To our knowledge, this retrospective study is the first systematic study on the incidence, risk factors, distribution and outcome of pleural effusion in sHLH. In the present study, we observed the distribution and possible mechanism of pleural effusion in sHLH. Furthermore, we demonstrated that pleural effusion on admission was associated with worse survival in sHLH.
Pleural effusion was found in 58.6% of the studied sHLH population at diagnosis, a higher percentage than the range of previously reported data for critical illness and haematologic malignancies[11, 12]. The higher incidence of pleural effusion in sHLH patients, similar to that of previous imaging characteristic analyses, may be due to their high inflammatory state.[13]. In recent years, mounting evidence has indicated that pleural effusion is common in paediatric or adult patients with HLH[7, 14]. Our findings suggest that pleural effusion developed more often in patients with lower PLT counts, HB and ALB levels and higher sCD25 levels. Moreover, through multivariate analyses, we determined that PLT ≤ 65×109/L and high levels of sCD25 were associated with an increased risk of pleural effusion.
It is well known that platelets and sCD25 play an important role when evaluating sHLH and are the diagnostic criteria set in the HLH-2004 criterion[15]. On the one hand, cytopenia, especially persistent severe thrombocytopenia, is a key laboratory marker of HLH and is mainly related to severe cytokine-mediated inflammation[6, 16]. Reportedly, the rapid onset of cytopenia suggests a consumptive process critically driven by TNF-α and INF-γ. At the same time, uncontrolled activation of macrophages will result in phagocytosis of platelets and other haematopoietic components by macrophages[16, 17]. Furthermore, previous studies have suggested that persistent thrombocytopenia is significantly associated with death[18]. On the other hand, sCD25 is the most studied cytokine/cytokine receptor to date in HLH and is considered a sensitive diagnostic test and disease marker[19]. Indeed, a high level of sCD25 linked the diagnosis of adult HLH with the defining features of hypercytokinemia[20]. Platelets and sCD25 can serve as diagnostic and disease markers in sHLH, and it is reasonable to presume that pleural effusion at diagnosis may be associated with higher inflammation in sHLH. Additional pleural effusion can develop during sHLH, especially at initial diagnosis, and should be considered when evaluating individual patients. Its elevation accompanied the severity of the disease. Therefore, maintaining awareness of the possibility of pleural effusion is important, especially in sHLH patients with significantly decreased haemoglobin, platelet, and albumin and significantly elevated sCD25.
Although the pathogenesis of sHLH-induced pleural effusion remains to be systematically investigated, three different theories have been proposed to offer some mechanistic insights. One theory, to which the authors subscribe, holds that the onset of pleural effusion is caused by excessive inflammatory cytokines resulting from HLH, though the association between pleural effusion and a higher inflammatory state was not sufficiently substantiated. In this theory, the release of a large number of inflammatory factors leads to widespread increases in vascular permeability that can result in progressive subcutaneous and body cavity oedema, including pleural effusion[21]. Previous studies have suggested that cytokines and other inflammatory mediators could induce gaps between endothelial cells by disassembling intercellular junctions, altering the cellular cytoskeletal structure, or directly damaging the cell monolayer. This creation of gaps can result in microvascular leak and pleural effusion[21–23]. Moreover, HLH was also described in severely ill patients during the COVID-19 pandemic, presenting with vascular injury resulting from hyperinflammation in the alveoli[24]. In one study, Weaver et al[25] reported that hyperinflammation, rather than hemophagocytosis, appears to be the driving cause of HLH pathology. As fluid retention events have been more frequently reported in pleural effusion patients, the second theory holds that it is tempting to attribute the occurrence of pleural effusion to a class effect on fluid overload, especially hypoproteinaemia[26]. However, an immune-mediated mechanism is more likely responsible for the sHLH-related pleural effusion, as our multivariate analysis has reported. The third theory holds that EB virus plays a role in the pathogenesis of pleural effusion, either by a direct cytopathic effect or uncontrolled immune response[27]. Instead, we obtained evidence that the incidence of pleural effusion in patients with different aetiologies of sHLH was not statistically significant.
We reviewed the radiological reports at diagnosis of 162 patients with sHLH, noting any presence of pleural effusion and its extent (minimal, moderate, or massive). A notable observation in our study was that pleural effusion often occurs early in the disease, and the incidence of early-onset effusion (58.6%) was higher than that of late-onset effusion (11.7%). Pleural effusion may be the first presentation of sHLH or may develop during the course of the disease. Although these findings need to be further validated, our results suggest that the early onset of pleural effusion and its association with HLH severity support a direct link to HLH or suggest that pleural effusion is in part due to HLH itself. A second finding in our study was the observation that pleural effusion at diagnosis in sHLH is characterized by minimal amounts and bilaterality. The present results were consistent with two paediatric HLH studies indicating that bilateral lung infiltrates and pleural effusions were the most common findings in HLH according to chest imaging[13, 28]. Additionally, the incidence of pelvic effusion, pericardial effusion, and ascites in sHLH patients with pleural effusion was higher than that in patients without pleural effusion. Moreover, only three of the 95 patients with pleural effusion in this study underwent pleural puncture and drainage. The reason was that most patients with sHLH were accompanied by severe hypothrombocytopenia and coagulation dysfunction, which increased the risk of bleeding. According to Light’s standard, the effusion samples of the three patients with sHLH was exudative effusion. There were no obvious abnormalities in biochemical, tumor markers, tuberculosis, bacterial culture and exfoliated cells of pleural effusion. Due to the small sample size, this paper cannot summarize the biochemical indexes and cytological characteristics of sHLH combined with pleural effusion.
More recent studies have shown that pleural effusion is an important prognostic factor for overall survival in critically ill patients and those with haematologic malignancies[29, 30], and at face value, this appeared to offer a more logical explanation for our present findings. It is generally believed that the prognosis of sHLH is known to be heavily dependent on the aetiology and treatment. However, based on fragmentary evidence, it appears that pleural effusion was an ominous sign[31]. Obviously, the relationships between pleural effusion and outcome are poorly understood, and only a few cases have been reported[32]. Benmiloud et al[33] described a boy presenting with HLH as an initial manifestation of Hodgkin’s lymphoma whose state worsened with the onset of pleural effusion. Our study showed that the presence of pleural effusion was independently associated with worse survival among patients with sHLH, and therefore, deeper knowledge of pleural effusion in sHLH is important for guiding physicians to evaluate the condition and formulate treatment in these patients. In addition, the results strongly imply that patients with moderate to massive amounts of pleural effusion have worse survival than patients with minimal amounts of pleural effusion, although no significant difference was present. Currently, there is no specific treatment for pleural effusion in sHLH, and active treatment of primary disease based on fluid therapy is a key measure. In our study, all 95 patients with pleural effusion received active treatment for the primary diseases and appropriate supplementation with diuretics, oxygen therapy, colloidal fluid and crystalloids. Furthermore, after the initial effective treatment of HLH, pleural effusion can be improved or disappear.
Our study also suffers from some limitations. First, the results are a retrospective cohort study from a single center, which may not be representative of the general sHLH population. Nevertheless, this also implies an advantage in terms of consistency in diagnosis, treatment and follow-up. Second, pleural effusion levels are a dynamic process, and their analyses did not account for development over time. Thus, our results must be interpreted with some caution.