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

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

The cellular immune response to antigens of Coxiella burneti

Canadian Journal of Microbiology ◽

10.1139/m74-101 ◽

1974 ◽

Vol 20 (5) ◽

pp. 657-662 ◽

Cited By ~ 6

Author(s):

John P. Heggers ◽

L. P. Mallavia ◽

David J. Hinrichs

Keyword(s):

Phase I ◽

Guinea Pigs ◽

Q Fever ◽

Delayed Hypersensitivity ◽

Migration Inhibition ◽

Microagglutination Test ◽

Cellular Immune ◽

Antibody Levels ◽

Circulating Antibody

Formalinized vaccines prepared from the Nine Mile, Phase I, strain of C. burneti or purified preparations of the Phase I antigen initiate a state of delayed hypersensitivity in guinea pigs as determined by the in vitro migration inhibition system. This delayed hypersensitivity is directed against the protein as well as the carbohydrate component of the Phase I antigen. Guinea pigs that had recovered from Q-fever demonstrated a similar state of delayed hypersensitivity. Circulating antibody levels as determined by the microagglutination test were readily apparent in both infected and vaccinated animals.

Download Full-text

Microbiological Challenges in the Diagnosis of Chronic Q Fever

Clinical and Vaccine Immunology ◽

10.1128/cvi.05724-11 ◽

2012 ◽

Vol 19 (5) ◽

pp. 787-790 ◽

Cited By ~ 18

Author(s):

Linda M. Kampschreur ◽

Jan Jelrik Oosterheert ◽

Annemarie M. C. Koop ◽

Marjolijn C. A. Wegdam-Blans ◽

Corine E. Delsing ◽

...

Keyword(s):

Phase I ◽

Q Fever ◽

Strong Association ◽

False Negative ◽

High Morbidity ◽

Igg Antibody ◽

Predictive Values ◽

Content Type ◽

Chronic Q Fever ◽

High Phase

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.

Download Full-text

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.

Download Full-text

Persistent High IgG Phase I Antibody Levels against Coxiella burnetii among Veterinarians Compared to Patients Previously Diagnosed with Acute Q Fever after Three Years of Follow-Up

PLoS ONE ◽

10.1371/journal.pone.0116937 ◽

2015 ◽

Vol 10 (1) ◽

pp. e0116937 ◽

Cited By ~ 8

Author(s):

Cornelia C. H. Wielders ◽

Anneroos W. Boerman ◽

Barbara Schimmer ◽

René van den Brom ◽

Daan W. Notermans ◽

...

Keyword(s):

Phase I ◽

Coxiella Burnetii ◽

Q Fever ◽

Acute Q Fever ◽

Antibody Levels

Download Full-text

The immune response in a cat-related outbreak of Q fever as measured by the indirect immunofluorescence test and the enzyme-linked immunosorbent assay

Canadian Journal of Microbiology ◽

10.1139/m90-050 ◽

1990 ◽

Vol 36 (4) ◽

pp. 292-296 ◽

Cited By ~ 14

Author(s):

J. Embil ◽

J. C. Williams ◽

T. J. Marrie

Keyword(s):

Immune Response ◽

Phase I ◽

Phase Ii ◽

Q Fever ◽

Elisa Test ◽

Enzyme Linked Immunosorbent Assay ◽

Whole Cells ◽

Chronic Q Fever ◽

Acute Q Fever ◽

Indirect Immunofluorescent

The isotypic immune response of 16 individuals who developed Q fever pneumonia following exposure to an infected parturient cat was studied. The enzyme-linked immunosorbent (ELISA) test was used to detect IgM, IgA, and IgG antibodies to phase I and phase II Coxiella burnetii whole-cell antigens and to the phase I lipopolysaccharide. The indirect immunofluorescent antibody (IFA) test was also used to detect antibodies to phase I and phase II whole cells. None of the 16 subjects developed antibodies to the phase I lipopoly saccharide. The ELISA was more sensitive than the IFA test. IgM antibodies to phase II antigen were detectable by ELISA in 80% of the subjects at the time of onset of symptoms and were still present in 7 of the 8 tested at 32 weeks following the onset of symptoms. In all instances (ELISA: IgG, IgM; IFA: IgG, IgM) phase II antibodies developed earlier and reached higher levels than did phase I antibodies. The absence of antibodies to phase I lipopolysaccharide in acute Q fever combined with our unpublished findings of antibodies to phase I lipopoly saccharide in chronic Q fever suggests that this test may be used to distinguish acute from chronic Q fever. Key words: Q fever, immune response, ELISA.

Download Full-text

Clinical Course of Factor VIII Inhibitors Developed after Exposure to a Pasteurised Dutch Concentrate Compared to Classic Inhibitors in Hemophilia A

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642508 ◽

1994 ◽

Vol 71 (05) ◽

pp. 703-706 ◽

Cited By ~ 31

Author(s):

E P Mauser-Bunschoten ◽

F R Rosendaal ◽

H K Nieuwenhuis ◽

G Roosendaal ◽

E Briëf ◽

...

Keyword(s):

Factor Viii ◽

Immune Tolerance ◽

Hemophilia A ◽

Clinical Course ◽

Treatment Success ◽

Response To Treatment ◽

Rapid Decline ◽

Inhibitor Level ◽

Recent Group ◽

Antibody Levels

SummaryAfter the introduction of a new pasteurised factor VIII concentrate (Factor VIII CPS-P) in The Netherlands in June 1990, an increase in the occurrence of inhibitors in hemophilia A patients was reported. The clinical course of this group of inhibitors (n = 12) was compared with hemophilia patients in whom an inhibitor developed before June 1990 (classic inhibitors) (n = 32). Striking differences were found between both groups not only in patient age (median 22 years versus 8 years) and number of exposure days (<50 − >1000 versus <50), as described in previous reports, but also in clinical course and response to treatment. In the recent group of inhibitors antibody titers showed a rapid decline when product was changed which was not the case in the group with classic inhibitors. In the group of classic inhibitors immune tolerance therapy with low dose factor VIII succeeded in 83%. Success was to a high degree dependent on the inhibitor level. In the group of recent inhibitors immune tolerance with the same concentrate was only successful in a single patient. However, once the patients were switched to another concentrate, antibody levels dropped to less than 2 BU/ml within 8 months in all patients.It seems likely that in this group of product associated inhibitors, treatment success was due to elimination of antigen stimulation rather than induction of immune tolerance.

Download Full-text

Dysregulation of Serum Gamma Interferon Levels in Vascular Chronic Q Fever Patients Provides Insights into Disease Pathogenesis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00078-15 ◽

2015 ◽

Vol 22 (6) ◽

pp. 664-671 ◽

Cited By ~ 3

Author(s):

Jeroen L. A. Pennings ◽

Marjolein N. T. Kremers ◽

Hennie M. Hodemaekers ◽

Julia C. J. P. Hagenaars ◽

Olivier H. J. Koning ◽

...

Keyword(s):

Transforming Growth Factor ◽

Q Fever ◽

Transforming Growth Factor Β ◽

Serum Levels ◽

Gamma Interferon ◽

Type I ◽

Content Type ◽

Chronic Q Fever ◽

Inducible Protein ◽

Acute Q Fever

ABSTRACTA large community outbreak of Q fever occurred in the Netherlands in the period 2007 to 2010. Some of the infected patients developed chronic Q fever, which typically includes pathogen dissemination to predisposed cardiovascular sites, with potentially fatal consequences. To identify the immune mechanisms responsible for ineffective clearance ofCoxiella burnetiiin patients who developed chronic Q fever, we compared serum concentrations of 47 inflammation-associated markers among patients with acute Q fever, vascular chronic Q fever, and past resolved Q fever. Serum levels of gamma interferon were strongly increased in acute but not in vascular chronic Q fever patients, compared to past resolved Q fever patients. Interleukin-18 levels showed a comparable increase in acute as well as vascular chronic Q fever patients. Additionally, vascular chronic Q fever patients had lower serum levels of gamma interferon-inducible protein 10 (IP-10) and transforming growth factor β (TGF-β) than did acute Q fever patients. Serum responses for these and other markers indicate that type I immune responses toC. burnetiiare affected in chronic Q fever patients. This may be attributed to an affected immune system in cardiovascular patients, which enables localC. burnetiireplication at affected cardiovascular sites.

Download Full-text