Fc RECEPTOR-MEDIATED INFECTION OF MYELOID CELLS BY SARS-CoV-2

Background: The role of myeloid cells in the pathogenesis of SARS-CoV-2 is well established, in particular as drivers of cytokine production and systemic inflammation characteristic of severe COVID-19. However, the potential for myeloid cells to act as bona fide targets of productive SARS-CoV-2 infection remains unclear. Method(s): Using anti-SARS-CoV-2 mAbs with a range of neutralisation potencies and binding specificities, we performed a detailed assessment of mAb-mediated infection of monocytes/macrophages. THP-1 cells were used as a model system, with results confirmed in primary macrophages. Result(s): Infection of THP-1 cells was seen via mAbs targeting the spike RBD, but not with those targeting the NTD or S2 subunit. mAbs with the most consistent potential to mediate infection targeted a conserved region of the RBD (group 1/class IV). No infection was seen with the same quantity of virus but in the absence of antibody, and pre-treating the cells with FcgammaRI and -II blocking antibodies inhibited infection. Thus, antibody-FcR interactions are able to expand the tropism of SARS-CoV-2. Time-course studies demonstrated high-level and productive infection. Studies performed in human iPSC-derived macrophages and primary monocyte-derived macrophages paralleled results seen in THP-1 cells but with lower infection levels. Up to 2% of macrophages were infected, with infected cells appearing multinucleated and syncytial. Addition of ruxolitinib, an inhibitor of JAK1/2 signalling, increased infection up to 10-fold, indicating limitation of infection through innate immune mechanisms. Sera from primary infections (n=80) mediated rare infection events, with a minority of samples (n=3) promoting significant infection. Competition assays confirmed results seen in sera, with the addition of neutralising mAbs diminishing the infection seen with infection-mediating mAbs. Thus, the presence of antibodies with potential to mediate infection is not sufficient to predict myeloid cell infection, rather, the context in which the antibodies are produced is key. Conclusion(s): We hypothesise that a nascent antibody response during peak viral replication in primary infection presents a window of opportunity for myeloid cells to become infected, while establishment of a robust polyclonal response via vaccination or prior infection reduces the likelihood of this occurring. Infection via antibody-FcR interactions could contribute to pathogenesis in primary infection, systemic virus spread or persistent infection.

Multi-facetic tropism of SARS-CoV-2.

SARS-CoV-2 has a predilection for cell groups that are rich in ACE2 and TMPRSS2 receptors, which are distributed throughout the human body, which means that, in addition to the primary site of contagion or primary infection, which is the respiratory system, the virus tends to spread by different mechanisms, affecting practically all the known organs, apparatuses and systems, with which its tropism becomes extensive, being able to condition diverse pictures together with the respiratory one.Copyright © 2023 Comunicaciones Cientificas Mexicanas S.A. de C.V.. All rights reserved.

SARS-CoV-2 in Pediatric Intensive Care Unit.

In a lesser extent than adults Intensive Care Units (ICUs), Pediatric ICUs (PICUs) had to deal with the SARS-CoV-2 pandemic. Pediatric intensivists managed serious pediatric forms of primary infections and then in a second stage, post-infectious systemic inflammatory attacks. Some of them helped with the management of adults with a severe form of SARS-CoV-2. Therefore, they had to adapt in record time. In this review, we report (i) the literature data on these two severe pediatric forms, the primary infection and the systemic inflammatory manifestations associated with SARS-CoV-2;(ii) the experience of PICUs in the management of critically ill adults with SARS-CoV-2 infection and (iii) and the impact of the pandemic on the place of families of children in critical situation in PICUs.Copyright © SRLF 2021.

Experimental SARS-CoV-2 human challenge in young adults

Rationale: To establish a novel SARS-CoV-2 human challenge model enabling controlled investigation of pathogenesis, correlates of protection and efficacy testing of interventions. Method(s): Thirty-six healthy 18-29-year-old subjects, without evidence of previous infection or vaccination, received 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Following inoculation, subjects resided in a high-containment quarantine, with 24-hour medical monitoring. The study's main objectives were to identify a virus dose that induced well-tolerated infection in >50% of subjects and assess virus and symptoms over time. AEs and longitudinal disease profiles are presented. Result(s): Eighteen of thirty-four evaluable (~53%) subjects became infected and developed serum antibodies. Viral load rose steeply and peaked ~5 days post-inoculation (PI). Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies/ml (median, 95% CI [8.41,9.53]). Viable virus was recoverable from the nose up to ~10 days PI, on average. Mild-to-moderate symptoms were reported by 16 (89%) infected subjects, beginning 2-4 days PI. Anosmia or dysosmia developed in 15 (83%) subjects. Results from lateral flow tests were associated with viable virus and modelling showed that twice-weekly rapid antigen tests could diagnose infection before 70-80% of viable virus had been generated. There were no overt lung function changes, CT abnormalities, or SAEs. Conclusion(s): This novel SARS-CoV-2 challenge of 18-29-year-olds was considered safe. Viral kinetics over the course of primary infection was established, with implications for public health recommendations and strategies to impact transmission.

Meta-analysis of SARS-CoV-2 reinfection rate in the world.

Objective We aimed to review the data available to explore prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection in the real world. Methods We searched observational cohort studies and case-control studies that described the SARS-CoV-2 reinfections in PubMed, Embase, Web of Science, CNKI and WanFang Data from inception to 11 Dec 2022. Studies, data extracted and quality assessed were selected according to strict inclusion exclusion criteria. All analyses were using Stata version 16.0. Results A total of 24 studies were included, involving 78 635 cases of SARS-CoV-2 reinfection and 6 616 869 cases of SARS-CoV-2 primary infection. In cases after the primary SARS-CoV-2 infection, the pooled prevalence of reinfection was 2.06% (95% CI: 1.73% - 2.40%). Compared with other age groups, the secondary infection rate was higher in those aged 40 - < 50 years 2.97% (95% CI: -1. 20%-7 14%) and 50-<60 years 2. 32% (95% CI: -0.74%-5.38%). In vaccination status group, the pooled prevalence was 5.47% (95% CI: 1.99%-8.95%) in unvaccinated cases, 1.85% (95% CI: 1.63%-2.08%) for those received partial COVID-19 vaccination, and 1.11% (95% CI: 0.34%-1.89%) for those received fully vaccination. In addition, the pooled prevalence of SARS-CoV-2 reinfection was 6.02% (95% CI: 5.67%-6. 37%) in the health care workers. Conclusions There is a risk of SARS-CoV-2 reinfection, but the results of this global real-world meta-analysis showed that the rate of reinfection is not high. It is recommended to scientifically understand the risk of SARS-CoV-2 reinfection, strengthen public health education, maintain healthy habits, and reduce the risk of SARS-CoV-2 reinfection.Copyright © 2023, Publication Centre of Anhui Medical University. All rights reserved.

Risk factors for breakthrough COVID-19 in 15,804 UK adults after primary and booster doses of SARS-CoV-2 vaccines

Background: Little is known on the relative influence of demographic, behavioural, and vaccine-related factors on risk of post-vaccination SARS-CoV-2 infection. Aim(s): To determine risk factors for SARS-CoV-2 infection after primary and booster vaccinations. Method(s): We did a prospective population-based study in SARS-CoV-2-vaccinated UK adults, including data up to Feb 3, 2022. We built two Cox regression models to explore associations between sociodemographic, behavioural, clinical, pharmacological, and nutritional factors and incident SARS-CoV-2 infection after a primary course of vaccination and after a booster dose. Finding(s): 1017 (6.4%) of 15,804 fully vaccinated participants and 697 (6.1%) of 11,382 boosted participants reported breakthrough SARS-CoV-2 infection. A primary course of ChAdOx1 nCoV-19 (ChAdOx1) vs BNT162b2 was associated with higher risk of post-primary infection (adjusted HR 1.61, 95% CI 1.39-1.87). This effect remained after an mRNA booster dose (1.24 [1.04-1.49] for ChAdOx1 + BNT162b2 and 1.44 [1.07-1.92] for ChAdOx1 + mRNA1273, vs BNT162b2 + BNT162b2). Older age was associated with lower risk of infection after primary (0.96 [0.96- 0.97] per year) and booster (0.97 [0.96-0.98]) vaccinations, while lower educational level (1.71 [1.38-2.12] post primary and 1.47 [1.11-1.95] post booster for primary/secondary vs postgraduate) and at least three weekly visits to indoor public places (1.37 [1.15-1.64] post primary and 1.54 [1.21-1.96] post booster vs no visits) were associated with higher risk. Conclusion(s): Vaccine type, socioeconomic status, and behaviours affect risk of breakthrough SARS-CoV-2 infection following a primary schedule and a booster dose.

Risk and severity of SARS-CoV-2 reinfection among patients with multiple sclerosis vs. the general population: a population-based study

Introduction: Reports of reinfection in immunocompromised patients increased concern regarding multiple sclerosis (MS) patients since they are mostly on immunosuppressant agents. Objective(s): to compare the risk of reinfection between multiple sclerosis (MS) patients and a control group without MS. Aim(s): Measure the rate of possible reinfection among MS patients and control, protection against reinfection, odd of reinfection among those who previously tested positive;and effect of rituximab on the protection Method: In thisretrospective study, data of all SARS-CoV-2 tests (n=793,301) and almost all MS patients (n=10639) in Isfahan province were collected from January 01, 2020 to August 22, 2021. Of the 2196 MS patients and 793,301 persons from the general population who had been tested at least once, 3 control for each MS patient were identified, leaving 1560 MS patients and 4680 controls without MS. We compared the risk of reinfection after 90 days of a primary infection between those with and without a previous positive COVID-19 test. Result(s): 736 (48.2%) MS patients and 2013 (43.0%) control individuals had at least one positive test. A total of 17 (2.3%) and 22 (1.1%) possible reinfections in MS and control groups were observed. The adjusted risk ratio (RR) of infection among previously infected patients compared to uninfected persons in all MS patients was 0.318 (95%CI: 0.188, 0.538), MS patients on rituximab was 0.426 (95%CI: 0.169, 1.070), MS patients on DMTs rather than rituximab was 0.280 (95% CI: 146, 0.537), and control individuals was 0.179 (95%CI: 0.115, 0.279). The estimated protection against reinfection in all MS patients, MS patients on rituximab, MS patients on DMTs rather than rituximab, and controls were 68.2% (46.3%, 81.2%), 57.4% (-0.1%, 83.5%), 71.5% (45.5%, 85.2%), and 82.1% (72.1%, 88.5%), respectively. We found no statistically significant difference in estimated protection (p=0.123) and odd of reinfection (adjusted OR: 2.01 [0.98, 4.08]) between all MS patients and control group.Two patients were hospitalized at first infection but none required hospitalization at reinfection event. Conclusion(s): Prior SARS-CoV-2 infection is protective against reinfection in MS patients. Those on rituximab may be at a greater risk of reinfection. We found no evidence regrading increased risk of severe reinfection compared to the primary infection Further studies are required to assess the risk of the second reinfection among the MS population.

DISSEMINATED INVASIVE ASPERGILLUS MASQUERADING AS AMIODARONE-INDUCED THYROTOXICOSIS

SESSION TITLE: Rare Pulmonary Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Aspergillus is a group of opportunistic endemic fungal species that causes pathology within the respiratory tract and sinuses of individuals with predisposing factors, such as immunosuppression. While less frequently discussed, aspergillosis thyroiditis represents the most common fungal thyroiditis. We present a case of this condition that was misdiagnosed as amiodarone induced thyrotoxicosis. CASE PRESENTATION: A 54-year-old male was evaluated in outpatient pulmonary clinic after a chest CT revealed new upper lobe mass-like pleural based infiltrates with accompanying symptoms of dyspnea on exertion and fevers. His medical history was significant for orthotopic heart transplant 6 months ago due to a combination of non-ischemic cardiomyopathy with further decompensation from COVID-19 infection. After transplant, he was diagnosed with thyrotoxicosis secondary to amiodarone that was being treated with prednisone and methimazole. Given the concern for infection on imaging, he was admitted to the hospital and underwent urgent bronchoscopic evaluation. During the procedure, he was noted to have severe extrinsic tracheal compression. His neck imaging was consistent with a nodular goiter. The BAL revealed Aspergillosis fumigatus and he was subsequently treated with isavuconazium. Given the compression on the trachea and persistent dyspnea, the decision was to pursue total thyroidectomy. Surgery occurred 2 months after treatment was initiated for the Aspergillosis and with improvement on serial chest CTs. Pathologic examination of the thyroid tissue revealed extensive invasive aspergillus with abscesses involving both lobes. DISCUSSION: Aspergillus infection leading to disseminated disease typically occurs in individuals that have a compromised immune system such as seen in malignancy, solid organ transplant, chronic steroid use, and poorly controlled diabetes mellitus. Recently, it has been cited that up to 15% of hospitalized COVID-19 patients requiring intensive care develop aspergillus infection. After initial aspergillosis infection has been established, the thyroid gland is a site for dissemination due to its rich vascular supply. In addition, due to the angioinvasive properties of the pathogen, the fungus can breakdown tissue planes and easily travel from its site of origin. Thereby a primary infection in the respiratory tract can lead to dissemination to the neck structures due to its proximity. When thyroid invasion occurs, the common complaints are neck pain and swelling. Thyroid laboratory findings encompass the full spectrum including hyperthyroidism, hypothyroidism, and euthyroid. Given these non-specific findings, clinicians need to be conscious of this disease entity. CONCLUSIONS: In patients with immunocompromising conditions, findings of neck pain, swelling, and abnormal thyroid laboratory values should broaden the differential for clinicians to include aspergillosis thyroiditis. Reference #1: Alvi, Madiha M et al. "Aspergillus thyroiditis: a complication of respiratory tract infection in an immunocompromised patient.” Case reports in endocrinology vol. 2013 (2013): 741041. doi:10.1155/2013/741041 Reference #2: Marui, Suemi, et al. "Suppurative thyroiditis due to aspergillosis: a case report.” Journal of Medical Case Reports 8.1 (2014): 1-3. Reference #3: Kuehn, Bridget M. "Aspergillosis Is Common Among COVID-19 Patients in the ICU.” JAMA 326.16 (2021): 1573-1573. DISCLOSURES: No relevant relationships by A. Whitney Brown, value=Honoraria Removed 04/03/2022 by A. Whitney Brown No relevant relationships by A. Whitney Brown, value=Honoraria Removed 04/03/2022 by A. Whitney Brown No relevant relationships by A. Whitney Brown, value=Consulting fee Removed 04/03/2022 by A. Whitney Brown No relevant relationships by Kristen Bussa Advisory Committee Member relationship with Boehringer Ingelheim Please note: 2019-2021 Added 04/03/2022 by Christopher King, value=Consulting f e Advisory Committee Member relationship with Actelion Please note: 2019-2022 Added 04/03/2022 by Christopher King, value=Consulting fee Advisory Committee Member relationship with United Therapeutics Please note: 2019-2022 Added 04/03/2022 by Christopher King, value=Consulting fee Speaker/Speaker's Bureau relationship with Actelion Please note: 2019-2022 Added 04/03/2022 by Christopher King, value=Consulting fee Speaker/Speaker's Bureau relationship with United Therapeutics Please note: 2020-22 Added 04/03/2022 by Christopher King, value=Consulting fee No relevant relationships by Haresh Mani No relevant relationships by Mary Beth Maydosz No relevant relationships by Alan Nyquist No relevant relationships by Anju Singhal No relevant relationships by Amy Thatcher

MISSED TB DIAGNOSIS DURING THE COVID-19 PANDEMIC: MYTH OR REAL

SESSION TITLE: COVID-19 Case Report Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Miliary Tuberculosis (TB) is a rare disorder caused by the hematogenous dissemination of Mycobacterium tuberculosis. Patients infected with Mycobacterium tuberculosis can develop Miliary TB from primary infection or reactivation of a latent infection. Many patients with Miliary TB will present with symptoms of classic tuberculosis and in the pandemic time overlaps with symptoms of Covid-19. Since the Covid-19 pandemic the reported TB diagnosis fell 20% in 2020 and remained 13% lower in 2021 as compared to pre-COVID-19 pandemic. Decrease in cases may be due to pandemic-related mitigation efforts, such as social distancing and wearing masks. CASE PRESENTATION: This patient is a 23-year-old undocumented male who presented to the ED, originally in January of 2021, with complaints of generally not feeling well. He reported feeling feverish and having a poor appetite for the past 2 weeks. At this visit, the patient received testing for COVID-19, Influenza and strep;all of which were negative. He was then discharged home and instructed to follow-up outpatient. In July of 2021, the patient again presented to the ED with complaints of weakness, fevers, cough, and weight loss that have progressively worsened. A chest x-ray and CT chest were performed at this time which were positive for innumerable bilateral upper lobe predominant peri-bronchial vascular nodular airspace opacities and patchy areas of consolidation with central cavitation, highly suspicious for tuberculosis. A QuantiFERON gold test was ordered and the patient underwent bronchoscopy. After 2 weeks of hospitalization, a NAAT test came back positive for Tuberculosis. At this point, the patient was immediately started on rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE). The patient received 2 weeks of RIPE treatment and after being hospitalized for 1 month, he was then discharged home on RIPE therapy with strict instructions to follow-up outpatient. DISCUSSION: Similarities in symptoms of TB and COVID-19 may mean that some people who have TB are being evaluated for COVID-19, but not tested for TB. The case was very unusual in that the infection of TB went undiagnosed during his initial emergency department (ED) during the Pandemic surges. It had not been discovered until presenting to the ED 5 months later with worsening symptoms. In presenting this case, we hope to further education on Miliary TB and prevent future missed diagnoses given the extremely infectious nature of the disease. CONCLUSIONS: The 2020 and 2021 declines may be related to factors associated with the COVID-19 pandemic like similarities in symptoms between COVID-19 and TB disease may have led to missed TB diagnoses;widespread disruptions to healthcare during the COVID-19 pandemic may have delayed TB diagnoses;and Efforts to prevent COVID-19, such as wearing masks and staying six feet away from others, may also reduce the spread of TB. Reference #1: Masahiro Narita, Grace Hatt, Katelynne Gardner Toren, Kim Vuong, Monica Pecha, John A Jereb, Neela D Goswami, Delayed Tuberculosis Diagnoses During the Coronavirus Disease 2019 (COVID-19) Pandemic in 2020—King County, Washington, Clinical Infectious Diseases, Volume 73, Issue Supplement_1, 15 July 2021, Pages S74–S76, https://doi.org/10.1093/cid/ciab387 Reference #2: Cleverley J, Piper J, Jones MM. The role of chest radiography in confirming COVID-19 pneumonia. BMJ 2020;370 : m2426. Reference #3: https://www.cdc.gov/media/releases/2022/s0324-tuberculosis-covid-19.html DISCLOSURES: No relevant relationships by Nawal Aamir No relevant relationships by Gabrielle Gerbino

A FOUR-BODING FUTURE: POLYVIRAL INFECTION WITH SARS-COV-2, PARAINFLUENZA VIRUS TYPE 3, INFLUENZA A, AND ADENOVIRUS

SESSION TITLE: COVID-19 Co-Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Over the past 2 years, SARS-CoV-2 has been undergoing research regarding its immunopathology, with its understanding continuously evolving. We present a case of severe respiratory failure from viral co-infection with SARS-CoV-2, parainfluenza virus III, influenza A, and adenovirus. CASE PRESENTATION: A 42-year-old female with no respiratory or immunological comorbidities, was admitted with respiratory failure that progressed within days to severe septic shock and refractory hypoxemia requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). On initial laboratory evaluation, her nasopharyngeal swab sample tested positive for SARS-CoV-2, Parainfluenza virus III, Influenza A, and Adenovirus on our institute's ROCHE PCR detection test. This was then confirmed with an endotracheal sample and a BAL sample, each of which tested positive for the above 4 viruses. The patient had no prior history of lung disease, autoimmune disorder, immunodeficiency, or malignancy. Serum immunoglobulin levels were within normal range, and the patient tested negative for HIV. She was not on any immunomodulators, and had no known contacts with individuals with polyviral infection. Her presentation had been usual, with 6 days of fever, shortness of breath, extreme fatigue, coughing, and diarrhea. She had initially received treatment with remdesivir, tocilizumab, and dexamethasone. But these tests were noted to be positive prior to her receiving any therapies. Her hospital course was complicated by septic shock, refractory hypoxemia, secondary ventilator associated pneumonia, and fungemia, requiring invasive mechanical ventilation, inhaled nitric oxide, vasopressors, broad spectrum antimicrobials, and eventually rescue by VV-ECMO. She slowly recovered over 6 weeks, received a tracheostomy and was discharged to a long-term acute care hospital for continued rehabilitation and weaning from mechanical ventilation. At 1 year follow up, she has made a full recovery with no residual respiratory limitation. DISCUSSION: Co-infection is defined as infection at diagnosis within 7 days of initial primary infection, whereas, secondary infection develops after 7 days. Co-infection of respiratory viruses, though uncommon, has been reported. Their detection has improved with the use of PCR testing. Simultaneous infection of COVID-19 and usual respiratory viruses has also been documented. Effect of co-infection on disease severity is a result of interaction of viruses among themselves and with the host. CONCLUSIONS: COVID-19 research has mainly focused on SARS-CoV-2 effects on the human host, but with it evolving into an endemic, its interaction and co- and superinfection with other pathogens is imperative. Further research into such interactions of SARS-CoV2 are required to help develop preventative and therapeutic measures. Reference #1: Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with covid-19: A systematic review and meta-analysis. SSRN Electronic Journal. 2020. Reference #2: Kim D, Quinn J, Pinsky B, Shah NH, Brown I. Rates of co-infection between SARS-COV-2 and other respiratory pathogens. JAMA. 2020;323(20):2085. Reference #3: DaPalma T, Doonan BP, Trager NM, Kasman LM. A systematic approach to virus–virus interactions. Virus Research. 2010;149(1):1-9. DISCLOSURES: No relevant relationships by Vinita Kusupati No relevant relationships by Jyoti Lenka No relevant relationships by Rachel Tan

Approach to Common Pediatric Upper Respiratory Tract Infections

Upper respiratory tract infection (URI) is one of the most frequent diseases observed at centers for pediatric care and results in significant morbidity worldwide. URI is the most common cause in children treated against acute respiratory infection. The difficulty found by clinicians in establishing the differential and etiologic diagnosis of URIs and the occasionally indiscriminate use of antimicrobial drugs. URIs range from the common, cold-typically a mild, self-limited, catarrhal syndrome of the nasopharynx to life-threatening illnesses such as epiglottitis. Viruses account for most URIs. Appropriate management in these cases may consist of reassurance, education, and instructions for symptomatic home treatment. Diagnostic tests for specific agents are helpful when targeted URI therapy depends on the results. Bacterial primary infection or superinfection may require targeted therapy. The upper respiratory tract includes the sinuses, nasal passages, pharynx, and larynx, gateways to the trachea, bronchi, and pulmonary alveolar spaces. Rhinitis, pharyngitis, sinusitis, epiglottitis, laryngitis, and tracheitis are specific manifestations of URIs. Most URIs are viral in origin. Typical viral agents that cause URIs include the Rhinoviruses, Coronaviruses, Adenoviruses, and Coxsackieviruses. In the emergency department, attention should be paid to the patient's vital signs, including temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation (if obtained). Neonates are obligate nose breathers and may be at greater risk for respiratory distress;hence practitioners should auscultate the lungs for adequate aeration and assess breathing quality. The cardiovascular examination should assess adequate distal perfusion and an appropriate-for-age heart rate. Finally, dehydration can be a complication of any viral illness, and therefore, an assessment of hydration should be a part of the initial evaluation. Tests of nasopharyngeal specimens for specific pathogens are helpful when targeted therapy depends on the results (e.g., group A streptococcal infection, gonococcus, pertussis). Specific bacterial or viral testing is also warranted in other selected situations, such as when patients are immunocompromised, during inevitable outbreaks, or provide specific therapy to contacts. Symptombased therapy represents the mainstay of URI treatment in immunocompetent adults. Antimicrobial or antiviral therapy is appropriate in selected patients.

Waning natural and vaccine-induced immunity leading to reinfection with SARS-CoV-2 Omicron variant.

We have investigated six COVID-19 recovered cases with two doses of Covishield vaccination followed by reinfection. The primary SARS-CoV-2 infection found to occur with B.1 and reinfection with Omicron BA.1 and BA.2 variants. The genomic characterization and duration between two infections confirms these cases as SARS-CoV-2 reinfection. The immune response determined at different time intervals demonstrated boost post two dose vaccination, decline in pre-reinfection sera post 7 months and rise post reinfection. In conclusion, it was observed that these cases got SARS-CoV-2 reinfection with declined hybrid immunity acquired from primary infection and two dose covishield vaccination. This findings suggests the need to protect the community through booster dose of vaccination and prevent further infections following personal hygiene and non-pharmaceutical interventions.

Reinfection of SARS-CoV-2 in kidney transplant recipient

Coronavirus disease-2019 (COVID-19) which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, and later became a pandemic. While infection is very common, reinfection with SARS-CoV-2 is rare because immune responses from past infection reduce the risk of reinfection. In this report, we describe the case of a kidney transplant recipient who was reinfected with SARS-CoV-2 after successfully recovering from moderate COVID-19, 6 months ago. The first infection occurred in September 2020 while the reinfection occurred in April 2021. Our case highlights that kidney transplant recipients can be reinfected with COVID-19, and therefore, recovery from a primary infection should not be taken as license to shun COVID-related precautions. The disease severity, clinical course, and outcome of reinfection may be different from the first infection.

Prospective Evaluation of Serial Protein Biomarker Measurements in Sepsis-Induced Acute Respiratory Distress Syndrome

RATIONALE: Protein biomarkers including soluble receptor for advanced glycation end-products (sRAGE), angiopoietin-2 (Ang- 2), and surfactant protein-D (SP-D) have been studied for diagnosis or prognostication in acute respiratory distress syndrome (ARDS). However, prior studies of ARDS biomarkers often included heterogeneous populations, and rarely examined serial measurements. Our aim was to determine the association between serially measured sRAGE, Ang-2, and SP-D levels and ARDS development in patients with sepsis. METHODS: Adult patients admitted to the medical ICU at Grady Memorial Hospital within 72 hours of sepsis diagnosis were enrolled into this prospective observational cohort study within 48 hours of ICU admission. Patients who already had ARDS at the time of screening were excluded. After obtaining informed consent, serial plasma samples were collected on day 1, 2, and 3 of enrollment, and were analyzed for sRAGE, Ang-2, and SP-D levels using ELISA. The patients were followed for up to 28 days for relevant clinical characteristics and outcomes. The primary outcome was ARDS development according to the Berlin Definition. The secondary outcome was mortality. Pulmonary sepsis was defined as the primary infection being pneumonia (including COVID19) or aspiration pneumonia. The biomarker levels and their changes from day 1 to days 2/3 were compared between those who developed ARDS versus those who did not. RESULTS: Among 80 patients with sepsis enrolled between September 1, 2020 and June 22, 2021, 15 patients (18.8%) developed ARDS and 65 patients (81.3%) did not. ARDS patients had higher proportions of pulmonary sepsis (14/15 [93.3%] vs. 30/65 [46.2%], p=0.001) and COVID19 (7/15 [46.7%] vs. 7/65 [10.8%], p=0.003) compared to non-ARDS patients. ARDS patients had higher SP-D levels on days 1 and 2, and had a greater increase in sRAGE levels from day 1 to day 3, compared to non-ARDS patients (Figure 1A- 1B). Within the ARDS group, those who died had higher sRAGE levels on day 1 compared to those who survived (Figure 1C). CONCLUSIONS: In this analysis, ARDS patients had higher SP-D and a greater increase in sRAGE over time compared to non- ARDS patients. Non-survivors of ARDS also had higher sRAGE compared to survivors. Our findings suggest that early serial biomarker measurements may be useful for identifying sepsis patients at risk of developing ARDS and adverse clinical outcomes, and for risk stratifying sepsis patients in ARDS clinical trials focused on early therapeutics and prevention. Larger studies are needed for more detailed analyses and confirmation of these findings.

SARS-CoV-2 NEUTRALIZING RESPONSE beyond 1 YEAR after INFECTION

Background: Understanding the determinants of long-term immune responses to SARS-CoV-2 and the concurrent impact of vaccination and emerging variants of concern will guide optimal strategies to achieve global protection against the COVID-19 pandemic. Methods: A prospective cohort of 332 COVID 19 patients was followed beyond one year. Plasma neutralizing activity was evaluated using HIV-based reporter pseudoviruses expressing different SARS-CoV-2 spikes and was longitudinally analyzed using mixed-effects models. Results: Long-term neutralizing activity was stable beyond one year after infection in mild/asymptomatic and hospitalized participants. However, longitudinal models suggest that hospitalized individuals generate both short-and long-lived memory B cells, while responses of non-hospitalized were dominated by long-lived B cells. In both groups, vaccination boosted responses to natural infection. In unvaccinated participants, viral variants, mainly beta, reduced the efficacy of long-term (>300 days from infection) neutralization. Importantly, despite showing higher neutralization titers, hospitalized patients showed lower cross-neutralization of beta variant compared to non-hospitalized. Multivariate analysis identified severity of primary infection as the factor that independently determines both the magnitude and the inferior cross-neutralization activity of long-term neutralizing responses. Conclusion: Neutralizing response induced by SARS-CoV-2 is heterogeneous in magnitude but stable beyond one year after infection. Vaccination boosts these long-lasting natural neutralizing responses and should help counteract the resistance to neutralization of variants of concern such as the beta variant. Severity of primary infection determines higher magnitude but poorer quality of long-term neutralizing responses.

GETTING HEPATITIS C AGAIN

Sharp declines in the incidence of hepatitis C virus (HCV) have coincided with unrestricted access to direct-acting antivirals (DAA) against HCV, particularly among PLHIV in clinical care. However, rates of HCV reinfection are still high among specific key populations at risk of or living with HIV. This presentation begins with a case highlighting one individual's experience with PrEP use and HCV re-infection. An overview is then provided of the most recent data on the risk of HCV primary and re-infection among key populations, focusing on MSM and PWID. The potential effect of COVID-19 restrictions on HCV infection rates is also addressed. Issues regarding the role of testing, early diagnosis, and treatment in the acute phase of HCV infection, as well as the implications surrounding chemsex, are explored and recommendations for a comprehensive strategy to prevent new HCV infections are provided.

INFECTIOUSNESS of BREAKTHROUGH INFECTIONS after VACCINATION and NATURAL INFECTION

Background: SARS-CoV-2 breakthrough infections in vaccinated individuals and in those who had a prior infection have been observed globally, but the transmission potential of these infections is unknown. Methods: Leveraging the national databases, effects of vaccination and of prior infection on SARS-CoV-2 infectiousness were investigated by comparing the RT-qPCR cycle threshold (Ct) values (inversely correlated with viral load and culturable virus) in matched cohorts of primary infections in unvaccinated individuals, reinfections in unvaccinated individuals, BNT162b2 (Pfizer-BioNTech) breakthrough infections, and mRNA-1273 (Moderna) breakthrough infections. Pairwise comparisons were conducted assuming linear and non-linear relationships. Results: Through analyses of the randomly diagnosed infections, the mean Ct value was higher in all cohorts of breakthrough infections compared to the cohort of primary infections in unvaccinated individuals. The Ct value was 1.3 (95% CI: 0.9-1.8) cycles higher for BNT162b2 breakthrough infections, 3.2 (95% CI: 1.8-4.5) cycles higher for mRNA-1273 breakthrough infections, and 4.0 (95% CI: 3.4-4.6) cycles higher for reinfections in unvaccinated individuals. A sensitivity analysis assuming that infectiousness is non-linearly proportional to viral load yielded similar results. Conclusion: Differences imply that breakthrough infections are at least 50% less infectious than primary infections in unvaccinated individuals. Public health benefits of vaccination may have been underestimated, as COVID-19 vaccines not only protect against acquisition of infection, but also appear to protect against transmission of infection.

EFFICACY of NATURAL IMMUNITY AGAINST REINFECTION with SARS-CoV-2 B.1.351 VARIANT

Background: Reinfections with emerging SARS-CoV-2 variants are a serious concern. This study estimated the efficacy of immunity induced by natural infection against reinfection with B.1.351 and B.1.1.7 variants. Methods: Two retrospective matched cohort studies were conducted in Qatar from March 8-April 21 to assess reinfection in the national cohort of individuals with a prior PCR-confirmed infection and the national cohort of antibody-positive individuals, matching each in a 1:1 ratio by demographic characteristics to the national cohort of antibody-negative individuals. Incidence risks (using the Kaplan-Meier estimator), incidence rates, and efficacy of natural infection against reinfection were estimated. Results: In the study comparing 44,821 individuals with a prior PCR-confirmed infection to antibody-negative individuals, the efficacy of natural infection against reinfection was 92.3% (95% CI: 90.3-93.8%) for B.1.351, 97.6% (95% CI: 95.7-98.7%) for B.1.1.7, and 87.9% (95% CI: 84.7-90.5%) for unidentified variants (mostly suspected B.1.351 cases based on weekly sequencing analysis). In the second study, comparing 20,406 antibody-positive to antibody-negative individuals, efficacy was 86.4% (95% CI: 82.5-89.5%) for B.1.351, 96.4% (95% CI: 92.1-98.3%) for B.1.1.7, and 83.1% (95% CI: 77.2-87.5%) for unidentified variants. Additional analyses and sensitivity analyses confirmed these results, albeit with slightly lower efficacies. Conclusion: Natural infection with SARS-CoV-2 induces robust protection of 80-90% against reinfection with B.1.351 even a year after the primary infection, but lower than that against B.1.1.7.

The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection-study protocol for a two-stage randomised phase II trial.

BACKGROUND: Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. METHODS: RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. DISCUSSION: The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. TRIAL REGISTRATION: The protocol is registered on Clinical. TRIALS: gov and EudraCT and has approval from UK Ethics and MHRA.

Prevalence of Diabetes Mellitus and Impaired Glucose Tolerance in Patients with Covid-19

Objective: The aim of this study is to determine the prevalence of diabetes mellitus and impaired glucose tolerance in patients with COVID-19. Study Design:Cross-sectional study Place and Duration:Conducted at department of Medicine, Khyber Teaching Hospital (KTH),Peshawer and Avicenna Teaching Hospital, Lahorefor the duration from July 2020 to December 2020. Methods: There were one hundred and fifteen patients of both genders had coronavirus disease were included in this study.Patients ranged in age from 25 to 80 years.After obtaining informed written permission, we collected detailed demographic information on all of the registered patients, including their age, gender, BMI, educational attainment and place of residence. All of the patients had their blood tested for corona disease using RT-PCR. After screening positive (fasting capillary glucose >100 mg/dl and 200 mg/dl) and each sixth consecutive negative (fasting capillary glucose <100 mg/dl) subjects, the 75-g oral glucose tolerance test was administered. The SPSS 23.0 software was used for analyzing of data. Results:Included patients had mean age 59.4±12.55 years with mean body mass index 29.12±11.76 kg/m2. There were 70 (60.9%) male patients and 45 (38.1%) females. Majority of the patients were illiterate 65 (56.5%) and 49 (42.6%) patients were from urban areas. Most common co-morbidities were hypertension, hyperlipidemia, chronic kidney disease and coronary artery disease. We found 62 (53.9%) patients had diabetes mellitus in which majority of the cases were pre-existing. Frequency of impaired glucose tolerance was found among 26 (22.6%) cases in which majority of the cases had pancreatic cancer. 28 (24.4%) cases had intubation. Overall mortality was found among 18 (15.3%) cases. Conclusion:This research found that people with diabetes and poor glucose metabolism are more likely to have severe Covid-19. A previously undiagnosed symptom of primary infection has been linked to a disorder in glucose metabolism. Pathways through which SARS-CoV-2 affects glucose metabolism must be investigated if disease aetiology is to be fully understood.