Do you want to buy antibiotics online without prescription? - This is pharmacy online for you!

Chapter 26
Clinical Disease in Domestic Animals
Clinical Disease in Humans

*Colonel, Medical Corps, U.S. Army; Chief, Genetics and Physiology Branch, Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare INTRODUCTION
Q fever is a zoonotic disease caused by Coxiella although a temporarily incapacitating, illness in burnetii, a rickettsia-like organism of low virulence humans. Even without treatment, the vast majority but remarkable infectivity. A single organism may of patients recover. Chronic disease as a result of Q initiate infection. In addition, despite the fact that fever is rare, although it is frequently fatal.
C burnetii is unable to grow or replicate outside host The primary reservoir for natural human infec- cells, there is a sporelike form of the organism that tion is livestock, particularly parturient females, is extremely resistant to heat, pressure, desiccation, and the distribution is worldwide. Outbreaks of Q and many standard antiseptic compounds; this al- fever are infrequently reported, however, and the lows C burnetii to persist in the environment for long disease may be endemic in areas where cases are periods (weeks or months) under harsh conditions.
rarely or never reported. Humans who work in This persistence, coupled with a primary mode of animal husbandry, especially those who assist dur- transmission by inhalation of infected aerosols, al- ing parturition (eg, calving or lambing) are at lows for the development of acute infection follow- risk for acquiring Q fever. However, a definite risk ing only indirect exposure to an infected source. In also exists for persons who live in close proximity contrast to this high degree of inherent resilience to, or who pass through, an area where animal and transmissibility, the acute clinical disease as- birthing is occurring, even if this occurred months sociated with Q fever infection is usually a benign, MILITARY RELEVANCE
Since the disease was described in 1937, thou- ver. Similar cases were observed in German troops sands of cases involving military personnel of many during World War II in Italy, Crimea, Greece, countries have been reported (an excellent review was published in 19781), and infection with C An outbreak of acute Q fever associated with an burnetii should be considered a possibility when- epidemic of spontaneous abortion in sheep and ever troops are present in an area with infected ani- goats occurred in 78 British troops stationed in Cyprus, from December 1974 to June 19757; Swed- American soldiers in Italy during World War II ish troops were also affected.8 Q fever outbreaks were affected, with 5 confirmed outbreaks of Q fe- have also been described1 among Swiss soldiers in ver during the winter of 1944 and spring of 1945,2 1948, Greek soldiers from 1946 to 1956, and Royal usually in troops occupying farm buildings recently Air Force airmen on the Isle of Man in 1958. These or concurrently inhabited by farm animals.3 This outbreaks occurred in the soldiers’ home countries degree of close contact with farm animals was not when the troops were stationed or training in close an absolute requirement for infection, however: proximity to sheep or goats, particularly parturi- approximately 1,700 cases occurred in late spring, ent animals. Outbreaks attributed to sheep or goat 1945, at an airbase in southern Italy as a result of exposure in deployed soldiers have been described1 sheep and goats herded in pastures nearby.4 Dur- in American airmen in Libya in 1951 and French ing World War II, cases of acute Q fever were also identified in soldiers in Virginia shortly after de- Among American military personnel in the Per- barking from a 9-day voyage from Naples, Italy,4,5 sian Gulf War, one case of meningoencephalitis as- and a single case was identified in a soldier sta- sociated with acute Q fever was reported, with the onset of symptoms 2 weeks after return from the Hundreds of cases consistent with Q fever were Persian Gulf.9 One other soldier, with acute Q fever observed in German soldiers in Serbia and south- pneumonia, was diagnosed in Saudi Arabia in ern Yugoslavia during World War II. Outbreaks March 1991.10 This occurred in a first sergeant in an occurred in the apparent absence of disease in the engineering battalion. Subsequent epidemiological indigenous population. The disease was most com- evaluation and serologic testing of the unit identi- monly referred to as “Balkengrippe”; infection with fied three additional acute seroconversions among C burnetii was not confirmed by laboratory testing, soldiers of the same battalion.11 Exposure to sheep, but the clinical and epidemiological features of the goats, or camels was identified in all of these infec- illness described were most consistent with Q fe- Q fever is probably endemic in Somalia,12 and The potential of C burnetii as a biological war- serologic evidence of acute Q fever was identified fare threat is directly related to its infectivity. It has in two American soldiers evaluated in Somalia for been estimated that 50 kg of dried, powdered C burnetii would produce casualties a rate equal to These reports all underscore the importance of that of similar amounts of anthrax or tularemia or- considering the diagnosis of Q fever in a febrile ganisms.14 Q fever has been evaluated as a poten- soldier in or recently returned from an area where tial biological warfare agent by the United States,15 the disease may be present. This is particularly true but munitions and stocks (except that required for if the soldier has been in close proximity to or in an vaccine research) were publicly destroyed by execu- area previously occupied by animals which may tive order of President Richard M. Nixon between Q fever was first described in 1937 by Edward Mountain Laboratory. He observed that a febrile Derrick,17 while he was the Director of Microbiol- illness resulted when ticks collected from the area ogy and Pathology for the Queensland (Australia) around the nearby Nine Mile Creek were allowed Health Department at Brisbane. In 1935, he was to feed on guinea pigs.20 The disease produced in contacted about a febrile illness that had been oc- guinea pigs did not, however, resemble Rocky curring among abattoir workers in Brisbane. When Mountain Spotted Fever. Herald Cox was subse- routine blood cultures and serologic testing did not quently able to characterize the organism (then reveal a diagnosis, Derrick suspected that he was called the “Nine Mile Agent”) as similar to rickett- dealing with a new illness. He thoroughly described sia and to cultivate this organism in the yolk sac the clinical characteristics and designated the dis- membrane of embryonated hen eggs.21 The relation ease Q (for query) fever. Derrick’s laboratory inves- of Q fever to the Nine Mile Agent was established tigation demonstrated that it was possible to trans- by Rolla Dyer, director of the National Institutes of mit the disease to animals by inoculating guinea Health at the time, after the spleens of infected mice pigs and mice with the blood of humans suffering were sent to him by Burnet. In an event that pre- from acute Q fever. Although Derrick had initially saged the problems of transmission of Q fever in concluded that the infectious agent was a virus, laboratory workers, Dyer himself acquired acute Q studies of a guinea pig liver emulsion sent to fever during a visit to Hamilton in 1938.22 MacFarlane Burnet in Melbourne subsequently in- The work of Ralph Parker, also at the Rocky dicated that the causative organism was a rickett- Mountain Laboratory, indicated that ticks are the sia,18 according to the terminology used at that time.
reservoir of the “Nine Mile Agent.” Derrick had also Interestingly, Derrick may not have been the first suspected tick transmission from a primary reser- to transfer the disease to laboratory animals. Hideyo voir, and from a secondary reservoir of domestic Noguchi, working at the Rockefeller Institute in animals. The significance of exposure to parturient New York City in 1925, may have passed C burnetii animals was not, however, recognized until 1950.
to guinea pigs from ticks that had been collected at The causative agent of Q fever was ultimately Saw Tooth Canyon by Ralph Parker at the Rocky designated Coxiella burnetii to recognize the out- Mountain Laboratory in Hamilton, Montana.19 This standing contributions of both Cox and Burnet to agent, however, was ultimately lost in animal the isolation and characterization of this new patho- gen.23 The disease, following clinical description About the same time that the investigations were and microbiological characterization of the etiologic being done in Australia, Gordon Davis was study- agent, has been identified in at least 51 countries ing Rocky Mountain Spotted Fever at the Rocky THE INFECTIOUS AGENT
Coxiella burnetii is classified in the family analysis is performed,25 thus the genus Coxiella has Rickettsiaceae, but is not included in the genus Rick- only one species. The closest relative according to ettsia and therefore is not a true rickettsia. It is not 16s ribosomal RNA analysis is Legionella,25,26 but closely related to any other bacterial species when Legionella has different growth characteristics comparative 16s ribosomal ribonucleic acid (RNA) (Legionella, being a facultative intracellular parasite, Medical Aspects of Chemical and Biological Warfare Fig. 26-1. Electron micrograph of Coxiella burnetii in the
phagolysosome of an infected yolk sac cell, demonstrat-
ing both large (LCV) and small (SCV) cell variants. The
bar in the lower right corner represents 0.6 µm. After copyright permission granted to the Borden Renografin (manufactured by Squibb Diagnostics, Institute, TMM, does not allow the Borden Princeton, NJ) purification, the cells were fixed with pri- Institute to grant permission to other users mary fixative and stained with potassium permangan- and/or does not include usage in electronicmedia. The current user must apply to the ate. The phagolysosome contains many pleomorphic C burnetii organisms. Multiplication by binary transverse permission to use this illustration in any type fission with septa formation (arrows) is seen.
The LCVs resemble Gram-negative bacteria, with outer and cytoplasmic membranes separated by aperiplasmic space. The LCV is more metabolically activethan the SCV, has less peptidoglycan in the cell wall, andis capable of production of the sporelike form. The looseouter membrane, increased periplasmic space, and blebformation of some of the LCVs probably indicate thatthey are undergoing deterioration or have been damagedduring preparation. The SCVs appear as extremely denseorganisms and are heat-resistant, relatively dormantstructures which have the ability to survive in an adverseenvironment. Reprinted with permission from McCaulTF, Williams JC. Developmental cycle of Coxiella burnetii:Structure and morphogenesis of vegetative and sporo-genic differentiations. J Bacteriol. 1981;147:1067.
is able to survive and multiply extracellularly) and Phase variation has been described with C causes a different clinical syndrome.
burnetii maintained in the laboratory.31 The virulent C burnetii must occupy an intracellular environ- organism, which is associated with natural infec- ment in order to grow or reproduce, similar to true tion and a smooth lipopolysaccharide (LPS), is des- rickettsia, although, as previously stated, the organ- ignated as Phase I. This phase is resistant to comple- ism has a sporelike form that is very resistant to ment and is a potent immunogen. Serial passage of heat and desiccation.27 This sporelike form may be C burnetii in eggs eventually results in the bacter- observed in human tissue.28 The particular cytologi- ium’s conversion to Phase II, which has a rough LPS cal niche occupied by C burnetii is the usually very and is much less virulent than Phase I. This phase destructive environment of the phagolysosome of is sensitive to complement and is a poor immuno- eukaryotic cells (Figure 26-1), which has a strongly gen. The conversion from Phase I to Phase II is irre- acidic milieu (normal pH is 4.5) and numerous di- versible32 and is the result of a mutation caused by gestive enzymes. While inhabiting the phagolyso- some, C burnetii usually lives in relatively peaceful Coxiella burnetii also contains several plasmids, coexistence with the host, causing little direct dam- and dissimilar plasmid types may be associated age to the cell, at least initially.
with different manifestations of disease.33 The cell Replication occurs by binary fission within the host wall of a Phase I C burnetii organism contains, in cell; the dormant, sporelike form, is produced under association with lipopolysaccharide, an immuno- certain circumstances.29 Dormant C burnetii can be modulatory complex,34 which produces toxic reac- stimulated to a brief period of growth by exposure to tions in mice (eg, hepatomegaly, splenomegaly, liver an acidic environment.30 Sustained growth and repli- necrosis) and lymphocyte hyporesponsiveness in cation of C burnetii outside a host cell is not possible.
The host range of C burnetii is very diverse and includes a large number of mammalian species Coxiella burnetii is extremely infectious. Under and arthropods. Among these, however, man is the experimental conditions, a single organism is capable only host identified that normally experiences an of producing infection and disease in humans.35 illness as a result of infection. A number of differ- ent strains of C burnetii have been identified world- • slaughterhouse workers in California44; wide, and different clinical manifestations and com- • faculty, laboratory workers, and staff ex- plications may be associated with the various posed to sheep at a medical school in Colo- Humans have been infected most commonly by • individuals exposed to sheep at a sheep re- contact with domestic livestock, particularly goats, cattle, and sheep. The risk of infection is substantially • laboratory animal personnel in Arkansas increased if humans are exposed to these animals at parturition. During gestation, the proliferation of • workers in an animal research laboratory C burnetii in the placenta facilitates aerosolization of large numbers of the pathogen during parturi- tion. Coxiella organisms thus produced may persistin the local environment, and produce infection, for Although reported outbreaks49,50 of Q fever in the United States have been relatively uncommon in C burnetii is also shed in the urine and feces recent years, underreporting undoubtedly occurs.
of infected animals, in addition to being present For example, although the first 2 cases of Q fever in the blood and tissues. Survival of the organism from 2 adjacent rural counties in Michigan were on inanimate surfaces, such as straw, hay, or cloth- reported in 1984, a study51 published just 4 years ing, allows for transmission to individuals who are later showed that 15% of the general population not in direct contact with infected animals; for ex- surveyed in those 2 counties and 43% of goat owners • soldiers sleeping in barns previously occu- Pathogenesis
• laundry workers handling infected cloth- Human infection with C burnetii is usually the result of inhalation of infected aerosols. Following • coworkers of an individual with an infected this, the organisms are phagocytized by host cells, predominately unstimulated macrophages. This • residents of an urban community living uptake of C burnetii by host phagocytic cells is not along a road utilized by farm vehicles.38 energy dependent, but is probably the result of con-tact by the pathogen with an existing receptor. Af- Investigation of outbreaks of Q fever frequently ter phagocytosis by host cells, conditions within the report a significant proportion of patients who have phagolysosome trigger growth and multiplication no identifiable risk factor. Human-to-human trans- of C burnetii, with little initial damage to the host mission has been reported,39 but it is a very rare cell. Eventually the cytoplasm becomes engorged with C burnetii organisms and lysis of the host cell As mentioned previously, the distribution of C occurs. Dissemination of the pathogen occurs as a burnetii is worldwide.24 With the exception of a few result of circulation of organisms free in the plasma, countries (New Zealand is an example), Q fever on the surface of cells, and carried by circulating cases have been identified practically everywhere that an attempt has been made to identify evidence In animals, infection frequently lasts for the life of infection, either in man or in animals.
of the animal, in a more-or-less dormant state, with In the United states, the epidemiology of Q fe- periodic increases in organism numbers during ver is variable. Sporadic but regularly occurring periods of relative immunosuppression, particu- cases have been observed40 in areas with endemic larly parturition,52 but also in laboratory animals foci in cattle, and clusters of cases have been de- treated with adrenocorticosteroids53 or irradiation.54 scribed41 in areas with infected dairy herds. Live- C burnetii causes little overt disease in animals (and stock is not the only source of Q fever infections in no apparent disease in ticks), except that luxuriant this country: a small outbreak in Maine associated growth in the placenta may increase the rate of with exposure to a parturient cat has been de- spontaneous abortion in some species. Edema and scribed,42 similar to an outbreak in Nova Scotia, thrombohemorrhagic lesions may be identified in Canada.43 Since 1985, outbreaks of Q fever in the United States have been reported in five states There is little host reaction at the initial portal of entry, either in the lung following inhalation of aero- Medical Aspects of Chemical and Biological Warfare sol or in the skin following a tick bite. Q fever de- In sheep, the infection tends to be transient, fol- velops without formation of a primary infectious lowed by spontaneous remission. Infected sheep focus in the area of the tick bite, and the organism will usually cease shedding the pathogen after a few does not infect the vascular endothelium as do true months and no longer be infectious to other ani- mals in the flock, except during parturition. Al- In man, polyclonal production of antibody rep- though C burnetii has frequently been recovered resents the initial immune response to C burnetii, from the placentas of sheep and has been associ- but humoral immunity alone is ineffective for con- ated with epidemic abortions, shedding in the milk trol of the organism, although the presence of anti- body does contribute significantly to antibody- By contrast, chronic shedding—over months or dependent cellular cytotoxicity later in the course years—of Coxiella in the milk of lactating cows can of the infection. Passive transfer of immune serum be expected. This aspect of the infection can facili- to laboratory animals does not improve clearance tate maintenance of Coxiella in a herd, particularly of organisms from the spleen.55 Pretreatment of a dairy herd. Infection in cows is also associated laboratory animals with cyclophosphamide, an an- with an increased incidence of spontaneous abor- tineoplastic agent that severely inhibits production tion and may be associated with infertility.
of antibody, does not adversely affect the course of Goats also show an increased disposition for infection.56 C burnetii organisms that have been abortion during epizootics of Q fever, and infection opsonized, however, are much more efficiently de- in a herd may be maintained by chronic shedding.
stroyed by host phagocytic cells than are unop-sonized organisms. Control of the infection by the Clinical Disease in Humans
host eventually results from the development ofspecific cell-mediated immunity, with killing by Man is the only host susceptible to infection by activated macrophage and natural killer cells. This C burnetii that commonly develops an illness as a process may result in a granulomatous reaction result of the infection. The incubation period var- without the scarring and tissue reaction observed ies from 10 to 40 days, with the duration of the in- cubation period being inversely correlated with the The host immune response in man appears to be magnitude of the inoculum.35 A higher inoculum modified by the C burnetii organism itself in chronic also increases the severity of the disease. Q fever in infection, in that the lymphocytes of patients with Q fever endocarditis exhibit profound hyporespon- seroconversion, acute illness, or chronic disease.
siveness to C burnetii antigen, although they retain The frequency of these manifestations parallels this order in decreasing magnitude. In epidemiological The presence of LPS on the cell surface of C surveys, most seropositive individuals do not re- burnetii protects the pathogen from host microbi- call having the illness. The frequency of chronic cidal activities. The phase variation previously de- disease (usually endocarditis) compared with acute scribed is the result of alteration of the LPS, with disease is difficult to determine precisely due to the virulent Phase I organism having a smooth LPS.
underreporting of acute infection but is probably The Phase II organism, the result of serial passage less than 1% of the total infected population.
of C burnetii in eggs, has a rough LPS, is much less The tendency for C burnetii to produce asymp- immunogenic than the Phase I, and is less virulent.58 tomatic seroconversion has been documented in Phase I organisms are resistant to the lytic action of several publications. In one study,35 experimental complement, while Phase II organisms are sensitive infection in humans showed that in 2 of 4 volun- to the alternate pathway of complement.59 teers infected with a single organism by aerosol, adiagnosis could be established by serologic conver- Clinical Disease in Domestic Animals
sion without clinical illness. Asymptomatic sero-conversion did not occur with higher infecting Except for spontaneous abortion, illness in do- doses (5–1,500 organisms). In an outbreak in Canada mestic animals as a result of C burnetii infection is attributed to indirect exposure to contaminated unusual, although the organism has a propensity clothing, 6 (37.5%) of 16 individuals diagnosed by for proliferation in the female reproductive sys- seroconversion did not have an associated illness.37 tem—particularly the uterus and the mammary In Switzerland in 1983, during the course of a glands. Differences between the manifestations in serosurvey to investigate a large outbreak of Q domestic animals, however, are worthy of comment.
fever, more than half of the 415 serologically con- firmed patients were asymptomatic or minimally TABLE 26-1
ill.60 These reports underscore the value of an epi-demiological investigation when even a single case SIGNS AND SYMPTOMS IN ACUTE Q FEVER
Infection with C burnetii has been reported61 to Signs and Symptoms
Frequency (%)
persist in humans, as it does in animals, in an asymp-tomatic state. Phase I C burnetii has been recovered from the placentas of asymptomatic women in- fected from 1 to 6 months,62 to 3 years63 previously.
Infection with Q fever may rarely affect the outcomeof pregnancy adversely.64 Acute Q Fever
There is no characteristic illness for acute Q fever, and manifestations may vary considerablybetween locations where the disease is acquired.
When symptomatic, the onset of Q fever may be abrupt or insidious, with fever, chills (including frank rigors), and headache being the most com-mon signs and symptoms (Table 26-1). The head- ache is usually described as severe, throbbing, and frontal or retro-orbital in location. Diaphoresis,malaise, fatigue, and anorexia are also very com- mon. Weight loss of 7 kg or more during the course of acute illness has been reported with surprisingfrequency, particularly when other general symp- toms lasted more than 2 weeks.2,65 Myalgias are also a frequent complaint, while arthralgias are rela-tively unusual. Cough tends to appear later in the illness than some of the other more common symp- toms, such as fever, chills, and headache, and maynot be a prominent complaint. Chest pain occurs in a minority of patients and may be pleuritic or a Relatively infrequent symptoms include sore *Some report gradual onset; others, abrupt onset; coincidentally, throat, gastrointestinal upset, and neck stiffness, although this last symptom has been severe enough Data sources: (1) Robbins FC, Ragan CA. Q fever in the Mediter- in reported cases of acute Q fever to warrant a lum- ranean area: Report of its occurrence in Allied troops, I: Clinical bar puncture to exclude bacterial meningitis. Al- features of the disease. Am J Hyg. 1946;44:6–22. (2) Feinstein M,Yesner R, Marks JL. Epidemics of Q fever among troops return- though nonspecific evanescent skin eruptions have ing from Italy in the spring of 1945, I: Clinical aspects of the been reported,66,67 there is no characteristic rash.
epidemic at Camp Patrick Henry, Virginia. Am J Hyg. 1946;44:72– Most patients appear mildly to moderately ill— 87. (3) Marrie TJ, Langille D, Papukna V, Yates L. Truckin’ pneu- when the onset is abrupt, Q fever has been mistaken monia—An outbreak of Q fever in a truck repair plant probablydue to aerosols from clothing contaminated by contact with a for influenza. The temperature tends to fluctuate, newborn kitten. Epidem Inf. 1989;102:119–127. (4) Langley JM, with peaks of 39°C to 40°C, and in approximately Marrie TJ, Covert A, et al. Poker players pneumonia: An urban one fourth of the cases is biphasic; in two thirds of outbreak of Q fever following exposure to a parturient cat. N Engl patients with acute disease, the febrile period lasts J Med. 1988;319:354–356. (5) Raoult D, Marrie TJ. State-of-the-artclinical lecture: Q fever. Clin Inf Dis. 1995;20:489–496. (6) Clark WH, 13 days or less. The duration of fever is usually Lennette EH, Railsback OC, Romer MS. Q fever in California.
Arch Intern Med. 1951;88:155–161. (7) Dupont HT, Raoult D, Neurological symptoms are not uncommon and Brouqui P, et al. Epidemiologic features and clinical presentation in one study65 were observed in up to 23% of acute of acute Q fever in hospitalized patients: 323 French cases. Am JMed. 1992;93:427–434. (8) Tselentis Y, Gikas A, Kofteridis D, et al.
cases. Encephalopathic symptoms, hallucinations Q fever in the Greek island of Crete: Epidemiologic, clinical, and (visual and auditory), expressive dysphasia, hemi- therapeutic data from 98 cases. Clin Inf Dis. 1995;20:1311–1316.
Medical Aspects of Chemical and Biological Warfare facial pain resembling trigeminal neuralgia, diplo- suggestive of chronic Q fever. An interesting epi- pia, and dysarthria were also reported. Other mani- demiological feature identified in the study was a festations involving the central nervous system, significantly higher percentage of smokers in the such as encephalitis, encephalomyelitis, optic neu- affected group than in the general population of the ritis, or myelopathy may also occur,9,69,70 particularly Physical findings in acute Q fever are as nonspe- Chronic Q Fever
cific as the clinical symptomatology. Rales are prob-ably the most commonly observed physical find- Chronic infection with C burnetii is usually mani- ing; evidence of pleural effusion (including friction fested by infective endocarditis, which is also the rub) and consolidation may also be noted, but not most severe complication of Q fever. In addition, a in the majority of infections. Although hepatome- report73 from France of 92 cases published in 1993 galy, splenomegaly, jaundice, pharyngeal injection, also listed hepatitis, infected vascular prostheses and hepatic and splenic tenderness have all been and aneurysms, osteomyelitis, pulmonary infection, reported, they are relatively unusual in acute in- cutaneous infection, and an asymptomatic form. In addition, 7 of the 92 patients described in this re- Reports of abnormalities on chest X-ray exami- port experienced fever only. Also noted was the nation vary with locale, but abnormalities are prob- observation that although 81% of patients had an ably seen in 50% to 60% of patients.71 An abnormal identifiable risk factor, only 31% lived in a rural chest radiograph may be seen in the absence of area. In addition, some form of immunodeficiency pulmonary symptoms, while a normal chest radio- was observed in 20% of the patients, raising the graph may be observed in a patient with pulmo- possibility that chronic Q fever occurs as a result of nary symptoms. The most common abnormality reactivation of latent infection.73 Inflammatory observed in a recent report from England was a pseudotumor of the lung as a chronic complication unilateral, homogenous infiltrate involving one or two lobes,71 although lobar consolidation and pleu- In Q fever endocarditis, fever has been recorded ral effusions72 may also be seen. Rounded opacities in 85% of patients, along with other systemic symp- and hilar adenopathy are not uncommon,43 at least toms, such as chills, headache, myalgias, and weight in Canada, and the diagnosis of Q fever should be loss, in a recent study73 of 84 cases. Fever was not at least be considered when these abnormalities are as prominent, however, in chronic compared to observed in the setting of acute pneumonia.
acute Q fever. Other frequently reported clinical Laboratory abnormalities of routine tests most features of Q fever endocarditis in this very large se- commonly involve tests of liver function, and pa- ries included congestive heart failure (76%), splenom- tients with acute Q fever may present with a clini- egaly (42%), hepatomegaly (41%), clubbing (21%), and cal picture of acute hepatitis. Depending on the cutaneous signs, often the result of a leuko- locale, reported elevations of aspartate aminotrans- cytoclastic vasculitis (22%). Approximately 90% of ferase, alanine transferase, or both, in the range of patients in this study had preexisting valvular heart 2- to 3-fold higher than the upper limit of normal, disease; more than half had a vascular prosthesis.
are observed in 50% to 75% of patients, while el- Routine blood cultures in Q fever endocarditis evation of the alkaline phosphatase is observed in are negative, and Q fever should be considered 10% to 15% of patients. The total bilirubin can be when culture-negative endocarditis is encountered.
expected to be elevated in 10% to 15% of patients The diagnosis of infective endocarditis secondary with acute Q fever. The white blood cell count is to Q fever is confirmed by serologic testing: anti- usually normal; the erythrocyte sedimentation rate body to Phase I organisms is usually higher than is elevated in one third of patients.65 Mild anemia that for Phase II, and, more significantly, immuno- or thrombocytopenia may also be observed.
globulin A (IgA) antibody to C burnetii is also Complications recorded in a recent outbreak in- volving 147 symptomatic cases of Q fever included2 of acute endocarditis, 2 of renal failure, and 1 of Diagnosis
reactive polyarthropathy.65 Persistent nonspecificsymptoms, such as fatigue and malaise, were re- Diagnosis of Q fever is usually accomplished by ported in 32% of the patients in this series, while serologic testing because culture of C burnetii is weight loss (defined as > 7 kg) was identified in potentially hazardous to laboratory personnel and 71%, although none developed serologic evidence requires animal inoculation or cell culture.
A number of serologic methods are used, includ- formed at the United States Army Research Insti- ing complement fixation (CF), indirect fluorescent tute of Infectious Diseases, Fort Detrick, Frederick, antibody (IFA), macroagglutination and microag- Maryland, can establish a diagnosis of acute Q fe- glutination, and enzyme-linked immunosorbent ver from a single serum specimen, with a sensitiv- assay (ELISA). Significant antibody titers are usu- ity of 80% to 84% in early convalescence and 100% ally not identifiable until 2 to 3 weeks into the ill- in intermediate and late convalescence.79 In general, ness. In 1987, the sensitivities of the different anti- antibodies to the rough Phase II organism are iden- body assay methods were reported77 as 94% for tified earlier in the illness, during the first few ELISA, 91% for IFA, and 78% for CF. Following in- months following infection, followed by a decline fection, significant antibody titers may be present in antibody to Phase II organisms and a rise in an- for years, particularly with more sensitive assays, tibody to the smooth, virulent Phase I organism.
Antibodies of the IgM type are usually observed Of the methods currently utilized for the diag- within the first 6 to 12 months following infection, nosis of Q fever, the ELISA is the most sensitive and with persistence of IgG antibodies afterward.
the easiest to perform. The utility of the ELISA Polymerase chain reaction (PCR) may also be for epidemiological screening and diagnosis of Q useful in the future for the diagnosis of Q fever,80–83 fever has recently been confirmed.78 This assay, per- but remains to be validated in acute clinical cases.
The treatment of Q fever was the subject of an ex- new macrolide, azithromycin, has also demonstrated cellent review that was published in 1993.84 Tetracy- efficacy in a few cases, but experience is very limited.86 clines have been the mainstay of therapy since the When chronic Q fever infection is manifested by 1950s. When initiated within the first few days of ill- infective endocarditis, treatment is very difficult; ness, treatment with a tetracycline shortens the course the mortality is 24% even when patients receive of the disease. Attempted prophylaxis with a tetracy- appropriate treatment.73 At least 2 years of therapy cline (20 g of oxytetracycline administered over 5–6 are required, usually with a tetracycline combined d), however, has produced mixed results.35 Initiation with rifampin or a quinolone, although tri- of the antibiotic early in the incubation period (24 h methoprim-sulfamethoxazole has also been used.84 after exposure) merely prolonged the incubation Quinolones alone or in combination have also been period, while initiation of therapy late in the incuba- effective. Most recently, the addition of hydroxy- tion period prevented the development of disease.
chloroquine to tetracycline has shown promising Macrolide antibiotics, such as erythromycin, are results both in vitro87 and in a small number of also effective for the treatment of acute Q fever.72,85 A PROPHYLAXIS
Q fever can be prevented by immunization. Vac- lymphocyte transformation in response to C burnetii cine prophylaxis for Q fever has been studied and antigen,93 although these tests are not positive in used almost since the discovery that the responsible all individuals previously infected with C burnetii.
organism could be propagated in the yolk sac of These long-lasting indicators of cell-mediated eggs. Immunization with formalin-killed C burnetii immunity develop in most individuals after natural confers protection against Q fever in laboratory infection, but are also seen after immunization,90,93 personnel,89 abattoir workers,90,91 and human vol- although to a lesser extent. Conversion from a nega- unteers experimentally exposed to aerosolized C tive lymphocyte proliferative response to a positive burneti.92 In Australian abattoir workers, the results was observed in 11 (85%) of 13 of the individuals of efficacy studies were impressive: a single injec- vaccinated.93 In the same study, only 5 (38%) of 13 tion of 30 µg of vaccine antigen (Q-Vax, manufac- of vaccinated subjects seroconverted, and 31 (60%) tured by CSL Ltd., Parkville, Victoria, Australia) of 52 developed a positive skin test following vac- conferred protective immunity that began 2 weeks cination. Therefore, although the whole cell Q fe- after immunization and persisted for at least 5 ver vaccine used in the Australian abattoirs confers years.90 Protection depends primarily on cell- protection, there does not appear to be a measur- mediated immunity, the presence of which may be able response reliably associated with protective detected by positive skin test reactions and in vitro Medical Aspects of Chemical and Biological Warfare C burnetii formalin-killed whole cell vaccines are a significant chronic reaction.90 The advisability of generally well tolerated after subcutaneous injec- prior skin testing was further reinforced when tion, although some individuals develop severe severe local reactions were observed in 3 of 10 in- local reactions at the site of injection. These reac- dividuals with a positive skin test to C burnetii tions can involve formation of sterile abscesses that antigen who mistakenly received a single dose of may drain spontaneously or may require surgical incision.94 The incidence of severe, persistent local Although an effective Q fever vaccine is licensed reactions is immunologically mediated by a delayed in Australia, all Q fever vaccines used in the United hypersensitivity response, resulting from previous States are currently investigational. Certain groups natural infection with C burnetii or repeated immu- of individuals should be considered for vaccine nization92; the risk of severe local reaction increases with the number of Q fever immunizations. Thisobservation led to the development of an intrader- • veterinarians, veterinary technicians, and mal skin test using 0.02 µg of specific formalin- killed whole cell vaccine to detect presensitized or contact with C burnetii–infected animals, Severe local reactions to the vaccine were found • laboratory investigators, technicians, and to be associated with induration of 5 mm or larger at the skin test site by 7 days after inoculation. Al- though cumbersome, inconvenient, and costly, this • abattoir workers who have contact with prior screening procedure proved to be very effec- cattle, sheep, or goats (particularly preg- tive in reducing the number of severe local reac- nant animals) that may be infected with C tions to Q fever vaccine. Subsequent experience with this skin test at the Rocky Mountain Labora-tory in Montana showed that there were no severe Research efforts are currently underway to de- local reactions in 80 individuals whose skin tests velop a Q fever vaccine that is safe to administer to were negative when they were immunized with one anyone, including Q fever–immune individuals.
or two doses of vaccine. Prior to the availability of The residue of C burnetii organisms following chloro- skin test screening, severe local reactions occurred form-methanol extraction (CMR vaccine) has been in 42 (45%) of 94 vaccinated individuals.95 Addition- tested for safety in nonimmune volunteers97 and is ally, in Australian abattoirs, more than 4,000 indi- currently being tested for safety in Q fever–immune viduals whose skin tests were negative received the individuals. Antibiotic prophylaxis of Q fever has formalin-killed vaccine during the course of vac- been tested with a tetracycline, as was discussed in cine efficacy studies, and of these, only 1 developed the treatment section of this chapter.
Q fever, a zoonotic disease caused by the rickett- The organism is also very resistant to pressure and des- sia-like organism Coxiella burnetii, is important to mili- iccation, and may persist in a sporelike form in the envi- tary medicine primarily because of its exceptional ronment for months after the source has left the area.
infectivity. The disease is transmitted mainly by in- Diagnosis of Q fever is performed by serologic halation of infected aerosols, and a single organism testing. Treatment with tetracyclines is effective.
may cause infection in humans. The disease is world- Prevention is possible with a formalin-killed, wide in distribution; the primary reservoir for human whole-cell vaccine, but prior skin testing to exclude infection is livestock, particularly goats, sheep, and immune individuals is necessary to avoid severe cattle. Contact with parturient animals or products of local reactions to the vaccine. A Q fever vaccine is conception poses especially high risk, since the organ- licensed in Australia, but not in the United States, ism is present in very high numbers in this setting.
where all Q fever vaccines are investigational.
1. Spicer AJ. Military significance of Q fever: A review. J R Soc of Med. 1978;71:762–767.
2. Robbins FC, Ragan CA. Q fever in the Mediterranean area: Report of its occurrence in Allied troops, I: Clinical features of the disease. Am J Hyg. 1946;44:6–22.
3. Robbins FC, Gauld RL, Warner FB. Q fever in the Mediterranean area: Report of its occurrence in Allied troops, II: Epidemiology. Am J Hyg. 1946;44:23–50.
4. The Commission of Acute Respiratory Diseases, Fort Bragg, North Carolina. Epidemics of Q fever among troops returning from Italy in the spring of 1945, III: Etiological studies. Am J Hyg. 1946;44:88–102.
5. Feinstein M, Yesner R, Marks JL. Epidemics of Q fever among troops returning from Italy in the spring of 1945, I: Clinical aspects of the epidemic at Camp Patrick Henry, Virginia. Am J Hyg. 1946;44:72–87.
6. Cheney G, Geib WA. The identification of Q fever in Panama. Am J Hyg. 1946;44:158–172.
7. Spicer AJ, Crowther RW, Vella EE, Bengtsson E, Miles R, Pitzolis G. Q fever and animal abortion in Cyprus.
Trans R Soc Trop Med Hyg. 1977;71(1):16–20.
8. Rombo L, Grandien M. Serum Q fever antibodies in Swedish UN soldiers in Cyprus. Scand J Inf Dis. 1978;10:157–158.
9. Ferrante MA, Dolan MJ. Q fever meningoencephalitis in a soldier returning from the Persian Gulf War. Clin Infect Dis. 1993;16:489–496.
10. Lennox J. Assistant Professor of Medicine, Emory University School of Medicine, and Acting Medical Director, Infectious Disease Program, Grady Memorial Hospital, Atlanta, Ga. Personal communication, May 1993.
11. Waag D. US Army Medical Research Institute of Infectious Diseases, Pathogenesis and Immunology Branch, Bacteriology Division, Fort Detrick, Frederick, Md. Personal communication, September 1994.
12. Gray GC, Rodier GR, Matras-Maslin VC, et al. Serologic evidence of respiratory and rickettsial infections among Somali refugees. Am J Trop Med Hyg. 1995;52(4):349–353.
13. Magill A. Major, Medical Corps, US Army. Infectious Diseases Officer, Department of Immunology, Division of Communicable Diseases and Immunology, Walter Reed Institute of Research, Walter Reed Army Medical Cen-ter, Washington, DC. Personal communication, September 1994.
14. World Health Organization. Health Aspects of Chemical and Biological Weapons: Report of a WHO Group of Consult- ants. Geneva, Switzerland: WHO; 1970.
15. Department of the Army. US Army Activity in the US Biological Warfare Program. Vol 2. Washington, DC: HQ, DA; 24 Feb 1977: D 1–2; Appendix 4, pp E4-1, 2. Unclassified.
16. Department of the Army. US Army Activity in the US Biological Warfare Program. Vol 2. Washington, DC: HQ, DA; 24 Feb 1977: L 1–6. Unclassified.
17. Derrick EH. “Q” fever, a new fever entity: Clinical features, diagnosis and laboratory investigation. Med J Aust.
18. Burnet FM, Freeman M. Experimental studies on the virus of “Q” fever. Med J Aust. 1937;2:299–305.
19. Noguchi H. A filter-passing infectious agent obtained from Dermacentor andersoni. J Exp Med. 1926;44:1–10.
20. Davis GE, Cox HR. A filter-passing infectious agent isolated from ticks, I: Isolation from Dermacentor andersoni, reactions in animals, and filtration experiments. Public Health Rep. 1938;53:2259–2267.
21. Cox HR. Studies of a filter-passing infectious agent isolated from ticks, V: Further attempts to cultivate in cell- free media. Suggested classification. Public Health Rep. 1939;54:2171–2178.
22. Dyer RE. A filter-passing infectious agent isolated from ticks, IV: Human infection. Public Health Rep. 23. Philip CB. Comments on the name of the Q fever organism. Public Health Rep. 1948;63:58.
Medical Aspects of Chemical and Biological Warfare 24. Kaplan MM, Bertagna P. The geographical distribution of Q fever. Bull WHO 1955;13:829–860.
25. Weisburg WG, Dobson ME, Samuel JE, et al. Phylogenetic diversity of the rickettsias. J Bacteriol. 1989;171:4202– 26. Tzianabos T, Moss CW, McDade JE. Fatty acid composition of rickettsiae. J Clin Microbiol. 1981;13:603–605.
27. Williams JC. Infectivity, virulence, and pathogenicity of Coxiella burnetii for various hosts. In: Williams JC, Thompson HA, eds. Q Fever: The Biology of Coxiella burnetii. Boca Raton, Fla: CRC Press; 1991: Chap 2, p 25,Table 2.
28. McCaul TF, Dare AJ, Gannon JP, Galbraith AJ. In vivo endogenous spore formation by Coxiella burnetii in Q fever endocarditis. J Clin Pathol. 1994;47:978–981.
29. McCaul TF, Williams JC. Developmental cycle of Coxiella burnetii: Structure and morphogenesis of vegetative and sporogenic differentiations. J Bacteriol. 1981;147:1063–1076.
30. Hackstadt T, Williams JC. Biochemical strategem for obligate parasitism of eukaryotic cells by Coxiella burnetii.
Proc Natl Acad Sci U S A. 1981;78:3240–3244.
31. Stoker MGP, Fiset P. Phase variation of the Nine Mile and other strains of Rickettsia burnetii. Can J Microbiol.
32. Baca OG, Paretsky D. Q fever and Coxiella burnetii: A model for host parasite interactions. Microbiol Rev.
33. Samuel JE, Frazier ME, Mallavia LP. Correlation of plasmid type and disease caused by Coxiella burnetii. Infect 34. Waag DM, Williams JC. Immune modulation by Coxiella burnetii: Characterization of a Phase I immunosup- pressive complex expressed among strains. Immunopharmacol Immunotoxicol. 1988;10:231–260.
35. Tigertt WD, Benenson AS. Studies on Q fever in man. Trans Assoc Am Phys. 1956;69:98–104.
36. Oliphant JW, Gordon DA, Meis A, et al. Q fever in laundry workers presumably transmitted from contami- nated clothing. Am J Hyg. 1949;49:76–82.
37. Marrie TJ, Langille D, Papukna V, Yates L. Truckin’ pneumonia—An outbreak of Q fever in a truck repair plant probably due to aerosols from clothing contaminated by contact with a newborn kitten. Epidem Inf. 1989;102:119–127.
38. Salmon MM, Howells B, Glencross EJG, et al. Q fever in an urban area. Lancet. 1982;1:1002–1004.
39. Mann JS, Douglas JG, Inglis JM, et al. Q fever: Person to person transmission within a family. Thorax. 1986;41: 40. Wisniewski HJ, Piraino FF. Review of virus infections in the Milwaukee area, 1955–1965. Public Health Reports.
41. Epidemiology of a Q fever outbreak in Los Angeles County, 1966. Health Services and Mental Health Administra- tion Health Reports. 1972;87:71–74.
42. Pinsky RL, Fishbein DB, Greene CR, Gensheimer KF. An outbreak of cat-associated Q fever in the United States.
J Inf Dis. 1991;164(July):202–204.
43. Langley JM, Marrie TJ, Covert A, et al. Poker players pneumonia: An urban outbreak of Q fever following exposure to a parturient cat. N Engl J Med. 1988;319:354–356.
44. Centers for Disease Control. Q fever among slaughterhouse workers—California. MMWR. 1986;35:223–226.
45. Meiklejohn G, Reimer LG, Graves PS, Helmick C. Cryptic epidemic of Q fever in a medical school. J Inf Dis. 46. Rauch AM, Tanner M, Pacer RE, Barrett MJ, Brokopp CD, Schonberger LB. Sheep-associated outbreak of Q fever, Idaho. Arch Intern Med. 1987;147:341–344.
47. Graham CJ, Yamauchi T, Rountree P. Q fever in animal laboratory workers: An outbreak and its investigation.
Am J Inf Con. 1989;17:345–348.
48. Hamedeh GN, Turner BW, Trible W, et al. Laboratory outbreak of Q fever. J Fam Pract. 1992;35:683–685.
49. D’Angelo LJ, Baker EF, Schlosser W. Q fever in the United States, 1948–1977. J Infect Dis. 1979;139:613–615.
50. Sawyer LA, Fishbein DB, McDade JE. Q fever in patients with hepatitis and pneumonia: Results of a labora- tory-based surveillance in the United States. J Infect Dis. 1988;158:497–498.
51. Sienko DG, Bartlett PC, McGee HB, Wentworth BB, Herndon JL, Hall WN. Q fever: A call to heighten our index of suspicion. Arch Intern Med. 1988;148:609–612.
52. Sidwell RW, Gebhardt LP. Studies of latent Q fever infection, III: Effects of parturition upon latently infected guinea pigs and white mice. Am J Epidemiol. 1967;84:132–137.
53. Sidwell RW, Thorpe BD, Gebhardt LP. Studies of latent Q fever infections, II: Effects of multiple cortisone injections. Am J Hyg. 1964;79:320–327.
54. Sidwell RW, Thorpe BD, Gebhardt LP. Studies of latent Q fever infections, I: Effects of whole body X-irradia- tion upon latently infected guinea pigs, white mice, and deer mice. Am J Hyg. 1964;79:113–124.
55. Humphres RC, Hinrichs DJ. Role of antibody in Coxiella burnetii infection. Infect Immun. 1981;31:641–645.
56. Kazar J, Rajcani J, Schramek S. Differential effects of cyclophosphamide on Coxiella burnetii infection in mice.
Acta Virol. 1982;26:174–182.
57. Koster FT, Williams JC, Goodwin JS. Cellular immunity in Q fever: Modulation of responsiveness by a sup- pressor T-cell monocyte circuit. J Immunol. 1985;135:1067–1072.
58. Hackstadt T, Peacock MG, Hitchcock PJ, Cole RL. Lipopolysaccharide variations in Coxiella burnetii: Intrastrain heterogenicity in structure and antigenicity. Infect Immun. 1985;48:359–365.
59. Vishwanath S, Hackstadt T. Lipopolysaccharide phase variation determines the complement-mediated se- rum susceptibility of Coxiella burnetii. Infect Immun. 1988;56:40–44.
60. Dupuis G, Petite J, Olivier P, Vouilloz. Int J Epidemiol. 1987;16:282–287.
61. Fergusson RJ, Shaw TRD, Kitchin AH, et al. Subclinical chronic Q fever. Q J Med. 1985;57:669–676.
62. Marrie TJ. Q fever in pregnancy: Report of two cases. Inf Dis Clin Pract. 1993;2:207–209.
63. Syrucek L, Sobeslavsky O, Gutvirth I. Isolation of Coxiella burnetii from human placentas. J Hyg Epidemiol Microbiol Immunobiol. 1958;2:29–35.
64. Friedland JS, Jeffrey I, Griffin GE, Booker M, Courtney-Evans R. Q fever and intrauterine death. Lancet. 65. Smith DL, Ayres JG, Blair I, et al. A large Q fever outbreak in the West Midlands: Clinical aspects. Respir Med.
Medical Aspects of Chemical and Biological Warfare 66. Clark WH, Lennette EH, Railsback OC, Romer MS. Q fever in California. Arch Intern Med. 1951;88:155–161.
67. Dupont HT, Raoult D, Brouqui P, et al. Epidemiologic features and clinical presentation of acute Q fever in hospitalized patients: 323 French cases. Am J Med. 1992;93:427–434.
68. Derrick EH. The course of infection with Coxiella burnetii. Med J Aust. 1973;1:1051–1057.
69. Hwang YM, Lee MC, Suh DC, Lee WY. Coxiella (Q fever)-associated myelopathy. Neurology. 1993;43:338–342.
70. Sempere AP, Elizaga J, Duarte J, et al. Q fever mimicking herpetic encephalitis. Neurology. 1993;43:2713–2714.
71. Smith DL, Wellings R, Walker C, et al. The chest x-ray report in Q fever: A report on 69 cases from the 1989 West Midlands outbreak. Br J Radiol. 1991;64:1101–1108.
72. Tselentis Y, Gikas A, Kofteridis D, et al. Q fever in the Greek island of Crete: Epidemiologic, clinical, and therapeutic data from 98 cases. Clin Inf Dis. 1995;20:1311–1316.
73. Brouqui P, Dupont HT, Drancourt M, et al. Chronic Q fever: Ninety-two cases from France, including 27 cases without endocarditis. Arch Intern Med. 1993;153:642–648.
74. Janigan DT, Marrie TJ. An imflammatory pseudotumor of the lung in Q fever pneumonia. N Engl J Med.
75. Lipton JH, Fong TC, Gill MJ, et al. Q fever inflammatory pseudotumor of the lung. Chest. 1987;92:756–757.
76. Peacock MG, Philip RN, Williams JC, et al. Serological evaluation of Q fever in humans: Enhanced phase I titers of immunoglobulins G and A are diagnostic for Q fever endocarditis. Infect Immun. 1983;41:1089–1098.
77. Peter O, Dupuis D, Bee R, et al. Comparison of enzyme-linked immunosorbent assay for diagnosis of Q fever.
J Clin Microbiol. 1987;25:1063–1067.
78. Uhaa IJ, Fishbein DB, Olson JG, et al. Evaluation of specificity of indirect enzyme-linked immunosorbent assay for diagnosis of human Q fever. J Clin Microbiol. 1994;32:1560–1565.
79. Waag D, Chulay J, Marrie T, England M, Williams J. Validation of an enzyme immunoassay for serodiagnosis of acute Q fever. Eur J Clin Microbiol Infect Dis. 1995;14(5):421–427.
80. Hoover TA, Vodkin MH, Williams JC. A Coxiella burnetii repeated DNA element resembling a bacterial inser- tion sequence. J Bacteriol. 1992;174:5540–5548.
81. Stein A, Raoult D. Detection of Coxiella burnetii by DNA amplification using polymerase chain reaction. J Clin Microbiol. 1992;30:2462–2466.
82. Willems H, Thiele D, Krauss H. Plasmid based differentiation and detection of Coxiella burnetii in clinical samples.
Eur J Epidemiol. 1993;9:411–418.
83. Fritz E, Thiele D, Willems H, Wittenbrink M-M. Quantitation of Coxiella burnetii by polymerase chain reaction and a colorimetric microtiter plate hybridization assay. Eur J Epidemiol. 1995;11:549–557.
84. Raoult D. Treatment of Q fever. Antimicrob Agents Chemother. 1993;37:1733–1736.
85. Sobradillo V, Zalacain R, Capelastegui A, Uresandi F, Corral J. Antibiotic treatment in pneumonia due to Q fever. Thorax. 1992;47:276–278.
86. Schonwald S, Skerk V, Petricevic I, Car V, Majerus-Misic L, Gunjaca M. Comparison of three-day and five-day courses of azithromycin in the treatment of atypical pneumonia. Eur J Clin Microbiol Infect Dis. 1991;10(10):877–880.
87. Maurin M, Benoliel AM, Bongard P, Raoult D. Phagolysosomal alkalinization and the bactericidal effect of antibiotics: The Coxiella burnetii paradigm. J Infect Dis. 1992;166:1097–1102.
88. Raoult D, Marrie TJ. State-of-the-art clinical lecture: Q fever. Clin Inf Dis. 1995;20:489–496.
89. Marmion BP. Development of Q fever vaccines, 1937–1967. Med J Aust. 1967;2:1074–1078.
90. Marmion BP, Ormsbee RA, Kyrkou M, et al. Vaccine prophylaxis of abattoir-associated Q fever: Eight years’ experience in Australian abattoirs. Epidemiol Infect. 1990:104:275–287.
91. Shapiro RA, Siskind V, Schofield FD, Stallman N, Worswick DA, Marmion BP. A randomized, controlled, double- blind, cross-over, clinical trial of Q fever vaccine in selected Queensland abattoirs. Epidemiol Infect. 1990;104:267–273.
92. Benenson AS. Q fever vaccine: Efficacy and present status. In: Smadel JE, ed. Symposium on Q fever by the Committee on Rickettsial Diseases. Washington, DC: Armed Forces Epidemiology Board; 1959: 47–60.
93. Izzo AA, Marmion BP, Worswick DA. Markers of cell-mediated immunity after vaccination with an inacti- vated, whole-cell Q fever vaccine. J Infect Dis. 1988;157:781–789.
94. Bell JF, Lackman DB, Meis A, Hadlow WJ. Recurrent reaction at site of Q fever vaccination in a sensitized person. Milit Med. 1964;124:591–595.
95. Lackman DB, Bell EJ, Bell JF, Pickens EG. Intradermal sensitivity testing in man with a purified vaccine for Q fever. Am J Publ Health. 1962;52:87–93.
96. Luoto L, Bell JF, Casey M, Lackman D. Q fever vaccination of human volunteers, I: The serologic and skin-test response following subcutaneous injections. Am J Hyg. 1963;78:1–15.
97. Fries LF, Waag DM, Williams JC. Safety and immunogenicity in human volunteers of a chloroform-methanol residue vaccine for Q fever. Infect Immun. 1993;61:1251–1258.
Interested readers will find thorough reviews of both organism and disease in the following outstanding mono-graphs: Marrie TJ, ed. Q Fever: The Disease. Vol 1. Boca Raton, Fla: CRC Press; 1990.
Williams TC, Thompson HA, eds. Q Fever: The Biology of Coxiella burnetii. Boca Raton, Fla: CRC Press; 1991.



La s ocietà atg tes t s ys tems Gmbh & Co. GG ha s ede in Ger mania, Zum S chlag 3 D-9 7 8 7 7 W er theim. Telefono 0 0 4 9 9 3 4 2 2 9 1 0 ,Fax 0 0 4 9 9 3 4 2 3 9 5 1 0 , s ito W eb. atg-tes t-s ys tems . de. É s tata fondata nel 1 9 7 9 ed ha pr es entato il s uo pr imo s is tema di col audo nel 1 9 8 0 . Oggi è par te del gr uppo Ever et Char les Technologies ed è pr es ente con filial

School reports on year 12 outcomes - media publication and supporting information

Category School reports on Year 12 outcomes – media publication and supporting The 2005 school reports on Year 12 outcomes will be published in Queensland metropolitan and regional newspapers on Monday 3 April 2006. The data will also be published on the QSA website at 12 noon on the same day. Attached are some questions and answers about the public release, possible uses and inte

Copyright © 2010-2014 Medical Pdf Finder