Early mortality remains significantly high in HLH patients. To characterizing HLH patients who were deceased within a short time after hospital administration, and to identify risk factors associated with early mortality, we examined clinical features among 160 HLH patients. The 7-day and 30-day OS were 88.8 and 70.1%, respectively. The identified strong risk factors (OR > 10 and p < 0.05) for 30-day mortality were myocardial damage, severe pneumonia, respiratory failure, coagulopathy, gastrointestinal disorder, and MODS. And the identified strong risk factors for 7-day mortality were sepsis, myocardial damage, shock, and respiratory failure.
In the HLH-2004 study, the estimated 5-year probability of survival was 61% (95%CI: 56, 67%) [8]; and 34 of 369 patients (9.2%) died without HSCT within the first 28 days of treatment. In our patient cohort, the 30-day OS was 70.1%. We identified another two large case series of pediatric HLH in Chinese population (n = 116 and 95), where the 30-day OS were 86 and 83.2%, respectively [9, 10]. By contrast, our 30-day OS was lower, possibly because over 40% of our patients were directly admitted to PICU at hospital admission. Many HLH patients admitted to the PICU because of delayed diagnosis or clinical features like persistent fever, hepatosplenomegaly, organ dysfunction, and neurological symptoms [3, 4, 16], and without timely diagnosis and treatment the mortality of HLH could be especially high. A PICU-based study in United State found that of 33 HLH patients [16], 26 (79%) survived to hospital discharge, and the 1-year OS was 58%. Although 30-day OS or OS at longer follow up were reported by many studies, fewer studies have reported the short-term survival of HLH. In the HLH-2004 study, among the 34 patients that died without HSCT and within the first 28 days of treatment, 17 (50%) died within the first ten days [8]. In our study, among the 46 HLH patients that died within 30 days after admission, 18 (39.1%) were died within the first seven days. Thus, to improve overall survival of HLH, it is important to investigate features of early death and to find targeted treatment strategies.
Our study found age was not significantly associated with 30-day mortality, which is consistent with previous reports [9, 14]. However, we observed that age younger than 12 months was associated with higher risk of 7-day mortality (OR = 3.53, 95%CI = 1.17, 10.67), suggesting infants with HLH should be identified as at higher risk of early death.
EBV-HLH has a high incidence in East Asian countries [12, 15, 17,18,19]. In our HLH patient cohort, 55% of patients were EBV infection positive. And our results showed that compared with HLH triggered by other causes, patients with EBV had lower risk of early death. This finding is in line with previous studies that showed the majority of promptly treated EBV-HLH patients usually have a good outcome [17, 18]. In our cohort, 60.6% patients fell within the diagnosis of sepsis, 53.8% patients were diagnosed with infection-confirmed sepsis, and 30% patients were diagnosed with both sepsis and EBV infection. Distinctions between severe sepsis and HLH remain blurred [20]. As the current diagnose criteria of HLH and sepsis are overlapped [1, 21], it is difficult to interpret the high rates of sepsis diagnosis among HLH patients: whether HLH and sepsis are overlapped conditions with or without causal relationship, or it is HLH mimicking features of sepsis. Studies have noticed that secondary HLH, both pediatric and adult forms, and severe sepsis share clinical and laboratory inflammatory phenotypes [20, 22]. Our results showed that the sepsis-like HLH was significantly associated with 7-day and 30-day mortality. Therefore, to improve treatments outcomes of this special and devastating form of HLH, it is critical for further researches to investigate the etiology of sepsis-like HLH and develop better therapeutic protocols.
Our investigations identified a variety of clinical features that significantly associated with early mortality, which were consistent with previous study findings [9,10,11,12,13,14,15, 23, 24]. What our study adds to the existing list of risk factors is their associations with 7-day outcome. Sepsis, myocardial damage, shock, and respiratory failure were found to be strongly associated with 7-day mortality (OR > 10, p < 0.05). Moreover, patients deceased within 7 days have all developed MODS. Since HLH first presents with a spectrum of non-specific symptoms, and can rapidly progress to multisystem organ failure, patients admitted to a tertiary hospital and/or a PICU could have already developed MODS [25]. We also observed that the number of risk factors was inversely associated with survival time. Notably, patients who deceased within 7 days had at least 4 risk factors, with the median number of 9, while patients survived longer than 30 days had a median number of 2 risk factors. The development of a series of abnormalities could be partially due to delayed diagnosis or treatment, yet could also be due to unresponsive to standard therapy [3].
Making a timely diagnosis and initiating adequate HLH-directed treatment strategies are the current challenges for treating patients with HLH [3, 5]. The present treatment strategy of HLH is controlling the hyperactivated immune system and supportive care; and HSCT is currently the only option for long-term cure for patients with familial, relapsing, or severe and persistent HLH [1, 3, 26]. The HLH-94 protocol included an 8-week initial therapy [6, 26]. Salvage therapy should be considered if partial response was not observed in patients within 2–3 weeks of therapy initiation [3, 26]. Our study showed that 39% of early death occurred within 7 days after hospital admission; these patients were present with a series of severe abnormalities and fewer patients in this groups received chemotherapeutic drugs. Early death before the initiation of chemotherapy were largely due to late diagnosis of HLH and rapid deterioration; and in some of the most severe cases, parents refused chemotherapy. Together with the standard treatment strategies, multidisciplinary discussion of salvage therapy were arranged for most of these patients, even so, failure to rescue demonstrated the need for more prompt diagnosis, earlier initiation of chemotherapy, as well as better treatment strategies.
Strengths of this study includes that it included a relatively large number of patients for a rare disease, and it described a variety of concomitant diagnoses. To our knowledge, this is the first study that summarized the characteristics of HLH patients who deceased within 7 days after hospital admission. Our findings provide references for the identification of high risk patients, and also reveal the need for future treatment improvements. Our study has several limitations. First, this is a single center study, in which selection bias would have affected the features of patients. The Hunan Children’s Hospital is the only tertiary referral children’s hospital in Hunan Province of China. Children identified as high risk patients in Hunan region tend to be admitted or transferred to this hospital, and this might partially explain the higher mortality among our HLH cohort. Besides, the Hunan Children’s Hospital was undertaken a national treatment and care program for sepsis, which could affect the proportion of concomitant sepsis among HLH patients. Second, as a retrospective study, the selection of study variables was depend on the data availability, resulting in missing some potentially important factors. One of the most important missing information was genetic test results for primary HLH. In our study, primary HLH was diagnosed and recorded if a family history of HLH was reported and/or a molecular diagnosis of HLH was made; however, the genetic tests were conducted by third-party companies and the test results were not documented in the medical records; therefore, these information were missing in our analysis. As genetic testing for familial HLH mutations was not routinely checked, the proportion of primary HLH could have been underestimated. Nevertheless, because HLH-associated gene defects are not fully understand yet, and it usually takes more than weeks to get genetic test results, initial treatment should not be delayed or altered because of the categorization of “primary” or “secondary” HLH [3]. Also, NK-cell activity and soluble CD25 were not routinely checked, which could lead to missed diagnosis of HLH in our hospital. Third, although the sample size was relatively large for such a rare disease, our results could still subject to sparse data bias because the lack of adequate case numbers for some combination of factors and outcome levels [27]. For example, the 95%CI for the OR of concomitant sepsis and the risk of 7-day mortality was 1.71–101.72. The wide CI was resulted in sparse data and should be interpreted with caution. Multi-center studies with larger sample size will enable more accurate estimations.
