Infectious Diseases

Coxiella Burnetti

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Coxiella burnetii — an intracellular gram-negative bacterium that can form spores

What is the best treatment?

Doxycycline 200 mg as a loading dose and 100 mg, orally, twice daily (po bid) for 10 days is the best treatment for acute Q fever. The evidence for doxycyline as the drug of choice comes from observational studies wherein fever resolution was faster compared with patients who were treated with erythromycin or a beta-lactam. A respiratory fluoroquinolone, such as levofloxacin or moxifloxacin, can be used in patients who cannot be treated with doxycycline.

The treatment of chronic Q fever is difficult and should be supervised, if possible, by someone who has had experience in the treatment of this illness. The best treatment is a combination of doxycycline and hydroxychlorquine. Hydroxychloroquine has no activity against C. burnetii, but it alkalinizes the phagolysosome, thereby rendering doxycylince bactericidal against C.burnetii. Hydroxychloroquine is administered in a dose of 400-600 mg per day to achieve a serum level of 1 mg/l of chlorquine. Doxycycline is given in a dose of 100 mg bid.

Treatment is monitored by following the antibody titers to phase I C. burnetii. Antibody titers should be done every 2 months for the first 6 months. A falling titer is indicative of successful treatment. Thereafter, the titers should be measured every 3-4 months. When an IgA titer of 1:200 or less to phase I antigen is attained, treatment can be discontinued. This usually takes 18 months for patients with native valve endocarditis and 2 years for those with prosthetic valve Q fever endocarditis. Thereafter, follow-up should be at yearly intervals.

At the beginning of therapy, it is important to liase with the laboratory that will be doing the antibody titers. All serum samples should be stored. The previous serum sample should be tested in parallel with the current sample and titers from both samples reported.

A combination of ciprofloxacin and rifampin has also been effective. Ciprofloxacin is used in a dose of 750 mg bid po and rifampin 300 mg once daily (od) po.

There is less experience with other combinations of antibiotics, but doxycycline plus a quinolone has also been used.

Q fever in pregnancy is treated differently but also for a prolonged period (defined as at least 5 weeks during pregnancy). As soon as Q fever is diagnosed during pregnancy, treatment should be started with C. co-trimoxaxole (320 mg of trimethoprim and 1600 mg of sulfamethoxazole) daily. When at least 5 weeks of such therapy was administered during pregnancy, the complication rate was reduced from 81 to 43.8%. Postpartum treatment with doxycline and hydroxychloroquine should be given for 1 year.

A special circumstance is the patient with valvular heart disease who has acute Q fever. In these instances, the risk of chronic Q fever is high (39% in one study). Hence, pre-emptive therapy with hydroxychloroquine and doxycycline for 1 year should be given in these circumstances.

Until very recently, susceptibility testing of C. burnetii was carried out in embryonated eggs or tissue culture. Such studies have confirmed the activity of tetracyline compounds. In some studies, there has been heterogeneity of susceptibility to fluoroquinolones and erythromycin. In two studies, C. burnetii was converted from susceptible to resistance for pefloxacin in one study and ciprofloxacin in the other. In both instances there was a substitution of Glu for Lys at the position corresponding to amino acid 87 of Escherichia coli in resistant strains.

The frequency of emergence of resistance during treatment, especially during treatment of chronic Q fever, is unknown, although it is likely that it can and does happen.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

Q fever is found worldwide with the exceptions of Antarctica and New Zealand. As a zoonosis, the epidemiology of Q fever is related to the host animals. Thus, exposure to infected pregnant or postpartum cattle, sheep, and goats and, occasionally, cats determines the epidemiology. There is a seasonality to Q fever infection, and it increases in the number of cases in a region are seen following birthing of the various animals. Q fever can occur in outbreaks or sporadically. The source of sporadic cases is often not apparent. It is useful to consider the epidemiology of Q fever in selected countries.

United States: Between 1948 and 1977, 1168 cases of Q fever were reported to the Centers for Disease Control and Prevention (CDC), an average of 58.4 cases per year. In 1999, Q fever became a notifiable disease in the United States. In the early years, 1946-1950, outbreaks of Q fever were noted in meat packing plants in Chicago and Texas. Early on, most of the cases were from California and were related to exposure to sheep and goats. From 2000 to 2004, an average of 51 cases per year was eported from 30 states. The highest rate was from Wyoming.

  • Only a small number of cases of chronic Q fever have been reported from the United States - likely this is an under estimate.

  • Sheep and goats are more likely to be seropositive than cattle in the United States. There is an extensive wildlife reservoir of C. burnetii, including coyotes, grey foxes, skunks, raccoons, rabbits, deer, mice, bears, birds, and opossums.

Germany: The highest rates are in the southern states at 4.1 cases per million per year compared with 1.1 cases per million per year for the rest of the country. In 40 outbreaks, sheep were implicated in 24, cattle in 6, and there were 2 laboratory outbreaks. Seasonality has changed over the past decades with a decrease in winter outbreaks and an increase in summer outbreaks. Also recently, outbreaks are more likely to occur in urban areas because of encroachment of urban areas onto sheep pastures.

Australia: In Australia, where Q fever was first recognized, cases continue to occur at a rate of about 30 per million per year or a range of 354-869 cases per year. The male:female ratio is 5.3:1. The introduction of Q fever vaccination for abbatoir workers has led to a marked decrease in the number of cases among this occupational group.

  • Kangaroo hunting is a risk factor for Q fever unique to Australia.

Canada: Most cases of Q fever in Canada have been reported from Nova Scotia. The epidemiology of Q fever in this province is unique in that most cases follow exposure to infected parturient cats and the most common manifestation of Q fever is pneumonia. There have been a few cases associated with exposure to infected parturient dogs in this province as well. At its peak of 60 cases per million per year, Nova Scotia has had the highest rate of Q fever in the world. After a period of 15 years, the number of cat related cases has markedly decreased, as have the overall number of cases of Q fever. An outbreak of Q fever in Ontario secondary to exposure to infected goats resulted in granulomatous hepatitis. Similar cases have been seen in Alberta.

France: France has a high rate of Q fever. Hepatitis is the most common manifestation of acute Q fever in France, accounting for about 40% of cases; pneumonia and hepatitis account for another 20%; pneumonia alone 17%; fever 17%; and meningoencephalitis, myocarditis, and pericarditis 1%, each while meningitis caused 0.7% of the cases. In France, there are a considerable number of cases of chronic Q fever, accounting for 23% of the cases in a series of 1070 cases. Females dominated among those with isolated fever.

Great Britain: Unique features to the recent epidemiology of Q fever in Great Britain are travel (outside Great Britain) in 7% of cases and an outbreak in a plant that manufactured corrugated cardboard products. No source could be found for the Q fever in this outbreak.

Netherlands: From 2007 to 2009, there have been 3,523 cases of Q fever in the Netherlands. Q fever abortions were registered on 30 dairy goat and dairy sheep farms between 2005 and 2009. The number of goats in the country quadrupled to more than 350,000 since 1995. The outbreak is due to a single subtype of C. burnetii. In an effort to curtail the outbreak, 40,000 pregnant goats on 60 farms were culled. This outbreak raises several questions:

  • Is it due to a more virulent strain of C. burnetii?

  • Is there a tipping point in the ecological balance between goats and humans?

Infection Control Issues

Person-to-person transmission of Q fever is highly unusual, so isolation is not recommended. There have been a very few cases transmitted following an autopsy on a person who died with Q fever and following delivery of an infected pregnant patient. Rarely, sexual transmission has been documented.

Only seronegative sheep or goats should be used, if these animals are part of experimental protocols. Failure to do so has resulted in laboratory outbreaks of Q fever.

Coxiella burnetii should only be isolated in a level three biosafety laboratory, and any work with this organism should also be performed in this biosafety level laboratory.

A vaccine is available but not widely used. However, in endemic areas, workers in high risk occupations, such as abbatoir workers and veterinarians, should likely be immunized.

Blood donations should not be accepted from those living in an area in which there is an outbreak of Q fever until at least 2 months following documented cessation of the outbreak.

Good animal husbandry is necessary for the control of Q fever. Aborting animals should be isolated for up to 14 days. Products of the abortion should be handled using gloves and masks, and they should be buried or burned. Feed bunks should be raised to prevent contamination by excreta. Consultation with government veterinarians is advisable.

Infected animals can be treated with tetracycline, but the effectiveness of this practice is unknown.

What host factors protect against this infection?

  • Younger age seems to be protective. In an outbreak in Switzerland, symptomatic Q fever was 5 times more likely to occur in those older than 15 years of age compared to those who were younger than 15 years of age. Prior to puberty, the male:female ratio is 1:1, whereas, after puberty, males are more commonly infected. 17-Beta estradiol has been shown to have a protective role against Q fever infection in mice, and it is likely then that estrogen is protective in post pubertal females.

  • Monocytes/macrophages are the target cells for C. burnetii. Attachment of phase I cells is mediated via the alpha v beta 3 integrin only. Toll-like receptor 4 also has a role in the uptake of virulent organisms. The acidic pH of the phagolysosome allows the entry of nutrients necessary for C. burnetii metabolism and protects the organisms from the action of antibiotics.

  • Apart from hepatitis, the histopathology of Q fever in humans has been inadequately studied because of an unavailability of tissue samples. Liver biopsies characteristically show granulomas, some of which have a central clear area, so called doughnut granuloma, and there is usually a fibrin ring surrounding the granuloma. The doughnut granuloma is not pathognomonic for Q fever hepatitis, as it may also be found in Boutonneuse fever, allopurinol hypersensitivity, cytomegalovirus infection, Epstein-Barr virus infection, Leishmaniasis, and systemic lupus erythematosis.

What are the clinical manifestations of infection with this organism?

The main clinical manifestations of Q fever are: self-limited fever; fever of uncertain origin; pneumonia; hepatitis; endocarditis, Q fever in pregnancy; and less commonly, aseptic meningitis, encephalitis, transverse myelitis, mononeuritis multiplex, optic neuritis, pericarditis, myocarditis, bone marrow necrosis, histiocytic hemophagocytosis, hemolytic anemia, lymphadenopathy, granulomatous lymphadenitis, splenic rupture, and erythema nodosum.

Pneumonia

Most studies of the epidemiology of pneumonia have not included C. burnetii. In the few that have, it seems that 1% or less of cases of community acquired pneumonia is due to C. burnetii. Pneumonia due to C. burnetii often occurs in small outbreaks or as sporadic cases. The pneumonia can be of gradual or sudden onset. The majority of patients have a severe headache, which can be a clue to the diagnosis. Cough is present in about 28% of patients, usually non-productive but can be productive of mucoid sputum.

Fever, fatigue, chills, sweats, myalgia, nausea, and vomiting are common. Pleuritic chest pain occurs in about one-quarter of the patients, and some patients have diarrhea. Physical examination of the chest is usually unremarkable; crackles can be heard, and, in patients with more severe pneumonia, the findings of consolidation are present. The majority of patients with pneumonia are mild to moderately ill. About 10% have severe pneumonia, rarely requiring assisted ventilation. About 50% have microscopic hematuria that resolves as the pneumonia resolves.

Rounded opacities (either single or multiple) radiographically are very suggestive of Q fever pneumonia, although septic pulmonary emboli and "cannon ball" metastates enter the differential diagnosis.

A low serum sodium concentration due to inappropriate antidiuretic hormone secretion and thrombocytosis of more than 1 million platelets per cubic mm sometimes complicate the pneumonia.

Q fever endocarditis

Q fever endocarditis should always be part of the differential diagnosis of culture negative endocarditis. If this approach is taken, diagnosis of Q fever endocarditis is easy. The problem is usually failure to think of Q fever in this setting in non-endemic areas. Patients travel, so they may have been in an endemic area when they became infected. Endocarditis is always a manifestation of chronic Q fever.

In a study from England and Wales, Q fever endocarditis accounted for 3% of all cases of endocarditis.

About 50% of the patients with Q fever endocarditis are afebrile, which often leads to a delay in diagnosis, and about one-half have hepatomegaly, splenomegaly, and clubbing of the digits. The latter can be quite pronounced. A purpuric rash is seen in about 20% of patients. In most instances, patients with Q fever endocarditis have an abnormal native valve or a valve prosthesis.

The vegetation in Q fever endocarditis may not be as readily detectable as in other forms of endocarditis, because they are not fibrin platelet bacteria aggregations; instead, they are nodular and may be small. However, serological diagnosis is very reliable. Patients with chronic Q fever have very high phase I titers. A phase 1 titer of 1:200 or higher using a complement fixation technique is diagnostic of chronic Q fever, as is a phase 1 IgG titer of 1:800 or greater by the immunofluorescence technique.

Morbidity and mortality can be substantial with Q fever endocarditis. Prosthetic valves may require replacement and, although the mortality rate now is much lower than in the past, it continues in the 15-20% range.

Q fever hepatitis

There are really three forms of Q fever hepatitis. The first is elevated liver enzymes as part of another Q fever illness, such as pneumonia. This is usually an incidental finding, and the hepatitis resolves as the pneumonia or other manifestation of Q fever resolves.

Occasionally, the presentation can be that of hepatitis (i.e., nausea, vomiting, jaundice), although this is unusual.

The most important form of Q fever for the clinician to be aware of is the form that presents as fever of uncertain origin with elevation of liver enzymes and granulomas on liver biopsy. The best way to describe this entity is by the following case presentation.

A 50 year-old highway maintenance worker (male) from Northern Alberta suffered a loss of consciousness during his morning shower. When assessed at his local hospital, a history of a 5-week illness was elicited. For the past 5 weeks, he had fever, drenching night sweats, diarrhea, and abdominal pain. His oral temperature was 40°C. Over the next 10 days, he was treated with a variety of antibiotics, including cefuroxime, azithromycin, ciprofloxacin, metronidazole, cefotaxime, ceftriaxone, and imipenem. He remained febrile, and, because of elevated liver enzymes, he was referred to a gastroenterologist at a tertiary care center in another city. The gastroenterologist noted fever, again a temperature of 40°C, right upper quadrant discomfort on palpation, and splenomegaly. A chest radiograph, whole body computed tomography, and a white cell scan were normal, apart from fatty liver noted on the CT scan. The AST was 49 IU, ALT 113 IU, LDH 280 IU, Alkaline Phosphatase 94 U, GGT - 243 U; C-reactive protein 198. Multiple blood cultures were negative. A liver biopsy showed granulomas with a fibrin ring. This liver biopsy finding plus the Q fever serology by microimmunofluorescence of a phase II titer of 1:1024 and a phase 1 titer of 1:16 was diagnostic of acute Q fever. Therapy with levofloxacin was begun with prompt resolution of fever.

Q fever in pregnancy

Q fever in pregnancy used to be a rare entity, but, as more and more cases of Q fever are diagnosed, there is now more experience with Q fever in pregnancy. Undoubtedly, the large prolonged (>2 years) outbreak of Q fever in the Netherlands will result in many cases of Q fever during pregnancy and will advance our knowledge in this area. In the first trimester, Q fever can result in abortion. Infection later in pregnancy can result in low birth weight babies and in premature babies. Intrauterine deaths have also been observed.

What common complications are associated with infection with this pathogen?

Post Q fever fatigue syndrome is associated with Q fever. A number of investigators, but especially those in Australia and the United Kingdom, have noted severe fatigue in some patients following resolution of Q fever. In a study of an outbreak of Q fever in Newfoundland and Labrador, 33% of the patients had significant fatigue 2 years later versus 4% of those in the same workplace who did not have Q fever.

There is some evidence that there may be a genetic basis for post Q fever fatigue syndrome in that cases are more likely to have differences in the IL-10 promoter and in intron 1 of the gamma interferon gene than control subjects.

How should I identify the organism?

In most instances, diagnosis of Q fever can be made serologically. The best test is the microimmunofluorescence test using C. burnetii Nine Mile strain as the antigen. It is important to know the cut off as the starting dilution in your area. For example, in Nova Scotia, a 1:8 starting dilution was used, whereas in France a 1:32 starting dilution was used. Positive and negative controls must be included with each test.

Acute Q fever is best diagnosed using acute and 2-4 week convalescent phase serum samples. A four-fold rise in titer to phase II antigen is diagnostic; a single titer of 1:512 or greater with a compatible clinical picture can also be taken as strong evidence of acute Q fever.

A phase 1 titer of 1:200 or higher using a complement fixation technique is diagnostic of chronic Q fever, as is a phase 1 IgG titer of 1:800 or greater by the immunofluorescence technique.

Coxiella burnetii can be isolated from tissue samples and from body fluids using a shell vial technique, but this should only be done in a biosafety level 3 laboratory.

Polymerase chain reaction (PCR) is useful diagnostically, but this test is not commercially available.

How does this organism cause disease?

Coxiella burnetii phase 1 is a virulence factor. It appears that those who develop Q fever endocarditis have a defect in cell mediated immunity against this microorganism.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Carcopino, X, Raoult, D, Bretelle, F, Boubi, L, Stein, A. "Managing Q fever during pregnancy: the benefits of long-term cotrimoxazole therapy". Clin Infect Dis. vol. 45. 2007. pp. 548-55.

(This source reports on 53 patients with Q fever during pregnancy—those who received long-term (defined as at least 5 weeks) therapy with cotrimoxazole had significant few obstetrical complications than the 81% complication rate experienced by the patients who did not receive long-term cotrimoxazole. GRADE – moderate)

Kuzman, I, Schonwald, S, Culy, J. "The efficacy of azithromycin in the treatment of Q fever. A retrospective study. Proceedings of the 4th international conference on macrolides, azolides, streptogramins and ketolides". 1998. pp. 47.

(Sixty-four patients with Q fever pneumonia were treated and the data retrospectively reviewed. Twenty-three received azithromycin, 15 doxycycline, 15 a variety of other antibiotics. The mean number of days until afebrile was 2.5, 2 and 3.5, respectively. GRADE – low)

Millon, M, Thuny, F, Richet, H, Raoult, D. "Long-term outcome of Q fever endocarditis: a 26-year personal survey". Lancet. vol. 10. 2010. pp. 527-31.

(This is the largest and the best study on the treatment of Q fever endocarditis. One hundred and four patients were followed long term - median 100 months. Using doxycycline and hydroxychloroquine, 20% of the patients likely died due to their Q fever endocarditis, another 10% died due to causes unrelated to the Q fever endocarditis. The authors indicate that 18 months is sufficient duration of treatment for native valve Q fever endocarditis and 24 months for prosthetic valve Q fever endocarditis. They define the risk factors for failure of treatment and for relapse. GRADE – high)

Sobradillo, V, Zalacain, R, Capesbastegui, A. "Antibiotic treatment in pneumonia due to Q fever". Thorax. vol. 47. 1992. pp. 276-8.

(This group carried out a prospective randomized double blind trial of doxycycline versus erythromycin for the treatment of patients with Q fever pneumonia. Twenty-three patients received doxycycline and 25 received erythromycin. The doxycyline group was afebrile in a mean of 3 plus or minus 1.6 days, whereas the erythromycin group was afebrile in 4.3 plus or minus 2 days (p = 0.05). GRADE – moderate)
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