Effect of Paxlovid Treatment on Long COVID Onset: An EHR-Based Target Trial Emulation from N3C (preprint)

Preventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. In this study, we examined whether treatment with Paxlovid in the acute phase of COVID-19 helps prevent the onset of PASC. We used electronic health records from the National Covid Cohort Collaborative (N3C) to define a cohort of 426,461 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation (TTE) framework to estimate the effect of Paxlovid treatment on PASC incidence. Our primary outcome measure was a PASC computable phenotype. Secondary outcomes were the onset of novel cognitive, fatigue, and respiratory symptoms in the post-acute period. Paxlovid treatment did not have a significant effect on overall PASC incidence (relative risk [RR] = 0.99, 95% confidence interval [CI] 0.96-1.01). However, its effect varied across the cognitive (RR = 0.85, 95% CI 0.79-0.90), fatigue (RR = 0.93, 95% CI 0.89-0.96), and respiratory (RR = 0.99, 95% CI 0.95-1.02) symptom clusters, suggesting that Paxlovid treatment may help prevent post-acute cognitive and fatigue symptoms more than others.

Fourth dose of Microneedle Array Patch of SARS-CoV-2 S1 Protein Subunit Vaccine Elicits Robust Long-lasting Humoral Responses in mice (preprint)

The COVID-19 pandemic has underscored the pressing need for safe and effective booster vaccines, particularly in considering the emergence of new SARS-CoV-2 variants and addressing vaccine distribution inequalities. Dissolving microneedle array patches (MAP) offer a promising delivery method, enhancing immunogenicity and improving accessibility through the skin's immune potential. In this study, we evaluated a microneedle array patch-based S1 subunit protein COVID-19 vaccine candidate, which comprised a bivalent formulation targeting the Wuhan and Beta variant alongside a monovalent Delta variant spike proteins in a murine model. Notably, the second boost of homologous bivalent MAP-S1(WU+Beta) induced a 15.7-fold increase in IgG endpoint titer, while the third boost of heterologous MAP-S1RS09Delta yielded a more modest 1.6-fold increase. Importantly, this study demonstrated that the administration of four doses of the MAP vaccine induced robust and long-lasting immune responses, persisting for at least 80 weeks. These immune responses encompassed various IgG isotypes and remained statistically significant for one year. Furthermore, neutralizing antibodies against multiple SARS-CoV-2 variants were generated, with comparable responses observed against the Omicron variant. Overall, these findings emphasize the potential of MAP-based vaccines as a promising strategy to combat the evolving landscape of COVID-19 and to deliver a safe and effective booster vaccine worldwide.

Differential host responses within the upper respiratory tract and peripheral blood of children and adults with SARS-CoV-2 infection (preprint)

Age is among the strongest risk factors for severe outcomes from SARS-CoV-2 infection. We sought to evaluate associations between age and both mucosal and systemic host responses to SARS-CoV-2 infection. We profiled the upper respiratory tract (URT) and peripheral blood transcriptomes of 201 participants (age range of 1 week to 83 years), including 137 non-hospitalized individuals with mild SARS-CoV-2 infection and 64 uninfected individuals. Among uninfected children and adolescents, young age was associated with upregulation of innate and adaptive immune pathways within the URT, suggesting that young children are primed to mount robust mucosal immune responses to exogeneous respiratory pathogens. SARS-CoV-2 infection was associated with broad induction of innate and adaptive immune responses within the URT of children and adolescents. Peripheral blood responses among SARS-CoV-2-infected children and adolescents were dominated by interferon pathways, while upregulation of myeloid activation, inflammatory, and coagulation pathways was observed only in adults. Systemic symptoms among SARS-CoV-2-infected subjects were associated with blunted innate and adaptive immune responses in the URT and upregulation of many of these same pathways within peripheral blood. Finally, within individuals, robust URT immune responses were correlated with decreased peripheral immune activation, suggesting that effective immune responses in the URT may promote local viral control and limit systemic immune activation and symptoms. These findings demonstrate that there are differences in immune responses to SARS-CoV-2 across the lifespan, including between young children and adolescents, and suggest that these varied host responses contribute to observed differences in the clinical presentation of SARS-CoV-2 infection by age.

Genome-wide Association Study of Long COVID (preprint)

Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.

Managing severe warm autoimmune haemolytic anaemia after the SARS-Cov- 2 vaccine with emergency splenectomy and eculizumab

Autoimmune haemolytic anaemia (AIHA) is rare but described after the SARS-CoV- 2 Pfizer-BioNTech vaccine. We present a case of severe refractory warm AIHA after this vaccine, managed with emergency splenectomy and complement inhibition with eculizumab. A male in his teens with a history of liver transplant for biliary atresia (aged 2 years) and AIHA (aged 6 years) presented to his district general hospital with jaundice, dark urine, fatigue and chest discomfort 48 h after the first dose of SARS-CoV- 2 Pfizer-BioNTech vaccine (BNT162b2 mRNA). Investigations revealed haemoglobin (Hb) of 70 g/L and bilirubin of 98 mumol/L, which was treated as AIHA. The patient initially responded to prednisolone (1 mg/kg, 60 mg) but subsequently deteriorated and failed to respond to second-line rituximab (375 mg/m2) and two units of packed red blood cells (PRBC). By day 29 the patient had developed life-threatening anaemia culminating in a Hb of 35 g/L (after transfusion), lactate dehydrogenase (LD) of 1293 units/L and bilirubin of 228 mumol/L. This necessitated an immediate transfer to our tertiary centre for specialist support. Further investigations revealed a haptoglobin <0.1 g/L and direct antiglobulin test (DAT) strongly positive for IgG (4+) and negative for C3d. The peripheral blood film showed severe anaemia, nucleated red cells, anisocytosis and spherocytes with no autoagglutination, schistocytes or platelet clumps. Thrombocytopaenia (platelets 49 +/- 109/L) was present. Differentials were ruled out, such as paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopaenia. HIV and hepatitis serology were negative, as were adenovirus, cytomegalovirus and Epstein-Barr virus PCR assays. A CT showed splenomegaly of 15.5 cm. Urinalysis found urobilinogen and bilirubin at high concentrations and negative urinary haemosiderin. Together, the investigations were consistent with warm AIHA. On day 29, four units of PRBC were transfused alongside 100 mg methylprednisolone and 1 g/kg IVIG. On day 30 the patient deteriorated despite the escalated treatment: Hb had only increased to 54 g/L, bilirubin was 200 mumol/L and LD was rising. Considering this life-threatening fulminant haemolysis, an emergency splenectomy was performed. This slowed haemolysis but did not completely ameliorate it: by day 33 the patient had received 15 units of PRBC. Thus, eculizumab, a terminal complement pathway inhibitor, was trialled to arrest intravascular haemolysis, alongside rituximab, repeat IVIG 1 g/kg, prednisolone 40 mg and tacrolimus 2 mg. This showed a favourable response, requiring less frequent transfusions and settling haemolysis. This case highlights the rare complication of warm AIHA with the SARS-CoV- 2 Pfizer-BioNTech vaccine, the use of emergency splenectomy for disease control, and the potential of eculizumab for refractory cases.

Longitudinal associations of social support, everyday social interactions, and mental health during the COVID-19 pandemic

Main effect models contend that perceived social support benefits mental health in the presence and the absence of stressful events, whereas stress-buffering models contend that perceived social support benefits mental health especially when individuals are facing stressful events. We tested these models of how perceived social support impacts mental health during the COVID-19 pandemic and evaluated whether characteristics of everyday social interactions statistically mediated this association – namely, (a) received support, the visible and deliberate assistance provided by others, and (b) pleasantness, the extent to which an interaction is positive, flows easily, and leads individuals to feel understood and validated. 591 United States adults completed a 3-week ecological momentary assessment protocol sampling characteristics of their everyday social interactions that was used to evaluate between-person average values and within-person daily fluctuations in everyday social interaction characteristics. Global measures of perceived social support and pandemic-related stressors were assessed at baseline. Psychiatric symptoms of depression and anxiety were assessed at baseline, at the end of each day of ecological momentary assessment, and at 3-week follow-up. Consistent with a main effect model, higher baseline perceived social support predicted decreases in psychiatric symptoms at 3-week follow-up (β = −.09, p =.001). Contrary to a stress-buffering model, we did not find an interaction of pandemic-stressors × perceived social support. The main effect of perceived social support on mental health was mediated by the pleasantness of everyday social interactions, but not by received support in everyday social interactions. We found evidence for both main effects and stress-buffering effects of within-person fluctuations in interaction pleasantness on daily changes in mental health. Results suggest the importance of everyday social interaction characteristics, especially their pleasantness, in linking perceived social support and mental health.

"I Don't Want to Go to Work": A Mixed-Methods Analysis of Healthcare Worker Experiences from the Front- and Side-Lines of COVID-19.

During the COVID-19 pandemic, healthcare workers (HCW) were categorized as "essential" and "non-essential", creating a division where some were "locked-in" a system with little ability to prepare for or control the oncoming crisis. Others were "locked-out" regardless of whether their skills might be useful. The purpose of this study was to systematically gather data over the course of the COVID-19 pandemic from HCW through an interprofessional lens to examine experiences of locked-out HCW. This convergent parallel mixed-methods study captured perspectives representing nearly two dozen professions through a survey, administered via social media, and video blogs. Analysis included logistic regression models of differences in outcome measures by professional category and Rapid Identification of Themes from Audio recordings (RITA) of video blogs. We collected 1299 baseline responses from 15 April 2020 to 16 March 2021. Of those responses, 12.1% reported no signs of burnout, while 21.9% reported four or more signs. Qualitative analysis identified four themes: (1) professional identity, (2) intrinsic stressors, (3) extrinsic factors, and (4) coping strategies. There are some differences in the experiences of locked-in and locked-out HCW. This did not always lead to differing reports of moral distress and burnout, and both groups struggled to cope with the realities of the pandemic.

Comparison of Survivorship and Failure Modes Between Anatomic and Reverse Total Shoulder Arthroplasty Across Multiple Government Joint Registries for a Single Platform Shoulder System

[...]recent years have seen a dramatic shift in utilization of rTSA in which rTSA is increasingly used to treat OA in patients with an intact rotator cuff, with a corresponding decline in use of aTSA.1-5 The reasons for this shift in usage are multi-factorial but may be due to the perceived lower risk of revision surgery with rTSA relative to aTSA, as the quality of the rotator cuff muscles and tendon are not necessary for a functional rTSA but are pre-requisite for a functional aTSA. Furthermore, these registries have high rates of government-mandated compliance such that all patients are enrolled and very few patients are lost to follow-up, thus minimizing the potential for selection bias that is inherently present in nearly all nongovernment registry clinical outcome studies. [...]to better understand the relative differences in primary aTSA and primary rTSA usage and performance, we analyzed two different government joint registries for survivorship and for reasons for revision associated with one platform shoulder system and compared trends in usage of aTSA and rTSA over a period of over 10 years to elucidate reasons for any market trends. Additionally, reasons for revision and the cumulative revision rate were assessed across the government joint registries to quantify and compare the performance of this platform shoulder prosthesis for primary aTSA and primary rTSA in each country over the study period. Over the period of analysis, use of primary aTSA and primary rTSA with the particular platform system has increased year to year in both Australia and the UK, with the exception of a decline in 2020 and 2021 due to COVID-19.

School-related violence during the COVID-19 pandemic

During a global pandemic, there are unique and unprecedented challenges to all segments of society. For more than 3 years, schools and families alike have been faced with compromising life situations that have resulted in forms of anxiety and violence. Early studies are provided as are directions for further research in this area. Addressed are issues related to violence in the home, issues related to quarantined situations, some of the stresses of the global COVID-19 pandemic on children, parents, teachers, and community members, and the lessons learned during this very difficult time frame. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

Past as Prologue: The Effects of the COVID-19 Economic Downturn on Medicaid Coverage for Podiatry Services.

As of 2016, Medicaid accounted for nearly 20% of state general fund budgets. Optional Medicaid services like podiatry are often subject to cost-cutting measures in periods of economic downturn, as was the case in the wake of the 2007 financial crisis. Although the cuts were intended as a cost-saving measure, research indicates they had the opposite effect. The restriction and limitation of these services during the Great Recession resulted in both poorer health outcomes for beneficiaries, and poorer financial outcomes for state Medicaid programs. With states citing record levels of unemployment as of April 2020 and projecting significant declines in annual revenue in 2021, the economic conditions resulting from the COVID-19 pandemic are likely to rival those of the Great Recession. Given the historical precedent for restricting or eliminating optional Medicaid services as a cost-saving measure, it is likely that podiatric services will once again come under scrutiny. Previous efforts by state-level podiatric societies have proven successful in lobbying for the reinstatement of coverage under Medicaid by conveying evidence of the negative outcomes associated with elimination to stakeholders. The specialty must once again engage policymakers by drawing on evidence gleaned and lessons learned from past cuts of optional Medicaid services to avert counterproductive coverage restrictions intended to mitigate the financial impact of the COVID-19 pandemic.

The Reports of my Death are Greatly Exaggerated: An Evaluation of Futility Cut-Points in Massive Transfusion.

BACKGROUND: Following COVID and the subsequent blood shortage, several investigators evaluated futility cut-points in massive transfusion. We hypothesized that early, aggressive use of damage control resuscitation, including whole blood (WB), would demonstrate that these cut-points of futility were significantly underestimating potential survival among patients receiving >50 units of blood in the first four hours. METHODS: Adult trauma patients admitted from 11/2017-10/2021 who received emergency-release blood products in prehospital or ED setting were included. Deaths within 30 min of arrival were excluded. Total blood products were defined as total RBC, plasma, WB in the field and in the first 4 hours after arrival. Patients were first divided into those receiving ≤50 or > 50 units of blood in the first 4 hours. We then evaluated patients by whether they received any WB or received only component therapy (COMP). 30-day survival was evaluated for all included patients. RESULTS: 2,299 patients met inclusion (2,043 in ≤50 U, 256 in >50 U groups). While there were no differences in age or gender, the >50 U group was more likley to sustain penetrating injury (47 vs 30%, p < 0.05). Patients receiving >50 U of blood had lower field and arrival blood pressure and larger prehospital and ED resuscitation volumes (p < 0.05). Patients in the >50 U group had lower survival than those in the ≤50 cohort (31 vs 79%; p < 0.05). Patients who received WB (n = 1,291) had 43% increased odds of survival compared to those who received COMP (n = 1,008)(1.09-1.87, p = 0.009) as well as higher 30-day survival at transfusion volumes >50 U. CONCLUSION: Patient survival rates in patients receiving >50 units of blood in the first 4 hours of care are as high as 50-60%, with survival still at 15-25% after 100 units. While responsible blood stewardship is critical, futility should not be declared based on high transfusion volumes alone. LEVEL OF EVIDENCE: Level III, Retrospective comparative study without negative criteria.

SARS-CoV-2 S1 Subunit Booster Vaccination Elicits Robust Humoral Immune Responses in Aged Mice.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has raised concerns about reduced vaccine effectiveness and the increased risk of infection, and while repeated homologous booster shots are recommended for elderly and immunocompromised individuals, they cannot completely protect against breakthrough infections. In our previous study, we assessed the immunogenicity of an adenovirus-based vaccine expressing SARS-CoV-2 S1 (Ad5.S1) in mice, which induced robust humoral and cellular immune responses (E. Kim, F. J. Weisel, S. C. Balmert, M. S. Khan, et al., Eur J Immunol 51:1774-1784, 2021, https://doi.org/10.1002/eji.202149167). In this follow-up study, we found that the mice had high titers of anti-S1 antibodies 1 year after vaccination, and one booster dose of the nonadjuvanted rS1Beta (recombinant S1 protein of SARS-CoV-2 Beta [B.1.351]) subunit vaccine was effective at stimulating strong long-lived S1-specific immune responses and inducing significantly high neutralizing antibodies against Wuhan, Beta, and Delta strains, with 3.6- to 19.5-fold increases. Importantly, the booster dose also elicited cross-reactive antibodies, resulting in angiotensin-converting enzyme 2 (ACE2) binding inhibition against spikes of SARS-CoV-2, including Omicron variants, persisting for >28 weeks after booster vaccination. Interestingly, the levels of neutralizing antibodies were correlated not only with the level of S1 binding IgG but also with ACE2 inhibition. Our findings suggest that the rS1Beta subunit vaccine candidate as a booster has the potential to offer cross-neutralization against broad variants and has important implications for the vaccine control of newly emerging breakthrough SARS-CoV-2 variants in elderly individuals primed with adenovirus-based vaccines like AZD1222 and Ad26.COV2.S. IMPORTANCE Vaccines have significantly reduced the incidences of severe coronavirus disease 2019 (COVID-19) cases and deaths. However, the emergence of SARS-CoV-2 variants has raised concerns about their increased transmissibility and ability to evade neutralizing antibodies, especially among elderly individuals who are at higher risks of mortality and reductions of vaccine effectiveness. To address this, a heterologous booster vaccination strategy has been considered as a solution to protect the elderly population against breakthrough infections caused by emerging variants. This study evaluated the booster effect of an S1 subunit vaccine in aged mice that had been previously primed with adenoviral vaccines, providing valuable preclinical evidence for elderly people vaccinated with the currently approved COVID-19 vaccines. This study confirms the potential for using the S1 subunit vaccine as a booster to enhance cross-neutralizing antibodies against emerging variants of concern.

The Suicidal Ideation Attributes Scale-Modified (SIDAS-M): Development and preliminary validation of a new scale for the measurement of suicidal ideation in autistic adults.

LAY ABSTRACT: Autistic people may be at higher risk of suicidal behavior than people in the general population. Suicidal behavior may include thinking about suicide or attempting to end one's own life by suicide. It is important to identify autistic people who may be thinking about suicide. People who are at risk of suicidal behavior can be identified by asking questions about whether they have been thinking about suicide. A specially designed questionnaire, or screening instrument, can help someone ask the best questions to find out if someone has been thinking about suicide. This information can help to identify supports to be put in place to prevent suicidal behavior, such as a suicide attempt. However, autistic people may interpret questions differently than non-autistic people. It is important to use screening tools that have been designed with, and for autistic people. In this study, we examined the Suicidal Ideation Attributes Scale (SIDAS). The SIDAS is an existing tool that was developed to screen for suicidal thinking in the general population. We modified SIDAS for use with autistic adults. We involved autistic people in the process of modifying SIDAS. We called the modified instrument the SIDAS-M. The results of our study showed SIDAS-M may be useful for screening for suicidal thinking in autistic adults who do not have an intellectual disability.

Data-driven analysis to understand long COVID using electronic health records from the RECOVER initiative.

Recent studies have investigated post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) using real-world patient data such as electronic health records (EHR). Prior studies have typically been conducted on patient cohorts with specific patient populations which makes their generalizability unclear. This study aims to characterize PASC using the EHR data warehouses from two large Patient-Centered Clinical Research Networks (PCORnet), INSIGHT and OneFlorida+, which include 11 million patients in New York City (NYC) area and 16.8 million patients in Florida respectively. With a high-throughput screening pipeline based on propensity score and inverse probability of treatment weighting, we identified a broad list of diagnoses and medications which exhibited significantly higher incidence risk for patients 30-180 days after the laboratory-confirmed SARS-CoV-2 infection compared to non-infected patients. We identified more PASC diagnoses in NYC than in Florida regarding our screening criteria, and conditions including dementia, hair loss, pressure ulcers, pulmonary fibrosis, dyspnea, pulmonary embolism, chest pain, abnormal heartbeat, malaise, and fatigue, were replicated across both cohorts. Our analyses highlight potentially heterogeneous risks of PASC in different populations.

Cigarette smoke preferentially induces full length ACE2 expression in differentiated primary human airway cultures but does not alter the efficiency of cellular SARS-CoV-2 infection

Background Cigarette smoking has many serious negative health consequences. The relationship between smoking and SARS-CoV-2 infection is controversial, specifically whether smokers are at increased risk of infection. We investigated the impact of cigarette smoke on ACE2 isoform expression and SARS-CoV-2 infection in differentiated primary human bronchial epithelial cells at the air-liquid-interface (ALI). We assessed the expression of ACE2 in response to CSE and therapeutics reported to modulate ACE2. We exposed ALI cultures to cigarette smoke extract (CSE) and then infected them with SARS-CoV-2. We measured cellular infection using flow cytometry and whole-transwell immunofluorescence. We found that CSE increased expression of full-length ACE2 (flACE2) but did not alter the expression of a Type I-interferon sensitive truncated isoform (dACE2) that lacks the capacity to bind SARS-CoV-2. CSE did not have a significant impact on key mediators of the innate immune response. Importantly, we show that, despite the increase in flACE2, CSE did not alter airway cell infection after CSE exposure. We found that nicotine does not significantly alter flACE2 expression but that NRF2 agonists do lead to an increase in flACE2 expression. This increase was not associated with an increase in SARS-CoV-2 infection. Our results are consistent with the epidemiological data suggesting that current smokers do not have an excess of SARS-CoV-2 infection. but that those with chronic respiratory or cardiovascular disease are more vulnerable to severe COVID-19. They suggest that, in differentiated conducting airway cells, flACE2 expression levels may not limit airway SARS-CoV-2 infection.

Local, regional, and global adaptations to a compound pandemic-weather stress event

Global food security can be threatened by short-term extreme events that negatively impact food production, food purchasing power, and agricultural economic activity. At the same time, environmental pollutants like greenhouse gases (GHGs) can be reduced due to the same short-term extreme stressors. Stress events include pandemics like COVID-19 and widespread droughts like those experienced in 2015. Here we consider the question: what if COVID-19 had co-occurred with a 2015-like drought year? Using a coupled biophysical-economic modeling framework, we evaluate how this compound stress would alter both agricultural sector GHG emissions and change the number of undernourished people worldwide. We further consider three interdependent adaptation options: local water use for crop production, regional shifts in cropland area, and global trade of agricultural products. We find that GHG emissions decline due to reduced economic activity in the agricultural sector, but this is paired with large increases in undernourished populations in developing nations. Local and regional adaptations that make use of natural resources enable global-scale reductions in impacted populations via increased global trade.

Blood RNA alternative splicing events as diagnostic biomarkers for infectious disease

Summary Assays detecting blood transcriptome changes are studied for infectious disease diagnosis. Blood-based RNA alternative splicing (AS) events, which have not been well characterized in pathogen infection, have potential normalization and assay platform stability advantages over gene expression for diagnosis. Here, we present a computational framework for developing AS diagnostic biomarkers. Leveraging a large prospective cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and whole-blood RNA sequencing (RNA-seq) data, we identify a major functional AS program switch upon viral infection. Using an independent cohort, we demonstrate the improved accuracy of AS biomarkers for SARS-CoV-2 diagnosis compared with six reported transcriptome signatures. We then optimize a subset of AS-based biomarkers to develop microfluidic PCR diagnostic assays. This assay achieves nearly perfect test accuracy (61/62 = 98.4%) using a naive principal component classifier, significantly more accurate than a gene expression PCR assay in the same cohort. Therefore, our RNA splicing computational framework enables a promising avenue for host-response diagnosis of infection. Graphical abstract Highlights • We present a computational framework for alternative splicing (AS) diagnostic markers• Our AS biomarkers outperform gene-expression biomarkers in COVID-19 detection• Microfluidic PCR diagnostic assay of AS biomarkers achieves greater than 98% accuracy• We interpret the biological importance of identified AS biomarkers Motivation Host-based response assays (HRAs) can often diagnose infectious disease earlier and more precisely than pathogen-based tests. However, the role of RNA alternative splicing (AS) in HRAs remains unexplored, as existing HRAs are restricted to gene expression signatures. We report a computational framework for the identification, optimization, and evaluation of blood AS-based diagnostic assay development for infectious disease. Using SARS-CoV-2 infection as a case study, we demonstrate the improved accuracy of AS biomarkers for COVID-19 diagnosis when compared against six reported transcriptome signatures and when implemented as a microfluidic PCR diagnostic assay. Host-based response assays can diagnose infectious disease earlier and more precisely than pathogen-based tests. However, the role of RNA alternative splicing (AS) remains unexplored. Zhang et al. present a computational framework for AS diagnostic biomarkers. Using SARS-CoV-2 as a case study, they demonstrate the improved accuracy of AS biomarkers for COVID-19 diagnosis.