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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONCASE 1CASE 2CASE 3CASE 4CASE 5CASE 6DISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE 1CASE 2CASE 3CASE 4CASE 5CASE 6DISCUSSIONREFERENCES |
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The diseases was first described in Australia in 1937 by Derrick6 as "Q(uery)" fever and is characterized acutely by fever, pneumonia (in 50% of patients), pleuro-pericardial symptoms, and hepatitis, which ordinarily disappear in 2–3 weeks.7–9 Moreover, about 60% of individuals seroconvert without significant clinical manifestations after primary infection. In ~ 5% of those infected, a chronic syndrome ensues expressing itself as endocarditis or hepatitis and hepatosplenomegaly, at times leading to hepatic fibrosis.10–13 It is interesting to note that in Canada, Spain, and Switzerland, pneumonitis is the most commonly recognized form of Q fever, whereas in France, California, and Australia, hepatitis is more frequent.14 Despite a large animal reservoir of domestic sheep, goats, and cattle throughout the United States, few cases of Q fever have been described. In 2002, only 61 cases were reported, and in 2003, 75 cases were reported to the US CDC because it is a notifiable disease in many states.15 Furthermore, nearly 90% of all cattle in Southern California are infected by Coxciella burnetii16 without manifesting signs of illness, whereas in Northern California, a similar situation exists with domestic sheep.
The Eisenhower Medical Center (EMC) is a 275-bed general hospital located in the arid Coachella Valley of Southern California. It provides medical care to about 300,000 permanent residents in its catchment area, which extends to the Arizona state line on the east, to the border with Mexico to the south, to the Nevada state line to the north, and to the Peninsula mountains to the west. There is virtually no large-scale animal husbandry in this area. However, for at least four decades, sheep from Montana, Wyoming, and Idaho have been exported to the Coachella Valley in the fall and kept there until the spring when they deliver their young. That locale was changed in 1985 to an area about 100 miles southeast around Blythe, CA, along the Colorado River.
Although there are ~ 500 native desert Peninsular bighorn sheep that range within the Santa Rosa and San Jacinto mountains of the Coachella Valley, human contact is uncommon, and these animals have been shown to demonstrate antibody to C. burnetii in < 10% of their population.17 However, this observation does not exclude the bighorn sheep as playing a role in human infection nor does it exclude other possible animal reservoirs. Six cases of Q fever seen at EMC during the past 33 years are described below.
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CASE 1 |
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TOPABSTRACTINTRODUCTIONCASE 1CASE 2CASE 3CASE 4CASE 5CASE 6DISCUSSIONREFERENCES |
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CASE 2 |
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TOPABSTRACTINTRODUCTIONCASE 1CASE 2CASE 3CASE 4CASE 5CASE 6DISCUSSIONREFERENCES |
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Laboratory studies revealed abnormal liver function tests and borderline neutropenia. Both a bone marrow aspiration and liver biopsy revealed non-caseating granulomata. On March 16, 1984, Q fever complement fixing antibodies were reported positive at a titer of 1:1,024. Therapy with tetracycline was begun at a dose of 4 g daily in four divided doses for 10 days, and she improved promptly. However, after only 10 days of treatment, she relapsed with malaise and afternoon fever, A second 10-day course of tetracycline resulted in a permanent cure. The patient denied any contact with domestic sheep or cattle. She did, however, work and live within three blocks of the imported sheep in Palm Desert.
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CASE 3 |
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TOPABSTRACTINTRODUCTIONCASE 1CASE 2CASE 3CASE 4CASE 5CASE 6DISCUSSIONREFERENCES |
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Of significance in her past medical history was an episode of rheumatic fever at age 9 while living in Israel and a Starr-Edwards valve replacement at a Los Angeles hospital in 1976 for mitral valve disease. She had since been maintained on warfarin anticoagulation.
All blood cultures were sterile, while liver function studies revealed abnormal transaminases, alkaline phosphatase, and lactic dehydrogenase. Although her white count, hemoglobin, and hematocrit were normal, the platelets were decreased to 108,000/mm3. Platelet-bound IgG antibody was markedly elevated. An IgG hypergammaglobulinemia was also noted, but circulating immune complexes were not defined. A transthoracic echocardiogram failed to define any vegetation. A liver biopsy was performed. A few doughnut type granulomata and a diffuse interstitial lymphocytic infiltrate were seen, suggesting Q fever, On October 9, 1983, phase 1 complement fixing antibody to C. burnetii was elevated to a titer > 1:5l2; IgA was > 128 and IgM was > 128. The patient was started on doxycycline 100 mg twice daily and trimethoprim/sulfamethoxazole (200/800 mg) twice daily and a concomitant reduction of warfarin dose. Despite this precaution, she developed gastrointestinal bleeding secondary to a prolonged prothrombin time.
After 6 months of therapy, she was feeling well, and the anti-microbials were discontinued. Hepatosplenomegaly was nearly gone, and her liver function studies had improved significantly, Four months later she again noted malaise, headache, and anorexia. These symptoms were accompanied by a worsening of the liver function studies and reappearance of hepatosplenomegaly, Oral therapy with doxycycline 100 mg twice daily and clindamycin 300 mg four times daily were prescribed, and after 2 months of therapy she felt well. There was improvement in the liver function studies. Phase 1 antibody to C. burnetii remained significantly elevated, however. In June 1989, the patient moved to Florida, and contact was lost. This patient’s source of infection was felt to be caused by her husband, a butcher who wore his work clothes when he was at home.
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CASE 4 |
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Physical examination was unremarkable, but laboratory studies revealed abnormal liver function studies with elevation of the transaminases, alkaline phosphatase, and the gamma glutamyl transpeptidase. Additionally, a chest x-ray revealed a mediastinal mass. Stool studies for the cause of his diarrhea were unremarkable. Because of his chest mass and diarrhea, a diagnosis of a probable neoplasm was made, assuming the diarrhea was caused by a paraneoplastic syndrome.
Thus, indomethacin was given, and within 24 hours, the diarrhea and fever had disappeared, consistent with a diagnosis of paraneoplastic syndrome. However, a needle biopsy of the lung lesion revealed granulomata and a liver biopsy defined a doughnut granulomatous pathology. Special stains for fungi and acid fast bacilli were negative. After the liver biopsy suggested doughnut granulomata, serologies were sent for C. burnetii antibody. They proved to be strongly positive for phase 2 IgG, IgM, and IgA globulins. Treatment with doxycycline at a dose of 100 mg, twice daily for 2 months, resulted in the disappearance of the mediastinal mass, abnormal liver function studies, and diarrhea. The etiology of the diarrhea and fever were both thought to be caused by cytokine overproduction, which has been described in patients with Q fever.14
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CASE 5 |
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TOPABSTRACTINTRODUCTIONCASE 1CASE 2CASE 3CASE 4CASE 5CASE 6DISCUSSIONREFERENCES |
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The patient and his family live adjacent to a field in Blythe where imported sheep live and deliver their lambs.
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CASE 6 |
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TOPABSTRACTINTRODUCTIONCASE 1CASE 2CASE 3CASE 4CASE 5CASE 6DISCUSSIONREFERENCES |
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The patient stated that he raised chickens on his ranch but had no exposure to domestic cattle, sheep, or goats. He also drank 10 bottles of beer daily. A liver biopsy was performed that revealed doughnut granulomas, and a Q fever IgG phase I screen was negative, but the IgM phase 1 screen was positive. A Q fever phase 2 screen was positive with IgM and IgG titers 
1:1,024. The phase 1 titer was 1:16. These serologies confirmed the diagnosis of acute Q fever hepatitis. The patient had ceased to be continuously febrile with the use of celecoxib, and he remained afebrile when doxycycline was initiated. After discontinuation of celecoxib and 3 weeks of doxycycline, the patient was well. Five months after treatment, he feels well, and liver function studies are normal. Phase 2 antibodies remain quite elevated, but phase 1 antibodies are positive at 1:16.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE 1CASE 2CASE 3CASE 4CASE 5CASE 6DISCUSSIONREFERENCES |
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This organism is commonly found in domestic ungulates and a variety of wildlife mammals worldwide, who when infected generally remain asymptomatic.20 Livestock handlers and those that work in slaughter houses dealing with contaminated laundry or wool as well as textile workers, butchers, laboratory technologists, and veterinarians21 are occupationally at risk and are most commonly infected. Sheep seem to be more infectious than cattle and goats, and most cases in Idaho occur during the post-lambing period, which lasts about 4 months.22 Idaho is second only to California in reporting clinical cases of Q-fever in the United States.23
However, as exemplified in this communication, a direct association with infected material often can not usually be incriminated.
The acute disease often resembles influenza, leptospirosis, or brucellosis and thus requires serologic studies as the mainstay of clinical diagnosis, particularly because an attempt to isolate the organism is particularly hazardous to laboratory technologists.
In most primary infections, IgM antibodies to phase II antigen appear early (from the second week onward) in Q fever and remain detectable for short periods of time (10–17 weeks) after the onset of the disease. Thereafter, IgA and IgG (usually IgG1) antibodies are measurable and are generally present 5–10 days later.24 These antibodies can be detected by complement fixation (CF; the least sensitive), indirect immunofluorescence (IFA), and enzyme-linked immunosorbent assay (ELISA).25 Antibodies to phase I antigens are generally elevated more than phase II antibodies in patients with chronic Q fever infection.25
We have diagnosed six cases of Q fever at EMC during the past 32 years. All but two patients had lived adjacent (< 0.25 mi) to the imported sheep habitat in the Coachella Valley or in Blythe near the Colorado River. One patient was married to a butcher and another raised chickens on his rural ranch in the desert. None drank unpasteurized milk. Unpasteurized cheese is brought into California from Mexico, but none of our patients consumed these cheeses, making ingestion of contaminated food an unlikely source of Q fever hepatitis.
All but one patient in our group had antibody directed at phase 2 antigen, and all patients responded to between 1 and 2 months of antimicrobial therapy with doxycycline. Only a single patient with Q fever chronic hepatitis who also carried a Starr-Edwards mitral valve prosthesis manifested greater phase 1 than phase 2 antibodies. This individual had undergone at least three trans-thoracic echocardiograms and a single trans-esophageal echocardiogram that failed to show vegetations on the mitral valve but does not definitely exclude concomitant endocarditis. She had received at least three courses of multi-drug anti-microbial therapy for each as long as 6 months without curing her Q fever or reducing her markedly elevated antibody titers.
Chronic Q fever was originally thought to be associated with endocarditis, which developed on abnormal or prosthetic valves. However, patients without obvious endocarditis have been reported,26,27 and it has been assumed that the liver could serve as a reservoir for C. burnetii.28 Indeed, hepatic fibrosis in conjunction with chronic Q fever hepatitis has been described,26,27 as well as recurrent episodes of granulomatous hepatitis. Although in our experience Q fever hepatitis occurs more commonly than pneumonitis, the hepatic lesions of chronic Q fever have been microscopically documented in only a small number of cases (< 10%) in patients with chronic Q fever. Our patient’s > 3-year course of fever and abnormal liver function studies with a liver biopsy 3 years later revealing granulomas and lymphocytic infiltrates certainly speaks for chronic hepatitis and not endocarditis as the etiology of her chronic Q fever. Other causes of chronic Q fever include endovascular infections of aneurysms or prostheses, osteomyelitis, infection during pregnancy, pseudotumor of the lung, and pulmonary fibrosis.9
The granulomas of Q fever are histologically characterized by a central lipid vacuole and or a dense fibrin ring termed a doughnut granuloma. These granulomas are thought to be characteristic of Q fever hepatitis and were noted in all of our patients described in this communication. Because of the characteristic histopathology in the liver, we felt confident that patient 5 was infected by C. burnetii despite a borderline low antibody titer.
Treatment of acute infection by C. burnetii is best achieved with doxycycline28 at a dose of 200 mg daily for 2 weeks. Macrolides and quinolones have been successfully used as alternative therapy.29,30 Antimicrobial therapy for chronic Q fever usually uses doxycycline in conjunction with clindamycin, trimethoprim-sulfamethoxazole, rifampin, or a quinolone. More recently, hydroxychloroquine was added to doxycycline to alter the pH in the acid phagolysosome that the organism needs for growth in the treatment of Q fever endocarditis.31 At least 3 years of therapy are recommended for chronic Q fever.
Although Q fever seems to be an uncommon clinically diagnosed disorder in the desert of Southern California, an unusual epidemiologic situation involving imported domestic sheep to graze and give birth to lambs during the fall and winter months in a warm climate is able to overcome the lack of a presumed natural reservoir in the area. Although coyotes, gray foxes, skunks, raccoons, rabbits, deer, and mice have been shown by serosurvey to have been infected in California,32 we still believe that imported domestic sheep likely causes the disease in humans in the Coachella Valley. Seroprevalence amongst farmers in Idaho is 19%,32 indicating significant exposure to Q fever occurs in that state with a large domestic sheep population that are imported into Southern California annually for several months to feed and lamb. It is likely that aerosolized dust from sheep excrement and placentas are the sources of infection in humans in this area of California.
All six patients manifested hepatitis as a major illness, and only one patient presented with a pulmonary lesion as well. A single patient manifested chronic Q fever. All patients with acute Q fever responded to doxycycline, and two instantly became afebrile with non-steroidal anti-inflammatory drugs.33
Received July 31, 2005. Accepted for publication January 29, 2006.
* Address correspondence to Lawrence A. Cone, Eisenhower Medical Center, Probst Professional Building, Suite 308, 39000 Bob Hope Drive, Rancho Mirage, CA 92270. E-mail: laconemedico{at}aol.com 
Authors’ addresses: Lawrence A. Cone, Noel Curry, Phillip Shaver, and Barbara E. Potts, Department of Medicine, Eisenhower Medical Center, Rancho Mirage, CA 92270, E-mail: laconemedico{at}aol.com. David Brooks, Department of Medicine, Palo Verde Hospital, Blythe, CA. James DeForge, Bighorn Institute, Palm Desert, CA.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
