Secondary Hemophagocytic Lymphohistiocytosis in severe COVID-19 - a retrospective cohort study
Our study assessed the rate of secondary HLH (sHLH) in critically ill COVID-19 patients as well as their mortality, and found an average H-Score of 94 ± 51 points; 8.7% had a score of ≥ 169, thus testing positive for sHLH. A positive score was associated with increased mortality rates.Viral infections, sHLH, and mortalitySecondary HLH can occur associated with a variety of triggers, but the most important is viral infection. In 74%, sHLH is triggered by Epstein-Barr virus (EBV), which also has the poorest prognosis, followed by infections with Cytomegalovirus (CMV) and human herpes virus 8 (HHV-8) as main triggers. Regarding mortality, data are very heterogeneous: Ishii et al. reported a 5-year overall survival rate of over 80% for patients with EBV- or other infection-associated HLH in Japan (19); a recently published study reported an overall HLH mortality rate of 40% (20); and even higher mortality rates of around 57% (regardless of HLH aetiology or specific treatment) were reported in a large ICU cohort of patients diagnosed with HLH in France (10). Within this wide range lie the results of our study with a 28-day mortality of two-thirds of all patients with COVID-19 and a positive score.(S)HLH and (severe) COVID-19In contrast to other published studies, our patient population shows an average H-Score in the entire study collective of 94 ± 51 points, with 8.7% scoring ≥ 169 and thus testing positive for sHLH. In addition, we report significantly higher mortality rates (two-thirds of all patients). In hospitalized paediatric and adult patients with a proven diagnosis of COVID-19 (n = 193), Bordbar et at. described a median H-Score of 43.0 (IQR 0–63), and, in general, a higher score in those who need intensive care and died of COVID-19. (16) Data from 19 patients with COVID-19 requiring an ICU stay showed 2% with a H-Score ≥ 169, and 16% of all subjects in this study died. (9) The significantly higher mortality rates also suggest that the population analysed in our study was likely to have been much more severely affected by the underlying disease. High rates of invasive mechanical ventilation and bacterial superinfection also support this. Of note, when assessing established ICU scores such as APACHE II, SAPS II, and SAPS III, the respective mortality rates fit patients without HLH but not those with HLH (in whom mortality was much higher than predicted by the scores). Accordingly, the H-score could potentially be a better predictor of ICU mortality in severe COVID-19 than the mentioned ICU scores. This must be further investigated.sHLH versus severe COVID-19COVID-19 and sHLH (with cytokine release syndrome (CRS) or hyperinflammatory syndrome (HIS)) have parallels but are two different entities; sHLH may or may not be present in COVID-19. Moreover, the H-Score without directing it at evaluating HLH is likely not appropriate for detecting hyperinflammatory states in “pure” COVID-19 and also not suitable to make statements regarding outcome. (21–26) Temperature peaks of > 39 °C, leukopenia, very high levels of ferritin, hypertriglyceridaemia, and low levels of fibrinogen (all paramters from the H-Score) are, however, no typical clinical features of COVID-19: Common laboratory findings among hospitalized COVID-19 patients include lymphopenia (27) with a varying total WBC (28) and elevated inflammatory markers (e.g., ferritin). In a large study with 5700 hospitalized COVID-19 patients, only 31% had a temperature of > 38 °C at presentation, the ferritin was 798 (411–1515; reference range 15–400) ng/mL, and the WBC 7.0 (5.2–9.5) G/L (29). Other authors published ferritin levels of 139 (66–403) ng/mL, fibrinogen of 386 (129) mg/dL (= 3.86 g/L) (30), and median triglyceride concentrations between 0.96 and 1.94 mmol/L (= 85.0 or 171.7 mg/dL, respectively). (31–33)Bone marrow aspiration and potential hemophagocytosis featuresAs in previous literature (16), no bone marrow punctures were performed in our study collective (see Limitations). However, the limited available data predict a very high rate of hemophagocytosis in patients with both HLH and severe COVID-19: Bichon et al. reported a bone marrow hemophagocytosis for 91% of patients in a general ICU-HLH collective (10), and haemophagocytes with erythrophagocytosis were detected in 67% of a collective of deceased individuals with severe COVID-19 (18). If we assume the same 2/3 rate in our subjects, we would have a rate of patients with an H-score ≥ 169 of 16.8% (N = 35). An adjustment of the score could be considered in the future, considering among other things that a puncture is time-consuming, can be associated with complications and is not very specific.Clinical implications and future outlookThe findings support regular collection of the H-Score, especially for COVID-19 ICU patients. An automatic warning of an ICU IT solution when a certain limit value is exceeded could be considered to be mindful of potential worse outcomes and a potential trigger for specific therapeutic options. Automatic HLH screening could be conducted daily by artificial intelligence, for instance.Of note, our findings should be validated in another COVID-19 cohort which is vaccinated against SARS-CoV-2-.LimitationsThe main limitation of this study was the lack of bone marrow aspiration and imaging data, as no one had a puncture, and some imaging was not documented. Therefore, up to 73 points (21.7% of a maximum of total score of 337) are missing in the score results. The lack of bone marrow analyses and knowledge about organomegaly was due to the beginning of the pandemic, where little was known about COVID-19, let alone respective sHLH, and these diagnostics were simply not performed routinely.Furthermore, 37 patients had to be excluded because of transfers to other ICUs or IMCUs. These patients had a maximum H-Score of 126 at the time of transfer, which is significantly higher than the average of the collective examined in this study (94 ± 51 points). Also, the percentage with a positive score was higher (13.5 vs. 8.7%). A possible reason could be the lack of availability of veno-venous extracorporeal membrane oxygenation in the ICU of the study site, which is often the last therapeutic option in the most severe COVID-19 cases. In general, the single-centre nature of a study is always fraught with disadvantages.Moreover, the timepoint of patients presenting to the emergency medical services, the emergency department, and the ICU naturally varied, depending on incubation time, clinical courses, and also the patients’ subjective feelings. Therefore, the H-score was determined at different stages of the disease.With regard to mortality, there could also be confounding factors that were not taken into account and could therefore play a role. In particular, we did not have detailed information about the treatment, how much the patients had previously been affected in their lives, or the causes of mortality.
