 4th edition. 2. CABI (2018). Invasive Species Compendium. Q Fever 3. Anderson, A., Bijlmer, H., & Fournier, P. (2013, March 23). Centers for Disease Control and Prevention. Diagnosis and Management of Q Fever United States, Sandoz KM, Popham DL, Beare PA, Sturdevant DE, Hansen B, et al. (2016) Transcriptional Profiling of Coxiella burnetii Reveals Extensive Cell Wall Remodeling in the Small Cell Variant Developmental Form. 5. CDC. (n.d.) Q Fever 6. Knight, J. P. (2014). Q fever. 7. Peterson JW. Bacterial Pathogenesis. In: Baron S, editor. (1998) Medical Microbiology. 4th edition. 8. Beare, P. A., Samuel, J. E., Howe, D., Virtaneva, K., Porcella, S. F., & Heinzen, R. A. (2006). Genetic Diversity of the Q Fever Agent, Coxiella burnetii, Assessed by Microarray-Based Whole-Genome Comparisons. 9. Keijmel S, Raijmakers R, Schoffelen T, Salet M, Bleeker-Rovers C. (2016, October ) A fatal case of disseminated chronic Q fever: a case report and brief

6 review of the literature. 10. PRADEEP J, STEPHEN S, AMBROISE S, GUNASEKARAN D. (2017, September) Diagnosis of Acute Q Fever by Detection of Coxiella burnetii DNA in Real Time PCR, Employing a Commercial Genesig Easy Kit. 11. Outbreak News Today. (2018). 12. Texas A&M Health Science Center (2015). ARMING OUR TROOPS: TEXAS A&M ON FRONT LINES OF Q FEVER VACCINE References Anderson, A., Bijlmer, H., & Fournier, P. (2013, March 23). Centers for Disease Control and Prevention. Diagnosis and Management of Q Fever United States, Retrieved February 20, 2018, from w Beare, P. A., Samuel, J. E., Howe, D., Virtaneva, K., Porcella, S. F., & Heinzen, R. A. (2006). Genetic Diversity of the Q Fever Agent, Coxiella burnetii, Assessed by Microarray- Based Whole-Genome Comparisons. Journal of Bacteriology, 188(7), Retrieved February 22, 2018 from CABI (2018). Invasive Species Compendium. Q Fever Wallingford, UK: CAB International. Retrieved February 18, 2018 from: CDC. (n.d.) Q Fever. Retrieved February 23, 2018, from Center for Disease Control and Prevention website: Keijmel S, Raijmakers R, Schoffelen T, Salet M, Bleeker-Rovers C. (2016, October ) A fatal case of disseminated chronic Q fever: a case report and brief review of the literature. Infection. 44(5): Ipswich, MA. Retrieved February 20, 2018, from cc.edu/l ogin.aspx?direct=true&db=ccm&an= &site=eds-live&scope=site Knight, J. P. (2014). Q fever. Salem Press Encyclopedia Of Health, Retrieved February 23, 2018, from: cc.edu/l ogin.aspx?direct=true&db=ers&an= &site=eds-live&scope=site Outbreak News Today Retrieved February 21, 2018: Peterson JW. Bacterial Pathogenesis. In: Baron S, editor. (1998) Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; Chapter 7. Retrieved February 23, 2018, from:

7 PRADEEP J, STEPHEN S, AMBROISE S, GUNASEKARAN D. (2017, September) Diagnosis of Acute Q Fever by Detection of Coxiella burnetii DNA in Real Time PCR, Employing a Commercial Genesig Easy Kit. Journal Of Clinical & Diagnostic Research 11(9): Retrieved February 20, 2018, from: cc.edu/l ogin.aspx?direct=true&db=a9h&an= &site=eds-live&scope=site Sandoz KM, Popham DL, Beare PA, Sturdevant DE, Hansen B, et al. (2016) Transcriptional Profiling of Coxiella burnetii Reveals Extensive Cell Wall Remodeling in the Small Cell 12 Variant Developmental Form. PLOS ONE 11(2): e Retrieved February 23, 2018: Texas A&M Health Science Center (2015). ARMING OUR TROOPS: TEXAS A&M ON FRONT LINES OF Q FEVER VACCINE. Retrieved February 20, 2018: vaccine/ Walker DH. Rickettsiae. In: Baron S, editor. (1996) Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; Chapter 38. Retrieved February 19, 2018:

Q Fever What men and women on the land need to know

Q Fever What men and women on the land need to know Dr. Stephen Graves Director, Australian Rickettsial Reference Laboratory Director, Division of Microbiology, Pathology North (Hunter) NSW Health Pathology,