Lessons of the month 3: Haemophagocytic lymphohistiocytosis following COVID-19 vaccination (ChAdOx1 nCoV-19).

A 36-year-old woman presented to hospital 9 days after receiving her first dose of the ChAdOx1 nCoV-19 vaccine with fever, myalgia and a sore throat. She was previously fit and well with no prior vaccine reactions.There was no clinical response to initial treatment with intravenous (IV) antibiotics. Microbiology tests including for COVID-19 were negative. At day 5, she developed pleuritic pain and a pericardial rub. Echocardiography and subsequent cardiac magnetic resonance imaging showed evidence of constrictive pericarditis. Computed tomography revealed gross hepatomegaly and moderate splenomegaly. Blood tests showed raised inflammatory markers, deranged clotting, low platelets and a marked hyperferritinaemia.A presumptive diagnosis of a multi-system inflammatory disorder secondary to recent COVID-19 vaccination was made and high-dose IV methylprednisolone initiated. Following a high 'H score' of 70%-80% a diagnosis of secondary haemophagocytic lymphohistiocytosis (HLH) was made. She was treated with IV immunoglobulin with subsequent clinical response.HLH is a rare syndrome of acute and rapidly progressive systemic inflammation characterised by cytopenias, excessive cytokine production and hyperferritinaemia. The adult form has multiple triggers, including recent vaccination. This case prompts awareness among clinicians of HLH as a rare complication of COVID-19 vaccination but should not discourage individuals from vaccination.

TNF-α Autocrine Feedback Loops in Human Monocytes: The Pro- and Anti-Inflammatory Roles of the TNF-α Receptors Support the Concept of Selective TNFR1 Blockade In Vivo.

Selective TNFR1 blockade in inflammatory diseases is emerging as a clinical strategy. We studied the roles of the two TNF-α receptors, TNFR1 and TNFR2, in human monocytes, the principal producer of TNF-α and central to many TNF-α driven diseases. We hypothesised that TNF-α has pro- and anti-inflammatory effects on monocytes, occurring differentially via TNFR1 and TNFR2. Monocytes were isolated from healthy human subjects and exposed to LPS, plus/minus the addition of blocking antibodies to TNF-α or its receptors. Pro- and anti-inflammatory cytokine production was quantified using real-time PCR and ELISAs. Cell surface expression of TNFR1/2 was measured by flow cytometry. We demonstrated that monocytes vary in the expression patterns of TNFR1 and TNFR2. Autocrine binding of TNF-α led to sustained upregulation of proinflammatory cytokines via TNFR1. In contrast, autocrine binding via TNFR2 upregulated the anti-inflammatory cytokine, IL-10, without proinflammatory effect. TNFR2 was responsible for binding soluble TNF-α secreted by monocytes, clearing the cytokine from the pericellular environment. TNFR1 blockade did not change the cell surface expression of TNFR2, leaving this receptor free to upregulate IL-10. These novel results support the concept of selective TNFR1 blockade in vivo in order that positive anti-inflammatory effects of TNF-α can be retained via TNFR2 ligation.

The rs361525 polymorphism does not increase production of tumor necrosis factor alpha by monocytes from alpha-1 antitrypsin deficient subjects with chronic obstructive pulmonary disease - a pilot study.

BACKGROUND: Polymorphisms in the TNF-A gene have been associated with chronic obstructive pulmonary disease (COPD) in some case-control studies. Previous work has shown that COPD/chronic bronchitis subjects with alpha-1 antitrypsin deficiency with the rs361525 TNF-α single nucleotide polymorphism have 100 times more TNF-in spontaneous sputum than disease matched controls. Our objective was to determine if the presence of this polymorphism increased TNF-α production by blood monocytes from COPD subjects. FINDINGS: Monocytes from 18 COPD/alpha-1 antitrypsin deficient subjects, with and without the rs361525 polymorphism, were cultured in the presence or absence of lipopolysaccharide. Cell-free supernatants were analyzed by ELISA and real-time PCR performed using cDNA from extracted RNA. Baseline expression of TNF-α messenger RNA was no different between the groups. No difference in messenger RNA or secreted protein was observed over time in un-stimulated cells. TNF-α messenger RNA expression and protein was not higher in lipopolysaccharide-stimulated monocytes from subjects with the polymorphism compared to cells from patients with the wild-type allele. CONCLUSIONS: This small pilot study did not provide an explanation for the findings of earlier observations of the association of the rs361525 polymorphism with TNF-α in airways secretions. Possible reasons for the lack of concordance include the study of blood rather than tissue cells, the use of a single stimulant rather than biological secretions and the need for far greater subject numbers to overcome intra-subject variation in monocyte TNF-α production.

Leukotriene receptor antagonists in allergic eye disease: a systematic review and meta-analysis.

BACKGROUND: Allergic eye diseases are common and cause significant morbidity. Leukotrienes are implicated in the pathogenesis of seasonal and perennial allergic conjunctivitis (AC), commonly seen in conjunction with allergic rhinitis, and in vernal keratoconjunctivitis and atopic keratoconjunctivitis. OBJECTIVES: To assess the available evidence for an effect of leukotriene receptor antagonists (LTRAs) on the ocular symptoms of allergic eye diseases. METHODS: Selected studies, identified with systematic review search methods, were single/double-blind, randomized, controlled trials that compared LTRAs with other common treatments. RESULTS: Eighteen trials, using the LTRA montelukast (in AC only), were identified. Six studies were suitable for meta-analysis, in patients with seasonal AC [treated over a 2-week period, symptoms scored 0 (mild) to 3 (severe)]. These trials were at low risk of bias without significant heterogeneity. Six trials were analyzed and showed that montelukast improved patients' ocular symptoms to a greater extent than placebo, with a difference in mean change-from-baseline score of -0.10 (95% CI, -0.14 to -0.07; P < .00001). Three trials compared montelukast with oral antihistamine. The difference in mean change-from-baseline score was 0.08 (95% CI, 0.02 to 0.14; P = .007), in favor of antihistamines. Two trials compared montelukast and oral antihistamine with placebo. The difference in mean change-from-baseline score was -0.30 (95% CI, -0.38 to -0.21; P < .00001), in favor of combination treatment. CONCLUSIONS: In seasonal AC LTRAs are more efficacious than placebo but less efficacious than oral antihistamines in adult patients. Clinical trials should be conducted to determine whether combination treatment with LTRA and oral antihistamine has a synergistic effect. Further research is required to clarify the role of LTRAs in other allergic eye diseases.

Mechanisms of neutrophil transmigration across the vascular endothelium in COPD.

Chronic obstructive pulmonary disease (COPD) is a common and important disease. Neutrophils have been shown to play a fundamental role in its development and progression. Understanding the mechanisms underlying the trafficking of neutrophils across the vascular endothelium into the lung could potentially allow the development of targeted biological treatments. The early stages of neutrophil tethering, adherence to and rolling on the endothelium have been determined. The later stages of diapedesis through the glycocalyx, endothelial cell (EC) layer and basement membrane, which are less well characterised, have been reviewed here. Evidence obtained from in vitro and in vivo work, concerning the implicated adhesion molecules on the neutrophil and endothelium, the mechanisms for neutrophil navigation through the EC junction (paracellular route) and evidence for transmigration through the body of an EC itself (transcellular route), is considered. The mechanisms are complex and are often disease and stimulus specific. There is evidence that a significant degree of redundancy occurs. Transmigration in the lung differs from that in other organs in that the neutrophil can exit the circulation either through the postcapillary venule in the systemic circulation or through the capillary in the pulmonary circulation. A number of factors make the mechanisms of transmigration within the lung and COPD model unique. These include physical differences between the flow through the capillary and the postcapillary venule, the modulating effect of the alveolar epithelium and other cells such as the macrophage, the presence of a 'diseased' neutrophil and indeed the presence or absence of acute, acute on chronic or chronic pulmonary disease.