NEJM original articles

Background. Highly pathogenic avian influenza A(H5N1) viruses have caused widespread infections in dairy cows and poultry in the United States, with sporadic human cases. We describe characteristics of human A(H5N1) cases identified from March through October 2024 in the United States.

Methods. We analyzed data from persons with laboratory-confirmed A(H5N1) virus infection using a standardized case-report form linked to laboratory results from the Centers for Disease Control and Prevention influenza A/H5 subtyping kit.

Results. Of 46 case patients, 20 were exposed to infected poultry, 25 were exposed to infected or presumably infected dairy cows, and 1 had no identified exposure; that patient was hospitalized with nonrespiratory symptoms, and A(H5N1) virus infection was detected through routine surveillance. Among the 45 case patients with animal exposures, the median age was 34 years, and all had mild A(H5N1) illness; none were hospitalized, and none died. A total of 42 patients (93%) had conjunctivitis, 22 (49%) had fever, and 16 (36%) had respiratory symptoms; 15 (33%) had conjunctivitis only. The median duration of illness among 16 patients with available data was 4 days (range, 1 to 8). Most patients (87%) received oseltamivir; oseltamivir was started a median of 2 days after symptom onset. No additional cases were identified among the 97 household contacts of case patients with animal exposures. The types of personal protective equipment (PPE) that were most commonly used by workers exposed to infected animals were gloves (71%), eye protection (60%), and face masks (47%).

Conclusions. In the cases identified to date, A(H5N1) viruses generally caused mild illness, mostly conjunctivitis, of short duration, predominantly in U.S. adults exposed to infected animals; most patients received prompt antiviral treatment. No evidence of human-to-human A(H5N1) transmission was identified. PPE use among occupationally exposed persons was suboptimal, which suggests that additional strategies are needed to reduce exposure risk. (Funded by the Centers for Disease Control and Prevention.).

Background. Patients receiving standard treatment for chronic subdural hematoma have a high risk of treatment failure. The effect of adjunctive middle meningeal artery embolization on the risk of treatment failure in this population remains unknown.

Methods. We randomly assigned patients with symptomatic chronic subdural hematoma to undergo middle meningeal artery embolization as an adjunct to standard treatment (embolization group) or to receive standard treatment alone (control group). Either surgical or nonsurgical standard treatment had been chosen for each patient before randomization. The primary efficacy outcome was a composite of the following events: recurrent or residual chronic subdural hematoma (measuring >10 mm) at 180 days; reoperation or surgical rescue within 180 days; or major disabling stroke, myocardial infarction, or death from neurologic causes within 180 days. The primary safety outcome was a composite of major disabling stroke or death from any cause within 30 days.

Results. Among 310 enrolled patients, 149 were randomly assigned to the embolization group and 161 to the control group; 189 patients were to receive surgical standard treatment and 121 nonsurgical standard treatment. The mean age of the patients was 73 years, and 70% were men. In the primary efficacy analysis, a primary-outcome event occurred in 19 of 120 patients (16%) in the embolization group, as compared with 47 of 129 patients (36%) in the control group (odds ratio, 0.36; 95% confidence interval, 0.20 to 0.66; P = 0.001). In the primary safety analysis, 4 of 144 patients (3%) in the embolization group and 5 of 166 patients (3%) in the control group either had a major disabling stroke or died within 30 days. Through 180 days, 12 patients (8%) in the embolization group and 9 patients (5%) in the control group had died, with death from neurologic causes occurring in 1 patient (1%) in the embolization group and in 3 patients (2%) in the control group.

Conclusions. Among patients with symptomatic chronic subdural hematoma, adjunctive middle meningeal artery embolization resulted in a lower risk of treatment failure than standard treatment alone, without resulting in an increased incidence of disabling stroke or death in the short term. Further study of longer-term safety outcomes is warranted. (Funded by Balt USA; STEM ClinicalTrials.gov number, NCT04410146.).

Background. Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and medical complications throughout life. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia.

Methods. In this phase 2 dose-finding study, we evaluated the safety and efficacy of oral infigratinib in children with achondroplasia between the ages of 3 and 11 years. A total of 72 children were enrolled in five sequential cohorts to receive daily infigratinib at doses of 0.016 mg per kilogram of body weight (cohort 1), 0.032 mg per kilogram (cohort 2), 0.064 mg per kilogram (cohort 3), 0.128 mg per kilogram (cohort 4), and 0.25 mg per kilogram (cohort 5) for 6 months, followed by 12 months of extended treatment in which the dose in cohorts 1 and 2 could be escalated to the next ascending level at months 6 and 12. The primary safety outcome was the incidence of adverse events that led to a decrease in the dose or discontinuation of infigratinib. The primary efficacy outcome was the change from baseline in the annualized height velocity.

Results. During treatment, all the children had at least one adverse event, most of which were mild or moderate in severity; none resulted in treatment discontinuation. In cohort 5, an increased annualized height velocity was observed, which persisted throughout the duration of the study, with a mean change from baseline at 18 months of 2.50 cm per year (95% confidence interval [CI], 1.22 to 3.79; P = 0.001). The mean change from baseline in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population at 18 months; the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI, -0.18 to -0.06).

Conclusions. The administration of oral infigratinib did not result in any apparent major safety signal and increased the annualized height velocity and z score and decreased the upper-to-lower body segment ratio at 18 months of treatment in cohort 5. (Funded by BridgeBio Pharma; PROPEL2 ClinicalTrials.gov number, NCT04265651.).

Background. B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.

Methods. We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or higher risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival.

Results. The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a higher relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone.

Conclusions. Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or higher risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).