Q Fever


Practice Essentials

Q fever (see the image below) is a zoonosis caused by Coxiella burnetii, an obligate gram-negative intracellular bacterium. Cattle, sheep, and goats are the primary reservoirs although a variety of species may be infected. Transmission to humans occurs primarily through inhalation of aerosols from contaminated soil or animal waste. Other rare modes of transmission include tick bites, ingestion of unpasteurized milk or dairy products, and human-to-human transmission.

A: Chest radiograph with normal findings. B: ChestA: Chest radiograph with normal findings. B: Chest radiograph demonstrating Q fever pneumonia.

Signs and symptoms

Acute Q fever

The 3 main clinical presentations of acute Q fever are as follows:

  • A self-limited, influenzalike febrile illness (up to 40°C) (88-100%) of abrupt onset, which is often accompanied by headache (68-98%) (typically retrobulbar), myalgia (47-69%) (arthralgia is uncommon), chills (68-88%), fatigue (97-100%), and sweats (31-98%); the temperature returns to normal within 5-14 days

  • Pneumonia (predominant in North America), usually mild in nature (crackles auscultated in 50% of cases) or as an incidental radiographic finding; when there is respiratory involvement, patients have a dry, nonproductive cough (24-90%), dyspnea, and pleuritic chest pain; this condition is rarely fulminant but occasionally progresses to acute respiratory distress syndrome (ARDS)

  • Hepatitis (predominant in Europe), usually with mild elevation of transaminases (2-3 times the reference range) and may be associated with antismooth muscle, antiphospholipid, or antinuclear antibodies; jaundice and acute gastrointestinal (GI) symptoms (nausea and vomiting, diarrhea [rare], right upper quadrant abdominal pain) are rare; manifestations resolve within 2-3 weeks.

Chronic Q fever

Endocarditis with negative culture findings and seropositivity (culture positivity and seropositivity or culture negativity and seronegativity are relatively uncommon) is the main clinical presentation of chronic Q fever, usually occurring in patients with preexisting cardiac disease including valve defects, rheumatic heart disease, and prosthetic valves.

Patients may present with heart failure or nonspecific symptoms, including low-grade fever, fatigue, chills, arthralgia, dyspnea, rash from septic thromboembolism, and night sweats.

See Clinical Presentation for more detail.

Diagnosis

Lab tests

Acute Q fever may present with the following laboratory results:

  • A complete blood cell (CBC) count usually shows a normal white blood cell (WBC) count (70-90%) (elevated WBC in as many as 30%), mild thrombocytopenia (25%) (followed by a reactive thrombocytosis during the convalescent period [1), and, in rare cases, hemolytic anemia
  • Liver function tests usually show mild elevation of transaminases (2-3 times the reference range in 70-85% of patient) and alkaline phosphatase (2-3 times the reference range) without hyperbilirubinemia
  • The erythrocyte sedimentation rate (ESR) is usually elevated (55 mm/h ± 30 mm/h)
  • Several positive autoimmune antibodies, including antismooth muscle and antiphospholipid, may be seen
  • Blood cultures are typically negative (Note that, although possible, attempting to isolate the organism from blood is a dangerous practice; cases of Q fever have developed in laboratory technicians)

In chronic Q fever, the following laboratory results may be observed:

  • Anemia of chronic disease
  • Elevated ESR
  • Elevated gamma globulins (polyclonal)
  • Elevated rheumatoid factor (RF)
  • Increased creatinine levels

Serology

The diagnosis of Q fever relies on a high index of suspicion as suggested by the epidemiologic features and is proven by serologic analysis. The 3 serologic techniques used for diagnosis are as follows:

  • Indirect immunofluorescence (IIF) (method of choice)

  • Complement fixation

  • Enzyme-linked immunosorbent assay (ELISA) (comparable to IIF)

See Workup for more detail.

Management

Acute Q fever

Doxycycline is the treatment of choice for acute Q fever, and 2 weeks of treatment is recommended for adults, children aged 8 years or older, and for severe infections in patients of any age.

Children younger than 8 years with uncomplicated illness may be treated with trimethoprim/sulfamethoxazole or a shorter duration (5 days) of doxycycline.

Women who are pregnant when acute Q fever is diagnosed should be treated with trimethoprim/sulfamethoxazole throughout the duration of pregnancy.

Chronic Q fever

Chronic Q fever is difficult to treat, therefore a prolonged antimicrobial regimen is recommended. The most current recommendation for endocarditis is combination treatment with doxycycline and hydroxychloroquine for at least 18 months to eradicate any remaining C burnetii and prevent relapses. An alternative option is combination of doxycycline and a fluoroquinolone for at least 3-4 years.

See Treatment and Medication for more detail.

Background

Q fever is a zoonosis caused by Coxiella burnetii, an obligate gram-negative intracellular bacterium. Most commonly reported in southern France and Australia, Q fever occurs worldwide (except in New Zealand).

C burnetii infects various hosts, including humans, ruminants (cattle, sheep, goats), and pets—and, in rare cases, reptiles, birds, and ticks. This bacterium is excreted in urine, milk, feces, and birth products. These products, especially the latter, contain large numbers of bacteria that become aerosolized after drying. C burnetii is highly infectious, and only a few organisms can cause disease.

Because of its sporelike life cycle, C burnetii can remain viable and virulent for months. Infection can be acquired via inhalation or skin contact, and direct exposure to a ruminant is not necessary for infection. Transmission by tick bite is well recognized but rare. Rare human-to-human transmissions involving exposure to the placenta of an infected woman and blood transfusions have been reported. Sexual transmission is also possible.

C burnetii infection in livestock often goes unnoticed. In humans, acute C burnetii infection is often asymptomatic or mistaken for an influenzalike illness or atypical pneumonia (see the following image). In rare cases, C burnetii infection becomes chronic, with devastating results, especially in patients with preexisting valvular heart disease. Because of its highly infectious nature and has an inhalational route of transmission, C burnetii is recognized as a potential agent of bioterrorism. The Centers for Disease Control and Prevention (CDC) classifies Q fever as a Category B agent. [2]

A: Chest radiograph with normal findings. B: ChestA: Chest radiograph with normal findings. B: Chest radiograph demonstrating Q fever pneumonia.

See also Rickettsial InfectionPediatric Bacterial EndocarditisInfective EndocarditisCommunity-Acquired PneumoniaTicks and Tick-Borne Diseases: Slideshow, and Remaining Vigilant Against Bioterrorism: Slideshow.

Historical information

Edward Derrick first described the illness Q (for query, owing to the elusiveness of its etiology) fever in 1937 during a cluster of acute febrile illness in abattoir workers in Brisbane, Queensland, Australia. [3The causative organism was later isolated from Derrick's patients by Burnet and Freeman as a Rickettsia species. Simultaneously, although primarily disseminated as an aerosol via inhalation or ingestion, Davis and Cox identified vector transmission when the same organism from ticks collected near Nine Mile Creek in Montana during an investigation of Rocky Mountain spotted fever in 1938. First named Rickettsia diaporica and Rickettsia burnetii, the current name of Coxiella burnetii was applied in 1948.

Pathophysiology

As noted earlier, Q fever is a ubiquitous zoonotic disease caused by C burnetii, with protean clinical manifestations that are not yet fully understood. [4C burnetii has a worldwide distribution from its reservoirs (including mammals, birds, and ticks), and the development of Q fever is strongly related to exposure to farm animals (primarily cattle, sheep, and goats) and particularly parturient animals (including cats and rabbits) because the organism is reactivated in pregnant animals. In one reported case, an obstetrician developed symptoms of Q fever 1 week after delivering a child to a woman who had Q fever. [5A characteristic of infection with C burnetii is that only humans regularly express the disease.

Initially classified as a species of the genus Rickettsia because of its obligatory intracellular growth requirements , C burnetii is now recognized as a bacterium within the gamma group of Proteobacteria. Genome and 16SrRNA sequencing have identified substantial homology with Legionella pneumophila, also a member of that taxonomic group.

C burnetii is a strict, intracellular, pleomorphic, gram-negative coccobacillus with an incubation period of 9-40 days; the average incubation period is 20 days (range, 18-21 d). Q fever is primarily transmitted by: (1) aerosolization from newborn animals, their placentas, [6and contaminated hides and fur; (2) ingestion of raw milk and goat cheese; (3) transfusions of blood products; (4) mother to offspring (ie, vertical) transmission; and (5) tick bites. Even wind patterns may make a difference by spreading aerosolized organisms downwind. [7Outbreaks of Q fever have occurred in an industrial setting from straw board that had been drilled open during part of the construction process. Although the respiratory system is the main organ system affected, the gastrointestinal (GI) and cardiac systems can also be affected.

Morphologic variants

C burnetii lives inside acidic lysosomes, a point that has therapeutic implications, [8and it has 2 morphologic variants [9: the small-cell variant (SCV) (0.2 x 0.7 microns), which survives well in the environment because of its resistance to heat and desiccation, pressure, and chemical agents [1; and the large-cell variant (LCV), which multiplies in the host monocyte and macrophage. [10These variants are antigenically different. [10]

The small-cell variant is a sporelike structure, enabling the organism to persist on fomites for more than 1 year. After passive entry into the host-cell phagosome, the organism delays the fusion of the phagosome with lysosomes, presumably using this delay to transform from the small-cell variant into the large-cell variant. Thereafter, the large-cell variant exploits and persists within the acidified phagolysosome of the monocytes and macrophages, using it as a nursery. [11]

C burnetii attaches to host macrophages by means of spectrin-binding proteins called ankyrin and is internalized into the cell, where it fuses with lysosomes to form phagolysosomes. The acidic environment of the phagolysosomes has little effect in defending the host against the invading organism, which multiplies and disseminates itself from this environment. This process is thought to occur mainly in the lungs, the main port of entry of C burnetii. Marrie and Raoult postulated that these morphologic variants create an impairment in the bacterial responses within the host, enabling the persistence of the illness in chronic cases. [3]

Proliferation of organisms within the phagolysosome eventually ruptures the host cell. The infected pulmonary macrophages are also transported systemically, with the reticuloendothelial system (liver, spleen, bone marrow [most commonly]) being the most heavily infected. Immune responses result in inflammation that manifests as formation of non-necrotizing granulomata, termed doughnut granulomata due to the characteristic appearance of a fibrin ring surrounding a fat vacuole. Although classically associated with acute Q fever, doughnut granulomata can develop in other conditions, such as visceral leishmaniasiscytomegalovirus or Epstein-Barr infections, Hodgkin lymphoma, and allopurinol hypersensitivity reaction.

Infectious phases

Like other gram-negative bacteria, C burnetii possesses a lipopolysaccharide as a virulence factor that is also responsible for an antigenic phase variation, an important property that was first utilized for serologic diagnosis by Bengtson in 1941. [1011123The infection has 2 phases, which are analogous to the lipopolysaccharide rough and smooth phase of Enterobacteriaceae organisms. Bacterial isolates from naturally infected and laboratory-infected eukaryotic cell hosts are virulent and have a phase I (smooth) lipopolysaccharide that helps protect the microorganism from the host’s defense mechanisms. Isolates obtained after repeated passages through embryonated hens’ eggs are rendered avirulent by chromosomal deletions and have a phase II (rough) lipopolysaccharide.

The phase 1 form is responsible for acute Q fever infections. The phase 2 form has been identified during transmission of C burnetii in immunoincompetent hosts, such as embryonated hen eggs or cell-culture systems. [13Variations between phase 1 and phase 2 appear to be correlated with changes in smooth or rough lipopolysaccharides.

Immune response

Antibodies against phase I and II antigens can be measured in sera of affected hosts. Phase II antibodies are positive in acute Q fever, whereas phase I antibodies remain elevated in chronic disease. During acute Q fever, immunoglobulin M (IgM) antibodies develop against phase 1 and phase 2 forms, whereas immunoglobulin G (IgG) antibodies develop only against the phase 2 form. In chronic Q fever, both IgG and immunoglobulin A (IgA) antibodies are formed against both phase 1 and phase 2 forms. The selective development of the antibodies against each of the 2 forms of C burnetii has become the basis for serologic testing for acute versus chronic Q fever.

The immune response against C burnetii is both cell mediated and humeral, with cell-mediated immunity appearing to be most important in fending off this organism. Individuals with certain conditions (eg, pregnancy, human immunodeficiency virus [HIV] infection, immunosuppression, heart-valve lesions, and vascular abnormalities) may be at greater risk for more severe disease [7and those with impaired cell-mediated immunity are at increased risk for chronic Q fever. Infected pregnant women are at risk for spontaneous abortion, premature labor, and intrauterine growth restriction (IUGR), as placental infection may cause direct infection of the fetus. [7]

Potential as biologic warfare agent

In addition to its high infectivity, C burnetii is an extremely virulent organism, as just a single bacterium can cause infection. [8This feature promoted its development as an agent for biologic warfare. C burnetii has been mass produced and weaponized. It is classified as a category B agent, because it lacks the capacity to cause mass fatalities while causing notable debilitation. The potential effect of an intentional release of 50 kg of C burnetii along a 2-km line upwind of a population of 500,000 is an estimated 150 deaths, 125,000 cases of acute illness, and 9000 cases of chronic illness, according to World Health Organization (WHO) estimates. [14]

Etiology

Q fever is most often related to inhalation of aerosolized organisms during animal exposure, occupational exposure, and tick bites (usually to domesticated household and farm animals). C burnetii —a strict, intracellular, pleomorphic, gram-negative coccobacillus classified as a Legionellae species—is the causative organism; it localizes in the mammary glands, uterus, and feces of domestic and small mammals. However, because of the persistence of Coxiella organisms in nature as a sporelike structure (making it highly resistant to inactivation; it can survive for months in dust and feces particles), C burnetii can infect people with no known contact with animals. For example, an outbreak of Q fever was reported in people living along a road on which farm vehicles contaminated with straw and manure traveled. Laboratory outbreaks have also occurred. Only 1 case of documented human-to-human transmission exists.

Why chronic Q fever develops in certain patients is unknown. Current understanding of chronic Q fever indicates activation of a previously asymptomatic infection.

Epidemiology

United States statistics

Q fever became a reportable disease in 1999, except for Delaware, Iowa, Oklahoma, Vermont, and West Virginia. [1Before then, the annual incidence rate was 21 cases. From 2000 to 2004, the mean annual incidence of Q fever rose to 51 cases, with the highest incidence in the Midwest states, although the largest total number of cases was reported in California. Indeed, Q fever was reported to be endemic to California during the 1950s. [15In 2005, 136 cases were reported to the CDC; in 2006, 169 cases were reported. Dairy and slaughterhouse workers are most at risk. In 2006, the incidence was reported to be 0.06 per 100,000 population.

More recently, Q fever has been reported in US military personnel deployed in Iraq and in Afghanistan, including some patients who were infected without known animal exposure. [12Indeed, since 2003, more than 200 cases of acute Q fever have been reported among US military personnel deployed to Iraq.

In May 2010, the Centers for Disease Control and Prevention (CDC) issued a health advisory warning about the potential for Q fever among travelers returning from Iraq and The Netherlands. [16There have been increasing reports of Q fever among deployed US military personnel and civilian contractors caused by endemic transmission in Iraq. In addition, a large ongoing outbreak of Q fever in the Netherlands may place travelers to these regions at risk for infection. [16In The Netherlands, almost 4000 cases of acute Q fever have been diagnosed since 2007, but none of those have involved US travelers. [16]

International statistics

First described in Australia in 1937, multiple international reports of Q fever clusters have been described over the years. The frequency ranges from 5% in urban areas to 30% in rural areas. Because Q fever infection can frequently be asymptomatic or present as a flulike illness in its milder forms, this results in an underrepresentation of the actual incidence. Epidemiological serological testing of specimens from blood donors has discovered a higher incidence throughout Africa, ranging from 18% to 37%, whereas "at-risk" farmers in the United Kingdom demonstrated 29% seropositivity. The United Kingdom reports approximately 100 cases annually.

In southern France and Spain, Q fever is highly prevalent; this disease is the second most common cause of community-acquired pneumonia and causing 5-8% of endocarditis cases. More recently, a few clusters of Q fever were reported in the province of Nova Scotia, Canada, and were related to exposure to parturient cats.

Q fever is endemic in the Middle East. Transmission may be influenced by hot, dusty conditions and livestock farming practices that may facilitate windborne spread.

In addition, a large number of Q fever cases have been reported in The Netherlands since 2007, with over 3700 human cases reported through March 2010. [1617Infected dairy goat farms are believed to be the source of the outbreak, and most human cases have been reported in the southern region of the country. [16]

Moreover, acute disease seems to have regional variations. An influenzalike illness is the most common presentation of Q fever in Australia. Hepatitis has been reported in France, southern Spain, and Ontario, Canada. Pneumonia is more common in Crete; Switzerland; Nova Scotia, Canada; and the Basque region of Spain. The reason for these variations is unknown, but animal studies suggest important strain differences could be a factor.

Racial, sexual, and age differences in incidence

Although Q fever has no reported racial predilection, there are differences between the sexes and variations among age groups.

Symptomatic Q fever is more common in males (ratio range, 1.5-3.5:1), [12accounting for 77% of Q fever cases reported in the United States. In Australia and France, males are 5-fold and 2.5-fold more likely than females to develop disease, respectively. Occupational and recreational exposure (eg, on farms, in industry [abattoirs], in work as veterinarians, while hunting) could represent a selection bias.

Adults are affected more often than children; the average age of infected individuals is approximately 45-50 years. Where cattle are the reservoir, the disease is most prevalent in active men aged 25-40 years. The incidence, as determined by the age at which seroconversion of blood donors occurs, can be deceptive because children, elderly persons, and sick persons do not donate blood.

Patients older than 15 years are more likely to present with clinical symptoms. Symptomatic Q fever is rare in children but, if present, manifests as in adults, whether acute or chronic. [12During the largest outbreak in Switzerland, symptomatic Q fever was 5 times more likely to occur in those aged 15 years or older than those younger than 15 years, [18whereas a study in Greece indicated that the prevalence of clinical cases in children increased with age.

Data from one study suggested an increasing incidence of hepatitis with young age and an increasing incidence of pneumonia with aging. Infection during pregnancy can lead to premature birth, low birth weight, and spontaneous abortion. Chronic Q fever has also been associated with recurrent miscarriages.

Prognosis

Acute Q fever is a self-limited disease (in 38% of cases) and has an excellent prognosis if properly diagnosed and treated. More than 50% of patients are asymptomatic, and only 2-4% require hospitalization. The mortality rate for symptomatic patients is less than 1%. Children are usually more mildly affected than adults.

Chronic Q fever requires prolonged antimicrobial therapy and close follow-up care with an infectious disease specialist. Frequent relapses (50%) are observed despite adequate therapy, and this disease carries mortality rates that can exceed 60%. The most common cause of chronic Q fever is endocarditis. Untreated endocarditis is almost universally fatal, although the mortality rate decreases to less than 10% with appropriate treatment; the overall mortality rate remains 10-25%.

Complications of Q fever may include the following:

  • Thrombocytopenia

  • Endocarditis caused by chronic infection as well as infection of vascular aneurysms and prostheses, which can lead to severe heart failure

  • Spontaneous abortion and premature labor

  • Reactivation during pregnancy

  • Meningoencephalitis

  • Increased rate of abortions

  • Chronic fatigue syndrome

Patient Education

Patient education focuses primarily on issues of avoidance and deterrence, such as the following:

  • Avoid ingestion of unpasteurized milk and dairy products, particularly goat cheese

  • Avoid parturient and farm animals and exposure to animal birth products (eg, placenta), especially in the setting of immunosuppression, pregnancy, or known valvular heart disease

  • Birthing should take place in indoor facilities

  • Properly dispose of placentae, fetal membranes, and aborted material

  • Minimize occupational exposure

  • Maintain appropriate precautions during periods of potential exposure

  • Take precautions to avoid tick bites, including using permethrin, diethyltoluamide (DEET), and other repellents (see Tick-borne Diseases)

  • Identify infections in domesticated animal populations

See also Prevention.

For patient education information, see Ticks.

CLINICAL PRESENTATION


History

Q fever is a protean disease that lacks a distinct clinical presentation. Almost 50% of patients are asymptomatic. Symptomatic infection is more common in adults than in children and is more common in men than in women. Common presentations vary geographically. For example, in the Basque region of northern Spain, pneumonia is a common finding, whereas in southern Spain, hepatitis predominates.

The primary factor leading to the identification of Q fever is the epidemiologic circumstance: a history of exposure, particularly occupational exposure, exposure to parturient animals or their newborn, or tick bites.

Most common symptoms include fever.

Acute Q fever

Sixty percent of patients with Q fever are asymptomatic, and others may have mild disease. The incubation period varies from 2 to 6 weeks (range, 14-39 d; average, 20 d). The 3 main clinical presentations are as follows [31519:

  • A self-limited, influenzalike febrile illness (up to 40°C) (88-100%) of abrupt onset, which is often accompanied by headache (68-98%) (typically retrobulbar), myalgia (47-69%) (arthralgia is uncommon), chills (68-88%), fatigue (97-100%), and sweats (31-98%); the temperature returns to normal within 5-14 days

  • Pneumonia (predominant in North America), usually mild in nature (crackles auscultated in 50% of cases) or as an incidental radiographic finding; when there is respiratory involvement, patients have a dry, nonproductive cough (24-90%), dyspnea, and pleuritic chest pain; this condition is rarely fulminant but occasionally progresses to acute respiratory distress syndrome (ARDS)

  • Hepatitis (predominant in Europe), usually with mild elevation of transaminases (2-3 times the reference range) and may be associated with antismooth muscle, antiphospholipid, or antinuclear antibodies; jaundice and acute gastrointestinal (GI) symptoms (nausea and vomiting, diarrhea [rare], right upper quadrant abdominal pain) are rare; manifestations resolve within 2-3 weeks.

Cardiovascular and neurologic manifestations develop in approximately 1% of patients and include pericarditis, myocarditis, acute endocarditis, and meningoencephalitis. A dissociation between heart rate and temperature occurs in one third of cases, some patients with acute Q fever pericarditis report chest pain, patients with myocarditis may experience palpitations, chest pain, or dyspnea. Rarely, individuals with acute Q fever may develop endocarditis, which appears to be an autoimmune complication of early infection and may be associated with antiphospholipid antibody syndrome. These cases may be associated with an IgG anticardiolipin antibody level of more than 100 immunoglobulin G-type phospholipid units. [202122Q fever endocarditis appears to occur primarily in men or in those who are older than 40 years, who are pregnant, who are immunocompromised, and/or who have underlying valvular disease. [23]

The 3 major neurologic syndromes of Q fever are meningoencephalitis or encephalitis, meningitis, and myelitis and peripheral neuropathy. Other neurologic symptoms may include headache, confusion, and neck stiffness. Persistent Q fever has been associated with ischemic stroke in elderly patients. [24]

Dermatologic manifestations in the form of erythema nodosum or other nonspecific exanthemas, maculopapular rash, or diffuse punctiform pruritic rash may also be associated with acute disease. Rash is not a typical feature of Q fever, but skin manifestations have been reported in up to 20% of French patients. [19]

Obstetric manifestations include spontaneous abortion. Rare presentations have included thyroiditis, mediastinal lymphadenopathy, pancreatitis, mesenteric panniculitis, epididymitis, orchitis, priapism, inappropriate secretion of antidiuretic hormone (SIADH), optic neuritis, Guillain-Barré syndrome, and extrapyramidal neurologic disease. Acute Q fever in pregnancy is more likely to be asymptomatic and to result in chronic infection than is acute Q fever in nonpregnant women.

Chronic Q fever

Among patients with acute infection, 0.2-1.4% may develop chronic infection, but few data are available regarding this. Chronic infection (defined as infection lasting longer than 6 months) may not manifest until months or even years after acute infection. [31519]

Endocarditis with negative culture findings and seropositivity (culture positivity and seropositivity or culture negativity and seronegativity are relatively uncommon) is the main clinical presentation of chronic Q fever, usually occurring in patients with preexisting cardiac disease including valve defects, rheumatic heart disease, and prosthetic valves. Patients in immunocompromised states (eg, due to acquired immunodeficiency syndrome [AIDS], renal failure, hematologic cancer [including lymphoma], and long-term corticosteroid use) are also susceptible. Patients may present with heart failure or nonspecific symptoms, including low-grade fever, fatigue, chills, arthralgia, dyspnea, rash from septic thromboembolism, and night sweats.

Other systemic manifestations include the following:

  • Vascular (infections of aneurysms, grafts, prostheses)
  • Osteoarticular (osteomyelitis, [6coxitis, spondylodiskitis, arthritis, septic arthritis, no associated host factors in children, immunocompromise or prosthetic joints in adults)
  • Obstetric (spontaneous abortion, premature labor [likely due to placentitis])
  • Hepatic (chronic hepatitis [usually associated with endocarditis])
  • Neurologic (mononeuritis, optic neuritis [6)
  • Pulmonary (interstitial fibrosis, pseudotumor)
  • Renal (glomerulonephritis)
  • Hematologic malignancy (B-cell lymphoma [25)

Chronic fatigue syndrome has also been described in approximately 10%-20% of patients, more than 6 months following acute Q fever. In addition, C burnetii could be added to the organisms involved in TORCH syndrome (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex). [26]

 

Physical Examination

Specific physical findings may be absent in acute Q fever. When present, physical findings vary with the clinical presentation. In chronic Q fever, findings consistent with endocarditis and hepatitis are more frequently found. Aseptic meningitis/encephalitis occurs in approximately 1% of acute and chronic Q fever cases.

Acute Q fever

Signs of acute Q fever may include the following:

  • Pneumonia: High-grade fever and nonspecific crackles, rales, rhonchi, or wheezing; dry cough, pleuritic chest pain, dyspnea, tachypnea; less frequently, signs of consolidation or pleural effusion

  • Isolated fever: Fever may be low grade but is usually as high as 40°C

  • Hepatitis: Hepatomegaly or, in rare cases, jaundice; fever, malaise, right upper quadrant abdominal pain may be present

  • Meningeal signs, pericardial rub (pericarditis), and signs of heart failure may be present; tachycardia, an irregular pulse, and a gallop rhythm (myocarditis)

  • Meningitis or encephalitis (rare, approximately 1%): Severe headache, stiff neck, fever

  • Nonspecific exanthemas (20%), most commonly a maculopapular rash on the trunk; erythema nodosum has also been described

Chronic Q fever

Endocarditis is the most common presentation of chronic disease and manifests as low-grade fever (or no fever), augmentation of a known heart murmur, signs of heart failure, hepatosplenomegaly and splenomegaly (approximately 50%), jaundice (occasional), clubbing, arterial emboli (approximated 33%), vegetations on any valve (although aortic and prosthetic valves are favored), and purpuric rash (approximately 20%). [3The aortic and mitral valves are more often involved.

DDx


Diagnostic Considerations

Q fever is difficult to diagnose, primarily because physicians tend not to think of it in the differential diagnosis. Failure to consider the diagnosis and failure to maintain an epidemiologic approach with any cluster of clinical presentations, particularly atypical pneumonia or hepatitis, eliminates any possibility of making the diagnosis.

The Centers for Disease Control and Prevention (CDC) recommends that physicians evaluate travelers, particularly military personnel and civilian contractors, for Q fever if they present with febrile illness, pneumonia, or hepatitis. [16Confirmed and suspected cases should be reported to local health departments.

Consider the possibility of tick-borne illnesses in all patients with febrile illnesses. Also, exposures to animals, animal by-products, and parturient animals are risk factors. In patients with culture-negative endocarditis, consider infection with C burnetii.

In this age of concern for terrorism with biologic agents, Q fever is on the list of possible agents. The initial diagnosis might be delayed by the fact that it is so uncommon in most locations. [8]

Other conditions that are considered in the differential diagnosis include the following:

  • Acute interstitial pneumonitis

  • Arbovirus encephalitis

  • Atypical pneumonia caused by viruses, Chlamydia species, or Mycoplasma

  • Bacterial and infective endocarditis, bacterial pericarditis

  • Brucellosis

  • Chlamydial infections

  • Connective-tissue diseases

  • Hepatitis: Drug-induced, granulomatous, viral

  • Ebstein-Barr virus

  • Leptospirosis

  • Mediterranean fever

  • Meningoencephalitis, aseptic meningitis

  • Osteomyelitis or osteoarticular Infection

  • Southern tick-associated rash illness (STARI)

  • Spontaneous abortion, placentitis

  • Tick-borne diseases (Colorado tick-borne diseases, ehrlichiosis, Lyme disease, relapsing fever, Rocky Mountain spotted fever, tularemia)

  • TORCH syndrome (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex infections)

  • Vascular graft infections

  • Visceral leishmaniasis

Differential Diagnoses

TREATMENT & MANAGEMENT

Approach Considerations

As with any patient with a febrile illness, the physician should maintain a sufficient level of suspicion about any patient with fever to exclude other potentially life-threatening diseases, which, in the case of tick-borne disease, involves presumptive antibiotic therapy.

Although specific antimicrobial therapy is indicated, most patients improve spontaneously. However, when Q fever is diagnosed, the administration of antibiotics is appropriate to prevent progression to chronic disease, which is far more resistant to treatment. In addition, supportive care with fluids, antitussives, and antipyretics may improve patient comfort. Patients should avoid ingestion of unpasteurized dairy products as well.

Surgical intervention may be necessary in some cases; for example, surgical treatment can affect survival in endovascular complications such as mycotic aneurysm or vascular graft infections. [12Valvular replacement is indicated for intractable heart failure. C burnetii can persist on endocardial tissue even after valve replacement; therefore, antibiotics should be continued following surgery. Surgical debridement is also recommended for osteoarticular infections. [12]

Consultations

Consultation with an infectious diseases specialist is warranted, particularly in cases of suspected chronic Q fever. In addition, consult an internist for admission and management of patients who are immunocompromised, elderly, or who have endocarditis.

In pregnant women, an obstetric consultation should also be considered. Cardiothoracic, vascular, and orthopedic surgeons as well as a cardiologist may be consulted in selected cases.

Management of Acute Q Fever

As many as 60% of patients with Q fever are asymptomatic. The disease is self-limiting and spontaneously resolves within 2 weeks in 38% of the remaining patients. However, antibiotic treatment has been shown to reduce the duration of disease, especially if initiated within 3 days of illness onset. The optimal duration of treatment has not been adequately studied, but antibiotics are generally given for 14-21 days, usually in an outpatient setting.

Doxycycline has been the agent most frequently investigated, [37and it is currently the treatment of choice.

Fluoroquinolones can be used as alternative antibiotic agents. Ofloxacin and pefloxacin have been used with success in patients. Ciprofloxacin demonstrated higher minimum inhibitory concentration (MIC) values than other fluoroquinolones and doxycycline. Levofloxacin showed bacteriostatic activity in vitro. [37]

Fluoroquinolones may offer a theoretical advantage in meningoencephalitis, because these agents possess better cerebrospinal fluid (CSF) penetration. A literature review demonstrated that the choice of antimicrobial therapy (doxycycline vs fluoroquinolones) did not affect resolution of acute disease or severity of neurologic sequelae. [12]

Macrolides, especially azithromycin and clarithromycin, can also be used as alternative agents, but some strains of C burnetii show resistance. [12Trimethoprim-sulfamethoxazole (TMP-SMZ) has also been used. [123]

No reliable regimen is available for children (< 8 y) or pregnant women. Macrolides or TMP-SMZ may be options in these populations. [1219]

Adjuvant corticosteroid treatment has been used in antimicrobial-nonresponsive hepatitis.

Management of Chronic Q Fever

Chronic C burnetii infections are very difficult to treat. A prolonged combined antimicrobial regimen is recommended. Hospitalization may be warranted for intractable heart failure.

No drug used alone has been shown to be bactericidal against C burnetii. Therefore, prolonged combination therapy is recommended because of the high rate of relapse with treatment of shorter duration. No consensus on the ideal duration of therapy has been reached, but serial measurement of antibody titers should likely be used as a guide to duration of therapy.

The most current recommendation for endocarditis is combination treatment with doxycycline and hydroxychloroquine for at least 18 months to eradicate any remaining C burnetii and prevent relapses. An alternative option is combination of doxycycline and a fluoroquinolone for at least 3-4 years. Other proposed alternatives include doxycycline or fluoroquinolones with rifampin therapy, although significant drug interactions could limit these regimens. [12]

The use of hydroxychloroquine is based on the assumption that it will elevate the pH within the phagolysosome vacuole of the monocyte, where C burnetii resides. This might affect the metabolism of the organism, rendering it more susceptible to the effects of doxycycline.

Endovascular complications should also be treated with doxycycline and hydroxychloroquine in combination, although the optimal regimen is not well defined. [12Osteoarticular infections should also be treated with prolonged antimicrobial combination therapy, along with surgical debridement. A regimen of doxycycline and hydroxychloroquine, with or without rifampin, has been suggested. [12]

Long-Term Monitoring

Although not a reportable condition in all 50 states (Delaware, Iowa, Oklahoma, Vermont, and West Virginia are excluded), physicians may consider notifying public health officials, depending on the circumstances and potential risk of others developing Q fever.

Patients should follow up with their primary care provider to confirm complete recovery. Patients with endocarditis or a history of valvular disease may require referral to a cardiologist or cardiothoracic surgeon for possible valve replacement.

Because of the risk of chronic infection, clinical and serologic follow-up for 2 years is recommended, particularly in individuals at risk. Patients with an IgG phase I >1:512 twelve months after treatment should undergo closer serological and clinical follow-up as they may have the highest risk to progress to chronic Q fever. [38]

The following includes a general summary of monitoring in acute and chronic Q fever.

Acute Q fever

Baseline transthoracic echocardiography should be performed to assess for vegetations. [12Follow-up serology should be performed at least twice over 6 months. If phase I immunoglobulin (IgG) antibodies are found in titers of 1:800 or more, transesophageal echocardiography should be performed along with serum polymerase chain reaction (PCR) measurements, when possible. [12]

Chronic Q fever

Monthly follow-up serology and clinical assessment are recommended during antimicrobial therapy and for the first 6 months following withdrawal, then every 6 months for 2 years, and possibly yearly thereafter. Phase I IgG titers of 1:200 or less are the best predictor of cure.

Perform echocardiography every 3 months during antimicrobial therapy and every 6 months for the first 2 years following drug withdrawal.

High-risk populations should be screened for glucose-6-phosphate dehydrogenase deficiency before receiving hydroxychloroquine. If hydroxychloroquine is used, a yearly ophthalmologic evaluation is required to rule out retinal toxicity.

Patients should be reminded of photosensitivity risk while on doxycycline therapy.

Prevention

C burnetii must be cultured in biosafety level 3 laboratories. Use only seronegative sheep in research facilities.

Isolation and decontamination with standard precautions are recommended for healthcare workers because person-to-person transmission is rare. Decontamination is accomplished with soap and water or after a 30-minute contact time with 5% quaternary ammonium compound (MicroChem plus; National Chemical Laboratories, Inc, Philadelphia, Pa), 5% hydrogen peroxide, or 70% ethyl alcohol.

Postexposure prophylaxis for 5 days by using tetracycline or doxycycline is effective if initiated within 8-12 days of exposure. [39Treatment with tetracycline during the incubation period may delay but not prevent the onset of symptoms.

If the patient's epidemiologic risk factor suggests that other people may share that risk factor (eg, an abattoir worker's coworkers and family members in a case contracted from a pregnant pet), the physician should notify the appropriate public health authorities.

Vaccine prophylaxis

Vaccine [101540is primarily used in at-risk people, such as veterinarians, abattoir workers, farmers, or others in occupations that require close contact with animals. No vaccine is available for children.

A whole-cell killed vaccine (Q-Vax) has been licensed in Australia since 1989, but it is not available in the United States. [8Prevaccination screening is essential and includes history, skin testing, and serology, usually by indirect immunofluorescence (IIF). All 3 components must be negative before vaccine administration. Occasionally, large local reactions are reported.

An investigational vaccine is only available in the United States after consultation with the US Army Medical Research Institute of Infectious Diseases (USAMRIID) (Official mailing address: Commander USAMRIID, Attn: MCMR-UIZ-R, 1425 Porter Street, Frederick, MD 21702-5011). The phase II USAMRIID study investigating the vaccine is currently suspended and has been since May 2011 (clinicaltrials.gov ID:NCT00584454). No other vaccine for Q fever is currently available in the United States, and there are no other investigation studies pending.

Acellular vaccines include a trichloroacetic-extracted vaccine (Chemovaccine) from the former Czechoslovakia and a chloroform-methanol residue vaccine (CMR) from the United States. They have been promoted to be as effective as Q-Vax, but with fewer side effects. Phase I human trials using CMR proved that vaccination was safe. Although its efficacy has been demonstrated in rodents, sheep, and nonhuman primates, human data are lacking.

MEDICATION


Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Antimicrobial therapy is essential (though most cases of acute Q fever improve without intervention) to minimize risk of chronic Q fever. Prolonged antibiotic therapy is critical in managing chronic Q fever, although exact antibiotics recommended for use are in a state of flux. Consultation with an infectious disease specialist is recommended to assist in the choice of antibiotics. The best studied are combinations of doxycycline plus an additional antibiotic (eg, fluoroquinolone, rifampin, trimethoprim-sulfamethoxazole).

Patients with Q fever who are misdiagnosed with legionellosis have responded well to intravenous (IV) erythromycin, which probably is effective for pregnant patients, although no controlled trials have been performed. Some investigators use lysosomal alkalinizing agents (eg, hydroxychloroquine) for patients with chronic Q fever to increase the effectiveness of antibiotics.

Treatment of pregnant women is complicated. Infectious disease and obstetric consultations should be sought.

Antibiotics, Other

Class Summary

Antibiotic drugs are used to provide in vivo or in vitro activity against Coxiella burnetii infections. However, empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the clinical setting.

Doxycycline is the drug of choice (DOC) in Q fever; however, in a series of pregnant patients with Q fever, trimethoprim-sulfamethoxazole (TMP-SMZ) was used with some success. [42In the chronic setting, the addition of chloroquine to doxycycline may improve outcomes, although data are sparse.

Doxycycline (Vibramycin, Doryx, Monodox)

Doxycycline is the first-line agent for both acute and chronic Q diseases. This agent is a bacteriostatic drug that interferes with bacterial protein and cell-wall synthesis during active multiplication by binding to 30S ribosome. For severe cases, administer intravenously (IV); for outpatients, oral administration (PO) is preferred.

Ofloxacin

Ofloxacin is an alternative antibiotic to doxycycline in acute Q fever. This quinolone agent is a derivative of pyridine carboxylic acid with broad-spectrum bactericidal effect. Quinolones are effective in treating Q fever alone or when combined with doxycycline; consultation with an infectious disease specialist is recommended before its use.

Rifampin (Rifadin)

Rifampin is used to treat all forms of tuberculosis in combination with at least one other antituberculous drug. This agent inhibits RNA synthesis in bacteria by binding to the beta subunit of DNA-dependent RNA polymerase, which in turn blocks RNA transcription. Cross-resistance has only been shown with other rifamycins; combination therapy with doxycycline should be continued for chronic Q fever for at least 18 months.

Sulfamethoxazole and Trimethoprim (Bactrim, Bactrim DS, Septra DS)

Sulfamethoxazole and trimethoprim inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. This would be a drug to use in pregnant women after consultation with the patient's obstetrician and an infectious disease specialist.

Azithromycin (Zithromax, Zmax)

Zithromax treats mild to moderate microbial infections by binding to the 50S ribosomal subunit of susceptible microorganisms and blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis, however, is not affected.

This agent concentrates in phagocytes and fibroblasts, as demonstrated by in vitro incubation techniques. In vivo studies suggest that the concentration in phagocytes may contribute to drug distribution to inflamed tissues. Plasma concentrations are very low, but tissue concentrations are much higher, giving azithromycin value in treating intracellular organisms. This drug has a long tissue half-life.

Tetracycline

Tetracycline treats susceptible both gram-positive and gram-negative bacterial infections, as well as infections caused by species of Mycoplasma, Chlamydia, and Rickettsia. This agent inhibits bacterial protein synthesis by binding with the 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Chloramphenicol

Chloramphenicol is used in patients who do not tolerate tetracycline. This agent binds to the 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Chloramphenicol is effective against gram-negative and gram-positive bacteria. In severe cases, administer intravenously (IV); for outpatients, administer orally (PO).

Ciprofloxacin (Cipro)

Ciprofloxacin is a quinolone that is effective in treating Q fever alone or when combined with doxycycline. Consultation with an infectious disease specialist is recommended before its use.

Antimalarials

Class Summary

Antimalarial agents are used for their alkalinizing action within the phagolysosomal compartment of monocytes, where C burnetii resides.

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine is used in chronic Q fever with doxycycline, which is more effective. This agent results in fewer relapses than that with doxycycline and ofloxacin, and its treatment duration can be shortened. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.

Analgesics, Other

Class Summary

Treatment of Q fever is symptomatic and supportive. Bed rest and mild analgesic-antipyretic therapy often help to relieve the lethargy, malaise, and fever associated with this disease.

Ibuprofen (Advil, Motrin, Caldolor, I-Prin)

Ibuprofen is usually the drug of choice (DOC) to treat mild to moderate headache unless contraindicated. This agent is also one of the few nonsteroidal anti-inflammatory drugs (NSAIDs) that is indicated for reduction of fever.

Acetaminophen (Tylenol, Feverall, Mapap, Aspirin Free Anacin)

Acetaminophen is the drug of choice (DOC) for treatment of pain in documented hypersensitivity to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and in gastrointestinal (GI) disease or with oral (PO) anticoagulants. This agent reduces fever by directly acting on hypothalamic heat-regulating centers, increasing the dissipation of body heat by vasodilation and sweating.

Salicylates

Class Summary

Acetylsalicylic agents are effective in alleviating headaches, possibly because of their inhibition of prostaglandin synthesis.

Aspirin (Anacin, Ecotrin, Bayer Aspirin Extra Strength, Bufferin)

Aspirin is used to treat mild to moderate pain and headache. This agent blocks prostaglandin synthetase action, which in turn inhibits prostaglandin synthesis and prevents formation of platelet-aggregating thromboxane A2. Aspirin enhances dissipation of heat by vasodilating peripheral vessels, causing a decrease in body temperature, as well as acts on the hypothalamus heat-regulating center to reduce fever.

Antitussives

Class Summary

Treatment of Q fever is symptomatic and supportive. Antitussives help to relieve the coughing associated with pneumonia, which is among the most common presenting symptoms. Few data on the effectiveness of expectorants outside the test tube have been reported. The prototype antitussive, codeine, was successfully used in models of chronic and induced cough, but clinical data for upper respiratory infections are limited. Existing data report the effectiveness of codeine to be somewhat equal to that of guaifenesin, dextromethorphan, or even placebo.

Dextromethorphan/guaifenesin (Mucinex DM, Robafen DM, Double Tussin DM)

Dextromethorphan is used for treatment of minor cough resulting from bronchial and throat irritation.

Benzonatate (Tessalon, Zonatuss)

Benzonatate is used for the symptomatic relief of cough. This agent suppresses cough by anesthetizing stretch receptors located in the respiratory passages, lungs, and pleura by dampening activity and reducing cough reflex.

Codeine/guaifenesin (Tussin-C, Allfen CD, ExeClear-C)

The combination of codeine and guaifenesin is used to treat minor cough resulting from bronchial and throat irritation