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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: NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. ZNFX1 deficiency in humans is very rare;to date, only fifteen cases have been reported by Vavassori S et al. (10.1016/j.jaci.2021.03.045). The disease presented in all cases as severe viral infections complicated by multisystem inflammation evolved to multiorgan failure with a high mortality rate. Pediatric Allergy and Immunology Section at Queen Rania Children's Hospital in Jordan had confirmed the diagnosis of ZNFX1 deficiency in an infant at his first presentation with severe viral illness based on the positive family history of one sibling death caused by complicated COVID-19 infection. Case presentation: A 12-month-old boy was born to consanguineous parents, full-term, with no NICU admission. He was doing well till the age of four months when he was admitted to the hospital with fever, hypoactivity, and maculopapular skin rash. On admission, he was ill, hypoactive, and febrile, and a physical exam showed hepatosplenomegaly and maculopapular skin rash. His lab showed thrombocytopenia, elevated transaminases, hyperferritinemia, and high CRP;he was treated with broad-spectrum antibiotics, but he continued to deteriorate, and his infectious workup was unrevealing, including COVID-19 PCR. His older sibling died at eight months in 2020 when she got a COVID-19 infection, deceased after rapid deterioration evolved to multiorgan failure. Unfortunately, she had no stored DNA, as she was treated at a peripheral hospital. Based on this presentation and the fatal COVID-19 infection, pediatric immunology service got consulted;we did an immunological workup, which showed normal lymphocyte subsets, Immunoglobulins, and bacterial antibodies. Whole exome sequencing showed a homozygous frameshift mutation in the ZNFX1 gene, protein change defect had detected;p.Tyr555MetfsTer6, and nucleotide change variant: c.1663_1665delTACinsAT. Family screening showed heterozygous for the same variant in both parents and a healthy sibling. The patient was diagnosed with the hemophagocytic lymphohistiocytosis-like disease and treated with steroids, intravenous immunoglobulin, and antimicrobials, he showed complete recovery, and we are going to do bone marrow transplantation as his brother is 8/8 HLA matched.Copyright © 2023 Elsevier Inc.
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BACKGROUND: The number of children infected with novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has increased during the outbreak of the Omicron strain. Hyperferritinemia has been reported in severe cases of COVID-19, and in children or neonates with multisystem inflammatory syndrome (MIS). Hyperferritinemia is considered to be one of the signs of MIS, but thus far, there have been few summarized reports on it. We retrospectively analyzed four infants less than 3 months of age with SARS-CoV-2 infections treated in our institution during the outbreak of the Omicron strain. RESULTS: most patients were in good condition, but hyperferritinemia was observed in all of four cases. CONCLUSIONS: Hyperferritinemia can be observed in infantile COVID-19 patients even with mild symptoms. It is necessary to carefully monitor their clinical course and monitor the patients.
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Background: Angiotensin-converting enzyme 2 (ACE2) is not only the entry route of SARS-CoV-2 infection but also triggers a major mechanism of COVID-19 aggravation by promoting a hyperinflammatory state, leading to lung injury, hematological and immunological dysregulation. The impact of ACE2 inhibitors on the course of COVID-19 is still unclear. The effect of ACE2 inhibitors on the course of acute respiratory distress syndrome (ARDS) during COVID-19 and other severe respiratory infections in conditions of hyperferritinemia (HF) was investigated. Methods: A cohort study of critically ill patients with COVID-19 and other respiratory diseases (widespread infection, pneumonia) who underwent treatment in The Critical Care Unit of the First University Clinic (Tbilisi, Georgia) during the 2020-2021 years was conducted. The impact of the ACE2 inhibitors on the course of the ARDS developed during COVID-19 and other severe respiratory infections in conditions of different severity of HF was evaluated. Results: In COVID-19-infected (I) and uninfected (II) patients with ARDS, ACE2 inhibitors reduce the levels of Ang II, C reactive protein (CRP) and D-dimer (I: from 1508.07 ± 26.68 to 48.51 ± 24.35, from 233.92 ± 13.02 to 198.12 ± 11.88, from 7.88 ± 0.47 to 6.28 ± 0.43; II: from 1000.14 ± 149.49 to 46.23 ± 88.21, 226.48 ± 13.81 to 183.52 ± 17.32, from 6.39 ± 0.58 to 5.48 ± 0.69) at moderate HF and Ang II, CRP levels (I: from 1845.89 ± 89.37 to 49.64 ± 51.05, from 209.28 ± 14.41 to 175.37 ± 9.84; II: from 1753.29 ± 65.95 to 49.76 ± 55.74, 287.10 ± 20.50 to 214.71 ± 17.32) at severe HF, reduce interleukin-6 (IL-6) expression at moderate HF (I: from 1977.23 ± 354.66 to 899.36 ± 323.76) and cause reduction of pCO2 index at severe HF (I: from 69.80 ± 3.22 to 60.44 ± 2.20) in COVID-19-infected patients. Conclusion: Study results show that the ACE2 inhibitors play an important role in the regulation of inflammatory processes in both COVID-19-infected and uninfected patients with ARDS. ACE2 inhibitors decrease immunological disorders, inflammation, and lung alveoli dysfunction, especially in COVID-19-infected patients.
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Introduction. The novel coronavirus infection caused by the SARS-CoV-2 remains the main problem, which is being studied by all the efforts of the global scientific community. Large clinical recourse has been accumulated that allows to conduct more effective treatment of patients, but there are still unresolved issues on the pathogenesis for development and course of the disease. Materials and methods. The study included 163 patients admitted to the infectious diseases hospital diagnosed with "Novel coronavirus infection caused by the SARS-CoV-2". Upon admission, all patient serum samples were quantified for IL- 6 level that allowed to stratify patients into three groups: A - 55 patients with IL-6 below 5.0 pg/ml. The mean age in the group was 57.3 +/- 14.9 years, body mass index (BMI) was 28.2 +/- 5.6 kg/m(2);C - 52 patients whose serum IL-6 level was in the range of 5-49 pg/ml. The average age in the group was 60.8 +/- 11.8 years, BMI 29.6 +/- 5.5 kg/m(2);C - 56 patients in whom the level of IL-6 in the blood serum ranged within 50-300 pg/ml. The average age in the group was 62.5 +/- 15.6 years, BMI - 28.8 +/- 5.6 kg/m(2). Patients at admission were analysed for serum level of IL-6, IL-8, and C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) were also determined on day 3 and 7. Results. The minimum production of IL-6 within the range of 0.1-5 pg/ml, corresponds to the minimum changes in IL-8, CRP, and ferritin as well as LDH that was within the range of physiological values. Moderate cytokinemia, IL-6 is within the range of 5-49 pg/ml was associated with elevated ferritin and LDH not tending to decline by the end of treatment. Significant cytokinemia, the level of IL-6 within the range of 50-300 pg/ml was associated with hyperferritinemia and increased LDH. The course of COVID-19 in such patients is characterized by increased ferritin by day 3 of treatment, consistently high level of LDH, without a significant trend towards a decline in the studied markers by the end of treatment. Conclusion. The risk of developing macrophage activation syndrome is not observed of the serum IL- 6 level was below 5 pg/ml, whereas ferritin and LDH were within the range of physiological values, with no/degree I ARF. Moderate macrophage activation syndrome is characterized by increased serum IL-6 level within the range 5-49 pg/ml, a moderate increase in LDH and ferritin, as well as signs of ARF I-II degree. Severe signs are diagnosed in case of serum IL-6 level exceeded 50 pg/ml, along with significant increase in LDH and ferritin, as well as signs of II-III degree ARF.
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Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology that presents with high-grade fever, arthritis, evanescent rash, and multiorgan involvement. It is a rare disorder and is a diagnosis of exclusion. AOSD is often misdiagnosed initially as viral exanthems or upper respiratory tract infections leading to a delay in diagnosis. Management includes non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and conventional or biologic disease-modifying antirheumatic drugs (DMARDs). We report a case of a 53-year-old female with prolonged fever, sore throat, arthralgia, and rash. She was initially presumed to have infectious pharyngitis but did not respond to antimicrobial therapy. After extensive evaluation that excluded infectious, malignant, and other rheumatological etiologies, she was noted to satisfy multiple Yamaguchi criteria and was subsequently diagnosed with AOSD. Glucocorticoids and biologic DMARDs were initiated, leading to improved clinical manifestations and a decline in inflammatory markers.
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Introduction: The first case of omicron infection was declared by the Moroccan Ministry of Health and Social Protection on December 15, 2021. Five days later, the Hassan II Hospital began receiving cases of COVID-19. The objective of our study is to describe the clinical, vaccination and evolutionary profile of patients hospitalized during the Omicron wave. Material(s) and Method(s): This was a descriptive and analytical cross-sectional study of the records of patients hospitalized in the COVID-19 conventional service at the Hassan II regional hospital of Agadir, from 20/12/2021 to 06/02/2022. The data analysis was done by SPSS statistical software version 20. Result(s): 112 patients were hospitalized, of which 56.3% were men. The mean age was 56.4 years. Diabetes was in 44.9% of patients, hypertension in 15.4% and heart disease in 14.1%. Influenza-like syndrome was present in 79.5% of patients. The abnormalities of biological parameters were : elevated C-reactive protein 48,2%, lymphopenia 33% et hyperferritinemia 32,1%. Chest CT Scan was indicated in 5.4% of patients. 69.6% had received at least one dose of COVID-19 vaccine, and 23.2% were not vaccinated. The average length of hospital stay was 5.21 days. The evolution was favorable in 83.9% of the patients, 14.3% were transferred to the intensive care unit, and 1.8% died. Conclusion(s): During the Omicron wave, comorbidities in elderly subjects and abnormalities of biological parameters are a predictive factor of hospitalization, but the evolution in most cases remains favorable.
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Aim: The aim of the study was to evaluate the management and outcomes of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a secondary hospital. Material(s) and Method(s): This study included 699 hospitalized patients who had positive rRT-PCR for SARS-CoV-2 and/or typical findings of COVID-19 on chest computed tomography (CT). Demographics, comorbidities, initial laboratory tests on admission, treatment modalities, complications and outcomes were evaluated retrospectively. Result(s): The mean age was 57.0+/-15.6 (range:16-94 years), and male to female ratio was 1.24;58.7% of the patients had at least one underlying comorbidity, the most common was hypertension;18.1% of the patients had lymphopenia, 35.7% hyperferritinemia, 58.3% had increased lactate dehydrogenase, and 58.5% had increased D-dimer. Chest CT revealed moderate and severe stages in 57.9% of the patients. Hydroxychloroquine was given to 37.2% and favipiravir to 67.1% of the patients. No significant difference was observed between treatment groups in terms of mortality (P=0.487);5.8% of the patients were transferred to the ICU, 75.6% of whom needed non-invasive and 36.5% invasive mechanical ventilation. The overall case-fatality rate was 0.9. Discussion(s): Older age, male gender, low lymphocyte count, CT findings, including bilateral involvement and severe stage were significantly associated with poor prognosis and mortality.Copyright © 2022, Derman Medical Publishing. All rights reserved.
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Iron is a mineral that plays an important role, especially to prevent anaemia through the production of red blood cells. Iron also plays a role in physiological processes, such as the activation of enzymes and hormones, as well as increasing the immune system in warding off various viral infections. Therefore, iron bioavailability needs to be considered to take the greatest benefit of iron. This review discussed the factors that can affect the bioavailability of iron, various technologies to increase the bioavailability, and its potential in enhancing the immune system. Iron bioavailability can be increased by fortification, fermentation, the addition of vitamin C, and iron encapsulation. Under conditions of adequate iron intake, iron plays an important role in enhancing the immune system through controlling lymphocytes and T cell proliferation. However, excess iron consumption can be at risk of weakening the host's immune response to viruses. Therefore, the appropriate level of iron intake must be maintained accurately to be used optimally and has the potential to ward off viral infections, including the Sars-CoV-2 virus as the cause of COVID-19.Copyright © 2023, Rynnye Lyan Resources. All rights reserved.
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Background: Mucormycosis is a serious fungal infection associated with uncontrolled diabetes and immunocompromised patients. This angioinvasive infection emerged as a post-covid complication worldwide especially in developing countries. Due to the common socio-demographic status of South Asian countries, we expected a surge in mucormycosis cases in Pakistan. This study aims to observe the frequency and survival of Covid associated mucormycosis patients at tertiary care hospitals in Pakistan during the third wave of Covid-19 in 2021. Materials and Methods: In this retrospective study, we collected the data of clinically and histopathologically confirmed cases of rhino-occipito-cerebral mucormycosis from three tertiary care hospitals of Lahore. These cases were analysed for history of Covid-19 and other associated comorbidities using SPSS28. History of steroid medication was also taken. Data were retrieved from May to July 2021 after the approval from the ethical review board. Results: Out of the total 43 reported patients of mucormycosis in the set time frame only 22 cases had a history of Covid-19. The mean age was 50 ± 13.27 years with slight male predilection (60%). Diabetes mellitus was the most common comorbidity (88.4%) and all the patients with covid associated mucormycosis (CAM) had taken corticosteroid regimen for covid management (p < 0.0001). The survival of the patient was not significantly different between CAM and non-CAM patients of Mucormycosis (p = 0.747). Conclusion: Covid-19 and mucormycosis make a lethal duo against the weakened health system of Pakistan. This problem can be prevented by avoiding nonjudicial use of corticosteroids and proper diabetes control program following Covid-19 infection. Furthermore, large-scale epidemiological studies should be carried out to evaluate the true burden of Mucormycosis in the population.
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Background: Ferritin has been recognized as a predictor of severity among Coronavirus-19 disease (COVID-19) patients. Studies have shown higher levels of ferritin in patients with COVID-19 than in healthy children. Patients with transfusion-dependent thalassemia (TDT) basically have high ferritin level due to iron overload. It is uncertain whether serum ferritin level in these patients is associated with COVID-19 infection. Objective: To evaluate ferritin levels in TDT with COVID-19 before, during, and after the course of infection. Methods: This retrospective study enrolled all TDT children with COVID-19 infection that were hospitalized in Ulin General Hospital Banjarmasin during the COVID-19 pandemic (March 2020 to June 2022). Data were collected from medical records. Results: There were 14 patients included in this study, 5 patients had mild symptoms and 9 patients were asymptomatic. The mean of hemoglobin level upon admission was 8.1 ± 3 g/dL and serum ferritin level were 5148.5 ± 2651.8 ng/mL. The average serum ferritin level during COVID-19 infection was 2373.2 ng/mL higher than before infection and then decreased by 952.4 ng/mL after infection. We found no association of increasing serum ferritin with patients' symptoms (p = 0.27). The severity of anemia also was not correlated with the presentation of COVID-19 infection (p = 0.902). Conclusion: Serum ferritin levels in TDT children may not reflect disease severity or predict poor outcomes during COVID-19 infection. However, the presence of other co-morbid conditions/confounders warrants cautious interpretation.
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This scoping review aimed to elucidate and summarize the predictive role of serum ferritin in critical pediatric illness. The Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology was employed to conduct a scoping review of five databases (MEDLINE, CENTRAL, ProQuest, ScienceDirect, and Epistemonikos) from the date of inception through January 24, 2022. Primary research studies involving subjects aged <18 years and serum ferritin levels were screened and reviewed independently following an a priori defined protocol. Of the 1,580 retrieved studies, 66 were analyzed. Summary statistics of serum ferritin levels for overall and condition-specific studies were reported in 30 (45.4%) and 47 (71.2%) studies, respectively. The normal range was defined in 16 studies (24.2%), whereas the threshold was determined in 43 studies (65.1%). A value of <500 ng/mL was most often the upper limit of the normal range. Serum ferritin as a numerical variable (78.9%) was usually significantly higher (80.8%) in the predicted condition than in controls, while as a categorical variable with preset thresholds, ferritin was a significant predictor in 84.6% of studies. A total of 22 predictive thresholds predicted mortality (12/46 [26.1%]), morbidity (18/46 [39.1%]), and specific (16/46 [34.8%]) outcomes in 15 unique conditions. Increased precision in serum ferritin measures followed by close attention to the threshold modeling strategy and reporting can accelerate the translation from evidence to clinical practice.
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Adult-onset Still's disease (AOSD) is an uncommon inflammatory disorder. AOSD and SARS-Cov-2 infection share clinical and laboratory features, including systemic inflammation. A 19-year-old woman had prolonged fever for 3 weeks, joint pain, and biological inflammatory syndrome. Post COVID-19 AOSD was diagnosed. SARS-Cov-2 infection induces many inflammatory diseases including AOSD.
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COVID-19 produces cytokine-mediated persistent inflammation and is associated with elevated iron stores and low circulating iron. It is believed that central to the pathophysiological mechanism is interleukin 6 and hepcidin. A state of iron overload, termed hyperferritinemia, and inflammatory anemia take place. Both conditions are linked to a worse result in critically ill patients. Blocking the interleukin 6-hepcidin pathway with Tocilizumab could present favorable outcomes. The aim of this study was to evaluate if Tocilizumab influences survival, the occurrence of sepsis, anemia and transfusions in critically ill patients suffering from COVID-19. This prospective observational study focused on levels of interleukin 6, hepcidin and blood iron parameters in patients treated with Tocilizumab. Data were compared before and after therapy as well as between treated and control groups. Results indicate that there is no difference in terms of survival nor in the rate of anemia or sepsis occurrence. Hepcidin was elevated and anemia ensued after treatment, which could indicate alternative pathways. In conclusion, when the classic interleukin 6-hepcidin pathway is blocked, inflammation seems to use alternative routes. Further understanding of these pathways is required and new pharmacological therapies need to be developed to treat persistent inflammation.
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Objective: Coronavirus disease 2019 (COVID-19) is primarily a respiratory illness causing thrombotic disorders. Pro-inflammatory cytokines are one of the responsible causes of cytokine storm syndrome in patients with COVID-19. Coagulopathy and inflammation are associated with COVID-19 severity. The coronavirus spike protein facilitates the entry of the virus into the target cells causing coagulopathy and inflammation.Other infections include direct viral toxicity, endothelial cell damage, inflammation, and deregulation of the immune response and renin-angiotensinaldosterone system. The study aims to estimate levels of D-Dimer and Serum Ferritin in symptomatic and asymptomatic COVID-19 patients and its comparison with healthy controls. Method(s): The study includes 30 healthy control and 30 symptomatic and 30 asymptomatic COVID-19 patients of both sexes. Analysis of serum ferritin was done on a fully automated immunology analyzer-SIEMENS based on the principle of chemiluminescence. D-dimer was estimated on mLab which is cartridge-based. Result(s): We observed that the levels of D-Dimer and Serum Ferritin significantly increased in symptomatic COVID-19 patients as compared to asymptomatic COVID-19 positive patients and healthy non-COVID-19 controls. Conclusion(s): The elevated serum ferritin and D-dimer were associated with a poor outcome and poor prognosis and could predict the worsening of COVID-19 patients. The significant increase showed that D-Dimer and serum ferritin accurately predicts patients developing severe COVID- infection. Copyright © 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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The article presents the discussion on world news briefs. Topics include cultivating food crops along with trees saving land and optimising the use of sunlight in fixing carbon;and possibility of transmitting the virus to the baby during pregnancy, birth, and breastfeeding where babies at risk of getting an infection from the COVID-19 positive mother.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a disease (COVID-19) with multisystem involvement. The world is now entering a phase of post-COVID-19 manifestations in this pandemic. Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory event triggered by viral infections, including SARS-CoV-2. Both Multisystem Inflammatory Syndrome-Adults (MIS-A) and Cytokine Storm Syndrome (CSS) are considered close differentials of sHLH and add to the spectrum of Post-acute COVID-19 syndrome (PACS). In this report, we presented the case of a middle-aged Asian man who was initially discharged upon recovery from severe COVID-19 infection after 17 days of hospitalization to a private institute and later came to our hospital 13 days post-discharge. Here, he was diagnosed with sHLH, occurring as an extension of CSS, with delayed presentation falling within the spectrum of PACS. The diagnosis of sHLH was made holistically with the HLH-2004 criteria. Our patient initially responded to intravenous immunoglobulin (IVIG) and dexamethasone, later complicated by disseminated Candida auris infection and had a fatal outcome. Though many cases of HLH during active COVID-19 and a few cases post COVID-19 recovery have been reported, based on H-score, which has limitations as a diagnostic tool. We report the first case report of post-COVID-19 sHLH using the HLH-2004 criteria, complicated by disseminated Candidemia, emphasizing that the care of patients with COVID-19 does not conclude at the time of hospital discharge. We highlight the importance of surveillance in the post-COVID phase for early detection of sHLH which may predispose to fatal opportunistic infections (OIs).
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SESSION TITLE: Management of COVID-19-Induced Complications SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Therapeutic plasma exchange (TPE) in the management of COVID-19-induced cytokine storm syndrome (CSS) has remained unclear since the pandemic's emergence. A recent meta-analysis by Beraud et. al examined the use of TPE for treatment of CSS in COVID-19 patients. Although inconsistencies were noted, they demonstrated a general downtrend in cytokine markers and acute phase reactants following TPE administration. TPE was associated with improvements in clinical outcomes and appeared safe in critically ill patients. The analysis highlighted an ongoing need to establish clear criteria to identify a target population. This case series presents 3 critically ill adult COVID-19 patients with CSS and extreme hyperferritinemia (>10,000 ng/mL) who received TPE. We propose the use of ferritin as a sole biomarker for guiding therapy in this patient demographic. CASE PRESENTATION: Patient 1 presented with ferritin 16,060 and CRP 8.22. Despite receiving standard COVID-19 therapies, she decompensated and required intubation. Repeat labs revealed ferritin 92,488 and CRP 9.75. TPE was initiated. Ferritin decreased following each TPE session as shown in Graph 1. Patients 2 and 3 also presented with extreme hyperferritinemia and showed a similar downtrend following TPE therapy. All 3 patients made successful recoveries. DISCUSSION: Hyperferritinemia is present across a range of inflammation-mediated disorders and considered a validated biomarker in various disease states, including COVID-19. There are many hypothesized mechanisms of elevated ferritin in COVID-19;one of which is cytokine release. Severe-to-critical COVID-19 patients have shown higher ferritin levels compared to mild-to-moderately ill patients, and non-survivors have shown higher levels than survivors. Unlike those reported by Beraud et. al, our patients presented with extreme hyperferritinemia. All 3 showed a consistent downtrend in ferritin after TPE sessions, and resolution or near-resolution of hyperferritinemia. CRP levels were also obtained, however 2 of 3 cases showed only mild elevation, and levels trended inconsistently after individual sessions. As such, it was not used to gauge treatment duration or efficacy. CONCLUSIONS: Since biomarker selection and thresholds for therapy remain unclear, we propose further investigation into a ferritin-guided approach to TPE therapy in critically ill COVID-19 patients with CSS. Additionally, the marked ferritin elevation seen in extreme hyperferritinemia may aid in establishing upper thresholds above which TPE would no longer be considered safe or effective. Lastly, given that previous studies showed clinical improvements in patients with mild-to-moderate elevation, we consider that the rate of and/or percentage change in ferritin level may yield a reliable algorithm to direct therapy. Establishing selection criteria in this patient population may prove critical for reducing morbidity and mortality. Reference #1: Beraud, M., Hashami, S. A., Lozano, M., Bah, A., & Keith, P. (2022). Role of therapeutic plasma exchange in the management of COVID-19-induced cytokine storm syndrome. Transfus Apher Sci, 103433. https://doi.org/10.1016/j.transci.2022.103433 Reference #2: Kaushal, K., Kaur, H., Sarma, P., Bhattacharyya, A., Sharma, D. J., Prajapat, M., Pathak, M., Kothari, A., Kumar, S., Rana, S., Kaur, M., Prakash, A., Mirza, A. A., Panda, P. K., Vivekanandan, S., Omar, B. J., Medhi, B., & Naithani, M. (2022). Serum ferritin as a predictive biomarker in COVID-19. A systematic review, meta-analysis and meta-regression analysis. J Crit Care, 67, 172-181. https://doi.org/10.1016/j.jcrc.2021.09.023 Reference #3: Krzych, L. J., Putowski, Z., Czok, M., & Hofman, M. (2021). What Is the Role of Therapeutic Plasma Exchange as an Adjunctive Treatment in Severe COVID-19: A Systematic Review. Viruses, 13(8). https://doi.org/10.3390/v13081484 DISCLOSURES: No relevant relationships by Stefani Delvecchio No relevant relationships by Sean Masi No relevant relationships by Chris Recker-Herman
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High serum ferritin (hyperferritinemia), a reliable hallmark of severe COVID-19 often associates with a moderate decrease in serum iron (hypoferremia) and a moderate increase in serum hepcidin. This suggests that hyperferritinemia in severe COVID-19 is reflective of inflammation rather than iron overload. To test this possibility, the expression status of ferritin heavy chain (FTH1), transferrin receptor 1 (TFRC), hepcidin (HAMP), and ferroportin (SLC40A1) genes and promoter methylation status of FTH1 and TFRC genes were examined in blood samples obtained from COVID-19 patients showing no, mild or severe symptoms and in healthy-donor monocytes stimulated with SARS-CoV-2-derived peptides. Severe COVID-19 samples showed a significant increase in FTH1 expression and hypomethylation relative to mild or asymptomatic COVID-19 samples. S-peptide treated monocytes also showed a significant increase in FTH1 expression and hypomethylation relative to that in controls; treatment with ECD or NP did not change FTH1 expression nor its methylation status. In silico and in vitro analysis showed a significant increase in the expression of the TET3 demethylase in S peptide-treated monocytes. Findings presented here suggest that S peptide-driven hypomethylation of the FTH1 gene promoter underlies hyperferritinemia in severe COVID-19 disease.
Subject(s)
COVID-19 , Hyperferritinemia , Apoferritins/genetics , COVID-19/genetics , DNA Methylation , Ferritins/metabolism , Hepcidins/genetics , Hepcidins/metabolism , Humans , Iron/metabolism , Oxidoreductases/metabolism , Receptors, Transferrin , SARS-CoV-2ABSTRACT
CASE: A 23-year-old female with a history of congenital deafness and HLAB27 positivity presented for two weeks of diffuse arthralgias, fever, and nausea. She had a history of an erythematous rash around her eyes and upper chest that had resolved with prednisone;however, her other symptoms persisted. She denied known tick exposures, drug use, sick contacts, or travel, but had recently been hiking. On presentation, she was febrile to 38.8°C and tachycardic to 130 beats/min. Her labs were notable for an AST of 232 U/L, ALT of 266 U/L, LDH of 680 U/L, haptoglobin <10 mg/dL, and ferritin of 12,230 ng/mL, with no cytopenias or leukocytosis. Her CRP was 127 mg/dL and ESR was normal. Her troponin and BNP were both elevated, to 54 ng/L and 468 pg/mL respectively. ANA and RF titers was negative. Viral studies including EBV, CMV, and SARSCoV-2 as well as bacterial studies were negative. She was started on doxycycline for possible tick-borne infection, but titers returned negative. Echocardiography and chest x-ray were unremarkable. CT scan demonstrated nonspecific para-aortic and mesenteric lymphadenopathy. The patient's presentation and labs were consistent with adult-onset Still's disease (AOSD), meeting the Yamaguchi criteria for diagnosis. She was started on IV hydrocortisone and anakinra with symptomatic improvement. Her liver function testing worsened due to concerns for macrophage activation syndrome (MAS). She was treated with ruxolitinib with gradual improvement in her liver function, followed by tofacitinib. She made a full recovery on discharge. IMPACT/DISCUSSION: Due to its rarity, AOSD can be challenging to diagnose. This case highlighted the key manifestations and distinguishing characteristics of the disorder. The patient presented with fever, rash, and polyarthralgias. While the location of the rash in AOSD varies, the upper chest as seen in this case is typical. While this patient did not have cytopenia or leukocytosis, she did have elevated transaminases and a disproportionately elevated ferritin, a hallmark of AOSD. Importantly, ANA and RF titers were negative, which helps to differentiate AOSD from other autoimmune disorders. The case also demonstrated a feared complication of AOSD, MAS, a form of hemophagocytic lymphohistiocytosis that occurs in 10-15% of patients with AOSD. This case highlighted the importance of remaining vigilant for MAS, as the patient's liver function continued to decline despite symptomatic improvement. While MAS is difficult to diagnose, hyperferritinemia and pancytopenia are thought to be relatively strong indicators. CONCLUSION: AOSD is a rare and debilitating disease, with an illness script that has significant overlap with other diseases. In addition to the combination of polyarthralgias, rash, and fevers, a markedly elevated ferritin is a strong indicator of AOSD. ANA and RF titers will be negative. It is crucial to remain vigilant for complications of the disease, such as MAS.