Pandemic stress induces systemic immune changes and placental inflammation independently of SARS-CoV-2 infection in pregnancies

Problem: Environmental stress during pregnancy has known impacts on both maternal and fetal health. In terms of theCOVID-19 pandemic, the majority of published work has focused on the impact of the infection itself, without considering the potential immune impact of pandemic related-stress.We, therefore, assessed the impact of pandemic stress, independently of SARS-CoV-2 infection, on the circulating and placental immune profiles of pregnant individuals. Method(s): Placentas from 239 patients were collected at the Sainte- Justine Hospital, Montreal, Canada. Of these, 199 patients delivered during the pandemic and were exposed to pandemic stress with (+: 79) or without (-: 120) SARS-CoV-2 infection, the latter exposed to pandemic stress only. Pre-pandemic historic controls (uncomplicated pregnancies, Ctrl: 40), were also included. Placental biopsies were collected to assess cytokine levels by ELISAs and histopathological lesions. A sub-study with 35 pre-pandemic pregnancies (unexposed) and 20 who delivered during the pandemic (exposed) was also conducted. The latter (exposed/unexposed) were all uncomplicated pregnancies. We collected maternal blood prior to delivery for immunophenotyping, and plasma/peripheral blood mononuclear cells (PBMCs) were isolated. Inflammatory mediators in the plasma were quantified by ELISAs. Co-culture assays with PBMCs and human umbilical vein endothelial cells (HUVECs) were performed to assess endothelial activation. Demographical/obstetrical data were obtained through chart review. Result(s): SARS-CoV-2+ patients were multiethnic (63.4%), had higher pre-pregnancyBMI (28.9 vs. 24.8 inCtrl, P<.05), and elevated preterm birth rate (16.5% vs. 5.8% in SARS-CoV-2-, P < .05 and 0.0% in Ctrl, P < .01). In the placentas, we observed an increase in the levels of IL- 1Ra (P < .05) and CRP (P < .05) in both SARS-CoV-2 groups, while IL-6 (P = .0790) and MCP-1 (P < .001) were elevated solely in SARS-CoV- 2-. These changes were predominant in placentas with inflammatory lesions on histopathological analysis. Moreover, we observed elevated CD45+ cells (P < .001) in the placentas from both SARS-CoV-2 groups versus Ctrl. Considering that the differences we observed were important in the SARS-CoV-2- group, we performed a study solely on uncomplicated pregnancies, either exposed or unexposed to pandemic stress. At the systemic level, we observed a decrease in the percentage of Th2 cells (P < .001), leading to a pro-inflammatory Th1/Th2 imbalance in exposed individuals. Decreased Treg (P < .05) and Th17 (P < .05) versus unexposed was also observed. Surprisingly, decreased levels of circulating IL-6 (P < .05), MCP-1 (P < .01), and CRP (P<.05) were seen in exposed versus unexposed individuals. Finally,we observed increased secretion of ICAM, a marker of endothelial activation, solely in endothelial cells co-cultured with PBMCs from exposed individuals. Conclusion(s): Overall, placental inflammatory profiles differed between pregnant individuals exposed to pandemic stress with or without SARS-CoV-2 infection. Moreover, we observed that the pandemic stress exposed group presented a systemic pro-inflammatory bias. This highlights the need to understand the differences between the effects of pandemic-related stress and the added burden of SARS-CoV-2 infection itself on maternal and fetal health. Our work also supports an association between an increased risk of hypertension/ preeclampsia and SARS-CoV-2 infection that might be driven in part by pandemic-related stress.

Pathogenic helper T cells as the novel therapeutic targets for immune-mediated intractable diseases.

Allergic diseases arise from a complex interplay between immune system and environmental factors. A link between the pathogenesis of allergic diseases and type 2 immune responses has become evident, with conventional and pathogenic type 2 helper T (Th2) cells involved in both. Recently, there has been a significant development in therapeutic agents for allergic diseases: IL-5 and IL-5 receptor antagonists, Janus kinase (JAK) inhibitors, and sublingual immunotherapy (SLIT). Mepolizumab, an IL-5, and Benralizumab, an IL-5 receptor antagonist, modulate eosinophilic inflammation mediated by IL-5-producing Th2 cells. Delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in atopic dermatitis, one of the common allergic diseases. SLIT has a significant effect on allergic rhinitis by reducing pathogenic Th2 cell numbers. More recently, novel molecules that are involved in pathogenic Th2 cell-mediated allergic diseases have been identified. These include calcitonin gene-related peptide (CGRP), reactive oxygen species (ROS) scavenging machinery regulated by the Txnip-Nrf2-Blvrb axis, and myosin light chain 9 (Myl9), which interacts with CD69. This review provides an updated view of the recent research on treatment of allergic diseases and their cause: conventional and pathogenic Th2 cells.

T HELPER CELL SUBSETS AND RELATED TARGET CELLS IN ACUTE COVID-19.

Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2-4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells - basophiles and eosinophils - were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased "regulatory" Tfh1 cell and increased "pro-inflammatory" Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of "naive" and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24- plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.Copyright © 2022 Saint Petersburg Pasteur Institute. All rights reserved.

AM3, a natural glycoconjugate, as adjuvant treatment for COVID-19 patients

We have been immersed in the COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for two years, and the availability of drugs for its treatment remains limited. Both in the general population and in patients, one of the most effective tools to prevent viral infections or limit their impact is strengthening the immune system. AM3, a polysaccharide/protein compound, has shown regulatory effects on the immune system. In this study, we have evaluated the potential effect of AM3/probiotic for the treatment of COVID-19 patients. We have included 83 patients with mild-moderate SARS-CoV-2 infection that were randomly assigned to receive either AM3/probiotic or placebo. All patients filled a 32-item questionnaire, which assesses symptom burden over a 2-week period. Blood samples were also obtained to investigate immune response by flow cytometry. The administration of AM3/probiotics decreased the number of symptoms and their intensities (Total score after 1 month: 11.0 (1.0-20.3) vs 24.0 (12.0-61.00)) in ambulatory patients with COVID-19, and the length of hospital stay in those that required hospitalization with respect to those receiving placebo (5.8+/-0.7 vs 6.4 +/-1.4 days). In general, the treatment with AM3/probiotic did not affect CD4+ T cells, including Th1, Th2, and Th17 cells. By contrast, central memory (CM) and effector memory (EM) CD8+ T lymphocytes showed a significant increment after the AM3/probiotic treatment that was not observed in patients receiving placebo. Conclusion(s): Our data suggest the beneficial use of AM3/probiotics supplementation in the treatment of patients with COVID-19. Further studies will confirm these findings and investigate the mechanisms.

Phototherapy to treat a COVID-19 vaccine reaction

A 59-year-old man presented with a widespread morbilliform rash after receiving the second dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. He had no significant medical history and no known allergies. He did not take any regular medication. He developed pruritus without rash 4 h after his first vaccine. This resolved after 10 days without intervention. One day after his second dose, he developed an extensive pruritic morbilliform eruption on his trunk and limbs, affecting 35% of his body surface area. with no mucous membrane involvement. The rash persisted for 4 weeks after his second vaccination and he was referred to dermatology. Eosinophils were raised at 0.54 and liver function tests were normal. Antinuclear antibodies and extractable nuclear antigen were negative. Complement levels were normal. Histology showed mild epidermal acanthosis, spongiosis and subcorneal vesicles. Within the superficial to mid-dermis, there was a mixed chronic inflammatory infiltrate comprising lymphocytes, plasma cells, neutrophils and numerous eosinophils. Direct immunofluorescence was negative. He received a tapering dose of oral prednisolone with mometasone topically. Despite substantial improvement with this regimen, his rash began to worsen 2 days following discontinuation of oral prednisolone. He was still using daily mometasone on cessation of oral steroids. He was trialled on oral doxycycline for 1 month, which led to a marked improvement in the morbilliform rash. Despite improvement in the rash, the patient reported ongoing intense daily pruritus which was having a marked impact on his quality of life. He has commenced on narrowband ultraviolet B (UVB) phototherapy to treat his persistent pruritis, with good effect to date. Morbilliform eruptions have been reported as a cutaneous manifestation of COVID-19 and as a side-effect of mRNA vaccines. Proposed mechanisms for the development of skin rashes post-mRNA vaccines include viral protein expression following vaccination, prior infection with COVID-19 causing cross-reaction with the mRNA vaccine encoded antigen and vaccine components acting as haptens inducing a T helper 2 inflammatory reaction characterized by interleukin (IL)-4 and IL-13 expression. Drug-induced maculopapular eruptions typically resolve within 7-14 days on withdrawal of the culprit medication. The persistent nature in our patient may imply a complex immune response. The use of phototherapy to treat inflammatory dermatoses and pruritic conditions such as nodular prurigo is well described. The antipruritic effect of phototherapy is thought to work via modulation of both the neural pathways involved in itch and local immune cells in the skin. Our case highlights that phototherapy can be used in the treatment of cutaneous side-effects that arise after COVID-19 vaccines. To the best of our knowledge, this case is one of the first to use narrowband UVB phototherapy to treat a cutaneous side-effect of an mRNA vaccine.

Herbal and Ayurvedic Plants as Remedial Approach for Viral Diseases with Focus on COVID-19: A Narrative Review

Background: Infectious diseases have posed a major threat to human survival for centu-ries and can devastate entire populations. Recently, the global outbreak of COVID-19 has increased exponentially, affecting more than 200 countries and millions of lives since the fall of 2019, largely due to the ineffectiveness of existing antiviral therapies. WHO announced it a public health emer-gency of international concern. A significant waiting period in antiviral therapy hindered by the rapid evolution of severe acute respiratory syndrome-coronavirus-2 aggravated the situation ensuing imposition of strict laws (e.g., communal dissociation, international travel restrictions, and mainte-nance of hygiene) that would help in inhibiting further outspread of COVID-19. Ayurveda system of medicine offers a holistic approach to the COVID-19 pandemic. Objective(s): This review aims to highlight the potential of medicinal herbs and Ayurvedic drugs as the remedial approach for viral diseases, such as COVID-19. Method(s): We reviewed the literature from journal publication websites and electronic databases, such as Bentham, Science Direct, Pub Med, Scopus, USFDA, etc. Result(s): The drugs used in the traditional system of medicine have the potential to prevent and cure the infected patient. Ayurvedic therapies are known for regulating immunity and rejuvenation properties that behold much promise in the management of COVID-19 disease. Government of India, Ministry of AYUSH recommends some precautionary fitness measures and an increase in immunity with special reference to respiratory health. Conclusion(s): While there is no medication for COVID-19 as of now, taking preventive measures and boosting body immunity is highly recommended. A number of medicinal plants that play an im-portant role in revitalizing the immune system are easily accessible in home remedies.Copyright © 2023 Bentham Science Publishers.

T HELPER CELL SUBSETS AND RELATED TARGET CELLS IN ACUTE COVID-19

Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2–4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells — basophiles and eosinophils — were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased "regulatory” Tfh1 cell and increased "pro-inflammatory” Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of "naïve” and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24– plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.

POST-COVID-19 EOSINOPHILIC PNEUMONIA

SESSION TITLE: Post-COVID-19 Infection Complications SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: We present two cases of symptomatic post-COVID eosinophilic pneumonia responsive to steroids. CASE PRESENTATION: Case 1: A 73-year-old gentleman with underlying asymptomatic rheumatoid arthritis (RA), was admitted with COVID pneumonia for which he received tocilizumab, remdesivir, and 12 days of dexamethasone. His course was complicated by MRSA pneumonia and bacteremia, so was discharged on IV Vancomycin. Six days post discharge, he redeveloped respiratory distress. Labs showed a WBC 18,000 and proBNP 2828. A chest CT revealed bilateral ground-glass opacities, worsening right upper lung airspace disease and bilateral pleural effusions. Despite receiving Furosemide, Vancomycin, and Ceftazidime, he required high-flow nasal cannula oxygenation (HFNC). Bronchoscopy demonstrated thick right bronchial secretions. BAL fluid revealed 7% eosinophils and grew MRSA. Case 2: A 70-year-old gentleman with extensive smoking history, emphysema, psoriasis, Guillain-Barré syndrome and a recent hospitalization for COVID pneumonia was discharged on a steroid taper. He returned 23 days post discharge in respiratory distress requiring HFNC, 5 days after discontinuing steroids. The chest CT revealed worsening fibrosis and bronchiectasis. Intravenous Levofloxacin and Vancomycin resulted in no clinical improvement. Bronchoscopy showed inflamed bronchi with secretions and BAL analysis revealed 6% eosinophils. For both patients, BAL was negative for fungi and PJP and CTA ruled out PE. Both patients were started on Prednisone with a prolonged taper. They improved clinically with decreased oxygen requirements to 4L nasal cannula and dramatic decrease in subjective dyspnea within 48 hours of starting steroids. DISCUSSION: The differential diagnosis for the clinical deterioration and worsening radiographs in both patients includes bacterial/fungal superinfection, PE, post-COVID-ILD and eosinophilic pneumonia. For the first patient, his RA was inactive. His BAL was positive for MRSA but did not improve until steroids were initiated. Neither of the patients were stable for VATS biopsy. Eosinophilic pneumonia is defined as pulmonary infiltrates with peripheral blood eosinophilia =500/ml, BAL eosinophils > 5% or eosinophilic infiltration on lung biopsy [1]. Both of our patients had >5% BAL eosinophils. Potentially, prolonged COVID-ILD stimulates T-Helper-2 cells, causing the release of IL-4/5/13 with recruitment of eosinophils. Studies report post-COVID-ILD biopsies show organizing pneumonia and fibrosis but have not yet been associated with eosinophilia. In both patients, we observed eosinophilia on BAL. It can be hypothesized that a delayed inflammatory response mediated by eosinophils play a role. CONCLUSIONS: Pulmonary eosinophilic pneumonia is a complication of post-COVID-ILD and can be successfully managed with steroids. Reference #1: De Giacomi F, Vassallo R, Yi ES, Ryu JH. Acute Eosinophilic Pneumonia. Causes, Diagnosis, and Management. Am J Respir Crit Care Med. 2018 Mar 15;197(6):728-736. doi: 10.1164/rccm.201710-1967CI. PMID: 29206477. DISCLOSURES: No relevant relationships by farrukh ahmad No relevant relationships by Deborah Markowitz No relevant relationships by Dhiraj Shah No relevant relationships by Garima Singh No relevant relationships by Aakriti Soni

IGG4-RELATED PLEURAL DISEASE: A CAUSE OF RECURRENT PLEURAL EFFUSION AFTER COVID-19 VACCINATION

SESSION TITLE: Challenging Disorders of the Pleura SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Great effort went into finding a vaccine to decrease the impact of COVID-19 virus. Pfizer vaccine which is a part of mRNA of the virus wrapped with lipid nanoparticles is one of them. Though its side effects are benign, rarely it can lead to IgG4 related lung disease (IgG4-RLD). Therefore, having a high degree of suspicion is important for early diagnosis and effective treatment. CASE PRESENTATION: The patient is a 71-year-old male with COPD, CAD, and prostate cancer developed dyspnea after receiving 2 doses of Pfizer vaccine. CT chest revealed a new left pleural effusion, 1.4L fluid was removed which was negative for malignant cells with lymphocytic predominance. After 10 days, his symptoms worsened and repeat CT scan revealed large left pleural effusion. Thoracoscopy was done with drainage of 2.5L pleural fluid followed by pleural biopsy and chemical pleurodesis with insertion of an indwelling tunneled catheter. Pleural biopsy revealed chronic organizing pleuritis with lymphoid and mesothelial hyperplasia. The tunneled catheter stopped draining after 3 months but oxygen requirement increased. A repeat CT scan revealed loculated pleural effusions and only 40 ml was drained due to bloody output. Thoracoscopy revealed multiloculated effusions with visceral pleural thickening and partial decortication was done. Pathology revealed pleural thickening and fibrosis with increased IgG4-positive plasma cells in pulmonary parenchyma. Blood IgG4 level was 268 mg/dl. He was diagnosed with IgG4-related disease (IgG4-RD) affecting lungs and pleura. DISCUSSION: Although IgG4 related nephritis after Pfizer vaccine has been reported(1), this is the 1st reported case of IgG4-RLD. Autoimmunity is a trigger for pathogenesis with involvement of Th-2 cell. The vaccine stimulates robust antigen-specific T-cell responses leading to antibody production that trigger autoimmune reactions due to molecular mimicry. Four patterns are observed including mediastinal, parenchymal, pleural, and airway involvement. Mediastinal and hilar lymphadenopathy is the commonest patterns(2). Our patient had loculated pleural effusion complicated by pleural thickening and fibrosis. For diagnosis of IgG4-RD, 3 criteria need to be fullfilled: consistent organ involvement;serum IgG4 level >135 mg/dL;histopathology showing marked lymphoplasmacytic infiltration(2). Our case fulfilled all 3 criteria and involved lungs;thus, diagnosed with IgG4-RLD. Most patients have a favorable response with corticosteroid therapy in 2 weeks. For steroid-refractory cases, immunosuppressants can be used(3). CONCLUSIONS: With increased COVID-19 vaccination, more autoimmune events including IgG4-RLD can happen. As multiple doses are offered, close observation is needed for prompt diagnosis and management of such diseases. Ultimately, theoretical risks must be balanced against known benefits, and discussion between providers and patients is important. Reference #1: Christophe M, Delphine K, Christine K A, Aurélie F, Gilles B, Mohamed H. Relapse of IgG4-related nephritis following mRNA COVID-19 vaccine. Kidney International. Vol 100, Issue 2, P465-466, August, 2021. DOI: https://doi.org/10.1016/j.kint.2021.06.002 Reference #2: Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J 2012;39:180–6 Reference #3: Campbell SN, Rubio E, Loschner AL. Clinical review of pulmonary manifestations of IgG4-related disease. Ann Am Thorac Soc 2014;11:1466–75. DISCLOSURES: no disclosure on file for Ola Al-Jobory;No relevant relationships by Ahmad Hallak No relevant relationships by Manish Patel No relevant relationships by Saria Tasnim

Conventional and pathogenic Th2 cells in inflammation, tissue repair, and fibrosis.

Type 2 helper T (Th2) cells, a subset of CD4+ T cells, play an important role in the host defense against pathogens and allergens by producing Th2 cytokines, such as interleukin-4 (IL-4), IL-5, and IL-13, to trigger inflammatory responses. Emerging evidence reveals that Th2 cells also contribute to the repair of injured tissues after inflammatory reactions. However, when the tissue repair process becomes chronic, excessive, or uncontrolled, pathological fibrosis is induced, leading to organ failure and death. Thus, proper control of Th2 cells is needed for complete tissue repair without the induction of fibrosis. Recently, the existence of pathogenic Th2 (Tpath2) cells has been revealed. Tpath2 cells produce large amounts of Th2 cytokines and induce type 2 inflammation when activated by antigen exposure or tissue injury. In recent studies, Tpath2 cells are suggested to play a central role in the induction of type 2 inflammation whereas the role of Tpath2 cells in tissue repair and fibrosis has been less reported in comparison to conventional Th2 cells. In this review, we discuss the roles of conventional Th2 cells and pathogenic Th2 cells in the sequence of tissue inflammation, repair, and fibrosis.

INTERLEUKIN 18 IN IMMUNE-MEDIATED RHEUMATIC DISEASES AND COVID-19

Immune-mediated rheumatic diseases (IMRDs), based on the leading mechanisms of pathogenesis, are conditionally classified into autoimmune, autoinflammatory, and «mixed pattern». In the spectrum of cytokines involved in the development of the immunopathological process in IMRDs, the “pro-inflammatory” cytokine interleukin (IL) 18, a member of the IL-1 family, plays an important role in the regulation of T-helper (Th) 1-, Th2- and Th17- types of immune response that induces the synthesis of interferon (IFN) γ, other pro-inflammatory cytokines and chemokines. The possibility of determining the concentration of IL-18 in IMRDs is discussed to improve diagnosis, identify subtypes of diseases, and predict the effectiveness of pharmacotherapy. IL-18 is a promising target for anticytokine therapy, primarily in patients with high activity of inflammation associated with hyperactivation of innate immunity.

T HELPER CELL SUBSETS AND RELATED TARGET CELLS IN ACUTE COVID-19

Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2–4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells — basophiles and eosinophils — were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased “regulatory” Tfh1 cell and increased “pro-inflammatory” Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of “naïve” and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24– plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.

Cellular immune responses in non-hospitalized COVID-19 cases undergoing pregnancy with immune modulation treatment

Introduction: In January 2020, the genome of the novel coronavirus, SARS-CoV-2, was sequenced, the etiologic RNA virus for COVID- 19. Several variants from the initial strain of SARS-CoV-2 have been reported, notably the Delta variant and most recently, the Omicron variant. However, how the virus affects the cellular immune system has been elusive. This study aims to investigate peripheral blood immunophenotype, natural killer (NK) cell cytotoxicity, and T helper (Th) 1/ Th2 ratios in pregnantwomen undergoing immunotherapy with a history of recurrent pregnancy losses (RPL) and repeated implantation failures (RIF). Materials and Methods: A prospective cohort study was performed on pregnant women with a history of RIF and RPL. The study group comprised 20 pregnant women with COVID-19, of whom eight had documented vaccinations. All were undergoing personalized immunemodulation and/or anticoagulation treatment. When they were diagnosed with COVID-19, immunomodulating medications were tapered off or decreased until recovery. Peripheral blood immunophenotype, NK cell cytotoxicity (NKC) at effector to target cell (E: T) ratio at 50:1 and 25:1, and Th1/Th2 cell ratios (TNF-a/IL-10, IFN-g/IL-10 producing Th cell ratios)were measured by flow cytometry within 5weeks before and after COVID-19. Statistical analysis was performed by using the student t-test. Results: Peripheral blood immunophenotypes including % CD3 (77.38 ± 2.15 % vs. 79.98 ± 1.65 %, P = 0.34), % CD19 (13.63 ± 1.63 % vs. 12.63 ± 1.79 %, P = 0.68), % CD56 (7.61 ±1.32 % vs. 6.15± 1.08 %, P = 0.40), % CD19/CD5 (4.68 ±1.41 % vs. 4.17 ± 0.72 %, P = 0.75) were not significantly different before and after COVID- 19. NKC at E: T ratio of 50:1 (Mean ±SE), before and after COVID- 19 were 21.16 ± 0.66% and 22.21 ± 1.06 % respectively (P = 0.40). NKC at E: T cell ratios of 25:1 were 15.71 ± 0.69 % and 16.44 ± 0.93 % respectively (P = 0.52). TNF-a/IL-10 (29.61 ± 2.43 vs 28.95 ±2.06, P = 0.83) and IFN-g/IL-10 (16.36 ±2.22 vs 12.61 ± 0.94, P = 0.14) producing Th1/Th2 cell ratios were comparable before and after COVID-19. Conclusions: Our findings suggest that even though patients are affected by the COVID-19 during the Omicron phase, ©2022 The Authors. American Journal of Reproductive Immunology ©2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. there were no significant flares in cellular immune responses when patients recovered from COVID-19 in not hospitalized cases.

House dust mite sublingual immunotherapy in patients with receiving subcutaneous immunotherapy maintenance phase: A randomized controlled trial

Background: Allergen-specific immunotherapy (AIT) is the only treatment that cures allergic diseases. Subcutaneous immunotherapy (SCIT) is a conventional treatment which introduced more than 100 years ago. Novel oral formulation sublingual immunotherapy (SLIT) has shown equal efficacy to SCIT, while it is safe without life-threatening allergic reaction. Amid a pandemic of COVID-19, patients are advised to avoid hospital visits. SLIT might be the right choice because patients can take the tablets at home and no need to go to the hospital for weekly injections like SCIT. However, no recent report on the efficacy of changing the route of immunotherapy from SCIT to SLIT. The study aims to assess the efficacy of switching SCIT to SLIT in patients with house dust mite (HDM) allergy. Method: A randomized controlled study was undertaken in 40 patients with allergic rhinitis with/without asthma and receiving maintenance phase of HDM SCIT (TCTR20200606002). HDM SLIT tablet was given daily for 12 weeks and compared to patients with continue SCIT. The principle outcome measure was symptom-medication score (SMS) and asthma control test (ACT) score. immunologic changes in fresh whole blood to monitor T cell subsets, including regulatory T cells (tregs), dysfunctional tregs, and T helper 2 cells were investigated by the flow cytometry method and Der p2-specific IgE, Der p2-specific IgG4 and Der p2-specific IgE/IgG4 were investigated by ELISA method at baseline and 12 weeks after switching treatment. Results: Of 40 patients, 19 patients in the SLIT group and 20 patients in the control group achieved the study. There were no significant differences in SMS and ACT scores between the SLIT group and SCIT group during 12 weeks of treatment. Significantly reduced SMS after 8 weeks compared to baseline (17.6 ± 2.9 to 14 ± 2.4, p = 0.028) was demonstrated in the patients with SLIT. T cell subsets' frequency, specific IgE, IgG4 and IgE/IgG4 ratio did not change significantly in both groups at the end of the study. No severe adverse drug reactions were reported.

Inhaled corticosteroids may have a protective effect against coronavirus infection.

BACKGROUND: Spain has been severely affected by the COVID-19 epidemic, with 195,944 persons infected and 20,453 deaths at the time of writing. Older people with respiratory or cardiac conditions are most at risk. OBJECTIVE: The aim was to compare respiratory symptoms in nursing home residents and patients with uncontrolled asthma, who are considered vulnerable to COVID-19. METHODS: We studied 134 nursing home residents and 139 patients with uncontrolled asthma, groups vulnerable to COVID-19. Demographic characteristics, clinical manifestations, outcomes, key laboratory results, and radiological images were collected from medical records. COVID-19 infection was detected by polymerase chain reaction (PCR). RESULTS: Thirteen (9.3%) patients with uncontrolled asthma, all receiving inhaled corticosteroids were infected by COVID-19. Eighty (60%) nursing home residents were infected; only 28, all of whom had received inhaled corticosteroids, had a good prognosis. CONCLUSIONS: Early treatment with inhaled corticosteroids may be helpful in COVID-19 infection. Persons with an allergy might have some protective mechanisms against coronavirus.