Method’s corner: Allergist’s guide to network meta-analysis

Network meta-analyses (NMAs) simultaneously estimate the effects of multiple possible treatment options for a given clinical presentation. For allergists to benefit optimally from NMAs, they must understand the process and be able to interpret the results. Through a worked example published in Pediatric Allergy and Immunology, we summarize how to identify credible NMAs and interpret them with a focus on recent innovations in the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation). NMAs build on traditional systematic reviews and meta-analyses that consider only direct paired comparisons by including indirect evidence, thus allowing the simultaneous assessment of the relative effect of all pairs of competing alternatives. Our framework informs clinicians of how to identify credible NMAs and address the certainty of the evidence. Trustworthy NMAs fill a critical gap in providing key inferences using direct and indirect evidence to inform clinical decision making when faced with more than two competing courses of treatment options. This document will help allergists to identify trustworthy NMAs to enhance patient care.     

Vaccines and vaccine resistance: Past,present and future

BackgroundEdward Jenner, by any definition would be considered the father of vaccinology. His use of cow pox virus for vaccinating against small pox is the prime example of a live vaccine. Using a virus that has very low virulence for humans and therefore, fits the definition of attenuated. Hesitancy towards a vaccine of this type, much before the science of microbiology and immunology were established, would have been justifiable. In the first half of 20th century, large number of vaccines became available for childhood diseases with significant morbidity and mortality. Around the same time global travel and trade led to escalation in the widespread transmission of diseases caused by microbes.ObjectiveThe objective of this narrative is to offer a balanced view of science behind vaccines, their current status and advances expected in the near future. At the same time the various types of reactions from public at large towards vaccines over past decades are reviewed.ContentThis narrative provides a historical perspective of vaccine development, reviews mechanisms of vaccine induced protection, currently available vaccine technologies and vaccines. The focus is on newer vaccines including those utilizing viral vectors and gene based vaccines. Based on the times during which this narrative is being written, messenger RNA vaccines are discussed in detail.ConclusionThe content and review of literature offered in this review makes the impact of vaccines on human life clear. It is also to be accepted that resistance and hesitation towards vaccines is nothing new or limited to vaccines being used during the ongoing pandemic of Covid 19. The continued development of science and products of vaccinology is necessary for further impact on human life. The development of a strong public health infrastructure by nations around the world is the key to improve upon current efforts at public awareness, proactive interventions and appropriate vaccine utilization during all times. Preparedness for epidemics and pandemics would then become more and more efficient than currently in existence.     

Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination – A report of two UK cases

Recent reports have highlighted rare, and sometimes fatal, cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia following the Vaxzevria vaccine. An underlying immunological mechanism similar to that of spontaneous heparin-induced thrombocytopenia (HIT) is suspected, with the identification of antibodies to platelet factor-4 (PF4), but without previous heparin exposure. This unusual mechanism has significant implications for the management approach used, which differs from usual treatment of CVST. We describe the cases of two young males, who developed severe thrombocytopenia and fatal CVST following the first dose of Vaxzevria. Both presented with a headache, with subsequent rapid neurological deterioration. One patient underwent PF4 antibody testing, which was positive. A rapid vaccination programme is essential in helping to control the COVID-19 pandemic. Hence, it is vital that such COVID-19 vaccine-associated events, which at this stage appear to be very rare, are viewed through this lens. However, some cases have proved fatal. It is critical that clinicians are alerted to the emergence of such events to facilitate appropriate management. Patients presenting with CVST features and thrombocytopenia post-vaccination should undergo PF4 antibody testing and be managed in a similar fashion to HIT, in particular avoiding heparin and platelet transfusions.     

4-Hydroxynonenal regulates mitochondrial function in human small airway epithelial cells

Prolonged exposure to oxidative stress causes Acute Lung Injury (ALI) and significantly impairs pulmonary function. Previously we have demonstrated that mitochondrial dysfunction is a key pathological factor in hyperoxic ALI. While it is known that hyperoxia induces the production of stable, but toxic 4-hydroxynonenal (4-HNE) molecule, it is unknown how the reactive aldehyde disrupts mitochondrial function. Our previous in vivo study indicated that exposure to hyperoxia significantly increases 4-HNE-Protein adducts, as well as levels of MDA in total lung homogenates. Based on the in vivo studies, we explored the effects of 4-HNE in human small airway epithelial cells (SAECs). Human SAECs treated with 25 μM of 4-HNE showed a significant decrease in cellular viability and increased caspase-3 activity. Moreover, 4-HNE treated SAECs showed impaired mitochondrial function and energy production indicated by reduced ATP levels, mitochondrial membrane potential, and aconitase activity. This was followed by a significant decrease in mitochondrial oxygen consumption and depletion of the reserve capacity. The direct effect of 4-HNE on the mitochondrial respiratory chain was confirmed using Rotenone. Furthermore, SAECs treated with 25 μM 4-HNE showed a time-dependent depletion of total Thioredoxin (Trx) proteins and Trx activity. Taken together, our results indicate that 4-HNE induces cellular and mitochondrial dysfunction in human SAECs, leading to an impaired endogenous antioxidant response.     

A novel human STAT3 mutation presents with autoimmunity involving Th17 hyperactivation

Mutations in STAT3 have recently been shown to cause autoimmune diseases through increased lymphoproliferation. We describe a novel Pro471Arg STAT3 mutation in a patient with multiple autoimmune diseases, causing hyperactivation of the Th17 pathway. We show that IL-17 production by primary T cells was enhanced and could not be further increased by IL-6, while IL-10 reduced Th17 cell numbers. Moreover, specific inhibition of STAT3 activation resulted in diminished IL-17 production. We show that the Pro471Arg STAT3 mutation yields both increased levels of IgA and IgG, probably due to high IL-21 levels. When remission was reached through medical intervention, IL-17 levels normalized and the clinical symptoms improved, supporting the idea that STAT3 gain-of-function mutations can cause hyperactivation of the Th17 pathway and thereby contribute to autoimmunity.     

人乳头瘤病毒感染与机体固有免疫反应

人乳头瘤病毒可引起多种疾病,如寻常疣、扁平疣、尖锐湿疣、鲍恩样丘疹病、宫颈癌等.人乳头瘤病毒可以有效地逃逸固有免疫识别,其可能原因包括嗜上皮性、非溶解性复制、高免疫原性的衣壳蛋白在免疫活跃的复层鳞状上皮基底层呈低水平表达等.人乳头瘤病毒的致癌性以及所致疾病的临床高发病率受到人们的广泛关注.机体对抗人乳头瘤病毒的固有免疫已成为研究热点.概述多种皮肤免疫细胞,如角质形成细胞、树突细胞、朗格汉斯细胞、浆细胞样树突细胞、自然杀伤细胞和恒定型自然杀伤T细胞对人乳头瘤病毒固有免疫反应的相关研究.