Intravenous anakinra for the treatment of haemophagocytic lymphohistiocytosis/macrophage activation syndrome: A systematic review.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) has a potentially high mortality rate. Anakinra, an interleukin-1 receptor antagonist, is now recommended early in HLH/MAS, with intravenous (IV) use proposed in critically unwell patients. This systematic review establishes the literature relating to IV anakinra in secondary HLH/MAS (sHLH/MAS). METHODS: We screened Embase, PubMed, and Medline, including all reports of IV anakinra for HLH or MAS. We extracted age, HLH/MAS trigger, continuous infusion or bolus dosing, and survival. RESULTS: Twenty-nine case reports/series identified 87 patients (median age 22 years, range 22 months to 84 years), all with sHLH. Amongst identifiable triggers, 43% were systemic infection, 33% rheumatological, 9% oncological. Children had predominantly a rheumatological trigger (48%), whilst adults were more commonly infection-driven (50%). Overall, rheumatologically triggered disease showed greater survival (83.3%), particularly compared with oncological triggers (42.9%). Children had a greater survival, particularly under 10 years (83%, vs. adults, 63%). CONCLUSIONS: Despite IV anakinra recipients likely to be critically unwell, this cohort had similar disease triggers and survival compared to large historical cohorts, and enhances awareness of age and trigger-specific survival patterns. IV anakinra had a wide therapeutic dosing range and tolerability, regardless of trigger, demonstrating substantial utility in severe sHLH/MAS.

Continuous intravenous anakinra for treating severe secondary haemophagocytic lymphohistiocytosis/macrophage activation syndrome in critically ill children.

The cytokine storm of secondary haemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) can cause life-threatening multiorgan failure. Interleukin-1 (IL-1) receptor blockade with anakinra can be effective in the management of sHLH/MAS. Subcutaneous (SC) dosing regimens are widely described; however, intravenous (IV) dosing is advantageous where time-critical intervention is vital and where SC oedema and/or hypoperfusion limits absorption. We review three critically ill children (aged 9, 11 and 17) with sHLH and rapidly progressive multiorgan dysfunction, successfully treated with continuous IV anakinra infusion. This case series significantly enhances the incipient knowledge regarding the safety and efficacy of IV anakinra for life-threatening sHLH.

Using ICD-10 diagnostic codes to identify 'missing' paediatric patients during nationwide COVID-19 lockdown in Oxfordshire, UK.

The study aims to identify 'missing' diagnoses amongst paediatric admissions during the UK's first national lockdown, compared with the previous 5 years. A retrospective observational cohort study of all children (0-15 years) attending for urgent care across Oxfordshire, during the first UK lockdown in 2020, compared to matched dates in 2015-2019, across two paediatric hospitals providing secondary care, including one with tertiary services. Our outcome measures were changes in numbers of patients attending and inpatient diagnoses (using ICD-10 classification) during the first 2020 lockdown, compared with the previous 5 years, were used. We found that total Emergency Department (ED) attendances (n = 4030) and hospital admissions (n = 1416) during the first UK lockdown were reduced by 56.8% and 59.4%, respectively, compared to 2015-2019 (5-year means n = 7446.8 and n = 2491.6, respectively). Proportions of patients admitted from ED and length of stay were similar across 2015-2020. ICD-10 diagnoses in lockdown of 2020 (n = 2843) versus matched 2015-2019 dates (n = 19,946) demonstrated significantly greater neoplasm diagnoses (p = 0.0123). Of diagnoses 'missing' in lockdown, 80% were categorised as infectious diseases or their sequelae and 20% were non-specific pains/aches/malaise and accidental injury/poisonings.Conclusions: Pandemic public health measures significantly altered paediatric presentations. Oxfordshire hospitals had a 58% reduction in ED attendances/inpatient admissions, with 'missing' diagnoses predominantly infection-related illnesses. These are likely driven by a combination of the following: (1) public health infection control measures successfully reducing disease transmission, (2) parents/carers keeping mild/self-limiting disease at home, and (3) pandemic-related healthcare anxieties. Prospective studies are needed to ensure referral pathways identify vulnerable children, those with social concerns, and avoid delayed presentation. What is Known: • Significant reductions of paediatric ED attendances and inpatient admissions are reported globally, throughout national and regional lockdowns for COVID-19. • Previous studies (supplemental table 5) examined only ED diagnoses or specific inpatient diagnoses during lockdown periods, demonstrating reductions of infectious diseases, accidents/injuries, and safeguarding referrals. What is New: • Using ICD-10 coding, robustly controlling for five historical years and adopting a hypothesis-independent analysis, demonstrating 80% of 'missing' inpatient diagnoses during national COVID-19 lockdown were infectious diseases or its sequelae, the remainder being non-specific aches/pains/malaise and accidental injuries/poisonings. • Greater numbers of neoplasms and other specific diagnoses were detected during lockdown, including greater documentation of co-morbidities and incidental findings.

Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders.

PURPOSE: Common variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients. METHODS: Germline variants were identified following targeted sequencing of n = 252 genes related to DNA repair in n = 38 patients. NanoString nCounter PlexSet assay measured gene expression in n = 20 CVID patients and n = 7 controls. DNA damage and apoptosis were assessed by flow cytometry in n = 34 CVID patients and n = 11 controls. RESULTS: Targeted sequencing supported enrichment of rare genetic variants in genes related to DNA repair pathways with novel and rare likely pathogenic variants identified and an altered gene expression signature that distinguished patients from controls and complex patients from those with an infections-only phenotype. Consistent with this, flow cytometric analyses of lymphocytes following DNA damage revealed a subset of CVID patients whose immune cells have downregulated ATM, impairing the recruitment of other repair factors, delaying repair and promoting apoptosis. CONCLUSION: These data suggest that germline genetics and altered gene expression predispose a subset of CVID patients to increased sensitivity to DNA damage and reduced DNA repair capacity.

Effects of placebos without deception compared with no treatment: A systematic review and meta-analysis.

OBJECTIVE: To investigate the clinical efficacy of open-label placebos compared with no treatment in a systematic review and meta-analysis. METHODS: We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations (OvidSP), EMBASE (OvidSP), and clinical trials registers and screened reference lists. The search was run on 27th April 2015. We included all randomized controlled trials of any medical condition with open-label placebo and no-treatment groups. Authors independently assessed records and extracted data. We excluded nonrandomized trials and nonclinical studies. Risk of bias was assessed using Cochrane criteria. We used random-effects model for meta-analysis. RESULTS: We screened 348 publications, assessed 24 articles for eligibility and identified five trials (260 participants) that met inclusion criteria. The clinical conditions were: irritable bowel syndrome, depression, allergic rhinitis, back pain, and attention deficit hyperactivity disorder. The risk of bias was moderate. We found a positive effect for nondeceptive placebos (standardized mean difference 0.88, 95% CI 0.62 to 1.14, P < 0.00001, I2 = 1%). CONCLUSIONS: Open-label placebos appear to have positive clinical effects compared to no treatment. Caution is warranted when interpreting these results due to the limited number of trials identified, lack of blinding, and the fact that positive messages were included alongside open-label placebos. Larger definitive trials are now warranted to explore the potential patient benefit of open-label placebos, to investigate the relative contributions of positive suggestions, and ethical implications.

Effects of placebos without deception compared with no treatment: protocol for a systematic review and meta-analysis.

INTRODUCTION: Placebos have long provided a robust control for evaluating active pharmacological preparations, but frequently demonstrate a variable therapeutic effect when delivered in double-blinded placebo-controlled trials. Delivery of placebos as treatment alone has been considered unethical, as it has been thought that deception is essential for their effect. However, recent evidence suggests that clinical benefit can be derived from placebos delivered without deception (unblinded/open-label) manner. Here, we present a protocol for the first systematic review and meta-analysis of studies of the effects of non-deceptive placebos compared with no treatment. METHODS AND ANALYSIS: This protocol will compare the effect of placebos delivered non-deceptively to no treatment. It will also assess the methods of delivery used for non-deceptive placebos. Studies will be sought through relevant database searches and will include those within disease settings and those among healthy controls. To be included, trials must include both non-deceptive (open-label) placebo and no treatment groups. All data extraction and analysis will be conducted by two independent reviewers. The analysis will evaluate any differences in outcome measures between the non-deceptive placebo and no treatment groups. Outcome measures will be the clinically-relevant outcomes detailed in the primary papers. The delivery methods, such as verbal instructions, which may provide positive expectations and outcomes, of non-deceptive placebos will also be assessed. Each study will be comprehensively assessed for bias. Subgroup analyses will identify any discrepancies among heterogeneous data. ETHICS AND DISSEMINATION: This review does not require ethical approval. The completed review will be widely disseminated by publication and social media where appropriate. This protocol has been registered on PROSPERO (2015:CRD42015023347).