Novel heterozygous PLCG2 variant presenting with very early-onset perianal abscess

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.

A contrasting diagnosis: iododerma

An 86-year-old woman presented to the emergency department with acute shortness of breath. She was treated with intravenous furosemide for acute-on-chronic heart failure. Her past medical history included atrial fibrillation, hypertension, diverticulosis and hypothyroidism. Rivaroxaban and levothyroxine were her only long-term medications. On day 5 of hospital admission, she developed painful haemorrhagic and purulent bullae on her dorsal hands, head and neck. These evolved to large suppurative, vegetative plaques over a 72 h period and she developed additional lesions on her trunk, upper back and thighs. The patient had routine blood tests, which showed a raised C-reactive protein at 260 mg L-1, and an acute kidney injury with a glomerular filtration rate of 54 mL-1 min-1. She had a negative COVID-19 swab, and swabs from the lesions for bacterial culture and viral polymerase chain reaction were negative. She had a normal serum protein electrophoresis, immunoglobulin, antinuclear antibody and antineutrophil cytoplasmic antibody. She had computed tomography of her chest 24 h prior to the onset of her lesions, which showed mild bilateral pleural effusions in keeping with fluid overload secondary to heart failure. A biopsy taken from her hand showed orthokeratosis and parakeratosis, and there was bulla formation subepidermally. There was a dense neutrophilic infiltrate with microabscess formation with scattered eosinophils and lymphocytes. There was no evidence of vasculitis. Direct immunofluorescence was negative and a tissue culture for atypical mycobacteria was negative. The patient was commenced on high-dose intravenous methylprednisolone at 500 mg for 3 days followed by 40 mg prednisolone orally for 1 week, but there was a limited response. Our initial differential was Sweet syndrome or pyoderma vegetans;however, the patient had no fevers and no risk factors (malignancy, inflammatory disease, infection, etc.). She also had no response to high-dose oral prednisolone. Given the timing of her CT examination in relation to her acute dermatosis and the use of radioiodine for contrast, we assessed the patient's serum iodine and urine iodine. These were both high at 1.02 mmol L-1 (reference interval 0.32- 0.63) and 3.46 mmol L-1 (reference interval 0.0-2.43), respectively. A diagnosis of iododerma was made. The patient's eruption slowly resolved and at 12 weeks there was evidence of postinflammatory skin changes only. Her urine and serum iodine were rechecked, and both had normalized. In the last 20 years there have been approximately 20 case reports of iododerma. Most have been following iodine contrast use in patients with abnormal kidney function, like our patient. Most describe an acneiform eruption that subsequently evolves to vegetative plaques (Chalela JG, Aguilar L. Iododerma from contrast material. N Engl J Med 2016;374: 2477). Iododerma is largely a diagnosis of exclusion, but histopathology and urine and serum iodine levels can help support diagnosis.

Changes in surface activity of lung surfactant and bronchoalveolar cell profile upon COVID-19-related Acute Respiratory Distress Syndrome

A contribution of Lung Surfactant (LS) inactivation to COVID-19-related ARDS (cvARDS) has been argued, but not been clearly demonstrated to date. In the present study, we have characterised the extent of lung neutrophil infiltration along with the surface-active properties and protein composition of LS in bronchoalveolar lavages (BALs) collected from 12 cvARDS patients. A control group of 9 subjects without respiratory diseases was also enrolled. BAL cell sorting was performed by flow cytometry. The adsorption of LS at the air-liquid interface was assessed by Surfactant Adsorption Test (SAT), whereas the level of surfactant hydrophobic proteins was measured by Western Blot analysis. Results were normalised by phosphatidylcholine (PC) total amount. Significant increase in neutrophil [61.3(47.5-84.6)% vs 1.6(0.9-4.9)%, p<0.0001] and decrease in macrophage percentages [13.6(6.1-28.9)% vs 90.8(87.1-92-6)%, p<0.0001] of total BAL cells were detected in cvARDS patients. A lower overtime LS adsorption/accumulation at the air-liquid interface was also observed in those patients compared to the control group from 60min onward [14003(10232-19736) vs 24501(16386-28489) RFU, p=0.0471]. Moreover, cvARDS patients under the acute phase showed the lowest surfactant activity at the end of SAT (12191(11588-20159) RFU, p=0.048). An increase in both SP-B and SP-C/PC was also evident in cvARDS BALs. Here, we report for the first time on the reduction of LS surface-active properties during the acute period and even under the recovery phases of cvARDS. This may confirm how LS inactivation may be involved in both early and late consequences of severe cvARDS.

Vulvar Aphthous Ulcers in Children with COVID-19: A case series

Background: Vulvar aphthous ulcers are defined by acute onset of painful genital lesions that are associated with viral illness. They classically present in non-sexually active girls and are diagnosed once other more common cause of genital ulcerations, including STIs or autoimmune bullous diseases, have been excluded. Previous reports of vulvar aphthous ulcers associated with COVID-19 have described treatment of the symptoms with either local or systemic corticosteroids. This case series illustrates the ability to manage these patients conservatively resulting in complete and spontaneous resolution of the ulcers. Case: Four females, ages ranging from 10 to 21, presented to the emergency department for vulvar pain. Each patient was diagnosed with vulvar aphthous ulcers based on physical examination. All four patients were diagnosed with COVID-19 with rapid antigen testing. With directed counseling, each patient and their family were instructed on a regimen of acetaminophen, sitz baths, and voiding in the bath. Topical analgesics such as lidocaine gel were not administered and steroids were not prescribed. All four patients were able to manage their symptoms at home and did not require admission to the hospital. All patients experienced spontaneous and complete restoration of anatomy in 1-2 weeks. Comments: The novel coronavirus pandemic caused by SARS-CoV02 has resulted in considerable morbidity and mortality. While immunocompromised hosts are more susceptible to complications of COVID-19, patients with intact immune systems may also experience distressing viral related symptoms. The pathogenesis of these ulcers has been hypothesized to be a result of non-specific inflammatory response to a viral systemic illness resulting in blistering of the mucosal genital surfaces It has been proposed that the ulcers are secondary to a cytokine storm that occurs in SARS-CoV-2 infections. Elevated cytokines, including TNF-alpha, result in neutrophil chemotaxis to mucosal tissue and subsequent ulceration of the tissue. Previous case studies discussing vulvar aphthous ulcers associated with COVID-19 all required hospitalization for pain control and/or urinary retention and treatment with steroids. Hospitalization can be a traumatic experience for both child and adolescent patients as well as their family. The added isolation and precautions required for treating COVID positive patients can have a further psychological impact. Through directive counseling, all patients in our case series were able to avoid hospitalization and supportive care of the genital lesions in the outpatient setting was sufficient.Copyright © 2023

Landscape Analysis of Quercetin: A Potential Candidate Against SARS-CoV-2

Fruit, vegetables, and green tea contain quercetin (a flavonoid). Some of the diet's most signifi-cant sources of quercetin are apples, onions, tomatoes, broccoli, and green tea. Antioxidant, anticancer, anti-inflammatory, antimicrobial, antibacterial, and anti-viral effects have been studied of quercetin. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, ribonucleic acid (RNA) polymer-ase, and other essential viral life-cycle enzymes are all prevented from entering the body by quercetin. Despite extensive in vitro and in vivo investigations on the immune-modulating effects of quercetin and vitamin C treatment. 3-methyl-quercetin has been shown to bind to essential proteins necessary to convert minus-strand RNA into positive-strand RNAs, preventing the replication of viral RNA in the cytoplasm. Quercetin has been identified as a potential SARS-CoV-2 3C-like protease (3CLpro) suppressor in recent molecular docking studies and in silico assessment of herbal medicines. It has been demonstrated that quercetin increases the expression of heme oxygenase-1 through the nuclear factor erythroid-related factor 2 (Nrf2) signal network. Inhibition of heme oxygenase-1 may increase bilirubin synthesis, an endoge-nous antioxidant that defends cells. When human gingival fibroblast (HGF) cells were exposed to lipo-polysaccharide (LPS), inflammatory cytokine production was inhibited. The magnesium (Mg+2) cation complexation improves quercetin free radical scavenging capacity, preventing oxidant loss and cell death. The main objective of this paper is to provide an overview of the pharmacological effects of quercetin, its protective role against SARS-CoV-2 infection, and any potential molecular processes.Copyright © 2022 Bentham Science Publishers.

Longitudinal profiling of the peripheral blood transcriptome identifies risk of Major Cardiac Events after Hospitalization for COVID-19

Introduction: SARS-CoV-2 infection has profound effects on endothelial and immune cell function and coagulation, and better understanding of these events in COVID-19 would allow for targeted cardiovascular treatment and followup. Method(s): Longitudinal observational study of patients with PCR-confirmed SARS-CoV-2 infection admitted to hospital at two UK sites. Patients were enrolled within 96 hours of admission, with sampling up to day 29. RNAstabilised whole blood was processed for mRNA sequencing. Gene expression levels were compared between patients who did and did not suffer a major cardiac event (MACE) from admission to 1-year post-hospitalization. Result(s): At day 1, in acute COVID-19, no differences in gene expression were observed between those with (n=23) and without (n=140) a MACE. However, 93 significant differentially expressed genes (DEGs;adjusted pvalue<0.05;Wald test with Benjamini-Hochberg correction) were identified at day 29 between patients who suffered a MACE (n=16) or not (n=85) post-hospitalization. Neutrophil elastase (ELANE), tissue factor pathways inhibitor (TFPI) and integrin subunit alpha-2 (ITGA2B) were significantly elevated in patients who suffered a MACE. Significantly enriched pathways associated with cardiovascular events included type I interferon signalling and neutrophil chemotaxis. Conclusion(s): COVID-19 patients who experienced a MACE demonstrated significant changes in peripheral blood transcriptome 29 days after hospital admission. Significant DEGs were related to neutrophil activity, coagulation and interferon signalling, suggesting a relationship between these pathways and increased cardiovascular risk.

SWEET SYNDROME IN ACUTE MYELOGENOUS LEUKEMIA- A CASE REPORT

CASE: Patient is a 63 y/o F with PMH of relapsed AML on treatment with Gilteritinib, Meniere's Disease, asthma, GERD, PRA positive, CKD Stage 3. She was on cycle 1 day + 20 of Gilteritinib when she presented with a neutropenic fever of 101.9. She reported congestion and headache. She was pan cultured and started on empiric Cefepime. Her blood cultures, COVID test and CXR were all negative for sources of infection. Eventually, Cefepime was stopped, and she was transited to PO Cefdinir and Cipro but redeveloped fevers and a maculopapular rash. Repeat pan-cultures were negative. Antibiotics were broadened to Merrem, Linezolid and Cresemba and her fevers improved. However, the rash continued to worsen. There was concern that nodular rash was secondary to infection or possible drug reaction from her antibiotics. Her rash showed no improvement with Benadryl or withholding drugs. She underwent skin punch biopsy before discharge. Biopsy showed florid superficial inflammation with benign ulcer that was highly suggestive of Sweet Syndrome given history of AML. IMPACT/DISCUSSION: Sweet syndrome (SS), or acute febrile neutrophilic dermatosis is a rare inflammatory condition characterized by painful cutaneous nodules and neutrophilic infiltrate in the dermis, in the absence of vasculitis. This syndrome is associated with malignancies with AML and MDS being the most reported. Malignancy associated Sweet Syndrome accounts for 15-20% of cases of SS. The atypical production of both pro-inflammatory cytokines (IL - 6, TNF - alpha) and signaling molecules demonstrated in AML is suspected to affect neutrophil function leasing to dermal clumping of the mature neutrophils. In our patient the fever presented prior to the rash with sudden onset of nodular as it has been commonly reported in literature review. Glucocorticoids, either topical or systemic, together with antibiotics and wound care, represent the mainstays of SS therapy. The rash heals without scarring if no ulcerations are present. The signs and symptoms of Sweet syndrome can mimic infection and be treated inaccurately, thus, it is important to make a correct diagnosis. Our patient's tissue cultures were negative for microorganisms. She was started on glucocorticoid with good response in regards to her rash but did have some scars and hyperpigmentation. Unfortunately due to her aggressive AML and complications patient elected to go to Hospice. CONCLUSION: When SS is established, the physician should keep a high index of suspicion to search underlying malignancies. Sweet Syndrome generally responds promptly to treatment with glucocorticoid.

PI3Kgamma inhibition reduces inflammation and promotes survival in cancer and SARS-CoV-2

Solid tumors are characterized by extensive immune suppressive inflammation, vascular leak, fibrosis and organ damage. Similarly, SARS-CoV-2 infections induce aberrant pulmonary and systemic inflammation, vascular leak, coagulation, fibrosis and fatal organ damage. We previously demonstrated that macrophages in solid tumors strongly expressed phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinately controls granulocyte and monocyte trafficking to tumors as well as wound-healing-type macrophage transcription in cancer and fibrosis. We also observed that macrophages in COVID-19 lungs strongly expressed PI3Kγ. To identify therapeutic strategies to suppress COVID-19-associated inflammation, we characterized lung tissue of COVID19 patients using multiplex immunohistochemistry and tissue transcriptomics. Lungs of deceased patients exhibited substantial infiltration by neutrophils and wound-healing macrophages, fibrosis and alveolar type II cell depletion. In animal models of lung inflammation, bacterial infections, viral infection and SARS-CoV-2 infection, PI3Kγ deletion or inhibition with the cancer therapeutic IPI-549 (eganelisib) suppressed pulmonary and systemic inflammation, reduced lung damage, and promoted survival. These studies demonstrate the essential role of PI3Kγ in inflammatory diseases as well as cancer and support the use of PI3Kγ inhibitors such as eganelisib to suppress inflammation and promote survival in pulmonary infections like SARS-CoV-2 and cancer.

A rare case of an acute ascending longitudinally extensive necrotizing transverse myelitis in a young woman: a severe post-COVID-19 infection neurological complication

Objective: N/A Background: Neurological injuries from severe acute respiratory syndrome coronavirus 2 (COVID-19) are becoming recognized in the central and peripheral nervous systems. Pathophysiology processes include a hyperinflammatory immune response due to the affinity of COVID-19 to human ACE2 receptors and multi-organ failure. CASE REPORT: This report highlights a unique presentation of a rapidly progressive, hyperacute to chronic, necrotizing transverse myelitis with associated COVID-19 long haul syndrome in a 31-year-old Venezuelan obese woman without other vascular risk factors. There was a preceding symptomatic COVID-19 infection. Symptoms included headaches, dysgeusia, asymmetric ascending proximal more than distal paresis, lumbago with dysesthesias, autonomic dysautonomia, hyperreflexia with clonus, and severe functional mobility impairment. Results: Neuraxis imaging showed a longitudinally extensive transverse myelitis (LETM) with T7-T9 enhancement and expansion throughout the thoracic spine (T4-T11). CSF studies showed lymphocytic pleocytosis with elevated protein. Aggressive empiric treatment included 1G of IV methylprednisolone, plasmapheresis (PLEX), and high-dose cyclophosphamide given the life-threatening progression of clinical symptoms. Repeat imaging post-treatment showed expansion of lesions to the cervical cord with sparing of the brainstem, stabilizing after cyclophosphamide initiation. Clinically, there was partial recovery of upper extremity sensation and strength. A T5-T6 tissue biopsy showed evidence of necrotizing myelitis with extensive neutrophil and lymphocyte infiltration. Given clinical progression, a repeat round of immunosuppression, including a monoclonal complement antibody, was pursued. Post-rehabilitation, the patient's symptoms improved above the thoracic spine but not below it. Conclusions: To our knowledge, this is the most severe form of COVID-19 associated necrotizing myelitis ever reported. Future research may clarify the molecular pathways that trigger neurological injury in patients with severe COVID-19 infection-associated spinal cord complications and increase therapeutic options.

Isolated pauci-immune pulmonary capillaritis associated with an extensive bilateral hemothorax and pleuro-pericarditis

Introduction: Isolated pauci-immune pulmonary capillaritis (IPIPC) is a rare disorder characterized by small vessel vasculitis limited to alveolar capillaries in the absence of systemic manifestations. There are very few case reports of this disorder in the medical literature. Case Report: A 37-yo male with no known history of autoimmune pathology who was admitted to the hospital for evaluation and treatment of dyspnea and thoracalgia. Peripheral blood cultures, serum studies to detect Legionella and Pneumococcus antigens, and a nasopharyngeal swab test for covid-19 were all negative. Chest imaging revealed bilateral pleural effusions from the base to the apices with concomitant atelectasis of the adjacent lung parenchyma. Although the results of an 18F-PET-CT scan revealed no pathological uptake, video-assisted thoracoscopy revealed diffusely edematous pleura with crater-like patches with new onset of venous vessel varicosities, intra-alveolar hemorrhages associated with disordered vascularization, suggesting small vessel vasculitis. Histologic findings included widespread intra-alveolar hemorrhage with organizing injury, hemosiderin-laden macrophages, scattered intra-arterial thrombi, and diffuse perivascular neutrophilic infiltrates consistent with a diagnosis of capillaritis. Conclusions: Given the negative immune studies (save for a weakly-positive lupus anticoagulant and no evidence for extra-pulmonary vasculitis, the diagnosis was Isolated pauci-immune pulmonary capillaritis. The patient recovered in response to immunosuppressive/anti-inflammatory therapy.

A Multicompartment Mathematical Model Based on Host Immunity for Dissecting COVID-19 Heterogeneity

Background: As of early August 2021, more than 190 million people have developed coronavirus disease (COVID-19), a pandemic that has killed approximately 4 million people. Caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 exhibited a highly variable clinical course, ranging from a high proportion of asymptomatic and mild infections to severe and fatal disease. However, the immunological determinants underlying the heterogeneity of COVID-19 remain to be fully elucidated. Methods: To systemically analyze the immunopathogenesis of COVID-19, a multicompartment mathematical model based on both immunological principles and COVID-19-related work performed by the scientific community was built to illustrate the dynamics of host immunity after SARS-CoV-2 infection. We used ordinary differential equations (ODEs) to simulate the time-dependent functions of immunologic variations in the four compartments, which were draining lymph nodes, peripheral blood, lung and distant lymph nodes and spleen. Our model consisted of equations for 109 immunologic variations, which contained 223 parameters. K was used to characterize the adequacy of the SARS-CoV-2-specific naïve T/B cell pool;K I represented the hill coefficient of antigen-presenting cell (APC) differentiation. Further, we used method of pseudo landscape to visualize the effect of APC capacity and the SARS-CoV-2-specific naïve T/B cell pool on clinical outcomes. Results: Based on both immunologic knowledge and extensive COVID-19-related work performed by the scientific community, we constructed a knowledge-driven mathematical model that incorporated SARS-CoV-2 infection, bacterial infection, leukocyte chemotaxis, innate immunity and adaptive immunity. The model simulated and predicted the different trajectories of the viral load, bacterial load, immune cells, cytokines and infected epithelial cells in patients with different severities. A higher viral load and longer virus-shedding period were observed in patients with higher severity, along with an increase in SARS-CoV-2-infected lung epithelial cells. The trajectories of both peripheral blood IL-6 and lymphocytes predicted COVID-19 outcomes. Based on the distribution, trafficking and differentiation of immune cells after SARS-CoV-2 infection, we proposed that early-stage lymphopenia is related to lymphocyte chemotaxis. The delayed initiation of both innate and adaptive immunity resulted in elevated SARS-CoV-2 shedding and was a pivotal cause of COVID-19 severity. Spatiotemporally, viral shedding and postviral bacterial infection evoked stronger innate immunity. Viral shedding could be restrained by the rapid initiation of APC, antibody-secreting cell (ASC) and cytotoxic T cell (CTL). Moreover, our model predicted that the insufficient SARS-CoV-2-specific naïve T/B cell pools and inactive APC caused a series of chain reactions, including viral shedding, bacterial infection, sepsis and cytokine storms. Finally, pseudopotential analysis revealed that a high state characterized by severe bacterial infections and cytokine storms was a stable attractor for patients with insufficient SARS-CoV-2-specific naïve T/B cells and inactive APC (Figure 1). Conclusion: Overall, our analysis provided a comprehensive view of the dynamics of host immunity after SARS-CoV-2 infection and highlighted that the antigen-specific naïve T/B cell pool and APC ability may essentially determine COVID-19 heterogeneity from an immunological standpoint. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Sweet syndrome induced by adenovirus vector CoViD-19 vaccine

Introduction: Sweet syndrome (SS) is a rare skin disease, characterized by rapid onset of plaques or nodules with extensive infiltration of neutrophils into epidermidis and dermis. Three main types of SS are known: classical or idiopathic, malignancy-associated, drug-induced. Case report: A 69 yo woman was admitted because of recent pirexya, painful and asymmetric erythematous plaques on legs and buttock, painful wrist and elbow tenderness for 6 days. History: hypertension and dyslipidemia. Eighteen days before she received Vaxzevria first dose. Physical examination revealed normal findings except of skin lesions. Biohumoral exams showed increased CRP, normal GB count;negative SARS-CoV-2 test, as well as HBV, HCV, CMV, EBV, Quantiferon, ANA, ANCA, LAC. C3 and C4 were normal. Blood and skin coltures were negative. Chest X-ray, ECG, ecocardiography, EGDS, colonscopy, PET TC were all normal. A broad spectrum antibiotic and anti-inflammatory therapy was initially set (vasculitis vs staphylococcus infection). Skin biopsy was performed: it showed a dense interstitial neutrophilic infiltrate of the dermis, according with SS. Corticosteroid therapy caused a prompt improvement of skin lesions. Conclusions: A classical SS induced by SARS-CoV-2 vaccine was diagnosed at the discharge. A vaccine-associated SS is well known: some post CoViD and post mRNA SARS-CoV-2 vaccine SS are described in literature. This is probably the first case of a SS induced by SARS-CoV-2 adenovirus vaccine. An alert was sent to AIFA.