Vaccination of Hemophilia Patients Varies in Germany and Should Be Reassessed to Minimize Fear, Survey Suggests

Recommendations for vaccination practices for patients with hemophilia should be reassessed in an effort to minimize fear and emphasize the importance of vaccination to prevent infections, suggests a survey among physicians in Germany.

Data from the PEDNET registry, a database of children with hemophilia, suggest that vaccination in close proximity to factor replacement therapies has no impact on the risk of developing inhibitors against the therapies.

The findings were summarized in a letter to the editor, titled “Vaccination in patients with haemophilia – Results from an online survey among haemophilia treatment centres in Germany,” in the journal Haemophilia.

Current therapy for hemophilia relies on the preventive (prophylactic) use of factor VIII or IX replacing therapies. These are administered in early childhood, with additional treatment being given for bleeding episodes. While life-saving, this strategy can lead to the development of inhibitory antibodies (alloantibodies) that are called against these factors — most against factor VIII — preventing the blood-clotting factors from functioning. The outcomes are, among others, increased morbidity and mortality.

The risk of forming alloantibodies is highest during the first 50 days of treatment of previously untreated hemophilia patients. Vaccinations and infections may increase the risk for production of inhibitory alloantibodies. Based on this, a 2010 consensus report recommended that subcutaneous (under the skin), rather than intramuscular, vaccination be used in hemophilia patients. However, some vaccination medicines are approved only for intramuscular injection.

Moreover, evidence from the PEDNET registry indicated that vaccinations given in close proximity to the factor substitution therapy did not increase the risk of inhibitory alloantibodies. Therefore, it has been suggested that vaccinations should be done after or in close proximity to factor substitution.

To understand how hemophilia patients were being vaccinated in Germany, a group of researchers analyzed the results of a survey that was sent to 40 physicians. The analysis revealed a large variation in the vaccination practices used on hemophilia patients.

Half of the physicians (53%) recommended the use of subcutaneous (under the skin) or intramuscular vaccination depending on the severity of the bleeding disorder. However, many physicians (28%) recommended that subcutaneous vaccination be used only, even for vaccines that have been approved specifically for intramuscular injection (33%).

“Only 13% recommend vaccinations strictly according to the approval status,” the authors wrote.

Rare side effects following subcutaneous vaccination were reported by 50% of the physicians, and no side effects were reported by 47%. For intramuscular vaccination, 69% of the physicians reported rare complications, and no complications were reported by 31%. The most common side effects after subcutaneous vaccination were local skin reactions, granuloma (small area of inflammation), bleeds, and fever. Following intramuscular vaccinations, the most frequent side effects were local skin reactions, bleeds, infections, local pain, and swelling.

Most (69%) of the physicians recommended a specific time interval between factor substitution and vaccination of hemophilia patients. However, the recommended time interval varied, and the majority of physicians advised a shorter time interval before intramuscular vaccination compared with subcutaneous injection. This may have been due to the potential bleeding risk that is associated with intramuscular vaccination.

However, 50% of the physicians recommended a time interval longer than 24 hours between factor substitution and intramuscular vaccination. This may indicate that these physicians prioritized the perceived risk of inhibitory alloantibody development over that of bleeding risk associated with intramuscular vaccination.

“Considering the data from the PEDNET Registry, there seems to be no evidence for an increased risk of inhibitor development, even in [previously untreated patients] being vaccinated within 24 hours after factor substitution. Hence, recommendations for vaccination practice in patients with haemophilia should be reassessed,” the researchers wrote.

They “believe these data can help to minimize the fear of vaccination as a potential danger signal and as bleeding risk,” and that “the importance of vaccination to prevent infections outweighs the associated risks in haemophilia patients all over the world.”

“To support this statement, further prospective randomized data are needed,” they concluded.