Hyperinflammatory Reaction Research Articles

Infection, inflammation and intervention: mechanistic modelling of epithelial cells in COVID-19.

While the pathological mechanisms in COVID-19 illness are still poorly understood, it is increasingly clear that high levels of pro-inflammatory mediators play a major role in clinical deterioration in patients with severe disease. Current evidence points to a hyperinflammatory state as the driver of respiratory compromise in severe COVID-19 disease, with a clinical trajectory resembling acute respiratory distress syndrome, but how this ‘runaway train’ inflammatory response emerges and is maintained is not known. Here, we present the first mathematical model of lung hyperinflammation due to SARS-CoV-2 infection. This model is based on a network of purported mechanistic and physiological pathways linking together five distinct biochemical species involved in the inflammatory response. Simulations of our model give rise to distinct qualitative classes of COVID-19 patients: (i) individuals who naturally clear the virus, (ii) asymptomatic carriers and (iii–v) individuals who develop a case of mild, moderate, or severe illness. These findings, supported by a comprehensive sensitivity analysis, point to potential therapeutic interventions to prevent the emergence of hyperinflammation. Specifically, we suggest that early intervention with a locally acting anti-inflammatory agent (such as inhaled corticosteroids) may effectively blockade the pathological hyperinflammatory reaction as it emerges.

Is COVID-19 infection more severe in kidney transplant recipients?

There are no studies which have compared the risk of severe COVID‐19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID‐19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single‐center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID‐19 or mortality. Severe COVID‐19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30‐day cumulative incidence of severe COVID‐19 did not differ between KTR and nontransplant patients; however, 30‐day COVID‐19‐related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C‐reactive protein (CRP) were associated with severe COVID‐19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID‐19‐related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID‐19‐related mortality compared to nontransplant hospitalized patients.

Stimulating the Resolution of Inflammation Through Omega-3 Polyunsaturated Fatty Acids in COVID-19: Rationale for the COVID-Omega-F Trial.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 triggers an immune response with local inflammation in the lung, which may extend to a systemic hyperinflammatory reaction. Excessive inflammation has been reported in severe cases with respiratory failure and cardiovascular complications. In addition to the release of cytokines, referred to as cytokine release syndrome or “cytokine storm,” increased pro-inflammatory lipid mediators derived from the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid may cause an “eicosanoid storm,” which contributes to the uncontrolled systemic inflammation. Specialized pro-resolving mediators, which are derived from omega-3 PUFA, limit inflammatory reactions by an active process called resolution of inflammation. Here, the rationale for omega-3 PUFA supplementation in COVID-19 patients is presented along with a brief overview of the study protocol for the trial “Resolving Inflammatory Storm in COVID-19 Patients by Omega-3 Polyunsaturated Fatty Acids - A single-blind, randomized, placebo-controlled feasibility study” (COVID-Omega-F). EudraCT: 2020-002293-28; clinicaltrials.gov: NCT04647604.

Adult-onset Still's disease possibly consequent to asymptomatic COVID-19

Background: In some patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]), an uncontrolled release of inflammatory cytokines is characteristic. COVID-19 and adult-onset Still’s disease (AOSD) have been included by some authors in the “hyperferritinemic syndromes.” Another hyperinflammatory syndrome (with variable features of Kawasaki disease) called multisystem inflammatory syndrome (MIS) has been described in patients who have had SARS-CoV-2 infection. Case Presentation: We present a previously healthy patient who developed hyperinflammatory reaction compatible with MIS; the clinical presentation is additionally compatible with AOSD, complicated with a mild myocarditis. The patient had a positive SARS-CoV-2 serology (immunoglobulins G and immunoglobulins M ), but multiple reverse transcription-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 on nasopharyngeal swab were negative or indeterminate, so we considered that it is possible that an asymptomatic SARS-CoV-2 infection could have been the trigger for Still’s disease. 24 hours after starting methylprednisolone treatment, the fever was resolved and symptoms improved over the next few days, with persistent arthralgias. Conclusion: Asymptomatic SARS-CoV-2 infection could trigger MIS with AOSD-like features.

Safety and Efficacy of the Combined Use of Ivermectin, Dexamethasone, Enoxaparin and Aspirina against COVID-19 the I.D.E.A. Protocol

From the first outbreak in Wuhan (China) in December 2019, until today (05/28/2020), the number of deaths worldwide due to the coronavirus pandemic exceeded 2.5 millions. Only in Argentina, 50,000 deaths have been confirmed so far. There haven’t been so far any clear diagnostic pattern for this exceptional entity except unilateral skin involvement, early onset of symptoms, positive ANA and negative tests for Borrelia burgdorferi. Hence, we report a new case of a young Moroccan man. No treatment tested worldwide has shown unquestionable efficacy in the fight against COVID-19, according to W.H.O, NIH and NICE reports and accumulated data. Our proposal consists of the combination of drugs, based on the pathophysiology of the virus. We have designed a treatment called I.D.E.A., based on four affordable drugs already available on the pharmacopoeia in Argentina, on the following rationale: -Ivermectin (IVM) solution to lower the viral load in all stages of COVID-19. -Dexamethasone 4 mg injection, as anti-inflammatory drug to treat hyperinflammatory reaction to COVID-infection. -Enoxaparin injection as anticoagulant to treat hypercoagulation in severe cases. -Aspirin 250 mg tablets to prevent hypercoagulation in mild and moderate cases. Except for Ivermection oral solution, which was used in a higher dose than approved for parasitosis, all other drugs were used in the already approved dose and indication. Regarding Ivermectin safety, several oral studies have shown it to be safe even when used at daily doses much higher than those approved already. A clinical study has been conducted on COVID-19 patients at Eurnekian Hospital in the Province of Buenos Aires, Argentina. The study protocol and its final outcomes are described in this article. Results were compared with published data and data from patients admitted to the hospital receiving other treatments. None of the patient presenting mild symptoms needed to be hospitalized. Only one patient died (0.59% of all included patients vs. 2.1% overall mortality for the disease in Argentina today, 3.1% of hospitalized patients vs. 26.8% mortality in published data). I.D.E.A. protocol has proved to be a very effective alternative to prevent disease progression of COVID-19 when applied to mild cases, and to decrease mortality in patients at all stages of the disease with a favorable risk-benefit ratio.

Methylene blue in covid-19

SARS-CoV-2 infection generally begins in the respiratory tract where it can cause bilateral pneumonia. The disease can evolve into acute respiratory distress syndrome and multi-organ failure, due to viral spread in the blood and an excessive inflammatory reaction including cytokine storm. Antiviral and anti-cytokine drugs have proven to be poorly or in-effective in stopping disease progression, and mortality or serious chronic damage is common in severely ill cases. The low efficacy of antiviral drugs is probably due to late administration, when the virus has triggered the inflammatory reaction and is no longer the main protagonist. The relatively poor efficacy of anti-cytokine drugs is explained by the fact that they act on one or a few of the dozens of cytokines involved, and because other mediators of inflammation – reactive oxygen and nitrogen species – are not targeted. When produced in excess, reactive species cause extensive cell and tissue damage. The only drug known to inhibit the excessive production of reactive species and cytokines is methylene blue, a low-cost dye with antiseptic properties used effectively to treat malaria, urinary tract infections, septic shock, and methaemoglobinaemia. We propose testing methylene blue to contrast Covid-related acute respiratory distress syndrome, but particularly suggest testing it early in Covid infections to prevent the hyper-inflammatory reaction responsible for the serious complications of the disease.

Secondary hemophagocytic syndrome in adult patients. Study of 91 patients

Background. Secondary hemophagocytic lymphohystiocytosis (sHLH) is a hyperinflammatory reaction provoked by some trigger (cancer, autoimmune or infection). The majority of affected patients are at high risk of fatal multiple organ failure without getting immunsupressive treatment.Objective. Clinical and laboratory profile of sHLH patients.Materials and methods. Retrospective study included clinical, instrumental and lab data from the 91 patients followed between June 2009 and June 2019. Diagnosis sHLH had been based on HLH-2004 and H-Score criteria. The analyzed parameters had been fever chart, liver and spleen enlargement, changes in the bone marrow; values levels of glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, bilirubin, triglycerides, total ferritin with percentage of glycosylation. All patients with rheumatic disorders or malignancies had received either immunosuppressive or cytotoxic therapy. Febrile patients received anti-infective treatment according to the local routine protocols.Results. The data from 91 patients (41 male and 50 female) had been analyzed. Median age was 58 (2–90) years. The sHLH trigger-diseases spectrum included leukemia/lymphoma (n = 52), infection diseases (n = 11), autoimmune disorders (n = 5), allogenic bone marrow transplantation (n = 13), unidentified (n = 10). A fever with an unknown origin and refractory to antibacterial treatment had been observed in 87 (96 %) patients. Morphological hemophagocytic evidences in the bone marrow had been found in 83 %. Breath shortening, liver failure, neurologic disturbances, systemic effusions, rash, heart failure had been registered in 83 % patients. Detected splenomegaly presented in 56 %. Laboratory changes, median were as following: serum glutamic-pyruvic transaminase (alanine aminotransferase, SGPT) – 92 (39.2–1060.8) IU/L; serum glutamic oxaloacetic transaminase (aspartate aminotransferase, SGOT) – 105 (40–4177) IU/L; alkaline phosphatase – 225 (120.9–989) IU/L; bilirubin – 50.5 (22–559) µmol/L; triglycerides – 3.2 (1.95–8.6) mmol/L; total ferritin – 10000 (597–255000) ng/mL with glycosylation percentage – 20.45 (0–37.8) %. 71 patients received various of HLH-directed therapy courses. The overall survival rate was 27 %, median follow-up – 540 days.Conclusion. The main clinical and instrumental findings in sHLH are fever, refractory to anti-infective treatment, elevation of transaminases, serum alkaline phosphatase, triglycerides, total ferritine with low glycosylated fraction. Early diagnosing and immunesupression are the main factors of survival.

Perspective: Reducing SARS-CoV2 Infectivity and Its Associated Immunopathology.

COVID-19 has become difficult to contain in our interconnected world. In this article, we discuss some approaches that could reduce the consequences of COVID-19. We elaborate upon the utility of camelid single-domain antibodies (sdAbs), also referred to as nanobodies, which are naturally poised to neutralize viruses without enhancing its infectivity. Smaller sized sdAbs can be easily selected using microbes or the subcellular organelle display methods and can neutralize SARS-CoV2 infectivity. We also discuss issues related to their production using scalable platforms. The favorable outcome of the infection is evident in patients when the inflammatory response is adequately curtailed. Therefore, we discuss approaches to mitigate hyperinflammatory reactions initiated by SARS-CoV2 but orchestrated by immune mediators.

A possible application of hinokitiol as a natural zinc ionophore and anti-infective agent for the prevention and treatment of COVID-19 and viral infections

Zinc and the combination with zinc ionophore have been reported in basic research and several clinical investigations as a potentially viable and economical preventive and therapeutic options for COVID-19 treatment. Zinc is a vital microelement that actively supports respiratory epithelium barrier integrity, innate and adaptive immune functions, and inflammatory regulations. Moreover, zinc may also prevent viral entry, suppress viral replication, and mitigate the damages due to oxidative stress and hyperinflammatory reaction in patients with respiratory infections. Hinokitiol (β-thujaplicin) is a natural monoterpenoid and is considered as a safe zinc ionophore to help zinc transport into cells. It has been widely used in skin and oral care, and therapeutic products for its potent antiviral, antimicrobial, antifungal, anti-inflammatory, and anticancer applications.The ongoing COVID-19 pandemic and the significant morbidity and mortality exist in the high-risk group of patients associated with other respiratory infections such as influenza, respiratory syncytial virus, and dengue fever. There is an urgent need for the development of inexpensive, safe, and effective therapeutics to prevent and treat these viral infections. Considering that hydroxychloroquine (HCQ), the most studied zinc ionophore drug for COVID-19, is linked to potentially serious side effects, we propose the implementation of hinokitiol as a zinc ionophore and anti-infective agent for the prevention and treatment of COVID-19 and other viral infections.

O uso de antimicrobiano na COVID-19 e as infecções: o que sabemos

Atualmente, o COVID-19 está ocasionando uma preocupante emergência de saúde pública e a mortalidade está aumentando rapidamente em todo o mundo. No momento atual da pandemia, apesar de ter havido muita persistencia para diagnosticar vários pacientes com sintomas ou contatos próximos, não existe diretrizes definitivas para a abordagem terapêutica inicial para eles e, portanto, muitos pacientes estão morrendo devido a uma reação imunológica hiperinflamatória rotulado como "tempestade de citocinas".O uso de antimicrobianos no tratamento e prevenção de COVID-19, causado pelo novo coronavírus SARS-CoV-2, está em ascensão.Antibióticos usado para tratar infecção por estafilococos, anteriormente mostrou eficácia para inibir o primeiro estágio do ciclo viral do MERScoronarivus em células humanas. Essa atividade é conservada no SARS-Cov-2, colocando esse emprego como um tratamento potencial para pacientes com esse vírus. Foi realizado uma revisão da literatura utilizando os bancos de dados PubMed, LILACS e Scielo, com os termos “Covid”, “antibiotico, “terapia “e “resistencia microbiana e equivalentes em inglês. Nesta revisão, discutimos alguns pontos importantes dedicados ao manejo de pacientes com COVID-19 em uso de antibioticos.

Role of regulatory T-cells in the systemic inflammatory response syndrome

Systemic inflammatory response syndrome is a complex multisyndromic, phase-specific pathological process that develops with systemic damage. Outcomes largely depend on the balance of multidirectional sequential stages: hyperinflammatory reaction and compensatory anti-inflammatory response syndrome (CARS). Regulatory T-cells (Tregs) are able to regulate adaptive and innate immune responses and contribute to the various stages ofthe systemic inflammatory response syndrome. At the initial hyperinflammatory stage, Tregs are able to limit self-inflicted damage. At the same time, Tregs contribute to CARS and the formation of induced immunosuppression, predisposing to a high susceptibility to nosocomial and opportunistic infections, with subsequent transition to multiple organ dysfunction syndrome. Regulatory T-cells and their functional changes are considered as predictors and prognostic markers of critical illness.

Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes.

Recent reports have shown a strong association between obesity and the severity of COVID-19 infection, even in the absence of other comorbidities. After infecting the host cells, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a hyperinflammatory reaction through the excessive release of cytokines, a condition known as “cytokine storm,” while inducing lymphopenia and a disrupted immune response. Obesity is associated with chronic low-grade inflammation and immune dysregulation, but the exact mechanisms through which it exacerbates COVID-19 infection are not fully clarified. The production of increased amounts of cytokines such as TNFα, IL-1, IL-6, and monocyte chemoattractant protein (MCP-1) lead to oxidative stress and defective function of innate and adaptive immunity, whereas the activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome seems to play a crucial role in the pathogenesis of the infection. Endothelial dysfunction and arterial stiffness could favor the recently discovered infection of the endothelium by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic microenvironment in obesity could provide a link for the increased cardiovascular events in these patients. The successful use of anti-inflammatory agents such as IL-1 and IL-6 blockers in similar hyperinflammatory settings, like that of rheumatoid arthritis, has triggered the discussion of whether such agents could be administrated in selected patients with COVID-19 disease.

Hepatic involvement in COVID-19 patients: Pathology, pathogenesis, and clinical implications.

During the clinical course of coronavirus disease 2019 (COVID-19), it has been observed that hepatic injury occurs in a significant proportion of patients, particularly in those with severe or critical illness. Mild increase in sinusoidal lymphocytic infiltration, sinusoidal dilatation, steatosis and multifocal hepatic necrosis are the pathologic changes reported. Direct viral-induced cellular injuries and potential hepatotoxicity from therapeutic drugs are two likely underlying mechanisms. In addition, the pre-existing chronic liver disease exacerbated during COVID-19, and COVID-19-related hyperinflammatory reactions may contribute to liver injury as well. Further studies of additional autopsy cases will help clarifying these possibilities.

Seven recommendations to rescue the patients and reduce the mortality from COVID-19 infection: An immunological point of view.

Now COVID-19 is causing a severe public health emergency and the mortality is rapidly increasing all over the world. In the current pandemic era, although there have been many efforts to diagnose a number of patients with symptoms or close contacts, there is no definite guideline for the initial therapeutic approach for them and therefore, many patients have been dying due to a hyperinflammatory immunological reaction labeled as “cytokine storm”. Severe patients are hospitalized and the treatment is done, though they have not been established yet. Currently, however, no treatment is provided for those who are isolated at home or shelter until they get severe symptoms, which will increase the harms to the patients. In this review, we discuss some important points dedicated to the management of patients with COVID-19, which should help reducing morbidity and mortality. In this era, we suggest 7 recommendations to rescue the patients and to reduce the morbidity and mortality due to COVID-19 based on the immunological point of view.

Limiting fatality in COVID-19 patients

Coronavirus Emerging evidence suggests that cytokine release syndrome (CRS), a systemic hyperinflammatory reaction, is a major cause of fatality in patients with severe coronavirus disease 2019 (COVID-19). CRS is observed in some other severe coronavirus infections, as well as in some cancer patients after receiving engineered T cell therapy. On the basis of this past experience, an emerging treatment for COVID-19 under investigation in the clinical setting is to antagonize key cytokine signaling pathways that drive CRS. In a Perspective, Moore and June discuss the current understanding of CRS immunopathology and the developments in repurposing drugs with a track record in treating CRS for treating patients with severe COVID-19. Science , this issue p. [473][1] [1]: /lookup/doi/10.1126/science.abb8925

A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis.

Articular joints are a major target of Borrelia burgdorferi, the causative agent of Lyme arthritis. Despite antibiotic treatment, recurrent or persistent Lyme arthritis is observed in a significant number of patients. The host immune response plays a crucial role in this chronic arthritic joint complication of Borrelia infections. During the early stages of B. burgdorferi infection, a major hinder in generating a proper host immune response is the lack of induction of a strong adaptive immune response. This may lead to a delayed hyperinflammatory reaction later in the disease. Several mechanisms have been suggested that might be pivotal for the development of Lyme arthritis and will be highlighted in this review, from molecular mimicry of matrix metallopeptidases and glycosaminoglycans, to autoimmune responses to live bacteria, or remnants of Borrelia spirochetes in joints. Murine studies have suggested that the inflammatory responses are initiated by innate immune cells, but this does not exclude the involvement of the adaptive immune system in this dysregulated immune profile. Genetic predisposition, via human leukocyte antigen‐DR isotype and microRNA expression, has been associated with the development of antibiotic‐refractory Lyme arthritis. Yet the ultimate cause for (antibiotic‐refractory) Lyme arthritis remains unknown. Complex processes of different immune cells and signaling cascades are involved in the development of Lyme arthritis. When these various mechanisms are fully been unraveled, new treatment strategies can be developed to target (antibiotic‐refractory) Lyme arthritis more effectively.

Pediatric COVID-19 and the Factors That May Mitigate Its Clinical Course

AbstractThe clinical manifestations of novel coronavirus disease 2019 (COVID-19) vary from mild flu-like symptoms to severe fatal pneumonia. However, children with COVID-19 may be asymptomatic or may have mild clinical symptoms. The aim of this study was to investigate clinical features of pediatric COVID-19 and to search for the factors that may mitigate the disease course. We reviewed the literature to realize the clinical features, laboratory, and radiographic data that may be diagnostic for COVID-19 among children. Also, we studied the factors that may affect the clinical course of the disease. Fever, dry cough, and fatigue are the main symptoms of pediatric COVID-19, sometimes flu-like symptoms and/or gastrointestinal symptoms may be present. Although some infected children may be asymptomatic, a recent unusual hyperinflammatory reaction with overlapping features of Kawasaki's disease and toxic shock syndrome in pediatric COVID-19 has been occasionally reported. Severe acute respiratory syndrome-coronvirus-2 (SARS-CoV-2) nucleic acid testing is the corner-stone method for the diagnosis of COVID-19. Lymphocyte count and other inflammatory markers are not essentially diagnostic; however, chest computed tomography is highly specific. Factors that may mitigate the severity of pediatric COVID-19 are home confinement with limited children activity, trained immunity caused by compulsory vaccination, the response of the angiotensin-converting enzyme 2 receptors in children is not the same as in adults, and that children are less likely to have comorbidities. As infected children may be asymptomatic or may have only mild respiratory and/or gastrointestinal symptoms that might be missed, all children for families who have a member diagnosed with COVID-19 should be investigated.

Diffuse Alveolar Hemorrhage in the Setting of an Acute Exacerbation of Chronic Hypersensitivity Pneumonitis Due to Drug Rash With Eosinophilia and Systemic Symptoms: A Case Report

Drug rash with eosinophilia and systemic symptoms (DRESS) is a well-recognized phenomenon that is considered to be a hyperinflammatory reaction in response to the administration of a drug. It is typical to have systemic signs of inflammation, and the most commonly reported pulmonary manifestations include pneumonitis, interstitial lung disease, and acute respiratory distress syndrome. Here, we present a 62-year-old woman with a history of chronic hypersensitivity pneumonitis who presented in respiratory distress with a new progressive rash. Bronchoscopy demonstrated diffuse alveolar hemorrhage (DAH), and a clinical diagnosis of DRESS was made. The patient was diagnosed with respiratory failure from DAH in the setting of acute exacerbation of chronic hypersensitivity pneumonitis and DRESS. We review the available literature on the pathophysiology, diagnosis, and clinical presentation of DRESS and DAH. To our knowledge, there is no reported case associating DRESS with DAH.

EPSTEIN BARR VIRUS INFECTION CAUSING SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MULTIPLE ORGAN FAILURE

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory immune disorder explained by an overactivation of monocytes, lymphocytes and macrophages resulting in overproduction of cytokines. Secondary HLH is caused by infection, malignant tumors and autoimmune disease. Amongst these, 70% of cases are triggered by Epstein-Barr virus (EBV). We present a case of EBV infection leading to HLH and multiple organ failure. CASE PRESENTATION: 64-year-old gentleman with a past medical history significant for ischemic cardiomyopathy status post biventricular implantable cardioverter defibrillator, chronic kidney disease, peripheral arterial disease status post right above knee amputation initially presented as a transfer from an outside facility with concerns for septic shock. He was afebrile, blood pressure of 94/35 mm mercury, heart rate of 73/ minute. He required mechanical ventilation and vasopressors soon thereafter. Patient was not improving despite receiving broad-spectrum antibiotics and antifungals. Upon further investigation, his serum was positive for EBV viremia with low viral load . His liver enzymes were markedly elevated, Ferritin was >4500, triglycerides 316, Natural killer cell activity was 5 and CD25 (soluble IL-2) 14,131. Bone marrow biopsy showed increased histiocytes containing fully formed cellular debris, fully formed peripheral blood and bone marrow precursor elements representing hemophagocytosis. All other infectious, viral, fungal and tick-borne work up was negative. He was given 10 mg/meter square of dexamethasone and one dose of etoposide. He was transferred to a tertiary center for further management. Unfortunately - his condition markedly declined, and treatment was stopped prematurely with home hospice measures. DISCUSSION: HLH is the extreme end of the spectrum with uncontrolled hyperinflammation leading to multiorgan failure. In EBV-HLH the virus infects CD8+T cells. After infection, the cells express EBV latent membrane protein (LMP-1) causing massive cytokine release, promote T lymphocyte proliferation and uncontrolled activation of macrophages. Diagnosis is based on HLH-2004 which includes 5 of 8 criteria consisting of fever, splenomegaly, bicytopenias, hypertriglyceridemia, elevated ferritin, increased sCD25 (soluble IL-2), decreased or absent NK cell activity and/or Hemophagocytosis in bone marrow, CSF or lymph nodes. EBV-HLH is a rapidly progressing disease with one-year mortality as high as 75%. Treatment consists of dexamethasone and etoposide based on HLH-94 and HLH-2004 protocols. Early initiation of treatment is crucial regarding a favorable prognosis. CONCLUSIONS: HLH is a hyperinflammatory reaction most often caused by infection. High clinical suspicion is necessary when patients present with multiorgan failure with otherwise unexplained symptoms. Initiation of treatment may improve survival rates although often rapid deterioration is seen. Reference #1: Wang Y, Wang Z, Zhang J, et al. Genetic features of late onset primary hemophagocytic lymphohistiocytosis in adolescence or adulthood. PLoS One. 2014; 9(9);e107386 Reference #2: Maakaroun NR, Moanna A, Jacob JT, et al. Viral Infections associated with haemophagocytic syndrome. Rev Med Virol. 2010;20(2):93-105 Reference #3: Janka GE. Familial and acquired haemophagocytic lymphohistiocytosis. Eur J Pediatr. 2007:166(2);95-109 DISCLOSURES: No relevant relationships by Cristian Dumitrescu, source=Web Response No relevant relationships by Hafiza Wajeeha Javaid, source=Web Response No relevant relationships by Kunal Mehta, source=Web Response No relevant relationships by Farrukh Munir, source=Web Response No relevant relationships by Vipul Singh, source=Web Response

Immune Response Resetting in Ongoing Sepsis.

Cure of severe infections, sepsis, and septic shock with antimicrobial drugs is a challenge because morbidity and mortality in these conditions are essentially caused by improper immune response. We have tested the hypothesis that repeated reactivation of established memory to pathogens may reset unfavorable immune responses. We have chosen for this purpose a highly stringent mouse model of polymicrobial sepsis by cecum ligation and puncture. Five weeks after priming with a diverse Ag pool, high-grade sepsis was induced in C57BL/6j mice that was lethal in 24 h if left untreated. Antimicrobial drug (imipenem) alone rescued 9.7% of the animals from death, but >5-fold higher cure rate could be achieved by combining imipenem and two rechallenges with the Ag pool (p < 0.0001). Antigenic stimulation fine-tuned the immune response in sepsis by contracting the total CD3+ T cell compartment in the spleen and disengaging the hyperactivation state in the memory T subsets, most notably CD8+ T cells, while preserving the recovery of naive subsets. Quantitative proteomics/lipidomics analyses revealed that the combined treatment reverted the molecular signature of sepsis for cytokine storm, and deregulated inflammatory reaction and proapoptotic environment, as well as the lysophosphatidylcholine/phosphatidylcholine ratio. Our results showed the feasibility of resetting uncontrolled hyperinflammatory reactions into ordered hypoinflammatory responses by memory reactivation, thereby reducing morbidity and mortality in antibiotic-treated sepsis. This beneficial effect was not dependent on the generation of a pathogen-driven immune response itself but rather on the reactivation of memory to a diverse Ag pool that modulates the ongoing response.