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Introduction: Query (Q) fever is a zoonosis caused by the bacterium Coxiella burnetii typically presenting as an influenza-like illness (ILI) with or without hepatitis. The infection may be missed by clinicians in settings of low endemicity, as the presentation is clinically not specific, and there are many more common differential diagnoses for ILI including SARS-CoV-2 infection., Methods: Residual serum samples were retrospectively tested for Phase 1 and 2 Q fever-specific IgM, IgG, IgA antibodies by indirect immunofluorescence and C. burnetii DNA by polymerase chain reaction. They had not been previously tested for Q fever, originating from undiagnosed patients with probable ILI, aged 10-70 years and living in regional New South Wales, Australia. The results were compared with contemperaneous data on acute Q fever diagnostic tests which had been performed based on clinicians requests from a geographically similar population., Results: Only one (0.2%) instance of missed acute Q fever was identified after testing samples from 542 eligible patients who had probable ILI between 2016-2023. Laboratory data showed that during the same period, 731 samples were tested for acute Q fever for clinician-initiated requests and of those 70 (9.6%) were positive. Probability of being diagnosed with Q fever after a clinician initiated request was similar regardless of the patients sex, age and the calendar year of sampling., Conclusion: In this sample, Q fever was most likely to be diagnosed via clinician requested testing rather than by testing of undiagnosed patients with an influenza like illness., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AL is a member of, and HFG has previously contributed to the Seqirus advisory board. No conflicts of interest for other authors., (Copyright: © 2024 Rodrigo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Coxiella burnetii is an underreported zoonotic pathogen in many rural regions globally. We investigated C. burnetii exposure in a remote indigenous tribe residing in the Sierra Nevada de Santa Marta, Colombia. The high seroprevalence of 35% (95% CI, 27-43%) demonstrates the need for One Health studies to identify risk factors, clinical impact, and potential medical, veterinary, and environmental interventions.

Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii . It is an occupational risk for employees of animal industries and is associated with contact with wildlife and domestic animals. Although Q fever infection may be asymptomatic, chronic sequelae such as endocarditis occur in 5% of symptomatic individuals. Disease outcomes may be predicted through measurement of immune correlates. Vaccination is the most efficient method to prevent Q fever. Currently, Q-VAX is the only licenced human vaccine. Q-VAX is highly effective; however, individuals previously exposed to C. burnetii are at risk of adverse reactions. This review examines the immunological responses of acute and chronic Q fever and the efforts to provide a safer and cost-effective Q fever vaccine.

Q fever is a zoonotic disease caused by the highly infectious Gram-negative coccobacillus, Coxiella burnetii ( C. burnetii ). The Q fever vaccine Q-VAX ® is characterised by high reactogenicity, requiring individuals to be pre-screened for prior exposure before vaccination. To date it remains unclear whether vaccine side effects in pre-exposed individuals are associated with pre-existing adaptive immune responses to C. burnetii or are also a function of innate responses to Q-VAX ® . In the current study, we measured innate and adaptive cytokine responses to C. burnetii and compared these among individuals with different pre-exposure status. Three groups were included: n=98 Dutch blood bank donors with unknown exposure status, n=95 Dutch village inhabitants with known natural exposure status to C. burnetii during the Dutch Q fever outbreak of 2007-2010, and n=96 Australian students receiving Q-VAX ® vaccination in 2021. Whole blood cytokine responses following ex vivo stimulation with heat-killed C. burnetii were assessed for IFNγ, IL-2, IL-6, IL-10, TNFα, IL-1β, IP-10, MIP-1α and IL-8. Serological data were collected for all three cohorts, as well as data on skin test and self-reported vaccine side effects and clinical symptoms during past infection. IFNγ, IP-10 and IL-2 responses were strongly elevated in individuals with prior C. burnetii antigen exposure, whether through infection or vaccination, while IL-1β, IL-6 and TNFα responses were slightly increased in naturally exposed individuals only. High dimensional analysis of the cytokine data identified four clusters of individuals with distinct cytokine response signatures. The cluster with the highest levels of adaptive cytokines and antibodies comprised solely individuals with prior exposure to C. burnetii , while another cluster was characterized by high innate cytokine production and an absence of C. burnetii -induced IP-10 production paired with high baseline IP-10 levels. Prior exposure status was partially associated with these signatures, but could not be clearly assigned to a single cytokine response signature. Overall, Q-VAX ® vaccination and natural C. burnetii infection were associated with comparable cytokine response signatures, largely driven by adaptive cytokine responses. Neither individual innate and adaptive cytokine responses nor response signatures were associated retrospectively with clinical symptoms during infection or prospectively with side effects post-vaccination., Competing Interests: AG is CEO and AS was employed at Innatoss Laboratories, and SW, PH, JE and JR are employees of Sullivan Nicolaides Pathology, both providing diagnostic screening for Q fever. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Raju Paul, Scholzen, Mukhtar, Wilkinson, Hobson, Dzeng, Evans, Robson, Cobbold, Graves, Poznansky, Garritsen and Sluder.)

Q fever (caused by Coxiella burnetii) is thought to have an almost world-wide distribution, but few countries have conducted national serosurveys. We measured Q fever seroprevalence using residual sera from diagnostic laboratories across Australia. Individuals aged 1-79 years in 2012-2013 were sampled to be proportional to the population distribution by region, distance from metropolitan areas and gender. A 1/50 serum dilution was tested for the Phase II IgG antibody against C. burnetii by indirect immunofluorescence. We calculated crude seroprevalence estimates by age group and gender, as well as age standardised national and metropolitan/non-metropolitan seroprevalence estimates. Of 2785 sera, 99 tested positive. Age standardised seroprevalence was 5.6% (95% confidence interval (CI 4.5%-6.8%), and similar in metropolitan (5.5%; 95% CI 4.1%-6.9%) and non-metropolitan regions (6.0%; 95%CI 4.0%-8.0%). More males were seropositive (6.9%; 95% CI 5.2%-8.6%) than females (4.2%; 95% CI 2.9%-5.5%) with peak seroprevalence at 50-59 years (9.2%; 95% CI 5.2%-13.3%). Q fever seroprevalence for Australia was higher than expected (especially in metropolitan regions) and higher than estimates from the Netherlands (2.4%; pre-outbreak) and US (3.1%), but lower than for Northern Ireland (12.8%). Robust country-specific seroprevalence estimates, with detailed exposure data, are required to better understand who is at risk and the need for preventive measures.

Q fever (caused by Coxiella burnetii) is a serious zoonotic disease that occurs almost worldwide. Occupational contact with animals increases the risk of exposure, and Q fever vaccination is recommended for veterinary workers in Australia. This study aimed to investigate C. burnetii seroprevalence among unvaccinated veterinary workers in Australia and determine factors associated with a positive serological result. During 2014 and 2015, convenience sampling at veterinary conferences and workplace vaccination clinics was undertaken. Participants completed a questionnaire and provided a blood sample for C. burnetii serology. Participants were predominantly veterinarians (77%), but veterinary support staff, animal scientists, and administration workers also participated. Blood samples (n = 192) were analysed by an immunofluorescence assay and considered positive where the phase I or phase II IgG titre was ≥1/50. Seroprevalence was 19% (36/192; 95% CI 14%-25%). A positive serological result was significantly associated with (a) working in outer regional/remote areas (odds ratio [OR] 6.2; 95% CI 1.9-20.8; reference = major cities; p = .009) and (b) having spent more than 50% of total career working with ruminants (OR 4.8; 95% CI 1.7-13.5; reference = <15% of career; p = .025). These findings confirm an increased risk of exposure to C. burnetii compared to the general population, providing new evidence to support Q fever vaccination of veterinary workers in Australia., (© 2019 Blackwell Verlag GmbH.)

Vaccination against Coxiella burnetii, the cause of Q fever, is reportedly the only feasible strategy of eradicating infection in ruminant herds. Preventive vaccination of seronegative goats is more effective in reducing shedding of C. burnetii than vaccinating seropositive goats. The age at which goats born on heavily-contaminated farms first seroconvert to C. burnetii has not yet been documented. In a 16-month birth cohort study, the age at which goats seroconverted against C. burnetii was investigated; 95 goats were bled every 2 weeks and tested for antibodies against C. burnetii. Risk factors for seroconversion were explored and goats shedding C. burnetii were identified by testing vaginal swabs taken at the goats' first kidding using a com1 polymerase chain reaction assay. The first surge in the number of goats with IgM to C. burnetii was observed at week 9. Thus, a first vaccination not later than 8 weeks of age to control C. burnetii in highly contaminated environments is indicated. The odds of seroconversion were 2.0 times higher [95% confidence interval (CI) 1.2, 3.5] in kids born by does with serological evidence of recent infection (IgM seropositive) compared to kids born by IgM seronegative does, suggesting either in utero transmission or peri-parturient infection. The rate of seroconversion was 4.5 times higher (95% CI 2.1, 9.8) during than outside the kidding season, highlighting the risk posed by C. burnetii shed during kidding, even to goats outside the kidding herd. Shedding of C. burnetii at kidding was detected in 15 out of 41 goats infected before breeding.

Coxiella burnetii may cause reproduction disorders in pregnant animals but subclinical infection in other animals. Unrecognised disease may delay implementation of control interventions, resulting in transmission of infection to other livestock and to humans. Seroreactivity to C. burnetii phase-specific antigens, is routinely used to interpret the course of human Q fever. This approach could be similarly useful in identifying new and existing infections in livestock herds to help describe risk factors or production losses associated with the infections and the implementation of disease-control interventions. This study aimed to elucidate the dynamics of C. burnetii infections using seroreactivity to phase-specific antigens and to examine the impact of infection on milk yield in goats in an endemically-infected farm that was associated with a Q fever outbreak in Australia. Seroreactivity pre- and post-partum and milk yield were studied in 164 goats (86 nulliparous and 78 parous). Post-partum, the seroprevalence of antibodies to C. burnetti increased from 4.7% to 31.4% throughout goats' first kiddings and from 47.4% to 55.1% in goats kidding for the second or greater time. Of 123 goats that were seronegative pre-partum, 26.8% seroconverted over the three-month peri-partum period, highlighting the importance of controlling infection throughout this time. The risk of seroconversion was comparable in first or later kidders, suggesting constant risk irrespective of parity. No loss in milk production associated with seroconversion to phase 2 was observed within the first nine weeks of lactation. However, seroconversion to only phase 1 was associated with extra 0.276L of milk per day (95% Confidence Interval: 0.010, 0.543; P=0.042), which warrants further investigation to ascertain whether or not the association is causal. Further studies on seroreactivity and milk production over longer periods are required, as milk production loss caused by C. burnetti may be an additional reason to control the disease in goat herds., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: A detailed description of the natural history of acute Q fever, caused by infection with Coxiella burnetii, AIM: : To significantly increase understanding of the illness., Design: Subjects with provisional acute Q fever (n = 115) were recruited from primary care in rural Australia, and followed prospectively by interview and blood collection including for serological confirmation. A nested series of subjects with prolonged illness (cases), and those without (controls), were investigated in detail., Methods: Total phase I and phase II anti-C. burnetii antibodies were detected by complement fixation test; and IgG, IgM and IgA phase I and phase II titres by immunofluorescence. Flow cytometric analysis was conducted to enumerate circulating T cells subsets, B cells, monocytes and natural killer cells., Results: Serological testing confirmed acute Q fever in 73 subjects (63%). The acute illness featured fever, headache, sweats, fatigue and anorexia; and varied widely in severity, causing an average of 8 days in bed and 15 days out of work or other role in the first month of illness. The illness course varied from 2 days to greater than a year. No cases of chronic, localized Q fever infection, such as endocarditis, were identified. Neither severe nor prolonged illness were associated with persistence of C. burnetii DNA, altered patterns of C. burnetii-specific IgG, IgM or IgA antibody production, or altered leucocyte subsets., Conclusions: The severity of acute Q fever alone predicted prolonged duration. Further studies are warranted to better understand the pathophysiology of prolonged illness after acute Q fever., (© The Author 2016. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Coxiella burnetii, the causative agent of Q fever, was first discovered in Australia in 1937. However, little is known about the strains of C. burnetii present in this country. In this study, six published genotyping methods were applied to 42 isolates from Australian patients with acute (n=39) and chronic (n=3) Q fever. All the isolates contained the plasmid QpRS and lacked the acute disease antigen A (adaA) gene. Two methods of genotyping based on single nucleotide polymorphisms (SNPs) also failed to discriminate between the isolates. However, results from the method based on SNPs within the multi-spacer sequence typing (MST) loci determined a novel MST genotype, with the Australian isolates forming a unique phylogenetic clade. Multi-locus variable number of tandem repeats (VNTR) analysis (MLVA) determined 14 genotypes, all of which were novel compared with those previously identified in strains from other countries. Many of these were single locus variants, differing from each other at just one of the 15 loci tested. Our results show that the Australian isolates exhibit significant diversity from previously characterised strains, but are genetically closely related to each other, supporting a model of evolution by clonal expansion in a geographically isolated location., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Although many studies have reported the indirect immunofluorescence assay (IFA) to be more sensitive in detection of antibodies to Coxiella burnetii than the complement fixation test (CFT), the diagnostic sensitivity (DSe) and diagnostic specificity (DSp) of the assay have not been previously established for use in ruminants. This study aimed to validate the IFA by describing the optimization, selection of cutoff titers, repeatability, and reliability as well as the DSe and DSp of the assay. Bayesian latent class analysis was used to estimate diagnostic specifications in comparison with the CFT and the enzyme-linked immunosorbent assay (ELISA). The optimal cutoff dilution for screening for IgG and IgM antibodies in goat serum using the IFA was estimated to be 1:160. The IFA had good repeatability (>96.9% for IgG, >78.0% for IgM), and there was almost perfect agreement (Cohen's kappa > 0.80 for IgG) between the readings reported by two technicians for samples tested for IgG antibodies. The IFA had a higher DSe (94.8%; 95% confidence interval [CI], 80.3, 99.6) for the detection of IgG antibodies against C. burnetii than the ELISA (70.1%; 95% CI, 52.7, 91.0) and the CFT (29.8%; 95% CI, 17.0, 44.8). All three tests were highly specific for goat IgG antibodies. The IFA also had a higher DSe (88.8%; 95% CI, 58.2, 99.5) for detection of IgM antibodies than the ELISA (71.7%; 95% CI, 46.3, 92.8). These results underscore the better suitability of the IFA than of the CFT and ELISA for detection of IgG and IgM antibodies in goat serum and possibly in serum from other ruminants., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

The Nine Mile phase II clone 4 (NMIIC4) strain of Coxiella burnetii is an attenuated phase II strain that has lost the genes for virulence determinant type 1 lipopolysaccharide. These bacteria were very virulent for severe combined immunodeficient (SCID) mice. The lethal dose 50 (LD50) was ~10 bacteria. Infected SCID mice died between Day 28 and Day 53 post-infection. At termination of the experiment (Day 60) only 5 of 24 mice had survived. The degree of splenomegaly was directly related to the bacterial load in the SCID mice spleens. The NMIIC4 was avirulent in immunocompetent wild mice and bacterial DNA copies in splenic tissue were extremely low. The SCID mice that were inoculated with high doses of heat inactivated NMIIC4 C. burnetii were all alive at Day 60 and without splenomegaly. It appears that the phase I lipopolysaccharide present in virulent Nine Mile phase I but not in attenuated NMIIC4 is not the only virulence factor for C. burnetii.

Coxiella burnetii is the etiological agent of Q fever. To identify its major seroreactive proteins, a subgenomic protein array was developed. A total of 101 assumed virulence-associated recombinant proteins of C. burnetii were probed with sera from mice experimentally infected with C. burnetii and sera from Q fever patients. Sixteen proteins were recognized as major seroreactive antigens by the mouse sera. Seven of these 16 proteins reacted positively with at least 45% of Q fever patient sera. Notably, HspB had the highest fluorescence intensity value and positive frequency of all the proteins on the array when probed with both Q fever patient sera and mouse sera. These results suggest that these seven major seroreactive proteins, particularly HspB, are potential serodiagnostic and subunit vaccine antigens of Q fever.

Q fever, a zoonotic disease caused by the bacterium Coxiella burnetii, can cause acute or chronic illness in humans. Transmission occurs primarily through inhalation of aerosols from contaminated soil or animal waste. No licensed vaccine is available in the United States. Because many human infections result in nonspecific or benign constitutional symptoms, establishing a diagnosis of Q fever often is challenging for clinicians. This report provides the first national recommendations issued by CDC for Q fever recognition, clinical and laboratory diagnosis, treatment, management, and reporting for health-care personnel and public health professionals. The guidelines address treatment of acute and chronic phases of Q fever illness in children, adults, and pregnant women, as well as management of occupational exposures. These recommendations will be reviewed approximately every 5 years and updated to include new published evidence.

Background: A cohort of 211 factory workers was exposed to a point source of Q fever in 2002. A total of 38 cases and 14 controls took part in a follow-up study 6 years after the outbreak., Aim: To compare Q fever serology, the presence of viable Coxiella burnetii, its DNA and fatigue between patients and controls., Design: Laboratory case study., Methods: Q fever serology was by microimmunofluroescence. Viable C. burnetii was detected by VERO cell culture and SCID mice inoculation with patient blood samples. Coxiella burnetii DNA was detected by qPCR (com1 gene) on patients' PBMC and on VERO cultures after 6 weeks incubation. Fatigue was measured by the Chalder Fatigue Scale., Result: At 6 years after the outbreak, 7 of the 38 patients had become seronegative and 4 of the 14 of the controls had become seropositive for Q fever. None of the patient/control peripheral blood mononuclear cells (PBMC) contained viable C. burnetii by VERO cell culture or by SCID mouse inoculation (death or splenomegaly) and none contained C. burnetii DNA by qPCR., Conclusion: Six years after acute Q fever, some patients had become seronegative but none contained viable C. burnetii or its DNA in their PBMC.

Background: Coxiella burnetii is the etiological agent of Q fever. The clinical diagnosis of Q fever is mainly based on several serological tests. These tests all need Coxiella organisms which are difficult and hazardous to culture and purify., Results: An immunoproteomic study of C. burnetii Xinqiao strain isolated in China was conducted with the sera from experimentally infected BALB/c mice and Q fever patients. Twenty of whole proteins of Xinqiao recognized by the infection sera were identified by mass spectrometry. Nineteen of the 20 proteins were successfully expressed in Escherichia coli and used to fabricate a microarray which was probed with Q fever patient sera. As a result, GroEL, YbgF, RplL, Mip, OmpH, Com1, and Dnak were recognized as major seroreactive antigens. The major seroreactive proteins were fabricated in a small microarray and further analyzed with the sera of patients with rickettsial spotted fever, Legionella pneumonia or streptococcal pneumonia. In this analysis, these proteins showed fewer cross-reactions with the tested sera., Conclusions: Our results demonstrate that these 7 Coxiella proteins gave a modest sensitivity and specificity for recognizing of Q fever patient sera, suggesting that they are potential serodiagnostic markers for Q fever.

Exposure to Coxiella burnetii is a risk in the Hunter New England (HNE) region of New South Wales (NSW), Australia, based on yearly reported cases of Q fever. We assessed seroprevalence of phase II antibodies to C. burnetii by indirect immunofluorescence assay (IFA; screening at 1/50 dilution) of residents of 24 local government areas (LGA) of the HNE region of NSW. A total of 2,438 randomly selected sera sent to the Hunter Area Pathology Service for routine diagnostic purposes (not Q fever testing) during the period of 2006-2009 were tested. The overall seroprevalence in sample group was 7%. The proportion of males (59%) was higher than females (41%). In age distribution, the largest proportion (37%) of seropositives was in the > 60 years age group. Lower prevalence was observed in 0-9 years (1%) and 10-19 years (5%) age groups. The seroprevalence in different LGAs varied between 0.5% and 22%. It was highest in Guyra (22%), Gunnedah (21%), Tenterfield (18%), and Narrabri (16%), with Newcastle (0.5%), Port Stephens (2%), Lake Macquarie (3%), and Singleton (3%) being the lowest. In most of the LGAs, seroprevalence was between 6% and 12%. This report indicates a considerable exposure to C. burnetii of residents in rural areas of the HNE region and is consistent with the high notification rate for Q fever in this part of Australia.

Introduction: Acute Q fever is an important zoonotic disease in some parts of rural Australia. Q Fever can lead to chronic disease such as endocarditis, this complication occurring more commonly in patients with underlying heart valve pathology or an impaired immune system. Untreated Q fever endocarditis has a high mortality rate, but even with appropriate therapy, 10% of patients will die. Cardiac assessment can identify patients at risk. The aim of this review was to examine recorded cardiac assessment of hospitalised Q fever patients within the regional area of Hunter New England (HNE), New South Wales (NSW)., Methods: Medical records of patients with Q fever admitted to hospitals in HNE during the period 2005-2009 were identified through the NSW Notifiable Diseases Database and the NSW Inpatient Statistics Collection. A standardised medical record review tool was used to undertake the review., Results: Eighty-nine records were reviewed. Over 50% of patients were admitted to a district hospital staffed by local GPs. Cardiac assessment was not routinely documented and for 91% there was no record of a cardiac history being taken. Approximately 25% had no record of a cardiac physical examination and only 6 cases had a record of a complete cardiac examination., Conclusion: Q Fever remains an important disease in some parts of rural Australia. Q Fever endocarditis is a serious sequel to acute Q fever and underlying heart valve pathology. Due to its indolent progression and poor outcome when diagnosis is delayed, a thorough cardiac assessment of all patients with suspected or confirmed Q fever is important. The level of documentation of cardiac assessment for Q fever patients is of concern because it may indicate cardiac assessments were not performed. General practitioners, especially in rural and regional areas, are encouraged to conduct cardiac assessments for all patients with acute Q fever to identify patients at risk of developing Q fever endocarditis.

Background: Previous studies of inciting factors for a prolonged post-infection fatigue syndrome after Q fever (variously termed QFS or Q fever associated CFS/ME in the literature) showed that after the acute infection a high proportion of asymptomatic and QFS patients had Q fever antibody and also low levels in PBMC and bone marrow of Coxiella burnetii (C.b.) DNA with PCR assays directed against three different target sequences in different parts of the coxiella genome. Attempts to isolate a strain of C.b. in A/J mice, and cell culture from PCR positive PBMC and bone marrow were consistently negative. The detailed composition of the persisting coxiella residues remains to be defined., Aim: To retest and provide detailed results on selected PCR positive samples from the Birmingham Q fever outbreak patients tested by a highly sensitive method to detect viable organisms and to determine the nature of the residual coxiella cell components., Design: Laboratory case study., Methods: NOD/SCID mice were inoculated with samples from the 1989 Q fever outbreak in Birmingham and followed for evidence of infection and the presence of coxiella DNA and specific antigens in spleen and liver macrophages. A significant, unexpected finding of specific antigen was followed by assessment of its ability to provoke production of inflammatory and non-inflammatory cytokines in mice, in THP-1 human macrophage cell cultures and to induce inflammatory lesions in the skin of guinea pigs hyperimmunized against Q fever vaccine., Results: Culture of samples from 10 Birmingham Q fever patients in NOD/SCID mice, 12 years from infection did not yield viable Coxiella burnetii, as shown earlier. However complexes of material with coxiella antigens were found in mouse spleens in all cases but in significantly greater amounts in samples from those with post Q fever fatigue syndrome. The antigenic complexes [now designated 'immunomodulatory complexes' (IMC)] were shown to stimulate cytokine release in the mice and in the THP-1 macrophages and to provoke an inflammatory reaction on intradermal injection into the skin of Q fever hyperimmunized guinea pigs., Conclusion: The study identifies a non-infective complex of C.b. antigens able to survive in the host and provoke aberrant humoral and cell medicated immunity responses - a possible pathogenic link between initial infection and a subsequent long-term post Q fever fatigue syndrome.

Acalculous cholecystitis has been described in association with Q fever. We describe the first known case of Q fever cholecystitis diagnosed by polymerase chain reaction on gallbladder tissue. The presence of Coxiella burnetii genome in the diseased gallbladder tissue argues for direct involvement of the organism in the pathogenesis of Q fever cholecystitis.

Background: Our previous studies of persistence of Coxiella burnetii in humans after an initial acute Q fever infection revealed raised, maintained antibody levels and low levels of coxiella genomic DNA at the age of 5 years from onset in Australian patients and at 12 years in patients in the 1989 Birmingham UK Q fever outbreak. Attempts to isolate the coxiella in standard cell culture and susceptible mice by serial passage of PCR positive PBMC and bone marrow were negative., Aim: To retest PCR positive patient samples by more sensitive methods for viable coxiellas and for the coxiella cell components of antigen and specific lipopolysaccharide (LPS). To re-interpret the previous results in the light of the new information. To review the pertinent literature for a concept of an immuno-modulatory complex generated by the current studies., Design: Laboratory case study., Methods: Stored patient samples were inoculated into SCID mice that were followed for 60 days. Mouse spleen and liver samples were then examined by PCR assay for targets in the COM1 and IS1111a sequences and for antigens by IFA with a polyclonal rabbit antiserum to C. burnetii Phase 1 and a monoclonal antiserum to Phase 1 LPS (details; O. Sukocheva et al., unpublished data)., Results: All specimens, including a recently excised heart valve from a Birmingham patient with late developing endocarditis, were infection negative in SCID mice. Dilutions of SCID mouse spleen and liver homogenates titrated in PCR assays were negative at dilutions attained by control mice inoculated with an endpoint dilution of a viable prototype strain of C. burnetii. Sections of the spleens from all specimens showed a complex of coxiella antigen-LPS by IFA. DISCUSSION/REVIEW: We advance a concept of long-term persistence of a non-infective, non-biodegraded complex of coxiella cell components with its antigens and specific LPS [so called Immunomodulatory complex (IMC)] associated with traces of genomic DNA that signalled its presence in our earlier studies. The IMC's survival in patients for at least 12 years, and in one patient for 70 years implies a capacity for serial passage in macrophages with effective down-regulation of their biodegrading functions. The review assesses the compatibility of the IMC concept in relation to cogent literature on C. burnetii interactions with macrophage and cell-mediated immunity. Some remaining gaps in our knowledge of the organ sites and duration of carriage of viable coxiellas after initial infection are also identified.

Background: A detailed description of the natural history of acute Q fever, caused by infection with Coxiella burnetii. Aim: To significantly increase understanding of the illness. Design: Subjects with provisional acute Q fever (n=115) were recruited from primary care in rural Australia, and followed prospectively by interview and blood collection including for serological confirmation. A nested series of subjects with prolonged illness (cases), and those without (controls), were investigated in detail. Methods: Total phase I and phase II anti-C. burnetii antibodies were detected by complement fixation test; and IgG, IgM and IgA phase I and phase II titres by immunofluorescence. Flow cytometric analysis was conducted to enumerate circulating T cells subsets, B cells, monocytes and natural killer cells. Results: Serological testing confirmed acute Q fever in 73 subjects (63%). The acute illness featured fever, headache, sweats, fatigue and anorexia; and varied widely in severity, causing an average of 8 days in bed and 15 days out of work or other role in the first month of illness. The illness course varied from 2 days to greater than a year. No cases of chronic, localized Q fever infection, such as endocarditis, were identified. Neither severe nor prolonged illness were associated with persistence of C. burnetii DNA, altered patterns of C. burnetii-specific IgG, IgM or IgA antibody production, or altered leucocyte subsets. Conclusions: The severity of acute Q fever alone predicted prolonged duration. Further studies are warranted to better understand the pathophysiology of prolonged illness after acute Q fever. [ABSTRACT FROM AUTHOR]

Background: A cohort of 211 factory workers was exposed to a point source of Q fever in 2002. A total of 38 cases and 14 controls took part in a follow-up study 6 years after the outbreak.Aim: To compare Q fever serology, the presence of viable Coxiella burnetii, its DNA and fatigue between patients and controls.Design: Laboratory case study.Methods: Q fever serology was by microimmunofluroescence. Viable C. burnetii was detected by VERO cell culture and SCID mice inoculation with patient blood samples. Coxiella burnetii DNA was detected by qPCR (com1 gene) on patients’ PBMC and on VERO cultures after 6 weeks incubation. Fatigue was measured by the Chalder Fatigue Scale.Result: At 6 years after the outbreak, 7 of the 38 patients had become seronegative and 4 of the 14 of the controls had become seropositive for Q fever. None of the patient/control peripheral blood mononuclear cells (PBMC) contained viable C. burnetii by VERO cell culture or by SCID mouse inoculation (death or splenomegaly) and none contained C. burnetii DNA by qPCR.Conclusion: Six years after acute Q fever, some patients had become seronegative but none contained viable C. burnetii or its DNA in their PBMC. [ABSTRACT FROM AUTHOR]

Background: Previous studies of inciting factors for a prolonged post-infection fatigue syndrome after Q fever (variously termed QFS or Q fever associated CFS/ME in the literature) showed that after the acute infection a high proportion of asymptomatic and QFS patients had Q fever antibody and also low levels in PBMC and bone marrow of Coxiella burnetii (C.b.) DNA with PCR assays directed against three different target sequences in different parts of the coxiella genome. Attempts to isolate a strain of C.b. in A/J mice, and cell culture from PCR positive PBMC and bone marrow were consistently negative. The detailed composition of the persisting coxiella residues remains to be defined.Aim: To retest and provide detailed results on selected PCR positive samples from the Birmingham Q fever outbreak patients tested by a highly sensitive method to detect viable organisms and to determine the nature of the residual coxiella cell components.Design: Laboratory case study.Methods: NOD/SCID mice were inoculated with samples from the 1989 Q fever outbreak in Birmingham and followed for evidence of infection and the presence of coxiella DNA and specific antigens in spleen and liver macrophages. A significant, unexpected finding of specific antigen was followed by assessment of its ability to provoke production of inflammatory and non-inflammatory cytokines in mice, in THP-1 human macrophage cell cultures and to induce inflammatory lesions in the skin of guinea pigs hyperimmunized against Q fever vaccine.Results: Culture of samples from 10 Birmingham Q fever patients in NOD/SCID mice, 12 years from infection did not yield viable Coxiella burnetii, as shown earlier. However complexes of material with coxiella antigens were found in mouse spleens in all cases but in significantly greater amounts in samples from those with post Q fever fatigue syndrome. The antigenic complexes [now designated ‘immunomodulatory complexes’ (IMC)] were shown to stimulate cytokine release in the mice and in the THP-1 macrophages and to provoke an inflammatory reaction on intradermal injection into the skin of Q fever hyperimmunized guinea pigs.Conclusion: The study identifies a non-infective complex of C.b. antigens able to survive in the host and provoke aberrant humoral and cell medicated immunity responses – a possible pathogenic link between initial infection and a subsequent long-term post Q fever fatigue syndrome. [ABSTRACT FROM AUTHOR]

Background: Our previous studies of persistence of Coxiella burnetii in humans after an initial acute Q fever infection revealed raised, maintained antibody levels and low levels of coxiella genomic DNA at the age of 5 years from onset in Australian patients and at 12 years in patients in the 1989 Birmingham UK Q fever outbreak. Attempts to isolate the coxiella in standard cell culture and susceptible mice by serial passage of PCR positive PBMC and bone marrow were negative. [ABSTRACT FROM PUBLISHER]