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Lymphopenia in Patients with Hemophagocytic Lymphohistiocytosis: Are B Cells Suppressed in These Patients?
Hemophagocytic Lymphohistiocytosis (HLH) is an immune regulatory disorder requiring allogeneic hematopoietic stem cell transfusion (HSCT) for long-term survival. More importantly, it is imperative to initiate treatment early as delays in treatment can be associated with significant mortality. Unfortunately, there can be significant overlap of the HLH diagnostic criteria with other non-HLH conditions, thereby considerably delaying diagnosis and therapy for HLH. Hence, surrogate markers are needed to aid in the diagnosis and prevent delays in initiating therapy in this life threatening disorder. Hypogammaglobulinemia has been a less commonly reported feature of HLH. It has been reported in SAP deficient patients +/- HLH. More recently, it has been reported in a few patients with XIAP deficiency and STXBP2 mutations in association with colitis. We have observed B-cell lymphopenia as well as hypogammaglobulinemia in patients with HLH at our institution. However, the actual incidence is not clear. In addition, lymphocyte subsets at presentation have not been investigated so far in HLH. Hence, we decided to retrospectively analyze lymphocyte subsets and quantitative immunoglobulin levels in additional to traditional diagnostic markers at presentation in patients with HLH.
Methods
We retrospectively analyzed the medical records of patients who received a diagnosis of HLH at our institution, believed to be familial or secondary HLH. Patients with SAP deficiency were excluded as hypogammaglobulinemia is a known association. Patients who had received HLH therapy prior to evaluation of lymphocyte subsets and immunoglobulin levels were also excluded from the analysis. Data at presentation was evaluable in 35 patients.
Results
Of the 35 patients, 26 had familial HLH and 9 had secondary HLH. 25 patients underwent allogeneic HSCT. Seven died secondary to complications post HSCT and 1 patient died prior to HSCT from refractory HLH. Identifiable genetic mutations associated with HLH were found in 20 patients. Analysis of their immune phenotype in additional to the diagnostic criteria revealed the following: 19(54%) had B-cell lymphopenia, including 7(20%) who had both T-cell and B-lymphopenia. 3(8%) patients had T-cell lymphopenia. Even in patients with B and T cell lymphopenia, the B-cell lymphopenia was proportionately lower. Hypogammaglobulinemia (low IgG levels) was seen in 4 patients.
Discussion
Although we noted hypogammoglobulinemia in a few patients, the predominant finding was the high incidence of B-cell lymphopenia. Interestingly, B-cell lymphopenia and hypogammaglobulinemia have also been noted perforin deficient mice with HLH at our institution (unpublished data). In conclusion, this study suggests that B-cell lymphopenia can serve as a surrogate marker for the diagnosis of HLH.