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Introduction: Macrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case Presentation: A 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron;however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. Discussion(s): MAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Formula presented] [Formula presented] [Formula presented]Copyright © 2023 Elsevier Inc.
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Background: The clinical course of coronavirus disease-2019 (COVID-19) varies from those who are asymptomatic, experience mild symptoms such as fever, cough, and dyspnea, to more severe outcomes including acute respiratory distress, pneumonia, renal failure, and death. Early reports suggested severe outcomes in patients with primary immunodeficiency (PID), particularly those with type 1 interferon signalling defects. This prompted a rigid approach to social distancing to protect this patient population, particularly children. To date, real-world data describing the course and outcome of COVID-19 in paediatric PID patients remains scarce. Method(s): In this retrospective case series, we describe the clinical course of 36 paediatric patients with underlying primary immunodeficiency (PID) followed by SickKids Hospital (Toronto, Canada) who were symptomatic and tested positive for SARS-CoV-2 infection between October 2020 to November 2022. Result(s): Our cohort consisted of patients with combined immunodeficiency (66.7%), antibody deficiency (22.2%), neutrophil dysfunction (8.3%), and immune dysregulation (2.8%). The median age was 7.5 years (range: 8 months - 17 years), with 21 male and 15 female patients. Three (8.3%) patients were post-hematopoietic stem cell transplant (HSCT) and 12 (33%) patients were on immunoglobulin replacement. Nine (25%) patients had underlying lung problems including bronchiectasis (1), interstitial lung disease on home oxygen therapy (1), and underlying asthma (7). Most patients had mild clinical course and were managed at home. The most common symptoms were fever (80%), cough (75%) and other upper respiratory tract symptoms (72%). Nineteen (52.7%) patients experienced other symptoms which included headache, lethargy, or gastrointestinal upset. At the time of the infection, 13 patients (36.1%) had received 2 doses of a SARS-CoV-2 vaccine, 5 patients (13.9%) had received 1 dose, and 18 (50%) were not vaccinated. None of the patients received antiviral or monoclonal antibody as prophylaxis or treatment. Only 1 patient required hospital admission out of precaution given the close proximity to HSCT. All patients recovered without complications. Conclusion(s): The paediatric patients with PID followed by our centre experienced mild to moderate COVID-19 symptoms and recovered fully without complications. These findings support the return of much needed social interactions among children, which were impacted severely during the COVID-19 pandemic.Copyright © 2023 Elsevier Inc.
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SARS-CoV-2, also known as COVID-19, is a novel coronavirus that began sweeping the globe at the end of 2019, causing mild illness in some patients while leading to devastating shock, immune dysregulation, multiorgan failure, and even death in others. Immune dysregulation may lead to increased susceptibility to severe disease from COVID-19. Immune enhancers could aid in immune regulation and protect against severe COVID-19 infection. Herbal supplements, spices, and lifestyle modifications have been shown to enhance immune responses to a number of pathogens, which may include COVID-19. These immune enhancers could be used adjunctively with vaccines, social distancing, and pharmacologic treatments to prevent life-threatening infection in susceptible patients. © 2023 Elsevier Inc. All rights reserved.
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Currently, 640 million cases of coronavirus disease 2019 (COVID-19) and 6.6 million deaths have been reported world-wide. Risk factors for severe COVID-19 are known, including those with compromised immunity. Among patients with inborn errors of immunity (IEI), early reports of severe outcomes lead to strict masking and social distancing measures. While this resulted in relatively low infection rates among those with IEI, real-world data describing the clinical course of COVID-19 in this patient population have remained limited. We performed a retrospective study of adult IEI patients followed by our center in which a positive test (rapid antigen or PCR) for COVID-19 was determined between November 2021-November 2022. Medical charts were reviewed, and patient interviews conducted. All patients provided informed consent. Twenty-nine patients were enrolled (22 females, 7 males), aged between 18-69 years (median: 20-29 years). The cohort included those with antibody deficiencies (41.37%), combined immunodeficiencies (34.48%;HIES, CARD11, STAT1-GOF), immune dysregulation disorders (20.69%;LRBA deficiency, AIRE deficiency) and phagocyte defect (3.45%;CGD). The duration of symptoms ranged between 3 days-4 weeks (median: < 1 week). Upper respiratory symptoms (including sore throat, congestion) were reported in 97% while fever was present in 41% of patients. Prior to infection, 14 (48%) patients had underlying asthma or bronchiectasis - 2 subsequently experienced shortness of breath and were treated with inhalers or Sotrovimab, respectively. No treatment was required in 65.5% of cases. The remaining received Paxlovid (10.3%), Sotrovimab (13.79%), or antibiotics (10.3%). Of the 2 patients with STAT1-GOF, one tested positive during a repeat episode of febrile neutropenia which required hospitalization. No other patients were hospitalized or needed ICU admission. No deaths were recorded. In light of these favourable outcomes, patients with IEI can gradually and safely return to normal activities.Copyright © 2023 Elsevier Inc.
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Background: Lymphoproliferation is the persistent proliferation of lymphoid cells and it's incidence in inborn errors of immunity varies from 0.7 to 18%. Material(s) and Method(s): This is a retrospective analysis of patients referred to the department of Immunology, B. J. Wadia Hospital for Children, Mumbai between March 2017 to December 2022. Inclusion criteria consisted of 3 months duration of significant lymphadenopathy and/or splenomegaly or history of lymphoma. The clinical characteristics, laboratory and molecular findings of the included patients were analyzed. Result(s): A total of 66 patients were included. There was a male preponderance with male:female ratio of 25:8. Median age of onset of lymphoproliferation was 4.75 years(Range 1 year to 60 years). Splenomegaly was seen in 75%. Infections included recurrent pneumonia (14/66), recurrent ear infections(5/66), COVID(4/66), one episode of pneumonia(6/66), herpes zoster(3/66), recurrent subcutaneous abscess (3/66), abdominal koch(3/66), chronic sinusitis(2/66), dermatophytosis(2/66), esophageal candidiasis(2/66), recurrent malaria(1/66), recurrent varicella(1/66), cryptococcal meningitis(1/66), gram negative sepsis(1/66), BCG adenitis(1/66), pseudomonas osteomyelitis(1/66), impetigo (1/66), pseudomonas urinary tract infection (1/66), chicken pox(1/66), herpes keratitis(1/66), dengue(1/66), Other manifestations included Evans plus phenotype(10/66), Evans phenotype(8/66), Autoimmune hemolytic anemia(5/66), bronchiectasis(5/66), Type 1 diabetes(3/66), hyper reactive airway disease(2/66), inflammatory bowel disease(4/66), autoimmune thrombocytopenia(2/66), stroke(3/66), hemophagocytic lymphohistiocytosis(2/66), hypertriglyceridemia(2/66), hypothyroidism(2/66), celiac disease(1/66), Type 2 diabetes(1/66), autoimmune encephalitis(1/66), autoimmune hepatitis(2/66), anti-parietal cell antibody(1/66), arthritis(1/66), autoimmune enteropathy(1/66), systemic lupus erythromatosus(1/66), primary biliary cirrhosis requiring liver transplant(1/66), nephrotic syndrome(1/66), lymphoedema(1/66), hypersplenism(1/66), recurrent oral ulcers(1/66), gout(1/66), dermatitis(1/66), ovarian teratoma(1/66), alopecia areata(1/66). Hodgkin's lymphoma(HL) was the most common malignancy(9/66), followed by non Hodgkin lymphoma(NHL)(6/66), transformation from NHL to HL(1/66), Burkitt to T-cell lymphoma(1/66), HL to DLBCL(1/66), HL to anaplastic T-cell lymphoma(1/66). EBV driven lymphoproliferation was seen in biopsy of21/66. Genetic testing showed mutations in LRBA(11/66), PIK3CD(5/66), CTLA4(3/66), TET2(2/66), IL2RA (1/66), IL12RB1(1/66), BACH2(1/66), PRKCD(1/66), TNFSFR13B(1/66), TNFAIP3(1/66), FAS(2/66), FASL(1/66), Caspase8(1/66), CARD11(1/66), RTEL1(1/66), AICD(1/66), PIK3R1(1/66), IKBKB(1/66). Treatment included IVIG, chemotherapy, rituximab, sirolimus, abatacept, HSCT. Conclusion(s): All children with persistent lymphoproliferation, with or without autoimmunity and/or infections should be worked up for an underlying monogenic disorder of immune dysregulation. Lymphomas presenting at abnormal site and/or age, relapse and EBV driven lymphomas require further evaluation. Presence of monogenic cause helps in providing targeted therapy.Copyright © 2023 Elsevier Inc.
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Cerebral microangiopathy (CMA) is one of the significant causes of depression in the elderly. Close associations of the risk of developing depression with white matter hyperintensity, the presence of lacunar infarcts, and other markers of vascular disease are shown. The available data suggest that various vascular mechanisms, in particular, involvement of small vessels of the brain, generalized microvascular and endothelial dysfunction, metabolic risk factors, - are risk factors for the development of depression. Pathogenetic mechanisms include cerebral hypoperfusion and immune dysregulation. Depression is also a common complication of coronavirus infection, occurring both in the acute and post-COVID periods. The same mechanisms as in vascular depression are involved in the pathogenesis of the development of post-COVID depressive disorders. Given the complexity of the mechanisms of development of depressive disorders in patients with CMA, the presence of severe comorbid vascular pathology, antidepressants with an optimal ratio of efficacy and safety should be preferred. Agomelatine (Valdoxan) is one of such drugs.Copyright © 2023 Ima-Press Publishing House. All rights reserved.
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The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is related with the COVID-19 pandemic. Recent spike protein variations have had an effect on the transmission of the virus. In addition to ACE-2, spike proteins can employ DC-SIGN and its analogous receptor, DC-SIGNR, for host evasion. Spike variations in the DC-SIGN interaction region and role of DC-SIGN in immune evasion have not been well defined. To understand the spike protein variations and their binding mode, phylogenetic analysis of the complete GISAID (Global Initiative for Sharing Avian Influenza Data) data of the SARS-CoV-2 spike protein was considered. In addition, an in silico knockout network evaluation of the SARS-CoV-2 single-cell transcriptome was conducted to determine the key role of DC-SIGN/R in immunological dysregulation. Within the DC-SIGN-interacting region of the SARS-CoV spike protein, the spike protein of SARS-CoV-2 displayed remarkable similarity to the SARS-CoV spike protein. Surprisingly, the phylogenetic analysis revealed that the SARS-CoV-2's spike exhibited significantly diverse variants in the DC-SIGN interaction domain, which altered the frequency of these variants. The variation within the DC-SIGN-interacting domain of spike proteins affected the binding of a limited number of variants with DC-SIGN and DC-SIGNR and affected their evolution. MMGBSA binding free energies evaluation differed for variants from those of the wild type, suggesting the influence of substitution mutations on the interaction pattern. In silico knockout network analysis of the single-cell transcriptome of Bronchoalveolar Lavage and peripheral blood mononuclear cells revealed that SARS-CoV-2 altered DC-SIGN/R signaling. Early surveillance of diverse SARS-CoV-2 strains could preclude a worsening of the pandemic and facilitate the development of an optimum vaccine against variations. The spike Receptor Binding Domain genetic variants are thought to boost SARS CoV-2 immune evasion, resulting in its higher longevity. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-023-00820-3.
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Coronavirus disease 2019 (COVID-19) has become a major threat to global public health.In addition to injury in the respiratory system, some patients may have varying degrees of liver injury.With reference to related articles, this article analyzes the etiological characteristics and pathogenesis of COVID-19 and discusses the possible causes of COVID-19 with liver injury, including the direct effect of virus, inflammatory cytokine storm, drug-induced liver injury, hypoxic liver injury, and immune dysfunction.It is suggested that reasonable drugs should be selected in clinical practice to protect the liver and reduce the incidence rate of liver injury. .Copyright © 2021 Editorial Board of Jilin University. All rights reserved.
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Post-infectious immunosuppression may cause repeated hospitalization after COVID-19 pneumonia. The results of the observational study of the Raphamin use for immunotherapy in the recovery period of COVID-19 pneumonia are presented. Aim(s): to estimate efficiency of Rafamin usage in patients who have completed the course of inpatient treatment for coronavirus pneumonia. Material and methods. Thirty patients aged 18 to 80 years after hospital treatment of COVID-19 pneumonia were included and randomized into 2 groups (1: 1). All patients received anticoagulants, antioxidants, metabolic drugs. Patients of the 1st group (n=15) were additionally prescribed Raphamin for 5 days. The primary endpoint was the number of repeated hospitalizations due to consequences of COVID-19 and/or new cases of acute respiratory infection for 28 days of follow-up. In addition, dynamic of immune and inflammatory markers (absolute lymphocyte count, C-reactive protein), proportion of patients with immune dysregulation, and duration of symptoms associated with COVID-19 were assessed. Results. The number of hospitalized patients in group 1 was 0 (vs 5 in group 2, p=0.0421). Study therapy reduced the risk of repeated hospitalizations in 1.44 times [relative risk 1.44;95% confidence interval 0.91-2.28];duration of breathlessness decreased from 24.5 to 15.3 days (p=0.0108), and duration of fatigue reduced from 23.6 to 16.8 days (p=0.0452). The proportion of patients with immune markers normalization was 2 times higher than in the comparison group on 14 day of observation. Conclusion. The immunomodulatory therapy may be recommended during the recovery period of COVID-19 pneumonia.Copyright © Eco-Vector, 2022.
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Background: Systemic hyperinflammation is key to the pathogenesis of severe, acute COVID-19. However, few studies have analysed inflammatory profiles in adults with mild/moderate COVID-19, or in those with post-acute sequelae of COVID-19 (PASC). We aimed to i) describe trajectories of cytokines in a prospective cohort of adults with mild to severe COVID-19, compared to uninfected, healthy controls and ii) identify early (< 4 weeks after illness onset onset) predictors of ongoing PASC and inflammation at 6 months after illness onset. Method(s): RECoVERED is a prospective cohort of adults with laboratoryconfirmed SARS-CoV-2 infection between May 2020 and June 2021 in Amsterdam, the Netherlands. Serum was collected at weeks 4, 12 and 24. Participants completed monthly symptom questionnaires. PASC was defined as having at least one ongoing symptom that originated < 1 month of illness onset. Cytokine concentrations were analysed by human magnetic Luminex screening assay. We performed random forest regression to identify early predictors of PASC and raised CRP/IL-6 at 24 weeks, using Shapley additive explanation values as measures of importance for the different predictors. Result(s): Of 349 RECoVERED participants, 186 (53%) had >=2 serum samples and were included in current analyses. Of these, 101 (54%: 45/101 [45%] female, median age 55 years [IQR=45-64]) reported PASC at 12 weeks after illness onset, of whom none recovered by 24 weeks. We included 37 uninfected controls (17/37 [46%] female, median age 49 years [IQR=40-56]). At 4 weeks after illness onset, levels of IP10, IL10, IL17, IL1beta, IL6 and TNFalpha were significantly elevated among participants infected with SARS-CoV-2 compared to controls. Ongoing PASC was independently associated with raised CRP at 24 weeks. Early raised IL1beta and sCD14 levels and greater BMI at illness onset were the strongest predictors of PASC at 24 weeks. Those with higher early sCD14 or IL1beta and TNFalpha levels were also more likely to have persistently raised CRP and IL6, respectively, at 24 weeks (Fig.1). Conclusion(s): Differences in cytokine concentrations between individuals with COVID-19 and uninfected controls largely were greatest < 4 weeks after illness onset. In our study, ongoing PASC was associated with persistently elevated CRP at 24 weeks. Early immune dysregulation was, alongside BMI, an important determinant for persistent PASC. Further investigation of individuals with PASC and long-term aberrant cytokine levels may help improve our understanding of the condition. (Figure Presented).
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Background: SARS-CoV-2 infection typically causes self-limited disease, but a subset of individuals experience more severe disease associated with respiratory manifestations, hospitalization and mortality. People living with HIV (PLWH) have been shown to have chronic immune activation and inflammation despite effective antiretroviral therapy. During the COVID pandemic, PLWH were found to have an increased risk of hospitalization and mortality with acute COVID-19. The immune response driving these worsened outcomes in PLWH is not defined. We analyzed immune activation and exhaustion markers, as well as antigen specific T cell responses during acute COVID-19 in PLWH versus HIV-seronegative controls to determine the impact of chronic HIV infection and inflammation on acute COVID-19. Method(s): We performed flow cytometric analyses on peripheral blood mononuclear cells from: 1) PLWH with acute COVID-19 (HIV+COVID), 2) HIVseronegative individuals with acute COVID-19 (COVID) and 3) pre-COVID-19 pandemic PLWH (HIV). COVID(+) samples were collected at an average of 4.7 (range 0-16) and 5.5 (range 0-20) days post-symptom onset for the COVID and HIV+COVID cohorts, respectively. Cells were stained for surface markers of activation/exhaustion and intracellular cytokines (with and without SARS-CoV- 2-specific antigen stimulation). Observed immune responses were correlated with disease severity. Result(s): PLWH with acute COVID-19 had increased classical (CD14+) monocytes compared to HIV-seronegative individuals with acute COVID-19. The HIV+COVID cohort also had higher expression of activation (OX40, CD137) and exhaustion (PD1, TIGIT) markers on CD4+ and CD8+ T cells compared to HIV-seronegative individuals. SARS-CoV-2 antigen stimulation resulted in similar response frequencies between the HIV+COVID and COVID cohorts. Conclusion(s): PLWH had increased activation and exhaustion and increased classical monocytes compared to HIV-seronegative presentations of COVID-19, highlighting the persistent immune dysregulation associated with chronic HIV infection. Our findings aid in further characterization of how chronic immune dysregulation impacts the immune response to acute SARS-CoV-2 infection. Future studies include characterizing the impact of acute SARS-CoV-2 infection duration, as well as how chronic immune dysregulation impacts the development of long COVID. (Table Presented).
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Background: Pediatric acute liver failure is a rare and serious life-threatening situation, principally for the 30 to 50% of children in whom the etiology of their liver failure is unclear or indeterminate. Treating these patients is challenging, requiring constant assessment over time with regular evaluation for possible liver transplantation. Children with pediatric acute liver failure of undetermined etiology have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups. Emerging evidence suggests that a subgroup of patients with indeterminate pediatric acute liver failure have clinical, laboratory, and liver biopsy features of immune dysregulation with a dense infiltration of CD8 T cells. Method(s): In 2022, we received percutaneous liver biopsies from three children with acute hepatic dysfunction that showed an increased number of lymphocytes including CD8 T cells. For each case, routine H&E stains with levels, special stains and immunostains were performed. The first biopsy was from an 18-month-old male who presented with COVID infection, pancytopenia, elevated transaminases, and synthetic liver dysfunction (elevated INR). The second was from a 9-year-old female with a history of elevated liver enzymes with no clear cause. The third case was from a 2-year-old male with elevated liver enzymes, coagulopathy, and cholestasis. Result(s): The three cases showed similar histopathologic findings;an acute liver injury pattern with lobular architectural disarray, giant cell formation, reactive changes, single cell necrosis, cholestasis and marked mixed lymphocytic infiltrates. The infiltrates were predominantly composed of CD8-positive T-lymphocytes with scattered neutrophils, eosinophils and rare plasma cells. Portal areas were mildly expanded with mild bile ductular proliferation and mild to moderate lymphocytic infiltrates. Immunostains for CD8 demonstrated that the infiltrates were predominantly composed of CD8-positive T-lymphocytes. All three patients received steroids and responded to treatment evidenced by normalization of liver enzymes and function. Conclusion(s): Dense hepatic CD8 T-cell infiltration is a major finding inactivated CD8 T-cell hepatitis. However, the percentage distribution of lymphocyte subtypes in the setting of hepatitis is not well established, and CD8 T-cell infiltration has also been described in cases of drug-induced hypersensitivity reactions, viral hepatitis, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome, as well as autoimmune hepatitis. Further investigation is needed to better understand the diagnostic criteria in this disease.
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Background: COVID-19 is a viral disease affecting mostly respiratory system with variable severity of the clinical course. Several clinical and laboratory parameters are associated with poor outcome. Progression of the clinical stage is associated with the exaggerated immune response and the cytokine storm. Method(s): We focused on the search of potential prognostic markers of fatal outcome among immune parameters. To this end, we examined the immune profile in 823 COVID-19 patients hospitalized in University Teaching Hospital in Martin (Slovakia) on admission and its changes over time during the first week of hospitalization. The examined immune profile consisted of the differential blood cell counts, serum concentration of immunoglobulins and basic complement compounds C4 and C3, flow cytometric lymphocyte subsets phenotyping and the measurement of selected activation and inhibition markers. Result(s): Although none of examined parameters alone had sufficient AUC value to be considered as a marker of (un)favourable outcome, we found several significant differences among different severity groups of patients, as well as between survivors and non-survivors. Severity of COVID-19 correlated with the severity of neutrophilia, thrombocytopenia, depletion of leukocyte (except for neutrophils) and lymphocyte subsets. In comparison to the fatal outcome, survival was associated with higher concentration of C3 and IgM, lower proportion of CD8+CD38+ cells, higher proportion of CD8+NKG2A+ and NK NKG2A+ cells on admission and with the significant increase in the expression on HLA-DR on both CD3+ and CD8+ cells over the first week. Conclusion(s): Our results point out to the dysregulated functional status of depleted CD8+ cells with their over-activation and possibly insufficient compensatory inhibition in COVID-19 non-survivors. Based on our results, the increase in HLA-DR expression on CD3+ and CD8+ cells is necessary for recovery.
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As of June 2022, children represent 18.9% of total cumulated cases of COVID-19 in the United States. While most children have mild symptoms, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect the central and peripheral nervous system function. The most common neurological symptoms in children with COVID-19 are headache, fatigue, anosmia, dysgeusia, and myalgia. In hospitalized children, the most common symptoms are headache, encephalopathy, and seizures. Neurological symptoms are associated with a more severe disease course, and up to a third of hospitalized children with COVID-19 require intensive care intervention. A rare and feared complication is multisystem inflammatory syndrome (MIS-C), a serious condition that involves severe inflammation of different organs, including the brain. Treatment for MIS-C has not been validated and primarily consists of supportive care and immune modulation. Some children with a history of COVID-19 develop persistent symptoms, also known as long COVID. However, recent evidence suggests that long COVID symptoms appear as frequently as in children without a history of COVID-19. Similarly, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2, is associated with differences in neurodevelopmental milestones. Almost 3years into the pandemic, the evidence in children is limited. Large-scale studies with adequate pre- and post-pandemic control groups are needed to establish the associations between COVID-19 and short and long-term neurological complications. © 2023 Elsevier Inc. All rights reserved
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Case report Background: Mutations in the PLCG2 gene can cause PLCG2-associated antibody deficiency and immune dysregulation (PLAID) or auto-inflammation with PLCG2-associated antibody deficiency and immune dysregulation (APLAID). PLAID is characterized by urticarial eruptions triggered by evaporative cooling along with cutaneous granulomas. APLAID may present with early-onset skin inflammation and non-infectious granulomas, uveitis, and colitis. Method(s): Case report and literature review. We performed in silico analysis for variants of uncertain significance (VUS). Result(s): A 29-day-old boy presented to emergency department for failure to thrive. He was found to be SARS-CoV2 positive, had an E. coli UTI in the setting of bilateral perinephric masses which subsequently resolved. He also had a perianal soft tissue abscess measuring 4cm in diameter. Mom reported a similar infection when she was age 2. She also reported intermittent diffuse urticaria triggered following perspiration evaporation.Abscess wall histology showed diffuse neutrophil and lymphocytic infiltration, with cultures growing polymicrobial enteric flora. His serum immunoglobulins G, A, M, and E were within reference range. Naive and memory CD4, CD8, CD19 lymphocyte subsets (including NK cells) were also within age-appropriate reference range. He had a normal neutrophil oxidative burst measured using dihydrorhodamine (DHR) flow cytometry following PMA stimulation, which ruled out a diagnosis of chronic granulomatous disease. On evaporative cooling, the patient had a 2mm wheal with surrounding erythema which resolved rapidly with warming. A targeted primary immunodeficiency panel showed a heterozygous VUS in PLCG2, c.688C > G (p.Leu230Val). The variant was absent from major databases and had a calculated CADD score of 17.77. He had symptomatic resolution after completing 3 weeks of ceftriaxone and metronidazole antimicrobials. Given the concern for PLCG2-associated very early-onset inflammatory bowel disease (VEO-IBD), a fecal calprotectin was obtained at 3 months and found to be elevated (157 mcg/g [ < = 49 mcg/g]). However, he had no symptomatic or macroscopic evidence for VEO-IBD. Conclusion(s): Presence of very early onset abscesses has not been previously described in patients with heterozygous PLCG2 deficiency. This case adds to the expanding variable phenotype of PLCG-2-associated immune dysregulation.
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Pulmonary sarcoidosis is typically recognized as an interstitial lung disease with an infrequent occurrence of alveolar filling or acinar pattern. This rare form of alveolar sarcoidosis is known to have a rapid progression. Several case reports showed the development/worsening of sarcoidosis after COVID-19 infection. We present a case of a 60-year-old male with chronic hypoxic respiratory failure since having COVID-19 disease followed by gradual progression in symptoms, who had atypical sarcoid-like alveolar opacities on radiography, two prior negative bronchoscopies, transbronchial biopsy and BAL, and third bronchoscopic transbronchial biopsy suggestive of findings of poorly formed granulomas with high suspicion of alveolar sarcoidosis after ruling out other comparative possibilities, and later having a drastic improvement with sarcoidosis management. Our patient's worsening symptoms after COVID-19 infection suggest impaired immunoregulation role of the infection in developing the disease process.
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Since the arrival of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, its characterization as a novel human pathogen, and the resulting coronavirus disease 2019 (COVID-19) pandemic, over 6.5 million people have died worldwide-a stark and sobering reminder of the fundamental and nonredundant roles of the innate and adaptive immune systems in host defense against emerging pathogens. Inborn errors of immunity (IEI) are caused by germline variants, typically in single genes. IEI are characterized by defects in development and/or function of cells involved in immunity and host defense, rendering individuals highly susceptible to severe, recurrent, and sometimes fatal infections, as well as immune dysregulatory conditions such as autoinflammation, autoimmunity, and allergy. The study of IEI has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. Indeed, this has been exemplified by assessing the impact of SARS-CoV-2 infection in individuals with previously diagnosed IEI, as well as analyzing rare cases of severe COVID-19 in otherwise healthy individuals. This approach has defined fundamental aspects of mechanisms of disease pathogenesis, immunopathology in the context of infection with a novel pathogen, and therapeutic options to mitigate severe disease. This review summarizes these findings and illustrates how the study of these rare experiments of nature can inform key features of human immunology, which can then be leveraged to improve therapies for treating emerging and established infectious diseases.
Subject(s)
COVID-19 , Communicable Diseases , Humans , SARS-CoV-2 , Disease SusceptibilityABSTRACT
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.
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As we near the third year of the COVID-19 pandemic, greater attention is now being paid to the potential long-term consequences of SARS-CoV-2 in the hundreds of millions of people infected globally. A syndrome termed "long COVID" has emerged, which predominantly manifests as persistent fatigue, dyspnea, chest pain, and cognitive dysfunction following acute infection. The incidence of long COVID is in the range of 15% based on current best evidence, and symptoms are likely a result of several different pathophysiological mechanisms including multi-organ injury from acute infection, systemic viral persistence, immune dysregulation, and/or autoimmunity. Pulmonary symptoms represent a significant component of long COVID, and there is a growing body of research describing the epidemiology, risk factors, physiology, and radiology of the respiratory manifestations of long COVID. In this clinical review, we examine the most recent evidence relating to "respiratory long COVID," discuss how innovative technologies such as Xenon-129 gas transfer magnetic resonance imaging (MRI) and respiratory oscillometry are helping to elucidate its unique pathophysiology, and consider the role of preventative strategies and possible treatments such as adapted pulmonary rehabilitation. The burden of respiratory long COVID is likely to continue to grow, and all healthcare professionals who care for patients with respiratory disease must prepare for this emerging chronic condition. This will require increased resources from healthcare decision makers, inventive approaches to healthcare delivery, further research, and the same spirit of collaboration that has enabled the many success stories to date in the global effort against COVID-19.Copyright © 2023 Canadian Thoracic Society.