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Suggested Publications
Autoinflammatory Recurrent Fever Syndromes
This week's recommended article, Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes, was published last May on NEJM. SUMMARY:Familial Mediterranean fever, mevalonate kinase deficiency, and the tumor necrosis factor receptor–associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases, that are characterized by recurrent fever episodes, with variable skin, joint, and serosal involvement, which affect functional capacity and quality of life. Colchicine is the standard treatment for familial Mediterranean fever, but it is ineffective or associated with unacceptable side effects in 5 to 10% of patients. No standard treatments are available for mevalonate kinase deficiency or TRAPS. Excessive interleukin (IL)-1β production has been reported in these three diseases, and small studies have suggested that its inhibition improves clinical and laboratory features of patients affected by these diseases. The authors reported the results of a phase 3 Canakinumab Pivotal Umbrella Study in Three Hereditary Periodic Fevers (CLUSTER), in which they evaluated the efficacy and safety of canakinumab, an anti–IL-1β monoclonal antibody, in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS.Patients ≥ 2 years, at their first flare were randomly assigned, in a 1:1 ratio, to receive subcutaneous canakinumab or placebo every 4 weeks. A flare was defined as a C-reactive protein (CRP) > 10 mg/L and a physician’s global assessment (PGA) score ≥ 2. All the patients were eligible for a blinded dose increase, if they had a persistent baseline flare between days 8 and 14. After day 29, patients were eligible for an open-label increase in the dose if they had a flare.  A total of 63 patients with colchicine-resistant familial Mediterranean fever, 72 with mevalonate kinase deficiency, and 46 with TRAPS underwent randomization.At week 16, significantly more patients, of all the three groups, receiving canakinumab had a complete response compared to those receiving placebo. The proportion of patients who had a complete response was higher with canakinumab than with placebo. Significantly more patients in the canakinumab group had a PGA score of < 2, and a CRP ≤ 10 mg/L compared to the placebo group.In epoch 3, an extended dosing regimen was evaluated: an absence of flares was maintained in approximately half the patients with colchicine-resistant familial Mediterranean fever and TRAPS. Among patients, who had a complete response in epoch 2, all the patients with colchicine-resistant familial Mediterranean fever, 82% of those with mevalonate kinase deficiency, and 83% of those with TRAPS maintained an absence of flares up to week 40. Also patients who did not have a complete response benefited from canakinumab: they had a lower number of days of fever per year than reported in the literature.No opportunistic infections, cases of tuberculosis, or deaths occurred. Overall, the most frequently reported adverse events were infections, which were more numerous in the canakinumab group than in the placebo group. The authors concluded that CLUSTER, which used a novel approach of grouping separate diseases with different genetic causes on the basis of a common targetable pathogenic mediator, provided evidence of a pathogenic role of IL-1β in colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS, and showed that the inhibition of IL-1β with canakinumab was efficacious in controlling and preventing flares. ARTICLE: Fabrizio De Benedetti, Marco Gattorno, Jordi Anton, et al.
UK malaria treatment guidelines 2016 - Review
This week's recommended reading is the article "Review of UK malaria treatment guidelines 2016 (Public Health England Advisory Committee on Malaria Prevention)", published at the beginning of May on the Archives of Disease in Childhood. Education and Practice Edition. SUMMARY: This guideline, written by the Public Health England Advisory Committee on Malaria Prevention (PHE ACMP) in 2016, in line with WHO guidelines, covers the diagnosis and management of malaria. Malaria is the most common imported tropical pathogen in the UK, and children comprise about 10% of the 1300–1800 UK cases per annum. Plasmodium falciparum (P. falciparum) is the most common agent and is associated with more severe disease. This guideline replaces the previous PHE ACMP UK malaria treatment 2007 guideline. The authors reported the main points of this guideline. Malaria should be considered in any unwell or feverish child, who has visited an endemic country, regardless of whether prophylaxis was taken. The time of infection presentation could widely vary from 6 days to a year post-travel.Malaria in children can be notoriously non-specific, even without fever. Thrombocytopenia is a common manifestation.Thick and thin blood films remain the gold diagnostic standard, but rapid diagnostic tests are almost as accurate for P. falciparum and P. vivax. If there is clinical suspicion with negative blood films, these should be repeated at 12–24 hours and again after a further 24 hours.Even in uncomplicated malaria, there can be rapid deterioration during the first 24 hours of treatment, so admission is recommended initially. Uncomplicated P. falciparum malaria should be treated with oral artemisinin combination therapy (ACT).Severe malaria (defined as the presence of the following manifestations: cerebral involvement, respiratory distress/metabolic acidosis, severe anemia, prostration, hypoglycemia, electrolyte disturbance, circulatory shock) should be managed in a pediatric intensive care or high dependency unit with advice from a pediatric infectious diseases specialist with malaria expertise.Intravenous artesunate gives a clear survival advantage over quinine and is the drug of choice.Fluid resuscitation should be cautious, even in the context of shock. Glucose monitoring is crucial, and broad-spectrum antibiotics should be given, until bacterial coinfection is excluded.For non-P. falciparum malaria, both ACT and chloroquine are effective for acute infection, although there is growing resistance to chloroquine in some Indonesian areas. To prevent relapse for P. vivax and P. ovale, primaquine treatment should overlap with ACT to ensure eradication of hypnozoites in the liver.All children receiving intravenous artesunate need a repeat full blood count at 2 weeks post-therapy as it is associated with delayed hemolysis.Family of infected children should be given information about malaria, and how to prevent and manage it.All malaria cases should be notified to PHE.The authors concluded reporting unresolved controversies: 1) the potential management of uncomplicated malaria as an outpatient, as it is probably better to hospitalized children, at least 24 hours, due to the risk of rapid deterioration and vomiting ACT; 2) how many films to perform to exclude malaria; 3) definition of severe malaria in non-endemic countries, as the WHO guideline has a more extensive list of severity features, whose relative importance in the non-endemic setting remains unclear. AUTHORS: Evans C., Fitzgerald F., Cunnington A. Click here to go to the article.
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