Chronic Q fever diagnosis­ consensus guideline versus expert opinion

Chronic Q fever, caused by Coxiella burnetii, has high mortality and morbidity rates if left untreated. Controversy about the diagnosis of this complex disease has emerged recently. We applied the guideline from the Dutch Q Fever Consensus Group and a set of diagnostic criteria proposed by Didier Raoult to all 284 chronic Q fever patients included in the Dutch National Chronic Q Fever Database during 2006­2012. Of the patients who had proven cases of chronic Q fever by the Dutch guideline, 46 (30.5%)would not have received a diagnosis by the alternative criteria designed by Raoult, and 14 (4.9%) would have been considered to have possible chronic Q fever. Six patients with proven chronic Q fever died of related causes. Until results from future studies are available, by which current guidelines can be modified, we believe that the Dutch literature-based consensus guideline is more sensitive and easier to use in clinical practice.

Galactomannan detection for invasive aspergillosis in immunocompromised patients.

BACKGROUND: Invasive aspergillosis is the most common life-threatening opportunistic invasive mycosis in immunocompromised patients. A test for invasive aspergillosis should neither be too invasive nor too great a burden for the already weakened patient. The serum galactomannan enzyme-linked immunosorbent assay (ELISA) seems to have the potential to meet both requirements. OBJECTIVES: To obtain summary estimates of the diagnostic accuracy of galactomannan detection in serum for the diagnosis of invasive aspergillosis. SEARCH METHODS: We searched MEDLINE, EMBASE and Web of Science with both MeSH terms and text words for both aspergillosis and the sandwich ELISA. We checked the reference lists of included studies and review articles for additional studies. We conducted the searches in February 2014. SELECTION CRITERIA: We included cross-sectional studies, case-control designs and consecutive series of patients assessing the diagnostic accuracy of galactomannan detection for the diagnosis of invasive aspergillosis in patients with neutropenia or patients whose neutrophils are functionally compromised. The reference standard was composed of the criteria given by the European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed quality and extracted data. We carried out meta-analysis using the bivariate method. We investigated sources of heterogeneity by adding potential sources of heterogeneity to the model as covariates. MAIN RESULTS: We included 54 studies in the review (50 in the meta-analyses), containing 5660 patients, of whom 586 had proven or probable invasive aspergillosis. When using an optical density index (ODI) of 0.5 as a cut-off value, the sensitivity of the test was 82% (73% to 90%) and the specificity was 81% (72% to 90%). At a cut-off value of 1.0 ODI, the sensitivity was 72% (65% to 80%) and the specificity was 88% (84% to 92%). At a cut-off value of 1.5 ODI, the sensitivity was 61% (47% to 75%) and the specificity was 93% (89% to 97%). None of the potential sources of heterogeneity had a statistically significant effect on either sensitivity or specificity. AUTHORS' CONCLUSIONS: If we used the test at a cut-off value of 0.5 ODI in a population of 100 patients with a disease prevalence of 9% (overall median prevalence), two patients who have invasive aspergillosis would be missed (sensitivity 82%, 18% false negatives), and 17 patients would be treated unnecessarily or referred unnecessarily for further testing (specificity 81%, 19% false negatives). If we used the test at a cut-off value of 1.5 in the same population, that would mean that four invasive aspergillosis patients would be missed (sensitivity 61%, 39% false negatives), and six patients would be treated or referred for further testing unnecessarily (specificity 93%, 7% false negatives). These numbers should, however, be interpreted with caution because the results were very heterogeneous.

Diagnosis and management of Q fever--United States, 2013: recommendations from CDC and the Q Fever Working Group.

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.

Galactomannan detection for invasive aspergillosis in immunocompromized patients.

BACKGROUND: Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mycosis in immunocompromized patients. A test for IA needs to be not too invasive and not too big a burden for the already weakened patient. The serum galactomannan ELISA seems to have potential for both requirements. OBJECTIVES: To obtain summary estimates of the diagnostic accuracy of galactomannan detection in serum for the diagnosis of IA. SEARCH STRATEGY: We searched MEDLINE, EMBASE and Web of Science with both Medical Headings and text words for both aspergillosis and the sandwich ELISA. We checked reference lists of included studies and review articles for additional studies. SELECTION CRITERIA: Cross-sectional studies, case-control designs and consecutive series of patients assessing the diagnostic accuracy of galactomannan detection for the diagnosis of IA in patients with neutropenia or patients whose neutrophils are functionally compromised were included. The reference standard was composed of the criteria given by the European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed quality and extracted data MAIN RESULTS: Thirty studies were included in the meta-analyses, with a median prevalence of IA (proven or probable) of 7.7%. Seven of these (901 patients) reported results for an Optical Density Index (ODI) of 0.5 as cut-off value. The overall sensitivity in these studies was 78% (61% to 89%) and overall specificity was 81% (72% to 88%). Twelve studies (1744 patients) reported the results for cut-off value of 1.0 ODI, overall sensitivity was 75% (59% to 86%) and mean specificity 91% (84% to 95%). Seventeen studies (2600 patients) reported the results for cut-off value 1.5 ODI, sensitivity was 64% (50% to 77%) and mean specificity 95% (91% to 97%). AUTHORS' CONCLUSIONS: At a cut-off value 0.5 ODI in a population of 100 patients with a disease prevalence of 8% (overall median prevalence), 2 patients who have IA, will be missed (sensitivity 78%, 22% false negatives), and 17 patients will be treated or further referred unnecessarily (specificity of 81%, 19% false negatives). If we use the test at cut-off value 1.5 in the same population, that will mean that 3 IA patients will be missed (sensitivity 64%, 36% false negatives) and 5 patients will be treated or referred unnecessarily (specificity of 95%, 5% false negatives). These numbers should however be interpreted with caution, because the results were very heterogeneous.

Immunogenicity of the Q fever skin test.

OBJECTIVES: The Q fever skin test is used to measure cell-mediated immunity to Coxiella burnetii in pre-vaccination screening to exclude individuals with pre-existing immunity. We investigated whether this in-vivo test influences subsequent measurements of immune response. METHODS: We assessed the humoral and cellular immune responses before, and 6 and 12 months after skin testing in 63 individuals who were not vaccinated because of either a positive skin test or positive serology in screening. IgG anti-C. burnetii antibodies were measured using immune-fluorescence assay (IFA). The cellular immune response was assessed by measuring in-vitro C. burnetii-specific interferon (IFN)-γ production in blood. RESULTS: Of the 35 subjects with a positive skin test and negative serology, 15/35 (43%) showed seroconversion at 6 months, and 7/32 (22%) seropositivity at 12 months. The mean ± SE specific IFN-γ production in this group increased from 185 ± 88 pg/mL (at baseline) to 422 ± 141 pg/mL at 6 months (P = 0.009) and 223 ± 91 pg/mL at 12 months (P = 0.17). Of the 28 subjects with positive serology (and unknown skin test results), 21/28 (75%) showed an increase in IgG anti-phase I titres at 6 months, and 11/25 (44%) at 12 months. The mean ± SE specific IFN-γ production was significantly increased at 6 months, but not at 12 months. CONCLUSIONS: Q fever skin testing causes higher antibody titres and higher in-vitro IFN-γ to C. burnetii, and therefore affects subsequent Q fever diagnostics.

Limited humoral and cellular responses to Q fever vaccination in older adults with risk factors for chronic Q fever.

OBJECTIVES: In the Netherlands, people at risk for chronic Q fever were vaccinated against Coxiella burnetii with the inactivated whole cell vaccine Q-vax®. We aimed to measure the immune responses to C. burnetii six and twelve months after vaccination in this relevant population. METHODS: In 260 vaccinees, antibody responses were assessed by immunofluorescence assay (IFA), complement fixation test and ELISA. The cellular immune responses were assessed by measuring C. burnetii-specific interferon (IFN)-γ production in blood. Serological results of 200 individuals with past Q fever were used for comparison. RESULTS: At six months, 46% of vaccinees showed low IFA antibody titres and 67% had a positive IFN-γ assay; At twelve months, both were 60%. In contrast, individuals with a past Q fever were seropositive in 99.5% at six and twelve months, with relatively higher IFA titres. Interestingly, vaccinees with positive IFN-γ assay pre-vaccination, showed a higher seroconversion rate than IFN-γ negative vaccinees: 74% vs. 41% (p < 0.001). CONCLUSIONS: The immune response after Q-vax® vaccination is lower and restricted to a smaller proportion than found after past Q fever and than previously described after vaccination, suggesting decreased vaccine immunogenicity in this high-risk population. A positive IFN-γ assay before vaccination in seronegative vaccinees likely points to pre-existing immunity resulting in boosting by vaccination.

Comparison of the performance of IFA, CFA, and ELISA assays for the serodiagnosis of acute Q fever by quality assessment.

The indirect immunofluorescence assay (IFA) is considered the reference method for diagnosing Q fever, but serology is also performed by complement fixation assay (CFA) or enzyme-linked immunosorbent assay (ELISA). However, comparability between these assays is not clear, and therefore a quality assessment was performed. A total of 25 serum samples from negative controls, Q fever patients, and a serial diluted high-positive sample were analyzed in 10 Dutch laboratories. Six laboratories performed CFA, 5 performed IFA, and 5 performed ELISAs. Three international reference laboratories from Australia, France, and the USA also participated in this study. Qualitative values between laboratories using the same methods were within close range, and all 3 methods correctly identified acute Q fever patients. The IFA, ELISA, and CFA are all suitable serodiagnostic assays to diagnose acute Q fever, but the IFA remains an important tool in the follow-up of patients and in identifying patients at risk for developing chronic Q fever.

[Laboratory diagnosis of acute Q fever]. / Laboratoriumdiagnostiek van acute Q-koorts.

In the Netherlands an increasing number of laboratories are involved in diagnosing acute Q-fever. More uniformity in diagnostics and interpretation is desirable. To enable this, a working group on diagnostics of acute Q-fever was created on the initiative of the National Institute for Public Health and the Environment (RIVM) and the Dutch Association for Medical Microbiology (NVMM). The diagnostics of acute Q-fever includes a diagnostic flow chart (algorithm) consisting of tests for DNA and for antibodies against the antigens that appear in the successive stages of the disease. Reporting of both confirmed and suspected cases of acute Q-fever is obligatory.