IMPORTANCESevere 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 PARTICIPANTSCase 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 MEASURESResults 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. RESULTSThe 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 RELEVANCEIn 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.

Background Long-term health sequelae of 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 centre, Nijmegen, The Netherlands, were consecutively invited to a multidisciplinary outpatient facility. Also, non-admitted patients with mild disease but with symptoms persisting &gt;6 weeks could be referred by general practitioners. Patients underwent a standardized assessment including measurements of lung function, chest CT/X-ray, 6-minute walking test, body composition, and questionnaires on mental, cognitive, health status and quality of life (QoL). Results 124 patients (age 59±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 lower limit of normal in 42% of discharged patients. Ninety-nine percent 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 diseases. 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 the 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.

We conducted a prospective study to update our knowledge of fever of unknown origin (FUO) and to explore the utility of a structured diagnostic protocol. From December 2003 to July 2005, 73 patients with FUO were recruited from 1 university hospital (n = 40) and 5 community hospitals (n = 33) in the same region in The Netherlands. FUO was defined as a febrile illness of >3 weeks' duration, a temperature of >38.3 degrees C on several occasions, without a diagnosis after standardized history-taking, physical examination, and certain obligatory investigations. Immunocompromised patients were excluded. A structured diagnostic protocol was used. Patients from the university hospital were characterized by more secondary referrals and a higher percentage of periodic fever than those referred to community hospitals. Infection was the cause in 16%, a neoplasm in 7%, noninfectious inflammatory diseases in 22%, miscellaneous causes in 4%, and in 51%, the cause of fever was not found (no differences between university and community hospitals). There were no differences regarding the number and type of investigations between university and community hospitals. Significant predictors for reaching a diagnosis included continuous fever; fever present for <180 days; elevated erythrocyte sedimentation rate, C-reactive protein, or lactate dehydrogenase; leukopenia; thrombocytosis; abnormal chest computed tomography (CT); and abnormal F-fluorodeoxyglucose positron emission tomography (FDG-PET). For future FUO studies, inclusion of outpatients and the use of a set of obligated investigations instead of a time-related criterion are recommended. Except for tests from the obligatory part of our protocol and cryoglobulins in an early stage, followed by FDG-PET, and in a later stage by abdominal and chest CT, temporal artery biopsy in patients aged 55 years or older, and possibly bone marrow biopsy, other tests should not be used as screening investigations.

van der Geest-Blankert Nannet , Wertheim Heiman . Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands, March 2020. Euro Surveill. 2020;25(16):pii=2000508. https://doi.

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Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time-consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin.

BackgroundInvasive fungal infections are very severe infections associated with high mortality rates, despite the availability of new classes of antifungal agents. Based on pathophysiological mechanisms and limited pre-clinical and clinical data, adjunctive immune-stimulatory therapy with interferon-gamma (IFN-γ) may represent a promising candidate to improve outcome of invasive fungal infections by enhancing host defence mechanisms.MethodsIn this open-label, prospective case series, we describe eight patients with invasive Candida and/or Aspergillus infections who were treated with recombinant IFN-γ (rIFN-γ, 100 μg s.c., thrice a week) for 2 weeks in addition to standard antifungal therapy.ResultsRecombinant IFN-γ treatment in patients with invasive Candida and/or Aspergillus infections partially restored immune function, as characterized by an increased HLA-DR expression in those patients with a baseline expression below 50%, and an enhanced capacity of leukocytes from treated patients to produce proinflammatory cytokines involved in antifungal defence.ConclusionsThe present study provides evidence that adjunctive immunotherapy with IFN-γ can restore immune function in fungal sepsis patients, warranting future clinical studies to assess its potential clinical benefit.Trial registrationClinicalTrials.gov - NCT01270490

Fever of unknown origin (FUO) and suspected focal infection or inflammation are challenging medical problems. The aim of this study was to assess the value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) in patients with FUO and patients with suspected focal infection or inflammation. All FDG PET scans ordered because of FUO or suspected focal infection or inflammation in the last 4 years were reviewed. These results were compared with the final diagnosis. Thirty-five FDG PET scans were performed in 35 patients with FUO. A final diagnosis was established in 19 patients (54%). Of the total number of scans, 37% were clinically helpful. The positive predictive value of FDG PET in these patients was 87% and the negative predictive value was 95%. Fifty-five FDG PET scans were performed in 48 patients with suspected focal infection or inflammation. A final diagnosis was established in 38 patients (82%). Of the total number of scans, 65% were clinically helpful. The positive predictive value of FDG PET in these 55 episodes of suspected infection or inflammation was 95% and the negative predictive value was 100%. It is concluded that FDG PET appears to be a valuable imaging technique in the evaluation of FUO and suspected focal infection or inflammation. Furthermore, FDG PET could become a useful tool for evaluating the effect of treatment of infectious and inflammatory processes that cannot reliably be visualised by conventional techniques. However, to assess the additional diagnostic value of this technique, prospective studies of FDG PET as part of a structured diagnostic protocol are warranted.