Infection with SARS-CoV-2 may alter the half-life of desmopressin (DDAVP) in children with central diabetes insipidus

Background: Central diabetes insipidus (CDI) is characterised by a central deficiency of arginine vasopressin (AVP) with polyuria and polydipsia. The etiology is heterogeneous. The treatment of choice is the oral or nasal application of DDAVP (synthetic analogue of AVP). CDI in the context of coronavirus disease 2019 (COVID19) has been reported in an individual case. Case Report: We present a 9-year old male with CDI of uncertain etiology. The reason for presentation was polydipsia (5 liters/ day) and polyuria/ nocturia. MRI showed a nodular thickening of the pituitary stalk and lack of T1w hyperintensity of the neurohypophysis. As expected, the level of CT-proAVP (copeptin) in serum was very low (< 2.7 pmol/litre) despite increased osmolality in serum of 306 mosm/kg. Sodium in serum was high with a maximum of 151 mmol/l. Laboratory analysis showed no involvement of other pituitary axis. Therapy was initiated with DDAVP at 1.2 mug in the morning and 0.6 mug in the evening (nasally). Treatment showed normalisation of polyuria, polydipsia, serum sodium levels and drinking quantity (2 liters/ day). The most recent dose was 6 mug in the morning and 1.8 mug in the evening. One year later the patient complained of sore throat. The pain was gone the following morning. A PCR test was positive for SARS-CoV-2. Surprisingly, with the onset of the sore throat, the half-life of the usual dosage of DDAVP therapy was significantly prolonged. Thus, the boy received the usual 1.8 mug of desmopressin in the evening (day of onset of symptoms). The effect lasted for 17 hours. Thus, the duration of action was prolonged by approximately 6 hours. The morning dose was skipped. The evening dose of 1.8 mug was then administered again at 1 p.m. at noon. This lasted for 18 hours. Thus, the duration of action was prolonged again by approximately 5 hours. After three days, the regular dosage and timing could be reintroduced. Furthermore, there was no adjustment of the dosage and no change of the manufacturer, pharmacy, application or storage of the preparation in the temporal context. Conclusion(s): In the context of a clinically mild infection with SARS-CoV-2, the half-life of DDAVP was significantly prolonged with the onset of clinical symptoms. Our case report is of clinical relevance, as even mild COVID19 may lead to a change in DDAVP pharmacokinetics. This knowledge may reduce the risk of dilutional hyponatremia.

Using a Patient Portal as a Recruitment Tool to Diversify the Pool of Participants in COVID-19 Vaccine Clinical Trials

Background. Because the COVID-19 pandemic disproportionately affected racial/ ethnic minorities in the US, there was a push to ensure diversity in COVID-19 vaccine clinical trials. Historically, minority groups have been underrepresented in research. We assessed the feasibility of recruiting racial/ethnic minorities through an electronic health record (EHR) patient portal. Methods. The UPenn Health System EHR was used to identify individuals ages 40 and older, living in zip codes with high rates of SARS-CoV-2 test positivity, with a risk factor associated with severe COVID-19 disease. Eligible individuals with an activated patient portal account were sent a message inviting them to participate in the COVID-19 vaccine clinical trial. A follow-up phone call was made to those who did not respond or declined, and reasons for or against participation were coded to extract themes. Results. In August 2020, a total of 13,779 patients fit the inclusion criteria, of which 5,614 (40.7%) had an activated patient portal account and were invited to participate. The majority, 5,426 (96.7%), identified as black, and 73 (1.3%) identified as Hispanic/Latinx. Only 301 (5.4%) of messaged individuals responded. Among respondents, 55 of 206 (26.7%) blacks, 5 of 7 (71.4%) Hispanic/Latinx, and 50 of 76 (65.8%) whites expressed interest. Among the 115 respondents who expressed interest, 24 agreed to a screening visit, and 9 were ultimately enrolled in the trial, which consisted of 6 black, 3 white, and 1 Hispanic/Latinx individual. During phone outreach to those who did not respond and those who declined, common reasons for declining included underlying health conditions, fears of an unproven vaccine, not wanting to be experimented upon, the rapid speed of vaccine development, and the lack of time to participate in a trial. Patient portal response rates by race/ethnicity Conclusion. Because of low rates of patient portal account activation and use, compounded with vaccine hesitancy, recruitment of racial/ethnic minorities into COVID-19 vaccine clinical trials through patient portal messaging yielded a small number of participants. Strategies to increase use of the patient portal combined with approaches to address concerns of trial participation should be considered to increase enrollment of racially/ethnically diverse groups into vaccine clinical trials.

Interdisciplinary Approach Is Essential for Sufficient Diagnosis and Therapy in Igg4-Related Disease Involving Multiple Organs

Introduction: IgG4-related disease (IgG4-RD) is a systemic, chronic inflammatory syndrome, with enlargement of involved organs, elevated serum levels of IgG4, dense lymphoplasmocytic infiltrates, rich in IgG4-positive plasma cells, and fibrosis in involved organs. The most frequently involved organs are the pancreato-hepatobiliary tract, salivary and lacrimal glands, the retroperitoneum, kidneys, lungs, and aorta. Often multiple organ systems are involved. As an initial treatment, glucocorticoids are recommended. In patients with relapse along with glucocorticoid dose reduction, various immunosuppressive agents have been reported. Aims & Methods: We reviewed 98 patients (2019-now) who were treated in the special outpatient unit for IgG4-RD at the University Hospital of Essen and identified 10 patients with IgG4-RD involving multiple organ systems. Result(s): The first patient is a 65-year-old male diagnosed with an IgG4- RD involving parotitis, lymphadenitis, sialadenitis with orbitopathy and elevated IgG4 serum level (7400 mg/l). Clinically response to therapy with steroids was documented. The second patient is a 63-year-old man with an IgG4-positive pancreatitis, sialadentis, lymphadenopathy, and elevated IgG4 serum level (3960 mg/l). Immunosuppression with tacrolimus leaded to clinical benefit. As the third patient, we report a 48-year-old man with IgG4-related inflammatory condition in pancreas and kidneys with high IgG4 serum levels. The patient was successfully treated with azathioprine and prednisolone. As the fourth patient, we demonstrate a 34-year-old man with IgG4-related autoimmune hepatitis, lymphadenitis, and pancreatitis. After treatment with tacrolimus in combination with rituximab, a significant decrease of IgG4-level was detected. The fifth patient, a 65-year-old man, was diagnosed with IgG4-related fibro- inflammatory pseudotumors in the liver, esophagitis, and lymphadenopathy combined with high serum levels of IgG4 (12000 mg/l). Clinically response to therapy with steroids and azathioprine was reported. As the sixth patient we demonstrate a 29-year-old male with IgG4-related lymphadenopathy, recurrent myocarditis, and pancreatitis. The patient has symptom-free episodes under low-dose prednisolone. We also found an IgG4-RD with multiple organ involvement in our seventh patient. A 54-year-old man with IgG4-related cholangitis, pancreatitis, prostatitis, and very high serum level of IgG4 (26700 mg/l) were treated with steroids and azathioprine. As our eight case, we present a 23-year-old man with congenital hepatic fibrosis, after living-donor liver transplantation, who developed an IgG4- related disease with high IgG4 serum levels (45300 mg/l) after infection with SARS-CoV-2. Pathologically enlarged lymph nodes were detected. In a biopsy of retroperitoneal lymph nodes, IgG4-positive plasma cells were detectable. Intestinal biopsies have shown numerous positive plasma cells in the IgG4-staining (40 IgG4 positive plasma cells/HPF). Treatment with rituximab is planned. The ninth patient is a 56-year-old woman with lymphadenitis and cholangitis, who clinically responded to a treatment with budesonide. As the last patient we present a 59-year-old man with an IgG4-related aortitis, cardiac fibrosis, cholangitis, hepatitis, exocrine pancreatic insufficiency and Hashimoto's thyroiditis responding very sufficient to rituximab. Conclusion(s): An interdisciplinary approach is essential for a sufficient diagnosis and therapy in IgG4-RD involving multiple organs. This collective is extremely heterogeneous, and treatment is often based on individual concepts.

PROMOTING EQUITY IN RATIONING AND BEYOND THOUGH DISADVANTAGE INDICES: ASSESSING THE POTENTIAL OF A NOVEL APPROACH

Background In the USA, Covid-19 exposed deep social, racial and ethnic inequities-but policy makers also deployed a major novel tool to promote equity within, and likely beyond, the pandemic, by modifying allocation frameworks with disadvantage indices (DIs, ie: place-based measures integrating census variables such as income, education or housing-situation, enabling ranking geographic areas as small as neighborhoods). Objective To assess to what extent DIs have been adopted, and what their potential is to improve equity in, and beyond, Covid-19 allocation-decisions. Methods A) structured review of US states' use of DIs in the initial vaccine roll-out, (Schmidt et al. 'Equitable allocation.' Nature Medicine (27) 2021), C) literature scoping review of use of dominant DI (Pubmed/Embase/WebSc), D) Conceptual analysis. Results In an unprecedented, rapid, and widespread effort, a majority of US states (n=34) added disadvantage indices in Covid-19 vaccine allocation plans. The dominant model is the CDC's Social Vulnerability Index (SVI), developed for natural disaster response efforts (mapping well onto a conceptualization in the philosophical literature: Wolff/De-Shalit, 'Disadvantage', OUP 2007, as well as public preferences: Schmidt et al. 'US adults' preferences.' JME, 2021). Main DI uses: planning dispensing site locations, targeted outreach/communication, increasing vaccine quantities, and monitoring uptake/ course-correcting. Adapted forms were also used for tests and antiviral treatment allocation. The scoping review of SVI uses is ongoing at the time of submission;preliminary findings are that around 50% of N=119 publications use DIs 'off-label', ie in non-emergency settings, indicating an unmet need. Emergent themes include: budgetary allocations, healthcare service access planning, targeted prevention. Discussion In Spring 2020, the dominant theme in Covid-19 allocation frameworks was maximizing overall benefits-often risking exacerbating existing inequities. The rapid and widespread DI adoption opened a major new chapter, holds major potential to improve equity in allocation beyond Covid-19, and should be explored further.

119 A comprehensive, adaptive approach to effective telehealth in a pediatric CF clinic

Background: At the onset of the 2020 COVID-19 pandemic, the VCU pediatric CF program decided to adapt our in-person model of clinical care to accommodate a new virtual environment for all routine CF clinic visits. Methods: With QI support from the Cystic Fibrosis Learning Network and our health system, we adapted to a new virtual model by testing and adopting strategies to promote a number of changes. 1) Optimal use of telehealth technology: We utilized Zoom-based clinics with a virtual check- in waiting room, patient breakout rooms, and team room for ongoing communication during clinic. 2) Pre-visit planning and coproduction: We sent pre-clinic messages to patients/families to solicit input on visit agenda and incorporated responses into virtual pre-clinic meetings;our pre-clinic message was revised to remind families of home health data to collect in preparation for visit. 3) Communication among team members and with patients/families: We improved team communication with the addition of post-clinic meetings, including live joint editing of individual post-visit summaries that we email to each patient/family after team meeting. 4) Telehealth visit optimization and readiness: Center discretionary funds were used to supplement CFF support to purchase ZephyRx spirometers for all patients >5yo, as well as home scales and tape measures for families in need of assistance. We arranged with microbiology to acquire and mail airway culture swabs with prepaid return packaging to patient homes. Various team members provided ongoing training and support in the use of these items. 5) Data tracking: A tracking spreadsheet and run charts were created to track implementation of process measures (team member encounters, acquisition of PFTs, weights, heights, airway cultures), reviewed weekly by care team and our family partners. Results: Pre-COVID, all routine clinic visits were in person;from March 2020 to March 2021, 93% of routine visits were virtual. The impact of this change to virtual visits on our metrics was negligible (Table 1). We were able to provide home spirometers to 100% of age-eligible patients, home throat swab kits to 67%, and weight scales to 100% of patients who indicated need. Patient feedback also has been positive. Responses to our center-specific telehealth satisfaction survey indicate that patients consider telehealth visits to be as effective as in-person visits, would prefer for most visits to continue to be virtual, and find virtual visits to be efficient, convenient, and accessible. (Table presented.) Conclusion: Participation in routine CF clinic visits was not significantly hindered by switching to a virtual model. We can equip patients with the tools they need to collect important health data from home and can provide virtual support. Effective coproduction and collaborative agenda setting can occur virtually. Patients/families approve of, and may prefer, a virtual model.

Updated results of the COVID-19 in MS global data sharing initiative validate consistent associations of anti-CD20 and other reported risk factors with severe COVID-19 outcomes

Background: As the COVID-19 pandemic continues, evidencebased clinical guidance for managing the care of people with multiple sclerosis (MS) is an ongoing concern. In recent months, data from cohorts of people with MS has indicated that certain demographic and clinical characteristics, including use of some disease- modifying therapies (DMTs), leads to worse outcomes from SARS-CoV-2 infection. The COVID-19 in MS global data sharing initiative, which now includes over 4,500 confirmed COVID- 19 cases in people with MS, gives the opportunity to corroborate previous findings with greater certainty. Methods: Clinician-reported data from 32 countries were aggregated into a dataset of 5,543 patients who had suspected or confirmed COVID-19. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes. These outcomes (hospitalisation, admission to ICU, requiring artificial ventilation, and death) were assessed in patients with suspected/ confirmed COVID-19 using multilevel mixed-effects logistic regression. All models were corrected for age, sex, EDSS, and MS type. DMTs were individually compared to glatiramer acetate (GA), as well as to pooled other DMTs and natalizumab. Results: Of 5,543 patients in the clinician-reported dataset, 909 with suspected and 4,634 with confirmed COVID-19 were included in the analysis. Previous demographic findings were confirmed: male sex, older age, progressive MS, and higher disability were associated with worse outcomes from SARS-CoV-2 infection. Use of anti-CD20 DMTs (ocrelizumab and rituximab) was associated with worse COVID-19 outcomes. Compared to GA, ocrelizumab and rituximab were associated with increased risk of hospitalisation (aOR=1.61(95%CI=1.06-2.43);aOR=2.42(95%CI=1.54-3.81) and ICU admission (aOR=3.13(95%CI=1.22-8.00);aOR=4.46 (95%CI=1.64-12.09)). Rituximab was associated with increased risk of artificial ventilation (aOR=3.57(95%CI=1.38-9.20));ocrelizumab showed a positive trend (aOR=1.86(95%CI=0.76-4.55). Rituximab showed a positive trend with increased risk of death (aOR=2.74(95%CI=0.68-11.09). Associations persisted on restriction to confirmed COVID-19 cases. Conclusions: Analysing the largest international real world dataset of people with MS who have suspected or confirmed COVID- 19 confirms previous findings that male sex, older age, progressive MS, higher disability, the use of anti-CD20 medication (ocrelizumab and rituximab) are associated with worse COVID-19 outcomes.

COVID-19 vaccine reactogenicity in persons with multiple sclerosis

Introduction: Limited data on SARS-CoV-2 vaccine reactogenicity in persons with multiple sclerosis (PwMS) exists and it is of interest due to the novel vaccine strategies deployed and the uncertain impact of disease modifying therapies (DMTs). Objective: To report real-world data on SARS-CoV-2 vaccine reactions in PwMS in the context of DMTs. Aim: To identify sociodemographic and clinical attributes associated with SARS-CoV-2 vaccine reactogenicity in PwMS. Methods: PwMS participating in iConquerMS (an online research network) completed detailed online surveys between 3/2021- 6/2021, and reported their SARS-CoV-2 vaccines, experiences of local (itch, pain, redness, swelling, or warmth at injection site) and systemic (fever, chills, fatigue, headache, joint pain, malaise, muscle ache, nausea, allergic, or other) reactions within 24 hours (reported as none, mild, moderate, or severe), and other attributes, including DMT use. Multivariable models characterized associations between predictors and reactogenicity after the 1st and 2nd vaccination. Results: In 719 PwMS, 64% reported a reaction and 17% reported a severe reaction after the 1st vaccine, which were primarily experiences of pain at injection site, fatigue, headache, and malaise. Younger age, being female, a prior SARS-CoV-2 infection, and receiving the ChAdOx1 nCoV-19 versus the BNT162b2 vaccine were independently associated with experiencing a reaction. Similar relationships were observed for experiencing a severe reaction, including higher reactogenicity for PwMS with greater physical impairment and lower reactogenicity for PwMS treated with an alpha4-integrin blocker or sphingosine-1-phosphate receptor modulator (SIPR). In 441 PwMS who received two vaccinations, 74% reported a reaction and 22% reported a severe reaction after the 2nd vaccine. Younger PwMS and those who received the mRNA-1273 versus the BNT162b2 vaccine reported higher reactogenicity, while those on a S1PR or fumarate reported fewer reactions. Similar relationships for age, vaccine type, and S1PR treatment were observed for experiencing a severe reaction after the 2nd vaccine. There were no differences in reactogenicity by MS subtype, disease duration, or for B-cell depleting DMTs across models. Conclusions: Factors associated with SARS-CoV-2 vaccine reactogenicity in the general population were similarly associated in PwMS. Intriguingly, PwMS on specific DMTs were significantly less likely to report vaccine reactions.

Global impact of the COVID-19 pandemic on stroke care and intravenous thrombolysis

Objective: The objectives of this study were to measure the global impact of the pandemic on the volumes for intravenous thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with two control 4-month periods. Background: The COVID-19 pandemic led to widespread repercussions on the delivery of health care worldwide. Design/Methods: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by ICD-10 codes and/or classifications in stroke center databases. Results: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95%CI,-11.7 to-11.3, p<0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95%CI,-13.8 to-12.7, p<0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95%CI,-13.7 to-10.3, p=0.001). There were greater declines in primary compared to comprehensive stroke centers (CSC) for stroke hospitalizations (-17.3% vs-10.3%, p<0.0001) and IVT (-15.5% vs-12.6%, p=0.0001). Recovery of stroke hospitalization volume (9.5%, 95%CI 9.2-9.8, p<0.0001) was noted over the two later (May, June) versus the two earlier (March, April) months of the pandemic, with greater recovery in hospitals with lower COVID-19 hospitalization volume, high volume stroke center, and CSC. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722/52,026) of all stroke admissions. Conclusions: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months, with greater recovery in hospitals with lower COVID-19 hospitalizations, high volume stroke centers, and CSCs.

Risk factors for COVID-19 infection in patients with multiple sclerosis: a nested case–control study

Background: Risk factors for COVID-19 infection among people with multiple sclerosis (PwMS) remain unconfirmed. While biological, socioeconomic and clinical risk factors have been identified among the general population, a comprehensive assessment of risk factors for COVID-19 infection among PwMS is lacking. Methods: A survey assessing personal experiences with COVID-19 in the USA was distributed online via the iConquerMS platform from December 18, 2020 to February 10, 2021. We conducted a retrospective nested case–control study of PwMS who self-reported testing positive for COVID-19 versus not. Risk factors evaluated include age, occupational setting, social determinants of health index, physical disability via Patient-Determined Disease Steps, disease-modifying therapy (DMT) and progressive disease. Results: Of 611 PwMS, 47 (7.7%) self-reported a positive COVID-19 test. DMT use (odds ratio [95% CI]: 2.10 [0.75–5.39]) and employment outside the home (2.79 [1.42–5.41]) increased risk of COVID-19 infection, while older age (0.97 [0.95–0.99]), increased disability (0.81 [0.69–0.94]) and progressive disease (0.42 [0.19–0.86]) decreased risk in univariate analyses. No risk factor remained significant in the multivariate model. Of the 47 PwMS with a positive test, seven were admitted to the hospital, of whom two required intensive care. Forty-three (91.5%) experienced common COVID-19 symptoms, and 23 (48.9%) reported concurrent new/worsening neurological symptoms. Conclusion: The prevalence of COVID-19 infection in this online study of PwMS approximated the US population's prevalence. When incorporating biological, socioeconomic and clinical risk factors for COVID-19, we did not find any independent risk factors for infection among PwMS in the USA.

Ultrasensitive detection of SARS-CoV-2 RNA and antigen using single-molecule optofluidic chip.

Nucleic acids and proteins are the two most important target types used in molecular diagnostics. In many instances, simultaneous sensitive and accurate detection of both biomarkers from the same sample would be desirable, but standard detection methods are highly optimized for one type and not cross-compatible. Here, we report the simultaneous multiplexed detection of SARS-CoV-2 RNAs and antigens with single molecule sensitivity. Both analytes are isolated and labeled using a single bead-based solid-phase extraction protocol, followed by fluorescence detection on a multi-channel optofluidic waveguide chip. Direct amplification-free detection of both biomarkers from nasopharyngeal swab samples is demonstrated with single molecule detection sensitivity, opening the door for ultrasensitive dual-target analysis in infectious disease diagnosis, oncology, and other applications.