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Q FEVER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Q fever is a ubiquitous worldwide zoonosis caused by the rickettsia-like bacteria Coxiella burnetii, an obligate intracellular microorganism, with a world wide geographic distribution, and which multiplies in the placenta of domestic ungulates, mostly cows, sheep and goats. Humans are most commonly infected by transmission of aerosolized particles from environments that have been contaminated by placental and birth fluids of infected livestock. The infection, which follows an incubation period of about 3 weeks, occurs as an acute or chronic disease. A self-limited febrile illness, with atypical pneumonia and granulomatous hepatitis, is the most frequent clinical presentation of acute Q fever, and endocarditis appears to be the primary manifestation of chronic Q fever.

Specific Substances

    1) Australian Q fever
    2) Balkan grippe
    3) Coxiella burnetii
    4) Derrick-Burnet disease
    5) Hiberno-vernal bronchopneumonia
    6) Nine mile fever
    7) Query fever
    8) Rickettsia burnetii

Available Forms Sources

    A) FORMS
    1) Coxiella burnetii, the causative agent of Q fever, is a strict obligate intracellular pleomorphic coccobacillus with a gram negative cell wall and is a parasite when infecting its host, but can also survive in the environment (Spryidaki et al, 1998; (Boyle & Hone, 1999).
    B) SOURCES
    1) Sources of infection include inhalation of Coxiella burnetii, aspiration of infected material, contaminated raw milk ingestion, exposure to aerosolized particles from products of conception from infected animals, and occasionally tick bites (Dambro & Griffith, 1999; Anon, 1997). Q fever is an occupational hazard among abattoir workers, farmers, slaughterhouse workers, veterinarians, and personnel working in research centers (Sawyer et al, 1987; Aw & Ratti, 1997; Garner et al, 1997).
    2) A heightened risk of disease exists in persons who work with animals, which includes ranchers, research laboratory workers, and persons in other occupations or with avocational interests resulting in close animal contacts with infected animals or tissues. Transmission of Q fever to research investigators and laboratory personnel has occurred when flocks of sheep used as experimental subjects were infected (Anon, 1997).
    3) Sources of secondary aerosols may include contaminated clothing, wool, hide, bedding, and soil (Rosen et al, 1998).
    C) USES
    1) Because of the stability of the C. burnetii organism, and its inhalational mode of transmission, this agent may be considered as a bio-terrorist agent in aerosol form. Particles less than 3 to 5 microns in diameter can reach the terminal bronchioles (Hornick, 1996). In nature, C. burnetii is very resistant to killing and may survive for several weeks; the organism can be spread by the wind (Maurin & Raoult, 1999).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) ACUTE Q fever is a flu-like illness, with severe headaches and cough, which is self-limiting (2 to 7 days) or easily treated with antibiotics. Clinical signs vary greatly from patient to patient. Five to ten percent of patients may develop prolonged fever, rash, atypical pneumonia, granulomatous hepatitis, neurological disorders (severe retrobulbar headache in 60% to 90% of cases), myocarditis, and pericarditis. The incubation period of Q fever ranges from 14 to 39 days, with an average of 20 days. Typically, 3 major presentations are described: a self-limited flu-like syndrome, pneumonia, and hepatitis.
    B) Pediatric patients have severity of illness ranging from subclinical infection to a febrile systemic illness with severe frontal headache, arthralgia, and myalgia often accompanied by respiratory symptoms. Fewer than 50% of children will have cough or pneumonia. Children are infrequently diagnosed with chronic Q fever.
    C) CHRONIC Q fever may occur with or without a recognized antecedent acute episode. It is a severe disease requiring prolonged antibiotic therapy due to infection resulting in culture-negative endocarditis, chronic hepatitis, osteoarthritis, and less frequently, vascular aneurysm and prosthesis infections. Risk of chronic infection is greater in patients with previous vascular or valvular disease or in patients with pre-existing immunodeficiency. It is described as lasting longer than 6 months after disease onset and occurs in approximately 5% of patients infected with C. burnetii. Prolonged follow-up is required because of the possibility of late relapse. C. burnetii multiplies in the macrophages and a permanent rickettsemia results in very high levels of persistent antibodies.
    1) A chronic, post-acute Q fever syndrome, which has been present for several years in some cases, resembles chronic fatigue syndrome. Symptoms include fatigue, joint aches, sleep disturbance, night sweats, myalgias, nausea, and persistent headache.
    0.2.3) VITAL SIGNS
    A) Q fever is characterized by an acute onset of high fever in most patients. Decreased pulse rate has been reported early in the course of illness.
    0.2.5) CARDIOVASCULAR
    A) Blood culture-negative endocarditis is the most prominent clinical feature of chronic Q fever.
    B) Pericarditis and/or myocarditis (frequently fatal) may occur in some cases of acute Q fever.
    0.2.6) RESPIRATORY
    A) Acute Q fever is generally regarded as a respiratory disease, with atypical pneumonia and pulmonary involvement occurring in up to 90% of patients.
    0.2.7) NEUROLOGIC
    A) Severe retrobulbar headache is a typical and outstanding clinical feature of acute Q fever.
    B) Lymphocytic meningitis secondary to Q fever has been reported.
    C) Nuchal rigidity may be a prominent clinical manifestation of acute Q fever.
    D) A post-acute Q fever fatigue syndrome, with fatigue and disability usually lasting for 6 to 9 months is not uncommon.
    0.2.8) GASTROINTESTINAL
    A) Abdominal pain, nausea and vomiting, which may be persistent, have been reported during acute stages of Q fever.
    B) Splenomegaly is commonly associated with the endocarditis of chronic Q fever.
    0.2.9) HEPATIC
    A) Hepatic dysfunction, with elevated serum liver enzyme values, is common, but generally self-limiting, in cases of acute Q fever.
    B) Granulomatous hepatitis is reported in acute and sometimes chronic forms of Q fever and may be due to a hypersensitivity mechanism.
    0.2.10) GENITOURINARY
    A) Acute renal failure is reported as an unusual major complication of acute Q fever.
    B) Albuminuria is common early in the course of illness.
    C) Glomerulonephritis, associated with chronic Q fever endocarditis, has been reported.
    D) Microscopic hematuria is commonly seen in chronic Q fever patients.
    0.2.13) HEMATOLOGIC
    A) Anemia is occasionally reported early in the course of acute Q fever.
    B) Thrombocytopenia may occur in patients with acute or chronic Q fever.
    C) Bone marrow biopsies have shown fibrin-ring granulomas in some patients with acute Q fever.
    0.2.14) DERMATOLOGIC
    A) The characteristic rickettsial rash is absent in patients with acute Q fever. A mild erythema or a transient maculopapular rash may occur.
    B) Profuse sweating is characteristic of acute Q fever.
    0.2.15) MUSCULOSKELETAL
    A) Myalgia and malaise are common during acute Q fever.
    B) Rare cases of rhabdomyolysis associated with acute Q fever have been reported.
    0.2.20) REPRODUCTIVE
    A) Q fever during pregnancy has resulted in significant morbidity and mortality. Infertility and spontaneous abortion may occur following infection of C. burnetii. Intrauterine transmission of Coxiella burnetii has been documented in humans.

Laboratory Monitoring

    A) Monitor CBC and platelet count, renal and hepatic function, and urinalysis. Diagnosis is confirmed by acute and convalescent serology. Chest x-ray is indicated for patients with pulmonary signs/symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Oral exposure to Coxiella burnetii is unusual, but may occur following ingestion of raw, contaminated milk or dairy products. Treatment measures should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    0.4.3) INHALATION EXPOSURE
    A) Antibiotics are the mainstay of treatment. Tetracycline or doxycycline is the drug of choice, and should be continued until the patient has been afebrile for 2 to 3 days. Chloramphenicol may be an alternative. Relapses of chronic Q fever are common, necessitating repeated courses of antimicrobial therapy. Coxiella burnetii can remain latent in tissues for years.
    B) Treatment of chronic endocarditis is prolonged and appears to be most effective when tetracycline or doxycycline is combined with rifampin, trimethoprim-sulfamethoxazole, or a fluoroquinolone (except in patients younger than 18 years old).
    C) Experimental inactivated whole cell vaccines for humans have proven effective, but are not yet commercially available outside Australia.
    0.4.4) EYE EXPOSURE
    A) Coxiella burnetii may be transmitted following the organism's penetration of skin abrasions or the conjunctivae, but this is uncommon. Treatment should include recommendations in the INHALATION EXPOSURE section.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Coxiella burnetii may be transmitted following the organism's penetration of skin abrasions or the conjunctivae, but this is uncommon. Treatment should include recommendations in the INHALATION EXPOSURE section.
    0.4.7) BITES/STINGS
    A) Very rarely, tick bites may be a cause of infection. Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Range Of Toxicity

    A) One Coxiella burnetii organism is capable of causing disease in humans. The organisms can survive a very long time in contaminated dust or aerosols, providing the potential for humans to acquire infection through inhalation. Person-to-person spread is rare.

Clinical Effects

Summary Of Exposure

    A) ACUTE Q fever is a flu-like illness, with severe headaches and cough, which is self-limiting (2 to 7 days) or easily treated with antibiotics. Clinical signs vary greatly from patient to patient. Five to ten percent of patients may develop prolonged fever, rash, atypical pneumonia, granulomatous hepatitis, neurological disorders (severe retrobulbar headache in 60% to 90% of cases), myocarditis, and pericarditis. The incubation period of Q fever ranges from 14 to 39 days, with an average of 20 days. Typically, 3 major presentations are described: a self-limited flu-like syndrome, pneumonia, and hepatitis.
    B) Pediatric patients have severity of illness ranging from subclinical infection to a febrile systemic illness with severe frontal headache, arthralgia, and myalgia often accompanied by respiratory symptoms. Fewer than 50% of children will have cough or pneumonia. Children are infrequently diagnosed with chronic Q fever.
    C) CHRONIC Q fever may occur with or without a recognized antecedent acute episode. It is a severe disease requiring prolonged antibiotic therapy due to infection resulting in culture-negative endocarditis, chronic hepatitis, osteoarthritis, and less frequently, vascular aneurysm and prosthesis infections. Risk of chronic infection is greater in patients with previous vascular or valvular disease or in patients with pre-existing immunodeficiency. It is described as lasting longer than 6 months after disease onset and occurs in approximately 5% of patients infected with C. burnetii. Prolonged follow-up is required because of the possibility of late relapse. C. burnetii multiplies in the macrophages and a permanent rickettsemia results in very high levels of persistent antibodies.
    1) A chronic, post-acute Q fever syndrome, which has been present for several years in some cases, resembles chronic fatigue syndrome. Symptoms include fatigue, joint aches, sleep disturbance, night sweats, myalgias, nausea, and persistent headache.

Vital Signs

    3.3.1) SUMMARY
    A) Q fever is characterized by an acute onset of high fever in most patients. Decreased pulse rate has been reported early in the course of illness.
    3.3.3) TEMPERATURE
    A) A fever to 40 degrees C (104 degrees F) or higher, with shaking chills, is a common clinical manifestation of acute Q fever (Rosen et al, 1998; Hornick, 1996) Sawyer et al, 1987; (Kosatsky et al, 1982; Derrick, 1937). Fever may persist for 10 to 14 days.
    1) Most pediatric patients will present with a fever of unknown origin (Dumler, 1996; Isaacs & Donald, 1998).
    3.3.5) PULSE
    A) Slow pulse rate, in comparison with the height of fever, has been reported early in the course of illness (Derrick, 1937).

Heent

    3.4.3) EYES
    A) Photophobia appears to be a prominent symptom of acute Q fever (Derrick, 1937).
    B) Optic neuritis is an uncommon clinical manifestation of acute Q fever (Fournier et al, 1998; (Murray & Tuazon, 1980).
    C) Uveitis and iritis have occasionally been reported as clinical manifestations of acute Q fever (Murray & Tuazon, 1980). Rare cases of choroidal neovascularization have been reported in the course of acute Q fever infection (Ruiz-Moreno, 1997).

Cardiovascular

    3.5.1) SUMMARY
    A) Blood culture-negative endocarditis is the most prominent clinical feature of chronic Q fever.
    B) Pericarditis and/or myocarditis (frequently fatal) may occur in some cases of acute Q fever.
    3.5.2) CLINICAL EFFECTS
    A) ENDOCARDITIS
    1) Blood culture-negative endocarditis is the most prominent clinical expression of chronic Q fever (Graham et al, 2000; Brouqui et al, 1993), with a reported incidence of 68% (57 of 84 chronic Q fever patients) and a reported mortality rate of 23.5% (Brouqui et al, 1993).
    a) Most Q fever patients who experience endocarditis have a history of valvular heart disease, particularly with aortic valve involvement. Brouqui et al (1993) reported 88.4% of cases had a pre-existent valvulopathy (Brouqui et al, 1993; Graham et al, 2000).
    b) Symptoms are nonspecific. The infection is difficult to eradicate (Graham et al, 2000; Hornick, 1996; Brouqui et al, 1993; Boyle & Hone, 1999).
    c) CASE REPORT - A 25-year-old Ethiopian woman with a significant history for mitral valve replacement due to a history of rheumatic heart disease developed chronic symptoms of increasing fatigue and fever along with a pruritic lower extremity rash, arthralgias and lower extremity edema. Chronic Q fever endocarditis was suspected. Blood cultures were negative for organisms; however, EIA studies were positive for Bartonella henselae and Coxiella burnetti. Despite antibiotic therapy the patient required urgent double valve replacement because of worsening congestive heart failure. The patient was found to have cross-reactivity between C. burnetii and R. rickettsii (Graham et al, 2000).
    d) Children have been reported to have chronic Q fever endocarditis, but this is uncommon (Al-Hajjar et al, 1997; Lupoglazoff et al, 1997).
    2) COMPLICATIONS - Arterial embolism has been reported in approximately 20% of these patients (Fournier et al, 1998). Signs of vasculitis are associated with endocarditis (Hornick, 1996).
    a) Jarisch-Herxheimer reaction, complicating the treatment of chronic Q fever endocarditis, has been reported. Documented elevations of serum cytokine concentrations (TNFa and IL-6) were noted (Kaplanski et al, 1998).
    3) Echocardiographic appearance of aortic valve vegetation and isolation of C. burnetii from a resected aortic valve may confirm the diagnosis of Q fever (Al-Hajjar et al, 1997).
    B) MYOCARDITIS
    1) Pericarditis and/or myocarditis (frequently fatal) may occur in some cases of acute Q fever (Fournier et al, 1998).
    C) PERICARDIAL EFFUSION
    1) Rare cases of pericardial effusion have been reported in patients with chronic Q fever (Fournier et al, 1998).

Respiratory

    3.6.1) SUMMARY
    A) Acute Q fever is generally regarded as a respiratory disease, with atypical pneumonia and pulmonary involvement occurring in up to 90% of patients.
    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) Even though Q fever is regarded as primarily a respiratory disease, the reported incidence of pulmonary involvement in Q fever is 0% to 90%. Reasons for the variations in incidence may include geographic strain variation, plasmids that may regulate virulence, and the source, route and dose of the infecting organism (Rosen et al, 1998; Murray & Tuazon, 1980; Merino et al, 1998; Kovacova et al, 1998a). Pneumonia does not appear until the third or fourth day of fever. An atypical pneumonia presentation of constitutional symptoms and extrapulmonary findings that often overshadow physical findings is common. A nonproductive cough, headache, and myalgias predominate. Symptoms vary from a benign self-limited disease to overwhelming pneumonia (Caron et al, 1998; Merino et al, 1998; Marrie et al, 1989).
    2) Chest films show patchy infiltrates, which frequently are multiple round, segmental opacities. Segmental (62%) and lobar (18%) areas of opacities are most commonly observed (Gikas et al, 1999). Consolidation may be seen in larger areas of the lungs, and linear atelectatic lesion occur in approximately 50% of pneumonia patients (Caron et al, 1998; Julius et al, 1999; Hornick, 1996; Kosatsky et al, 1982). No correlation appears to exist between extent of pulmonary involvement and course of the disease. Complete resolution of radiographic findings generally occurs in a mean of 39 days (Gikas et al, 1999).
    3) Pathologic findings of lungs at autopsy have shown consolidation similar to that of other bacterial pneumonias. Microscopic examinations have shown an exudate with many histocytes and no polymorphonuclear leukocytes, compatible with a nonbacterial process. Histologic features are those of a severe intra-alveolar, focally necrotizing, hemorrhagic pneumonia with accompanying necrotizing bronchitis and bronchiolitis (Hornick, 1996).
    B) CHEST PAIN
    1) Chest pain, sometimes pleuritic, is present in less than 20% of acute Q fever cases (Rosen et al, 1998; Murray & Tuazon, 1980; Merino et al, 1998).
    C) FIBROSIS OF LUNG
    1) Pulmonary interstitial fibrosis has been rarely reported in cases of chronic Q fever (Fournier et al, 1998).

Neurologic

    3.7.1) SUMMARY
    A) Severe retrobulbar headache is a typical and outstanding clinical feature of acute Q fever.
    B) Lymphocytic meningitis secondary to Q fever has been reported.
    C) Nuchal rigidity may be a prominent clinical manifestation of acute Q fever.
    D) A post-acute Q fever fatigue syndrome, with fatigue and disability usually lasting for 6 to 9 months is not uncommon.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Severe retrobulbar headache, reported in 60% to 90% of patients, is a typical and outstanding clinical manifestation of acute Q fever, and persists for several days after onset of the disease (Rosen et al, 1998; Sawyer et al, 1987; Derrick, 1937). Retroorbital pain has been reported in 10% to 15% of patients (Hornick, 1996). Severe headache has been described in pediatric patients with acute Q fever (Isaacs & Donald, 1998).
    B) MENINGITIS
    1) Lymphocytic meningitis secondary to Q fever has been reported (Schattner et al, 1993; Rosen et al, 1998). Aseptic meningitis and/or encephalitis has been reported in 0.2% to 1.3% of patients with acute Q fever (Fournier et al, 1998) and are rarely accompanied by seizures or coma. Acute encephalopathy with impairment of consciousness and abnormal pattern on EEG and CT scans of the brain have been reported following severe infections (Dumler, 1996).
    C) OPTIC NEURITIS
    1) Optic neuritis and uveitis are uncommon clinical manifestations of acute Q fever (Fournier et al, 1998; Murray & Tuazon, 1980).
    D) INCREASED MUSCLE TONE
    1) Nuchal rigidity may be a prominent clinical manifestation of acute Q fever (Murray & Tuazon, 1980).
    E) FATIGUE
    1) A post-acute Q fever fatigue syndrome, with fatigue and disability usually lasting for 6 to 9 months is not uncommon (Marmion, 1997; Ayres et al, 1998). Q fever fatigue syndrome has been reported to last as long as 5 to 10 years in some patients. Symptoms include incapacitating fatigue, myalgia and arthralgia, constant headache, profuse sweating, muscle fasciculation, blurred vision, ethanol intolerance, lymph node pain and a range of cerebral symptoms.
    F) CEREBELLAR DISORDER
    1) Sawaishi et al (1999) reported a 9-year-old boy with acute cerebellitis as a result of acute Q fever. Following 10 days of fever, the child developed a decreased level of consciousness. Other cerebellar signs which developed included ataxia, intention tremor, and dysarthria. CSF examination showed pleocytosis, and increased level of protein, and negative bacterial and viral studies. During convalescence, Coxiella burnetii was isolated from the CSF.

Gastrointestinal

    3.8.1) SUMMARY
    A) Abdominal pain, nausea and vomiting, which may be persistent, have been reported during acute stages of Q fever.
    B) Splenomegaly is commonly associated with the endocarditis of chronic Q fever.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Abdominal pain, nausea, and vomiting, which may be persistent, have been reported in acute Q fever (Sawyer et al, 1987; Kosatsky et al, 1982; Isaacs & Donald, 1998; Modol et al, 1999; Derrick, 1937). Acute abdominal pain requiring surgical laparotomy has been reported (Modol et al, 1999). Diarrhea may occur in up to 15% of patients (Sawyer et al, 1987).
    B) CONSTIPATION
    1) Constipation may occur in Q fever patients (Derrick, 1937).
    C) PANCREATITIS
    1) An uncommon manifestation of acute Q fever is pancreatitis (Fournier et al, 1998).
    D) SPLENOMEGALY
    1) Splenomegaly is commonly associated with the endocarditis of chronic Q fever (Hornick, 1996). Splenic rupture is a rare complication of acute Q fever (Fournier et al, 1998).

Hepatic

    3.9.1) SUMMARY
    A) Hepatic dysfunction, with elevated serum liver enzyme values, is common, but generally self-limiting, in cases of acute Q fever.
    B) Granulomatous hepatitis is reported in acute and sometimes chronic forms of Q fever and may be due to a hypersensitivity mechanism.
    3.9.2) CLINICAL EFFECTS
    A) LARGE LIVER
    1) Hepatic dysfunction is usually minimal, although hepatic involvement in cases of acute Q fever may be common (Rosen et al, 1998). Elevated serum liver enzyme values, indicating mild liver cell damage, may be common in mild forms of Q fever (Hornick, 1996). Hepatosplenomegaly is common in patients with chronic Q fever. Approximately 85% of Q fever patients have hepatic involvement (Hornick, 1996). Children may have increases in serum hepatic aminotransferases that spontaneously normalize within 20 to 30 days (Dumler, 1996). Hepatosplenomegaly has been described in pediatric patients with acute Q fever (Isaacs & Donald, 1998).
    B) TOXIC HEPATITIS
    1) Granulomatous hepatitis is reported in acute and sometimes chronic forms of Q fever (Yale et al, 1994; Rosen et al, 1998; Crespo et al, 1999) and may be due to a hypersensitivity mechanism. Granulomatous hepatitis complicating acute Q fever may respond to steroids (Crespo et al, 1999).
    2) Hepatitis, an uncommon clinical manifestation of chronic Q fever may be complicated by hepatic fibrosis and cirrhosis (Fournier et al, 1998).
    3) Liver biopsy generally shows a typical doughnut granuloma with fatty necrosis and is quasi-specific to Q fever (also seen in tuberculosis) (Yale et al, 1994; Rakel, 1999; Hornick, 1996).

Genitourinary

    3.10.1) SUMMARY
    A) Acute renal failure is reported as an unusual major complication of acute Q fever.
    B) Albuminuria is common early in the course of illness.
    C) Glomerulonephritis, associated with chronic Q fever endocarditis, has been reported.
    D) Microscopic hematuria is commonly seen in chronic Q fever patients.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) Acute renal failure secondary to acute Q fever has been reported as an unusual major complication (Morovic et al, 1993; Rosen et al, 1998).
    B) ALBUMINURIA
    1) Early in the course of illness, albuminuria is common (Derrick, 1937; Julius et al, 1999).
    C) GLOMERULONEPHRITIS
    1) Mesangial proliferative glomerulonephritis with acute renal failure, related to antiphospholipid antibodies, is reported as an uncommon complication of acute Q fever (Korman et al, 1998; Fournier et al, 1998). Most reports of glomerulonephritis are associated with chronic Q fever endocarditis.
    D) BLOOD IN URINE
    1) Microscopic hematuria has been reported in up to 80% of patients (20/25) with chronic Q fever (Sawyer et al, 1987).

Hematologic

    3.13.1) SUMMARY
    A) Anemia is occasionally reported early in the course of acute Q fever.
    B) Thrombocytopenia may occur in patients with acute or chronic Q fever.
    C) Bone marrow biopsies have shown fibrin-ring granulomas in some patients with acute Q fever.
    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) Early in the course of acute Q fever, hemolytic anemia and transient hypoplastic anemia may occasionally occur (Fournier et al, 1998; Sawyer et al, 1987).
    B) THROMBOCYTOPENIC DISORDER
    1) Patients with chronic Q fever may experience thrombocytopenia (12 of 22 patients, or 55%). Also reported are petechial or purpuric rash, splinter hemorrhages, and arterial emboli (Sawyer et al, 1987).
    C) GRANULOMA
    1) Bone marrow biopsy series have shown fibrin-ring granulomas present in four of seven specimens from different patients. A similar distinctive granulomatous pattern was also present in the liver of patients with acute Q fever (Yale et al, 1994; Sawyer et al, 1987).

Dermatologic

    3.14.1) SUMMARY
    A) The characteristic rickettsial rash is absent in patients with acute Q fever. A mild erythema or a transient maculopapular rash may occur.
    B) Profuse sweating is characteristic of acute Q fever.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) Patients with acute Q fever are reported to have an absence of a characteristic rickettsial rash, unlike typhus (Hornick, 1996; Murray & Tuazon, 1980; Derrick, 1937), but they may develop mild erythema or a transient maculopapular rash. Cutaneous lesions have been reported in approximately 22% of patients with chronic Q fever endocarditis (Granel et al, 1999) Brouqui, et al, 1993).
    2) A maculopapular or purpuric exanthema has been reported in up to 10% of patients with acute Q fever after the first week of fever (Fournier et al, 1998).
    B) ERYTHEMA NODOSUM
    1) A rare complication of acute Q fever is reported to be erythema nodosum (Fournier et al, 1998).
    C) EXCESSIVE SWEATING
    1) Profuse sweating and high fever are characteristic clinical manifestations of acute Q fever (Marmion, 1997).
    D) LOCAL INFECTION OF WOUND
    1) A chronic sternal wound infection developed in a patient in whom Q fever endocarditis was subsequently diagnosed. Cutaneous manifestations of chronic Q fever are rare, and generally limited to purpuric rash and erythema nodosum. In this case, Coxiella burnetii was detected by PCR methodology in the sternal wound specimen (Ghassemi et al, 1999).
    E) LIVEDO RETICULARIS
    1) A case of livedo reticularis, revealing a latent infective endocarditis due to Coxiella burnetii, was reported. Serodiagnosis was used to confirm Q fever; chronic Q fever and livedo regressed following antibiotic therapy (Granel et al, 1999).

Musculoskeletal

    3.15.1) SUMMARY
    A) Myalgia and malaise are common during acute Q fever.
    B) Rare cases of rhabdomyolysis associated with acute Q fever have been reported.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) Myalgia and malaise are common clinical manifestations of acute Q fever (Sawyer et al, 1987; (Rosen et al, 1998).
    B) ARTHRITIS
    1) Osteoarthritis and osteomyelitis are uncommon features of chronic Q fever (Brouqui et al, 1993).
    C) RHABDOMYOLYSIS
    1) Rare cases of rhabdomyolysis associated with acute Q fever have been reported (Carrascosa et al, 1997).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) THYROIDITIS
    1) Occasionally, thyroiditis may occur in acute cases of Q fever (Fournier et al, 1998).
    B) ABNORMAL ANTI-DIURETIC HORMONE
    1) A rare complication reported with Q fever is inappropriate secretion of antidiuretic hormone (Fournier et al, 1998).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) LYMPHADENOPATHY
    1) An uncommon manifestation of acute Q fever is lymphadenopathy, mimicking lymphoma (Fournier et al, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Q fever during pregnancy has resulted in significant morbidity and mortality. Infertility and spontaneous abortion may occur following infection of C. burnetii. Intrauterine transmission of Coxiella burnetii has been documented in humans.
    3.20.2) TERATOGENICITY
    A) INFECTION
    1) Intrauterine transmission of Coxiella burnetii has been documented, but the consequences of congenital Q fever are as yet undetermined (Fournier et al, 1998; Stein & Raoult, 1998; Tellez et al, 1998). Infection during pregnancy followed by fetal infection and death has been reported (Raoult & Stein, 1994; Stein & Raoult, 1998). Intrauterine growth retardation or death has been associated with human placental infection (Dumler, 1996; Raoult & Stein, 1994).
    3.20.3) EFFECTS IN PREGNANCY
    A) INFECTION
    1) Q fever during pregnancy may present as either the acute or chronic form. Significant morbidity and mortality have been associated with the disease during pregnancy. Q fever may be reactivated during subsequent pregnancies (Stein & Raoult, 1998). Placental infection in pregnant women has been documented by Coxiella burnetii culture; placental infection does not necessarily imply fetal infection since the placenta appears to act as an efficient barrier for the organism (Tellez et al, 1998).
    B) ABORTION
    1) Abortions, premature births, and low weight newborn infants have been reported in women with Q fever infections during pregnancy (Maurin & Raoult, 1999). Evidence exists for human intrauterine infection (Anon, 1997; Stein & Raoult, 1998). Coxiella burnetii has been isolated from the placentas of asymptomatic pregnant women (Raoult & Stein, 1994).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Coxiella burnetii has been isolated from the breast milk of mothers who acquired Q fever infection from 3 years to approximately 2 months prior to delivery (Sawyer et al, 1987).
    3.20.5) FERTILITY
    A) FERTILITY DECREASED FEMALE
    1) Female infertility is an unusual manifestation of infection with C. burnetii (Sawyer et al, 1987).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC and platelet count, renal and hepatic function, and urinalysis. Diagnosis is confirmed by acute and convalescent serology. Chest x-ray is indicated for patients with pulmonary signs/symptoms.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Leukocyte count is usually normal, however, up to 25% of patients may exhibit an elevated leukocyte count ranging from 14 x 10(9)/liter to 21 x 10(9)/liter (Brouqui et al, 1993). The leukocyte count in chronic Q fever may be elevated, normal or decreased (Fournier et al, 1998).
    2) Erythrocyte sedimentation rate may be elevated in acute Q fever patients.
    3) Thrombocytopenia may be noted in approximately 25% of patients with acute Q fever (Fournier et al, 1998; Maurin & Raoult, 1999). Thrombocytopenia is commonly found in chronic Q fever.
    4) Thrombocytosis may occur during the convalescence period of acute Q fever (Fournier et al, 1998).
    5) Autoantibodies are commonly found in patients with acute Q fever; their significance is unknown but they may be responsible for severe complications. Antimitochondrial antibodies and anti-smooth muscle antibodies are among autoantibodies found during Q fever (Fournier et al, 1998). The antibodies are generally transient and disappear during convalescence.
    a) Autoantibodies, particularly rheumatoid factor, anti-smooth muscle, or antinuclear antibodies, are commonly reported in patients with chronic Q fever (Fournier et al, 1998).
    B) BLOOD/SERUM CHEMISTRY
    1) Elevation of liver enzymes may be seen in up to 85% of acute Q fever patients, with transaminase levels increasing from 2 to 10 times normal values. During episodes of prolonged fever, it is common to find normal leukocyte counts, thrombocytopenia, and elevated hepatic enzyme levels (Fournier et al, 1998; Maurin & Raoult, 1999).
    a) In chronic Q fever, thrombocytopenia and elevated hepatic enzyme levels are commonly found (Fournier et al, 1998).
    2) Creatine phosphokinase has been reported to be elevated in approximately 20% of acute Q fever patients (Fournier et al, 1998).
    3) Elevated serum creatinine levels are common in patients with chronic Q fever (Fournier et al, 1998) and may be elevated in 29% to 40% of patients with acute Q fever (Maurin & Raoult, 1999).
    4.1.3) URINE
    A) URINALYSIS
    1) Microhematuria is a common finding in patients with chronic Q fever (Fournier et al, 1998).
    4.1.4) OTHER
    A) OTHER
    1) CEREBROSPINAL FLUID
    a) A mild lymphocytic pleocytosis is often noted in the spinal fluid of Q fever patients with meningoencephalitis (Fournier et al, 1998).
    2) CULTURES
    a) Due to its infectivity, isolation and cultivation of Coxiella burnetii is designated for biosafety level 3 laboratories (Graham et al, 2000; Fournier et al, 1998). DNA amplification can be done from blood, cerebrospinal fluid, bone marrow, cardiac valve biopsy, vascular aneurysm or graft, bone biopsy, or liver biopsy specimens; milk; placenta; fetal specimens in cases of abortion; and cell culture supernatants (Fournier et al, 1998).
    1) In chronic Q fever endocarditis, conventional blood cultures remain negative (Graham et al, 2000; Fournier et al, 1998).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Atypical pneumonia is present in some Q fever patients. Chest x-ray is indicated for patients with pulmonary signs/symptoms. Chest films may show patchy infiltrates, which frequently are multiple round, segmental opacities (Caron et al, 1998). Segmental (62%) and lobar (18%) areas of opacities are most commonly observed (Gikas et al, 1999). Consolidation may be seen in larger areas of the lungs, and linear atelectatic lesion occur in approximately 50% of pneumonia patients (Hornick, 1996; Kosatsky et al, 1982).

Methods

    A) IMMUNOASSAY
    1) Due to laboratory hazards associated with cultivation of Q fever rickettsiae, isolation of C. burnetii is not recommended for routine diagnosis. Biosafety level 3 laboratories are designated to perform isolation and cultivation procedures. Serologic tests, instead, are the preferred diagnostic tests, with complement fixation, microagglutination test, microimmunofluorescence test and enzyme-linked immunosorbent assay (ELISA) for detection of post-infection antibody response in human sera described for detection of acute and chronic Q fever (Kovacova et al, 1998; Kovacova et al, 1998a).
    2) Available techniques for serum diagnosis of Q fever include complement fixation and/or indirect immunofluorescence (the most commonly used and most reliable), with cases having seroconversion or a 4-fold antibody titer rise considered as positive for Q fever (Merino et al, 1998; Fournier & Raoult, 1999). Due to variances in acute or chronic Q fever, diagnosis relies on serology. ELISA and micro-agglutination are reliable methods, but may not be as readily available for diagnosis of Q fever. Devine et al (1997) reported the IgM and IgA ELISAs as showing significant correlation with the complement fixation test, with sensitivity of 100% and specificity of 87% reported for each assay.
    a) Immunofluorescence assay titers reach maximum levels 4 to 8 weeks following the onset of acute Q fever, then gradually decrease over the following 12 months (Fournier et al, 1998).
    b) Titers of phase II IgG of >1:200 and titers of phase II IgM of >1:50 are suggested for the diagnosis of acute Q fever (Fournier & Raoult, 1999; Capo et al, 1998). In forms of the disease, eg, endocarditis, elevated levels of phase I IgG of >1:800 are diagnostic of chronic Q fever.
    c) Following serological testing cross-reactivity with C. burnetti has been reported in patient's with chronic Q fever. Previous studies have indicated that C. burnetti has cross-reacted with Legionella pneumophila, Legionella micdadei, Chlamydia species and the agent of human granulocytic ehrlichiosis. In one patient with chronic Q fever endocarditis, serological testing indicated that cross-reactivity between C. burnetti and R. rickettsii had also occurred (not previously reported) (Graham et al, 2000).
    3) Other methods used for diagnosis include enzyme immunoassay and immune adherence hemagglutination antibody tests using paired serum specimens. Specific IgM, IgG, and IgA tests with immunofluorescence or enzyme immunoassay methods are generally available in reference and research laboratories. Immunoblotting techniques are used to diagnose chronic Q fever, polymerase chain reaction (PCR) is used to detect small numbers of organisms in tissue, and DNA hybridization in conjunction with polymerase chain reaction will detect small numbers of organisms in blood, urine, and tissue (Anon, 1997). Nested PCR has been described for detection of C. burnetii specific DNA in blood samples (Kato et al, 1998) Zhang et al, 1998).
    4) A positive serum Weil-Felix is NOT elicited from an infection with Coxiella burnetii (Anon, 1997).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) Acute Q fever is usually a self-limiting disease, which is easily treated with antibiotics. Cases of chronic Q fever with endocarditis need aggressive and chronic antibiotic therapy, generally for a period of 3 years or more.
    6.3.4) DISPOSITION/EYE EXPOSURE
    6.3.4.3) CONSULT CRITERIA/EYE
    A) Persons with conjunctiva exposure to blood, body fluids, secretions, or excretions from a patient with suspected Q fever should receive medical evaluation and follow-up management.

Monitoring

    A) Monitor CBC and platelet count, renal and hepatic function, and urinalysis. Diagnosis is confirmed by acute and convalescent serology. Chest x-ray is indicated for patients with pulmonary signs/symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DECONTAMINATION
    1) Oral decontamination measures following exposure to Coxiella burnetii have not been proven to be effective and are NOT recommended.
    2) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    3) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.5.2) PREVENTION OF ABSORPTION
    A) DECONTAMINATION
    1) Oral decontamination measures would not be expected to be effective in Coxiella burnetii infectious processes. Irrigate oral mucous membranes copiously.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.2) TREATMENT
    A) SUPPORT
    1) Treatment of acute Q fever is symptomatic and supportive. Antibiotics are the mainstay of therapy for acute and chronic Q fever. Vaccines are not yet readily available outside Australia. Human to human transmission does not occur, and respiratory isolation for infected patients is not required. Q fever is not currently a notifiable disease in most states. Laboratory work with the organism, Coxiella burnetii, is designated as biosafety level-3.
    B) ANTIBIOTIC
    1) GENERAL
    a) Recovery of acute Q fever with no antibiotics is greater than 99%. However, early institution of antibiotics reduces the febrile course by half. Prognosis is excellent following treatment of acute Q fever. Effective antibiotics include doxycycline, tetracycline, or alternatively quinolones or rifampin. Treatment of endocarditis of chronic Q fever is more difficult. Doxycycline, quinolones and rifampin have been somewhat effective, however, mortality rate remains high (24%) and cures have not been achieved even after 2 years of continuous therapy in some cases (Hornick, 1996; Dumler, 1996; Sawyer et al, 1987). Hydroxychloroquine added to the antibiotic therapies has been shown to increase effectiveness of therapy (Raoult et al, 1999).
    2) ACUTE Q fever
    a) ADULTS: Doxycycline 100 milligrams orally twice daily for 2 to 3 weeks, or until the patient has been afebrile for one week.
    b) ADULTS: Tetracycline 500 milligrams orally four times daily for 2 to 3 weeks, or until the patient has been afebrile for one week.
    c) CHILDREN (over 8 years old): Tetracycline 25 milligrams/kilogram/day, in divided doses, for 2 to 3 weeks.
    d) ADULTS: Ofloxacin 200 milligrams orally every 12 hours for 2 to 3 weeks, or until the patient has been afebrile for one week.
    e) ADULTS: Pefloxacin 400 milligrams intravenously or orally every 12 hours for 2 to 3 weeks, or until the patient has been afebrile for one week.
    3) MANAGEMENT GUIDELINES FOR LABORATORY EXPOSURES
    a) BACKGROUND - Laboratory researchers working with potential Rickettsial agents (Coxiella burnetii) are vaccinated with Q Fever vaccine (0.5 cc subcutaneously; not FDA approved) with booster doses given as needed per titer. The vaccine is now administered every 10 years and no titers are obtained (Rusnak et al, 2004).
    b) POSTEXPOSURE ANTIBIOTIC PROPHYLAXIS REGIMENS - Based on work conducted by the Special Immunizations Program at the United States Army Medical Research Institute of Infectious Diseases, the following recommendations are suggested for postexposure prophylaxis (antibiotic therapy) in laboratory workers exposed to bioterrorism agents. The guidelines are based on the risk of exposure, the virulence of the organism, and vaccination status of the individual (Rusnak et al, 2004a)
    1) ASSESSMENT OF POST-EXPOSURES
    a) MODERATE/HIGH RISK
    1) INHALATION - defined as not wearing a respirator with direct splash of an infectious agent or aerosolized dried agent outside of BSC; or exposure from centrifuge accident with viable organism; or break in respiratory protection in an environment with an infectious agent or animal with potential to be aerosolized.
    2) PERCUTANEOUS/CUTANEOUS - Percutaneous exposure to any of the following: needle or blade with prior contact with a solution containing the agent; or contact with blood/fluids of an infected animal that is ill or likely to have the organism in the blood/fluids. Cuts from any source that might contain the infectious agent or contact with intact skin, but a delay in cleaning the area.
    b) MINIMAL-RISK EXPOSURE
    1) INHALATION - defined as an exposure to an organism that is unlikely to be aerosolized or spill that is contained within the BSC or an exposure to an infectious agent that is unlikely to be aerosolized.
    2) PERCUTANEOUS/CUTANEOUS - Percutaneous exposure to any of the following: from needle or blade with prior blood/fluids of an animal infected with an agent, but the animal not likely to be bacteremic or shedding organisms; or scratch or bite from an animal infected with an agent, but not likely to be ill. Direct contact with infectious agent to skin, but cleaned immediately.
    c) NEGLIGIBLE OR NO RISK-EXPOSURE
    1) INHALATION or PERCUTANEOUS - No discernible contact with either an aerosolized or percutaneous/cutaneous (eg, needle stick, abrasion or cuts to skin) infectious agent or an infected animal. Injury or break in laboratory technique, but not in the presence of an infected animal or organism.
    1) Currently, the guidelines recommend prophylactic antibiotic therapy for all moderate or high-risk exposures regardless of vaccination status. Prophylaxis was also recommended for unvaccinated individuals with minimal risk exposures. Lastly, clinical judgement should guide prophylactic antibiotic therapy on a case-by-case basis (Rusnak et al, 2004a)
    2) PROPHYLACTIC REGIMEN - Doxycycline for 14 days (Note: illness may be prolonged if started before day 8 postexposure) (Rusnak et al, 2004a).
    3) Antibiotic prophylaxis was effective if administered 8 to 12 days after exposure, but may only prolong the onset of disease if given within 7 days of exposure (Rusnak et al, 2004).
    4) CHRONIC Q fever
    a) ADULTS: Doxycycline 200 milligrams orally daily for 3 years to lifetime or ofloxacin 400 to 600 milligrams orally daily for 3 years to lifetime. Chloroquine or hydroxychloroquine has been added to these therapy regimens in order to alkalize fluids to potentiate eradication of organisms in phagocytes (Hornick, 1996). Rifampin or trimethoprim may be added to the doxycycline regimen (Sawyer et al, 1987). Ciprofloxacin has been effective when added to the doxycycline regimen (Yale et al, 1994).
    1) Because the low pH of phagolysosomes inhibits the bactericidal effect of doxycycline, the addition of a lysosomotropic agent, such as hydroxychloroquine which raises the pH of vacuoles, is often recommended in conjunction with doxycycline. Lupoglazoff et al (1997) have recommended doxycycline 200 mg/day together with hydroxychloroquine 600 mg/day orally for at least 3 years.
    2) Raoult et al (1999) found that treatment with doxycycline 100 milligrams orally twice daily in conjunction with hydroxychloroquine 200 milligrams orally 3 times daily for 18 months shortened the total duration of therapy as compared with other regimens, and reduced the number of relapses. The authors suggest patients take this combination for a minimum of 18 months or a maximum of 4 years.
    3) Several investigators have suggested treatment for 3 years, then if the level of IgG against phase I antigen is less than 1:400 and no IgA antibody against phase I is found, discontinue therapy. Another investigator suggested treatment until the patient had IgG anti-phase I antigen titers greater than 1:200 and IgA anti-phase I antigen titers greater than 1:25 (Yale et al, 1994).
    b) ADULTS: Other drugs and drug combinations reported for therapy of chronic Q fever include (Raoult et al, 1999):
    1) Tetracycline
    2) Tetracycline and rifampin
    3) Lincomycin
    4) Tetracycline and lincomycin
    5) Tetracycline and sulfamethoxazole/trimethoprim
    6) Tetracycline and chloramphenicol
    7) Tetracycline and rifampin
    8) Doxycycline and rifampin
    9) Doxycycline and ciprofloxacin
    10) Fluoroquinolones and hydroxychloroquine
    11) Erythromycin and rifampin
    C) VACCINE
    1) There are no commercially available vaccines for prevention of Q fever in the United States, but vaccine is available commercially in Australia. Investigational vaccines, using either phase I or phase II organisms, have been shown effective in disease prevention in volunteers and are available in the United States. Vaccine may be obtained under an investigational new drug (IND) application for use in persons at high risk (Hornick, 1996; Sawyer et al, 1987).
    a) A formalin-inactivated whole cell vaccine is available as an investigational agent. Pre-vaccination skin testing for existing immunity is required. One subcutaneous dose (20 to 30 micrograms) provides relative immunity to aerosol challenge within 3 weeks. No booster injections are required (Wiener, 1996).
    2) In Australia, efficacy of a formalin-inactivated whole cell C. burnetii Phase I vaccine (Q-Vax, CSL) was tested in 2555 employees of abattoirs. Protective efficacy was shown to be 100% with single subcutaneous doses of either 20 micrograms or 30 micrograms (0.5 mL). It appeared the vaccination was effective for at least 5 years (Ackland et al, 1994).
    3) In the United States, the Rocky Mountain Laboratory in Montana vaccinated laboratory workers with one dose of 22 micrograms of a whole-cell Phase I vaccine (Q58-A). No cases of Q fever were reported in vaccinated workers, although Q fever was reported in non-immune workers. Protective potency in guinea pigs was reported for 20 years (Ackland et al, 1994).
    a) Q fever was confirmed by serological titers in a US military researcher vaccinated (not currently approved by the FDA for commercial use) against Q fever due to accidental inhalational exposure of high concentrations of of C. burnetii. Symptoms resolved completely following doxycycline (Rusnak et al, 2004).
    D) CORTICOSTEROID
    1) GRANULOMATOUS HEPATITIS complicating acute Coxiella burnetii infection, which may be due to a hypersensitivity reaction, may respond to treatment with corticosteroids. Crespo et al (1999) suggested treatment with moderate doses of oral prednisone (0.5 mg/kg/day) if fever persists following appropriate antibiotic therapy. Following improvement of symptoms, steroid dose can be tapered over a one month period.
    E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) One Coxiella burnetii organism is capable of causing disease in humans. The organisms can survive a very long time in contaminated dust or aerosols, providing the potential for humans to acquire infection through inhalation. Person-to-person spread is rare.

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) The usual incubation period is 20 days (range 14 to 39 days), with one organism capable of causing disease in humans (Tigertt et al, 1961; Fournier et al, 1998). Subsequent disease complications may occur depending on the initial infecting dose (Boyle & Hone, 1999). An inverse dose-incubation period relationship exists, with the length of the incubation period dependent on the size of the initial infecting dose (Tigertt et al, 1961).
    2) Coxiella burnetii organisms survive a very long time in contaminated dust or aerosols, providing the potential for humans to acquire infection through inhalation. Person-to-person spread is rare (Hawker et al, 1998).
    3) Administering the coxiella by the intraperitoneal route or by inhalation in the guinea pig has produced a similar type of disease process. By either route of infection, the guinea pig model appears to be closely similar to man infected by inhalation (Tigertt et al, 1961). Primary multiplication of the organism at the site of initial contact in the lung probably is not important in the disease initiation process and disease cycle.

Toxicity Information

    7.7.1) TOXICITY VALUES

Pharmacology Toxicology

Toxicologic Mechanism

    A) Coxiella burnetii phase II enters human monocyte-derived macrophages via the CR3 receptor, while the infectious phase I Coxiella burnetii blocks entry via the CR3 receptor and binds to human monocytes via the complex of LRI (leukocyte response integrin) and IAP (integrin-associated protein). Natural phase I organisms are only poorly internalized by monocytes and macrophages but can survive within these cells. Phase II organisms are readily internalized by monocytes and macrophages but are rapidly killed via the phagolysosomal pathway (Maurin & Raoult, 1999).
    1) Coxiella burnetii has adapted to the phagolysosomes of eukaryotic cells and multiplies in acidic vacuoles at pH 4.7 to 5.2. It is an acidophilic bacterium whose metabolism is enhanced at the acidic pH. The organism undergoes a complex intracellular cycle, which leads to the formation of spore-like forms.
    B) Following infection, Coxiella burnetii organisms enter the vascular endothelial cells of vessels and multiply, thus destroying the cells, resulting in an inflammatory process and vasculitis (Ruiz-Moreno, 1997). In rare instances, a choroidal neovascularization has occurred, probably as a result of the inflammatory and vasculitis process of Q fever infection.
    C) The Coxiella burnetii organism resides uniquely inside the phagolysosome in the cytoplasm of the infected cell. The main portal of entry of these organisms is the respiratory tract, with small particles less than 3 to 5 microns in diameter reaching the terminal bronchioles and causing an atypical pneumonia (Hornick, 1996).
    1) It has been shown in a mouse model that the organisms enter pneumatocytes, histocytes, and fibroblasts. It is thought that the self-limiting nature of Q fever is due to the destruction of the organism in the macrophages. However, since C. burnetii may persist for 2 months inside those cells, some of the macrophages may be damaged, resulting in an inflammatory response. A cellular immune mechanism may attack these cells, which may contribute to the pathogenesis of pneumonia.
    D) A cytokine dysregulation has been found in post Q fever fatigue syndrome patients, with peripheral blood mononuclear cells (PBMC) releasing more IL6 and interferon gamma and less IL2 when stimulated with Q fever antigens than those of controls without Q fever fatigue syndrome (Marmion, 1997). PCR amplification has suggested that very small numbers of the coxiella may be present in these patients resulting in continuing immune stimulation and cytokine dysregulation.
    E) Glomerulonephritis of chronic Q fever appears to be due to immune complex deposition, which is consistent with granular deposits demonstrated by immunofluorescence of renal biopsy specimens (Korman et al, 1998).

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