key: cord-1014118-iebu1kyw
authors: Ruscitti, Piero; Bruno, Federico; Berardicurti, Onorina; Acanfora, Chiara; Pavlych, Viktoriya; Palumbo, Pierpaolo; Conforti, Alessandro; Carubbi, Francesco; Di Cola, Ilenia; Di Benedetto, Paola; Cipriani, Paola; Grassi, Davide; Masciocchi, Carlo; Iagnocco, Annamaria; Barile, Antonio; Giacomelli, Roberto
title: Lung involvement in macrophage activation syndrome and severe COVID-19: results from a cross-sectional study to assess clinical, laboratory and artificial intelligence–radiological differences
date: 2020-07-21
journal: Ann Rheum Dis
DOI: 10.1136/annrheumdis-2020-218048
sha: 1632c80505113462859504ce1efa19ca6d318985
doc_id: 1014118
cord_uid: iebu1kyw

OBJECTIVES: To evaluate the clinical pictures, laboratory tests and imaging of patients with lung involvement, either from severe COVID-19 or macrophage activation syndrome (MAS), in order to assess how similar these two diseases are. METHODS: The present work has been designed as a cross-sectional single-centre study to compare characteristics of patients with lung involvement either from MAS or severe COVID-19. Chest CT scans were assessed by using an artificial intelligence (AI)-based software. RESULTS: Ten patients with MAS and 47 patients with severe COVID-19 with lung involvement were assessed. Although all patients showed fever and dyspnoea, patients with MAS were characterised by thrombocytopaenia, whereas patients with severe COVID-19 were characterised by lymphopaenia and neutrophilia. Higher values of H-score characterised patients with MAS when compared with severe COVID-19. AI-reconstructed images of chest CT scan showed that apical, basal, peripheral and bilateral distributions of ground-glass opacities (GGOs), as well as apical consolidations, were more represented in severe COVID-19 than in MAS. C reactive protein directly correlated with GGOs extension in both diseases. Furthermore, lymphopaenia inversely correlated with GGOs extension in severe COVID-19. CONCLUSIONS: Our data could suggest laboratory and radiological differences between MAS and severe COVID-19, paving the way for further hypotheses to be investigated in future confirmatory studies.

The COVID-19 pandemic has brought attention to a virally induced hyperinflammatory lung injury, sometimes evolving to multiple-organ failure and death. 1 This finding mirrors what has been observed in macrophage activation syndrome (MAS), 2 3 a secondary form of haemophagocytic lymphohistiocytosis (HLH), complicating rheumatic diseases, mostly adult-onset Still's disease (AOSD), rapidly evolving into multiple-organ failure and death in a large percentage of patients. 4 5 Recently, during AOSD and its juvenile counterpart, pulmonary involvement has been strictly associated with MAS and poor outcome. 3 6 7 Thus, the analysis of chest CT associated with artificial intelligence (AI) tools may be of crucial importance to assess these patients. 8 9 A scientific debate is being raised about the possibility that severe COVID-19 may be considered part of the HLH spectrum due to overlapping clinical features. 1 10 11 To assess how similar these two diseases are, we evaluated the clinical pictures,

What is already known about this subject? ► Severe COVID- 19 laboratory tests and AI imaging of patients with lung involvement, either from COVID-19 or MAS. Finally, we correlated the specific laboratory abnormalities observed in our patients with the extension of lung involvement.

The present work has been designed as a cross-sectional singlecentre study to compare clinical, laboratory and AI-radiological findings between patients with lung involvement either from MAS or severe COVID-19. Patients with MAS, diagnosed by previous criteria, 12 were retrospectively selected from our database. Their underlying disease was AOSD, diagnosed according to Yamaguchi criteria, 13 without documented lung involvement, and treated with glucocorticoids, 0.2-0.3 mg/kg/day of prednisone equivalent and non-steroidal anti-inflammatory drugs, on-demand, during acute flares. MAS was triggered in all patients by a new acute AOSD flare, in the context of a polycyclic disease pattern. 14 Patients with MAS were matched with consecutive patients with severe COVID-19 attending our institution and admitted to intensive or subintensive care units (online supplementary figure S1 and table S1). All patients with severe COVID-19 showed severe acute respiratory syndrome coronavirus 2 infection confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). Pulmonary and other infections were excluded in both groups by a specific diagnostic workup including blood cultures, bone marrow cultures, serology, RT-PCR analyses, chest X-rays, chest CT scan, and heart and abdominal echographies. All data were collected before starting any immunosuppressive therapy for MAS or severe COVID-19. Informed consent was obtained from each patient for the use of clinical and laboratory data for study purposes. In reporting the results, we followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (online  supplementary table S2 ).

CT examinations were performed using a multidetector CT scanner with a single spiral acquisition obtained from the apex to the base of the lungs, with the patient in supine position at full inspiration. Scanning parameters were as follows: 250-330 mm field of view (FOV), 512×512 matrix, 120 kV, 100-150 mAs and tube rotation time of 0. Epidemiology parenchymal involvement, after automated segmentation, from the same CT examinations.

Data were collected during scheduled examinations for each patient by reviewing the clinical charts. Institutional Picture Archiving and Communication System was searched for available chest CT examinations, which were also screened for image quality. To overcome the issue of MAS rarity, we increased the number of severe COVID-19 patients to a ratio of about 4:1 to improve the power, without a specific sample size estimation. Although this rise is not linear, an equally small number of controls would provide little ability to retrieve possible associations. 16 We minimised the effects of possible biases and missing data by a careful definition of each variable and a relatively simple study design.

Data were collected, organised and analysed through XLSTAT V. 

All 47 patients with COVID-19 showed ground-glass opacities (GGOs), whereas this finding was observed in 60% of patients with MAS (p=0.028). The proportion of basal, bilateral and peripheral distributions of GGOs was significantly higher in patients with COVID-19 than in patients with MAS (95.7% vs 50%, p=0.022; 97.8% vs 50%, p=0.009; and 95.7% vs 50%, p=0.014, respectively). No significant differences were observed in parenchymal consolidations between groups, except for the more frequent apical consolidations in COVID-19 than in MAS (23.4% vs 0%, p=0.005). Other CT findings are summarised in table 2. About 30% of patients in both groups showed cardiomegaly without any sign of infections or myopericarditis. By assessing AI-reconstructed images (figure 1), the extension of consolidation was higher in COVID-19 than in MAS 

Severe COVID-19 and MAS are challenging disorders characterised by overlapping clinical pictures, and it is still matter of debate if severe COVID-19 is part or not of the HLH spectrum. 1 10 11 Although all patients showed fever and dyspnoea, laboratory differences were retrieved, since MAS patients showed thrombocytopaenia, whereas severe COVID-19 patients were characterised by lymphopaenia and neutrophilia. During MAS, thrombocytopaenia may depend on haemophagocytosis and severe cytokine-mediated inflammation. 4 Differently, COVID-19 is characterised by isolated lymphopaenia, since the virus might infect lymphocytes, inducing their apoptosis. 17 Both diseases showed increased ferritin levels, with the highest levels observed in MAS, which maybe related to the magnitude of the hyperinflammation. 18 D-dimer levels were increased in both groups: in MAS, due to disseminated intravascular coagulation; and in severe COVID-19, for pulmonary intravascular coagulopathy and associated right heart strain. 19 20 All MAS patients achieved H-score diagnostic cut-off (>169) but only 10% of severe COVID-19 patients did it, suggesting the need of further studies to assess its usefulness in severe COVID-19.

AI-reconstructed chest CT images showed that apical, basal, peripheral and bilateral distributions of GGOs were more represented in severe COVID-19 patients. Furthermore, these patients showed more frequent apical consolidations, with a larger extension than in MAS. AI-quantitative assessment of lung involvement permitted to correlate these radiological findings with the specific laboratory abnormalities observed in our patients. In fact, we observed that CRP directly correlated with GGOs extension in both diseases. Furthermore, lymphopaenia inversely correlated with GGOs extension in severe COVID-19. These results may suggest the possible predictive role for some specific biomarkers and may help physicians in identifying more severe patients.

Although providing a comprehensive comparison of clinical, laboratory and radiological findings between MAS and severe COVID-19, our study is affected by some limitations due to the single-centre study design and the relatively low number of patients with MAS, which may limit the external validity. However, it must be pointed out that MAS is a rare disease, and to plan large and multicentre studies is very challenging.

In conclusion, our data showed laboratory and AI-radiological differences between MAS and severe COVID-19; the latter did not appear as being part of the HLH spectrum, thus paving the way for further hypotheses to be investigated in future and larger confirmatory studies.

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Emergent high fatality lung disease in systemic juvenile arthritis

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All the authors met all criteria for authorship in the ICMJE Recommendations, since all authors made substantial contributions to the conception or design of the work, and the acquisition and interpretation of data.This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

Onorina Berardicurti http:// orcid. org/ 0000-0002-2808-1581 Francesco Carubbi http:// orcid. org/ 0000-0003-1958-5136 Paola Di Benedetto http:// orcid. org/ 0000-0003-2927-8703 Roberto Giacomelli http:// orcid. org/ 0000-0003-0670-9638

All authors contributed to the critical review and revision of the manuscript and approved the final version. All the authors agreed to be accountable for all aspects of the work.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Ethics approval The local ethics committee (Comitato Etico Azienda Sanitaria Locale 1 Avezzano/Sulmona/L'Aquila, L'Aquila, Italy; protocol number 0095184/20) approved the study, which was performed according to good clinical practice guidelines and the Declaration of Helsinki.Provenance and peer review Not commissioned; externally peer reviewed.Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.