The severe COVID-19: A sepsis induced by viral infection? And its immunomodulatory therapy

COVID-19 is known for its magical infectivity,fast transmission and high death toll based on the large number of infected people.From the perspective of the clinical manifestation,autopsy examination and pathophysiology,the essence of COVID-19 should be viewed as a sepsis induced by viral infection,and has the essential characteristics as sepsis induced by other pathogens.Therefore,in addition to etiological and supportive treatment,immunomodulatory therapy is also appropriate to severe COVID-19.Although there is still a lack of consensus on immunotherapy for sepsis so far,relatively rich experiences have been accumulated in the past decades,which will help us in the treatment of severe COVID-19.This article will elaborate immunotherapy of sepsis,though it may not be consistent.

Immunomodulatory therapies for acute pancreatitis

It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3rd d to the 14th d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

Antioxidant and immunomodulatory effects of Viusid in patients with chronic hepatitis C

AIM:To investigate the efficacy of Viusid,a nutritional supplement,as an antioxidant and an immunomodulator in patients with chronic hepatitis C.METHODS:Sixty patients with chronic hepatitis C who were non-responders to standard antiviral treatment were randomly assigned to receive Viusid(3 sachets daily,n=30) or placebo(n=30) for 24 wk.The primary outcome was the change in serum malondialdehyde and 4-hydroxyalkenals(lipid peroxidation products).Secondary outcomes were changes in serum tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ) and interleukin-10(IL-10).RESULTS:Statistically significant reductions in serum 4-hydroxyalkenals and malondialdehyde levels were observed in both groups in comparison with pretreatment values,but the patients who received Viusid showed a more marked reduction as compared with the control group(P=0.001).TNF-α levels significantly increased from 6.9 to 16.2 pg/mL(P< 0.01) in the patients who received placebo in comparison with almost unchanged levels,from 6.6 to 7.1 pg/mL(P=0.26),in the patients treated with Viusid(P=0.001).In addition,IL-10 levels were markedly increased in the patients treated with Viusid(from 2.6 to 8.3 pg/mL,P=0.04) in contrast to the patients assigned to placebo(from 2.8 to 4.1 pg/mL,P=0.09)(P=0.01).Likewise,the administration of Viusid markedly increased mean IFN-γ levels from 1.92 to 2.89 pg/mL(P< 0.001) in comparison with a reduction in mean levels from 1.80 to 1.68 pg/mL(P=0.70) in the placebo group(P< 0.0001).Viusid administration was well tolerated.CONCLUSION:Our results indicate that treatment with Viusid leads to a notable improvement of oxidative stress and immunological parameters in patients with chronic hepatitis C.

Ocular cicatricial pemphigoid:diagnosis and systemic management

Ocular cicatricial pemphigoid(OCP)is a subcategory of mucous membrane pemphigoid(MMP)where the conjunctiva is the main site of inflammation.It is a chronic and autoimmune disease characterized by acute and chronic conjunctivitis that can progress to severe conjunctival cicatrization,corneal opacification,ocular surface keratinization,and eyelid abnormalities.OCP can lead to structural damage that can result in visual impairment,visual loss,and blindness,and can have a significant impact in a patient’s quality of life.Patients may manifest with varying symptoms,degrees of severity and may have different rates of progression.Early diagnosis and appropriate systemic immunosuppression are of utmost importance for prompt and adequate disease control.Various systemic immunomodulatory therapies(IMTs),including anti-metabolites,alkylating,and biologic agents have been utilized to achieve inflammation control and remission.Careful monitoring of disease progression is important to assess response and to modify and escalate therapy if needed.Treatment to alleviate symptoms of dry eye disease and address trichiasis and other eyelid abnormalities is recommended as well.A multidisciplinary approach to optimize clinical care is recommended in the management of patients with OCP.This review will address the immunopathogenesis,clinical features,keys to diagnosis and staging of patients with OCP.It will highlight the current immunomodulators utilized for disease management and proposed stepladder strategies.This review will discuss the updated roles of combination therapy,novel use of biologics as well as the recent use of adrenocorticotropic hormone(ACTH)analog in severe recalcitrant cases.

Inflammatory bowel disease in liver transplanted patients

Most common hepatobiliary manifestation of inflammatory bowel disease(IBD) are primary sclerosing cholangitis(PSC) and autoimmune hepatitis, ranking them as the main cause of liver transplantation(LT) in IBD setting. Course of pre-existing IBD after LT differs depending on many transplant related factors. Potential risk factors related to IBD deterioration after LT are tacrolimus-based immunosuppressive regimens, active IBD and cessation of 5-aminosalicylates at the time of LT. About 30% patients experience improvement of IBD after LT, while approximately the same percentage of patients worsens. Occurrence of de novo IBD may develop in 14%-30% of patients with PSC. Recommended IBD therapy after LT is equivalent to recommendations to overall IBD patients. Antitumor necrosis factor alpha appears to be efficient for refractory IBD. Due to potential side effects it needs to be applied with caution. In average 9% of patients require proctocolectomy due to medically refractory IBD or colorectal carcinoma. The most frequent complication in patients who undergo proctocolectomy with ileal-pouch anal anastomosis is pouchitis. It is still undeterminable if LT adds to risk of developing pouchitis in PSC patients. Annual colonoscopies are recommended as surveillance and precaution of colonic malignancies.

Sepsis-induced immunosuppression:mechanisms,diagnosis and current treatment options

Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of death and increased health care costs in modern intensive care units.The use of antibiotics,fluid resuscitation,and organ support therapy have limited prognostic impact in patients with sepsis.Although its pathophysiology remains elusive,immunosuppression is now recognized as one of the major causes of septic death.Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis.It is characterized by the release of antiinflammatory cytokines,abnormal death of immune effector cells,hyperproliferation of immune suppressor cells,and expression of immune checkpoints.By targeting immunosuppression,especially with immune checkpoint inhibitors,preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance.Here,we comprehensively discuss recent findings on the mechanisms,regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.

Update on the diagnosis and treatment of Vogt-Koyanagi-Harada syndrome

Vogt-Koyanagi-Harada syndrome(VKH)is a bilateral granulomatous panuveitis associated with serous retinal detachments and vitritis,and can be associated with extraocular manifestations of meningismus,poliosis,vitiligo,hearing loss,and headaches.It is mediated by CD4+T cells that target melanocytes in the eye,ear,meninges,and skin.It classically presents in 4 different phases:prodromal,uveitic,convalescent,and recurrent.There have been considerable advances in our understanding of the disease in recent years,and options for treatment have also expanded beyond systemic corticosteroids though these remain the mainstay of therapy in patients with VKH.This brief review will focus on updates in the diagnosis and treatment of VKH,specifically advances in imaging techniques including the use of optical coherence tomography angiography(OCTA)and enhanced depth imaging(EDI)optical coherence tomography(OCT).OCT parameters that are diagnostically predictive of acute VKH compared to other exudative maculopathies include the presence of subretinal membranous structures,a high retinal detachment,subretinal hyperreflective dots,and RPE folds.Evaluations of choroidal thickness using EDI-OCT demonstrate predominant involvement of the outer choroid in the acute inflammatory phase of VKH,consistent with histopathological analysis.OCTA may emerge as an alternative to fluorescein angiography(FA)and indocyanine angiography(ICGA)but is limited at this time due to its small field of view.While the mainstay of treatment of acute VKH continues to be systemic corticosteroids,biological response modifiers(BRMs)such as adalimumab and infliximab have been shown to be effective in the management of adult and pediatric VKH with one benefit being a faster onset of action compared to conventional immunosuppression.Literature Search:A literature search was done in PubMed using the words“Vogt Koyanagi Harada”“imaging”“diagnosis”“treatment”“therapy“posterior uveitis”.

Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis.To provide clinical practice recommendations on the immune function in sepsis,an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed.Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed,Web of Science,and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire.Then,the Delphi method was used to form consensus opinions,and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions.This consensus achieved satisfactory results through two rounds of questionnaire survey,with 2 statements rated as perfect consistency,13 as very good consistency,and 9 as good consistency.After summarizing the results,a total of 14 strong recommended opinions,8 weak recommended opinions and 2 non-recommended opinions were produced.Finally,a face-to-face discussion of the consensus opinions was performed through an online meeting,and all judges unanimously agreed on the content of this consensus.In summary,this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

Non-paraneoplastic Anti-NMDAR Encephalitis： First Confirmed Adult Case Report in Latvia

Anti-NMDAR （Anti-N-Methyl-D-aspartic acid） encephalitis is a rare autoimmune condition mainly affecting young women. It is associated with an underlying tumor in about 50% of reported cases. Antibodies directed against the GIuN1 subunit of the NMDA receptor are responsible for the disease pathogenesis and their detection in the patient＇s serum and cerebrospinal fluid are required to make a definite diagnosis. Classical clinical presentation consists of flu-like symptoms, followed by psychiatric disturbances and impaired consciousness, epileptic seizures and movement disorders. During the past decade, it has become an emerging area of research and discussion as more than 1,000 cases have been reported since the first description of this specific disease entity in 2007. Despite a rather typical clinical course it is frequently diagnosed and treated with a delay up to many months. Overall prognosis tends to be favorable. However, it strongly depends on early diagnosis and rapid treatment initiation. While diagnostic criteria for probable and definite anti-NMDAR encephalitis have been proposed, there are no evidence based guidelines for specific treatment strategies. Glucocorticoids, plasma exchange and IVIG are generally used as 1 st line treatment, in patients who do not respond, 2nd line treatment with Cyclophosphamide or Rituximab is used. We report a case of a confirmed non-paraneoplastic anti-NMDAR encephalitis with a rather classical manifestation in a Latvian woman who is first hospitalized in a psychiatric clinic then transferred to an ICU （intensive care unit）, treated with glucocorticoids, plasma exchange and later Cyclophosphamide with a good outcome.

Diagnosis and treatment of autoimmune retinopathy

Autoimmune retinopathy(AIR)refers to both paraneoplastic and non-paraneoplastic forms of a rare,acquired retinal degeneration thought to be mediated by the production of antiretinal antibodies.However,the mechanisms underlying AIR pathogenesis are incompletely understood,and it remains a diagnosis of exclusion given the lack of definitive testing as well as its protean clinical presentation.This review summarizes the current literature on the epidemiology,diagnosis,and management of AIR,with a focus on non-paraneoplastic disease and the potential role of immunomodulatory therapy.A recent expert consensus statement on diagnosis and management of non-paraneoplastic AIR served as a framework for interpreting the limited data available,a process that was complicated by the small sample sizes,heterogeneity,and retrospective nature of these studies.Additional work is needed to characterize AIR patients on the basis of cytokine and immunogenetic profiling;to establish the pathogenicity of antiretinal antibodies;and to standardize treatment regimens as well as assessment of clinical outcomes.

Immunomodulatory and Antiviral Therapy Improved Functional Cure Rate in CHB Patients with High HBsAg Level Experienced NA

Background and Aims:A functional cure,or hepatitis B virus(HBV)surface antigen(HBsAg)loss,is difficult to achieve in patients with hepatitis B virus e antigen(HBeAg)-positive chronic hepatitis B.The HBV vaccine and granulocyte-macrophage colony-stimulating factor(GM-CSF)have been reported to help reduce HBsAg levels and promote HBsAg loss.In this prospective randomized trial,we evaluated HBsAg loss in patients receiving pegylated interferon α2b(PEGIFN-α2b)and tenofovir disoproxil fumarate(TDF),with and without GM-CSF and HBV vaccination.Methods:A total of 287 patients with HBeAg positive chronic hepati-tis B and seroconversion after nucleot(s)ide analog treat-ment were assigned randomly to three treatment groups for 48 weeks,TDF alone(control),PEGIFN-α2b+TDF,and PEGIFN-α2b+TDF+GM-CSF+HBV vaccine.The prima-ry endpoints were the proportions of patients with HBsAg loss and seroconversion at 48 and 72 weeks.Resu/ts:The cumulative HBsAg loss rates in the control,PEGIFN-α2b+TDF,and PEGIFN-α2b+TDF+GM-CSF+HBV vaccine groups at week 48 were 0.0%,28.3%,and 41.1%,respec-tively.The cumulative HBsAg seroconversion rates in these groups at week 48 were 0.0%,21.7%,and 33.9%,respec-tively.Multivariate regression analysis showed that GM-CSF use plus HBV vaccination was significantly associated with HBsAg loss(p=0.017)and seroconversion(p=0.030).Con-clusions:In patients with HBeAg-positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment,immunomodulatory/antiviral treatment regimens effective-ly improved HBsAg loss,and the regimen including GM-CSF and HBV vaccination was most effective.

Treatment of patients with severe sepsis using Ulinastatin and Thymosin al： a prospective, randomized, controlled pilot study

Background Tradition treatment of sepsis and new therapies, including high dose corticosteroids and non-steroidal anti-inflammatory drugs, have proven unsuccessful in improving survival. This study aimed to evaluate the potential efficacy of immunomodulating therapy using Ulinastatin （UTI） plus Thymosin al （Tal） for improving organ function and reducing mortality in patients with severe sepsis. Methods A prospective study was carried out with randomized and controlled clinical analysis of 114 patients conforming to the enrollment standard. All patients had severe sepsis and received standard supportive care and antimicrobial therapy. Fifty-nine patients were also administered UTI plus Tal （defined as Group A）, 55 patients were given a placebo （defined as Group B）. Clinical parameters were determined by evaluation with the Acute Physiology and Chronic Health Evaluation II （APACHE II）, multiple organ failure （MOF） and the Glasgow Coma Scores （GCS） on entry and after therapy on the 3rd, 8th, and 28th day. By flow cytometery and ELISA lymphocyte subsets and cytokines were analyzed. Survival analysis was determined by the Kaplan-Meier method at 28, 60, and 90 days. Results Based on comparison of the two groups, patients in Group A exhibited a better performance in organ failure scores which was noticeable soon after initiation of treatment. Patients in Group A also demonstrated a better resolution of pre-existing organ failures during the observation period. After initiation of treatment, significant improvements in the CD4^＋/CD8^＋ ratio, a quicker balance between proinflammatory mediators such as tumor necrosis factor a, interleukin 6 and anti-inflammatory cytokines including interleukin 4 and interleukin 10 were found. This was followed by cumulative survival increases of 17.3% at 28 days, 28.9% at 60 days, and 31.4% at 90 days in Group A. The reduction in mortality was accompanied by a considerably shorter stay in the ICU and a shorter length of supportive ventilation, antimicrobial and dopamine therapy. Conclusion UTI plus Tal has a beneficial role in the treatment of severe sepsis.