Epsom and St Helier University Hospitals NHS Trust

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Despite growing interest from both patients and healthcare providers, there is little clinical guidance on how mobile apps should be utilized to add value to patient care. We categorize apps according to their functionality (e.g. preventative behavior change, digital self-management of a specific condition, diagnostic) and discuss evidence for effectiveness from published systematic reviews and meta-analyses and the relevance to patient care. We discuss the limitations of the current literature describing clinical outcomes from mHealth apps, what FDA clearance means now (510(k)/de novo FDA clearance) and in the future. We discuss data security and privacy as a major concern for patients when using mHealth apps. Patients are often not involved in the development of mobile health guidelines, and professionals' views regarding high-quality health apps may not reflect patients' views. We discuss efforts to develop guidelines for the development of safe and effective mHealth apps in the US and elsewhere and the role of independent app reviews sites in identifying mHealth apps for patient care. There are only a small number of clinical scenarios where published evidence suggests that mHealth apps may improve patient outcomes.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

BACKGROUND: There is increasing evidence that lack of facilities, equipment, and expertise in district hospitals across many low- and middle-income countries constitutes a major barrier to accessing surgical care. However, what is less clear, is the extent to which people perceive barriers when trying to access surgical care. METHODS: PubMed and EMBASE were searched using key words ("access" and "surgery," "barrier" and "surgery," "barrier" and "access"), MeSH headings ("health services availability," "developing countries," "rural population"), and the subject heading "health care access." Articles were included if they were qualitative and applied to illnesses where the treatment is primarily surgical. RESULTS: Key barriers included difficulty accessing surgical services due to distance, poor roads, and lack of suitable transport; lack of local resources and expertise; direct and indirect costs related to surgical care; and fear of undergoing surgery and anesthesia. CONCLUSIONS: The significance of cultural, financial, and structural barriers pertinent to surgery and their role in wider health care issues are discussed. Immediate action to improve financial and geographic accessibility along with investment in district hospitals is likely to make a significant impact on overcoming access and barrier issues. Further research is needed to identify issues that need to be addressed to close the gap between the care needed and that provided.

BACKGROUND: Obesity is associated with an increased risk of adverse pregnancy outcomes. Lifestyle-intervention studies have not shown improved outcomes. Metformin improves insulin sensitivity and in pregnant patients with gestational diabetes it leads to less weight gain than occurs in those who do not take metformin. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned pregnant women without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of more than 35 to receive metformin, at a dose of 3.0 g per day, or placebo (225 women in each group) from 12 to 18 weeks of gestation until delivery. The BMI was calculated at the time of study entry (12 to 18 weeks of gestation). The primary outcome was a reduction in the median neonatal birth-weight z score by 0.3 SD (equivalent to a 50% reduction, from 20% to 10%, in the incidence of large-for-gestational-age neonates). Secondary outcomes included maternal gestational weight gain and the incidence of gestational diabetes and of preeclampsia, as well as the incidence of adverse neonatal outcomes. Randomization was performed with the use of computer-generated random numbers. The analysis was performed according to the intention-to-treat principle. RESULTS: A total of 50 women withdrew consent during the trial, which left 202 women in the metformin group and 198 in the placebo group. There was no significant between-group difference in the median neonatal birth-weight z score (0.05 in the metformin group [interquartile range, -0.71 to 0.92] and 0.17 in the placebo group [interquartile range, -0.62 to 0.89], P=0.66). The median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P<0.001), as was the incidence of preeclampsia (3.0% vs. 11.3%; odds ratio, 0.24; 95% confidence interval, 0.10 to 0.61; P=0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes. CONCLUSIONS: Among women without diabetes who had a BMI of more than 35, the antenatal administration of metformin reduced maternal weight gain but not neonatal birth weight. (Funded by the Fetal Medicine Foundation; ClinicalTrials.gov number, NCT01273584; EudraCT number, 2008-005892-83.).

By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy. By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy. The novel coronavirus 2019 (or coronavirus disease 2019 [COVID-19]) infection, which originated in the city of Wuhan, in Hubei province, China, in December 2019 shares close similarities in its genomic structure with the severe acute respiratory syndrome coronavirus (SARS-CoV) that caused the SARS global pandemic in 2003 and the Middle East respiratory syndrome (MERS) epidemic in 2012 (MERS-CoV), and even closer similarities to bat SARS-like betacoronavirus (bat-SL-CoVZC45 betacoronavirus and bat-SL-CoVZXC21).1Wu F. Zhao S. Yu B. et al.A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579: 265-269Crossref PubMed Scopus (7720) Google Scholar,2Lu R. Zhao X. Li J. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (8314) Google Scholar Between December 31, 2019, and March 27, 2020, 532,692 COVID-19 cases and 24,077 deaths worldwide have been identified as being caused by a newly identified enveloped RNA virus named SARS-CoV-2.3Johns Hopkins University of Medicine—Coronavirus Resource CenterCoronavirus COVID-19 global cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. March 27, 2020.https://coronavirus.jhu.edu/map.htmlDate accessed: March 27, 2020Google Scholar In the United Kingdom, between January 31, 2020, and March 20, 2020, 3983 cases were identified with 177 (4% of tested patients) deaths.4UK Government. Number of coronavirus (COVID-19) cases and risk in the UK 2020. Available at: https://www.gov.uk/government/publications/covid-19-track-coronavirus-cases. Accessed April 14, 2020.Google Scholar Due to widespread nature, COVID-19 was declared as a pandemic by World Health Organization on March 11, 2020, and 176 countries are affected as of March 27, 2020.3Johns Hopkins University of Medicine—Coronavirus Resource CenterCoronavirus COVID-19 global cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. March 27, 2020.https://coronavirus.jhu.edu/map.htmlDate accessed: March 27, 2020Google Scholar The SARS pandemic was reported to affect both pediatric and adult kidney transplant recipients in Hong Kong, with less severe disease in the pediatric population.5Chiu M.C. Suggested management of immunocompromised kidney patients suffering from SARS.Pediatr Nephrol. 2003; 18: 1204-1205Crossref PubMed Scopus (16) Google Scholar One liver transplant patient died with the SARS-CoV infection in 2003.6Kumar D. Tellier R. Draker R. et al.Severe Acute Respiratory Syndrome (SARS) in a liver transplant recipient and guidelines for donor SARS screening.Am J Transplant. 2003; 3: 977-981Crossref PubMed Scopus (122) Google Scholar The MERS coronavirus infection had a variable impact on kidney transplant recipients. In 1 report of 2 kidney transplant patients, one died of progressive respiratory disease and acute kidney injury while the other survived.7AlGhamdi M. Mushtaq F. Awn N. Shalhoub S. MERS CoV infection in two renal transplant recipients: case report.Am J Transplant. 2015; 15: 1101-1104Crossref PubMed Scopus (84) Google Scholar To the best of our knowledge, only 1 patient with kidney transplantation has been reported in the literature who suffered from COVID-19 infection in Wuhan, China, and improved 13 days after hospital admission.8Zhu L, Xu X, Ma K, et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression [e-pub ahead of print]. Am J Transplant. https://doi.org/10.1111/ajt.15869. Accessed March 27, 2020.Google Scholar The 63-year-old kidney transplant recipient presented with fever, chest pain, cough, low lymphocyte, high serum C-reactive protein (CRP), and abnormal chest computed tomography scan on February 2, 2020. Tacrolimus and mycophenolate administration was discontinued. He was treated with oxygen, methyl prednisolone, umifenovir, moxifloxacin, biapenem, i.v. Ig, inhaled interferon-α, and pantoprazole. He made a successful recovery and was discharged on day 13. We report here the first 7 cases of COVID-19 in kidney transplant recipients in south London hospitals. We have seen 7 cases of kidney transplant recipients with proven COVID-19 infection in south London in March 2020. These patients are described herein, and their main characteristics are summarized in Tables 1 and 2.Table 1Clinical characteristics and outcome of 7 kidney transplant patients with COVID-19 infectionPatientAge/sexTx dateComorbiditiesRespiratory and renal involvementBaseline creatinine (eGFR ml/min per 1.73 m2)Baseline immunosuppression and treatmentACEI or ARBOutcome148/M1989HTNo350 (15–18)Aza/PredNo changeNoStayed at home, full recovery267/F03/2019T2D/HTYes, ARDS + AKI (CVVH)150 (45)Tac/MMF/PredMMF stoppedYes ACEIDied354/F12/2019PTDM/CMVYes, ARDS + AKI (CVVH)132 (48)Tac/MMF/PredTac and MMF stoppedNoAlive, ventilated465/M08/2018Wheelchair/HTNNo ARDS180 (23)Tac/MMF/PredMMF stoppedNoAlive, in medical ward569/F02/2020DM/HTNo ARDSAKI165 (31)Tac/MMF/PredMMF stoppedNoBrief ITU stay, not intubated; stepped down to ward654/M05/2013Hemolytic anemia/HTNo ARDS187 (47)Tac/MMFMMF stoppedNoStayed at home, still has cough and some flu-like symptoms745/M09/2017 (2nd Tx)HTNo ARDSAKI (HD)450 (12–16)Tac/Aza/AzaAza stoppedTac dose reducedNoAdmitted, managed in the ward; severe AKIACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ARDS, acute respiratory distress syndrome; Aza, azathioprine; CMV, cytomegalovirus; COVID-19, coronavirus disease 2019; CVVH, continuous venovenous hemofiltration; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; F, female; ITU, intensive therapy unit; M, male; MMF, mycophenolate mofetil; Pred, prednisolone; PTDM, post-transplant diabetes mellitus; T2D, type 2 diabetes; Tac, tacrolimus; Tx, treatment(s). Open table in a new tab Table 2Blood parameters during COVID-19 infectionPatientWhite cell count (× 109/l) (3.5–10)Lymphocyte count (× 109/l) (1–3.5)Serum CRP (mg/l) (<5)Serum ferritin (μg/l) (25–200)Serum D dimer (μg/l) (0–500)Serum LDH (U/l) (100–240)Serum troponin I (ng/l) (<34)1———————26 (D1)0.8 (D1)83 (D1)2032 (D3), >6000 (D10)1226 (D10)78 (D1), 395 (D10)311.25 (D1)0.5 (D1)329 (D1)————4———————59.4 (D1)0.3 (D1)————30 (D4)aSerum troponin T (0–14 ng/l).610 (D1)4.0 (D1)—————75.5 (D1)0.3 (D1)198 (D1)6919 (D3)1907 (D3)502 (D3)35 (D7)COVID-19, coronavirus disease 2019; CRP, C-reactive protein; D, day after admission; D1, day of admission; LDH, lactate dehydrogenase.a Serum troponin T (0–14 ng/l). Open table in a new tab ACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ARDS, acute respiratory distress syndrome; Aza, azathioprine; CMV, cytomegalovirus; COVID-19, coronavirus disease 2019; CVVH, continuous venovenous hemofiltration; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; F, female; ITU, intensive therapy unit; M, male; MMF, mycophenolate mofetil; Pred, prednisolone; PTDM, post-transplant diabetes mellitus; T2D, type 2 diabetes; Tac, tacrolimus; Tx, treatment(s). COVID-19, coronavirus disease 2019; CRP, C-reactive protein; D, day after admission; D1, day of admission; LDH, lactate dehydrogenase. A 48-year-old man with deceased donor kidney transplant in 1989 with failing transplant kidney (estimated glomerular filtration rate [eGFR]: 15–18 ml/min per 1.73 m2) called the National Health Service (111) helpline in the first week of March 2020 with cough, fever, and mild shortness of breath. He tested positive for COVID-19 by nose and throat swabs taken on March 2. As he was clinically well, he was asked to stay at home and self-isolate. His immunosuppression was azathioprine 75 mg once daily (OD) and prednisolone 5 mg OD, which was not changed. He was not on angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker at the time of presentation. He has made a full recovery. The transplant kidney function remained stable. A 67-year-old woman with insulin-dependent type 2 diabetes and end-stage kidney disease on hemodialysis therapy for 4 years received a deceased donor kidney transplant in March 2019. Her eGFR was 45 to 55 ml/min per 1.73 m2. She was maintained on tacrolimus with levels between 5 and 8 ng/ml, mycophenolate mofetil (MMF) 250 mg twice a day (BD), and prednisolone 5 mg OD. Her other medications included ramipril, aspirin, alfacalcidol, and amiloride. She presented on March 5 with cough, fever, and shortness of breath. Chest X-ray revealed bilateral patchy consolidation (Figure 1a). SARS-CoV-2 RNA polymerase chain reaction tests from nose and throat viral swabs were positive. Bronchial washing for pneumocystis polymerase chain reaction was negative, as was blood polymerase chain reaction for cytomegalovirus DNA. There was no other positive microbiological diagnosis. She was hypoxic with peripheral oxygen saturation of 86% and a respiratory rate of 26 breaths/min, so she was transferred to intensive therapy unit (ITU) and commenced noninvasive ventilation (continuous positive airway pressure for type 1 respiratory failure) and subsequent intubation and ventilation as her clinical condition deteriorated. Serum CRP on admission was 83 mg/l, hemoglobin 110 g/l, with normal total white cell count, and mild lymphopenia (lymphocyte count 0.8 × 109/l). She was treated with broad spectrum antibiotics. No specific were MMF was tacrolimus was but 1 day day admission, she acute kidney injury with a serum creatinine to She remained on the with oxygen and in on chest X-ray (Figure but on March with high serum lactate and lactate levels and an acute of CRP to She severe to on continuous venovenous to an and/or She and died on March A woman with a of adult kidney disease, end-stage kidney disease in was on hemodialysis for 7 and received a deceased donor kidney transplant in December 2019. she an of cytomegalovirus infection and post-transplant diabetes Her medications included of tacrolimus mg and MMF mg and of prednisolone 5 5 75 2 and mg and mg and Three months after deceased donor kidney on March she presented with shortness of to the her oxygen were with rate of and blood pressure of She was on continuous positive airway pressure and her oxygen improved to of the chest revealed widespread and her chest X-ray bilateral She was to be positive for SARS-CoV-2 Her and other respiratory viral with pneumonia were There was no other positive microbiological diagnosis. She features of acute respiratory distress syndrome and AKI Her respiratory in the and she required intubation 8 and to be MMF was on March and tacrolimus on March spectrum and were She was treated for pneumocystis with high dose Serum CRP from on day of admission to 7 days She and continuous venovenous which Her chest X-ray some of the A with a of and end-stage renal disease in and received a deceased donor kidney transplant in months after kidney he presented to hospital with shortness of and chest and was to He was with COVID-19 infection on March MMF was and he with tacrolimus and He was discharged from the ITU and is to a medical still requiring 4 to oxygen to function remained stable. A woman with and end-stage kidney disease was on therapy 2012 and hemodialysis therapy she received a deceased donor kidney transplantation on February and was discharged on March Her included MMF, and Other medications included as as 4 mg and 1 mg as She presented with shortness of and on March 13. Her chest X-ray of on March 13 that on March and She tested positive for SARS-CoV-2 RNA on March 14, 2020. She was with oxygen saturation of and blood pressure saturation improved to with 4 oxygen by was g/l, serum of and serum Her count on day of admission to × and has remained Tacrolimus was and MMF was from March She was treated with and blood She was to ITU on March for respiratory but not more 5 oxygen and transferred to on March March 20, her serum creatinine was She an and is being managed in a A man with and of received a kidney transplant 7 years He presented on March with cough and and tested positive for SARS-CoV-2 RNA on March 13. He was and were stable. He received and medications the mg OD, MMF mg mg OD, mg at mg OD, mg OD, 8 mg 1 OD, and 250 mg OD. He AKI with a in creatinine from to was cell are in Table 2. He remained on March 21 with cough and mild fever. As the symptoms were not MMF was and he has managed to stay at A man with a kidney transplant from presented with fever, flu-like cough for 7 and shortness of for 1 He had with no other He was a recipient with at and was maintained on long-term azathioprine in from MMF due to and prednisolone mg OD. admission on March he was and hypoxic with oxygen saturation of on which was to on 4 oxygen and throat swabs were positive for SARS-CoV-2 He AKI with serum creatinine and eGFR 5 ml/min per 1.73 He was with count of × × 109/l) with normal hemoglobin and white cell function tests were normal on admission, but up to on day Chest X-ray revealed bilateral was on admission, tacrolimus and prednisolone to mg OD. he 1 hemodialysis He is from respiratory of and as of March 2020, the oxygen are on 2 He stable. In report we our first 7 cases of COVID-19 infection in kidney transplant recipients from south United age of transplant recipients was 54 years 4 7 patients, 2 were managed on an and at home, with the remaining 5 requiring hospital admission. the required ITU admission, and 1 is being managed in the renal 4 patients to ITU, 2 intubation and the other 2 were managed with oxygen and noninvasive ventilation There was 1 in of 7 patients rate of All patients with severe disease were and had Two patients presented within months of kidney transplantation within 2 while kidney transplant was months or more in the remaining 5 The patients were managed in and the total of transplant patients in was with patients from December 2019, to March 2020, during the patients are at higher risk due to immunosuppression, chronic kidney disease, and other in diabetes and which are as that outcomes in patients with COVID-19 F. Yu R. et and risk for of adult with COVID-19 in Wuhan, a cohort 2020; 395: Full Text Full Text PDF PubMed Scopus Google Scholar Three of our patients had chronic kidney disease 4 to with 1 at home and 1 requiring hospital admission but ITU admission. The remaining 4 patients had chronic kidney disease of which 2 had severe disease requiring intubation and ventilation and 1 of died. patients who had severe COVID-19 the one who died had diabetes immunosuppression in patients is and of COVID-19 infection, associated and time In transplant patients with mild to the is to or in the dose of but high in patients to hospital with COVID-19 we that are not on the of we suggest that and be at the time of admission to dose of prednisolone be or and tacrolimus dose be In severe infections intubation and an can be made for while therapy. The of and due to as a of severe respiratory disease and acute respiratory distress syndrome has been the of disease in December 2019, of and case for in patients. A can be made for but more is is risk of with in immunosuppression but the high rate of COVID-19 infection in patients, on their patients with a of of to it is likely that the in the United have requiring with or All patients in received therapy at time of et risk and of immunosuppression in renal transplant Nephrol. 2020; PubMed Scopus Google Scholar of the 7 patients presented here were Two patients with mild who not hospital admission and at home were on immunosuppression on azathioprine prednisolone and 1 on tacrolimus to therapy with angiotensin-converting enzyme receptor in with UK and of were not discontinued. One of our 7 patients which is a rate of it is to on likely in of patients. Two of our patients presented within months after transplantation and 1 presented within 2 UK National Health Service and and have guidelines on COVID-19 in deceased and the transplant are risk and recipients kidney transplantation. is a high-risk during pandemic due to the risk of COVID-19 infection from the donor to the recipient as as risk of recipient severe disease higher levels of immunosuppression in the first months We suggest that from transplantation is not during for recipients with in We have donor and are in to deceased donor In to about the of COVID-19 on patients, about to ITU in the and of to care to for of COVID-19 patients, it is likely that deceased donor be within of the UK AKI has been described with COVID-19 infections in up to patients, and of or has been In our the that 4 of 7 patients had AKI may be an that transplant patients are at higher risk of AKI with COVID-19 infection, with AKI in patients of in Wuhan, X, Yu Xu et al. and outcomes of patients with SARS-CoV-2 pneumonia in Wuhan, a [e-pub ahead of print]. 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OBJECTIVES: Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in ≥1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor-responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Final consensus was obtained during 3 face-to-face meetings of the Gastroenterology Committee and 1 teleconference. RESULTS: The cornerstone of treatment is an elimination diet (targeted or empiric elimination diet, amino acid-based formula) and/or swallowed, topical corticosteroids. Systemic corticosteroids are reserved for severe symptoms requiring rapid relief or where other treatments have failed. Esophageal dilatation is an option in children with EoE who have esophageal stenosis unresponsive to drug therapy. Maintenance treatment may be required in case of frequent relapse, although an optimal regimen still needs to be determined. CONCLUSIONS: EoE is a chronic, relapsing inflammatory disease with largely unquantified long-term consequences. Investigations and treatment are tailored to the individual and must not create more morbidity for the patient and family than the disease itself. Better maintenance treatment as well as biomarkers for assessing treatment response and predicting long-term complications is urgently needed.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Selective laser melting (SLM), a method used in the nuclear, space, and racing industries, allows the creation of customized titanium alloy scaffolds with highly defined external shape and internal structure using rapid prototyping as supporting external structures within which bone tissue can grow. Human osteoblasts were cultured on SLM-produced Ti6Al4V mesh scaffolds to demonstrate biocompatibility using scanning electron microscopy (SEM), fluorescence microscopy after cell vitality staining, and common biocompatibility tests (lactate dihydrogenase (LDH), 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), 5-bromo-2-deoxyuridine (BrdU), and water soluble tetrazolium (WST)). Cell occlusion of pores of different widths (0.45-1.2 mm) was evaluated. Scaffolds were tested for resistance to compressive force. SEM investigations showed osteoblasts with well-spread morphology and multiple contact points. Cell vitality staining and biocompatibility tests confirmed osteoblast vitality and proliferation on the scaffolds. Pore overgrowth increased during 6 weeks' culture at pore widths of 0.45 and 0.5 mm, and in the course of 3 weeks for pore widths of 0.55, 0.6, and 0.7 mm. No pore occlusion was observed on pores of width 0.9-1.2 mm. Porosity and maximum compressive load at failure increased and decreased with increasing pore width, respectively. In summary, the scaffolds are biocompatible, and pore width influences pore overgrowth, resistance to compressive force, and porosity.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

OBJECTIVE: Previous in vitro and animal studies have suggested that vitamin D, in particular, its metabolite 25-hydroxyvitamin D (25[OH]D), may have immunomodulatory effects. To study further the potential immunomodulatory effects of vitamin D in humans, we explored the hypothesis that serum vitamin D metabolites may be inversely associated with current disease activity, severity, and functional disability in patients with early inflammatory polyarthritis (IP). METHODS: We studied 206 consecutive patients with IP who were enrolled in the Norfolk Arthritis Register between January 2000 and November 2003 inclusive. Patients were studied within 6 months of symptom onset. None of the patients was taking steroids, and all had received <6 weeks of disease-modifying therapy. Associations between serum levels of 25(OH)D and 1,25-dihydroxyvitamin D (1,25[OH](2)D) at baseline and the swollen and tender joint counts, Health Assessment Questionnaire (HAQ) scores, C-reactive protein (CRP) levels, and the Disease Activity Score 28-joint assessment (DAS28) scores at baseline and 1 year were assessed. RESULTS: The median age at symptom onset was 59 years (range 20-88 years), with a median disease duration of 4 months. At baseline, there was an inverse relationship between 25(OH)D levels and the tender joint count, DAS28 score, and HAQ score. The only inverse relationship with 1,25(OH)(2)D was with the HAQ score. Each 10-ng/ml increase in the level of 25(OH)D was associated with a decrease in the DAS28 score of 0.3 and in the CRP level of approximately 25%. At 1 year, the only significant result was an inverse association between baseline vitamin D metabolite levels and the HAQ score; that is, those with higher metabolite levels had lower HAQ scores. CONCLUSION: These data provide further support that vitamin D plays an immunomodulatory role in inflammatory arthritis. This association needs to be examined in other cohorts of patients with early IP, as well as in longitudinal studies. If confirmed, the clinical response to vitamin D supplementation should be examined in early IP.

Artificial intelligence (AI) is a rapidly evolving tool revolutionizing many aspects of healthcare. AI has been predominantly employed in medicine and healthcare administration. However, in public health, the widespread employment of AI only began recently, with the advent of COVID-19. This review examines the advances of AI in public health and the potential challenges that lie ahead. Some of the ways AI has aided public health delivery are via spatial modeling, risk prediction, misinformation control, public health surveillance, disease forecasting, pandemic/epidemic modeling, and health diagnosis. However, the implementation of AI in public health is not universal due to factors including limited infrastructure, lack of technical understanding, data paucity, and ethical/privacy issues.

<h3>ABSTRACT</h3> Chronic kidney disease (CKD) is a common condition associated with significant amenable morbidity and mortality, primarily related to the substantially increased risk of cardiovascular disease (CVD) in this population. Early detection of people with CKD is important so that treatment can be initiated to prevent or delay kidney disease progression, reduce or prevent the development of complications, and reduce the risk of CVD. Classification of CKD by the estimated glomerular filtration rate and urine albumin to creatinine ratio identifies those at greatest risk of adverse outcomes. This concise guideline highlights the key recommendations of the National Institute for Health and Care Excellence guideline <i>Chronic kidney disease in adults: assessment and management: Clinical guideline [CG182]</i>, published in July 2014. It focuses on recommendations most relevant to secondary care physicians.

Hydroxyapatite (HAP) and tricalcium phosphate (TCP) are two very common ceramic materials for bone replacement. However, in general HAP and TCP scaffolds are not tailored to the exact dimensions of the defect site and are mainly used as granules or beads. Some scaffolds are available as ordinary blocks, but cannot be customized for individual perfect fit. Using computer-assisted 3D printing, an emerging rapid prototyping technique, individual three-dimensional ceramic scaffolds can be built up from TCP or HAP powder layer by layer with subsequent sintering. These scaffolds have precise dimensions and highly defined and regular internal characteristics such as pore size. External shape and internal characteristics such as pore size can be fabricated using Computer Assisted Design (CAD) based on individual patient data. Thus, these scaffolds could be designed as perfect fit replacements to reconstruct the patient's skeleton. Before their use as bone replacement materials in vivo, in vitro testing of these scaffolds is necessary. In this study, the behavior of human osteoblasts on HAP and TCP scaffolds was investigated. The commonly used bone replacement material BioOss(R) served as control. Biocompatibility was assessed by scanning electron microscopy (SEM), fluorescence microscopy after staining for cell vitality with fluorescin diacetate (FDA) and propidium iodide (PI) and the MTT, LDH, and WST biocompatibility tests. Both versions were colonised by human osteoblasts, however more cells were seen on HAP scaffolds than TCP scaffolds. Cell vitality staining and MTT, LDH, and WST tests showed superior biocompatibility of HAP scaffolds to BioOss, while BioOss was more compatible than TCP. Further experiments are necessary to determine biocompatibility in vivo. Future modifications of 3D printed scaffolds offer advantageous features for Tissue Engineering. The integration of channels could allow for vascular and nerve ingrowth into the scaffold. Also the complex shapes of convex and concave articulating joint surfaces maybe realized with these rapid prototyping techniques.

Extended spectrum β-lactamases (ESBLs) are enzymes produced by a variety of Gram negative bacteria which confer an increased resistance to commonly used antibiotics. They are a worrying global public health issue as infections caused by such enzyme-producing organisms are associated with a higher morbidity and mortality and greater fiscal burden. Coupled with increasing prevalence rates worldwide and an ever diminishing supply in the antibiotic armamentarium, these enzymes represent a clear and present danger to public health. This article aims to give an overview of the current situation regarding ESBLs, with a focus on the epidemiology and management of such infections.

BACKGROUND: Migraine is a common, disabling condition and a burden for the individual, health services, and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Naproxen is a non-steroidal anti-inflammatory drug (NSAID); its efficacy in acute migraine has not been established by systematic reviews. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine headaches. OBJECTIVES: To determine the efficacy and tolerability of naproxen, alone or in combination with an antiemetic, compared with placebo and other active interventions in the treatment of acute migraine headaches in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, and the Oxford Pain Relief Database, together with two online databases (www.gsk-clinicalstudyregister.com and www.clinicaltrials.gov) and reference lists, for studies to 22 May 2013. SELECTION CRITERIA: We included randomised, double-blind, placebo- or active-controlled studies, with at least 10 participants per treatment arm, using naproxen alone or with an antiemetic to treat a migraine headache episode. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratios and numbers needed to treat (NNT) or harm (NNH) compared with placebo or a different active treatment. MAIN RESULTS: We included six studies using naproxen 275 mg, 500 mg, or 825 mg to treat attacks of moderate or severe pain intensity. Overall, 1241 participants took naproxen (275 mg to 825 mg), 229 took sumatriptan 50 mg, 173 took naratriptan 2.5 mg, and 1092 took placebo. No studies combined naproxen with an antiemetic. Studies using naproxen 275 mg provided no useable data for analysis.Naproxen (500 mg and 825 mg) was better than placebo for pain-free response and headache relief. At two hours, the NNT for pain-free response was 11 (17% response with naproxen, 8% with placebo; risk ratio 2.0 (95% CI 1.6 to 2.6), moderate quality) and for headache relief was 6.0 (45% response with naproxen, 29% with placebo; risk ratio 1.6 (1.4 to 1.8), moderate quality). The NNT for sustained pain-free response during the 24 hours post dose was 19 (12% response with naproxen, 6.7% with placebo), and for sustained headache relief during the 24 hours post dose was 8.3 (30% response with naproxen, 18% with placebo). Analysing only the lower dose of 500 mg of naproxen did not significantly change the results. Adverse events, which were mostly mild or moderate in severity and rarely led to withdrawal, were more common with naproxen than with placebo when the 500 mg and 825 mg doses were considered together, but not when the 500 mg dose was analysed alone.There were insufficient data for analysis of naproxen compared with sumatriptan, and no data suitable for analysis of naproxen compared with naratriptan. AUTHORS' CONCLUSIONS: Naproxen is statistically superior to placebo in the treatment of acute migraine, but the NNT of 11 for pain-free response at two hours suggests that it is not a clinically useful treatment. Cochrane reviews examining other commonly used analgesics for acute migraine have reported better (lower) NNT results for the same outcome. Naproxen is not clinically useful as a stand-alone analgesic in acute migraine, as it is effective in fewer than 2 people in 10.

A Cross-sectional study was undertaken at a specialist centre in the United Kingdom investigating duration and causes of delay in the diagnosis of endometriosis. One hundred and one women completed a self-reported questionnaire containing 20 items about their psychosocial, symptoms and experiences. The statistical analysis included a Mann-Whitney U test. A p value of .05 was considered statistically significant. The Spearman’s rank correlation was also calculated. Overall, there was a median delay of 8 years (Q1–Q3: 3–14) from the onset of symptoms to a diagnosis of endometriosis. Factors such as menstrual cramps in adolescence, presence of rectovaginal endometriosis, normalisation of pain and the attitudes of health professionals contributed to a delayed diagnosis (p values<.05). There was a negative correlation indicating the earlier the onset of symptoms, the greater the delay to diagnosis (Spearman’s Rank Correlation Coefficient –0.63, p<.01). The results of this study highlight a considerable diagnostic delay associated with endometriosis and the need for clinician education and public awareness.Impact statementWhat is already known on this subject? The diagnostic delay of 7–9 years with endometriosis has been reported globally. In an effort to standardise surgical treatment, improve outcomes, and shorten delays specialist endometriosis centres were introduced in 2011. There has been no recent quality improvement assessment since the establishment of such centres.What do the results of this study add? This is the most recent evaluation in the United Kingdom since the introduction of specialist endometriosis centres. There is a considerable diagnostic delay associated endometriosis in the United Kingdom with a median of 8 years. The delays seem not to have improved over the last two decades. We have identified medical and psychosocial factors that may contribute to such delays. These include factors such as menstrual cramps in adolescence, presence of rectovaginal endometriosis, normalisation of pain and attitudes of health professionals contribute to a delayed diagnosis.What are the implications of these findings for clinical practice and/or further research? The results of this study, highlight the need for clinician education and public awareness to decrease the long term-morbidity and complications that result from untreated endometriosis.

The revised BSPGHAN guidelines for the diagnosis and management of coeliac disease represent an important shift in diagnostic strategy, aimed at simplifying and shortening the diagnostic process in selected cases. Guidance is given concerning the indications for testing for coeliac disease, which is still significantly underdiagnosed in the UK. While screening data suggest a likely incidence of 1 in 100 persons, only 10%-20% of this figure is currently being diagnosed.The BSPGHAN guidelines follow the new ESPGHAN guidelines in overall diagnostic strategy, while providing more didactic stratagems, which should be of assistance for paediatricians in specialties other than gastroenterology.

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).

Older people have paid a huge toll in terms of mortality during the coronavirus disease-19 (COVID-19) pandemic. Frailty may have contributed to the vulnerability of older people to more severe clinical presentation. We aimed at reviewing available evidence about frailty and COVID-19. We searched PUBMED, Web of Science, and EMBASE from 1 December 2019 to 29 May 2020. Study selection and data extraction were performed by three independent reviewers. Qualitative synthesis was conducted and quantitative data extracted when available. Forty papers were included: 13 editorials, 15 recommendations/guidelines, 3 reviews, 1 clinical trial, 6 observational studies, 2 case reports. Editorials and reviews underlined the potential clinical relevance of assessing frailty among older patients with COVID-19. However, frailty was only investigated in regards to its association with overall mortality, hospital contagion, intensive care unit admission rates, and disease phenotypes in the few observational studies retrieved. Specific interventions in relation to frailty or its impact on COVID-19 treatments have not been evaluated yet. Even with such limited evidence, clinical recommendations on the use of frailty tools have been proposed to support decision making about escalation plan. Ongoing initiatives are expected to improve knowledge of COVID-19 interaction with frailty and to promote patient-centered approaches.