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Correlation of the Autopsy Findings of Bone Marrow Haemophagocytosis

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Correlation of the Autopsy Findings of Bone Marrow Haemophagocytosis Original research J Clin Pathol: first published as 10.1136/jclinpath-2020-207337 on 15 March 2021. Downloaded from Secondary haemophagocytic lymphohistiocytosis in COVID-19: correlation of the autopsy findings of bone marrow haemophagocytosis with HScore Claudia Núñez- Torrón ,1 Ana Ferrer- Gómez,2 Esther Moreno Moreno,2 Belen Pérez- Mies,2,3,4 Jesús Villarrubia,1 Sandra Chamorro,5 Javier López- Jiménez,1,3 J Palacios,2,3,4 Miguel Piris- Villaespesa,1 Mónica García- Cosío2,3,4 1Hematology, Hospital Ramón y ABSTRACT play a crucial role in the pathogenesis of the severe Cajal, Madrid, Spain Background Secondary haemophagocytic complications of patients with COVID-19, as has 2Pathology, Hospital Ramón y lymphohistiocytosis (sHLH) is characterised by a hyper been suggested by the favourable evolution of some Cajal, Madrid, Spain 7 8 3Faculty of Medicine, University activation of immune system that leads to multiorgan patients treated with their receptor antagonists. of Alcalá de Henares, Madrid, failure. It is suggested that excessive immune response Secondary haemophagocytic lymphohistio- Spain 4 in patients with COVID-19 could mimic this syndrome. cytosis (sHLH), cytokine release syndrome and CIBER- ONC, Instituto de Salud Some COVID-19 autopsy studies have revealed the macrophage activation syndrome are overlap- Carlos III, Madrid, Spain 5Infectious Diseases, Hospital presence of haemophagocytosis images in bone marrow, ping syndromes characterised by an activation of Ramón y Cajal, Madrid, Spain raising the possibility, along with HScore parameters, of lymphocytes and macrophages with a subsequent sHLH. excessive immune response, cytokine storm and Correspondence to Aim Our objective is to ascertain the existence of sHLH haemophagocytosis, which leads to multiorgan Dr Mónica García- Cosío, in some patients with severe COVID-19. damage.9–12The most frequent triggers of this Pathology, Hospital Ramón y Methods We report the autopsy histological findings syndrome are infections and malignancies. Among Cajal, Madrid 28034, Spain; monica. garciacosio@ salud. of 16 patients with COVID-19, focusing on the presence viral infections, the most frequent causative agent is madrid. org of haemophagocytosis in bone marrow, obtained from Epstein- Barr virus, but other viruses like respiratory rib squeeze and integrating these findings with HScore syncytial virus, rotavirus and adenovirus infections CN- T and AF- G are joint first parameters. CD68 immunohistochemical stains were have been reported.13–15 authors. MP- V and MG- C are joint senior used to highlight histiocytes and haemophagocytic cells. Clinical presentation of sHLH consists of fever, authors. Clinical evolution and laboratory parameters of patients hepatosplenomegaly, cytopenias, acute liver failure, were collected from electronic clinical records. high ferritin and CD25 soluble (sCD25), coagulop- Received 11 December 2020 Results Eleven patients (68.7%) displayed moderate athy, dermatologic manifestations as Kawasaki- like Revised 19 January 2021 histiocytic hyperplasia with haemophagocytosis (HHH) in syndrome and neurological symptoms.10 Around Accepted 15 February 2021 bone marrow, three patients (18.7%) displayed severe 50% of patients develop respiratory symptoms.15 http://jcp.bmj.com/ HHH and the remainder were mild. All HScore parameters Diagnosis of sHLH is based on clinical and labo- were collected in 10 patients (62.5%). Among the ratory criteria. Until recently, the criteria were patients in which all parameters were evaluable, eight extrapolated from the primary haemophago- patients (80%) had an HScore >169. sHLH was not cytic lymphohistiocytosis (HLH2004 criteria).16 clinically suspected in any case. However, in 2014, Fardet et al proposed a new Conclusions Our results support the recommendation score validated in patients with reactive HLH, on September 30, 2021 by guest. Protected copyright. of some authors to use the HScore in patients with called the HScore.17 It is based on nine variables: severe COVID-19 in order to identify those who could three clinical features, five laboratory parameters benefit from immunosuppressive therapies. The presence and one pathological finding, which is the presence of haemophagocytosis in bone marrow tissue, despite of haemophagocytosis in bone marrow. not being a specific finding, has proved to be a very In accordance, some authors suggest that the useful tool in our study to identify these patients. immune response seen in COVID-19 could mimic sHLH and, therefore, recommend using the HScore to identify patients who could benefit from immu- nosuppressive therapies.18 INTRODUCTION The presence of haemophagocytosis in bone © Author(s) (or their The outbreak of the novel coronavirus pandemic is marrow could raise the possibility of sHLH in employer(s)) 2021. No supposing a medical challenge worldwide. The main patients with severe COVID-19. Wood et al, based commercial re- use. See rights clinical features of COVID-19 vary from asymp- on intensive care unit (ICU) patients’ study, have and permissions. Published by BMJ. tomatic or mild symptoms such as fever, cough and considered that HScore has limited application in myalgia to severe pneumonia with acute respira- severe patients with COVID-19. Nevertheless, they To cite: Núñez- Torrón C, tory distress syndrome (ARDS), requiring at times calculated HScore without bone marrow biopsy.19 Ferrer- Gómez A, Moreno ventilatory support.1–5 Severe patients also display Various autopsy series on patients with COVID-19 Moreno E, et al. J Clin Pathol Epub ahead of print: signs of high systemic inflammatory response with have begun to emerge in the literature. Only few of [please include Day Month altered pattern of inflammatory chemokines and them include the study of bone marrow tissue for Year]. doi:10.1136/ cytokines and high ferritin levels, known as cytokine the presence of haemophagocytosis. Some of these jclinpath-2020-207337 storm.4 6IL-1/IL-6 pathway dysregulation seems to studies, based on the hypothesis above described, Núñez- Torrón C, et al. J Clin Pathol 2021;0:1–7. doi:10.1136/jclinpath-2020-207337 1 Original research J Clin Pathol: first published as 10.1136/jclinpath-2020-207337 on 15 March 2021. Downloaded from correlate this finding, along with HScore, with a possible hyper- systems (Roche). CD68 immunohistochemical stains were used inflammatory status and hypercytokinemia/sHLH, reporting to highlight the histiocytes and haemophagocytic cells. Double contradictory results about the presence of haemophagocytosis staining glycophorin C/CD68 was performed in order to identify and the convenience of using the HScore in these patients due more precisely haemophagocytic cells. to a potential lack of sensitivity.20–25 In order to ascertain the existence of sHLH in patients with COVID-19, we report the Bone marrow histiocytic quantification histological findings from 16 COVID-19 autopsies, one of the Only histiocytes showing engulfment of one or more nucleated largest series published until now that focuses on the presence of host blood cells, including plasma cells and lymphocytes, were haemophagocytosis in bone marrow integrating these findings counted as haemophagocytosis. Moreover, morphological evalu- with clinical and laboratory criteria for sHLH diagnosis. ation of histiocytic hyperplasia with haemophagocytosis (HHH) was graded in bone marrow tissue based on Suster et al score28 METHODS such as: mild HHH (haemophagocytosis was present only when Patient selection searched for in several high- power fields (HPF)), moderate We performed a single-centre retrospective analysis in 16 (haemophagocytosis was present in one to three cells per HPF) patients with COVID-19 disease in a tertiary care hospital. We and severe (haemophagocytosis was present more than three considered as confirmed cases the patients with compatible clin- cells per HPF). This classification considers as pathological HHH ical symptoms or a suggestive chest image and a positive reverse only those cases demonstrating moderate to severe haemophago- transcription- PCR for SARS- Cov-2 nucleic acid on upper respi- cytic activity. Nevertheless, since the HScore requires only the 26 ratory swap. presence of haemophagocytosis in bone marrow to meet this parameter,17 we used this classification in order to establish a Clinical and laboratory data possible association between sHLH diagnosis and HHH degree. We calculated the HScore for all patients. The HScore is freely We also calculated the percentage of histiocytes in each sample available online (http:// saintantoine. aphp. fr/ score/). As previous by counting the number of histiocytes stained with CD68 in 500 recommendations for this score, we used a cut-off point of 169 bone marrow cells. In normal conditions, the histiocytic cellu- points, corresponding to a sensitivity of 93% and a specificity of larity in bone marrow is inconspicuous. Histiocytic hyperplasia 86% for the diagnosis of sHLH.17 Clinical evolution and labora- was considered in our study when the percentage was 5% or tory parameters were collected from electronic clinical records. superior. For the laboratory parameters, the value corresponding to the Moreover, following the Gars et al study,29 we searched for the maximum score during evolution was considered. Organomegaly presence of multiple nucleated cells within a single haemophago- was obtained from physical exploration or from radiological cyte in each case. findings. Missing data were scored as 0 points. The presence of haemophagocytosis
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