Continuing Education Activity

Coxiella burnetii is the causative agent of Q fever, which is a zoonotic disease. Q fever can present as a febrile illness, pneumonia, or hepatitis. If it is not appropriately treated, it can lead to complications such as osteomyelitis, endocarditis, and vascular infections. It is, therefore, important to promptly identify and treat this condition. This activity reviews the evaluation and treatment of Q fever and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology and epidemiology of Q fever.
• Review the typical presentation of a patient with Q fever.
• Outline the treatment and management options available for Q fever.
• Summarize the importance of collaboration and communication amongst the interprofessional team to improve the outcomes for patients affected by Q fever.

Introduction

Coxiella burnetii is the causative agent of Q fever. Q fever is a zoonotic disease seen mostly in people who work with farm animals. While most of the cases remain asymptomatic, the symptomatic patients most commonly develop a febrile illness. Effective treatment and vaccines are available for this condition. However, if not treated appropriately, it can become a chronic infection affecting multiple organs, including the heart, bones, and lungs. The workers in the animal industry should be educated about the risk of contracting this disease and the appropriate measures for prevention.

Etiology

Coxiella burnetii is an obligate intracellular, pleomorphic gram-negative rod-shaped bacteria that causes Q fever. It exhibits phase variation, which is a form of antigenic shift. It exists in phase I form in animals, which is highly infectious and in noninfectious phase II form when subcultured in cells or embryonated eggs.[1]

Epidemiology

C. burnetii is ubiquitous, with outbreaks of Q fever reported from all over the globe, except for New Zealand. Due to its high infectivity, aerosol transmission, and environmental stability, it has the potential of being used as a biological weapon. Humans usually acquire this infection by inhalation of aerosols from the reservoir animals (cows, goats, and sheep) and their products.[2][3] The main reservoir of C. burnetii is the tick. Sheep, goat manure, ovine manure, wild animals, pets (cats and dogs) have been reported as the sources of outbreaks. Human to human transmission is uncommon and has been reported via blood transfusion and by coming in contact with infected parturient women.[1][3]

Pathophysiology

Similar to other intracellular microorganisms like Mycobacterium leprae and Leishmania, the acute infection leads to antibody response against the phase II antigen, and the immunity is provided by the cellular response. In immunocompromised individuals, due to the lack of cellular immune response, chronic infection occurs where immune complexes formed due to high levels of antibodies are responsible for the majority of clinical signs and symptoms.[1]

Histopathology

The inflammatory response may lead to granuloma formation, which are often distinctive doughnut-shaped, with a clear central space in liver and bone marrow biopsy specimens. Relapses can occur as the immunity is not lasting. In immunocompetent patients, the biopsy specimen shows an inflammatory response with few microorganisms. In immunosuppressed patients, due to the absence of cellular immune response, the biopsy specimen is mostly comprised of many microorganisms leading to chronic infection.[1]

History and Physical

The diagnosis of Q fever is mainly based on the epidemiological circumstances, with exposure to a parturient or newly born animal being a major risk factor. The incubation period varies from 2-6 weeks.[1]

The spectrum of severity of Q fever can vary from being asymptomatic to having severe clinical features. The clinical manifestation varies with the route of infection and the size of the inoculum. Pneumonia and hepatitis have been associated with respiratory and intraperitoneal routes, respectively, while myocarditis has been associated with high inocula.[4][5] The most frequent manifestation is a self-limited febrile illness (91%), which may be associated with headache, myalgia, arthralgia, and cough. Atypical pneumonia and abnormal chest X-rays are common.[6]

The usual spectrum of Q fever:

• Febrile illness: Fever, usually accompanied by a headache that plateaus in 2 to 4 days and returns to normal in 5 to 14 days, is the most common outcome of the infection. The fever lasts longer in untreated patients (up to 57 days) and in elderly patients.
• Atypical pneumonia: It is characterized by nonproductive cough, fever, and minimal auscultatory findings with nonspecific findings on a chest X-ray.
• Hepatitis: It may present in three ways, including hepatitis without clinical manifestations, hepatitis with hepatomegaly, and hepatitis with granulomas on liver biopsy presenting as prolonged fever of unknown origin. These patients develop fever, abdominal pain (mostly in the right upper quadrant), nausea, vomiting, diarrhea, and anorexia.[5]
• Cardiac involvement: Myocarditis and pericarditis are seen in some of the patients with Q fever. Myocarditis is one of the major causes of death in these patients.[7]
• Exanthema associated with fever: Though uncommon, a pink macular or papular rash, may be seen on the trunk in 5 to 21% patients.[8]
• Neurological involvement: Q fever may cause encephalitis/meningoencephalitis, lymphocytic meningitis, and peripheral neuropathy.[9]

Evaluation

C. burnetii can be isolated in a lab in cell culture media, but since laboratory transmission has been reported, growing it in a lab can be hazardous. Its culture and manipulation of the contaminated specimens should only be allowed in biosafety level 3 laboratories.[3] While the organism can be identified by using immunological techniques applied to biopsy specimens and polymerase chain reaction, the most commonly used and convenient tool is serology. Indirect immunofluorescence is the reference method that offers high sensitivity and specificity.[1][10]

Lab findings seen in patients with acute Q fever include normal white blood cell count (90%), thrombocytopenia (25%), raised transaminase levels (70%), smooth muscle autoantibodies (65%) and anti-phospholipase antibodies (50%). In chronic patients, leukocytosis (25%),leukopenia (15%), increased transaminase levels (40%-60%), thrombocytopenia (26%-50%), anemia (40%), increased creatinine levels (65%), smooth muscle autoantibodies (40%), circulating immune complexes (90%), antinuclear antibodies (35%) and rheumatoid factor (60%) are seen.[1]

Treatment / Management

Symptomatic patients and pregnant women, even if asymptomatic, should be treated for acute Q fever. The treatment is most effective if initiated within the first three days of symptoms onset.[11]

Treatment regimens for acute Q fever:

• Children: Doxycycline 100mg/day for 10 to 14 days, trimethoprim-sulfamethoxazole (TMP-SMX) 8 to 12 mg/kg/day
• Adults: Doxycyline 100mg/day for 14 days (preferred); alternatives- fluoroquinolones, minocycline, TMP-SMX
• Pregnant: TMP-SMX (320mg to 1600mg) until the end of the 7 month

Fluoroquinolones can enter the cerebrospinal fluid and are preferred for Q fever meningoencephalitis. For chronic Q fever, a combination of doxycycline and hydroxychloroquine is given for at least 18 months.[5][12][13] The vaccine against Q fever is available for both humans and animals. A whole-cell formalin-inactivated vaccine is available for humans, and a chloroform-methanol residue extracted vaccine is available for animals.[14] Due to the risk of severe local reaction, the vaccine is only given to individuals who have not developed immunity due to prior exposure.[15]

Differential Diagnosis

Given the broad spectrum of the clinical presentation of Q fever, a number of etiologies should be considered in the differential diagnosis. Viral hepatitis, pneumonia due to pneumococcus and atypical organisms, meningococcal meningitis, Lyme disease, rocky mountain spotted fever, brucellosis, and leptospirosis are some of the differentials that should be considered.

Prognosis

Very good results are seen with an adequate and timely treatment of patients with Q fever. With the advancement in the diagnosis and treatment, the mortality rate for chronic Q fever patients has fallen to less than 5%. The prognosis is poor in the absence of treatment.[16]

Complications

If not treated adequately, patients with acute Q fever can progress to chronic Q fever, months to years after the initial infection. Chronic Q fever may manifest in the form of bacterial culture-negative endocarditis (75%), osteomyelitis, vascular infection, aortic graft infection, chronic hepatitis in patients with alcoholism, and pseudotumors of spleen and lungs.[17][18] Chronic infections occur exclusively in patients with predisposing conditions like heart valve lesions, vascular abnormalities, and immunosuppression.[19] 

Q fever in pregnancy is associated with increased mortality and morbidity. It can lead to premature delivery, spontaneous abortion, intrauterine fetal growth restriction, or intrauterine fetal death. The effects on the fetus due to transplacental passage of infection are unknown.[13]

Deterrence and Patient Education

• Treatment of manure with lime or 0.4% calcium cyanide should be done before spreading on fields.
• Proper disposal with incarceration and burial should be done for infected fetal fluids and membranes, placenta, aborted fetuses, and contaminated beddings.
• Appropriate tick control strategies and good hygiene should be undertaken.
• Milk and milk products should not be consumed without pasteurization.
• The best way to prevent this infection is to avoid contact with infected animals.
• The chronic consequences in the lack of proper treatment should be explained to patients.
• The patients should be reassured that Q fever is treatable with proper medications.
• The risk factors for acquiring Q fever should be fully explained to the workers in the animal industry.
• Infected animals should be removed from the herd, and imported animals should be quarantined.
• Animals used in research labs should be tested before being brought into the facility.[3]

Enhancing Healthcare Team Outcomes

Healthcare practitioners should make sure that the patient knows the course of the disease and the appropriate treatment available for the disease. The complications with the lack of proper treatment should be described to ensure proper compliance. The pharmacist should play a role to ensure that patients take the right dosage of the drug and that teratogenic drugs, including doxycycline, are not prescribed to pregnant women. The individuals working in the laboratories should follow all the protocols while handling the suspected or confirmed specimens so as to prevent the accidental spread of the organism within the facility.