By Anne McLeod, MD

2009-12-08

The molecular basis of sickle cell disease (SCD) was uncovered more than 60 years ago, but there have been few fast answers to the problems of managing patients with this devastating disease, and new challenges and complications await us. Although it has been previously found that seasonal influenza is 50 times more frequent in children with sickle cell disease, we have had little time to study the impact of pandemic H1N1 on any of our high-risk patient populations.

Yesterday at the Hemoglobinopathies, Excluding Thalassemia: Vascular and Organ Dysfunction Oral Session moderated by Drs. Gregory Kato and Gerhard Hildebrandt, Dr. John Strouse of Johns Hopkins University presented data (abstract #264) on the impact of H1N1 on children and young adults with  SCD. Dr. Strouse’s group searched hospital databases at Johns Hopkins Hospital to identify patients admitted with SCD and a respiratory infection. His team was able to identify 99 SCD patients with a confirmed diagnosis of seasonal influenza A (64 patients), seasonal influenza B (25 patients), or pandemic H1N1 (10 patients). Clinical symptoms were similar in the three groups: fever, cough, and rhinorrhea. However, those patients with pandemic H1N1 demonstrated a three-fold increased risk of acute chest syndrome and a nine-fold increased risk of intensive-care admission compared to those with other forms of influenza. The authors stressed the importance of vaccination for children and young adults with SCD and their families — an important message to convey to our patients and colleagues.

Later in the day, hopes for a fast answer to the problem of pulmonary hypertension in SCD patients were dashed with the presentation of the results of the Walk-PHaSST trial (abstract #571) by Dr. Mark Gladwin. During the Hemoglobinopathies, Excluding Thalassemia: Pulmonary Hypertension, Hemolysis, and Nitric Oxide Oral Session, Dr. Machado described a multicenter, placebo-controlled, double-blind 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of SCD patients older than 12 years with pulmonary hypertension. Pulmonary hypertension is a frequent and often silent killer of patients with SCD, so there was great hope that sildenafil would prove to be an effective, safe intervention.

Unfortunately, the Walk-PHaSST trial was prematurely stopped after the enrollment of 74 subjects, due to a statistically significant increase in serious adverse events in the sildenafil treatment arm. The chief contributor to this was an increase in sickle cell anemia crises requiring hospitalization (35% vs. 11%; p=0.025). Patients in the treatment arm also reported worsening pain during walking and less enjoyment of life compared with the placebo group. There were no adverse events classified as life-threatening, and there was one death in the placebo arm and none in the treatment arm.

The premature termination of the study for safety reasons limited the ability of the investigators to reach any conclusions about efficacy in the treatment arm. This is clearly a disappointing outcome.  However, the investigators suggest that this finding opens up new pathways for the investigation of the pathobiology of veno-occlusive crises and sickle cell pain. We hope the 2010 ASH Annual Meeting will shed new light on these difficult issues.

Dr. McLeod indicated no relevant conflicts of interest.

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