Efficacy of BCG Vaccination Against Respiratory Tract Infections in Older Adults During the Coronavirus Disease 2019 Pandemic.

BACKGROUND: Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (COVID-19). The tuberculosis BCG vaccine may provide heterologous protection against nontuberculous infections and has been proposed as a potential preventive strategy against COVID-19. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned older adults (aged ≥60 years; n = 2014) to intracutaneous vaccination with BCG vaccine (n = 1008) or placebo (n = 1006). The primary end point was the cumulative incidence of respiratory tract infections (RTIs) that required medical intervention, during 12 months of follow-up. Secondary end points included the incidence of COVID-19, and the effect of BCG vaccination on the cellular and humoral immune responses. RESULTS: The cumulative incidence of RTIs requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio, 1.26 [98.2% confidence interval, .65-2.44]). In the BCG vaccine and placebo groups, 51 and 48 individuals, respectively tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with polymerase chain reaction (subdistribution hazard ratio, 1.053 [95% confidence interval, .71-1.56]). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokine responses after influenza, and also partially associated after SARS-CoV-2 stimulation. In patients diagnosed with COVID-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG vaccine. CONCLUSIONS: BCG vaccination had no effect on the incidence of RTIs, including SARS-CoV-2 infection, in older adult volunteers. However, it improved cytokine responses stimulated by influenza and SARS-CoV-2 and induced stronger antibody titers after COVID-19 infection. CLINICAL TRIALS REGISTRATION: EU Clinical Trials Register 2020-001591-15 ClinicalTrials.gov NCT04417335.

Targeted Screening for Chronic Q Fever, the Netherlands.

Early detection of and treatment for chronic Q fever might prevent potentially life-threatening complications. We performed a chronic Q fever screening program in general practitioner practices in the Netherlands 10 years after a large Q fever outbreak. Thirteen general practitioner practices located in outbreak areas selected 3,419 patients who had specific underlying medical conditions, of whom 1,642 (48%) participated. Immunofluorescence assay of serum showed that 289 (18%) of 1,642 participants had a previous Coxiella burnetii infection (IgG II titer >1:64), and 9 patients were suspected of having chronic Q fever (IgG I y titer >1:512). After medical evaluation, 4 of those patients received a chronic Q fever diagnosis. The cost of screening was higher than estimated earlier, but the program was still cost-effective in certain high risk groups. Years after a large Q fever outbreak, targeted screening still detected patients with chronic Q fever and is estimated to be cost-effective.

Individualizing the use of [18F]FDG-PET/CT in patients with complicated Staphylococcus aureus bacteremia: experiences from a tertiary care center.

PURPOSE: [18F]FDG-PET/CT scanning can help detect metastatic infectious foci and reduce mortality in patients with Staphylococcus aureus bacteremia (SAB), but it is unknown if patients with SAB and an indication for prolonged treatment because of possible endovascular, orthopaedic implant, or other metastatic infection still need [18F]FDG-PET/CT. METHODS: In a retrospective single-center cohort study, we included all consecutive adult patients with SAB between 2013 and 2020 if an [18F]FDG-PET/CT scan was performed and antibiotic treatment was planned for ≥ 6 weeks prior to [18F]FDG-PET/CT. We aimed to identify patients for whom treatment was adjusted due to the results of [18F]FDG-PET/CT, and assessed concordance of [18F]FDG-PET/CT and clinical diagnosis for infected prosthetic material. RESULTS: Among 132 patients included, the original treatment plan was changed after [18F]FDG-PET/CT in 22 patients (16.7%), in the majority (n = 20) due to diagnosing or rejecting endovascular (graft) infection. Antibiotic treatment modifications were shortening in 2, iv-oral switch in 3, extension in 13, and addition of rifampicin in 4 patients. Ninety additional metastatic foci based on [18F]FDG-PET/CT results were found in 69/132 patients (52.3%). [18F]FDG-PET/CT suggested vascular graft infection in 7/14 patients who lacked clinical signs of infection, but showed no infection of prosthetic joints or osteosynthesis material in eight patients who lacked clinical signs of such an infection. CONCLUSION: [18F]FDG-PET/CT can help refine treatment for SAB in patients with clinically suspected endovascular infection or vascular grafts, even if 6 weeks treatment is already indicated, but can be safely omitted in other patients who are clinically stable.

Outcome in Patients after Autologous Femoral Vein Reconstruction for Primary Aortic Infection and Aortic Graft Infection: A Case Series.

BACKGROUND: For surgical treatment of primary aortic infection and aortic graft infection, in situ reconstruction with autologous vein(s) has the lowest rates of re-infection and of graft thrombosis. In this study, we have assessed the outcome after autologous femoral vein reconstruction in patients with aortic (graft) infection and we provide insights into the specific technical surgical considerations of the procedure. METHODS: In this retrospective single-center study, all patients who underwent autologous femoral vein reconstruction because of primary aortic infection or aortic graft infection between January 2012 and January 2020 were included. The primary outcome parameter was 30-day mortality. RESULTS: Twenty-nine patients with autologous femoral vein reconstruction for a primary aortic infection (n = 3) or aortic graft infection (n = 26) were included. An aorto-enteral fistula was detected in 13 patients (49%). Venous reconstruction of the aorta was performed with a single femoral vein in 17 patients (59%), and two femoral veins in 12 patients (41%). Thirty-day mortality was 17%. Relapse of infection occurred in two patients (7%) and no amputations were needed. One year after surgery, only three patients (10%) still needed stockings and after 2 years none of the patients used stockings. CONCLUSIONS: Central aortic reconstruction with femoral veins is a durable solution for primary aortic and aortoiliac graft infections with a low incidence of reinfections, amputations, and venous hypertension.

Still New Chronic Q Fever Cases Diagnosed 8 Years After a Large Q Fever Outbreak.

BACKGROUND: Chronic Q fever usually develops within 2 years after primary infection with Coxiella burnetii. We determined the interval between acute Q fever and diagnosis of chronic infection, assessed what factors contribute to a longer interval, and evaluated the long-term follow-up. METHODS: From 2007 to 2018, patients with chronic Q fever were included from 45 participating hospitals. The interval between acute and chronic infection was calculated in patients with a known day of first symptoms and/or serological confirmation of acute Q fever. Chronic Q fever-related complications and mortality were assessed by 2 investigators based on predefined criteria. RESULTS: In total, 313 (60.3%) proven, 81 (15.6%) probable, and 125 (24.1%) possible chronic Q fever patients were identified. The date of acute Q fever was known in 200 patients: in 45 (22.5%), the interval was longer than 2 years, with the longest observed interval being 9.2 years. Patients in whom serological follow-up was performed after acute Q fever were diagnosed less often after this 2-year interval (odds ratio, 0.26; 95% confidence interval, 0.12-0.54). Chronic Q fever-related complications occurred in 216 patients (41.6%). Chronic Q fever-related mortality occurred in 83 (26.5%) of proven and 3 (3.7%) of probable chronic Q fever patients. CONCLUSIONS: Chronic Q fever is still being diagnosed and mortality keeps occurring 8 years after a large outbreak. Intervals between acute Q fever and diagnosis of chronic infection can reach more than 9 years. We urge physicians to perform microbiological testing for chronic Q fever even many years after an outbreak or acute Q fever disease.

Comprehensive Health Assessment 3 Months After Recovery From Acute Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Long-term health sequelae of coronavirus disease 2019 (COVID-19) may be multiple but have thus far not been systematically studied. METHODS: All patients discharged after COVID-19 from the Radboud University Medical Center, Nijmegen, the Netherlands, were consecutively invited to a multidisciplinary outpatient facility. Also, nonadmitted patients with mild disease but with symptoms persisting >6 weeks could be referred by general practitioners. Patients underwent a standardized assessment including measurements of lung function, chest computed tomography (CT)/X-ray, 6-minute walking test, body composition, and questionnaires on mental, cognitive, health status, and quality of life (QoL). RESULTS: 124 patients (59 ±â€…14 years, 60% male) were included: 27 with mild, 51 with moderate, 26 with severe, and 20 with critical disease. Lung diffusion capacity was below the lower limit of normal in 42% of discharged patients. 99% of discharged patients had reduced ground-glass opacification on repeat CT imaging, and normal chest X-rays were found in 93% of patients with mild disease. Residual pulmonary parenchymal abnormalities were present in 91% of discharged patients and correlated with reduced lung diffusion capacity. Twenty-two percent had low exercise capacity, 19% low fat-free mass index, and problems in mental and/or cognitive function were found in 36% of patients. Health status was generally poor, particularly in the domains functional impairment (64%), fatigue (69%), and QoL (72%). CONCLUSIONS: This comprehensive health assessment revealed severe problems in several health domains in a substantial number of ex-COVID-19 patients. Longer follow-up studies are warranted to elucidate natural trajectories and to find predictors of complicated long-term trajectories of recovery.

Intravenous to Oral Switch in Complicated Staphylococcus aureus Bacteremia Without Endovascular Infection: A Retrospective Single-Center Cohort Study.

In this retrospective cohort study, selected patients with disseminated Staphylococcus aureus bacteremia, but without endovascular infection on echocardiography and 18F-FDG-PET/CT, were free of relapse after IV-oral switch. Mortality was low and similar to patients who received prolonged intravenous treatment. IV-oral switch was associated with a shorter length of hospital stay.

Chest CT in the Emergency Department for Diagnosis of COVID-19 Pneumonia: Dutch Experience.

Background Clinicians need to rapidly and reliably diagnose coronavirus disease 2019 (COVID-19) for proper risk stratification, isolation strategies, and treatment decisions. Purpose To assess the real-life performance of radiologist emergency department chest CT interpretation for diagnosing COVID-19 during the acute phase of the pandemic, using the COVID-19 Reporting and Data System (CO-RADS). Materials and Methods This retrospective multicenter study included consecutive patients who presented to emergency departments in six medical centers between March and April 2020 with moderate to severe upper respiratory symptoms suspicious for COVID-19. As part of clinical practice, chest CT scans were obtained for primary work-up and scored using the five-point CO-RADS scheme for suspicion of COVID-19. CT was compared with severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction (RT-PCR) assay and a clinical reference standard established by a multidisciplinary group of clinicians based on RT-PCR, COVID-19 contact history, oxygen therapy, timing of RT-PCR testing, and likely alternative diagnosis. Performance of CT was estimated using area under the receiver operating characteristic curve (AUC) analysis and diagnostic odds ratios against both reference standards. Subgroup analysis was performed on the basis of symptom duration grouped presentations of less than 48 hours, 48 hours through 7 days, and more than 7 days. Results A total of 1070 patients (median age, 66 years; interquartile range, 54-75 years; 626 men) were included, of whom 536 (50%) had a positive RT-PCR result and 137 (13%) of whom were considered to have a possible or probable COVID-19 diagnosis based on the clinical reference standard. Chest CT yielded an AUC of 0.87 (95% CI: 0.84, 0.89) compared with RT-PCR and 0.87 (95% CI: 0.85, 0.89) compared with the clinical reference standard. A CO-RADS score of 4 or greater yielded an odds ratio of 25.9 (95% CI: 18.7, 35.9) for a COVID-19 diagnosis with RT-PCR and an odds ratio of 30.6 (95% CI: 21.1, 44.4) with the clinical reference standard. For symptom duration of less than 48 hours, the AUC fell to 0.71 (95% CI: 0.62, 0.80; P < .001). Conclusion Chest CT analysis using the coronavirus disease 2019 (COVID-19) Reporting and Data System enables rapid and reliable diagnosis of COVID-19, particularly when symptom duration is greater than 48 hours. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Elicker in this issue.

Long-term serological follow-up after primary Coxiella burnetii infection in patients with vascular risk factors for chronic Q fever.

We evaluated the long-term serological follow-up of patients with vascular risk factors for chronic Q fever that were previously Coxiella burnetii seropositive. C. burnetii phase I IgG titers were reevaluated in patients that gave informed consent or retrospectively collected in patients already deceased or lost to follow-up. Of 107 patients, 25 (23.4%) became seronegative, 77 (72.0%) retained a profile of past resolved Q fever infection, and five (4.7%) developed chronic Q fever. We urge clinicians to stay vigilant for chronic Q fever beyond two years after primary infection and perform serological testing based on clinical presentation.

Optimal use of [18F]FDG-PET/CT in patients with fever or inflammation of unknown origin.

BACKGROUND: [18F]FDG-PET/CT is one of the most important diagnostic techniques in the work-up of patients with fever of unknown origin (FUO)/inflammation of unknown origin (IUO). Little is known on how to optimize the diagnostic value of [18F]FDG-PET/CT in patients with FUO/IUO. METHODS: Retrospective study in all patients who underwent [18F]FDG-PET/CT during the work-up of FUO/IUO in a tertiary expert center between 2005 and 2014. Data were extracted from medical records. RESULTS: One hundred and four patients were identified, of whom 68 had a final diagnosis (65.4%). Mainly infections (30.8%) and non-infectious inflammatory diseases (30.8%). [18F]FDG-PET/CT contributed to the final diagnosis in 47 of the 68 patients (69.1%). In 21 patients [18F]FDG-PET/CT did not help making a diagnosis. In ten of these patients [18F]FDG-PET/CT was performed while body temperature, CRP and ESR were normal or unknown. Sixteen of 104 patients underwent repeated [18F]FDG-PET/CT. The second scan contributed to the final diagnosis in five of these patients. In two of these patients, the first scan retrospectively was truly non-contributory. In both patients the first [18F]FDG-PET/CT was made while CRP/ESR was low and fever was not present or not measured. A third or fourth scan never contributed to the final diagnosis when the second one did not. CONCLUSIONS: [18F]FDG-PET/CT contributed to the final diagnosis in 45.2% of patients, but never contributed when both inflammatory parameters and body temperature were normal. Repeating [18F]FDG-PET/CT should only be done in patients with a non-contributory [18F]FDG-PET/CT when new symptoms or signs appear, or when the first scan was made in absence of fever or elevated inflammatory parameters.

Cost-effectiveness of Screening Program for Chronic Q Fever, the Netherlands.

In the aftermath of a large Q fever (QF) epidemic in the Netherlands during 2007-2010, new chronic QF (CQF) patients continue to be detected. We developed a health-economic decision model to evaluate the cost-effectiveness of a 1-time screening program for CQF 7 years after the epidemic. The model was parameterized with spatial data on QF notifications for the Netherlands, prevalence data from targeted screening studies, and clinical data from the national QF database. The cost-effectiveness of screening varied substantially among subpopulations and geographic areas. Screening that focused on cardiovascular risk patients in areas with high QF incidence during the epidemic ranged from cost-saving to €31,373 per quality-adjusted life year gained, depending on the method to estimate the prevalence of CQF. The cost per quality-adjusted life year of mass screening of all older adults was €70,000 in the most optimistic scenario.

A possible link between recurrent upper respiratory tract infections and lower cytokine production in patients with Q fever fatigue syndrome.

Besides fatigue, many Q fever fatigue syndrome (QFS) patients also complain of frequently recurring upper respiratory tract infections with severe symptoms. We investigated whether immunologic dysregulation contributes to these complaints. Cytokine and chemokine production was measured after stimulating monocytes of QFS patients and age- and sex-matched healthy controls with LPS and several viral ligands. The H3K4me3 mark of open chromatin was measured at the promoter regions of cytokines and chemokines that differed significantly from healthy controls. Monocytes of QFS patients produced significantly less TNF-α (p = 0.032), IL-1ß (0.004, 0.024, and 0.008), IL-6 (0.043), RANTES (0.033), IP-10 (0.049), MCP-1 (0.022), IL- 13 (0.029), and IL-10 (0.026) than healthy controls when stimulated with various ligands. H3K4me3 expression was significantly lower in QFS patients than in healthy controls on the promoter regions of IL-1ß (p = 0.004), MCP-1 (<0.001 and <0.001), IP-10 (<0.001), IL-10 (0.041), and IL-13 (<0.001, <0.001, and 0.001). QFS patients showed diminished cytokine responses to various stimuli compared to age- and sex-matched healthy controls, likely due to epigenetic remodeling and long-term memory as a result from the acute Q fever infection. This might explain the upper respiratory tract ailments in QFS.

Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome.

BACKGROUND: Q fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences. The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC). METHODS: The study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach. RESULTS: Inflammatory markers, including 4E-BP1 (P = 9.60-16 and 1.41-7) and MMP-1 (P = 7.09-9 and 3.51-9), are significantly more expressed in both QFS and CFS patients compared to HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism. When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobacteria (with emphasis on Ruminococcus and Bifidobacterium spp.). When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found. CONCLUSIONS: We show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.

Public health response to two imported, epidemiologically related cases of Lassa fever in the Netherlands (ex Sierra Leone), November 2019.

On 20 November 2019, Lassa fever was diagnosed in a physician repatriated from Sierra Leone to the Netherlands. A second physician with suspected Lassa fever, repatriated a few days later from the same healthcare facility, was confirmed infected with Lassa virus on 21 November. Comprehensive contact monitoring involving high- and low-risk contacts proved to be feasible and follow-up of the contacts did not reveal any case of secondary transmission in the Netherlands.

Presence of Genetic Variants Among Young Men With Severe COVID-19.

Importance: Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants: Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments. Exposure: Severe COVID-19. Main Outcome and Measures: Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. Results: The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance: In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

Coxiella burnetii Epitope-Specific T-Cell Responses in Patients with Chronic Q Fever.

Infection with Coxiella burnetii, the causative agent of Q fever, can result in life-threatening persistent infection. Reactogenicity hinders worldwide implementation of the only licensed human Q fever vaccine. We previously demonstrated long-lived immunoreactivity in individuals with past symptomatic and asymptomatic Coxiella infection (convalescents) to promiscuous HLA class II C. burnetii epitopes, providing the basis for a novel T-cell targeted subunit vaccine. In this study, we investigated in a cohort of 22 individuals treated for persistent infection (chronic Q fever) whether they recognize the same set of epitopes or distinct epitopes that could be candidates for a therapeutic vaccine or aid in the diagnosis of persistent infection. In cultured enzyme-linked immunosorbent spot (ELISpot) assays, individuals with chronic Q fever showed strong class II epitope-specific responses that were largely overlapping with the peptide repertoire identified previously for convalescents. Five additional peptides were recognized more frequently by chronic subjects, but there was no combination of epitopes uniquely recognized by or nonreactive in subjects with chronic Q fever. Consistent with more recent/prolonged exposure, we found, however, stronger ex vivo responses by direct ELISpot to both whole-cell C. burnetii and individual peptides in chronic patients than in convalescents. In conclusion, we have validated and expanded a previously published set of candidate epitopes for a novel T-cell targeted subunit Q fever vaccine in treated patients with chronic Q fever and demonstrated that they successfully mounted a T-cell response comparable to that of convalescents. Finally, we demonstrated that individuals treated for chronic Q fever mount a broader ex vivo response to class II epitopes than convalescents, which could be explored for diagnostic purposes.

Improving the Diagnostic Performance of 18F-Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography in Prosthetic Heart Valve Endocarditis.

BACKGROUND: 18F-Fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) was recently introduced as a new tool for the diagnosis of prosthetic heart valve endocarditis (PVE). Previous studies reporting a modest diagnostic accuracy may have been hampered by unstandardized image acquisition and assessment, and several confounders, as well. The aim of this study was to improve the diagnostic performance of FDG PET/CT in patients in whom PVE was suspected by identifying and excluding possible confounders, using both visual and standardized quantitative assessments. METHODS: In this multicenter study, 160 patients with a prosthetic heart valve (median age, 62 years [43-73]; 68% male; 82 mechanical valves; 62 biological; 9 transcatheter aortic valve replacements; 7 other) who underwent FDG PET/CT for suspicion of PVE, and 77 patients with a PV (median age, 73 years [65-77]; 71% male; 26 mechanical valves; 45 biological; 6 transcatheter aortic valve replacements) who underwent FDG PET/CT for other indications (negative control group), were retrospectively included. Their scans were reassessed by 2 independent observers blinded to all clinical data, both visually and quantitatively on available European Association of Nuclear Medicine Research Ltd-standardized reconstructions. Confounders were identified by use of a logistic regression model and subsequently excluded. RESULTS: Visual assessment of FDG PET/CT had a sensitivity/specificity/positive predictive value/negative predictive value for PVE of 74%/91%/89%/78%, respectively. Low inflammatory activity (C-reactive protein <40 mg/L) at the time of imaging and use of surgical adhesives during prosthetic heart valve implantation were significant confounders, whereas recent valve implantation was not. After the exclusion of patients with significant confounders, diagnostic performance values of the visual assessment increased to 91%/95%/95%/91%. As a semiquantitative measure of FDG uptake, a European Association of Nuclear Medicine Research Ltd-standardized uptake value ratio of ≥2.0 was a 100% sensitive and 91% specific predictor of PVE. CONCLUSIONS: Both visual and quantitative assessments of FDG PET/CT have a high diagnostic accuracy in patients in whom PVE is suspected. FDG PET/CT should be implemented early in the diagnostic workup to prevent the negative confounding effects of low inflammatory activity (eg, attributable to prolonged antibiotic therapy). Recent valve implantation was not a significant predictor of false-positive interpretations, but surgical adhesives used during implantation were.

A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and chronic fatigue syndrome.

BACKGROUND: Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. It has been hypothesized that low grade inflammation plays a role in its aetiology. In this study, we aimed to identify transcriptome profiles that could aid to better understand the pathophysiology of QFS. METHODS: RNA of monocytes was collected from QFS patients (n = 10), chronic fatigue syndrome patients (CFS, n = 10), Q fever seropositive controls (n = 10), and healthy controls (n = 10) who were age- (± 5 years) and sex-matched. Transcriptome analysis was performed using RNA sequencing. RESULTS: Mitochondrial-derived peptide (MDP)-coding genes MT-RNR2 (humanin) and MT-RNR1 (MOTS-c) were differentially expressed when comparing QFS (- 4.8 log2-fold-change P = 2.19 × 10-9 and - 4.9 log2-fold-change P = 4.69 × 10-8), CFS (- 5.2 log2-fold-change, P = 3.49 × 10-11 - 4.4 log2-fold-change, P = 2.71 × 10-9), and Q fever seropositive control (- 3.7 log2-fold-change P = 1.78 × 10-6 and - 3.2 log2-fold-change P = 1.12 × 10-5) groups with healthy controls, resulting in a decreased median production of humanin in QFS patients (371 pg/mL; Interquartile range, IQR, 325-384), CFS patients (364 pg/mL; IQR 316-387), and asymptomatic Q fever seropositive controls (354 pg/mL; 292-393). CONCLUSIONS: Expression of MDP-coding genes MT-RNR1 (MOTS-c) and MT-RNR2 (humanin) is decreased in CFS, QFS, and, to a lesser extent, in Q fever seropositive controls, resulting in a decreased production of humanin. These novel peptides might indeed be important in the pathophysiology of both QFS and CFS.

Chronic Q fever associated with systemic sclerosis.

BACKGROUND: After the Q fever outbreak in the Netherlands between 2007 and 2010, more than 300 patients with chronic Q fever have been identified. Some patients were also diagnosed with systemic sclerosis, a rare immune-mediated disease. We aimed to increase awareness of concomitant chronic Q fever infection and systemic sclerosis and to give insight into the course of systemic sclerosis during persistent Q fever infection. MATERIALS AND METHODS: Chronic Q fever patients were identified after the Dutch Q fever outbreak in 2007-2010. Systemic sclerosis was diagnosed by a scleroderma expert and patients fulfilled the 2013 Classification Criteria for Systemic Sclerosis. RESULTS: Four cases presented with chronic Q fever, persistent Coxiella burnetii infection, shortly preceded or followed by the diagnosis of limited cutaneous systemic sclerosis. The three male patients of 60 years or older developed a relatively mild systemic sclerosis, which did not require immunosuppressive therapy during adequate treatment of the chronic Q fever infection. The 58-year-old female patient used immunosuppressives for her newly diagnosed systemic sclerosis at the time she likely developed a chronic Q fever infection. CONCLUSIONS: In this case series, chronic Q fever preceding systemic sclerosis was associated with a mild course of systemic sclerosis without the necessity of immunosuppressive drugs, while chronic Q fever development due to immunocompromised state was associated with a more deteriorating course of systemic sclerosis.

Viable Coxiella burnetii Induces Differential Cytokine Responses in Chronic Q Fever Patients Compared to Heat-Killed Coxiella burnetii.

Cytokine responses of chronic Q fever patients to the intracellular bacterium Coxiella burnetii have mostly been studied using ex vivo stimulation of immune cells with heat-killed C. burnetii due to the extensive measures needed to work with viable biosafety level 3 agents. Whether research with heat-killed C. burnetii can be translated to immune responses to viable C. burnetii is imperative for the interpretation of previous and future studies with heat-killed C. burnetii Peripheral blood mononuclear cells (PBMCs) of chronic Q fever patients (n = 10) and healthy controls (n = 10) were stimulated with heat-killed or viable C. burnetii of 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. burnetii antibodies. When stimulated with viable C. burnetii, PBMCs of chronic Q fever patients and controls produced fewer proinflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha, and IL-1ß) after 24 h than after stimulation with heat-killed C. burnetii In the presence of Q fever seronegative serum, IL-10 production was higher after stimulation with viable rather than heat-killed C. burnetii; however, when incubating with anti-C. burnetii antibody 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 viable C. burnetii stimulatory conditions. Results from previous and future research with heat-killed C. burnetii should be interpreted with caution for innate cytokines, but heat-killed C. burnetii-induced adaptive cytokine production is representative of stimulation with viable bacteria.