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6/2020
vol. 16
 
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Letter to the Editor

Tocilizumab in severe COVID-19

Nicola Lucio Liberato
1
,
Andrea De Monte
2
,
Giuseppe Caravella
3

1.
Department of Medicine, ASST Melegnano e della Martesana, Vizzolo Predabissi (MI), Italy
2.
Department of Oncology, ASST Melegnano e della Martesana, Vizzolo Predabissi (MI), Italy
3.
Department of Pharmacy, ASST Melegnano e della Martesana, Vizzolo Predabissi (MI), Italy
Arch Med Sci 2020; 16 (6): 1457–1458
Online publish date: 2020/07/16
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Clinical and biological data suggest that the occurrence of a cytokine storm may be crucial in determining the clinical features and severity of COVID-19, with interleukin-6 playing a major role; thus, inhibiting its activity by blocking its binding to the specific receptor could be useful [1].

Here we report on the use of tocilizumab (RoActemra©, Roche), a humanised anti-human interleukine-6 receptor antibody, in 20 hospitalised patients with SARS-CoV-2 infection confirmed by reverse transcriptase-polymerase chain reaction assay and severe pneumonia (PaO2/FiO2 ratio < 300) undergoing high flow oxygen or noninvasive positive-pressure ventilation with interleukin-6 serum levels higher than 20 pg/ml; mechanically ventilated patients were excluded. In these patients, tocilizumab 8 mg/kg intravenously (maximum 800 mg) were added to standard treatment (hydroxychloroquine, prophylactic enoxaparin, oxygen, and nutritional support); a further identical dose was administered 12 h later if no significant amelioration could be found. The drug was prescribed as off-label, and local Ethics Committee approval and informed consent were obtained for each patient. Patients were followed until discharge or death; 1 patient is still hospitalised.

The age range was 32 to 78 years (median 60 years) (Table I). At baseline, 18 patients were receiving noninvasive positive-pressure ventilation, and 2 patients recieved high-flow oxygen; median PaO2/FiO2 ratio was 137 (range: 101–210). The median duration of symptoms before tocilizumab therapy was 10.5 days (range: 3–21 days), and tocilizumab was administered a median of 2.5 days after admission (range: 0–13). Four patients underwent mechanical ventilation during follow-up: 1 patient died, 2 patients were extubated and discharged, and 1 patient was extubated but still in intensive care due to intervening septic complications. The time to cessation of high-flow oxygen or noninvasive positive-pressure ventilation was 5.5 days, and the median duration of hospitalisation was 15 days (range: 7–52 days). The mortality rate was 5%, and there were no clinical and laboratory differences between patients who required or did not require mechanical ventilation during hospitalisation. No adverse drug reaction was reported.

Table I

Demographic and clinical characteristics of the patients

Parametervalue
Male/female19/1
Age, median (IQR) [year]60 (55–67)
Age category, n (%):
 < 50 years2 (10)
 50 to 70 years14 (70)
 ≥ 70 years4 (20)
Oxygen-support category, n (%):
 High-flow oxygen2 (10)
 Noninvasive positive-pressure ventilation18 (90)
Time from admission to tocilizumab therapy, median (IQR) [days]2.5 (1.7–4)
Duration of symptoms before tocilizumab therapy, median (IQR) [days]10.5 (7.7–12.2)
Laboratory values, median (IQR):
 White blood cells [109/l]8.3 (6.8–9.7)
 Lymphocytes [109/l]1.2 (0.8–1.6)
 AST [IU/l]54 (38–94)
 ALT [IU/l]46 (17–86)
 Creatinine [mg/dl]0.98 (0.95–1.35)
 Ferritin [ng/ml]786 (442–1198)
 C-reactive protein [mg/l]146 (75–240)
 D-dimer [ng/ml]1574 (1145–6285)
 LDH [IU/l]429 (337–573)
 IL-6 [pg/ml]132 (90–160)
Hospitalisation, median (IQR) [days]15 (13–19.5)
Death rate, n (%)1/20 (5%)

[i] IQR – interquartile range, ALT – alanine aminotransferase, AST– aspartate aminotransferase, LDH – lactate dehydrogenase, IL-6 – interleukin-6.

It is still a matter of debate whether the clinical course of COVID-19 is different in patients with rheumatic disease or in those undergoing a disease-modifying treatment [2, 3]. A previous report from China showed that tocilizumab could be an effective treatment, able to reduce the mortality of COVID-19 patients [4]. Data from our preliminary report seems to confirm such an effect and compare well with those from other studies: the mortality rate was 14% in severe Chinese patients [5], 22% in patients treated with lopinavir-ritonavir [6], and 13% in patients treated with remdesivir [7], while the aggregated data of death and intubation was 20% (4 patients) in our series, and 32.3% in patients treated with hydroxychloroquine alone [8]. Adding Tocilizumab to standard treatment in patients with severe COVID-19 could therefore be useful.

Our study has significant shortcomings: mainly the small size of the treated cohort and the lack of a control (possibly randomised) group, which limit the interpretation of the results.

These preliminary data therefore need confirmation in larger populations by case-control studies and mainly by randomised studies.

Acknowledgments

We thank Margherita Algeri, Francesca Boni, Marco Brina, Francesco Cassola, Riccardo Centenaro, Alberto Chiesa, Rita Cursano, Denise Dal Lago,Domenica Damiani, Cristina Donati, Francesca Giovannelli, Sara Job, Chiara Lubatti, Roberta Marenzi, Donatella Menta, Maria Mercuri, Ruggero Merlini, Alberto Passera, Alessia Petillo,Vincenzo Piacentini, Manuela Poggiato, Delia Pugliese, Giovanni Saccà, Elena Siciliani, Lorenzo Vitali, and Giovanna Vitaliani for their helpful suggestions and invaluable activity for our COVID patients.

Conflict of interest

The authors declare no conflict of interest.

References

1 

Liu B, Li M, Zhou Z, et al. , authors. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020. 111:p. 102452

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Salvarani C, Bajocchi G, Mancuso P, et al. , authors. Susceptibility and severity of COVID-19 in patients treated with bDMARDS and tsDMARDs: a population-based study. Ann Rheum Dis. 2020. DOI: 10.1136/annrheumdis-2020-217903

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D’Silva KM, Serling-Boyd N, Wallwork R, et al. , authors. Clinical characteristics and outcomes of patients with Coronavirus Disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US “Hoit Spot”. Ann Rheum Dis. 2020. DOI: 10.1136/annrheumdis-2020-217888

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Xu X, Han M, Li T, et al. , authors. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA. 2020. 117:p. 10970–5

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Wu Z, McGoogan JM , authors. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020. 323:p. 1239–42

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Cao B, Wang Y, Wen D, et al. , authors. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020. 382:p. 1787–99

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Grein J, Ohmagari N, Shin D, et al. , authors. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020. 382:p. 2327–36

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Geleris J, Sun Y, Platt J, et al. , authors. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020. 382:p. 2411–8

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