Q Fever

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 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.[4][5]

Epidemiology

Q fever has been a notifiable disease since 1999 in the United States due to its potential as a biowarfare agent. However, 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, the elderly, Hispanics, and impoverished individuals. Soft ticks and other arthropods harbor Coxiella, infecting 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 (April and May), 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, eg, 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 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.[6][7][8]

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, eg, the QPH1 plasmid-containing strain is more virulent than the QPRS plasmid strain. Based on the host's immune response, the 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, possibly explaining Q fever fatigue syndrome.[9][10]

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 a self-limiting acute febrile illness lasting 1 to 3 weeks and an incubation period of approximately 20 days (range 14 to 39).[11] The onset is usually abrupt, with high-grade fevers (104°F or 40°C), headache, fatigue, and myalgias being the most commonly recognized symptoms. Headaches are commonly associated with photophobia. Atypical or rapidly progressive pneumonia is the next common clinical presentation, especially in older adults. It may be associated with chills, sweats, myalgia, pleuritic chest pain, nausea, vomiting, and diarrhea. Pleural effusion is uncommon but not absent. Symptoms typically last from 10 to 90 days. Mortality rates are low compared to the symptoms (ranging from 0.5 to 1.5 percent).[12] A rash is commonly seen in children. Acute hepatitis is also common in younger adults and can be complicated as cholestatic jaundice or acalculous cholecystitis. Along with transaminitis, patients can present with prolonged fever of unknown origin with characteristic granulomas on liver biopsy. The granulomas are "doughnut-like" because of the presence of a lipidic vacuole surrounded by a fibrinoid ring.[13] Aseptic meningitis or encephalitis has also been reported 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. A small number of patients may also develop acute endocarditis, which appears to be an autoimmune complication of early infection and is associated with the antiphospholipid antibody syndrome.[14]

Chronic Q Fever

Persistent, localized infections occur in approximately 1 to 5 percent of patients infected with C. burnetii.[15] 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.[16] 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.[17] Residual neurological impairment includes weakness, recurrent meningismus, blurry vision, sensory loss, and paraesthesias.[18][19][20][21]

Q Fever In Pregnant Patients

Although the infection is usually asymptomatic in pregnant patients, it can result in obstetrical complications such as spontaneous abortion, oligohydramnios, fetal growth restriction, fetal death, and preterm birth.[22][23] The consequences of congenital Q fever remain to be studied.[24]

Post-Q Fever Fatigue Syndrome

About 20% of patients develop a post-Q fever fatigue syndrome after an episode of acute Q fever. Symptoms include severe fatigue, nausea, headache, night sweats, myalgias, arthralgia, lymphadenopathy, decreased concentration, depression, difficulty sleeping, and impaired short-term memory. It can occur in patients who spontaneously resolved their symptoms and those who were treated with antibiotics. Moreover, the risk varies according to geographical location. For instance, compared with France, post-Q fever fatigue syndrome occurs more in the United Kingdom.[9]

Evaluation

In acute Q fever, the 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 polymerase chain reaction testing (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 acute and chronic Q fever is an indirect immunofluorescent test. This test detected two different IgG antibodies: Anti phase I IgG antibody and anti-phase II IgG antibody. Seroconversion typically occurs in the second week, and most patients have detectable antibodies in the third week.[13] In acute Q fever, anti-phase II IgG antibody is higher (typically >1 in 128) than anti-phase I IgG antibody. A fourfold rise in anti-phase II titers between acute and convalescent samples is diagnostic of acute Q fever.

PCR testing is employed to diagnose patients in whom acute infection is suspected, but initial serologic testing does not support the diagnosis.[25] It can also help confirm the serologic diagnosis of endocarditis or vascular infection in patients with persistent IgG anti-phase I titer elevations.[26] PCR testing can be performed on serum, cerebrospinal fluid, pleural fluid, excised heart valve tissue from the site of active infection (even if frozen or embedded in paraffin), bone marrow, bone and liver biopsies, fetal tissue, breast milk, and placenta. Samples should ideally be obtained during the first two weeks of the onset of symptoms, either before or shortly after (within 24 to 48 hours) the first antibiotic shot. However, DNA testing can be positive in an epidemic and may not be associated with clinical disease.[27] Due to extreme infectivity, C. burnetii must be cultured in a biosafety level 3 containment setting. 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).[28][29][30] Magnetic resonance imaging and computed tomography can help support the diagnosis. Some case reports also suggest that 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging is found to help establish the diagnosis of Q fever prosthetic joint infections and endocarditis.[31][16]

Treatment / Management

The best treatment for acute Q fever is doxycycline 100 mg orally twice daily for 14 days.[26] In cases of resistance or intolerance to doxycycline,  minocycline (100 mg twice daily), trimethoprim-sulfamethoxazole (TMP-SMX; 160 mg TMP and 800 mg SMX twice a day in patients with normal kidney function), or clarithromycin (500 mg twice a day), are reasonable alternatives.[32] In pregnancy, acute non-life-threatening Q fever should be treated with trimethoprim-sulfamethoxazole (160 mg TMP and 800 mg SMX, orally twice a day, in patients with normal renal function) 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).[33][26] Folic acid should be prescribed to minimize the risk of congenital abnormalities. Informed decision-making should guide therapy, and doxycycline should be used for life-threatening infections or reactions to trimethoprim-sulfamethoxazole. Serologic follow-up is essential at 3, 6, 12, 18, and 24 months post-delivery. Future pregnancies require resumption of serological monitoring, and treatment with trimethoprim-sulfamethoxazole is necessary with a four-fold rise in titers.(B3)

Pregnant patients with persistent, localized infections are managed with TMP-SMX. 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 Q fever fatigue syndrome.[34][35][36] An effective whole-cell vaccine for Q fever has been developed and is administered to humans with occupational risk in Australia. It is not recommended in the United States.(A1)

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 are used to identify these infections. Atypical pneumonia caused by Legionella and Mycoplasma needs to be considered. They can be ruled out by detecting urine antigen or serum antibody titers. Tick-borne illnesses such as Lyme disease, relapsing fever, and Rocky Mountain spotted fever manifest with fever and 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 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 vascular prosthesis infection 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. When not treated, pregnant females with Q fever have poor fetal outcomes, including abortion.