Continuing Education Activity

Q fever is a zoonotic febrile disease affecting workers involved in farming livestock. It is an underreported disease with lesser recognition. This activity will help in understanding its causes, epidemiology, evaluation, and management of the condition by an interprofessional team.

Objectives:

• Identify the etiology of Q fever.
• Outline the appropriate evaluation of Q fever.
• Review the management options available for Q fever.
• Summarize interprofessional team strategies for improving care coordination and communication to advance Q fever diagnosis and improve outcomes.

Introduction

Q fever, an acute zoonotic febrile illness with a worldwide distribution, was discovered first in Australia in 1935 among meat workers. As a cause could not be identified, it was labeled “Q (query) fever.” This disease has occurred as outbreaks among livestock and farm workers handling ungulates. Clinical presentation is often a self-limited febrile illness, but severe manifestations can occur.[1][2]

Etiology

The microorganism causing Q fever is Coxiella burnetii, a gram-negative pleomorphic intracellular coccobacillus, phylogenetically related to Legionella. It can survive in the low pH of the host cell, which is also essential for its survival. It transforms into a spore-like form to survive in the rigid external environment for long periods. It undergoes two types of phase variation in response to its environmental changes. First is a virulent phase seen in lab animals and nature, associated with a delayed IgG response. The second is an avirulent phase (via alterations in capsular lipopolysaccharide) seen in culture media after repeated passage.[3][4]

Epidemiology

Q fever has been a notifiable disease since 1999 in the United States due to its potential as a biowarfare agent. It is an underreported and underrecognized disease. The male to female ratio is 3 to 1. The positive seroprevalence rate is 3.1% in Americans, more common in males, elderly, Hispanics, and impoverished individuals. Soft ticks and other arthropods harbor Coxiella and infect domestic and wild animals via bites or contaminating host skin with their excreta. Common reservoirs are domestic cattle, sheep, and goats, followed by horses, dogs, swine, camels, pigeons, ducks, geese, and turkeys. Wild birds, squirrels, mice, rats, cats, and rabbits can also serve as reservoirs. Although Q fever can occur at any time of the year, most cases occur in the spring and early summer months (April and May), which is the birthing season for cattle, sheep, and goats.

Urine, feces, milk, and placenta of infected animals contain a high concentration of Coxiella; hence workers handling contaminated laundry, consuming contaminated raw milk, who have exposure to the placenta of infected animals, live cell therapy with processed animal fetal cells are all sources of infection. Thus, it is an occupational disease involving workers with direct contact with infected animals, e.g., farmers, veterinarians, and slaughterhouse employees. Indirect exposure via tainted manure, straw, and dust from farm vehicles can also cause the disease via contaminated aerosols. Transmission to humans can also occur via blood transfusions, autopsies, during clinical care (delivery of infected pregnant women), infected hardware removal, and raw milk consumption.

Recent outbreaks in European countries were due to sheep and goat farming in urban areas, with increased attack rates in individuals living close to the sheep meadows. Urbanized goat farming was responsible for the recent 2007 to 2010 outbreaks in the Netherlands. HIV positive and other immunocompromised individuals are at a higher risk for severe symptoms.[2][5][6][7][8][9][10][11]

Pathophysiology

Inhalation of aerosols from an infected animal placenta at parturition, animal excreta, straw, or dust from a farm or farm vehicle is the suspected mode of transmission. The digestive route of transmission is another mode suspected in humans. The average incubation period is 20 days for acute Q fever. Inhaled Coxiella bacteria multiply in the lungs resulting in bacteremia, during which systemic manifestations occur. The virulence of the bacterial strain and the infecting dose determine illness severity, e.g., QPH1 plasmid containing strain is more virulent than QPRS plasmid strain. Based on the host's immune response, primary infection can be symptomatic (Q fever) or asymptomatic. Both can progress to endocarditis, depending on host characteristics. Children and women, including the pregnant, are more likely to remain asymptomatic. Despite remaining asymptomatic pregnant women and those with preexisting valvular heart disease, arterial aneurysms, or cancer are at higher risk for endocarditis. Endocarditis is associated with elevated IL-10 and anticardiolipin IgG antibodies. Chronic infection results in an aberrant immune response, a possible explanation for Q fever fatigue syndrome (QFFS).[12][13][14][15]

History and Physical

The clinical presentation varies based on age, underlying immune status, and geography. Acute Q fever is more common and is a systemic illness, whereas chronic Q fever is seen in less than 5% as a persistent, localized infection of a specific organ system.

Acute Q Fever

The most common presentation is that of a self-limiting acute febrile illness lasting for 1 to 2 weeks. Atypical or rapidly progressive pneumonia is the next common clinical presentation, especially in older adults. Severe headache, fatigue, chills, sweats, myalgia, pleuritic chest pain, nausea, vomiting, and diarrhea can all occur. A rash is commonly seen in children. Acute hepatitis is also a common presentation in younger adults and can complicate as cholestatic jaundice or acalculous cholecystitis. Aseptic meningitis or encephalitis have also been reported along with neurological complications such as cerebellar dysfunction, cranial nerve palsies, extrapyramidal disease, and demyelinating polyradiculoneuritis. Hematological involvement results in hemolytic anemia and histiocytic hemophagocytosis. Infection during the first trimester of pregnancy carries a high risk of abortion. QFFS is seen in 20%, characterized by arthralgia, myalgia, fatigue, headaches, blurry vision, intermittent diaphoresis, muscle fasciculation, and tender lymphadenopathy

Chronic Q Fever

Infective endocarditis is the most common manifestation, followed by infection of the vascular prosthesis and existing aneurysms, pseudotumor of the lung, granulomatous hepatitis, and rarely, osteomyelitis or interstitial pulmonary fibrosis. Preexisting abnormalities in native valves and prosthetic valves predispose to infection. It is typically culture-negative endocarditis and is included as one of the typical organisms in the modified Duke criteria. It is also associated with an increased risk for lymphoma. Residual neurological impairment includes weakness, recurrent meningismus, blurry vision, sensory loss, and paraesthesias.[6][16][17][18]

Evaluation

In acute Q fever, white cell count can be normal or elevated; the platelet count can be elevated or decreased. A frequent finding is an elevation in liver enzymes, while serum bilirubin can be normal. CSF reveals mononuclear pleocytosis with elevated protein levels. Chest X-ray reveals opacities that are multiple, rounded, can be segmental or nonsegmental, or pleural-based, along with hilar adenopathy. An echocardiogram may reveal vegetations, but often in only half of the cases of chronic Q fever. Diagnosis is confirmed by serology or PCR.

Tissue samples obtained from Q fever patients should be handled under biosafety level 3 for culture as they are highly infectious. The serological test of choice to diagnose both acute and chronic Q fever is an indirect immunofluorescent test. In this test, two different IgG antibodies are detected: Anti phase I IgG antibody and anti-phase II IgG antibody. Seroconversion typically occurs in the second week. In acute Q fever, anti-phase II IgG antibody is higher (typically >1 in 128) than anti-phase I IgG antibody, and a fourfold rise in anti-phase II titers between acute and convalescent samples is diagnostic of acute Q fever. A positive blood culture, PCR, and or anti-phase I IgG antibody titer ≥ 1:800 (>1:1024 in the U.S.) is diagnostic of chronic Q fever (endocarditis).[19][20][21][22]

Treatment / Management

The best treatment for acute Q fever is doxycycline 100 mg orally twice a day for 14 days. In cases of resistance or intolerance to doxycycline, trimethoprim-sulfamethoxazole and moxifloxacin are valid options. Defervescence is quicker with doxycycline, and both doxycycline and moxifloxacin reduce both the severity and duration of illness. In pregnancy, acute non-life-threatening Q fever should be treated with trimethoprim-sulfamethoxazole 160 mg to 800 mg twice daily from diagnosis till 32 weeks of pregnancy (high risk of hyperbilirubinemia in the last eight weeks), despite being a pregnancy category C drug because the risk of untreated Q fever (stillbirth or miscarriage) is higher for the fetus than the adverse effects of trimethoprim-sulfamethoxazole (intra-uterine growth retardation and premature delivery). Informed decision making should guide therapy, and for life-threatening infection or reaction to trimethoprim-sulfamethoxazole, doxycycline should be used. Serologic follow up is essential at 3, 6, 12, 18, and 24 months post-delivery. Future pregnancies will require resumption of serological monitoring, and treatment with trimethoprim-sulfamethoxazole is necessary with a four-fold rise in titers.

Chronic Q fever that occurs during pregnancy is treated with doxycycline 100 mg twice daily and hydroxychloroquine 200 mg three times daily for a year post-delivery. For Q fever endocarditis, the therapeutic regimen includes doxycycline and hydroxychloroquine, given for 18 months in native valve endocarditis and 24 months for prosthetic valve endocarditis. A fourfold decrease in IgG antibody levels implies treatment completion. Hydroxychloroquine enhances the antibacterial action of doxycycline as it increases the pH of the phagolysosome. Ciprofloxacin or rifampin can substitute hydroxychloroquine in cases of intolerance or contraindication. Valve surgery is a must in prosthetic valve involvement. Antibiotic treatment is not effective for QFFS.[23][24][25][26]

Differential Diagnosis

Patients with acute viral infections such as Epstein Barr virus, cytomegalovirus, influenza, hepatitis A, B, or C virus, have similar presenting complaints such as febrile illness, hepatitis, and myalgia. Serological tests and PCR assays used to identify these infections. Atypical pneumonia caused by Legionella and Mycoplasma needs to be considered. They can be ruled out by the detection of urine antigen or serum antibody titers. Tick-borne illnesses such as Lyme disease, relapsing fever, and Rocky Mountain spotted fever manifest with fever headache with or without a rash. Anaplasmosis and ehrlichiosis present with fever, headache, and hepatitis with a lesser incidence of rash. Tick-borne diseases are detected via PCR and/or serology. Zoonotic diseases such as brucellosis and leptospirosis can manifest as an acute flu-like illness with a history of exposure to animals or animal products.

Prognosis

Acute Q fever has an excellent prognosis when promptly diagnosed and treated. Patients with known valvular heart disease and pregnant females with acute Q fever are at risk of developing endocarditis. Monitoring serology at frequent intervals and an echocardiogram for elevated serologic titers is recommended. Q fever treatment in pregnancy often results in better outcomes. For endocarditis, treatment outcomes are better with dual therapy than monotherapy.

Complications

Acute Q fever can result in fatal interstitial pneumonia, myopericarditis, aseptic meningitis, encephalitis, and cholecystitis. Immunocompromised patients are at higher risk of developing complications. Chronic Q fever can result in infection of the vascular prosthesis and prosthetic valve infections. Endocarditis, if not treated, can result in serious cardiac complications. Chronic persistence can result in Q fever fatigue syndrome, hemolytic anemia, and bone marrow necrosis. Pregnant females with Q fever, when not treated, have poor fetal outcomes, including abortion.

Deterrence and Patient Education

Consumption of pasteurized milk and its byproducts must be encouraged. The public should be advised on the appropriate removal and dispensation of infected animal products. Education resources on sources of infection and how to prevent it should be provided to livestock and farm workers handling ungulates and their byproducts. 

Pearls and Other Issues

Q fever is infrequently fatal, and no precise data exist on whether to screen pregnant women for infection during an outbreak. The mortality rate is 2.4%. Some authors strongly advocate serology monitoring after an episode of acute Q fever for two years for earlier detection of chronic Q fever or endocarditis. The reason for this is an increased risk (39%) of endocarditis in patients with valvular lesions. In such a population, a transthoracic screening echocardiogram can be done to detect endocarditis. If the echocardiogram is negative and the serological titers rise, additional tests such as PCR of blood and positron emission tomography to look for a focus of persistent infection may help.

Serological and drug level monitoring is recommended during the treatment of endocarditis. If hydroxychloroquine is replaced by ciprofloxacin or rifampin, then the patient will need long-term serological follow-up. Biannual eye evaluation is a must when a patient is on hydroxychloroquine to monitor for visual deficits. Aneurysmal and vascular prosthetic device infections are associated with higher mortality. Patients with Q fever and persistent lymphadenopathy may need to undergo evaluation for lymphoma.[2][27][28][29]

Enhancing Healthcare Team Outcomes

Vaccination of individuals employed in high-risk occupations is an efficient approach in halting the disease. The formalin-killed, whole-cell vaccine Q-VAX is 92% to 98% effective at clinical disease prevention. Vaccination is recommended after skin testing as priorly exposed individuals are more likely to have untoward reactions. Coxevac is an inactivated vaccine used in veterinary animals. Isolation in a hospital is recommended if an infected patient undergoes a procedure that can result in aerosolization of contaminated tissue (autopsies, obstetrical/gynecological procedures). Avoiding raw milk, ectoparasite containment, promoting safe veterinary practices, and disinfection of infected tissue are strategies to decrease exposure. For decontamination, commercial disinfectants containing benzalkonium chloride or 5% hydrogen peroxide are successful.[30]

Prevention and management of Q fever are best handled with an interprofessional healthcare team using open communication and collaborative efforts to achieve optimal patient results. This team will include clinicians, infectious disease specialists, mid-level practitioners (PAs and NPs), nurses, and pharmacists, coordinating their activities and information sharing to improve patient outcomes.