COVID-19 Related Predisposition to Diabetic Ketoacidosis.

Background and aims Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can exacerbate hyperglycemia and can cause life-threatening diabetic ketoacidosis (DKA) in patients with diabetes mellitus (DM). The objective of this study is to compare the characteristics of diabetic COVID-19 patients with and without DKA and to determine the predictors of mortality in the setting of COVID-19 and DKA. Methods This is a retrospective single-center cohort study including patients admitted to our hospital with COVID-19 and DM from March 2020 to June 2020. Patients with DKA were filtered as per the diagnostic criteria set by the American Diabetes Association (ADA). Patients with hyperosmolar hyperglycemic state (HHS) were excluded. A retrospective analysis was performed, which included those who developed DKA and those with neither DKA nor HHS. The primary outcome measurement was mortality rate and predictors of mortality for DKA. Results Out of 301 patients with COVID-19 and DM, 30 (10%) had DKA and five (1.7%) had HHS. Mortality was significantly higher in the DKA group compared to the non-DKA/HHS group (36.6% vs 19.5%; OR: 2.38; p=0.03). After adjusting for parameters used for multivariate logistic model for mortality, DKA was no longer associated with mortality (OR: 2.08, p=0.35). The independent predictors for mortality were age, platelet count, serum creatinine, C-reactive protein, hypoxic respiratory failure, need for intubation, and need for vasopressors. Conclusion Our study demonstrates higher mortality rate in diabetic COVID-19 patients with DKA. Though direct and independent statistical association of mortality with DKA could not be proven in our multivariate logistic model, physicians must be vigilant in risk-stratifying and managing these patients in a timely manner.

The Comprehensive Appraisal of COVID-19: Its' Clinical Panorama from Virology till Management and Beyond

Severe acute respiratory syndrome, caused by SARS-CoV-2 disease (COVID-19), was first reported in China, and has laid the entire globe at a standstill, with an uncertain future, and a possible economic disaster. The World Health Organization (WHO), on March 11th 2020, avowed COVID-19 a pandemic considering its global pervasiveness. The multi-dimensional challenges include the combat with present available treatment options while simultaneously hastening scientific research for the development of definitive therapeutics and vaccine for this pandemic. The research advancement related to earlier epidemics of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) by the same coronavirus family provides the understanding of basic and clinical virology, pathogenesis and therapeutics of SARS-CoV-2. The dearth of definitive therapeutics and vaccine ren-ders COVID-19 pandemic a public health challenge globally. This comprehensive review of virology, pathogenesis, and management will abet quarters of public health authorities and medical fraternity to better understand COVID-19.Copyright © 2020 Bentham Science Publishers.

Regulation of lymphocyte apoptosis in intensive care patients with COVID-19

Severity of a new coronavirus infection (COVID-19) caused by the SARS-COV-2 virus is largely due to abnormal immune condi-tion in these patients. Lymphopenia is observed in 85% of patients with severe COVID-19 that may be associated with enhanced apoptosis of lymphocytes. Objective. To analyze apoptotic death of lymphocytes and changes in proteins regulating apoptosis in patients with severe COVID-19. Material and methods. We analyzed 93 ICU patients. All patients were divided into three groups depending on severity and outcomes of disease: group 1 consisted of 53 patients with favorable course and outcomes of disease, group 2 included 26 patients with unfavorable course and favorable outcomes of disease, group 3 included 14 patients with unfavorable course and outcomes of disease. Blood sampling for analysis of apoptosis markers was carried out in 5-12 and 14-18 days after clinical manifestation of disease. Quantitative parameters of lymphocyte apoptosis were evaluated using flow cytometry. Regulatory proteins of apop-tosis (phosphorylated AKT, JNK, BAD, BCL-2, p-53, active caspase 8 and 9) were determined on the Luminex platform. We also assessed concentration of leukocytes, relative and absolute lymphocyte count, concentration of C-reactive protein (CRP), procal-citonin and lactate dehydrogenase. Results. Study groups significantly differed in NEWS score (p=0.001), SOFA score (p=0.001), CRP level (p=0.001), severity of lymph-openia (p=0.001) and level of CD14+HLA-DR+ monocytes (p=0.001). Quantitative parameters of lymphocyte apoptosis did not cor-relate with lymphopenia. The highest rates of lymphocyte apoptosis were observed in patients with favorable course and outcomes of disease. There was no correlation between concentration of lymphocytes in venous blood and level of proteins regulating apoptosis. Conclusion. Patients with severe COVID-19 are characterized by abnormal induction of lymphocyte apoptosis through external and internal activation pathways in response to viral aggression. In deceased patients, pro-apoptotic factors prevailed while activity of anti-apoptotic factors was decreased. © 2023, Media Sphera Publishing Group. All rights reserved.

Laboratory characteristics of cytokine storm syndrome in COVID-19 infection

In COVID-19, pneumonia develops simultaneously with cytokine storm syndrome (CSS). A number of cytokines and inflammation parameters were measured in 226 patients with COVID-19 pneumonia (median lung involvement of 60%) and 36 COVID-19 related deaths, during first wave of epidemic. The comparison group consisted of 49 MAS and 52 SS fatal cases, collected, retrospectively. Profile of cytokines and laboratory biomarkers in lethal COVID-19 cases resembled both pathologies, but in COVID-19 it was distinguished by high NLR/IL-6 and low IFN-γ/TNF-α. The new CSS score integrated serum levels of IL-6, IL-10, IL-18, and PCT, giving a range of 0-4 points for each biomarker, and sum from 0 to 12 points. Over five points indicated higher risk of unfavorable outcome. CSS score was validated on separate cohort of 121 patients. Surprisingly CSS parameters were higher in patients of risk groups (older and comorbid). Integrated CSS score can predict severe cases of COVID-19 disease. © 2023 Elsevier Inc. All rights reserved.

Rapid Radiological Worsening and Cytokine Storm Syndrome in COVID-19 Pneumonia.

BACKGROUND: In June 2020, a large randomised controlled clinical trial in the UK found that dexamethasone was effective in reducing the number of deaths in patients with severe coronavirus disease 2019 (COVID-19). CASE DESCRIPTION: We describe a patient with rapid worsening of COVID-19 pneumonia and its dramatic improvement under corticosteroids. DISCUSSION: Corticosteroids could be useful in patients with an inflammatory profile, considering that acute respiratory distress syndrome may be the consequence of cytokine storm syndrome. LEARNING POINTS: One of the main pathophysiological hypotheses for severe COVID-19 pneumonia is inappropriate immunological hyperactivation.Corticosteroid therapy may be useful in these patients.

Severe COVID-19-Induced Hemophagocytic Lymphohistiocytosis.

We reported a case of secondary hemophagocytic lymphohistiocytosis (HLH), a rare and life-threatening condition, which was suspected to have been triggered by a severe case of coronavirus disease 2019 (COVID-19). A 50-year-old man with a past medical history of ulcerative colitis with recent pancolitis status post colectomy and ileostomy two weeks before presentation presented to the emergency department with one week of subjective fevers, weakness, watery diarrhea, and decreased oral intake. A CT scan showed fluid in the rectum and post-surgical changes from his recent colectomy along with diffuse reticulonodular opacities of the lungs. His COVID-19 reverse transcriptase-polymerase chain reaction (RT-PCR) test was positive. Over the subsequent days, the patient's condition worsened as he developed worsening acute hypoxic respiratory failure with diffuse lymphadenopathy, splenomegaly, worsening cytopenias, and increased ferritin of >100,000 ng/ml on hospital day six. Hematology oncology was consulted and he was started on empiric steroid therapy followed by etoposide. However, his condition continued to worsen, and eventually, the patient passed away on hospital day eight.

In the Eye of the Cytokine Storm: A Tale of SARS-CoV-2-Induced Acute Macular Neuroretinopathy.

Acute macular neuroretinopathy (AMN) commonly affects young to middle-aged females and is considered a relatively rare retinal disease, and the etiology is complex. Advances in multimodal imaging provide a better characterization of retinal disorders and have helped identify that one of the etiologies of AMN is microvascular in nature. This case is clinically relevant as it adds to the literature that the pathophysiology of AMN is vascular-driven. Our case is a 24-year-old Black female with no past medical history, the only medication she was taking was an oral contraceptive pill, who presented to the emergency room with a 24-hour history of left central field vision loss and endorsed a recent upper respiratory tract infection preceding the acute vision loss. It was subsequently found on admission that the patient tested positive for and had a SARS-CoV-2 infection. A retina specialist performed optical coherence tomography (OCT), which showed disruption in the outer segment junction, including the ellipsoid zone and outer plexiform. The use of multimodal imaging like OCT helped confirm AMN; therefore, prompt examination by ophthalmology is critical to confirm a correct diagnosis. This patient's vision improved and remained stable five months later. This case demonstrates that, like other viruses, SARS-CoV-2 has the potential to cause retinal disease complications such as AMN. These findings reinforce and add to the current literature that SARS-CoV-2 can cause multiple-organ system dysfunction at a vascular level through immune-mediated pathways.

[Kawasaki disease cytokine release syndrome and Kawasaki disease shock syndrome: A case report]. / Síndrome de tormenta de citocinas y síndrome de choque por enfermedad de Kawasaki: reporte de un caso.

BACKGROUND: Kawasaki disease is a vasculitis of small and medium vessels, with a high prevalence throughout the world. In addition to coronary aneurysms, this vasculitis can lead to a number of systemic complications, including Kawasaki disease shock syndrome and Kawasaki disease cytokine storm syndrome. CASE REPORT: : Case report: A 12-year-old male patient, who began his condition with heartburn, sudden fever of 40 ºC and jaundice, for which he was prescribed treatment with antipyretics and bismuth subsalicylate, without satisfactory reaction. Gastroalimentary content was added three times, and centripetal maculopapular dermatosis. After 12 hospital stays, he was evaluated by personnel from the Pediatric Immunology service, who reported data on hemodynamic instability due to persistent tachycardia for hours, immediate capillary refill, intense pulse, oliguria of 0.3 mL/kg/h of partial urinary output with condensed urine; the systolic blood pressure figures were below the 50% percentile, and there was polypnea and limit saturation in 93%. In the paraclinical studies, the rapid decrease in platelet count (from 297,000 to 59,000 in 24 hours), as well as a neutrophil-lymphocyte index of 12, drew attention. The concentrations of NS1 size, IgM and IgG for dengue and PCR for SARS virus were determined. -CoV-2, which were negative. The definitive diagnosis of Kawasaki disease was established with Kawasaki disease shock syndrome. The evolution of the patient was satisfactory, with a decrease in fever after the administration of gamma globulin on the tenth day of hospitalization, and a new protocol with prednisone (50 mg/day) was started, when the cytokine storm syndrome due to illness was integrated. Kawasaki syndrome simultaneous with pre-existing disorders, that is, Kawasaki disease and Kawasaki disease shock syndrome due to thrombocytopenia, hepatosplenomegaly, fever, lymphadenopathy; in addition, ferritin of 605 mg/dL and transaminasemia. The control echocardiogram did not show coronary abnormalities and hospital discharge was granted 48 hours after starting treatment with the corticosteroid, with a 14-day follow-up plan. CONCLUSIONS: Kawasaki disease is an autoimmune vasculitis that can worsen with simultaneous syndromes associated with high mortality. It is important to know this type of alterations and their differences to properly discern and implement effective and timely treatment.

INTRODUCCIÓN: La enfermedad de Kawasaki es una vasculitis de pequeños y medianos vasos, con elevada prevalencia en todo el mundo. Además de los aneurismas coronarios, esta vasculitis puede generar diversas complicaciones sistémicas, como el síndrome de choque por enfermedad de Kawasaki y el síndrome de tormenta de citocinas por enfermedad de Kawasaki. REPORTE DE CASO: Paciente masculino de 12 años de edad, que inició su padecimiento con pirosis, fiebre súbita de 40 ºC e ictericia, por lo que se le prescribió tratamiento con antipiréticos y subsalicilato de bismuto, sin reacción satisfactoria. Se agregó vómito de contenido gastroalimentario en tres ocasiones y dermatosis maculopapular centrípeta. Después de 12 horas de estancia intrahospitalaria fue valorado por personal del servicio de Inmunología Pediátrica, quienes informaron datos de inestabilidad hemodinámica por taquicardia persistente, llenado capilar inmediato, pulso intenso, oliguria de 0.3 mL/kg/h de gasto urinario parcial con orina condensada; las cifras de tensión arterial sistólica se encontraban debajo del percentil 50%, y había polipnea y saturación limítrofe en 93%. En los estudios paraclínicos llamó la atención el rápido descenso del conteo plaquetario (de 297,000 a 59,000 en 24 horas), así como el índice neutrófilo-linfocito de 12. Se determinaron las concentraciones de antígeno NS1, IgM e IgG para dengue y PCR para virus SARS-CoV-2, que resultaron negativas. Se estableció el diagnóstico definitivo de enfermedad de Kawasaki con síndrome de choque por enfermedad de Kawasaki. La evolución del paciente fue satisfactoria, con disminución de la fiebre luego de la administración de gammaglobulina en el décimo día de hospitalización, y se inició un nuevo protocolo con prednisona (50 mg/día), al integrarse el síndrome de tormenta de citocinas por enfermedad de Kawasaki simultáneo con las alteraciones preexistentes, es decir: enfermedad de Kawasaki y síndrome de choque por enfermedad de Kawasaki por trombocitopenia, hepatoesplenomegalia, fiebre, adenopatías; además, ferritina de 605 mg/dL y transaminasemia. El ecocardiograma de control no mostró modificaciones coronarias y se otorgó el alta hospitalaria después de 48 horas de iniciar el tratamiento con el corticosteroide, con plan de seguimiento en 14 días. CONCLUSIONES: La enfermedad de Kawasaki es una vasculitis autoinmunitaria que puede agravarse con síndromes simultáneos asociados y generar elevada mortalidad. Es importante conocer este tipo de alteraciones y sus diferencias para discernir de forma adecuada e implementar el tratamiento eficaz y oportuno.

Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

AIMS: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). METHODS: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 µg/L or D-dimers >1500 µg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. RESULTS: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 µg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. CONCLUSIONS: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

Hypocomplementemic urticarial vasculitis case with hemophagocytic lymphohistiocytosis following SARS-CoV-2 mRNA vaccination.

A 61-year-old man with no previous record of autoimmune disease developed fever, polyarthralgia, purpura, and urticaria-like rash 2 weeks after the first dose of the Moderna mRNA-1273 vaccine, and symptoms deteriorated following the second dose. He presented reduced erythrocyte and platelet counts, hyperferritinemia, high sIL-2R levels, and severe hypocomplementemia. We diagnosed hypocomplementemic urticarial vasculitis (HUVS), and his symptoms as well as laboratory findings improved following treatment with mPSL 1000 mg/day for 3 days and PSL 40 mg/day. Twelve weeks following treatment initiation, the patient relapsed with fever, sore throat, pancytopenia, and hyperferritinemia when the PSL dose was reduced to 12.5 mg/day. Bone marrow biopsy and MRI presented fatty marrow and hemophagocytosis. The patient's blood cells started recovering using ATG + CsA + EPAG therapy for hemophagocytic lymphohistiocytosis (HLH). This is the first case report of HUVS and HLH following SARS-CoV-2 mRNA vaccination. It is presumed that SARS-CoV-2 mRNA vaccine can induce the excessive production of certain types of cytokines, such as TNF-α, IL-1, IL-4, IL-5, IL-6, and IL-17 as a consequence of IL-6 Amplification (IL-6 Amp). SARS-CoV-2 mRNA-vaccines can cause disruption of immune homeostasis in healthy individuals. An extremely rare disease of HUVS complicated by HLH can be developed as a consequence.

An Intelligent Graphene-Based Biosensing Device for Cytokine Storm Syndrome Biomarkers Detection in Human Biofluids.

Abnormal elevated levels of cytokines such as interferon (IFN), interleukin (IL), and tumor necrosis factor (TNF), are considered as one of the prognosis biomarkers for indicating the progression to severe or critical COVID-19. Hence, it is of great significance to develop devices for monitoring their levels in COVID-19 patients, and thus enabling detecting COVID-19 patients that are worsening and to treat them before they become critically ill. Here, an intelligent aptameric dual channel graphene-TWEEN 80 field effect transistor (DGTFET) biosensing device for on-site detection of IFN-γ, TNF-α, and IL-6 within 7 min with limits of detection (LODs) of 476 × 10-15 , 608 × 10-15 , or 611 × 10-15 m respectively in biofluids is presented. Using the customized Android App together with this intelligent device, asymptomatic or mild COVID-19 patients can have a preliminary self-detection of cytokines and get a warning reminder while the condition starts to deteriorate. Also, the device can be fabricated on flexible substrates toward wearable applications for moderate or even critical COVID-19 cases for consistently monitoring cytokines under different deformations. Hence, the intelligent aptameric DGTFET biosensing device is promising to be used for point-of-care applications for monitoring conditions of COVID-19 patients who are in different situations.

Natural Immunomodulators Treat the Cytokine Storm in SARS-CoV-2.

Recently, the world has been dealing with a destructive global pandemic Coronavirus disease 2019 (COVID-19) infection, since 2020; there were millions of infections and hundreds of thousands of deaths worldwide. With sequencing generations of the virus, around 60% are expected to become infected during the pandemic. Unfortunately, no drug or vaccine has been approved because no real evidence from clinical trials in treatment was reached. According to current thinking, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mortality is caused by a cytokine storm syndrome in patients with hyper-inflammatory conditions, resulting in acute respiratory distress and finally death. In this review, we discuss the various types of natural immune-modulatory agents and their role in the management of SARS-CoV-2, and cytokine storm syndrome. For example, Polyphenols as natural products can block the binding of SARS-CoV-2 spike protein to host cell receptor ACE2, stop viral entry into the host cell and block viral RNA replication. Also, saikosaponins (A, B2, C, and D), triterpene glycosides, which are isolated from medicinal plants exert antiviral action against HCoV-22E9, and Houttuynia cordata water extract has antiviral effects on SARS-CoV. Moreover, eucalyptus oil has promising potential for COVID-19 prevention and treatment. There is an urgent need for research to improve the function of the human immune system all over the world. As a result, actions for better understanding and improving the human immune system are critical steps toward mitigating risks and negative outcomes. These approaches will be strongly recommended for future emerging viruses and pathogens.

Case Report: Secondary Hemophagocytic Lymphohistiocytosis (sHLH) and Candida auris Fungemia in Post-acute COVID-19 Syndrome: A Clinical Challenge.

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).

Biomarkers in Systemic Juvenile Idiopathic Arthritis, Macrophage Activation Syndrome and Their Importance in COVID Era.

Systemic juvenile idiopathic arthritis (sJIA) and its complication, macrophage activation syndrome (sJIA-MAS), are rare but sometimes very serious or even critical diseases of childhood that can occasionally be characterized by nonspecific clinical signs and symptoms at onset-such as non-remitting high fever, headache, rash, or arthralgia-and are biologically accompanied by an increase in acute-phase reactants. For a correct positive diagnosis, it is necessary to rule out bacterial or viral infections, neoplasia, and other immune-mediated inflammatory diseases. Delays in diagnosis will result in late initiation of targeted therapy. A set of biomarkers is useful to distinguish sJIA or sJIA-MAS from similar clinical entities, especially when arthritis is absent. Biomarkers should be accessible to many patients, with convenient production and acquisition prices for pediatric medical laboratories, as well as being easy to determine, having high sensitivity and specificity, and correlating with pathophysiological disease pathways. The aim of this review was to identify the newest and most powerful biomarkers and their synergistic interaction for easy and accurate recognition of sJIA and sJIA-MAS, so as to immediately guide clinicians in correct diagnosis and in predicting disease outcomes, the response to treatment, and the risk of relapses. Biomarkers constitute an exciting field of research, especially due to the heterogeneous nature of cytokine storm syndromes (CSSs) in the COVID era. They must be selected with utmost care-a fact supported by the increasingly improved genetic and pathophysiological comprehension of sJIA, but also of CSS-so that new classification systems may soon be developed to define homogeneous groups of patients, although each with a distinct disease.

Role of therapeutic plasma exchange in the management of COVID-19-induced cytokine storm syndrome.

The risk of mortality in patients with coronavirus disease 2019 (COVID-19) is largely related to an excessive immune response, resulting in a hyperinflammatory and hypercoagulable condition collectively referred to as cytokine storm syndrome (CSS). Management of critically ill patients with COVID-19 has included attempts to abate this process, prevent disease progression, and reduce mortality. In this context, therapeutic plasma exchange (TPE) offers an approach to eliminate inflammatory factors and cytokines, offset the pathologic coagulopathy, and reduce the CSS effects. The aim of this review is to analyze available data on the use of TPE for the treatment of CSS in patients with COVID-19. Systematic searches of PubMed, Scopus and COVID-19 Research were conducted to identify articles published between March 1, 2020 and May 26, 2021 reporting the use of TPE for the treatment of COVID-19-induced CSS. A total of 34 peer-reviewed articles (1 randomized controlled trial, 4 matched case-control series, 15 single-group case series, and 14 case reports), including 267 patients, were selected. Despite the low evidence level of the available data, TPE appeared to be a safe intervention for critically ill patients with COVID-19-induced CSS. Although inconsistencies exist between studies, they showed a general trend for decreased interleukin-6, C-reactive protein, ferritin, D-dimer, and fibrinogen levels and increased lymphocyte counts following TPE, supporting the immunomodulatory effect of this treatment. Moreover, TPE was associated with improvements in clinical outcomes in critically ill patients with COVID-19. While TPE may offer a valuable option to treat patients with COVID-19-induced CSS, high-quality randomized controlled clinical trials are needed to confirm its potential clinical benefits, feasibility, and safety. Moreover, clear criteria should be established to identify patients with CSS who might benefit from TPE.

Interleukin-6 inhibitors: from the therapy of immuno-inflammatory rheumatic diseases to use in COVID-19

The key role in the development of chronic autoimmune inflammation is played by pro-inflammatory cytokines, in particular, interleukin 6 (IL-6). The introduction into clinical practice of monoclonal antibodies inhibiting IL-6 is a significant event in rheumatology and is currently considered as a promising direction in the treatment of immuno-inflammatory rheumatic diseases. The first inhibitor of IL-6 (IL-6), which entered the practice of rheumatologists, was tocilizumab (TCZ), the second – sarilumab (SAR). Numerous studies have shown the high effectiveness of iIL-6: the use of drugs leads to a rapid decrease in the clinical manifestations of rheumatoid arthritis (RA) and a decrease in laboratory signs of inflammation, contributing to the achievement of low activity or remission, improves the quality of life of patients, and also slows down the X-ray progression of the disease. At the same time, iIL-6 has a satisfactory safety profile. The universal problem of our time – the pandemic of a new coronavirus infection – has led to attempts to use IL-6 in patients with severe and critical disease, since IL-6 plays an important role in the pathogenesis of COVID-19, which is confirmed by the results of numerous studies. However, data on the efficacy and safety of these drugs in COVID-19 are contradictory, which requires conducting larger-scale controlled studies. This review examines the issues of the effectiveness and safety of TCZ and SAR in rheu-matological patients and in patients with COVID-19. The review is illustrated with examples from real clinical practice. © 2022.

Comprehensive Cytokine Profiling of Patients with COVID-19 Receiving Tocilizumab Therapy.

Coronavirus disease 2019 (COVID-19) is characterized by immune activation in response to viral spread, in severe cases leading to the development of cytokine storm syndrome (CSS) and increased mortality. Despite its importance in prognosis, the pathophysiological mechanisms of CSS in COVID-19 remain to be defined. Towards this goal, we analyzed cytokine profiles and their interrelation in regard to anti-cytokine treatment with tocilizumab in 98 hospitalized patients with COVID-19. We performed a multiplex measurement of 41 circulating cytokines in the plasma of patients on admission and 3-5 days after, during the follow-up. Then we analyzed the patient groups separated in two ways: according to the clusterization of their blood cytokines and based on the administration of tocilizumab therapy. Patients with and without CSS formed distinct clusters according to their cytokine concentration changes. However, the tocilizumab therapy, administered based on the standard clinical and laboratory criteria, did not fully correspond to those clusters of CSS. Furthermore, among all cytokines, IL-6, IL-1RA, IL-10, and G-CSF demonstrated the most prominent differences between patients with and without clinical endpoints, while only IL-1RA was prognostically significant in both groups of patients with and without tocilizumab therapy, decreasing in the former and increasing in the latter during the follow-up period. Thus, CSS in COVID-19, characterized by a correlated release of multiple cytokines, does not fully correspond to the standard parameters of disease severity. Analysis of the cytokine signature, including the IL-1RA level in addition to standard clinical and laboratory parameters may be useful to define the onset of a cytokine storm in COVID-19 as well as the indications for anti-cytokine therapy.

From the Oligonucleotide purUUpurU to Cytokine Storm, Elevated Blood Viscosity, and Complications of Coronavirus Disease 2019.

Background Coronavirus disease 2019 (COVID-19) can be associated with pathologic inflammation. The authors hypothesize that a high copy number of a purine-uridine-rich nucleotide motif is present in the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hyperactivates innate immunity. Methods The number of purine-uridine-uridine-purine-uridine (purUUpurU) motifs was counted in the genomes of SARS-CoV-2 and other single-strand RNA viruses. The nucleotides of SARS-CoV-2 in random order were used as a control. Results PurUUpurU occurred 2.8 times more often in the actual SARS-CoV-2 genome than the randomized genome. The number of purUUpurU motifs correlates with the potential severity of acute illness caused by these viruses, except for influenza A. Conclusion The large number of purUUpurU in SARS-CoV-2 may hyperactivate innate immunity, potentially causing the markedly increased concentrations of cytokines, acute phase reactants, and blood viscosity that can be seen in COVID-19.

RISE OF MICROBES AND PANDEMICS IN SHAPING HUMAN CIVILIZATION

Until less than a few decades ago, the virus caused diseases wereout of the limelight;hence the research in this area was meager. In 2002 and consecutive years the stages changed drastically with the findings of new pathogenic viruses, including Severe Acute Respiratory Syndrome (SARS-CoV-1), Middle Eastern Respiratory Syndrome (MERS-CoV) and the recent zoonotic SARS-CoV-2, has caused alarm across the globe. SARS-CoV-2 is an airborne disease circulated by symptomatic patients and also asymptomatic individuals undergoing incubation of the disease. SARS-CoV-2 causes a “cytokine storm syndrome”, characterized by a severe and fatal uncontrolled systemic inflammatory response enhanced by the activation of interleukin 6 (IL-6) and that can lead to organ failure and mortality. Risk factors include old age, hypertension, diabetes, cardiovascular disease and can be categorized as a multi-organ disease. Epidemiology is crucial to the fight against any disease. The knowledge of how diseases spread, and why, has figured high in the struggle to understand, contain and respond to COVID-19. Investigations of data on infections and deaths, that model the virus’s spread, have driven policy judgments all over the globe.This review summarizes the current knowledge on the history of the pandemic in detail from plagueto COVID-19. © 2022 by Nova Science Publishers, Inc.

Drugs for paediatric hyperinflammatory syndromes.

Background: Many syndromes are associated with exaggerated inflammation. Children with hyperinflammatory syndromes often present with vague and non-specific symptoms that pose diagnostic and management challenges. The recent literature seems biased towards referring these syndromes only to the multisystem inflammatory syndrome in children (MIS-C) that is associated with COVID-19. The purpose of this paper is to provide an updated narrative review on the pathophysiology, manifestations and management approaches for common hyperinflammatory syndromes. Methods: An extensive PubMed search of all publications in the English literature was performed with Clinical Queries for various hyperinflammatory syndromes and conditions using the undermentioned Medical Subject Headings: "hyperinflammation", "hyperinflammatory syndromes", "sepsis syndrome", "severe inflammatory response syndrome" and "acute respiratory distress syndrome". Categories were limited to reviews and clinical trials for the age range from birth to 18 years. Results: The criteria, presentation and management of these hyperinflammatory syndromes are described. Hyperinflammatory syndromes refer to a basket of inflammatory syndromes often associated with multisystem involvement and aberrant cytokine release and should be differentiated from autoinflammatory, autoimmune and hyperimmune syndromes. The major subtypes of hyperinflammatory syndromes, including macrophage activation syndrome, haemophagocytic lymphohistiocytosis, cytokine release syndrome and cytokine storm syndrome, are described. MIS-C associated with SARS-CoV-2 represents the latest addition. It must be understood that the syndrome is not exclusive to COVID-19 but could be caused by various viral infections. Early recognition, prompt and proactive treatment can reduce potential complications and improve outcomes and survival rates in paediatric patients. Anti-inflammatory medications for the management of these syndromes are described. Conclusion: The incidence of these hyperinflammatory conditions is generally low in comparison to other disease conditions. Except for paediatric inflammatory multisystem syndrome/MIS-C, the mortality is high and the hospital stay is prolonged in affected patients. Acute and critical care physicians must be aware of these conditions and their initial management. Corticosteroids are often used in the initial phrase but various disease-specific drugs and biologics are needed in subsequent management and expert management of these often-difficult conditions is crucial.