Microbiological Challenges in the Diagnosis of Chronic Q Fever

ABSTRACTDiagnosis of chronic Q fever is difficult. PCR and culture lack sensitivity; hence, diagnosis relies mainly on serologic tests using an immunofluorescence assay (IFA). Optimal phase I IgG cutoff titers are debated but are estimated to be between 1:800 and 1:1,600. In patients with proven, probable, or possible chronic Q fever, we studied phase I IgG antibody titers at the time of positive blood PCR, at diagnosis, and at peak levels during chronic Q fever. We evaluated 200 patients, of whom 93 (46.5%) had proven, 51 (25.5%) had probable, and 56 (28.0%) had possible chronic Q fever. Sixty-five percent of proven cases had positiveCoxiella burnetiiPCR results for blood, which was associated with high phase I IgG. Median phase I IgG titers at diagnosis and peak titers in patients with proven chronic Q fever were significantly higher than those for patients with probable and possible chronic Q fever. The positive predictive values for proven chronic Q fever, compared to possible chronic Q fever, at titers 1:1,024, 1:2,048, 1:4,096, and ≥1:8,192 were 62.2%, 66.7%, 76.5%, and ≥86.2%, respectively. However, sensitivity dropped to <60% when cutoff titers of ≥1:8,192 were used. Although our study demonstrated a strong association between high phase I IgG titers and proven chronic Q fever, increasing the current diagnostic phase I IgG cutoff to >1:1,024 is not recommended due to increased false-negative findings (sensitivity < 60%) and the high morbidity and mortality of untreated chronic Q fever. Our study emphasizes that serologic results are not diagnostic on their own but should always be interpreted in combination with clinical parameters.

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Prevalence of Chronic Q Fever in Patients with a History of Cardiac Valve Surgery in an Area Where Coxiella burnetii Is Epidemic

Clinical and Vaccine Immunology ◽

10.1128/cvi.00185-12 ◽

2012 ◽

Vol 19 (8) ◽

pp. 1165-1169 ◽

Cited By ~ 24

Author(s):

Linda M. Kampschreur ◽

Jan Jelrik Oosterheert ◽

Andy I. M. Hoepelman ◽

Peter J. Lestrade ◽

Nicole H. M. Renders ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Q Fever ◽

Risk Groups ◽

Valve Surgery ◽

Cardiac Valve ◽

Content Type ◽

Cardiac Valve Surgery ◽

Chronic Q Fever ◽

History Of

ABSTRACTChronic Q fever develops in 1 to 5% of patients infected withCoxiella burnetii. The risk for chronic Q fever endocarditis has been estimated to be ∼39% in case of preexisting valvulopathy and is potentially even higher for valvular prostheses. Since 2007, The Netherlands has faced the largest Q fever outbreak ever reported, allowing a more precise risk estimate of chronic Q fever in high-risk groups. Patients with a history of cardiac valve surgery were selected for microbiological screening through a cardiology outpatient clinic in the area where Q fever is epidemic. Blood samples were analyzed for phase I and II IgG againstC. burnetii, and if titers were above a defined cutoff level,C. burnetiiPCR was performed. Chronic Q fever was considered proven ifC. burnetiiPCR was positive and probable if the phase I IgG titer was ≥1:1,024. Among 568 patients, the seroprevalence ofC. burnetiiantibodies (IgG titer greater than or equal to 1:32) was 20.4% (n= 116). Proven or probable chronic Q fever was identified among 7.8% of seropositive patients (n= 9). Valve characteristics did not influence the risk for chronic Q fever. Patients with chronic Q fever were significantly older than patients with past Q fever. In conclusion, screening of high-risk groups is a proper instrument for early detection of chronic Q fever cases. The estimated prevalence of chronic Q fever is 7.8% among seropositive patients with a history of cardiac valve surgery, which is substantially higher than that in nonselected populations but lower than that previously reported. Older age seems to increase vulnerability to chronic Q fever in this population.

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Questing one Brazilian query: reporting 16 cases of Q fever from Minas Gerais, Brazil

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652006000100002 ◽

2006 ◽

Vol 48 (1) ◽

pp. 5-9 ◽

Cited By ~ 18

Author(s):

Paulo Sérgio Gonçalves da Costa ◽

Marco Emilio Brigatte ◽

Dirceu Bartolomeu Greco

Keyword(s):

Phase I ◽

Phase Ii ◽

Fever Of Unknown Origin ◽

Q Fever ◽

Acute Infection ◽

Case Series ◽

Febrile Illness ◽

Unknown Origin ◽

Clinical Form ◽

Chronic Q Fever

Q fever has been considered non-existing in Brazil where reports of clinical cases still cannot be found. This case-series of 16 patients is a result of a systematic search for such illness by means of clinical and serologic criteria. Serologic testing was performed by the indirect microimmunofluorescence technique using phase I/II C. burnetii antigens. Influenza-like syndrome was the most frequent clinical form (eight cases - 50%), followed by pneumonia, FUO (fever of unknown origin), mono-like syndrome (two cases - 12.5% each), lymphadenitis (one case - 6.3%) and spondylodiscitis associated with osteomyelitis (one case - 6.3%). The ages varied from four to 67 years old with a median of 43.5. All but one patient had positive serologic tests for phase II IgG whether or not associated with IgM positivity compatible with acute infection. One patient had both phase I and phase II IgG antibodies compatible with chronic Q fever. Seroconvertion was detected in 10 patients. Despite the known limitations of serologic diagnosis, the cases here reported should encourage Brazilian doctors to include Q fever as an indigenous cause of febrile illness.

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Correlation between Ratio of Serum Doxycycline Concentration to MIC and Rapid Decline of Antibody Levels during Treatment of Q Fever Endocarditis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.7.2673-2676.2005 ◽

2005 ◽

Vol 49 (7) ◽

pp. 2673-2676 ◽

Cited By ~ 49

Author(s):

Jean-Marc Rolain ◽

Areen Boulos ◽

Marie-Noëlle Mallet ◽

Didier Raoult

Keyword(s):

Phase I ◽

Q Fever ◽

Serum Levels ◽

Response To Treatment ◽

Rapid Decline ◽

Shell Vial ◽

Real Time Quantitative Pcr ◽

Chronic Q Fever ◽

Antibody Levels ◽

Quantitative Pcr Assay

ABSTRACT Endocarditis is the major clinical manifestation of chronic Q fever. Although doxycycline along with hydroxychloroquine remains the mainstay of medical therapy for Q fever endocarditis, there are wide variations in the rapidity of the patient's decline of antibody levels during such therapy. We undertook a retrospective examination of whether there was any correlation between the ratio of serum concentration to MIC of doxycycline and response to treatment in patients with Q fever endocarditis. Included herein are 16 patients from whom Coxiella burnetii was isolated from cardiac valve materials. Serology and measurement of doxycycline and hydroxychloroquine serum levels were performed and recorded after 1 year of treatment. The MIC of doxycycline for C. burnetii isolates was determined using the shell vial assay in a real-time quantitative PCR assay. At the completion of a yearlong therapy with doxycycline-hydroxychloroquine, all those that showed a low decline of antibody levels (n = 6) (i.e., <2-fold decrease in antibody titer to phase I C. burnetii antigen) had a ratio of serum doxycycline concentration to MIC between 0.5 and 1. In contrast, those having a ratio of ≥1 showed a rapid decline of phase I antibody levels (n = 9; P < 0.05). The only patient who died had a serum doxycycline-to-MIC ratio of <0.5, and the isolate of C. burnetii cultured from this patient was resistant to doxycycline (MIC = 8 μg/ml). The ratio of serum doxycycline concentration to MIC should be monitored during the course of therapy in patients with Q fever endocarditis.

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Animals withCoxiella burnetiiInfection Demonstrate a Western Immunoblot Profile of Chronic Q Fever in Humans

Canadian Journal of Infectious Diseases ◽

10.1155/1996/853518 ◽

1996 ◽

Vol 7 (1) ◽

pp. 45-48

Author(s):

TJ Marrie ◽

Linda Yates

Keyword(s):

Immune Response ◽

Phase I ◽

Phase Ii ◽

Coxiella Burnetii ◽

Q Fever ◽

Western Immunoblotting ◽

Western Immunoblot ◽

Chronic Q Fever

Western immunoblotting was used to compare the immune response toCoxiella burnetiiphase I and phase II antigens of humans with acute and chronic Q fever with that of infected cats, rabbits, cows and raccoons. The cats, rabbits, cows and raccoons had an immunoblot profile similar to that of the human with chronic Q fever.

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Com1 as a Promising Protein for the Differential Diagnosis of the Two Forms of Q Fever

Pathogens ◽

10.3390/pathogens8040242 ◽

2019 ◽

Vol 8 (4) ◽

pp. 242 ◽

Cited By ~ 3

Author(s):

Vranakis ◽

Mathioudaki ◽

Kokkini ◽

Psaroulaki

Keyword(s):

Differential Diagnosis ◽

Phase I ◽

Clinical Diagnosis ◽

Q Fever ◽

Control Group ◽

Virulence Potential ◽

Chronic Q Fever ◽

Candidate Protein ◽

Immunogenic Proteins ◽

Human Infections

Coxiella burnetii is the causative agent of acute and chronic Q fever in humans. Although the isolates studied so far showed a difference in virulence potential between those causing the two forms of the disease, implying a difference in their proteomic profile, the methods used so far to diagnose the two forms of the disease do not provide sufficient discriminatory capability, and human infections may be often misdiagnosed. The aim of the current study was to identify the outer membrane Com1 (CBU_1910) as a candidate protein for serodiagnostics of Q fever. The protein was cloned, expressed, purified, and used as an antigen in ELISA. The protein was then used for the screening of sera from patients suffering from chronic Q fever endocarditis, patients whose samples were negative for phase I immunoglobulin G (IgG), patients for whom at least one sample was positive for phase I IgG, and patients suffering from any kind of rheumatoid disease. Blood donors were used as the control group. Following statistical analysis, 92.4% (122/132) of the samples tested agreed with the negative clinical diagnosis, and 72.2% (26/36) agreed with the positive clinical diagnosis. Moreover, a significant correlation to the presence of the disease (p = 0.00) was calculated. The results support the idea that a Com1 antigen-based serodiagnostic test may be useful for differential diagnosis of chronic Q fever. Further studies are required to compare more immunogenic proteins of the bacterium against samples originating from patients suffering from different forms of the disease.

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Early Diagnosis and Treatment of Patients with Symptomatic Acute Q Fever Do Not Prohibit IgG Antibody Responses to Coxiella burnetii

Clinical and Vaccine Immunology ◽

10.1128/cvi.00322-12 ◽

2012 ◽

Vol 19 (10) ◽

pp. 1661-1666 ◽

Cited By ~ 8

Author(s):

C. C. H. Wielders ◽

L. M. Kampschreur ◽

P. M. Schneeberger ◽

M. M. Jager ◽

A. I. M. Hoepelman ◽

...

Keyword(s):

Early Diagnosis ◽

Phase I ◽

Phase Ii ◽

Coxiella Burnetii ◽

Q Fever ◽

Antibody Responses ◽

Igg Antibody ◽

Antibody Titers ◽

Acute Q Fever

ABSTRACTLittle is known about the effect of timing of antibiotic treatment on development of IgG antibodies following acute Q fever. We studied IgG antibody responses in symptomatic patients diagnosed either before or during development of the serologic response toCoxiella burnetii. Between 15 and 31 May 2009, 186 patients presented with acute Q fever, of which 181 were included in this retrospective study: 91 early-diagnosed (ED) acute Q fever patients, defined as negative IgM phase II enzyme-linked immunosorbent assay (ELISA) and positive PCR, and 90 late-diagnosed (LD) acute Q fever patients, defined as positive/dubious IgM phase II ELISA and positive immunofluorescence assay (IFA). Follow-up serology at 3, 6, and 12 months was performed using IFA (IgG phase I and II). High IgG antibody titers were defined as IgG phase II titers of ≥1:1,024 together with IgG phase I titers of ≥1:256. At 12 months, 28.6% of ED patients and 19.5% of LD patients had high IgG antibody titers (P= 0.17). No statistically significant differences were found in frequencies of IgG phase I and IgG phase II antibody titers at all follow-up appointments for adequately and inadequately treated patients overall, as well as for ED and LD patients analyzed separately. Additionally, no significant difference was found in frequencies of high antibody titers and between early (treatment started within 7 days after seeking medical attention) and late timing of treatment. This study indicates that early diagnosis and antibiotic treatment of acute Q fever do not prohibit development of the IgG antibody response.

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ViableCoxiella burnetiiInduces Differential Cytokine Responses in Chronic Q Fever Patients Compared to Heat-KilledCoxiella burnetii

Infection and Immunity ◽

10.1128/iai.00333-18 ◽

2018 ◽

Vol 86 (10) ◽

Author(s):

Anne F. M. Jansen ◽

Annemieke Dinkla ◽

Hendrik-Jan Roest ◽

Chantal P. Bleeker-Rovers ◽

Teske Schoffelen ◽

...

Keyword(s):

Mononuclear Cells ◽

Q Fever ◽

Ex Vivo ◽

Future Research ◽

Peripheral Blood Mononuclear ◽

Necrosis Factor Alpha ◽

Content Type ◽

Cytokine Responses ◽

Chronic Q Fever ◽

Viable Bacteria

ABSTRACTCytokine responses of chronic Q fever patients to the intracellular bacteriumCoxiella burnetiihave mostly been studied usingex vivostimulation of immune cells with heat-killedC. burnetiidue to the extensive measures needed to work with viable biosafety level 3 agents. Whether research with heat-killedC. burnetiican be translated to immune responses to viableC. burnetiiis imperative for the interpretation of previous and future studies with heat-killedC. burnetii. Peripheral blood mononuclear cells (PBMCs) of chronic Q fever patients (n= 10) and healthy controls (n= 10) were stimulated with heat-killed or viableC. burnetiiof two strains, Nine Mile and the Dutch outbreak strain 3262, for 24 h, 48 h, and 7 days in the absence or presence of serum containing anti-C. burnetiiantibodies. When stimulated with viableC. burnetii, PBMCs of chronic Q fever patients and controls produced fewer proinflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha, and IL-1β) after 24 h than after stimulation with heat-killedC. burnetii. In the presence of Q fever seronegative serum, IL-10 production was higher after stimulation with viable rather than heat-killedC. burnetii; however, when incubating with anti-C. burnetiiantibody serum, the effect on IL-10 production was reduced. Levels of adaptive, merely T-cell-derived cytokine (gamma interferon, IL-17, and IL-22) and CXCL9 production were not different between heat-killed and viableC. burnetiistimulatory conditions. Results from previous and future research with heat-killedC. burnetiishould be interpreted with caution for innate cytokines, but heat-killedC. burnetii-induced adaptive cytokine production is representative of stimulation with viable bacteria.

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Predominant Immunoglobulin A Response to Phase II Antigen of Coxiella burnetii in Acute Q Fever

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.6.2.173-177.1999 ◽

1999 ◽

Vol 6 (2) ◽

pp. 173-177 ◽

Cited By ~ 1

Author(s):

Pierre-Edouard Fournier ◽

Didier Raoult

Keyword(s):

Phase I ◽

Phase Ii ◽

Rural Areas ◽

Q Fever ◽

Immunoglobulin A ◽

Immunoglobulin M ◽

Retrospective Case ◽

Chronic Q Fever ◽

Antibody Titers ◽

Acute Q Fever

ABSTRACT Diagnosis of acute Q fever is usually confirmed by serology, on the basis of anti-phase II antigen immunoglobulin M (IgM) titers of ≥1:50 and IgG titers of ≥1:200. Phase I antibodies, especially IgG and IgA, are predominant in chronic forms of the disease. However, between January 1982 and June 1998, we observed anti-phase II antigen IgA titers of ≥1:200 as the sole or main antibody response in 10 of 1,034 (0.96%) patients with acute Q fever for whom information was available. In order to determine whether specific epidemiological or clinical factors were associated with these serological profiles, we conducted a retrospective case-control study that included completion of a standardized questionnaire, which was given to 40 matched controls who also suffered from acute Q fever. The mean age of patients with elevated phase II IgA titers was significantly higher than that usually observed for patients with acute Q fever (P = 0.026); the patients were also more likely than controls to live in rural areas (P = 0.026) and to have increased levels of transaminase in blood (P = 0.03). Elevated IgA titers are usually associated with chronic Q fever and are directed mainly at phase I antigens. Although the significance of our findings is unexplained, we herein emphasize the fact that IgA antibodies are not specific for chronic forms of Q fever and that they may occasionally be observed in patients with acute disease. Moreover, as such antibody profiles may not be determined by most laboratories, which test only for total antibody titers to phase I and II antigens, the three isotype-specific Ig titers should be determined as the first step in diagnosing Q fever.

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Optimal Length of Cultivation Time for Isolation of Propionibacterium acnes in Suspected Bone and Joint Infections Is More than 7 Days

Journal of Clinical Microbiology ◽

10.1128/jcm.01435-16 ◽

2016 ◽

Vol 54 (12) ◽

pp. 3043-3049 ◽

Cited By ~ 49

Author(s):

Daniel A. Bossard ◽

Bruno Ledergerber ◽

Patrick O. Zingg ◽

Christian Gerber ◽

Annelies S. Zinkernagel ◽

...

Keyword(s):

Propionibacterium Acnes ◽

Joint Infection ◽

False Negative ◽

Predictive Values ◽

Content Type ◽

Cultivation Time ◽

Joint Infections ◽

Bone And Joint Infections ◽

Time To Positivity ◽

Two Samples

Diagnosis of Propionibacterium acnes bone and joint infection is challenging due to the long cultivation time of up to 14 days. We retrospectively studied whether reducing the cultivation time to 7 days allows accurate diagnosis without losing sensitivity. We identified patients with at least one positive P. acnes sample between 2005 and 2015 and grouped them into “infection” and “no infection.” An infection was defined when at least two samples from the same case were positive. Clinical and microbiological data, including time to positivity for different cultivation methods, were recorded. We found 70 cases of proven P. acnes infection with a significant faster median time to positivity of 6 days (range, 2 to 11 days) compared to 9 days in 47 cases with P. acnes identified as a contamination ( P < 0.0001). In 15 of 70 (21.4%) patients with an infection, tissue samples were positive after day 7 and in 6 patients (8.6%) after day 10 when a blind subculture of the thioglycolate broth was performed. The highest sensitivity was detected for thioglycolate broth (66.3%) and the best positive predictive values for anaerobic agar plates (96.5%). A prolonged transportation time from the operating theater to the microbiological laboratory did not influence time to positivity of P. acnes growth. By reducing the cultivation time to 7 days, false-negative diagnoses would increase by 21.4%; thus, we recommend that biopsy specimens from bone and joint infections be cultivated to detect P. acnes for 10 days with a blind subculture at the end.

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Infection by Coxiella burnetii in a patient from a rural area of Monteria, Colombia

Revista de Salud Pública ◽

10.15446/rsap.v16n6.40086 ◽

2015 ◽

Vol 16 (6) ◽

pp. 958-961 ◽

Cited By ~ 4

Author(s):

Salim Mattar V ◽

Verónica Contreras C ◽

Marco Gonzalez T ◽

Francisco Camargo ◽

Jaime Alvarez ◽

...

Keyword(s):

Phase I ◽

Rural Area ◽

Phase Ii ◽

Coxiella Burnetii ◽

Indirect Immunofluorescence ◽

Q Fever ◽

Immunofluorescence Assay ◽

Indirect Immunofluorescence Assay ◽

Igg Antibody ◽

Antibody Titers

Q fever is a zoonosis caused by Coxiella burnetii. In Colombia, there have been very few human cases reported to date. This report describes the case of a 56-year-old patient with a background in agriculture and livestock handling. An indirect immunofluorescence assay (IFA) showed high titers of IgG for C. burnetii anti-phase I (1: 256) and anti-phase II (1:1024). For the next six months the patient’s IgG antibody titers remained high, and, after treatment with doxycycline, the IgG antibody titers decreased to 50 % (anti-phase I 1:128 and anti-phase II 1:512); this profile suggests an infection of C. burnetii.

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