To the Editor,
1.
The spleen is one of the first organs injured in sickle cell disease (SCD) [1]. Splenic impairment in SCD children can silently progress toward functional asplenia, exposing patients to an increased risk of invasive bacterial infections, or it can manifest abruptly as acute splenic sequestration crisis (ASSC), a life‐threatening event whose recurrence may justify a splenectomy [1]. In recent years, subtotal splenectomy has emerged as an alternative to total splenectomy with the aim of preserving splenic functions, including clearance of pathogenic erythrocytes and protection against bacterial infections. However, some studies have reported that subtotal splenectomy may lead to a higher incidence of intraoperative and postoperative complications [2]. Furthermore, concerns persist regarding the lack of significant long‐term benefit of subtotal over total splenectomy, as progression of SCD usually results in auto‐splenectomy of the remaining spleen tissue [3, 4].
We conducted a single‐center retrospective study in a French university hospital to compare clinical outcomes and splenic function, assessed by pocked red blood cell (RBC) count [5], in SCD children after total versus subtotal splenectomy (supporting information). Between January 2010 and December 2022, 68 SCD patients underwent splenectomy in our hospital to prevent recurrence of ASSC. Among them, 38 underwent subtotal splenectomy and 30 total splenectomy (Table S1). Children who underwent subtotal splenectomy were younger (median age 4.6 [3.9–5.7] years vs. 5.8 [4.6–9] years, p = 0.01), and had a higher incidence of ASSC before surgery (median annual rate 0.46 [0.32–0.78] vs. 0.37 [0.12–0.49], p = 0.02) compared with those who underwent total splenectomy. No other significant differences were observed between the two groups.
We first compared early postoperative outcomes during hospitalization for splenectomy (Table S2). Postoperative fever was more frequent in the subtotal splenectomy group (47% vs. 7%, p < 0.001), possibly reflecting the release of pro‐inflammatory cytokines by the remaining splenic tissue. In patients requiring morphine, the median duration of treatment was longer after subtotal splenectomy than after total splenectomy (3 [2–4] days vs. 1 [1] day, p = 0.01). Also, the median length of stay in the intensive care unit was longer in the subtotal splenectomy group (3 [1.5–3] days vs. 1 [1] day, p = 0.04).
We then compared the incidence of vaso‐occlusive crisis (VOC) and acute chest syndrome (ACS) during the first and second year following splenectomy between the two groups (Table S3). During the first year, patients who underwent subtotal splenectomy experienced more episodes of VOC (mean 1.6 ± 1.5 vs. 0.8 ± 1.2, p = 0.02) and ACS (mean 0.6 ± 0.8 vs. 0.1 ± 0.4, p = 0.01). By contrast, during the second year, no difference was observed between the two groups. In addition, the temporal distribution of vaso‐occlusive events (VOC and ACS) during the 2 years following splenectomy was analyzed, using successive 3‐month time windows (Figure 1). This analysis revealed a higher proportion of patients experiencing VOC or ACS in the subtotal splenectomy group during the early postoperative period, particularly during the first 9 months, after which the proportion decreased to become comparable to that of the total splenectomy group. Of note, 57% of the patients who experienced a vaso‐occlusive event within the first 3 months following splenectomy also experienced VOC or ACS in the next 3 months and 38% of them experienced another vaso‐occlusive event between 6 and 9 months after splenectomy, highlighting the increased risk of recurrence of VOC and ACS in the months following a first vaso‐occlusive event. Because inflammation is a well‐known trigger of vaso‐occlusion, this increased risk observed in the first months after subtotal splenectomy might be due to increased postoperative inflammation. Patients who underwent subtotal splenectomy likely also had more severe SCD, as suggested by younger age at splenectomy and higher incidence of ASSC before surgery.
FIGURE 1.
Temporal distribution of vaso‐occlusive events after subtotal versus total splenectomy. Bars represent the percentage of patients experiencing at least one vaso‐occlusive event (VOC or ACS) over successive 3‐month periods during the 2 years following splenectomy. Lines indicate the corresponding temporal trends.
Bacterial infections during the 2 years following splenectomy consisted of 8 pneumonias, 3 arthritis, 2 tonsillitis, 2 pyelonephritis, and 1 Serratia marcescens bacteremia in the subtotal splenectomy group, and 8 pneumonias, 1 pleuropneumonia, 1 arthritis, 1 tonsillitis, and 1 Streptococcus oralis septicemia in the total splenectomy group. No significant difference was observed between the two groups regarding the incidence of bacterial infections (Table S4). This might be explained by the relative rarity of these complications in patients treated with rigorous penicillin prophylaxis and pneumococcal vaccinations. However, an increased risk of pneumococcal infection after surgical splenectomy has been reported in SCD children [6], and multicenter studies will be needed to determine if subtotal splenectomy can mitigate this risk in the context of new circulating highly invasive pneumococcal serotypes.
No significant difference was observed between the two groups for hemoglobin level (8.4 [7.8–9.2] g/dL vs. 8.7 [7.5–9.6] g/dL, p = 0.89) and platelet count (423 [372–522] G/L vs. 446 [360–558] G/L, p = 0.74), measured 1 year after splenectomy. However, a higher proportion of patients were treated with hydroxyurea (82% vs. 20%, p < 0.001) in the subtotal splenectomy group, which may have increased their hemoglobin level. Annual ultrasounds of the spleen revealed no splenic regrowth in either group.
Pocked RBC counts were measured between January 2021 and August 2023 in 54 patients who had given their consent for an assessment of residual splenic function, 32 after subtotal splenectomy and 14 after total splenectomy. To enrich the analysis, 8 additional patients who underwent total splenectomy in other French centers before being followed in our hospital were included (Table S5 and Figure S1). The longer median time between surgery and pocked RBC measurement in the total splenectomy group (7.9 [5.4–9.6] years) compared to the subtotal splenectomy group (2.8 [1.8–4.6] years) was due to the retrospective nature of the study, with a gradual shift in practices toward subtotal splenectomy during the study period. However, the length of this delay in the total splenectomy group was considered inconsequential as a change in splenic function over time was not expected after total splenectomy. Patients with subtotal splenectomy had significantly lower pocked RBC percentages, measured by differential interference contrast (DIC) microscopy, than those with total splenectomy (39.5 [30–46] vs. 44.2 [41–49] %, p = 0.02) (Figure 2). A majority (53%) of patients in the subtotal splenectomy group had pocked RBC percentages within the hyposplenic range, defined by pocked RBC count ≤ 40% [5], whereas a majority (77%) of those in the total splenectomy group presented profiles consistent with functional asplenia (> 40%). Similar results were obtained by imaging flow cytometry (IFC) (Figure S2).
FIGURE 2.
Pocked RBC percentages measured by DIC according to the type of splenectomy. In the subtotal splenectomy group (n = 32) and the total splenectomy group (n = 22), each dot represents an individual patient. Median values and interquartile ranges are shown by the boxplots. Dashed horizontal lines indicate thresholds corresponding to normal splenic function (< 10%), hyposplenism (10%–40%), and asplenia (> 40%).
Among the 32 patients who underwent subtotal splenectomy and in whom pocked RBC counts were measured by DIC microscopy, 11 patients had two successive measurements with a median interval of 1.9 [1.4–2.0] years (Figure S3). Eight patients (73%) showed a decrease in the percentage of pocked RBCs, while 3 (27%) showed an increase, with no statistically significant difference between the two measurement times. Similar results were obtained by IFC (Figure S4). These findings are encouraging as the 2 years following splenectomy represent a critical period of high vulnerability to severe invasive bacterial infections. Indeed, recent alerts about pneumococcal meningitis have reminded the medical community of the high vulnerability of SCD patients, particularly before the age of 5, even with strict prophylactic measures. Therefore, partial preservation of splenic function after subtotal splenectomy could offer valuable protection during this high‐risk period. Furthermore, the recent demonstration that, despite signs of hyposplenism, the spleen of children with SCD can retain its ability to clear pathological erythrocytes, strengthens the rationale for spleen preservation strategies aimed at maintaining, at least partially, splenic filtration function [5]. In a retrospective study of 188 SCD children who underwent total splenectomy, the authors found that splenectomy before the age of 3 years was associated with an increased incidence of cerebral vasculopathy [1]. This could reflect a more severe disease phenotype, but could also reflect a deleterious effect of circulating altered RBCs, no longer retained in the spleen, on the endothelium of cerebral vessels after early total splenectomy.
Our results challenge those of a previous study of 9 SCD patients, in which the median time to loss of splenic function after subtotal splenectomy was only 12 months [3]. However, the median age at splenectomy in this study was particularly high, of 11 years compared to 4.6 years in our study, which may explain the discrepancy in these results. Also, splenic function was assessed using a less robust technique, based notably on remnant spleen perfusion by ultrasound.
In conclusion, our data suggest that splenic function can persist, at least partially, beyond the first postoperative years in children who underwent subtotal splenectomy at a young age, before the natural progression to functional asplenia. The benefit of subtotal splenectomy in preserving splenic function may, however, be limited for patients with signs of early functional asplenia. Therefore, the choice between subtotal and total splenectomy could depend in part on pocked RBC measurement. To limit postoperative vaso‐occlusive events after splenectomy, achieving a preoperative HbS level of less than 30% should be considered. Also, continuing transfusion therapy in the first few months following surgery, while increasing hydroxyurea to the maximum tolerated dose, may be discussed.
Future multicenter prospective studies, ideally stratified according to initial splenic function and hydroxyurea exposure, are needed to determine the optimal modalities for subtotal splenectomy in SCD children.
Author Contributions
A.A., A.S., C.C., P.B., and S.A. collected, analyzed, interpreted data, and wrote the manuscript. C.C., M.M., V.B., J.B., M.B., C.R., L.D., and A.C. helped in the discussions, assisted in writing, and finalized the manuscript.
Funding
This work was supported by state funding from the Agence Nationale de la Recherche ANR (RS30J20ANR29_SPLEENMARK) and the National Institutes of Health NIH (contract R21087HH).
Ethics Statement
The study was approved by a medical ethics committee (GR‐Ex/CPP‐DC2016‐2618/CNIL‐MR01).
Consent
Written informed consent was obtained from all children's parents or legal guardians.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Patient characteristics at the time of splenectomy.
Table S2: Early postoperative clinical outcomes during hospitalization for splenectomy.
Table S3: VOC and ACS during the first and second year following splenectomy.
Table S4: Bacterial infections during the first and second year following splenectomy.
Table S5: Characteristics of patients who underwent total splenectomy in other centers.
Figure S1: Patient flowchart.
Figure S2: Pocked RBC percentages measured by IFC according to the type of splenectomy. In the subtotal splenectomy group (n = 26) and the total splenectomy group (n = 19), each dot represents an individual patient. Median values and interquartile ranges are shown by the boxplots. Dashed horizontal lines indicate thresholds corresponding to normal splenic function (< 10%), hyposplenism (10%–40%), and asplenia (> 40%).
Figure S3: Intra‐patient evolution of pocked RBC percentage, measured by DIC microscopy, after subtotal splenectomy. Each pair of dots connected by a line represents an individual patient (n = 11).
Figure S4: Intra‐patient evolution of pocked RBC percentage, measured by IFC, after subtotal splenectomy. Each pair of dots connected by a line represents an individual patient (n = 9).
Acknowledgments
The authors thank Sandra Manceau and the InIdex GR‐Ex. They also thank the patients and their parents, who agreed to participate in this study. Open access publication funding provided by COUPERIN CY26.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Patient characteristics at the time of splenectomy.
Table S2: Early postoperative clinical outcomes during hospitalization for splenectomy.
Table S3: VOC and ACS during the first and second year following splenectomy.
Table S4: Bacterial infections during the first and second year following splenectomy.
Table S5: Characteristics of patients who underwent total splenectomy in other centers.
Figure S1: Patient flowchart.
Figure S2: Pocked RBC percentages measured by IFC according to the type of splenectomy. In the subtotal splenectomy group (n = 26) and the total splenectomy group (n = 19), each dot represents an individual patient. Median values and interquartile ranges are shown by the boxplots. Dashed horizontal lines indicate thresholds corresponding to normal splenic function (< 10%), hyposplenism (10%–40%), and asplenia (> 40%).
Figure S3: Intra‐patient evolution of pocked RBC percentage, measured by DIC microscopy, after subtotal splenectomy. Each pair of dots connected by a line represents an individual patient (n = 11).
Figure S4: Intra‐patient evolution of pocked RBC percentage, measured by IFC, after subtotal splenectomy. Each pair of dots connected by a line represents an individual patient (n = 9).
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.