Several scoring systems have been designed.[2,9] The Hscore postulated by Fardet et al[5] makes a quick evaluation possible. anakinra was developed and administered. Outcomes: One patient survived the ICU stay. Two other patients, in whom sHLH was diagnosed too late, deceased. Lessons: A routine testing of COVID-19 patients for secondary HLH by using the HScore is usually feasible; especially those patients deteriorating clinically with Tebuconazole no sufficient response to shock management might be at particular high risk. A stepwise therapeutic approach comprising corticosteroids, immunoglobulins and anakinra, accompanied by immunoadsorption, may dampen cytokine storm effects, and potentially reduce mortality. Keywords: coronavirus disease 2019, hemophagocytic lymphohistiocytosis, macrophage activation syndrome Key Points Secondary hemophagocytic lymphohistiocytosis may be highly prevalent in critically-ill COVID-19 patients not responding to shock management. A stepwise treatment regimen of corticosteroids, immunoglobulins, anakinra, and immunoadsorption may dampen cytokine storm effects, and potentially reduce mortality. 1.?Introduction A sepsis-like clinical picture has repeatedly been reported in coronavirus disease 2019 (COVID-19), creating a yet not fully understood syndrome. Tebuconazole Hyperinflammation, cytokine storm, and secondary hemophagocytic lymphohistiocytosis (sHLH) are discussed as aggravating factors.[1,2] Both sHLH mortality rates in non-COVID-19 patients (around 40%) and in critically-ill COVID-19 patients (around 65%) are high, and viral infections are known as sHLH triggers.[1,2] Immunosuppression has been suggested as a treatment option,[3,4] and first reports are promising.[1] In this context, more data on clinical management of sHLH triggered by COVID-19 are urgently expected 2.?Methods 2.1. Patients We examined COVID-19 patients admitted to an intensive care unit in Vienna, Austria between April and May 2020, who were diagnosed with sHLH. Patients clinical-, imaging-, and laboratory data (observe Supplements, http://links.lww.com/MD/F969 and the supplemental figure, http://links.lww.com/MD/F968) were assessed. 2.2. SARS-CoV-2 diagnosis Testing for the presence of severe acute respiratory syndrome coronavirus 2 RNA in pharyngeal or tracheal respiratory specimens was performed by Real-Time qPCR. Positive results (Ct value >35) were confirmed by repeated screening. 2.3. sHLH diagnosis sHLH was diagnosed using the HScore:[5] Nine variables are assessed: core heat, hepato- and/or splenomegaly, quantity of cytopenias, levels of TG, fibrinogen, ferritin and ASAT, history of immunosuppression, and (if feasible) presence of bone marrow haemophagocytosis. A positive result yields a 93% sensitivity and 86% specificity for HLH. 2.4. Immunosuppressive therapy Immunosuppressive CD84 treatment for sHLH was conducted in a stepwise approach: 1. 1?g of methylprednisolone intravenously once daily for 3 days, 2. 1?g/kg of Pentaglobin (50?mg/ml human plasma protein containing 95% of immunoglobulin [6?mg IgM, 6?mg IgA, 38?mg IgG], Tebuconazole Biotest Corp., Dreieich, Germany) via continuous infusion over 48?hours, 3. 200?mg of anakinra subcutaneously twice daily until clinical improvement. Anakinra was used as an off-label salvage treatment. 2.5. Patient consent and ethical evaluate All data have been anonymized. Informed consent for publication of anonymized data from the patient or their relatives have been obtained. Ethical review was not necessary for case reports following local respective guidelines. 2.6. Patient 1 A 51-12 months aged male (BMI 26.2) with a fever for 6?days was hospitalized due to respiratory failure and tested positive for SARS-CoV-2. Showing acute respiratory distress syndrome (ARDS), he was intubated and mechanically ventilated. Acute kidney injury (AKI) necessitated continuous renal replacement therapy (CRRT), upgraded with an immunoadsorption filter (day 5 of hospitalization) against cytokine storm. Despite noradrenaline support, the hemodynamic profile deteriorated. Dobutamine was added due to heart failure with reduced ejection portion and impaired left ventricular function. While levosimendan, argipressin, and landiolol led to a transient clinical improvement, hemodynamics further worsened. Around the 21st day of hospitalization, sHLH was diagnosed (Table ?(Table1),1), and immunosuppressive therapy was started with methylprednisolone for 72?hours, followed by Pentaglobin (see without serious adverse events. Markers of cytokine storm and sHLH regressed, and CRRT and hemodynamic support could be halted. After 35?days of ICU-care and negative assessments for SARS-CoV-2, the patient entered a successful weaning process and was still alive at a follow-up on day Tebuconazole 85. 3.?Conversation 3.1. Complex pathophysiology All 3 COVID-19 patients showed cytokine storm, and their clinical course is usually in line with common clinical- (fever, hypoxia, delirium) and laboratory (hyperferritinemia, lymphopenia, elevated IL-6, and CRP) features of critically-ill COVID-19 patients in general,[3,6] and those with severe cardiac injury or coagulopathy.[3,7] A surge of inflammatory cytokines, ensuing hyperinflammation and tissue damage, is suspected as the main mechanism for multiorgan failure.[2,3,7] This suggests a considerable percentage of critically-ill COVID-19 patients suffering from sHLH, which C if left undiagnosed C could explain high mortality rates.[3,4] COVID-19 cytokine profiles resemble those in sHLH, strengthening this theory.[8] 3.2. An under-diagnosed syndrome sHLH is usually often unrecognized and remains a diagnostic challenge. Several scoring systems have been developed.[2,9] The Hscore postulated by Fardet et al[5] makes.