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. burnetiido 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.

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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.

For more in-depth information about the diagnosis of Q fever, please visit: http://www.bt.cdc.gov/agent/qfever/clinicians/diagnosis.asp

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

• Adults: 100 mg every 12 hours
• Children under 45 kg (100 lbs): 2.2 mg/kg body weight given twice a day
Doxycycline is the first line treatment for children with severe illness of all ages and adults:
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.

http://www.cdc.gov/qfever/symptoms/index.html

Prevention

In the United States, Q fever outbreaks have resulted mainly from occupational exposure involving veterinarians, meat processing plant workers, sheep and dairy workers, livestock farmers, and researchers at facilities housing sheep. Prevention and control efforts should be directed primarily toward these groups and environments.

The following measures should be used in the prevention and control of Q fever:

• Educate the public on sources of infection.
• Appropriately dispose of placenta, birth products, fetal membranes, and aborted fetuses at facilities housing sheep and goats.
• Restrict access to barns and laboratories used in housing potentially infected animals.
• Use only pasteurized milk and milk products.
• Use appropriate procedures for bagging, autoclaving, and washing of laboratory clothing.
• Vaccinate (where possible) individuals engaged in research with pregnant sheep or live C. burnetii.
• Quarantine imported animals.
• Ensure that holding facilities for sheep should be located away from populated areas. Animals should be routinely tested for antibodies to C. burnetii, and measures should be implemented to prevent airflow to other occupied areas.
• Counsel persons at highest risk for developing chronic Q fever, especially persons with pre-existing cardiac valvular disease or individuals with vascular grafts.

A vaccine for Q fever has been developed and has successfully protected humans in occupational settings in Australia. However, this vaccine is not commercially available in the United States. Persons wishing to be vaccinated should first have a skin test to determine a history of previous exposure. Individuals who have previously been exposed to C. burnetiishould not receive the vaccine because severe reactions, localized to the area of the injected vaccine, may occur. A vaccine for use in animals has also been developed, but it is not available in the United States.

Significance for Bioterrorism

Coxiella burnetii is a highly infectious agent that is rather resistant to heat and drying. It can become airborne and inhaled by humans. A single C. burnetii organism may cause disease in a susceptible person. This agent has a past history of being developed for use in biological warfare and is considered a potential terrorist threat.

Annual Cases of Q Fever in the United States

Q fever was first recognized as a human disease in Australia in 1935 and in the United States in the early 1940’s. The "Q" stands for "query" and was applied at a time when the causative agent was unknown. Human Q fever is now known to be the result of infection with the obligate, intracellular bacterium, Coxiella burnetii. Cattle, sheep, and goats are commonly infected and may transmit infection to humans when they give birth. Coxiella burnetii can survive for long periods of time in the environment, and may be spread by wind and dust. The disease is global in distribution, with cases reported sporadically or occasionally as outbreaks. However, because Q fever may resemble other diseases, be mild, or even cause no symptoms in some people, cases of human Q fever are likely under recognized in the United States and elsewhere. Around 3% of the healthy adult U.S. population and 10-20% of persons in high-risk occupations (veterinarians, farmers, etc.) have antibodies to C. burnetii, suggesting past infection.

Q fever was made a notifiable disease condition in the United States in 1999 in order to better understand the epidemiology and magnitude of the disease. CDC compiles the number of cases reported by state and local health departments. The number of Q fever cases reported to CDC increased since the disease became reportable, from 17 cases with onset in 2000, to 167 cases with onset in 2007. The incidence (the number of cases for every million persons) of Q fever increased similarly, from less than 0.1 case per million persons in 2000 to 0.6 cases per million persons in 2007. The surveillance case definition for Q fever was modified in 2008 to revise laboratory criteria for diagnosis and to allow for the separate reporting of acute and chronic Q fever. During 2008 –2010, the number of reported cases decreased slightly, relative to 2007, and the incidence rated has decreased to 0.4 cases per million persons. One hundred thirty-one cases of Q fever were reported with onset in 2010; of these, 106 were acute Q fever and 25 were chronic Q fever.

Number of annual Q fever cases 1998 – 2010:

The graph displays the number of human cases of Q fever cases reported to CDC annually from 1998 through 2010. Cases of Q fever increased steadily from 13 cases in 1999 when the disease became nationally notifiable, to 167 cases in both 2006 and 2007. Cases decreased significantly in 2008 and 2009 with total cases at their lowest in 2009 (n=113) with a slight increase in 2010. Beginning in 2008, cases were differentiated as acute or chronic. Acute cases generally make up 80-90% of cases reported.
Hospitalization Rates

Illness among patients with recognized and reported Q fever may be severe with complications requiring hospitalization that may include endocarditis, encephalitis, pneumonia, hepatitis, and splenomegaly. Rates of hospitalization among Q fever cases for which information was available averaged over 50% during 2002 to 2008. However, it is likely that mild Q fever infections which do not require hospitalization may be more likely to be under-recognized and therefore under-represented in current national surveillance systems.
Q fever hospitalization rate, 2002 – 2010:

This figure shows the proportion of hospitalized cases among cases reported to CDC between 2002 and 2010. The lowest rate of hospitalization was in 2002 at 25%. Highest proportions of hospitalized cases were reported in 2007 and 2009, both of which reported hospitalization rates of roughly 70%.

Geography

Cases of Q fever are most frequently reported from western and plains states where ranching and rearing of cattle are common. In other states, areas where sheep, goat, and cattle ranching are locally practiced may demonstrate increased incidence. Seven states (California, Colorado, Illinois, Kentucky, Missouri, Tennessee, and Texas) have accounted for more than half (52%) of all cases since human Q fever became notifiable. Cases of Q fever are reported less frequently in the eastern United States. Sporadic reports of cases may result from patients involved in animal research work and from patient travel to other states.
Geographic distribution of Q fever incidence in 2010:

This figure shows the incidence of Q fever cases by state in 2010 per million persons. Q fever was not notifiable in Iowa, New Hampshire, and Vermont in 2010. The incidence rate was zero for Alabama, Alaska, Connecticut, Delaware, Hawaii, Idaho, Indiana, Kentucky, Louisiana, Maine, Massachusetts, Mississippi, Oklahoma, Rhode Island, South Carolina, Utah and West Virginia. Incidence ranged between 0.1 to 0.4 cases per million persons for Florida, Georgia, Maryland, Minnesota, North Carolina, Ohio, Pennsylvania, Tennessee and Virginia. Annual incidence ranged from 0.4 to 1.0 case per million persons in Arizona, California, Colorado, Illinois, Michigan, Missouri, New Jersey, New York, Texas, Washington, and Wisconsin. The highest incidence rates, ranging from 1.0 to 4.9 cases per million persons were found in Arkansas, the District of Columbia, Kansas, Montana, Nebraska, Nevada, New Mexico, North Dakota, Oregon, South Dakota and Wyoming.

Seasonality

Although cases of Q fever can occur during any month of the year, most cases report onset of illness during the spring and early summer months, peaking in April and May. These increases coincide with increases in human outdoor activity, and with the birthing season for a number of domestic animal species.
Percent of Q Fever cases reported each month of onset 1998 – 2010:

This figure shows the percent of cases reported from 1998 through 2010 by month of onset to give the seasonality of cases. There are cases reported in each month of the year, ranging from 3% reported in November, to 14% of cases reported in May. November is the only month in which less than 5% of cases are reported, and the majority (58%) of cases are reported between March and July.

Persons at Risk

The frequency of reported cases of Q fever increases with age and is highest among males, which may reflect occupational risks for exposure among livestock handlers. A past history of heart valve defects, endocarditis, or valvular implants may increase the risk of chronic infection and severe disease outcome. Infection is also more common in patients with compromised immune systems (such as may occur through cancer treatments, advanced human immunodeficiency virus (HIV) infection, prior organ transplants, or some medications). Individuals who reside or spend time near ranches and livestock rearing facilities are at increased risk for infection.

Q Fever Incidence by Age Group, 2000 – 2010

This figure shows the average annual incidence of Q fever per million persons by age groups for 2000 through 2010. The graph shows that cases have been reported in every age group with increased incidence as age increases. The highest rate of incidence, more than 0.7 cases per million persons, is seen in persons ages 60 – 64 years.

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Q Fever Reporting and Surveillance

The 1999 Q fever surveillance case definition was used to classify cases with onset years 2000 – 2007 into the categories probable and confirmed. The 2008 case definition became official as of January 1, 2008 and allows the categories probable and confirmed to be further categorized to acute and chronic manifestations of the disease. The 2008 case definition was again corrected in 2009 to clarify laboratory supportive serologic evidence. The 2009 case definition will remain current until a future revision is proposed and accepted. For more information on how to report cases of Q fever and to download a Q fever case report form (CRF) , visit the “In-Depth Information” section.

Further Reading

McQuiston JH, Holman RC, McCall CL, Childs JE, Swerdlow DL, Thompson HA. National Surveillance and the Epidemiology of Human Q Fever in the United States, 1978 – 2004. American Journal of Tropical Medicine and Hygiene 75(2006),36 – 40
Parker NR, Barralet JH, Bell AM. Q fever. Lancet 367(2006),679 – 88
McQuiston JH, Childs JE. Q Fever in Humans and Animals in the United States. Vector Borne and Zoonotic Diseases 2(2002),179 – 91

Raoult D, Tissot-Dupont H, Foucault C, Gouvernet J, Fournier PE, Bernit E, Stein A, Nesri M, Harle JR, Weiller PJ. Q Fever 1985 – 1998: Clinical and Epidemiologic Features of 1,383 Infections. Medicine 79(2000),109 – 23
Morbidity and Mortality Weekly Reports (MMWR), CDC. Q Fever --- California, Georgia, Pennsylvania, and Tennessee, 2000--2001. 51(2002),924-7

http://www.cdc.gov/qfever/stats/index.html