Neutralising antibodies (NAbs) against SARS-CoV-2 in BNT162b2 vaccine recipients with a history of advanced HIV infection: cPass as a simpler alternative to gold-standard tests

Background: Established SARS-CoV-2 NAb tests are labor-intensive. We prospectively measured NAbs vs Wuhan-1 and Omicron BA.2 using the novel GenScript cPass assay and examined correlations with responses measured by gold-standard plaque reduction neutralisation test (PRNT) (Cotugno, Ruggiero et al. Cell Rep 2021) and with anti-Spike IgG quantified by Roche Elecsys. Given the paucity of data, we selected BNT162b2 vaccine recipients with a history of advanced HIV infection (prior AIDS-defining conditions and/or nadir CD4 <200 cells). Method(s): In Mar 2021-Apr 2022, 55 PWH received 2 vaccine doses median 3 weeks apart [IQR 3-3] and a 3rd dose 27 weeks later [23-31]. Plasma samples (n=147) were stored immediately before dose-1 (T0), median 4 weeks [3-5] after dose-2 (T1) and median 13 weeks [9-19] after dose-3 (T2) for batch testing. Result(s): Participants' characteristics: 74% male, 85% white, all on ART, 82% HIV-RNA <50 cps/ml;median age 55 years, ART duration 7 years, nadir CD4 83 cells [36-211], current CD4 440 cells [270-710], CD4:CD8 ratio 0.6 [0.4-1.0];73% had a history of advanced HIV infection;15% received a COVID-19 diagnosis during the study. At T0, T1 and T2, proportions with quantifiable anti-S IgG (>0.8 U/ml) were 11/49 (22%), 50/54 (93%) and 43/43 (100%), respectively;their median anti-S IgG titres were 30 [15-124], 15949 [596-3389] and 8527 [3146-17190] U/ml. Proportions showing Wuhan-1 neutralisation by cPass were 6/50 (12%), 45/53 (85%) and 40/43 (93%), with median neutralisations of 67% [47-70], 97% [91-98] and 98% [98-98] and corresponding NAb titres of 1332 [792-1436], 5354 [3529-6187] and 6242 [5765-6766] U/ml. At T2, 25/28 (89%) showed BA.2 neutralisation by cPass (median 83% [68-93];NAb titre 7836 [3172-12173] U/ml) (Fig 1A). Two participants lacking NAbs at T2 had a history of advanced HIV infection. cPass data were highly correlated with anti-S IgG titres (rho 0.82;p<0.0001) and with PRNT data for both Wuhan-1 (n=27, Fig 1B) and Omicron BA.2 (n=28, Fig 1C). Conclusion(s): cPAss offers a simple methodology for measuring SARS-CoV-2 NAbs. Despite prior advanced HIV infection, neutralising activity improved with successive vaccinations and most participants showed NAbs against both Wuhan-1 and Omicron BA.2 after 3 vaccine doses. (Figure Presented).

Impact of Gut Microbiota on Immunogenicity to Covid-19 Vaccines in Plwh

Background: Immune responses to SARS-CoV-2 vaccines in people living with HIV (PLWH) have been the focus of several recent studies. As the gut microbiome can influence vaccine immunogenicity, in this study we are the first to investigate whether the baseline gut microbiota can predict immune responses to the BNT162b2 SARS-CoV-2 vaccine in people living with HIV (PLWH) and healthy controls (HC). Method(s): Fecal samples were collected from PLWH (n=68) and HC (n=75) at baseline, prior to the first vaccine dose, to extract DNA for 16S rRNA sequencing. The individuals were part of the COVAXID Clinical trial, where humoral and cellular responses to SARS-CoV-2 vaccine were evaluated on day 35 after the first dose. Comprehensive bioinformatic tools were used for bacterial identification to further reveal the associations between gut microbiota and SARS-CoV-2 antibody, spike CD4+ T cell responses, and clinical parameters such as age, gender, CD4/CD8 ratio, and length of antiretroviral (ART) treatment. Result(s): At day 35 post vaccination, HC showed significantly higher spike IgG titers than PLWH (p=0.0001). Interestingly, both phylogenetic and alpha-diversity were negatively correlated with antibody titers, in the whole cohort and within groups. Similarly, individuals with low alpha-diversity had higher levels of spike specific CD4+T-cell responses. Agathobacter, Lactobacillus, Bacteroides, and Lachnospira were positively correlated with both antibody levels and spike-specific CD4+ T-cell responses while Methanobrevibacter, Marvinbryantia, Cloacibacillus, and Succinivibrio have a negative one. Within the PLWH group, the gut microbiota taxa associated with CD4+ counts, such as Lachnospira (p=0.002), Oscillibacter (p=0.019) and Flavonifractor (p=0.017), were found to be positively correlated with spike IgG levels. Additionally, the length of ART treatment and CD4/CD8 ratio displayed a positive association with bacterial diversity. Notably, different microbiome profiles and immune status in PLWH, affect their immune responses to vaccination. Conclusion(s): Our results show potential associations between gut microbiota diversity and spike IgG responses after COVID-19 vaccination. These findings were consistent in the whole cohort, albeit group differences between the microbiome compositions in PLWH and HC were observed. Based on our findings, we propose that microbiome modulation could optimize immunogenicity to SARS-Cov-2 vaccines.

Lymphocyte Trajectories and Outcomes of Covid-19 Infection in People with Hiv

Background: Studies have shown that lymphopenia and a decreased CD4/ CD8 ratio are correlated with the severity of COVID-19 infections. As people with HIV (PWH) can have altered CD4/CD8 ratios at baseline, this study examined the relationship between lymphocyte and T-cell subsets with COVID-19 disease outcomes among PWH. Method(s): This retrospective study included adult PWH (identified by HIV ICD codes, HIV RNA or antibody results, or antiretroviral therapy use excluding preexposure prophylaxis) in the Optum COVID-19 EHR database with positive SARSCoV- 2 PCR or antigen tests from February 2020 to December 2021. Outcomes included 30-day hospitalization, ICU stay, mechanical ventilation, and death from COVID-19. Absolute lymphocyte counts and percent and CD4:CD8 ratios were collected prior to SARS-CoV-2 positivity (baseline) and then weekly for four weeks post-SARS-CoV-2 positivity. We examined lymphocyte trajectories in PWH who had available data at all time points, and we compared changes in counts and percentages at each week post-SARS-CoV-2 to baseline values, using Wilcoxon rank sum test. Result(s): Of a total of 4,525 PWH who tested positive for SARS-CoV-2, 102 PWH had available lymphocyte counts at all study time points. Compared to non-hospitalized PWH (n=38), hospitalized PWH (n=64) and PWH who were in the ICU (n=32) or ventilator dependent (n=27) experienced a larger drop in lymphocyte percentage in the first two weeks post-SARS-CoV-2 diagnosis with only a partial recovery in subsequent weeks. In patients who died (n=19), lymphocyte percentage recovered even more slowly. Hospitalized PWH, as compared to non-hospitalized PWH, had a significant decrease in lymphocyte percentage post-SARS-CoV-2 infection in the first week (-0.19 vs -0.05;< 0.001), second week (-0.23 vs -0.02;< 0.001), third week (-0.20 vs 0.00;< 0.001), and fourth week (-0.10 vs 0.00;0.001), a trend seen in the ICU, mechanically ventilated, and deceased groups as well (Table 1). By the first week, CD4/CD8 ratio in COVID-19 positive patients was lower in the deceased (-0.18 vs 0.00;p=0.4), ventilator dependent (-0.15 vs 0.00;p=0.2), and ICU (-0.15 vs 0.00;p=0.4) groups. Conclusion(s): Our study showed that not only is lymphopenia a marker of COVID-19 disease severity in PWH but also a failure of lymphocyte percentage recovery is associated with worse outcomes. There was also a trend towards worse outcomes associated with a lower CD4/CD8 ratio in the first week after COVID-19 infection. (Figure Presented).

BASELINE AND TEMPORAL DIFFERENCES IN PROTEOMICS FOLLOWING SARS-CoV-2 INFECTION IN PWH

Background: COVID-19 may be more severe in persons with HIV (PWH). However, underlying biological mechanisms associated with the development of COVID-19 and its clinical severity among antiretroviral therapy (ART) treated PWH are largely unknown. Therefore, we wished to evaluate temporal changes in plasma proteins following SARS-CoV-2 infection and identify pre-infection proteomic markers associated with future COVID-19. Method(s): We analyzed the data of clinical, antibody-confirmed COVID-19 ARTtreated PWH from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). Individuals were matched on geographic region, age, and sample timing to antibody-negative controls. For cases and controls, pre-COVID-19 pandemic specimens were obtained prior to January 2020 to assess temporal changes and baseline differences in protein expression in relationship to COVID-19 severity, using mixed effects models adjusted for false-discovery rate. Result(s): We compared 257 unique plasma proteins (Olink Proteomics) in 94 COVID-19 antibody-confirmed clinical cases and 113 matched antibody-negative controls, excluding COVID-19 vaccinated participants (median age 50 years, 73% male). 40% of cases were characterized as mild;60% moderate to severe. Median time from COVID-19 infection to follow-up sampling was 4 months. Temporal changes in protein expression differed based on COVID-19 disease severity. Among moderate to severe cases vs. controls, NOS3 increased, whereas ANG, CASP-8, CD5, GZMH, GZMB, ITGB2, and KLRD1 decreased. Higher baseline circulating concentrations of granzymes A, B and H (GZMA, GZMB and GZMH) were associated with the future development of moderate-severe COVID-19 in PWH and were related to immune function, including CD4, CD8 and the CD4/ CD8 ratio. Conclusion(s): We identified temporal changes in novel proteins in closely linked inflammatory, immune, and fibrotic pathways which may relate to COVID-19-related morbidity among ART-treated PWH. Further, we identified key granzyme proteins, serine proteases expressed by cytotoxic T lymphocytes and NK cells in response to foreign antigens, associated with future COVID-19 in PWH. Our results provide unique insights into the biological susceptibility and responses to COVID-19 infection in PWH. (Figure Presented).

EXERCISE CAPACITY IS REDUCED IN HIV INDEPENDENT OF SARS-CoV-2 INFECTION

Background: Reduced exercise capacity occurs as a post-acute sequela of COVID-19 ("PASC" or "Long COVID"). Cardiopulmonary exercise testing (CPET) is the gold standard for measuring exercise capacity and identifying reasons for exercise limitations. Only one prior study used CPET to examine exercise limitations among people living with HIV (PLWH). Extending our prior findings in PASC, we hypothesized that PLWH would have a greater reduction in exercise capacity after SARS-CoV-2 co-infection due to chronotropic incompetence (inability to increase heart rate). Method(s): We performed CPET within a COVID recovery cohort that included PLWH (NCT04362150). We evaluated associations of HIV and prior SARS-CoV- 2 infection with or without PASC with: (1) exercise capacity (peak oxygen consumption, VO2) and (2) adjusted heart rate reserve (AHRR, marker of chronotropic incompetence) using linear regression with adjustment for age, sex, and body mass index. Result(s): We included 83 participants (median age 54, 35% female, 10% hospitalized, 37 (45%) PLWH) who underwent CPET at 16 months (IQR 14-17) after SARS-CoV-2 infection. Among PLWH (median duration living with diagnosed HIV 21 years (IQR 15-28), all virally suppressed on antiretroviral therapy), 14 (39%) had not had SARS-CoV-2 infection, 12 (32%) had prior SARSCoV- 2 infection without PASC, and 11 (30%) had PASC (Long COVID symptoms at CPET). Median CD4 count was 608 (370-736) and CD4/CD8 ratio 0.92 (0.56-1.27). Peak VO2 was reduced among PLWH compared to individuals without HIV with an achieved exercise capacity only 80% vs 99% (p=0.005, Fig.), a difference in peak VO2 of 5.5 ml/kg/min (95%CI 2.7-8.2, p< 0.001). Exercise capacity did not vary by SARS-CoV-2 infection among PLWH (p=0.48 for uninfected vs infected;p=0.25 for uninfected vs no PASC;p=0.32 no PASC vs PASC). Chronotropic incompetence was present in 38% of PLWH vs 11% without HIV (p=0.002), and AHRR (normal >80%) was significantly reduced among PLWH vs individuals without HIV (60% vs 83%, p< 0.0001, Fig.). Heart rate response varied by SARSCoV- 2 status among those with HIV: namely, 3/14 (21%) without SARS-CoV-2, 4/12 (25%) with SARS-CoV-2 without PASC, and 7/11 (64%) with PASC (p=0.04 PASC vs no PASC). Among PLWH, CD4 count, CD4/CD8 ratio, and hsCRP were not associated with peak VO2 or AHRR. Conclusion(s): Exercise capacity is reduced among PLWH, with no differences by SARS-CoV-2 infection or PASC. Chronotropic incompetence may be a mechanism of reduced exercise capacity among PLWH. (Figure Presented).

A Retrospective Study of the Safety and Immunogenicity of MVC-COV1901 Vaccine for People Living with HIV.

BACKGROUND: This study aimed to assess the safety and immunogenicity of MVC-COV1901, a recombinant COVID-19 protein vaccine, containing S-2P protein adjuvanted with CpG 1018 and aluminum hydroxide, for people living with HIV (PWH). METHODS: A total of 57 PWH of ≥20 years of age who are on stable antiretroviral therapy were compared with 882 HIV-negative participants. Participants received two doses of MVC-COV1901 28 days apart. RESULTS: No vaccine-related serious adverse events (SAEs) were recorded. Seroconversion rates (SCRs) of 100% and 99.8% were achieved in PWH and comparators, respectively, 28 days after the second dose. After adjusting for sex, age, BMI category, and comorbidity, the adjusted GMT ratio of comparator/PWH was 3.2 (95% CI 2.5-4). A higher CD4/CD8 ratio was associated with a higher GMT (R = 0.27, p = 0.039). MVC-COV1901 has shown robust safety but elicited weaker immune responses in PWH. CONCLUSIONS: Further investigations may be needed to determine whether PWH require distinct immunization strategies with improved immunogenicity. The main study is registered at ClinicalTrials.gov (NCT04695652).

Children with Acute Severe Hepatitis of Undetermined Etiology Have a Systemic T Cell Activation and Interferon Gamma (Ifn-G) Activity Reminiscent of Hemophagocytic Histiocytosis: A Potential Role for T Cell and Ifn-G Directed Therapies

Background: Pediatric acute liver failure (PALF) cause is indeterminate in 30-50% of cases (iPALF). Children with acute severe hepatitis of unknown etiology (SH-u) may evolve to iPALF. Hemophagocytic Lymphohistiocytosis (HLH), a hyper-inflammatory state with marked T-cell activation (ACT) often involves the liver. SH-u evolving to iPALF could have hyperinflammatory immune signatures before fulfilling PALF criteria, and may overlap with HLH. We compared immune dysregulation signatures of SH-u, HLH, known PALF, and healthy controls (HC). Method(s): From 2019-2021, 15 patients (pts) hospitalized with SH-u and 7 pts with known PALF were prospectively enrolled. Age dependent standard diagnostic studies were performed. SH-u was defined as ALT>500, INR <2, and no hepatic encephalopathy. HLH enrollees met 2004 criteria. High dimension T-cell immunophenotyping, cytokine and chemokine profiling was done for SH-u, HLH (n=5), and HC (n=16) blood samples. T cell ACT was identified by co-expression of surface ACT markers HLA-DR and CD38. CD8 effector memory (EM) ACT of >9% identified pts with significant T cell ACT vs HC. Normally distributed data were compared by a two-tailed t-test or an ordinary One-Way Anova test with Turkey's multiple comparison test. Non-normally distributed data were compared by the Mann-Whitney test or KruskalWallis test with Dunn's multiple comparisons test. P values <0.05 were significant. Result(s): Pts ranged from 4days to 19years old. No age/sex differences existed between groups. One SH-u pt had a prior COVID infection. No pts met MIS-c criteria. Two SH-u pts ultimately met PALF criteria (INR>2). All pts with SH-u had higher CD8 EM T-cell ACT (mean +/- SEM = 43.7+/-6.3%;range 9.2 to 81.3%) than HC (2.9+/-0.5%) or PALF (4.0+/-0.9%);p<0.0001. T-cell ACT in SH-u was < HLH (90.3+/-2.7%;p<0.0001;Figure 1). T cell ACT was noted in the CD4 compartment, but CD8 compartment ACT was much > CD4. SH-u CD4/CD8 ratio was reduced compared to PALF pts. Though T cell ACT was greater in SH-u vs PALF, ferritin was lower in SH-u compared to PALF (1212+/-568 vs. 39517+/-32149;p<0.01) and very significantly < HLH (32415 +/-14845;p =0.002). Ferritin was <500 mg/L in 47% of SH-u pts. Despite overlapping T cell ACT with HLH, only 2 pts SH-u pts had cytopenia. IFN-gamma driven chemokines, CXCL9 and CXCL10, were elevated in SH-u, compared to HCs but similar to HLH pts. As a proof of concept, 2 patients with SH-u were treated with Emapalumab (an IFN-gamma blocking antibody) along with other immune modulators resulting in complete liver and immune function recovery. Conclusion(s): SH-u is associated with T-cell ACT. HLH and SH-u with T cell ACT have similarly increased IFN-gamma activity. Ferritin, however, may not be a reliable screening for SH-u patients with significant T cell ACT. If validated in larger studies of SH-u, the findings suggest a role for IFN-gamma blocking agents in a subgroup of SH-u prior to the development of PALF or possible bone marrow failure.

CARTITUDE-2 Cohort A: Updated Clinical Data and Biological Correlative Analyses of Ciltacabtagene Autoleucel (cilta-cel) in Lenalidomide-Refractory Patients With Progressive Multiple Myeloma (MM) After 1-3 Prior Lines of Therapy (LOT)

Context: CARTITUDE-2 (NCT04133636) Cohort A is assessing cilta-cel in lenalidomide-refractory patients with progressive MM after 1-3 prior LOT. Objective(s): To present updated results from CARTITUDE-2 Cohort A. Design(s): Phase 2, multicohort study. Patient(s): Lenalidomide-refractory patients with progressive MM after 1-3 prior LOT (PI and IMiD included) and no previous exposure to BCMA-targeting agents. Intervention(s): Single cilta-cel infusion (target dose 0.75x106 CAR+ viable T-cells/kg) after lymphodepletion Main Outcome Measure(s): Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Management strategies were used to reduce risk of movement/neurocognitive adverse events (MNTs). Pharmacokinetics (PK) (Cmax/Tmax of CAR+T-cell transgene levels), cytokine release syndrome (CRS)-related cytokines over time, peak cytokine levels by response/CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+T-cell CD4/CD8 ratio by response/CRS/ICANS are being evaluated. Result(s): As of January 2022 (median follow-up [MFU] 17.1 months), 20 patients (65% male;median age 60 years;median 2 prior LOT;95% refractory to last LOT) received cilta-cel. Overall response rate was 95% (90% >=complete response;95% >=very good partial response). Median times to first and best response were 1.0 month and 2.6 months, respectively. All 16 MRD-evaluable patients achieved MRD negativity at 10-5. Median duration of response was not reached. At 12 months, event-free rate was 79% and progression-free survival rate was 75%. 95% of patients had CRS (gr3/4 10%);median time to onset was 7 days and median duration was 3 days. Neurotoxicity was reported in 30% of patients (5 gr1/2;1 gr3/4) and ICANS in 15% (all 3 gr1/2);1 patient had gr2 facial paralysis. No MNTs were observed. 1 death occurred due to COVID-19 (treatment-related), 2 due to progressive disease, and 1 due to sepsis (not treatment-related). Preliminary PK analyses showed peak CAR-T cell expansion at day 10.5;median persistence was 153.5 days. Conclusion(s): At MFU of 17.1 months, a single cilta-cel infusion resulted in deep and durable responses in lenalidomide-refractory MM patients with 1-3 prior LOT. We will present updated PK/cytokine/CAR-T subset analyses and clinical correlation to provide novel insights into biological correlates of efficacy/safety in this population. Copyright © 2022 Elsevier Inc.

HEMOPTYSIS AS PRIMARY MANIFESTATION IN A WOMAN WITH CHORIOCARCINOMA WITH PULMONARY METASTASIS

SESSION TITLE: Systemic Diseases Causing Pulmonary Havoc SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Choriocarcinoma is the most common type of gestational trophoblastic neoplasm (GTN) and can occur in association with any pregnancy [1]. The main risk factors are advanced or very young maternal age, ethnicity, ectopic pregnancy, abortion, and prior molar pregnancy. The most common sites of choriocarcinoma metastasis are lungs, liver, and brain [2]. This case describes a patient with choriocarcinoma that presented with hemoptysis. CASE PRESENTATION: The patient is a 22 year-old G2P1 female presenting at 36 weeks-gestation with one week of hemoptysis. She denied any other symptoms. On presentation, she was tachycardic. Physical examination demonstrated bibasilar crackles. Admission chest x-ray revealed diffuse bilateral infiltrates (Fig 1). Hs-troponin was elevated to 144 ng/L;however, EKG did not show ischemic changes. Cultures were obtained prior to empirically initiating antibiotics. Despite antibiotic treatment, hemoptysis worsened over her course and oxygen requirements increased. Infectious workup was negative. CT obtained for pulmonary embolism revealed bilateral patchy airspace opacities in lungs, suspected due to multifocal pneumonia (Fig 2). AFB smear and quantiferon were negative. After an emergent C-section for increased oxygen requirements, bronchoscopy with BAL was obtained and demonstrated diffuse alveolar hemorrhage. BAL was only positive for mildly increased CD4:CD8 ratio. Transbronchial biopsy was aborted due to bleed risk. Subsequent right lobe wedge biopsy confirmed metastatic choriocarcinoma. Her serum human chorionic gonadotropin (ß-hCG) level was found to be 20,713 milli-international units/mL. DISCUSSION: The etiology of hemoptysis was initially thought to be secondary to pneumonia. Differential diagnoses also included an acute COVID infection, alveolar hemorrhage, tuberculosis in a recently-immigrated patient, myocarditis, autoimmune etiology, and malignancy. Patient's risk factors included a prior miscarriage. Rarely, bleeding can occur as a result of metastatic lesions and may result in abdominal pain, hemoptysis, melena, or evidence of increased intracranial pressure from intracerebral hemorrhage [2]. Patients, such as the one described in this case, can exhibit pulmonary symptoms of dyspnea, cough, and chest pain caused by lung metastases. Upon closer examination of the CT scans, several of the opacities are nodular and consistent with GTN. Patients treated with surgery, chemotherapy, or a combination of both demonstrated similar treatment outcomes;chemotherapy may still be the preferred option. The overall cure rate in treating these tumors is currently > 90% [2]. CONCLUSIONS: GTN, although rare, should be considered as a differential diagnosis in women with a pregnancy history and risk factors that present with the primary symptom of hemoptysis. High index of suspicion and awareness of these neoplasms are necessary for timely diagnosis. Reference #1: Savage P. Winter M. Parker V. et al. Demographics, natural history and treatment outcomes of non-molar gestational choriocarcinoma: a UK population study. BJOG. 2020;127: 1102-1107 Reference #2: Lurain, J., 2010. Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. American Journal of Obstetrics and Gynecology, 203(6), pp.531-539. DISCLOSURES: No relevant relationships by Crystal Ajja No relevant relationships by Heba Osman No relevant relationships by James Rowley

*CHILDREN WITH ACUTE SEVERE HEPATITIS OF UNDETERMINED ETIOLOGY HAVE A SYSTEMIC T CELL ACTIVATION AND INTERFERON GAMMA (IFN-gamma) ACTIVITY REMINISCENT OF HEMOPHAGOCYTIC HISTIOCYTOSIS: A POTENTIAL ROLE FOR T CELL AND IFN-gamma DIRECTED THERAPIES

Background: 30-50% of pediatric acute liver failure (PALF) is of unknown cause, or indeterminate PALF (iPALF), which frequently results in transplantation. A subset of iPALF is characterized by T-cell activation. Some children with acute severe hepatitis of unknown etiology (SH-u) can evolve to iPALF. Hemophagocytic Lymphohistiocytosis (HLH) is a well-defined hyper-inflammatory condition characterized by marked T-cell activation and frequent severe liver involvement. We postulated SH-u evolving to iPALF has hyper-inflammatory immune signatures that are identifiable before fulfilling PALF criteria, and might overlap with those seen in HLH. We compared the immune dysregulation signatures of children with HLH to children with SH-u, PALF cases with known etiologies, and healthy pediatric controls (HC). Method(s): Between 2019-2021, we prospectively enrolled 14 patients hospitalized with SH-u and 7 patients with PALF of known etiologies. Age dependent standard of care diagnostic studies were performed. SH-u was defined as ALT> 500, INR < 2, and no hepatic encephalopathy. HLH enrollees fulfilled the 2004 diagnostic criteria. High dimension T-cell immunophenotyping, cytokine and chemokine profiling (71-plex) was done for SH-u, HLH (n=5), and HC (n= 16) peripheral blood samples. T cell activation was prospectively identified by co-expression of surface activation markers HLA-DR and CD38. Based on immune studies in HC, CD8 effector memory (EM) activation of >9% distinguished patients with significant T cell activation from HC. This cutoff of >9% was therefore used to identify SH-u patients with T cell activation. Normally distributed data were compared by either a two-tailed t-test or an ordinary One-Way Anova test with Turkey's multiple comparison test. Non-normally distributed data were compared by either the Mann-Whitney test or Kruskal-Wallis test with Dunn's multiple comparisons test. P Values < 0.05 were deemed significant. Result(s): Subjects ranged in age from 4 days to 19 years old. There were no age or sex differences between the groups. One SH-u patient had prior COVID infection, but no subject met MIS-c criteria. Two SH-u patients ultimately evolved to PALF criteria with INR> 2. All patients with SH-u had higher CD8 EM T-cell activation (mean +/- SEM = 43.7+/-6.3%;range 9.2 to 81.3;p<0.0001), which was significantly higher than HC (2.9+/-0.5%) and PALF of known etiology (4.0+/-0.9%) . However, the amplitude of T-cell activation was lower in the SH-u group relative to the HLH group (90.3+/-2.7%;p<0.0001), as shown in Figure 1. A similar trend in T cell activation was noted in the CD4 compartment. Overall, the activation in the CD8 compartment was much greater than in CD4. SH-u patients had a decreased CD4/CD8 ratio compared to the PALF group. Despite higher T cell activation in patients with SH-u compared to PALF, ferritin, often used to screen for hyper-inflammation, was lower in the SH-u group when compared to PALF group (1240+/-609 vs. 39517+/-32149;p<0.05) and very significantly lower than HLH (32415 +/- 14845;p =0.002). 50% of patients with SH-u etiology had ferritin < 500 mg/L. Cytopenia (hemoglobin < 9 g/dL, ANC < 1000/mL, platelets < 100,000/mL) is characteristic of patients with HLH. Despite overlapping T cell activation with HLH, the SH-u cohort had only 2 patients with this feature: one with thrombocytopenia and one with neutropenia. Supportive of this higher T cell activation, we noted chemokines driven by IFN-gamma, CXCL9 and CXCL10, to be elevated in SH-u compared to HCs and comparable to HLH patients. As a proof of concept, 1 patient with SH-u and thrombocytopenia underwent treatment with Emapalumab (an IFN-gamma blocking antibody) along with other immune modulators both with complete liver, immune, and platelet count recovery. Conclusion(s): Our cohort of SH-u was associated with significant T-cell activation. In addition, our patients with HLH and SH-u with T cell activation had similar increased IFN-gamma activity. Despite this T cell activation, ferritin values were significantly lower in SH-u compared to PALF without T cell activation. Ferritin may not be a reliable screening test to identify SH-u patients with significant T cell activation. If validated in a larger well-defined population of SH-u, the results may suggest a role for IFN-gamma blocking agents in a subgroup of SH-u prior to PALF or before bone marrow failure development.

CILTACABTAGENE AUTOLEUCEL IN LENALIDOMIDE-REFRACTORY PATIENTS WITH PROGRESSIVE MULTIPLE MYELOMA AFTER 1-3 PRIOR LINES OF THERAPY: CARTITUDE-2 BIOLOGICAL CORRELATIVE ANALYSES AND UPDATED CLINICAL DATA

Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is assessing ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in patients with multiple myeloma (MM) who received 1-3 prior lines of therapy (LOT) and were refractory to lenalidomide (len). This population is difficult to treat and has poor prognosis. Aims: To present updated results from CARTITUDE-2 Cohort A. Methods: All patients provided informed consent. Eligible patients had progressive MM after 1-3 prior LOT that included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Patients were len-refractory and had no prior exposure to BCMA-targeting agents. Patients received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) after lymphodepletion. Cilta-cel safety and efficacy were assessed. The primary endpoint was minimal residual disease (MRD) negativity at 10-5 by next generation sequencing. Patient management strategies were used to reduce the risk of movement and neurocognitive adverse events (MNTs). Other assessments included pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood), levels of cytokine release syndrome (CRS)-related cytokines (e.g., IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow-up: 17.1 months [range: 3.3-23.1]), cilta-cel was administered to 20 patients (male: 65%;median age: 60 years [range: 38-75]). Median number of prior LOT was 2 (range: 1-3);median time since MM diagnosis was 3.5 years (range: 0.7-8.0). 95% of patients were refractory to their last LOT;40% were triple-class refractory. Overall response rate was 95%, with 90% of patients achieving ≥complete response and 95% achieving ≥very good partial response. Median time to first response was 1.0 month (range: 0.7-3.3);median time to best response was 2.6 months (range: 0.9-13.6). All MRD-evaluable patients (n=16) achieved MRD negativity at 10-5. Median duration of response was not reached. The 12-month progression-free survival rate was 75% and the 12-month event-free rate was 79%. CRS occurred in 95% of patients (grade 3/4: 10%), with a median time to onset of 7 days (range: 5-9) and median duration of 3 days (range: 2-12). 30% of patients had neurotoxicity (5 grade 1/2 and 1 grade 3/4). ICANS occurred in 3 patients (15%;all grade 1/2);1 patient had facial paralysis (grade 2). No MNTs were observed. 1 death due to COVID-19 occurred and was assessed as treatment-related by the investigator;2 deaths due to progressive disease and 1 due to sepsis (not related to treatment) also occurred. Based on preliminary PK analyses of CAR transgene by qPCR, peak expansion of CAR-T cells occurred at day 10.5 (range: 8.7-42.9);median persistence was 153.5 days (range: 57.1-336.8). Summary/Conclusion: A single cilta-cel infusion led to deepening and durable responses at this longer follow-up (median 17.1 months) in patients with MM who had 1-3 prior LOT and were len-refractory. Follow-up is ongoing. We will present updated and detailed PK, cytokine, and CAR-T subset analyses as well as clinical correlation to provide novel insights into biological correlates of efficacy and safety in this difficult-to-treat patient population, which is being further evaluated in the CARTITUDE-4 study (NCT04181827;enrollment concluded).

Biological correlative analyses and updated clinical data of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in lenalidomide (len)-refractory patients (pts) with progressive multiple myeloma (MM) after 1-3 prior lines of therapy (LOT): CARTITUDE-2, cohort A

Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is evaluating cilta-cel safety and efficacy in pts with MM who received 1-3 prior LOT and were len-refractory - a difficult- to-treat population with poor prognosis. We present updated results. Methods: Pts had progressive MM after 1-3 prior LOT, including a PI and IMiD, were len-refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) was given post lymphodepletion. Safety and efficacy were assessed, and the primary endpoint was MRD negativity at 10-5. Management strategies were implemented to minimize risk of movement/neurocognitive AEs (MNTs). Pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood) are being conducted, as well as analyses of levels of CRS-related cytokines (eg, IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with ICANS, and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow- up [MFU] 17.1 mo [range 3.3-23.1]), 20 pts (65% male;median age 60 y [range 38-75]) received cilta-cel. Pts received a median of 2 (range 1-3) prior LOT, and a median of 3.5 y (range 0.7-8.0) since MM diagnosis. 95% were refractory to last LOT, and 40% were triple-class refractory. ORR was 95%, 90% achieved CR or better, and 95% had ≥VGPR. Median times to first and best response were 1.0 mo (range 0.7-3.3) and 2.6 mo (range 0.9-13.6), respectively. 16 pts were MRDevaluable, all of whom achieved MRD negativity at 10-5. Median DOR was not reached and 12-mo event-free rate was 79%. The 12-mo PFS rate was 75%. Median time to onset of CRS was 7 d (range 5-9) and occurred in 95% of pts (gr 3/4: 10%), with median duration of 3 d (range 2-12). Neurotoxicity occurred in 30% of pts (5 gr 1/2;1 gr 3/4). 3 pts (15%) had ICANS (all gr 1/2);1 pt had gr 2 facial paralysis. No MNTs were seen. 1 death occurred due to COVID-19 (assessed as tx-related by the investigator), 2 due to progressive disease, and 1 due to sepsis (not related to tx). Preliminary PK analyses indicate that peak expansion of CAR-T cells occurred at d 10.5 (range 8.7-42.9) and median persistence was 153.5 d (range 57.1-336.8). Conclusions: At a longer MFU of 17.1 mo, a single cilta-cel infusion led to deepening and durable responses in pts with MM who had 1-3 prior LOT and were lenrefractory. Follow-up is ongoing. Updated and in-depth PK, cytokine, and CAR-T subset analyses and clinical correlation will be presented and provide novel insights into biological correlates of efficacy and safety in this pt population. This pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827), which has concluded enrollment.

A case of acute hepatitis and morbilliform eruption after mRNA COVID-19 vaccination

Objectives: A 36-year-old Caucasian woman developed acute hepatitis and morbilliform eruption arising ten days after the first dose of the mRNA BNT162b2 SARS-CoV-2 vaccine. Materials and Methods: The patient was asymptomatic apart from the skin rash. Liver function tests showed predmoninantly severe transaminitis (AST 523 U/L, ALT 1550 U/L, GGT 151 U/L, ALP 128 U/L, bilirubin 12 umol/L). Only the ANA 1:160 was abnormal. Other serology for autoimmune and infectious diseases were negative. Multiphase computed tomography of the abdomen was unremarkable. The SARS-CoV-2 anti-spike IgG titre was 67.5 AU/mL (cut-off[15 AU/mL). The skin histology revealed spongiotic reaction pattern with focal interface lymphocytic inflammation. Multiple eosinophils and a few plasma cells were present. The epidermal lymphocytes were composed of CD2, CD3, C4, CD5, CD7 and CD8-positive T cells, with a CD4:CD8 ratio of 1:5. A small number stained positive with TIA1, PD1 and granzyme B. CD56 staining was negative. A liver biopsy was performed after 2 days of steroids. Liver histology showed mild steatosis and mild inflammatory portal infiltrate comprising mainly of small lymphocytes that were CD3 positive with retained staining for CD7 and CD8. Lobular architecture was preserved with inconspicuous interface hepatitis or piecemeal necrosis. Results: The patient was treated with intravenous hydrocortisone (400 mg/day) followed by prednisone (50 mg/day). There was rapid improvement in her liver function tests and cutaneous manifestations (Fig. 1). Conclusion: mRNA COVID-19 vaccine induced hepatitis is a rare phenomenon that is steroid-responsive and has associations with cutaneous eruptions. Our patient's lack of hepatic histological abnormalties is most likely due to early immunosuppression. She had epidermal lymphocytosis with predominance of CD8-positive T cells that were not of cytotoxic phenotype and we are uncertain as to their significance. There is limited guidance on the safety of SARS-CoV-2 vaccination in those who have had developed significant hepatic and cutaenous reactions. Further work is needed.

Low risk of bacterial co-infection, opportunistic diseases, and persistent immunosuppression in people living with HIV and COVID-19.

PURPOSE: SARS-CoV-2 infection produces lymphopenia and CD4+ T-cell decrease, which could lead to a higher risk of bacterial co-infection or impair immunological evolution in people living with HIV (PLWH). METHODS: We investigated the rate of co-infection and superinfection, and the evolution of CD4+ count and CD4+/CD8+ ratio, in hospitalized PLWH with COVID-19. RESULTS: From March to December 2020, 176 PLWH had symptomatic COVID-19 and 62 required hospitalization (median age, 56 years, 89% males). At admission, 7% and 13% of patients had leukocytosis or increased procalcitonin values and 37 (60%) received empiric antibiotic therapy, but no bacterial co-infection was diagnosed. There were seven cases of superinfection (12%), and one case of P. jiroveci pneumonia during ICU stay. No significant change in CD4+ count or CD4+/CD8+ ratio was observed after discharge. CONCLUSION: Bacterial co-infection is not frequent in PLWH with COVID-19. Immune recovery is observed in most of patients after the disease.

Individuals With Higher CD4/CD8 Ratio Exhibit Increased Risk of Acute Respiratory Distress Syndrome and In-Hospital Mortality During Acute SARS-CoV-2 Infection.

Background: CD4/CD8 ratio has been used as a quantitative prognostic risk factor in patients with viral infections. This study aims to assess the association between in-hospital mortality and at admission CD4/CD8 ratio among individuals with acute SARS-CoV-2 infection. Methods: This is a longitudinal cohort study with data of all consecutive patients admitted to the COVID-19 unit at Hospital del Mar, Barcelona, Spain for ≥48 h between March to May 2020. The CD4+ CD8+ T-cell subset differentiation was assessed by flow cytometry at admission as well as a complete blood test. Patients were classified according to CD4/CD8 ratio tertiles. The primary outcome was in-hospital mortality and the secondary outcome was acute respiratory distress (ARDS). Results: A total of 338 patients were included in the cohort. A high CD4/CD8 ratio (third tertile) was associated with a higher in-hospital mortality [adjusted Cox model hazard ratio (HR) 4.68 (95%CI 1.56-14.04, p = 0.006), reference: second tertile HR 1]. Similarly, a high CD4/CD8 ratio (third tertile) was associated with a higher incidence of ARDS [adjusted logistic regression model OR 1.97 (95%CI 1.11-3.55, p = 0.022) reference: second tertile HR 1]. There was a trend of higher in-hospital mortality and incidence of ARDS in patients within the first tertile of CD4/CD8 ratio compared with the second one, but the difference was not significant. No associations were found with total lymphocyte count or inflammatory parameters, including D-dimer. Conclusion: CD4/CD8 ratio is a prognostic factor for the severity of COVID-19, reflecting the negative impact on prognosis of those individuals whose immune response has abnormal CD8+ T-cell expansion during the early response to the infection.

Metastatic Pulmonary Epithelioid Hemangioendothelioma: A Case Report

Introduction: Pulmonary Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor;with approximately 248 cases of reported in the literature, making diagnosis and management challenging. Case: A 57-year-old female with past history of hypertension, hyperthyroidism and scoliosis was admitted with worsening chronic right flank pain. Initial lab workup was unremarkable. revealed COVID-19 PCR test was negative. CT chest revealed bilateral pleural effusions and CT abdomen showed 2.8 x2.0cm vague hypo-attenuating lesion in the right hepatic lobe. A repeat CT scan following thoracentesis demonstrated multiple bilateral pulmonary nodules, with the largest located in the right lower lobe (RLL) measuring 2.1cm (Image). Flowcytometry on bronchoalveolar lavage fluid was significant for a CD4/CD8 ratio of 5;however, the transbronchial biopsy was unremarkable. Differential diagnosis included sarcoidosis and hence patient was discharged on prednisone with Bactrim prophylaxis. She underwent VATS lung biopsy. RLL and pleural biopsies revealed EHE. Following the prednisone taper, patient was placed on pazopanib 800mg. The dose of medication subsequently reduced to 300-600mg due to adverse events. Repeat CT scans at 3 months demonstrated minimal change in size of the nodules. Patient continues to be followed on regular basis with a stable clinical status. Discussion: EHE is a low-intermediate grade malignancy which affects mostly liver, lungs and bones;although it can be found in any bodily tissue. Up to 50- 76% of patients are asymptomatic at diagnosis, with the most common symptomatic being local pain. Radiologically, Pulmonary EHE consists of bilateral perivascular nodularity. Our case describes the clinical course of a rare and poorly understood disease. Clinicians must be aware of the characteristics of unusual diseases and pursue robust diagnostic approach. In our case, biopsy led to the definitive diagnosis of EHE. Because of its rarity, there is no standard therapy for metastatic disease. Pazopanib has demonstrated prolonged long-term disease control in observational studies. Some other reports have shown response to cytotoxic chemotherapy such as doxorubicin-containing regimens, however, long-term survival is compromised. Lenalidomide, sorafenib and sunitinib have also been used, but the experience is limited. Our patient is currently on her 4th month of treatment with pazopanib, with 3-month follow-up showing no progression of disease. (Figure Presented).

Neurosarcoidosis after infection with COVID-19, a case report and review of the literature

Objective: N/A Background: The full scope of the mid- and long-term effects of SARS-CoV2 infection is currently being reported. The immune response might contribute not only to the development of ARDS, but also to other systemic complications after the acute setting. Some disorders, including those of autoimmune or presumed autoimmune etiology, have been reported to be triggered, exacerbated, or unmasked during the COVID-19 pandemic. Sarcoidosis is a multi-systemic inflammatory disorder believed to occur due to an exaggerated immune response to unknown antigens in the setting of genetic susceptibility. We present a case of neuro-sarcoidosis after COVID-19. Design/Methods: Descriptive study, case report. Results: A 51-year-old right-handed female presented with multiple cranial neuropathies and paresthesia after a mild case of COVID-19. Her symptoms included vertigo, hypoacusis, balance issues, left facial palsy, and paresthesia in her upper extremities. Her brain MRI with contrast showed bilateral enhancement of the VII and VIII cranial nerves. CSF analysis showed mild protein elevation and elevated CD4:CD8 ratio. Serum sIL-2R was also elevated. Her chest CT scan was abnormal, prompting a lymph node biopsy that was consistent with non-caseating granulomas. A diagnosis of probable neuro-sarcoidosis was made and she showed improvement with steroids. She was later started on methotrexate as a steroid sparing agent in the outpatient setting. Conclusions: To our knowledge, neuro-sarcoidosis has not been previously described in temporal association with COVID-19. It might be that this infection acts as one of the triggers for sarcoidosis. Some common pathways shared by these conditions could explain the possibility of such a trigger. These pathways include the ACE2 receptor, the TMRPPS gene, and certain cytokines. When aberrant, causing incomplete clearance of an antigen, these pathways might lead to the formation of granulomas. Further research surrounding the non-immediate effects of the novel coronavirus is needed to better delineate possible autoimmune consequences of this serious infection.

HOW HIV MODULATES the SAFETY and IMMUNOGENICITY of the BNT162b2 COVID-19 VACCINE

Background: The pivotal BNT162b2 trials included only ∼60 vaccine recipients, all with well controlled HIV, and there is a need to gather more information on vaccine safety and immunogenicity in diverse populations. This prospective study evaluated solicited and unsolicited adverse events (AEs) and anti-S and anti-NC serological profiles in a diverse cohort of people with HIV undergoing BNT162b2 vaccination (2 doses 3 weeks apart). Methods: Participants completed structured questionnaires modelled on the BNT162b2 trials (FDA submission, Nov 2020) to report solicited and unsolicited AEs in the 7 days after each vaccine dose, indicating severity and duration. Serum samples collected prior to dose-1 (T0) and 3-6 weeks after dose-2 (T1) underwent qualitative anti-NC and quantitative anti-S testing by Elecsys®. Factors associated with T1 anti-S titres were explored in linear regression models including all available parameters. Results: Overall, 259 adults received dose-1 (26% female, 77% white, 44% MSM, 44% history of advanced disease, 31% ≥1 comorbidity, 10% HIV RNA >50 cps/ml [median 122 cps], 7% prior COVID-19 diagnosis, 15% anti-NC positive;median age 48 years, ART duration 7 years, nadir/current CD4 count 225/708 cells/mm3, CD4:CD8 ratio 0.8);257 received dose-2. Local AEs were more common after dose-1 than dose-2 (70% vs. 62%, p=0.015), whereas systemic AEs increased with dose-2 (50% vs 60%;p=0.006) (Fig 1a-c);22% experienced moderate-severe systemic AEs after dose-2. Unsolicited AEs (mainly nausea and light-headedness) were reported by 7% after dose-1 and 9% after dose-2. Among 206 participants with T1 samples, 205 (99%) had measurable anti-S (>0.8 U/ml). Anti-S levels were significantly lower at CD4 counts <200 cells/mm3 (Fig 1d). In adjusted regression analyses, factors associated with anti-S titres comprised anti-NC positivity (fold-change 7.39;95% CI 3.92-13.91;p<0.01), HIV viraemia (FC 0.24;0.11-0.50;p<0.01), reporting moderate-severe systemic AEs after dose-2 (FC 1.77;1.03-3.04;p=0.04) and either the CD4 count (FC 1.01;1.00-1.01;p=0.04) or CD4:CD8 ratio (FC 1.05;1.00-1.10;p=0.05). Conclusion: In this cohort with HIV, AE patterns after vaccination were similar to those seen in the pivotal BNT162b2 trials and most AEs were mild and short-lived. Whilst prior exposure to SARS-CoV-2 predicted higher anti-S responses, CD4 counts <200 cells/mm3 and low-level viraemia predicted reduced anti-S responses, thus identifying a subset potentially vulnerable to reduced vaccine efficacy.

Lymphocyte subgroup analysis by flow cytometric method in patients diagnosed with covid 19

BACKGROUND AND AIM: Multiparametric flow cytometry method is considered as the gold standard for the determination of lymphocyte subgroup analysis. In this study, it was aimed to perform lymphocyte subgroup analysis in patients with COVID-19 and to compare it with the healthy group. METHODS: The study included 50 patients with COVID-19 who applied to Diskapi Yildirim Beyazit Training and Research Hospital after approval of the ethics committee. All COVID-19 patients (n=50) and healthy controls (n=30) are equal in age and gender. Whole blood samples were taken into an EDTA tube and measured by a hemogram analyzer within 2 hours. Lymphocyte subgroup analyses (CD3, CD4, CD8, CD19, CD56, CD16) and activated T lymphocytes(HLADR) were performed using the flow cytometric method in the same samples. Lymphocyte counts were calculated using the dual platform. RESULTS: White blood cell and lymphocyte counts were significantly low in the patients with COVID- 19 (respectively, p=0.036). Flow cytometric analysis revealed that the CD3+ T lymphocyte counts and CD19+ B lymphocytes counts and percentage were significantly lower (p=0.008, <0.001, 0.004) in disease group compared to the controls but no difference observed in NK cells. In T lymphocytes, CD4+ T and CD8+ T lymphocyte counts were significantly lower (p=0.007, <0.05), but their percentages and CD4/CD8 ratios was not significantly different. The percentage of HLADR expression in T lymphocytes was significantly increased compared to the healthy group (p=0.001). CONCLUSIONS: T and B lymphocyte counts were low in COVID 19 patients. Activated T lymphocytes may be involved in the pathogenesis of the disease.

Oral Chinese Herbal Medicine on Immune Responses During Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

BACKGROUND: Cellular immune responses including lymphocyte functions and immune effector cells are critical for the control of coronavirus infection. Chinese herbal medicine (CHM) potentially has a therapeutic effect for treatment of coronavirus disease 2019 (COVID-19). Nevertheless, there are limited clinical practice suggestions on immunogenicity of the CHM against SARS-CoV-2. To assess the effect of oral CHM on immunogenicity and whether oral CHM improves the clinical parameters through the immunity profile during COVID-19, we performed the present study. METHODS: For this systematic review and meta-analysis, 11 databases were searched for relevant studies assessing oral CHM for COVID-19 on November 20, 2020 (updated March 9, 2021). Primary outcomes mainly included immunity profiles. Secondary outcomes included all-cause mortality; the remission time of fever, cough, chest tightness, and fatigue. The random effect was used to estimate the heterogeneity of the studies. Summary relative risks, weight mean difference and standardized mean difference were measured with 95% confidence intervals. Modified Jadad scale and Newcastle-Ottawa Scale were used to assess the risk of bias of randomized controlled trials (RCTs) and observational studies, respectively. The certainty of evidence was evaluated using the GRADE approach. RESULTS: We analyzed findings from 3,145 patients in 30 eligible studies. Compared with routine treatment, oral CHM, as an adjuvant medicine, improved lymphocyte counts, CD4+, and CD4+/CD8+ ratio with low quality of evidence; improved CD3+ with moderate quality of evidence; and reduced TNF-α with low certainty of evidence. Besides, oral CHM, as an adjuvant medicine reduced the time to clinical symptoms remission with a lower risk of all-cause mortality, compared with routine treatment alone. CONCLUSION: CHM may be recommended as an adjuvant immunotherapy for disease modification and symptom relief in COVID-19 treatment. However, large RCTs objectively assessing the efficacy of CHM on immune responses in COVID-19 are needed to confirm our findings.