Jamie C. E. Meekelenkamp

Follow-up of 686 patients with acute Q fever and detection of chronic infection

BACKGROUND Recent outbreaks in the Netherlands allowed for laboratory follow-up of a large series of patients with acute Q fever and for evaluation of test algorithms to detect chronic Q fever, a condition with considerable morbidity and mortality. METHODS For 686 patients with acute Q fever, IgG antibodies to Coxiella burnetii were determined using an immunofluorescence assay at 3, 6, and 12 months of follow-up. Polymerase chain reaction (PCR) was performed after 12 months and on earlier serum samples with an IgG phase I antibody titer ≥ 1:1024. RESULTS In 43% of patients, the IgG phase II antibody titers remained high (≥ 1:1024) at 3, 6, and 12 months of follow-up. Three months after acute Q fever, 14% of the patients had an IgG phase I titer ≥ 1:1024, which became negative later in 81%. IgG phase I antibody titers were rarely higher than phase II titers. Eleven cases of chronic Q fever were identified on the basis of serological profile, PCR results, and clinical presentation. Six of these patients were known to have clinical risk factors at the time of acute Q fever. In a comparison of various serological algorithms, IgG phase I titer ≥ 1:1024 at 6 months had the most favorable sensitivity and positive predictive value for the detection of chronic Q fever. CONCLUSIONS The wide variation of serological and PCR results during the follow-up of acute Q fever implies that the diagnosis of chronic Q fever, necessitating long-term antibiotic treatment, must be based primarily on clinical grounds. Different serological follow-up strategies are needed for patients with and without known risk factors for chronic Q fever.

Antibodies against Coxiella burnetii and pregnancy outcome during the 2007-2008 Q fever outbreaks in the Netherlands

BackgroundQ fever has become a major public health problem in the Netherlands. Infection with Coxiella burnetii (Q fever) during pregnancy has resulted in adverse pregnancy outcome in the majority of reported cases. Therefore, we aimed to quantify this risk by examining the earliest periods corresponding to the epidemic in the Netherlands.MethodsSerum samples that had been collected from the area of highest incidence by an existing national prenatal screening programme and data from the Netherlands Perinatal Registry (PRN) on diagnosis and outcome were used. We performed indirect immunofluorescence assay to detect the presence of IgM and IgG antibodies against C. burnetii in the samples. The serological results were analyzed to determine statistical association with recorded pregnancy outcome.ResultsEvaluation of serological results for 1174 women in the PRN indicated that the presence of IgM and IgG antibodies against phase II of C. burnetii was not significantly associated with preterm delivery, low birth weight, or several other outcome measures.ConclusionThe present population-based study showed no evidence of adverse pregnancy outcome among women who had antibodies to C. burnetii during early pregnancy.

Evaluation of Commonly Used Serological Tests for Detection of Coxiella burnetii Antibodies in Well-Defined Acute and Follow-Up Sera

ABSTRACT In this study, we compared Coxiella burnetii IgG phase I, IgG phase II, and IgM phase II detection among a commercially available enzyme-linked immunosorbent assay (ELISA) (Virion/Serion), an indirect fluorescent antibody test (IFAT) (Focus Diagnostics), and a complement fixation test (CFT) (Virion/Serion). For this, we used a unique collection of acute- and convalescent-phase sera from 126 patients with acute Q fever diagnosed by positive Coxiella burnetii PCR of blood. We were able to establish a reliable date of onset of disease, since DNA is detectable within 2 weeks after the start of symptoms. In acute samples, at t = 0, IFAT demonstrated IgM phase II antibodies in significantly more sera than did ELISA (31.8% versus 19.7%), although the portion of solitary IgM phase II was equal for IFAT and for ELISA (18.2% and 16.7%, respectively). Twelve months after the diagnosis of acute Q fever, 83.5% and 62.2% of the sera were still positive for IgM phase II with IFAT and ELISA, respectively. At 12 months IFAT IgG phase II showed the slowest decline. Therefore, definitive serological evidence of acute Q fever cannot be based on a single serum sample in areas of epidemicity and should involve measurement of both IgM and IgG antibodies in paired serum. Based on IgG phase II antibody detection in paired samples (at 0 and 3 months) from 62 patients, IFAT confirmed more cases than ELISA and CFT, but the differences were not statically significant (100% for IFAT, 95.2% for ELISA, and 96.8% for CFT). This study demonstrated that the three serological tests are equally effective in diagnosing acute Q fever within 3 months of start of symptoms. In follow-up sera, more IgG antibodies were detected by IFAT than by ELISA or CFT, making IFAT more suitable for prevaccination screening programs.

Proximity to Goat Farms and Coxiella burnetii Seroprevalence among Pregnant Women

During 2007–2009, we tested serum samples from 2,004 pregnant women living in an area of high Q fever incidence in the Netherlands. Results confirmed that presence of antibodies against Coxiella burnetii is related to proximity to infected dairy goat farms. Pregnant women and patients with certain cardiovascular conditions should avoid these farms.

Evaluation of a Diagnostic Algorithm for Acute Q Fever in an Outbreak Setting

ABSTRACT In the peak of the 2009 Q fever outbreak in the Netherlands, we introduced a diagnostic algorithm for acute Q fever with an enzyme-linked immunosorbent assay for immunoglobulin M antibodies to Coxiella burnetii phase II antigens (MII screen) as an initial step. Subsequently, an immunofluorescence assay or PCR was performed depending on the MII screen outcome, date of onset of disease, and inpatient or outpatient setting. The impact of MII screen on the number of immunofluorescence assays performed and the contribution of PCR to diagnosis were retrospectively evaluated in 825 patients referred in a 17-day period. Acute Q fever was diagnosed in 256 patients. The introduction of MII screen reduced the number of immunofluorescence assays performed by more than 80%. In 103 patients, PCR analysis contributed to the diagnosis of acute Q fever. Q fever diagnostics were hampered by the fact that for a high number of patients the date of onset of disease was not provided and the requested follow-up serum samples were not received.

Comparison of ELISA and indirect immunofluorescent antibody assay detecting Coxiella burnetii IgM phase II for the diagnosis of acute Q fever

A commercially available enzyme-linked immunosorbent assay (ELISA) detecting Coxiella burnetii phase II-specific IgM for the diagnosis of acute Q fever was compared with indirect immunofluorescent antibody assay (IFA). IFA is the current reference method for the detection of antibodies against C. burnetii, but has disadvantages because the judgment of fluorescence is subjective and tiring, and the test is expensive and automation is not possible. To examine whether phase II IgM ELISA could be used as a screening assay for acute Q fever, we compared the sensitivity and specificity of IFA and ELISA. The sensitivity of the IFA and ELISA tests were 100 and 85.7%, respectively, with a specificity of 95.3 and 97.6%, respectively. Because of the high sensitivity and specificity of the ELISA in combination with the practical disadvantages of the IFA, we introduced a new algorithm to screen samples of patients with symptoms of acute Q fever infection.

Cost-effectiveness of a screening strategy for Q fever among pregnant women in risk areas: a clustered randomized controlled trial

BackgroundIn The Netherlands the largest human Q fever outbreak ever reported in the literature is currently ongoing with more than 2300 notified cases in 2009. Pregnant women are particularly at risk as Q fever during pregnancy may cause maternal and obstetric complications. Since the majority of infected pregnant women are asymptomatic, a screening strategy might be of great value to reduce Q fever related complications. We designed a trial to assess the (cost-)effectiveness of a screening program for Q fever in pregnant women living in risks areas in The Netherlands.Methods/designWe will conduct a clustered randomized controlled trial in which primary care midwife centres in Q fever risk areas are randomized to recruit pregnant women for either the control group or the intervention group. In both groups a blood sample is taken around 20 weeks postmenstrual age. In the intervention group, this sample is immediately analyzed by indirect immunofluorescence assay for detection of IgG and IgM antibodies using a sensitive cut-off level of 1:32. In case of an active Q fever infection, antibiotic treatment is recommended and serological follow up is performed. In the control group, serum is frozen for analysis after delivery. The primary endpoint is a maternal (chronic Q fever or reactivation) or obstetric complication (low birth weight, preterm delivery or fetal death) in Q fever positive women. Secondary aims pertain to the course of infection in pregnant women, diagnostic accuracy of laboratory tests used for screening, histo-pathological abnormalities of the placenta of Q fever positive women, side effects of therapy, and costs. The analysis will be according to the intention-to-screen principle, and cost-effectiveness analysis will be performed by comparing the direct and indirect costs between the intervention and control group.DiscussionWith this study we aim to provide insight into the balance of risks of undetected and detected Q fever during pregnancy.Trial registrationClinicalTrials.gov, protocol record NL30340.042.09.

Q fever across the Dutch border in Limburg province, Belgium.

Data from three different data sources were compiled to estimate the presence of Coxiella burnetii in the Belgian Limburg province for both humans and livestock. First, serological data of all samples sent to the Belgian reference centre (2003–2010) for human Q fever were analysed, showing evidence for an acute Q fever infection in 1–5% of the cases. Second, a multi-centre prospective survey was conducted in Limburg in 2010 to detect undiagnosed human cases; evidence for a recent infection with Coxiella burnetii was found in three out of 100 patients from which clinicians suspected a Mycoplasma pneumoniae infection. Third, we analyzed data from the Belgian livestock screening program (2009–2010) which consisted of investigating all reported abortions, sampling tank milk, and serological screening of cattle. The results suggest an endemicity in the Limburgian livestock which seems to be especially high in cattle.

(Cost-)Effectiveness of a Screening Strategy for Q Fever among Pregnant Women in Risk Areas : A Clustered Randomized Controlled Trial

Background: Two case reports of polymyalgia rheumatica (PMR) and one case-report of PMR and temporalis arteritis (AT) suggest that the use of statins may have triggered the development of these inflammatory rheumatic diseases. PMR is closely linked to the disease arteritis temporalis which makes it difficult for physicians to distinguish these two diseases. Data on the association between the use of statins and PMR and/or AT are scarce. Objectives: To assess the association between statin use and the occurrence of PMR/AT. Methods: A case/non-case study based on individual case safety reports (ICSR) listed in the World Health Organisation (WHO) global ICSR database (Vigibase) was conducted. According to WHO adverse reaction terminology, cases were defined as reports of PMR. Each case was matched with five non-cases by age, gender and time of reporting. Non-cases were all other ADR-reports. Use of statins was classified according to the Anatomical Therapeutic Chemical (ATC) classification code system (C10AA, C10BA, C10BX). Potential confounders in the analysis, i.e., use of corticosteroids, immunosuppressive drugs, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, anti-epileptics, proton pump inhibitors and cardiovascular drugs were determined. Multivariate logistic regression was used to calculate the reporting odds ratios (RORs) with 95% confidence intervals (CI). In addition, three case-reports from the VigiBase were studied in detail. Results: We identified 327 reports of PMR/AT as cases and 1635 reports of other ADRs as non-cases. Among cases statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were statistically significantly associated with reports of PMR/AT (ROR 14.21; 95% CI 9.89-20.85). Conclusions: The result of this study underlines findings of the case reports that the use of statins may be associated with the occurrence of PMR/AT.Background: In The Netherlands, the largest outbreak of Q fever worldwide is ongoing. A particular risk group concerns pregnant women in which the infection is mostly asymptomatic. Q fever during pregnancy may cause both obstetric complications as well as chronic infection in the mother. Long term antibiotic treatment of infected women may reduce the risk of complications. Objectives: A clustered randomized controlled trial to assess the effects of screening for Q fever during pregnancy is ongoing (trial register number NL30340.042.09). The primary endpoint is a maternal or obstetric complication in Q fever positive women. Methods: Midwife centers in high-risk Q fever areas were randomized to recruit pregnant women for the screening or control strategy. In both groups a blood sample was taken between 20 and 32 weeks of gestation. In the screening group this sample was immediately analyzed with indirect immunofluorescence assay for the detection of IgG and IgM antibodies. Every positive sample was fully titrated. In case of acute or chronic infection antibiotic treatment advice was given. In the control group serum was frozen for analysis after delivery. Results: In all, 55 of 99 eligible midwife centers were randomized. They recruited 1222 pregnant women from which a blood sample was taken; 534 for the screening group and 688 for the controle group. Fourteen percent in both groups had serologic evidence for an acute or previous Q fever infection. Only 7 participants in the intervention group had evidence for an acute infection and were treated with antibiotics (erythromycin or cotrimoxazole). Three of them experienced side-effects, mainly gastro-intestinal, of which one consulted the gynecologist due to the side-effects. Since a part of the participants still have to deliver, data collection on clinical outcome is still ongoing. Conclusions: Fourteen percent of the pregnant women in high-risk Q fever areas have evidence of Q fever infection. Only a very small part has an acute infection, in which treatment is though to be needed. Clinical outcome data and cost-effectiveness analyses are expected in spring and will be presented.

(Cost-)Effectiveness of a Screening Strategy for Q Fever among Pregnant Women in Risk Areas

Background: Two case reports of polymyalgia rheumatica (PMR) and one case-report of PMR and temporalis arteritis (AT) suggest that the use of statins may have triggered the development of these inflammatory rheumatic diseases. PMR is closely linked to the disease arteritis temporalis which makes it difficult for physicians to distinguish these two diseases. Data on the association between the use of statins and PMR and/or AT are scarce. Objectives: To assess the association between statin use and the occurrence of PMR/AT. Methods: A case/non-case study based on individual case safety reports (ICSR) listed in the World Health Organisation (WHO) global ICSR database (Vigibase) was conducted. According to WHO adverse reaction terminology, cases were defined as reports of PMR. Each case was matched with five non-cases by age, gender and time of reporting. Non-cases were all other ADR-reports. Use of statins was classified according to the Anatomical Therapeutic Chemical (ATC) classification code system (C10AA, C10BA, C10BX). Potential confounders in the analysis, i.e., use of corticosteroids, immunosuppressive drugs, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, anti-epileptics, proton pump inhibitors and cardiovascular drugs were determined. Multivariate logistic regression was used to calculate the reporting odds ratios (RORs) with 95% confidence intervals (CI). In addition, three case-reports from the VigiBase were studied in detail. Results: We identified 327 reports of PMR/AT as cases and 1635 reports of other ADRs as non-cases. Among cases statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were statistically significantly associated with reports of PMR/AT (ROR 14.21; 95% CI 9.89-20.85). Conclusions: The result of this study underlines findings of the case reports that the use of statins may be associated with the occurrence of PMR/AT.Background: In The Netherlands, the largest outbreak of Q fever worldwide is ongoing. A particular risk group concerns pregnant women in which the infection is mostly asymptomatic. Q fever during pregnancy may cause both obstetric complications as well as chronic infection in the mother. Long term antibiotic treatment of infected women may reduce the risk of complications. Objectives: A clustered randomized controlled trial to assess the effects of screening for Q fever during pregnancy is ongoing (trial register number NL30340.042.09). The primary endpoint is a maternal or obstetric complication in Q fever positive women. Methods: Midwife centers in high-risk Q fever areas were randomized to recruit pregnant women for the screening or control strategy. In both groups a blood sample was taken between 20 and 32 weeks of gestation. In the screening group this sample was immediately analyzed with indirect immunofluorescence assay for the detection of IgG and IgM antibodies. Every positive sample was fully titrated. In case of acute or chronic infection antibiotic treatment advice was given. In the control group serum was frozen for analysis after delivery. Results: In all, 55 of 99 eligible midwife centers were randomized. They recruited 1222 pregnant women from which a blood sample was taken; 534 for the screening group and 688 for the controle group. Fourteen percent in both groups had serologic evidence for an acute or previous Q fever infection. Only 7 participants in the intervention group had evidence for an acute infection and were treated with antibiotics (erythromycin or cotrimoxazole). Three of them experienced side-effects, mainly gastro-intestinal, of which one consulted the gynecologist due to the side-effects. Since a part of the participants still have to deliver, data collection on clinical outcome is still ongoing. Conclusions: Fourteen percent of the pregnant women in high-risk Q fever areas have evidence of Q fever infection. Only a very small part has an acute infection, in which treatment is though to be needed. Clinical outcome data and cost-effectiveness analyses are expected in spring and will be presented.