Symptoms, Diagnosis, and Treatment

Q fever can cause acute or chronic illness in humans, who usually acquire infection after contact with infected animals or exposure to contaminated environments. The acute symptoms caused by infection with Coxiella burnetii usually develop within 2-3 weeks of exposure, although as many as half of humans infected withC. burnetii do not show symptoms.
The following is a list of symptoms commonly seen with acute Q fever. However, it is important to note that the combination of symptoms varies greatly from person to person.

• high fevers (up to 104-105°F)
• severe headache
• general malaise
• myalgia
• chills and/or sweats
• non-productive cough
• nausea
• vomiting
• diarrhea
• abdominal pain
• chest pain

Although most persons with acute Q fever infection recover, others may experience serious illness with complications that may include pneumonia, granulomatous hepatitis (inflammation of the liver), myocarditis (inflammation of the heart tissue) and central nervous system complications. Pregnant women who are infected may be at risk for pre-term delivery or miscarriage. The estimated case fatality rate (i.e. the proportion of persons who die as a result of their infection) is low,  at < 2% of hospitalized patients. Treatment with the correct antibiotic may shorten the course of illness for acute Q fever.
Chronic Q fever is a severe disease occurring in <5% of acutely infected patients. It may present soon (within 6 weeks) after an acute infection, or may manifest years later.  The three groups at highest risk for chronic Q fever are pregnant women, immunosuppressed persons and patients with a pre-existing heart valve defects. Endocarditis is the major form of chronic disease, comprising 60-70% of all reported cases. The estimated case fatality rate in untreated patients with endocarditis is 25-60%. Patients with endocarditis require early diagnosis and long-term antibiotic treatment (at least 18 months) for a successful outcome.   Other forms of chronic Q fever include aortic aneurysms and infections of the bone, liver or reproductive organs, such as the testes in males.
Coxiella burnetii has the ability to persist for long periods of time in the host after infection. Although the majority of people with acute Q fever recover completely, a post-Q fever fatigue syndrome has been reported to occur in 10-25% of some acute patients. This syndrome is characterized by constant or recurring fatigue, night sweats, severe headaches, photophobia (eye sensitivity to light), pain in muscles and joints, mood changes, and difficulty sleeping.

Physician Diagnosis

There are several aspects of Q fever that make it challenging for healthcare providers to diagnose and treat.  The symptoms vary from patient to patient and can be difficult to distinguish from other diseases.  Treatment is more likely to be effective if started in the first three days of symptoms. Diagnostic tests based on the detection of antibodies will frequently appear negative in the first 7-10 days of illness.  For this reason, healthcare providers must use their judgment to treat patients based on clinical suspicion alone. Healthcare providers may find important information in the patient’s history and physical examination that may aid clinical diagnosis. Information such as recent travel to rural or agricultural communities where infected livestock may be present, or employment in high risk occupations such as veterinarians or farmers can be helpful in making the diagnosis.  Chronic Q fever is a risk for anyone with a history of acute Q fever illness, particularly those persons with valvular disease, blood vessel abnormalities, immunosuppressed persons, and women who were pregnant when they became infected.
The healthcare provider should also look at routine blood tests, such as a complete blood cell count or a chemistry panel. Clues such as a prolonged fever with low platelet count, normal leukocyte count, and elevated liver enzymes are suggestive of acute Q fever infection, but may not be present in all patients.  After a suspect diagnosis is made based on clinical suspicion and treatment has begun, specialized laboratory testing should be used to confirm the diagnosis of Q fever.
Suspect diagnosis of Q fever is made based on signs and symptoms and a high index of clinical suspicion.  Diagnosis can later be confirmed using specialized confirmatory laboratory tests. Treatment should never be delayed pending the receipt of laboratory test results, or be withheld on the basis of an initial negative laboratory result.
Laboratory Confirmation
During the acute phase of illness, a sample of whole blood can be tested by polymerase chain reaction (PCR) assay to determine if a patient has Q fever. This method is most sensitive in the first week of illness, and rapidly decreases in sensitivity following the administration of appropriate antibiotics. PCR or immunohistochemistry of biopsy specimens has also been used to diagnose Q fever. These tests may be appropriate for endocarditis patients undergoing valve replacement surgery or patients with hepatitis. Although a positive PCR result is helpful, a negative result does not rule out the diagnosis, and treatment should not be withheld due to a negative result. Culture isolation of C. burnetii is only available at specialized laboratories; routine hospital blood cultures cannot detect the organism.
When a person develops Q fever, their immune system produces antibodies to C. burnetii, with detectable antibody titers usually observed by 7-10 days after illness onset.  It is important to note that a negative test during the first week of illness does not rule out Q fever as a cause of illness. There are two distinct antigenic phases to which humans develop antibody responses. In acute infection, an antibody response to C. burnetii Phase II antigen is predominant and is higher than Phase I antibody response; the reverse is true in chronic infection which is associated with a rising Phase I IgG titer (according to current U.S. case definitions >1:800) that is often much higher than Phase II IgG.  The gold standard serologic test for diagnosis of acute Q fever is the indirect immunofluorescence assay (IFA) using C. burnetii antigen, performed on paired serum samples to demonstrate a significant (four-fold) rise in antibody titers. The first sample should be taken as early in the disease as possible, preferably in the first week of symptoms, and the second sample should be taken 2 to 4 weeks later. In most cases of Q fever, the first IgG IFA titer is typically low, or “negative,” and the second typically shows a significant (four-fold) increase in IgG antibody levels. IgM antibodies usually rise at the same time as IgG near the end of the first week of illness and remain elevated for months or longer.  Also, IgM antibodies are less specific than IgG antibodies and more likely to result in a false positive.  For these reasons, physicians should request both Phase I and Phase II IgG and IgM serologic titers for diagnostic confirmation of acute and chronic Q fever.  Antibodies to C. burnetii may remain elevated for months or longer after the disease has resolved, or may be detected in persons who were previously exposed to antigenically related organisms.  Approximately 3% of currently healthy people in the U.S. general population and up to 20% of people in high-risk professions (veterinarians, ranchers, etc.) have elevated antibody titers due to past exposure to C. burnetii. Therefore, if only one sample is tested it can be difficult to interpret the findings.
Paired samples taken 2-3 weeks apart demonstrating a significant (four-fold) rise in antibody titer provides the best evidence for a correct diagnosis of acute Q fever. Diagnosis of chronic Q fever is confirmed by elevated Phase I IgG antibody (according to current U.S. case definitions >1:800 and higher than Phase II IgG) and an identifiable persistent focus of infection (e.g. endocarditis).  Elevated Phase I titers alone do not confirm a chronic Q fever diagnosis and would not warrant treatment in a clinically normal patient. Because chronic Q fever involves lengthy persistence of the organism in the body, the antibody levels are often quite high and you will not see a rising titer between paired serum specimens.

Treatment

Doxycycline is the first line treatment for all adults, and for children with severe illness. Treatment should be initiated immediately whenever Q fever is suspected.
Use of antibiotics other than doxycycline or other tetracyclines is associated with a higher risk of severe illness. Doxycycline is most effective at preventing severe complications from developing if it is started early in the course of disease. Therefore, treatment must be based on clinical suspicion alone and should always begin before laboratory results return.
If the patient is treated within the first 3 days of the disease, fever generally subsides within 72 hours.  In fact, failure to respond to doxycycline suggests that the patient’s condition might not be due to Q fever. Severely ill patients may require longer periods before their fever resolves. Resistance to doxcycline has not been documented. 
There is no role for prophylactic antimicrobial agents in preventing Q fever after a known exposure and prior to symptom onset; attempts at prophylaxis will likely extend the incubation period by several days but will not prevent infection from occurring.
Recommended Dosage for Acute Q fever
Doxycycline is the first line treatment for children with severe illness of all ages and adults:

• Adults: 100 mg every 12 hours
• Children under 45 kg (100 lbs): 2.2 mg/kg body weight given twice a day

Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement. Standard duration of treatment is 2-3 weeks.
Recommended Dosage for Chronic Q fever

• Adults: Doxycycline 100 mg every 12 hours and hydroxychloroquine 200 mg every 8 hours.

Standard duration of treatment is 18 months.

Treating children

The use of doxycycline is recommended to treat Q fever in children of all ages who are hospitalized or are severely ill. Unlike older generations of tetracyclines, doxycycline has not been shown to cause staining of permanent teeth, and most experts consider the benefit of doxycycline in treating Q fever in children younger than 8 years of age with severe illness or who are hospitalized greater than the potential risk of dental staining.  Children with mild illness who are less than 8 years of age may be treated with co-trimoxazole, but therapy should be switched to doxycycline if their course of illness worsens.

Other Treatments

In cases of life threatening allergies to doxycycline and in pregnant patients, physicians may need to consider alternate antibiotics. Treatment of pregnant women diagnosed with acute Q fever with once daily co-trimoxazole throughout pregnancy has been shown to significantly decrease the risk of adverse consequences for the fetus.