Vaccination Rates in Primary Immune Thrombocytopenia Adult Patients Exposed to Rituximab or Splenectomy. a Nationwide Population-Based Study in France
Authors: Moulis Guillaume , Lapeyre-Mestre Maryse , Montastruc Jean-Louis , Godeau Bertrand , Sailler Laurent 
Published: October 2019

Abstract
Background: International guidelines on immune thrombocytopenia (ITP) management recommend vaccination against Streptococcus pneumoniae (S.p.), Haemophilus influenza b (Hib) and Neisseiria meningitidis (N.m.) before splenectomy. French guidelines, published in 2009, state that these vaccines should be administered at least two weeks before splenectomy. They also recommend these vaccinations at least two weeks before rituximab, because 80% of rituximab-treated patients may relapse and may be candidate to splenectomy, while seroconversion is compromised the semester following rituximab. The aim of this study was to assess the application of these recommendations in France.
Methods:The study was conducted in the database of the French national health insurance system (SNIIRAM). The French Adult Immune Thrombocytopenia: a French pHarmacoepidemiological study (FAITH, n°ENCEPP/SDPP/4574) is aimed at following in the SNIIRAM the cohort of all incident primary persistent or chronic ITP adult patients treated in France from 2009. The SNIIRAM collects prospectively all data regarding hospitalizations, disabling diseases, drug and procedure reimbursements. They are linkable with demographic data. On the 2009-2011 SNIIRAM data, ITP patients were identified with hospital and disabling disease diagnosis codes (D69.3 code of the International Classification of diseases, version-10 – ICD-10). The date of diagnosis was refined thanks to out-hospital drug exposures. Secondary ITPs were excluded thanks to diagnosis codes of diseases associated to ITP, searched in the year before and the semester after the diagnosis. We restricted to incident patients, excluding those with a diagnosis during the first semester of the study. Lastly, the FAITH cohort includes the patients persistently treated (at least three monthly consecutive dispensing of ITP drug, or exposure to rituximab or splenectomy).
Among the 1106 patients of the FAITH cohort identified from July 2009 to June 2011, 427 non-splenectomized patients were exposed to rituximab and 178 underwent splenectomy (67 out of these had been previously exposed to rituximab).
We assessed vaccine exposure to S.p., Hib and N.m. and detailed the moment of vaccinations. Vaccination was said “recommended” when it occurs prior to 2 weeks before rituximab or splenectomy. Other indications for vaccination (e.g. chronic pulmonary disease for S.p.vaccine) were searched through disabling diseases and in-hospital diagnosis codes before exposure to rituximab or splenectomy, using validated ICD-10 algorithms.
Results: Among the 423 non-splenectomized patients exposed to rituximab, 137 (31.6%) were vaccinated against S.p., 80 (18.9%) against Hib, and 16 (3.8%) against N.m. Only 54 (12.8%) patients benefitted from a recommended vaccination against S.p. A similar pattern of recommended/non-recommended vaccination was observed for Hib and N.m. vaccines. Among the patients vaccinated after the first rituximab infusion, 28.5% (S.p.), 33.7% (Hib) and 37.5% (N.m.) were vaccinated during the 6 months following rituximab, corresponding to the time of maximal B-cell depletion. Forty-one patients (9.7%) had another reason for being vaccinated (mainly heart failure, n=23 and chronic pulmonary disease, n=13). Among them, 6 were vaccinated against S.p., 3 against Hib and none against N.m.
Among the 111 splenectomized patients not previously exposed to rituximab, vaccination rates were 52.2% for S.p., 30.6% for Hib and 8.1% for N.m. When vaccinated against S.p., most patients (90.6%) benefitted from a recommended vaccination schedule (80.9% and 81.8% for Hib and N.m. vaccinations, respectively).
Among the 67 patients exposed to rituximab before splenectomy, vaccination rates were 64.2% for S.p., 38.8% for Hib and 10.5% for N.m. Among S.p vaccinated patients, 79.6% had a recommended vaccination schedule before splenectomy (70.3% and 77.8% for Hib and N.m. vaccinations, respectively). However, 53.3 % of these recommended vaccinations occurred during the semester following a rituximab infusion (maximal B-cell depletion period).
Seven of the 178 splenectomized patients had another reason for being vaccinated. Among them, 4 were vaccinated against S.p. and Hib, and 1 against N.m.
Conclusions: Vaccination coverage is low before splenectomy or rituximab in ITP patients in France. Most of the vaccinations are dispensed during a non-recommended period.

Disclosures
No relevant conflicts of interest to declare.