Secondary HLH is uncommon in severe COVID‐19

Abstract

Severe cases of COVID-19, caused by novel coronavirus SARS-CoV-2, have been associated with a hyperinflammatory state.1 This has been described as a form of secondary haemophagocytic lymphohistiocytosis (sHLH)2 that may contribute to increased mortality.3 Screening with the HScore4 to identify cases has been recommended to guide immunosuppressive therapy.5 In our hospital, a multidisciplinary panel was created to advise on the use of cytokine directed therapies, such as the anti-interleukin-6 receptor antibody tocilizumab, in these patients.6 We performed a single-centre, cross-sectional study of 40 COVID-19 patients being treated in intensive care units on May 1, 2020, who had tested positive for SARS-CoV-2 by polymerase chain reaction. We calculated the HScore on each day of admission using the most recent results for each variable contributing to the score.4, 7 All but two patients had positive SARS-CoV-2 results from samples taken within 2 days of admission. Patient characteristics are listed in Table 1. Despite evidence of hyperinflammation in this cohort, with high fevers, peak serum C-reactive protein (CRP) levels of >300 mg/l in 35 patients (87·5%) and peak serum ferritin >10 000 μg/l in seven (17·5%), only three (7·5%) achieved an HScore >169: the cutoff used to identify sHLH at a sensitivity of 93% and specificity of 86%.4 The low number of patients with HScore >169 was consistent with the absence of certain cardinal features of sHLH. Neither hepatomegaly nor splenomegaly was identified in any of the patients assessed by ultrasound or computed tomography imaging (n = 15). Fibrinogen levels of ≤2·5 g/l were seen in only two patients (5%). Anaemia was frequently observed, seen in 95% of the cohort, with haemoglobin falling to ≤92 g/l at a median of 8 days after admission. Neutropenia was rare, with only one patient having a neutrophil count of <1 × 109/l. Conversely, we found that these patients tended to have high white blood cell counts (WBC), reaching >20 × 109/l in 25 patients (62·5%), and elevated fibrinogen levels were seen in 38 (95%). Ferritin levels reached >500 μg/l in all patients, but were >6000 μg/l in only nine (22·5%). Peak values of HScore parameters, HLH 2004 criteria and other inflammatory markers are shown in Table 1. The time at which peak/nadir values of HScore parameters and other inflammatory markers were reached is shown in Fig 1A. Fig 1B shows the distribution of the peak values of selected markers, HScore and HLH 2004 criteria.2 As of May 15, 2020, 28 patients (70%) remained on intensive care, nine (22·5%) had been stepped down to medical wards and three (7·5%) had died. The median (range) peak HScores for each group were 114 (52–196), 98 (33–150) and 98 (83–147), respectively. One patient achieved a peak HScore of 196, associated with fever, ferritin 56 362 μg/l, WBC 107·6 × 109/l and CRP 400·2 mg/l, and was the only patient treated with tocilizumab (single dose of 8 mg/kg), which was followed by a rapid drop in ferritin, CRP and resolution of fever. He subsequently developed secondary bacterial pneumonia. Serum cytokine levels (interleukin-1β, interleukin-6, tumour necrosis factor-α and interleukin-8) were measured in 11 patients. Surprisingly, comparison of HScore and cytokine levels (Fig 1C) indicated a non-significant trend towards a negative association. The only patient with very high IL-6 levels (4336 pg/ml) was the patient who was treated with tocilizumab, and this was consistent with the known cytokine rise following IL-6 receptor blockade. We observed an unexpected phenomenon of leucoerythroblastic (LE) features on peripheral blood film8 (immature granulocyte precursors and nucleated red cells—normally restricted to the bone marrow) in association with high WBC. These features occurred at a median of 14 days from admission and were delayed in comparison to peak CRP and ferritin (Fig 1A). Of 17 patients for whom blood films were available, 10 (58·8%) showed LE features. Leucoerythroblastic reaction associated with COVID-19 has recently been identified in a single case report, but our data indicate that this may be much more common, suggesting that severe COVID-19 can have profound effects on the bone marrow. Our experience indicates that HScore has limited application in severe COVID-19 and that the hyperinflammatory state lacks a number of the key features of sHLH.9 Thus, it may not be appropriate to use HScore to guide use of immunomodulatory therapy.

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