Prolonged Disease Course of COVID-19 in a Patient with CTLA-4 Haploinsufficiency.

Patients with primary immunodeficiencies are especially vulnerable to developing severe coronavirus disease 2019 (COVID-19) after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an important regulator of immune responses, and patients who suffer from CTLA4 haploinsufficiency have hyperactivation of effector T cells and infiltration of various organs. Overexpression of CTLA4 has been associated with a more severe disease course in patients with COVID-19, but there have only been a few reports on the disease course of COVID-19 in patients with CTLA4 haploinsufficiency. We report on a 33-year-old female with a history of immune thrombocytopenia, autoimmune haemolytic anaemia, granulomatous-lymphocytic interstitial lung disease, and common variable immunodeficiency who developed COVID-19. She was admitted and discharged from the hospital several times in the months thereafter and remained symptomatic and had a positive SARS-CoV-2 PCR for up to 137 days after the first symptoms. No SARS-CoV-2 antibodies were identified in the patients' serum. The disease was finally controlled after repeated infusions of convalescent plasma and treatment of concurrent bacterial and fungal infections. Genetic analysis revealed a likely pathogenic variant in CTLA4, and CTLA4 expression on regulatory T-cells was low. This case illustrates that patients with primary immunodeficiencies who have a protracted disease course of COVID-19 could benefit from convalescent plasma therapy.

Serologic response to a third dose of an mRNA-based SARS-CoV-2 vaccine in lung transplant recipients.

Lung transplant recipients have an increased risk for severe coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A third dose of a SARS-CoV-2 vaccine has been recommended for all solid organ transplant recipients, but data from lung transplant recipients specifically are scarce. In this study, the serologic response to a third dose of an mRNA-based SARS-CoV-2 vaccine was measured in 78 lung transplant recipients. Sixty-two percent (n = 48) had a serological response to vaccination, which was significantly higher than after the second vaccine dose (27 patients (35%); p = 0.0013). A positive serologic response was associated with having had COVID-19 (p = 0.01), and higher serum IgG level and complement mannose binding lectin pathway activity prior to vaccination (p = 0.04 and p = 0.03, respectively). Serologic response was not associated with the dose of mycophenolate mofetil or prednisone or other immune status parameters. Eleven patients (14%) developed COVID-19 after the second or third vaccine dose, but this did not associate with serologic response after the second vaccine dose (9% in patients who developed COVID-19 versus 39% in patients who did not develop COVID-19 (p = 0.09)), or with serologic response above cut-off values associated with clinical protection in previous studies. In conclusion, the response to mRNA-based SARS-CoV-2 vaccines in lung transplant recipients improves significantly after a third vaccine dose. Factors associated with a positive serologic response are having had COVID-19 prior to vaccination, and serum IgG and complement mannose binding lectin pathway activity prior to vaccination. Serologic response did not associate with clinical protection against COVID-19 in this study.

Humoral Immune Status in Relation to Outcomes in Patients with Idiopathic Pulmonary Fibrosis.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease, in which inflammation is thought to only play a secondary role. Several factors associated with acute exacerbations of IPF (AE-IPF) have been identified, including infections. This study investigated whether humoral immunodeficiency or increased inflammatory markers at diagnosis were associated with AE-IPF and survival. METHODS: Four-hundred-and-nine patients diagnosed with IPF between 2011 and 2017 were retrospectively included. Immune status investigations at diagnosis included measurement of serum immunoglobulins (available in 38%), leukocyte and lymphocyte subsets in blood and bronchoalveolar lavage (BAL) fluid (available in 58%), as well as response to pneumococcal vaccination (available in 64%). RESULTS: Serum immunoglobulins or IgG subclass levels were below the lower limit of normal in 6%. The response to pneumococcal vaccination was severely impaired in 1%. Thirteen percent of patients developed an AE-IPF (4.7% per year). AE-IPF were associated with elevated lymphocytes in BAL fluid at diagnosis (p = 0.03). Higher serum IgA and IgG at diagnosis were associated with worse survival (p = 0.01; and p = 0.04), as were an increased BAL lymphocyte percentage (p = 0.005), and higher blood leukocytes and neutrophils (p = 0.01; and p = 0.0005). In a multivariate model, only BAL lymphocyte count retained statistical significance (p = 0.007). CONCLUSION: The prevalence of humoral immunodeficiencies was low in patients with IPF and not associated with AE-IPF or survival. Elevated lymphocytes in BAL were associated with the development of AE-IPF and worse survival. Higher serum immunoglobulins and immune cells in blood were also associated with worse survival. The local immune response in the lungs may be a target for future therapies.

ONCOR: design of the Dutch cardio-oncology registry.

BACKGROUND: The relative new subspecialty 'cardio-oncology' was established to meet the growing demand for an interdisciplinary approach to the management of cancer therapy-related cardiovascular adverse events. In recent years, specialised cardio-oncology services have been implemented worldwide, which all strive to improve the cardiovascular health of cancer patients. However, limited data are currently available on the outcomes and experiences of these specialised services, and optimal strategies for cardio-oncological care have not been established. AIM: The ONCOR registry has been created for prospective data collection and evaluation of cardio-oncological care in daily practice. METHODS: Dutch hospitals using a standardised cardio-oncology care pathway are included in this national, multicentre, observational cohort study. All patients visiting these cardio-oncology services are eligible for study inclusion. Data collection at baseline consists of the (planned) cancer treatment and the cardiovascular risk profile, which are used to estimate the cardiotoxic risk. Information regarding invasive and noninvasive tests is collected during the time patients receive cardio-oncological care. Outcome data consist of the incidence of cardiovascular complications and major adverse cardiac events, and the impact of these events on the oncological treatment. DISCUSSION: Outcomes of the ONCOR registry may aid in gaining more insight into the incidence of cancer therapy-related cardiovascular complications. The registry facilitates research on mechanisms of cardiovascular complications and on diagnostic, prognostic and therapeutic strategies. In addition, it provides a platform for future (interventional) studies. Centres with cardio-oncology services that are interested in contributing to the ONCOR registry are hereby invited to participate.

Pneumococcal vaccination in lung transplant patients.

Introduction: This review analyzes the efficacy of pneumococcal vaccinations in lung transplant patients before and after transplantation.Areas covered: This review addresses the risk for respiratory infections, in particular pneumococcal infections, in lung transplantation patients in the context of immunodeficiency and immunosuppressive medication. Vaccination is recommended to counteract the increased risk of pneumococcal infection, and the relevant guidelines are discussed in this review. The design of specific vaccination schedules is required because of the impaired antibody response in specific patient categories.Expert opinion: Lung transplantation candidates should be vaccinated with pneumococcal vaccines prior to transplantation. Currently, the 23-valent pneumococcal polysaccharide vaccine offers the broadest coverage, but the antibody response should be monitored. New generation pneumococcal conjugate vaccines with equally broad serotype coverage could be used in the future. During the post-transplantation period, the immune status of the patients should be monitored regularly, and vaccination should be repeated when indicated.

Lung Transplantation Has a Strong Impact on the Distribution and Phenotype of Monocyte Subsets.

BACKGROUND: Lung transplantation (LTx) is a last treatment option for patients with an end-stage pulmonary disease. Chronic lung allograft dysfunction, which generally manifests as bronchiolitis obliterans syndrome (BOS), is a major long-term survival limitation. During injury, inflammation and BOS monocytes are recruited. We determined whether changes in count, subset distribution, and functionality by surface marker expression coincided with BOS development. METHODS: Fresh whole-blood samples were analyzed from 44 LTx patients, including 17 patients diagnosed with BOS, and compared with 10 age-matched healthy controls and 9 sarcoidosis patients as positive controls. Monocytes were quantified and analyzed using flow cytometry. Based on surface marker expression, classical, intermediate, and nonclassical subsets were determined, and functional phenotypes were investigated. RESULTS: The absolute count of monocytes was decreased in LTx and slightly increased in BOS patients. The relative count shifted toward classical monocytes at the expense of nonclassical monocytes in LTx and BOS. Surface marker expression was highest on intermediate monocytes. The expression of both CD36 and CD163 was significantly increased in the LTx and BOS cohort. The difference between the BOS cohort and the LTx cohort was only subtle, with a significant decrease in HLA-DR expression on nonclassical monocytes in BOS. CONCLUSIONS: Monocyte subsets and surface marker expression changed significantly in transplantation patients, while BOS-specific changes were understated. More research is needed to determine whether and how monocytes influence the disease process and how current immunosuppressants affect their normal function in vivo.

Pneumococcal conjugate vaccination response in patients after community-acquired pneumonia, differences in patients with S. pneumoniae versus other pathogens.

OBJECTIVES: The goal of this study is to investigate the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in former pneumococcal CAP patients. We hypothesize that an impaired or suboptimal humoral immune response against (specific) pneumococcal serotypes might explain the vulnerability for pneumococcal disease. METHODS: Hospitalised adult CAP patients who participated in two trials (2004-2006 (n=201) and, 2007-2009 (n=304)) were screened. Patients eligible for inclusion had CAP caused by either S. pneumoniae (pneuCAP) or due to another well-defined pathogen (otherCAP). Serotype-specific pneumococcal antibody concentrations (total IgG and IgG2/IgG1) before and 3-4weeks after PCV13 administration were measured (Luminex) and compared between pneuCAP and otherCAP patients. RESULTS: We vaccinated 60 patients:i.e. 34 pneuCAP and 26 otherCAP patients. In the pneuCAP group, 74% of patients were categorized as good responders (≥9/13 serotypes with concentration≥1300ng/ml), versus 77% in the otherCAP group. Significantly fewer full responders (i.e. 13/13 serotypes with a concentration≥1300ng/mL) were identified in the pneuCAP group (15% vs 42% respectively, p=0.02). For serotype 1, total IgG and IgG2/IgG1 subset post-vaccination concentrations were significantly lower among pneuCAP patients. Our additional case-series showed that of 16 pneuCAP patients who were infected by a serotype included in PCV13 three patients did not respond against the serotype originally responsible for their CAP episode, including one former bacteraemic pneumococcal CAP patient who also failed to show a response against the serotype responsible for CAP during infection. Thirteen patients did respond to the previously infecting serotype following PCV13 including three patients who had bacteraemic pneumococcal pneumonia and did not show a response during infection against the serotype responsible for CAP. CONCLUSIONS: Our results confirm the immunogenic properties of PCV13 in former pneumococcal CAP patients including patients previously regarded as potential hyporesponders. A slightly diminished overall humoral response to polysaccharides characterizes the former pneumococcal CAP patients. ClinicalTrials.gov Identifier: NCT02141009.

TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis.

Pulmonary fibrosis is a frequent manifestation of telomere syndromes. Telomere gene mutations are found in up to 25% and 3% of patients with familial disease and sporadic disease, respectively. The telomere gene TINF2 encodes an eponymous protein that is part of the shelterin complex, a complex involved in telomere protection and maintenance. A TINF2 gene mutation was recently reported in a family with pulmonary fibrosis. We identified a heterozygous Ser245Tyr mutation in the TINF2 gene of previously healthy female patient that presented with progressive cough due to pulmonary fibrosis as well as panhypogammaglobulinemia at age 52. Retrospective multidisciplinary evaluation classified her as a case of possible idiopathic pulmonary fibrosis. Telomere length-measurement indicated normal telomere length in the peripheral blood compartment. This is the first report of a TINF2 mutation in a patient with sporadic pulmonary fibrosis, which represents another association between TINF2 mutations and this disease. Furthermore, this case underlines the importance of telomere dysfunction and not telomere length alone in telomere syndromes and draws attention to hypogammaglobulinemia as a manifestation of telomere syndromes.

A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation.

Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, single-nucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p = 0.047) and fibroblast growth factor ß (p = 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation.

Anti-ETAR and anti-AT1R autoantibodies are elevated in patients with endstage cystic fibrosis.

Autoantibodies against endothelin-1 type A receptor (ETAR) are present in systemic sclerosis complicated by lung fibrosis and pulmonary hypertension. As increased serum levels and local overproduction of endothelin-1 in the airways are reported in cystic fibrosis (CF) patients, we reasoned that anti-ETAR antibodies could be prevalent in endstage CF patients prior to lung transplantation (LTx). Also, ETAR autoantibodies are frequently associated with autoantibodies against the angiotensin II type 1 receptor (AT1R). We analyzed the presence of anti-ETAR and anti-AT1R autoantibodies in 43 LTx patients (chronic obstructive pulmonary disease (COPD), n=20; CF, n=13; interstitial lung disease (ILD), n=1). We observed overall higher anti-ETAR and anti-AT1R autoantibody titers in sera taken prior to LTx in the CF patient group as compared to COPD. No difference was found in autoantibody levels between patients with CF versus ILD. In sera taken post-LTx we found the same difference in anti-ETAR and anti-AT1R autoantibody titers between patients with CF versus COPD. No difference was found in antibody titers between sera taken prior to or 6 months after LTx. There was no association between autoantibody levels and other relevant demographic parameters, and we found no association between autoantibody titers and the development of the bronchiolitis obliterans syndrome. Both autoantibody titers were strongly correlated. We hypothesize that due to prolonged exposure to bacterial infection, increased levels of AT1R and ETAR result in a deregulated immune response causing autoantibody formation. Further research is expedient to elucidate the occurrence of autoantibodies against ETAR and AT1R and their role in disease progression.

Damage control radiology in the severely injured patient: what the anaesthetist needs to know.

In the treatment of severely injured patients, the term 'damage control radiology' has been used to parallel the modern concept of damage control surgery and the allied development of continuous damage control resuscitation from patient retrieval, through all transfers, to appropriate primary treatment. The aims of damage control radiology are (i) rapid identification of life-threatening injuries including bleeding sites, (ii) identification or exclusion of head or spinal injury, and (iii) prompt and accurate triage of patients to the operating theatre for thoracic, abdominal, or both surgeries or the angiography suite for endovascular haemorrhage control. If we are to achieve these aims, patients must have immediate access to modern multidetector computed tomography (MDCT) which is without doubt the most potent weapon in the diagnostic armamentarium. The most severely injured patients are those who have the most to benefit from early diagnosis and life-saving therapies. The traditional teaching that these patients should go immediately to surgery is challenged by technological developments in MDCT and recent clinical evidence.

Response to pneumococcal vaccination in mannose-binding lectin-deficient adults with recurrent respiratory tract infections.

Mannose-binding lectin (MBL)-deficiency is associated with an increased susceptibility to pneumococcal infections and other forms of disease. Pneumococcal vaccination is recommended in MBL-deficient patients with recurrent respiratory tract infections (RRTI). The response to pneumococcal vaccination in MBL-deficient individuals has not yet been studied in detail. An impaired response to pneumococcal polysaccharides in MBL-deficient patients might explain the association between MBL deficiency and pneumococcal infections. This study investigates the antibody response to pneumococcal vaccination in MBL-deficient adult patients with RRTI. Furthermore, we investigated whether there was a difference in clinical presentation between MBL-deficient and -sufficient patients with RRTI. Eighteen MBL-deficient and 63 MBL-sufficient adult patients with RRTI were all vaccinated with the 23-valent pneumococcal polysaccharide vaccine and antibodies to 14 pneumococcal serotypes were measured on a Luminex platform. There were no differences observed in the response to pneumococcal vaccination between MBL-sufficient and -deficient patients. Forty-three MBL-sufficient patients could be classified as responders to pneumococcal vaccination and 20 as low responders, compared to 15 responders and three low responders in the MBL-deficient patients. We found no clear difference in clinical, radiological, lung function and medication parameters between MBL-sufficient and -deficient patients. In conclusion, our study suggests that MBL-deficient adults with RRTI have a response to a pneumococcal capsular polysaccharide vaccine comparable with MBL-sufficient patients. Moreover, we did not find a clear clinical role of MBL deficiency in adults with RRTI. As MBL deficiency is associated with an increased susceptibility to pneumococcal infections, pneumococcal vaccination might be protective in MBL-deficient patients with RRTI.

YKL-40 and matrix metalloproteinases as potential biomarkers of inflammation and fibrosis in the development of bronchiolitis obliterans syndrome.

BACKGROUND AND OBJECTIVE: The development of bronchiolitis obliterans syndrome (BOS) after lung transplantation is characterized by inflammation, remodeling and fibrosis. Both YKL-40 and matrix metalloproteinase (MMP)-9 have shown to be involved in these processes. We measured serial YKL-40 and MMP-9 serum levels in lung transplant recipients and assessed their usefulness as biomarker for BOS. Furthermore, we investigate the relationship between these two potential biomarkers of BOS and MMP-7. DESIGN: Ten patients with BOS (BOS(pos)) and 10 matched patients without BOS (BOS(neg)) were included. Serial serum samples were collected after lung transplantation and prior to BOS. YKL-40, MMP-9 and MMP-7 serum levels were determined by ELISA. RESULTS: The median concentrations of YKL-40 did not differ between BOS(pos) and BOS(neg) patients (p > 0.05). The median concentration of MMP-9 in BOS(pos) patients was significantly higher than in BOS(neg) patients (p < 0.0001). For MMP-9 as possible risk factor for BOS, a cut off value of 145 ng/ml has a sensitivity of 90% and a negative predictive value of 83%. Longitudinal analysis of YKL-40 and MMP-9 serum levels from the early post-transplant period onwards did not reveal a significant trend in time in both serum levels preceding BOS. In BOS(neg) patients MMP-9 showed an inverse relationship with MMP-7, that was absent in BOS(pos) patients. CONCLUSIONS: From the moment of transplantation onwards, patients who eventually developed BOS had significantly increased MMP-9 serum levels in comparison with patients who did not develop BOS. Therefore, increased MMP-9 serum levels might be useful as risk factor for BOS.

ImaGiNe Seldinger: first simulator for Seldinger technique and angiography training.

In vascular interventional radiology, procedures generally start with the Seldinger technique to access the vasculature, using a needle through which a guidewire is inserted, followed by navigation of catheters within the vessels. Visual and tactile skills are learnt in a patient apprenticeship which is expensive and risky for patients. We propose a training alternative through a new virtual simulator supporting the Seldinger technique: ImaGiNe (imaging guided interventional needle) Seldinger. It is composed of two workstations: (1) a simulated pulse is palpated, in an immersive environment, to guide needle puncture and (2) two haptic devices provide a novel interface where a needle can direct a guidewire and catheter within the vessel lumen, using virtual fluoroscopy. Different complexities are provided by 28 real patient datasets. The feel of the simulation is enhanced by replicating, with the haptics, real force and flexibility measurements. A preliminary validation study has demonstrated training effectiveness for skills transfer.

Compression of the dorsalis pedis artery: a novel cause of blue toe syndrome.

Blue toe syndrome (BTS) is an important vascular condition characterized by painful blue discoloration of one or more digits. It is frequently due to emboli and is important because of the risk of progressive ischemia and tissue loss. A 53-year-old male presented with recurrent episodes of painful blue discoloration and blistering of the skin of the right hallux. On examination, the patient was found to have a cool, blue-purple great toe; all peripheral pulses were present. The patient was investigated for coagulopathy and potential sources of emboli, but the only abnormality was significant stenosis of the dorsalis pedis artery due to extrinsic compression by the extensor hallucis brevis tendon. In the absence of any other embolic source or abnormality, we believe that this case presents a novel and potentially remediable cause of BTS and indicates the need for a careful search for an underlying lesion when common causes of BTS have been excluded.

Radiology curriculum for undergraduate medical studies--a consensus survey.

AIM: To establish an expert consensus of what, when, and how the teaching of radiology should be incorporated into the core undergraduate medical curriculum. METHODS AND MATERIALS: This Delphi survey consisted of four iterative rounds, with feedback given at the start of each successive round in the form of the results of the previous round. The participants consisted of both radiologists and non-radiologists with significant interest and involvement in radiology and undergraduate/Foundation training. The study addressed the questions of how, where, when, and by whom radiology should be taught. RESULTS: The number of responses in rounds 1-4 was 20, 23, 41, and 25 (25, 22, 31, and 61% response rate, respectively). There was good consensus amongst the responders on the following: radiology teaching must be delivered in conjunction with anatomy and clinical case-based teaching, if possible in the department of radiology on picture archiving and communication system (PACS) workstations, and the teaching should be delivered by a competent and credentialled individual. Case-based assessment was the most agreed method of assessment. The majority of the responders concurred that the curriculum should include general indications for commonly requested radiological investigations, consent and safety issues around radiological tests, and their basic interpretation. CONCLUSION: The consensus points reached by the present study not only serve as directive principles for developing a more comprehensive radiology curriculum, but also places emphasis on a broader range of knowledge required to promote the best use of a department of radiology by junior doctors in an attempt to improve patient experiences and care.

Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.

AIMS: The aims of the study are to investigate the prevalence of diabetes in patients with cystic fibrosis compared with patients without cystic fibrosis, and its impact on the outcome after lung transplantation. METHODS: Data were reviewed from 77 lung transplantation recipients in our centre between 2001 and 2010; 43 patients had cystic fibrosis and 34 patients had other lung diseases (no cystic fibrosis). To define diabetes, we used the American Diabetes Association definition. RESULTS: Before lung transplantation, diabetes was diagnosed in 63% of patients with cystic fibrosis and 6% of patients without cystic fibrosis (P<0.001). In both groups, approximately 60% of the patients at risk developed new-onset diabetes after transplantation. The mortality in patients with cystic fibrosis was higher in patients with diabetes diagnosed before lung transplantation compared with those without (44 vs. 6%, P=0.04). Diabetes remained an independent factor in multivariate analyses. CONCLUSIONS: Diabetes diagnosed before lung transplantation has a negative effect on survival after lung transplantation in patients with cystic fibrosis. Pre-existing diabetes is common in patients with cystic fibrosis, in contrast to patients without cystic fibrosis. Development of new-onset diabetes after transplantation is similar in both groups.