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Suggested Publications
Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa
The article WAidid suggests this week, Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa, was published last April on NEJM. SUMMARY:Trachoma-control programs have distributed more than 600 million doses of oral azithromycin in an effort to eliminate the ocular strains of chlamydia, that cause the disease. Azithromycin has been effective against trachoma, although it has caused gastrointestinal side effects and selected for macrolide-resistant strains of Streptococcus pneumoniae and Escherichia coli. There are also evidences of possible benefits of azithromycin for prevention of other infectious diseases (malaria, infectious diarrhea, pneumonia). The results of a case–control study and a cluster randomized trial in an area of Ethiopia, in which trachoma is endemic, suggested that mass distribution of azithromycin might reduce childhood mortality. So, the authors tested the hypothesis that twice-yearly mass distributions of oral azithromycin would reduce mortality in children. 1533 communities in Malawi, in Niger, and in Tanzania were enrolled, based on census information. All children 1 to 59 months of age, who weighed at least 3800 g, received a single directly observed dose (at least 20 mg/Kg) of oral azithromycin or placebo; both placebo and azithromycin were donated by Pfizer, which reviewed the protocol. Children who were known to be allergic to macrolides were excluded.97,047 children were enrolled in the azithromycin group and 93,191 in the placebo group. A house-to-house census was performed during five prescribed 6-month periods. At follow-up censuses, the vital status and residence information were recorded.Mortality was 13.5% lower overall in the azithromycin group than in the placebo group (P < 0.001). Children in the youngest age group (1 to 5 months of age) had the highest overall mortality and the largest observed difference in mortality with azithromycin as compared with placebo (24.9% lower with azithromycin; P=0.001).In a random sample of 250 verbal autopsies, 41% of the deaths were due to malaria, 18% to diarrhea or dysentery, and 12% to pneumonia, with a significant difference among the countries (P<0.001).20 hospitalizations and life-threatening illnesses were reported, but it was not possible to determine whether any serious adverse event was caused by azithromycin. Nonserious adverse events were difficult to detect, and they were reported less frequently than serious adverse events. No assessment of antimicrobial resistance was made.The authors highlighted that all-cause mortality was significantly lower (approximately 14%) among children who received a twice-yearly dose of oral azithromycin, compared to those who received placebo. The highest number of deaths and the largest observed effect was seen in Niger.Azithromycin was most effective among children 1 to 5 months of age, preventing 1 of 4 deaths expected among children in this age group. The Food and Drug Administration has not approved azithromycin for children in this age group, and the World Health Organization does not currently recommend including them in distributions to control trachoma.This trial did not investigate the mechanism by which azithromycin reduced mortality.The authors underlined some limitations: 1) little information was collected on each individual child and community; 2) deaths were determined by consecutive censuses; 3) no effort was made to follow children after they moved; 4) with twice-yearly distributions, a child’s first treatment might not have been administered until 7 months of age; 5) although mortality is seasonal, communities were treated in a rolling fashion over each 6-month period; 6) the results obtained in these three geographical sites may not be generalizable.The authors concluded that further investigation is required to identify specific mechanisms by which azithromycin reduced mortality, and that any policy, that recommends mass distribution of oral azithromycin to address childhood mortality, would need to consider not only cost, but also the risk of side effects, especially the potential for the induction or amplification of antibiotic resistance. AUTHORS: Jeremy D. Keenan, Robin L. Bailey, Sheila K. West, Ahmed M. Arzika, John Hart, Jerusha Weaver, Khumbo Kalua, Zakayo Mrango, Kathryn J. Ray, Catherine Cook, Elodie Lebas, Kieran S. O’Brien, et al. To go to the article, click here.
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.
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