EBV-related lymphoproliferative disease in Wiskott-Aldrich Syndrome patient

Case: Wiskott-Aldrich Syndrome (WAS) is a rare X-linked inborn error of immunity caused by mutations in the WAS gene. It is classically characterized by immunodeficiency, eczema, and micro-thrombocytopenia. It has been known since the 1960s that patients with WAS have an increased risk of lymphoproliferative disease though the exact incidence remains unknown in the American population. Limited case reports have discussed EBV-related lymphoproliferative disease in patients with WAS. We present a case of a 9-year-old boy with known WAS complicated by eczematous rash, thrombocytopenia, recurrent ear infections, and monoclonal gammopathy who was found to have submandibular EBV-associated lymphoid hyperplasia with associated lung and retroperitoneal lymphadenopathy. Family had been offered treatment with hematopoietic stem cell transplant but declined multiple times in the past. Earlier in the year, he presented with possible MIS-C with negative SARS-CoV-2 PCR. He presented to our hospital with mastoiditis and lymphadenopathy. Physical examination showed severe eczema on hands and tender right mastoid. Laboratory evaluation showed thrombocytopenia, elevated IgG of 6290, IgA of 744, IgE of 827, low IgM of 41, and 14% response to pneumococcal titers. He was empirically treated with intravenous antibiotics. ENT performed right postauricular incision and drainage and the culture grew Hemophilus influenza. Throughout his hospital stay, his submandibular lymphadenopathy became more prominent despite treatment. Core needle biopsy of right submandibular lymph node was suggestive of EBV-associated lymphoid hyperplasia. EBV PCR and antibodies were both positive. CT chest, abdomen, and pelvis revealed multifocal pulmonary lymphadenopathy and a diffuse, bilateral nodularity as well as retroperitoneal and mesenteric lymphadenopathy. He was given four doses of weekly Rituximab, which successfully decreased EBV viremia below linear detectability. Immunoglobulin replacement therapy (IgRT) was initiated. Bronchoalveolar lavage and lung biopsy were performed and are results are currently pending. Discussion(s): We present a case of a 9-year-old boy with known WAS awaiting transplant who was found to have submandibular EBV-associated lymphoid hyperplasia with associated lung and retroperitoneal lymphadenopathy. While lymphoproliferative disease is a known complication of WAS, EBV-related lymphoproliferative disease in WAS patients has only been reported as case reports and remains a rare but known complication of patient with WAS.Copyright © 2023 Elsevier Inc.

Development of warm autoimmune hemolytic anemia after initiation of Ruxolitinib in a patient with STAT1 gain-of-function mutation

Introduction: STAT1 gain-of-function (GOF) disease is associated with chronic mucocutaneous candidiasis (CMC) and a broad spectrum of infectious, inflammatory, and vascular manifestations. The Janus Kinase inhibitor ruxolitinib has been used successfully for CMC and autoimmune phenomena. We describe a case of warm autoimmune hemolytic anemia (WAIHA) in a patient with STAT1 GOF disease after initiating ruxolitinib. Case report: A 36-year-old man with STAT1 c.850G>A (p.Glu284Lys) mutation presented with CMC as well as recurrent viral and bacterial infections, lymphadenopathy, enteritis, nodular regenerative hyperplasia (NRH) and splenomegaly. Immune workup confirmed a combined immunodeficiency with hypogammaglobulinemia and T-cell lymphopenia. Ruxolitinib was initiated at 5 mg twice daily (due to pre-existing thrombocytopenia) with up titration over 3 months to 20 mg twice daily. He improved with weight gain, increased energy, resolution of chronic anemia, and improved lymphadenopathy and splenomegaly on imaging. Serum CXCL9 only minimally decreased from 4660 pg/ml to 3990 pg/ml. Soon after reaching ruxolitinib 20 mg twice daily, he developed JC viremia, prompting dose reduction to 15 mg BID. Within two weeks, he developed a non-COVID upper respiratory tract infection followed by fatigue, shortness of breath with ambulation, and dark urine. Emergency evaluation revealed warm antibody positive hemolytic anemia with a hemoglobin of 5 g/dL, and worsened thrombocytopenia. He was treated with blood transfusions, pulse steroids, and high-dose IVIG with stabilization but continued hemolysis. Due to the JC viremia, there was concern to give rituximab with increased PML risk. Bone marrow showed trilineage hematopoiesis, a mild increase in megakaryocytes and RBC precursors, and a loss of B-cell progenitors with retention of mature B cells. His B and T lymphocyte numbers had increased since prior to ruxolitinib, with a predominance of Tfh1-cells (58.7% of total Tfh-cells). He was started on sirolimus with a slow taper of prednisone with continued stable hemoglobin and platelets, and resolution of hemolysis after 3 months. Conclusion(s): To our knowledge, this is the first case of a STAT1 GOF patient developing WAIHA while receiving ruxolitinib therapy. Treatment choices were complicated by the risks of PML. Sirolimus combined with ruxolitinib allowed wean of corticosteroid and subsequent resolution of hemolysis.Copyright © 2023 Elsevier Inc.

Successful ECMO course in an Acquired Immune Deficiency Syndrome (AIDS) patient with ARDS complicated by pneumocystis jirovecii pneumonia and COVID-19: A unique case

Objectives: Reviewing current literature and case reports of patients placed on Venous-Venous ECMO support for HIV and AIDS, with confection with Pneumocystis pneumonia and covid-19 pneumonia. The use of extracorporeal membrane oxygenation (ECMO) in patients who have acute respiratory distress syndrome has been shown to have very good outcomes. However, there is limited data to support the initiation of ECMO in patients who have human immunodeficiency virus infection with or without acquired immune deficiency syndrome. Method(s): We present a unique and challenging case of a 30 year old male, with no known past medical history, unvaccinated against covid-19, who presented with one week of progressive shortness of breath. On admission he was found with moderate bilateral infiltrates and was diagnosed with covid-19 pneumonia. Despite appropriate medical therapy, patient developed worsening hypoxic respiratory failure. Found to have elevated (1- 3)-7beta;-d-glucan and tested positive for HIV. CD4 count 11, HIV viral load 70,000. The patient remained severely hypoxemic despite mechanical ventilation, sedation, paralytics and proning. Venous venous extracorporeal membrane oxygenation was initiated. Considering his non improvement with variety of antivirals and antibiotics and with elevated (1-3)-7beta;-d-glucan in the setting of AIDS he was treated for presumed Pneumocystis pneumonia. The patient tolerated proning while on VV ECMO and his course was complicated with bilateral pneumothorax necessitating chest tube placement. Result(s): The patient successfully completed 64 days on VV ECMO, where he was treated for PCP pneumonia, covid pneumonia, CMV viremia and tolerated initiation of anti-retroviral therapy. Patient was successfully decannulated, and ultimately discharged from the hospital. Conclusion(s): VV-ECMO can be a beneficial intervention with successful outcomes in severely immunocomprimised patients with AIDS. This case highlights the importance of minimizing sedation and early mobilization on ECMO support. (Figure Presented).

A baby girl with TBX1 haploinsufficiency who died after elective cardiac repair surgery due to suspected enteroviral meningitis

Introduction: TBX1 haploinsufficiency is an inborn error of immunity with the phenotype of DiGeorge Syndrome. DiGeorge Syndrome has variable immunodeficiency associated with grade of thymic hypoplasia ranging from mild with no infections to severe requiring thymus implant. Enterovirus is an example of an opportunistic infection that can be fatal in these patients. Case Presentation: A 1 year old girl with TBX1 haploinsufficiency complicated by Tetralogy of Fallot, pulmonary atresia, high arched palate, and vesicovaginal fistula presented for elective cardiac repair surgery from another country due to failure to thrive and cyanosis. She had no prior infectious history but was on sulfamethoxazole-trimethoprim for prophylaxis. She was asymptomatic with a negative COVID test but no other infectious studies performed. Immediately postoperatively, she was febrile and nasal respiratory viral panel was positive for rhinovirus/enterovirus with increased procalcitonin and leukocytosis with left shift. She decompensated with multi-organ failure and cardiac arrest on postoperative day two. She was cannulated to veno-arterial extracorporeal membrane oxygenation (ECMO). Pre-operatively, she had a normal absolute lymphocyte count. No thymus tissue was observed in surgery. She had profound CD3 lymphopenia to 130 cells/cmm when critically ill. Enteroviral meningitis was suspected as no infectious, cardiac, or other pathology could be identified causing decompensation. Enteroviral serum polymerase chain reaction (PCR) test was negative while lumbar puncture deferred due to clinical status. She was treated with immunoglobulin. Offlabel investigational drug pocapavir was considered but deferred to patient's irreversible neurological status. The patient was disconnected from ECMO and expired. Discussion(s): Though we cannot confirm that this patient had enteroviral meningitis, invasive enteroviral infections are associated with elevated transaminases, coagulopathy, and seizures all present in our patient. There has also been reported negative serum enteroviral PCR but positive CSF enteroviral PCR in an immunodeficient patient. Additionally, this case highlights the importance of immunologic evaluation in patients with DiGeorge Syndrome and questions if asymptomatic viral screening for viruses like enterovirus should be considered pre-operatively in patients with inborn errors of immunity. This case highlights potential treatment options for invasive enteroviral infections in patients with inborn errors of immunity: high dose immunoglobulin, fluoxetine, and pocapavir.Copyright © 2023 Elsevier Inc.

Prevalence of SARS-CoV-2 Viremia in Presymptomatic Blood Donors in the Delta and Omicron Variant Eras.

Presymptomatic plasma samples from 1596 donors reporting coronavirus disease 2019 infection or symptoms after blood donation were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and anti-S and anti-N antibodies. Prior infection and vaccination both protected from developing SARS-CoV-2 RNAemia and from symptomatic infection. RNAemia rates did not differ in the Delta and Omicron variant eras.

The kinetics of SARS-CoV-2 viremia in COVID-19 patients receiving remdesivir.

Detection of SARS-CoV-2 RNA in serum, viremia, has been linked to disease severity and outcome. The kinetics of viremia in patients receiving remdesivir has not been thoroughly studied and could help predict treatment response and outcome. We investigated the kinetics of SARS-CoV-2 viremia and factors associated with baseline viremia, viral clearance and 30-day mortality in patients receiving remdesivir. An observational study including 378 hospitalised patients (median age 67 years, 67% male) sampled with serum SARS-CoV-2 RT-PCR within ± 24 h of initiation of remdesivir treatment. Baseline viremia was present in 206 (54%) patients with a median Ct value of 35.3 (IQR = 33.3-37.1). In patients with baseline viremia, the estimated probability of viral clearance was 72% by day 5. Ct values decreased significantly during remdesivir treatment for viremic patients, indicating an increase in viral load. In total, 44 patients (12%) died within 30 days, and mortality was significantly associated with viremia at baseline (OR = 2.45, p = 0.01) and lack of viral clearance by day 5 (OR = 4.8, p = < 0.01). Viral clearance was not associated with any individual risk factor. Viremia appears to be a prognostic marker before and during remedesivir treatment. The resolution of viremia was similar to patients not receiving remdesivir in other studies, and the decrease in Ct values during treatment questions the antiviral capacity of remdesivir in vivo. Prospective studies are warranted to confirm our findings.

HIV care during the SARS-COV-2 pandemic for Black people with HIV in the UK

Background: The COVID-19 pandemic disproportionally affected black communities but the impact on HIV care in this group remains poorly understood. We evaluated measures of HIV care during the COVID-19 pandemic in the GEN-AFRICA cohort of black people with HIV living in the U.K. Method(s): We evaluated interruptions to HIV care during the COVID-19 pandemic (01/2020-09/2022) in the GENAFRICA cohort at nine UK clinics who provided HIV outcomes for >80% of their participants. We ascertained death, transfers of care, loss to follow up for >12 months, the highest HIV viral load and interruptions to antiretroviral therapy (ART). We evaluated factors associated with the composite outcome of HIV viraemia (viral load >200 c/mL) and/or an ART interruption using logistic regression analysis;factors associated (P<0.1) in univariable analysis were included in the multivariable model. We also summarized reasons for ART interruptions where recorded. Result(s): 2321 participants (mean age 51.3 years;55.8% women;pre-pandemic current/nadir CD4 of 500/204 cells/mm3 and HIV RNA <200 c/mL in 92.3%) were in care on 01/01/2020. Thirty (1.3%) subsequently died, 24 (1.0%) transferred care and 48 (2.1%) became lost to follow up. 523 (22.7%) reported an episode of COVID-19 and 1771 (87.1%) having been vaccinated against SARSCoV- 2. The composite outcome could be evaluated in 2130 (91.8%);259 (11.2%) had a documented HIV VL >200 c/mL, 228 (9.8%) an ART interruption and 325 (14%) had HIV viraemia/ART interruption. In multivariable analysis, older age, a pre-pandemic HIV RNA <200 c/mL and being vaccinated against SARS-CoV-2 were associated with reduced odds of HIV viraemia/ART interruption (Table) while sex, CD4 (current/nadir), comorbid status and having had COVID-19 were not associated. Reasons for ART interruption were available for 52 participants;38% cited domestic logistic reasons, 27% issues related to foreign travel, 19% psychological reasons, 12% lockdown or changes to the daily routine and 4% personal choice. Conclusion(s): During the COVID-19 pandemic, one in seven black people with HIV experienced an ART interruption and/or HIV viraemia. Pre-pandemic measures of suboptimal engagement in care, pandemic restrictions, and wider health beliefs as reflected by COVID-vaccination, contributed to these undesirable HIV outcomes. (Table Presented).

Hiv Infection Increases Risk of Pasc While Covid-19 Vaccination Is Protective

Background: People with HIV (PWH) are at a higher risk of severe acute COVID-19;however, their risk of subsequently developing post-acute sequelae of SARS-CoV2 (PASC) remains unclear. Furthermore, although vaccination has been shown to be protective against PASC in the general population, few studies have evaluated its effectiveness in PWH. Method(s): We used the TriNetX health research database to source data from 69 healthcare organizations within the US. We included any adults aged >= 18 years with positive SARS-CoV-2 between January 1, 2020 and September 16, 2022 and categorized them based on their HIV status, baseline sociodemographic characteristics, comorbidities and COVID-19 vaccination status. The primary outcome was risk of PASC, compared by HIV and vaccination status after 1:1 propensity score matching. PASC was defined as either the persistence of COVID-attributable symptoms or the occurrence of new-onset health conditions at least 28 days following COVID-19 diagnosis. For all analysis, statistical significance was set at p < 0.05. Result(s): Of 3,048,792 people with confirmed SARS-CoV-2 infection, 1% (n=28,904) were PWH, with 9% of PWH (n=2592) vaccinated. At 28 days post-COVID-19 diagnosis, PWH had lower mortality compared with their non-HIV counterparts (OR 0.78, 95% CI 0.70-0.87), but higher risk of developing new-onset diabetes (DM) (OR 1.26, 95% CI 1.11-1.42), heart disease (OR 1.27, 95% 1.14-1.41), malignancy (OR 1.66, 95% CI 1.45-1.89), thrombosis (OR 1.25, 95% CI 1.12-1.39) and mental health disorders (OR 1.70 (95% CI 1.53-1.90). Furthermore, vaccinated PWH had significantly lower odds of death (OR 0.63, 95% CI 0.42- 0.93) and each new-onset PASC outcome, as follows: DM (OR 0.51, 95% CI 0.32- 0.82), heart disease (OR 0.44, 95% CI 0.29-0.67), malignancy (OR 0.43 (95% CI 0.25-0.74), thrombosis (OR 0.51, 95% CI 0.33-0.78) and mental health disorders (OR 0.49, 95% CI 0.30-0.79). The risk of PASC was higher during the pre-Delta variant period but did not vary based on CD4 count or HIV viremia. Conclusion(s): HIV infection confers a higher risk of PASC. Importantly, COVID-19 vaccination significantly lowered mortality and was protective against PASC among PWH. With the increase in the number of COVID-19 survivors, vaccination offers an effective preventive strategy to address a burgeoning public health problem. (Table Presented).

Epidemiological and Molecular Evolution of the Hiv-1 Crf94: Birth of Crf132

Background: In 2018 we reported the emergence of the new HIV-1 recombinant CRF94-02BF2 involved in a large transmission cluster of 49 French MSM mostly infected in 2016-2017. This CRF94 raised concerns of enhanced virulence. Prevention actions were undertaken in the area and population affected. This study reported the molecular and epidemiological evolution of this CRF94 until June 2022. Method(s): In 2021-2022, French sequence databases were screened for patients infected with HIV-1 subtype CRF94 or similar strain. HIV subtyping was confirmed by phylogenetic analysis of genes encoding both protease and reverse transcriptase (1070bps), and integrase (696bps) using IQ-Tree. Five whole genomes, related but distinct from CRF94, were obtained with the DeepChek assay Whole Genome kits. Recombination breakpoints were estimated using RDP4 and SimPlot. Mann-Whitney and LogRank tests were used for statistical analyses to compare patients' characteristics. Result(s): In June 2022, 49 new HIV-1 sequences were collected: 14 clustered with the 49 previous CRF94, 32 formed a new cluster next to but distinct from CRF94, and 3 strains could not be classified. Analysis of 5 whole genomes from the new cluster revealed a new recombinant, the CRF132-94B, mainly consisting of CRF94 which recombined with subtype B in the POL and accessory genes. Vif gene changed from the F2 to the B subtype. Both CRF94 and 132 clusters involved >95% of MSM, mostly infected < 1 year before diagnosis. However, there were differences: 97% were diagnosed in 2013-2019 for CRF94 vs 90% in 2020-2022 for CRF132. At time of diagnosis, 33% of patients infected with CRF94 knew the Prep vs 95% for CRF132. In the cluster CRF94, patients were older (34 vs 30 years, p=0.02), had higher viral loads (5.42 vs 4.42 log10 copies/Ml;p< 0.001), a lower CD4 cell counts (358 vs 508 /mm3, p=0.002). On treatment, the patients with the CRF94 reached viremia < 50 copies/Ml significantly later than those infected with CRF132 (p=0.0002). The prevention activities targeting the CRF94 cluster could explained the few patients infected with this strain after 2018. The CRF132 is mainly located in another Paris region area, but no specific transmission place has been identified. Conclusion(s): After 2019, the CRF94 spread seems greatly slowed down but the very close CRF132-94B has given birth to a new highly active cluster in 2020- 2022, despite the COVID social-distancing and a strong knowledge of the Prep. CRF132 appears to be less virulent perhaps due to the Vif gene change. Identified breakpoints positions of the new HIV-1 CRF132-94B. GenBank accession numbers of the five references : ON901787 to ON901791.

HIV CARE DURING THE SARS-CoV-2 PANDEMIC IN BLACK PEOPLE WITH HIV IN THE UK

Background: The COVID-19 pandemic disproportionally affected black communities but the impact on HIV care in this group remains poorly understood. We evaluated measures of HIV care during the COVID-19 pandemic in the GEN-AFRICA cohort of black people with HIV living in the United Kingdom. Method(s): We evaluated interruptions to HIV care during the COVID-19 pandemic (01/2020-09/2022) in the GEN-AFRICA cohort at nine UK clinics who provided HIV outcomes for >80% of their participants. We ascertained death, transfers of care, loss to follow up for >12 months, the highest HIV virus load, and interruptions to antiretroviral therapy (ART). We evaluated factors associated with the composite outcome of HIV viraemia (virus load >200 c/mL) and/or an ART interruption using logistic regression analysis;factors associated (P< 0.1) in univariable analysis were included in the multivariable model. We also summarized reasons for ART interruptions where recorded. Result(s): On 01/01/2020, 2321 GEN-AFRICA study participants (mean age 51.3 years;55.8% women;pre-pandemic current/nadir CD4 of 500/204 cells/mm3 and HIV RNA < 200 c/mL in 92.3%) were under active HIV follow up. Thirty (1.3%) subsequently died, 24 (1.0%) transferred care, and 48 (2.1%) became lost to follow up;523 (22.7%) reported an episode of COVID-19 and 1771 (87.1%) having been vaccinated against SARS-CoV-2. The composite outcome could be evaluated in 2130 (91.8%);259 (11.2%) had a documented HIV VL >200 c/mL, 228 (9.8%) an ART interruption, and 325 (14%) had HIV viraemia/ ART interruption. In multivariable analysis, older age, a pre-pandemic HIV RNA < 200 c/mL and being vaccinated against SARS-CoV-2 were associated with reduced odds of HIV viraemia/ART interruption (Table) while sex, CD4 (current/nadir), comorbid status and having had COVID-19 were not or no longer associated. Reasons for ART interruption were available for 52 participants;38% cited domestic logistic reasons, 27% issues related to foreign travel, 19% psychological reasons, 12% lockdown or changes to the daily routine, and 4% personal choice. Conclusion(s): During the COVID-19 pandemic, one in seven black individuals with HIV experienced an ART interruption and/or HIV viraemia. Pre-pandemic measures of suboptimal engagement in care, pandemic restrictions, and wider health beliefs as reflected by SARS-CoV-2 vaccination status, contributed to these undesirable HIV outcomes.

Three Doses of Covid-19 Vaccines in Pwh: Immunogenicity and Effects on Hiv Reservoir

Background: People with HIV (PWH) older than age 55 have an enhanced risk of complications from SARS-CoV-2 infection. It is unclear whether COVID-19 vaccines with a booster are as durable in terms of immunogenicity in this cohort or whether these vaccines can destabilize HIV reservoirs. Method(s): We prospectively studied 91 PWH on cART aged 55 or over (n=91) and 23 age-matched individuals without HIV (control group, CG) who received three doses of COVID-19 vaccines (D1-D3) over 48 weeks. Participants received combinations of BNT162b2, mRNA-1273, and ChAdOx1. Of PWH, 42 were immune responders (IR), 20 were non-responders (INR), and 3 had a low-level viremia (LLV). Total and neutralizing Abs to SARS-CoV-2 spike (S) and RBD in sera and saliva, frequency of anti-RBD/NTD memory B cells (spectral flow cytometry), S-specific T cell immunity (IFN-g, IL-2 ELISpot) and HIV reservoirs in peripheral CD4+ T cells (IPDA) were measured. Result(s): No significant differences in vaccine regimens or dosing intervals were observed between PWH and CG. Vaccines elicited equally strong anti-S IgG in PWH vs CG in serum and saliva, and RBD IgG in serum. Serum Abs peaked at 4w after D3. Week 48 serum IgG in PWH vs CG were 916 vs 919 BAU/ mL for S (p=0.624) and 706 vs 752 for RBD (p=0.198), respectively. Week 48 median saliva S IgG: 48.1% AUC of the positive control in PWH vs 95.9% for CG (p=0.384). S IgA: 3.83 vs 20.5 in PWH vs CG (p=0.039). Median neutralizing titers post-D2 were significantly lower in PWH than in CG (NT50 82.9 vs 535, p< 0.001). However, after D3, at 48w, PWH had similar titers as CG: 309 vs 269 (p=0.745), mirroring an increase in RBD/NTD-specific B cells in PWH. Anti-S T cell cytokine responses were stronger in IR PWH after D2 and D3 than in CG. Week 48 S IL-2 responses: median 135 SFC/106 PBMC vs 43.8 (p< 0.001), but only 12.5 in INR (p=0.001 vs IR). COVID-19 vaccines did not affect the size of HIV reservoir in PWH (change in median frequency of intact proviruses from baseline: 95.0 vs 90.9, p=0.952), except in three LLV PWH (mean increase 93.7% at 48w). Conclusion(s): PWH aged 55 and over show diminished neutralizing Ab responses to SARS-CoV-2 with two vaccine doses which are 'rescued' after a booster. PWH have lower S-specific IgA in saliva after vaccination which may affect protection. Enhanced S-specific T cell immunity in PWH suggests Th1 imprinting from preexistent HIV infection. COVID-19 vaccines did not destabilize the HIV reservoir in most PWH but may pose potential risk in unsuppressed viremia.

IMMUNE STATUS AND SARS-CoV-2 VIRAL DYNAMICS

Background: Immunocompromised persons are disproportionately affected by severe SARS-CoV-2 infection, but immune compromise is heterogenous, which may impact viral dynamics. We hypothesized that higher degrees of compromised immunity are associated with higher viral shedding and slower viral clearance in the absence of COVID-19 therapeutics. Method(s): Participants enrolled in ACTIV-2/A5401, a platform trial for COVID-19 therapeutics in non-hospitalized adults within 10 days of symptom onset, received either an active treatment or placebo between 8/2020 and 7/2021. Participants were categorized based on the extent of immunosuppression into none, mild, moderate and severe categories at enrollment (day 0). Longitudinal anterior nasal (AN) and plasma SARS-CoV-2 levels were measured with a quantitative PCR assay. Regression models assessed associations between immunocompromise severity and viral levels (VL) at day 0, and longitudinally among those on placebo with quantifiable RNA at day 0. Multivariate analyses adjusted for demographics and symptom duration and vaccination status at day 0. Result(s): Immunocompromised (mild 383, moderate 159, severe 35) and immunocompetent (1956) participants had comparable symptom durations at day 0 (median 6 days) and most were unvaccinated (~95%). AN VL at day 0 was higher in the moderate/severe group compared to the immunocompetent group (adjusted difference in means: 0.47 log10 copies/mL, 95% CI 0.12, 0.83). While AN VL decayed at similar rates among all groups from day 0 to 3, there was a trend towards higher cumulative AN VLs across the 28-day follow-up in the moderate/severe group compared to immunocompetent group (adjusted fold difference in VL AUC 1.63, 95%CI 0.95, 2.77). The mild group showed no differences in day 0 VL or AUC compared to the immunocompetent group. The frequency of detectable plasma SARS-CoV-2 RNA was similar at day 0 across all groups (overall 21%), but there appeared to be a higher proportion of immunocompromised participants with detectable plasma viral RNA at day 7 (moderate/severe 2/23 [9%], mild 5/44 [11%]) compared to the immunocompetent group (8/282, 3%). Conclusion(s): Before emergence of Omicron and widespread vaccination, moderate/severe immunocompromised status was associated with higher nasal viral levels at study enrollment and showed a trend towards higher cumulative AN viral load, and all immunocompromised groups appeared to have more persistent plasma viremia during follow-up.

BREAKTHROUGH HIV-1 INFECTION IN SETTING OF LONG-ACTING CABOTEGRAVIR FOR PrEP

Background: Long-acting cabotegravir (CAB-LA) is highly effective as HIV PrEP and superior to daily oral F/TDF in sexually active adults. We report a 28-yearold gender diverse patient assigned male at birth who acquired HIV-1 91 days after transitioning from F/TAF to CAB-LA despite on-time dosing. Method(s): Electronic medical records were reviewed to assess patient history and CAB-LA administration details. Plasma 4th generation HIV-1/2 Ag/Ab combination immunoassay and HIV-1 RNA quantitative PCR were performed at each injection visit. Result(s): Patient was on daily F/TAF for ten months prior to CAB-LA with acceptable adherence, missing 1 dose per week. Their medical history included hypothyroidism on levothyroxine and unconfirmed hypogonadism with illicit use of IM testosterone cypionate complicated by significantly elevated total testosterone levels. They were sexually active with cisgender men, endorsing condomless oral and anal sex with one primary partner and 20-30 unique partners per month. In the past 6 months, patient was diagnosed with syphilis and mpox. Patient was given 600mg of CAB-LA into their left gluteal medius on Day 0, 27, and 91. Day 0 and 27, plasma HIV 1/2 Ag/Ab was non-reactive and HIV-1 RNA PCR was not detected. Patient reported flu-like illness on Day 76 with positive SARS-COV-2 PCR;they completed a five-day course of nirmatrelvirritonavir with rapid resolution of symptoms. At the third injection of 600mg CAB-LA on Day 91, their plasma HIV 1/2 Ag/Ab was non-reactive but the HIV-1 RNA PCR test was detected at 1.48log c/mL. On repeat testing on Day 100, plasma HIV 1/2 Ag/Ab was reactive with HIV-1 Ab detected on differentiation assay and HIV-1 RNA PCR was detected at 1.30 log c/mL. Patient's primary partner was living with HIV resistant to NRTIs (65R, 118I) and INSTIs (92G) with undetectable plasma HIV-1 RNA for the past 24 months. Patient's viremia was below the threshold to perform standard HIV-1 sequencing;HIV-1 DNA qualitative PCR and HIV-1 proviral DNA resistance testing are currently pending. Patient ultimately started on F/TAF/DRV/COBI and DTG on Day 112. Conclusion(s): This patient's history suggests HIV-1 infection despite on-time and appropriate CAB-LA injections. To our knowledge, this is the first case of CAB-LA PrEP failure outside the setting of a clinical trial and highlights the diagnostic and management challenges that may arise with such breakthrough infections in the real world.

PROLONGED SARS-CoV-2 VIRAL BURDEN IN SIV-SARS-CoV-2 COINFECTED MACAQUES

Background: Individuals living with HIV are at increased risk of morbidity and mortality from COVID-19. Furthermore, SARS-CoV-2 infection in immunocompromised HIV infected individuals poses a risk to prolonged infection and viral shedding and the emergence of new variants of concern (VOCs). Using the SIV macaque model for AIDS, we are investigating the hypothesis that immune dysfunction during HIV infection will prolong SARSCoV- 2 viral infection, promote enhanced COVID-19 disease, and accelerate viral evolution. Here, we report the impact of SIV-CoV-2 co-infection on immune responses and pathogenesis. Method(s): Eight female rhesus macaques (aged 7-15 years, 5.5-9.9kg) were infected with SIVmac251 via low dose intravaginal challenge and then inoculated with 6.5x105 TCID50/mL SARS-CoV-2 (WA-1) at 17-34 weeks post-SIV infection via combined intranasal and intratracheal routes. Blood, bronchoalveolar lavage (BAL), stool, and nasal, oral, and rectal swabs were collected pre-infection through 14 days post-infection (DPI) to measure immune responses and viremia. ELISAs, ELISPOT, qRT-PCR, lung pathology, cytokine multiplex, and virus neutralization assays were performed to measure viral loads, pathogenesis, and immune responses. Result(s): Three days post-SARS-CoV-2 infection, we observed a transient decrease in CD4 counts, but there were no changes in clinical symptoms or plasma SIV viral loads. However, SARS-CoV-2 replication persisted in the upper respiratory tract, but not the lower respiratory tract. In addition, SARS-CoV-2 IgG seroconversion was delayed and antigen-specific T-cell responses were dampened. Notably, viral RNA levels in nasal swabs were significantly higher 7-14 DPI in SIV+ compared to previously published results using the same SARS-CoV-2 challenge virus in SIV- rhesus (PMCID: PMC8462335, PMC8829873). In addition, SIV/CoV-2 co-infected animals exhibited elevated levels of myeloperoxidase (MPO), a marker of neutrophil activation and increased lung inflammation. Conclusion(s): Here we provide evidence for the utility of the rhesus macaque in modeling human HIV-SARS-CoV-2 co-infection. Our results suggest that immunosuppression during SIV infection impairs de novo generation of anti-SARS-CoV-2 immunity, that may contribute to prolonged SARS-CoV-2 viral shedding, increased transmission windows, altered disease pathogenesis, and lower protection against subsequent SARS-CoV-2 exposures. Studies in progress will determine if SARS-CoV-2 viral evolution is accelerated in SIV-infected macaques.

EFFECTS OF COVID-19 mRNA VACCINATION ON HIV VIREMIA AND RESERVOIR SIZE IN PWH ON ART

Background: Transient viremia has been reported after COVID-19 mRNA vaccination in ART-suppressed PWH, suggesting a stimulatory effect on the HIV reservoir. A recent study also reported that Nef-specific CD8+ T cells increased and acquired granzyme-B effector function following COVID-19 mRNA vaccination, and that this correlated with markers of immune-mediated suppression of HIV-transcribing cells. That study however did not investigate HIV viremia, nor did it detect significant reservoir size changes in the 13 participants assessed. We investigated changes in HIV viremia and reservoir size following COVID-19 mRNA vaccination in 62 ART-treated PWH. Method(s): Participants (55 male;7 female) were sampled pre-vaccination, and one month after the first and second doses. Plasma HIV loads (pVL) were measured using the Cobas 6800 (LLOQ 20 copies/mL). Intact and total HIV copies/million CD4+ T cells were measured using the Intact Proviral DNA Assay. Anti-SARS-CoV-2 S serum antibody concentrations were measured using the Roche Elecsys Anti-S assay. Result(s): Pre-vaccination, 82% of participants had pVL < 20 copies/mL (max 110 copies/mL). No significant changes in pVL were observed post-vaccination (all p >0.4): one month post-first and second doses, 79% and 85% of participants had pVL < 20 copies/mL (max 183 and 79 copies/mL), respectively. Pre-vaccination, the median intact reservoir size was 80 (IQR:28-197;n=46) HIV copies/million CD4+ T cells. Intact reservoir size did not change significantly post-vaccination (all p >0.2): one month post-first and second doses, medians were 85 (IQR: 29-184;n=46) and 65 (IQR:22-168;n=29) copies/million CD4+ T cells, respectively. No significant changes in total, nor 5' and 3' defective proviral burdens were observed post-vaccination (all p >0.1), nor were any significant changes observed in any outcome upon stratification by sex, COVID-19 vaccine regimen, or ART regimen (here, multiple tests were addressed using q-values). Finally, no correlations were observed between the SARS-CoV-2 anti-S antibody response magnitude, and either the magnitude of change in reservoir size, nor the observation of detectable viremia, following the first and second vaccine doses (all p >0.2). Conclusion(s): Despite evidence that COVID-19 mRNA vaccination may induce HIV-specific immune responses, we observed no measurable changes in reservoir size nor lasting plasma viremia following COVID-19 mRNA immunization, regardless of anti-SARS-CoV-2 antibody response magnitude. (Figure Presented).

NK CELLS ARE CRITICAL FOR IN VIVO CONTROL OF SARS-CoV-2 REPLICATION AND DISEASE

Background: Natural killer (NK) cells play a critical role in control of viral infections. However, empirical evidence thus far has been unclear on the role of NK cells in pathogenesis and control of SARS-CoV-2 infection with some research suggesting NK cell accumulation as beneficial while others indicate it as deleterious. To address this crucial deficit in understanding, we employed a non-human primate infection model with a validated experimental NK cell depletion technique. Method(s): A total of 12 experimentally naive (75% female) cynomolgus macaques (CM) of Cambodian origin were used in this study. Six CM were NK cell-depleted using an anti-IL-15 neutralizing antibody, while six controls received placebo, prior to intranasal and intratracheal challenge with the SARS-CoV-2 Delta variant at a TCID50 of 1X105. The cohort was monitored for five weeks with scheduled blood, colorectal (CR) biopsies, and lymph node (LN) collections. Total envelope and sub-genomic viral loads (VL) were measured in the nasal cavity, throat, and bronchoalveolar lavage (BAL). 23-color flow cytometry, pathology, and 27-plex inflammatory analyte Luminex analyses were conducted. Statistical tests used were Mann-Whitney U and Spearman's Correlation. Result(s): Control CM exhibited an increase in the frequency of circulating NK cells, reaching a peak at 10 days post-infection (DPI) and returning to baseline by 22DPI. Simultaneously, NK cells expressing activation and tissue retention marker, CD69, also significantly increased. Cytotoxic NK cells were positively associated with VL (r=0.66;p=0.02), suggestive of a virus-induced mobilization. Total experimental NK cell ablation was verified in blood, CR, and LN of NK celldepleted CM, which had higher VL compared to controls in all tissues evaluated, reaching significance at 10DPI (p=0.01) and demonstrated a longer duration of viremia. Although Luminex measures were similar in plasma, BAL samples from NK cell-depleted CM had universally higher concentrations of inflammatory mediators, most notably a 25-fold higher concentration of IFN-alpha compared to controls. Lung pathology scores were also higher in NK cell-depleted CM with increased evidence of fibrosis, syncytia, pneumocyte hyperplasia, and endothelialitis. Conclusion(s): Overall, we find significant and conclusive evidence for NK cell-mediated control of SARS-CoV-2 virus replication and disease pathology. These data suggest adjunct therapies for infection could largely benefit from NK cell-targeted approaches.

Comparing clinical presentation, viremia, and immunological factors at various severity presentations in hospitalized children affected by COVID-19: A cross-sectional study.

Background and Aims: Although SARS-CoV-2 infection usually leads to mild COVID-19 in children, sometimes it causes serious complications, especially in those with underlying diseases. Several factors have been identified in determining disease severity in adults, and limited studies have been conducted in children. The prognostic implications of SARS-CoV-2 RNaemia as an important factor in determining disease severity in children are not well understood. Methods: In this study, we aimed to prospectively assess the relationship between disease severity and immunological factors and viremia in 47 COVID-19 hospitalized children. In this research, 76.5% of children experienced mild and moderate COVID-19, while 23.5% experienced severe and critical forms of the disease. Results: The presence of underlying diseases in different groups of pediatric patients differed significantly from each other. On the other hand, clinical symptoms such as vomiting and chest pain as well as laboratory parameters including erythrocyte sedimentation rate were significantly different in different groups of patients. Viremia was seen in only two children, and this had no significant relationship with the severity of COVID-19. Conclusion: In conclusion, our data confirmed that COVID-19 severity differed in SARS-CoV-2 infected children. Some clinical presentation and lab data parameters were different in various presentation of patients. Viremia was not associated with severity in our study.

COVID-19 convalescent plasma: Mechanisms of action and rationale for use: A narrative review

The use of convalescent plasma (CP) transfusions for patients with coronavirus disease 2019 (COVID-19) has gained great interest during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. This review aims at summarizing the literature on the potential mechanisms of action of COVID-19 CP (CCP) and the rationale for use. A narrative review of the literature was conducted using PubMed, Google Scholar, and the Cochrane Database through October 2020. The rationale of CCP deployment was based on historical use in other outbreaks and pandemics and the emergent need at the time of lack of proven therapies and vaccines. There are many proposed mechanisms of action including direct neutralization and suppression of viremia, antibody-dependent cellular cytotoxicity, modification of the inflammatory response, restoration of the coagulation factors, immunomodulation of the hypercoagulable state and the potential role of ABO naturally occurring iso-agglutinins. Many donor, product, and patient factors can impact the response to CCP, such as antibody titer in the CCP product, CCP dose, frequency of administration, the severity of underlying illness, and the timing of administration from time of disease onset. Based on current evidence, CCP appears to be safe. However, it remains unknown whether it impacts the improvement of clinical symptoms, time to death, and all-cause mortality. In conclusion, the use of CCP offers quick access as an empirical therapy when specific therapies are not available or under development. Ongoing clinical trials are expected to add to the breadth of knowledge on the safety and efficacy of CCP use in patients with COVID-19.Copyright © 2021 AME Publishing Company.

The Effect Of Covid-19 Infection On Sirolimus Metabolism In Heart Transplant

Introduction: Limited knowledge exists regarding the effect of Covid-19 on heart transplant recipients. Monitoring immunosuppressant levels is an important management strategy concerning the risk of graft rejection. Furthermore, how Covid-19 and its treatment affect sirolimus metabolism in solid organ transplants is not well understood. Here, we present a case of a heart transplant recipient with elevated sirolimus levels following Covid-19 infection. The elevated sirolimus levels occurred after previously being therapeutic on a steady dose and persisted despite significant dose reductions and no other known drug-drug interactions. Case Presentation: The patient is a 58-year-old male with a history of ischemic cardiomyopathy;status post orthotopic heart transplantation on 8/17/2009. The postoperative course was complicated by atrial tachycardia without rejection status post-ablation in 8/2020 and end-stage renal disease on hemodialysis. In January of 2022, the patient was instructed to present to the ER after missing dialysis due to Covid-like symptoms including generalized weakness, nausea, and shortness of breath. Covid-19 PCR returned positive. Before infection, the patient had been maintained on a steady dose of sirolimus 0.5 mg daily for 5 months with associated trough levels between the goal range of 4-8 ng/mL. At the time of infection, the patient's sirolimus was held due to elevated trough levels, and he was subsequently maintained on a dose of 0.5 mg every other day for the next few days. Seeing no improvement, the dose was then decreased to 0.25 mg every other day for the remainder of his admission. He expired on 2/09/2022 from Covid-19. Figure 1 shows the sirolimus trough:dose ratio before and after diagnosis of Covid-19. Discussion(s): To our knowledge, this is the first case presented of a heart transplant recipient with altered sirolimus metabolism status post Covid-19 infection without apparent drug-drug interactions. This may suggest a relationship between SARS-COV-2 viremia with sirolimus metabolism.Copyright © 2022

Severe immune thrombocytopenia that developed immediately after COVID-19 in a school-aged patient: A case report.

Immune thrombocytopenia (ITP) is an autoimmune disorder that is sometimes triggered by a preceding viral infection and is characterized by a transient or persistent decrease in the platelet (Plt) count. Herein, we report the first pediatric case of severe ITP that developed immediately after the diagnosis of coronavirus disease 2019 (COVID-19) in a school-aged girl. A previously healthy six-year-old girl was diagnosed with COVID-19 a day before experiencing a high fever, sore throat, and headache. She also presented with gingival hemorrhage, petechiae around both eyes and on the chest, and ecchymosis on her right leg. Based on the mucosal hemorrhage and a very low Plt count of 3 × 103/µl, we diagnosed her with severe ITP and urgently treated her with intravenous immunoglobulin (IVIG) to prevent life-threatening hemorrhage. The Plt count increased to 266 × 103/µl one week after treatment with IVIG. Given the possibility of severe ITP secondary to COVID-19, patients with COVID-19 should be carefully examined for the signs of ITP, such as mucosal hemorrhage. Their Plt counts should also be monitored.