Current guidelines recommend delaying the start of immune tolerance induction (ITI) until the inhibitor titre is <10 Bethesda units (BU) to improve success. This study was conducted to evaluate ITI outcome relative to time to start ITI from inhibitor detection irrespective of inhibitor titre. Data were retrospectively collected from two U.S. haemophilia treatment centres (HTCs) on subjects with severe/moderate factor VIII (FVIII) deficiency with inhibitors who underwent ITI. Outcomes were defined pragmatically: success--negative inhibitor titre and ability to use FVIII concentrate for treatment/bleed prevention; partial success--inhibitor titre 1 to <5 BU with ability to use FVIII concentrate for treatment of bleeding; failure--ITI ongoing >3 years without achieving success/partial success, or ITI discontinuation. Fifty-eight subjects were included; 32 of 39 (82%) with high-responding inhibitor (HRI) achieved success, 7 failed. HRI subjects were subdivided based on ITI start time: 23/39 subjects started within 1 month of detection and 22/23 (96%) achieved success. Of these 23, 13 started ITI with an inhibitor titre ≥10 BU; all were successes. Eleven of 39 HRI subjects had an interval >6 months until ITI start; 7 (64%) achieved success. Time from inhibitor detection to ITI start may play a critical role in outcome. A titre ≥10 BU at ITI start did not influence outcome in subjects when ITI was initiated within 1 month of detection. Prompt ITI should be considered a viable therapeutic option in newly identified patients with inhibitors regardless of current inhibitor titre.

Congenital plasminogen deficiency is caused by mutations in , the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered IV at 6.6 mg/kg every 2 to 4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary end point was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary end point was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), nonvisible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid, as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu-plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.

This study investigated the clinical features of immunocompetent children with adenovirus infection requiring hospitalization. The files of 78 children (mean age 17 +/- 10 months) with community-acquired adenovirus infection admitted over a 2-year period were reviewed. The children were referred after 5.7 +/- 3.4 days of illness, all with fever (mean peak 39.8 +/- 0.8 degrees C). Temperature normalized after 3.5 +/- 2 days. Duration of hospitalization (mean, 7.0 +/- 3.9 days) correlated with lethargy, lung crackles, cracked lips, hypoxia, impaired liver tests, and high serum lactic dehydrogenase (LDH) concentration at admission. Serum LDH concentrations and hypoxemia predicted 70% of the variance in hospital stay. All patients recovered. Adenovirus infection may cause considerable morbidity, even in immunocompetent children. Disease severity, defined by duration of hospitalization, correlates with serum LDH concentrations and oxygen saturation at admission.

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