Faced with the rapidly evolving COVID-19 pandemic, in March 2020 the UK Government advocated strict self-isolation ('shielding') to protect extremely vulnerable patient groups deemed at high risk of severe SARS-CoV-2 infection. 1 These included children and adults with sickle cell anemia (HbSS). On the advice of the National Hemoglobinopathy Panel (NHP), a multidisciplinary expert advisory group, shielding guidance was extended to all sickle cell disease (SCD) sub-types. Patients with transfusion dependent (TDT) and non-transfusion dependent thalassemia (NTDT), Diamond-Blackfan anemia (DBA) and other rare inherited anemias were also advised to shield if considered at high risk based on agreed clinical criteria. These included severe iron overload, splenectomy, diabetes and cardiac disease. 2 Data provided by two participating centers with the largest thalassemia cohorts indicate up to 30% of patients meet these criteria. In order to evaluate the impact of these measures and inform guidance on the clinical management of COVID-19 and public health policy, a real-time survey of confirmed and suspected cases of COVID-19 in hemoglobinopathy and rare inherited anemia patients was initiated on behalf of the NHP and National Health Service (NHS) England Clinical Reference Group for Hemoglobinopathies. Data were submitted weekly by the 14 Hemoglobinopathy Coordinating Centers (HCC) in England, providing national coverage. HCC were encouraged to follow World Health Organization (WHO) case definitions which include both confirmed and clinically suspected COVID-19. 3 Anonymised data were collected using a standardised report template (see the Online Supplementary Data) and presented weekly to the NHP. Between April 8 and May 6, 2020, a total of 195 confirmed or suspected COVID-19 cases (male: 87; female: 108) were reported. The timeline of case accrual is shown in Figure 1A. The median age was 33 years (range: 6 weeks to 92 years). The distribution according to age and sex is shown in Figure 1B. PCR for SARS-CoV-2 RNA was positive in 99 of 157 (63%) cases tested (Figure 2A). Laboratory confirmation was not available for 34 (17.4%) cases, 31 of which were managed in the community for suspected COVID-19 before widespread testing became available. SCD accounted for 166 (85.1%) of cases reported, with 129 (77.7%) severe (HbSS or HbSβ 0-thalassemia) and 37 (22.3%) mild (HbSC, HbSβ +-thalassemia or HbSE) genotypes (Figures 2A-B). There were 149 adults and 17 children (defined as ≤18 years). Ninety-five (57%) were female. One hundred and twenty-eight (77.1%) SCD patients were admitted to hospital of whom 15 (11.7%), all adults, required non-invasive and/or mechanical ventilation (Figure 2B). The proportion of patients who required critical care was higher in mild genotypes, 8 of 29 (27.6%), than severe genotypes, 7 of 99 (7.1%) (Figure 2B). Sixty of 154 (39%) patients for whom data were available received transfusion (red cell exchange 46 [29%]; simple [top-up] transfusion 15 [10%]) during the COVID-19 episode. The proportion of tr...

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Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein, we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumors that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition.

The objective of this retrospective cohort study from two tertiary centres in the UK was to describe the pregnancy outcomes of women with sickle cell disease (SCD) who booked at these centres between 2004 and 2008, and to compare this with historical data. The study population comprised 122 singleton pregnancies in women with SCD: homozygous sickle cell disease 64, sickle cell haemoglobin C disease 45, sickle b plus thalassaemia 11, sickle cell haemoglobin E disease 1 and sickle cell delta disease 1 from 2004 to 2008 managed in the joint haematology/obstetric antenatal clinics in two tertiary teaching hospitals. The main outcome measures were the frequency of sickle cell crises and obstetric complications. Age and gestation at booking were 18-43 years (mean 29.7) and 9-36 weeks gestation (mean 17.3), respectively. Complications of SCD occurred in 25% of pregnancies. Fifty-four percent of women had induction of labour and 39% were delivered by emergency caesarean section. Thirty-three percent had a postpartum haemorrhage. Nineteen percent of women delivered before 37 completed weeks. Birth weight below 2500 g occurred in 20% of singleton pregnancies. Three neonates developed transient complications related to maternal opiate exposure postnatally. Three intrauterine deaths occurred at 24, 29 and 34 weeks. Two of these had congenital defects, and the other severe intrauterine growth restriction. No maternal deaths occurred. Successful pregnancy outcomes can be achieved in SCD. There has been an improvement in fetal and maternal morbidity and mortality compared with historical data. Pregnancy in women with SCD remains high risk. Early access to antenatal care and to expertise in SCD is essential. A matched control population from the same time period and prospective data collection is needed to address confounders such as ethnicity and deprivation.

Background:Anakinra is a recombinant interleukin-1 receptor antagonist licensed in Europe for the treatment of rheumatoid arthritis, periodic fever and auto-inflammatory syndromes1. It is increasingly recognised as an adjunct in the treatment of macrophage activation syndrome/secondary haemophagocytic lymphohistiocytosis (HLH)2.Objectives:To analyse the indication, patient demographic and outcomes of critically unwell patients receiving anakinra for suspected HLH.Methods:Retrospective cohort analysis of adult patients who received anakinra over a 12-month period at Imperial College Healthcare NHS Trust, London.Results:Eleven patients received anakinra (both sub-cutaneous and intravenous, dose range 100– 460 mg daily), ten alongside conventional treatments for HLH. 64% were male. Median age at presentation was 32 years (range 27-73 years). Serum ferritin was significantly elevated (median 17371 (range 4335 – 160,664 micrograms per litre) in all cases.Ten of eleven cases underwent bone marrow examination which showed haemophagocytosis in all cases. Underlying diagnoses were: T-cell Lymphoma (n=3), Mantle Cell Lymphoma (n=1), gastric MALT Lymphoma (n=1), infection (n =3: Group A streptococcus in a patient with inflammatory arthritis (bone marrow not performed), EBV and CMV), retained products of conception (n=1), post-transplant-related lymphoproliferative disorder in a case of systemic lupus with renal transplant (n=1), unknown (n=1).Overall mortality was 55%. The underlying diagnosis were: T –cell Lymphoma (n=3), gastric MALT Lymphoma (n=1), CMV infection in a post-renal transplant immunosuppressed patient (n=1, sarcoidosis underlying diagnosis), unknown (n=1). 100% of cases with T-cell lymphoma as the cause of HLH died, despite two of the three receiving standard chemotherapy to treat the lymphoma. The third case was diagnosed with non-hepatosplenic gamma delta T-cell lymphoma post-mortem.In the five cases that survived, anakinra led to rapid recovery in three cases (underlying diagnoses: Mantle Cell lymphoma (managed entirely steroid free), HLH secondary to retained products of conception, and inflammatory arthritis with Group A Streptococcal pneumonia). The two remaining cases had underlying PTLV and EBV-driven HLH. Anakinra led to rapid resolution of fever, improvement in respiration and dramatic decreases in serum ferritin (up to 98% reduction in three weeks).There were no identifiable complications from anakinra use. One case remains on anakinra, a young male with inflammatory arthritis and Group A Streptococcus pneumonia, who rapidly flared again two days after cessation with full recovery once anakinra was re-instigated.Conclusion:Anakinra can be a useful adjunct in the treatment of suspected HLH but appears to be less efficacious in those with underlying haematological malignancy, where mortality remains high. In critically ill patients we have used it intravenously, and in higher doses, where the half-life is shorter and twice daily dosing is required.Anakinra was well tolerated and its short half-life ma...