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We thank Jain and Sharma1 for their interest in our recent report on interleukin-6 (IL-6) receptor blockade with subcutaneous tocilizumab (324 mg, given in two concomitant 162 mg doses) in patients with severe COVID-19 pneumonia and hyperinflammation.2 Jain and Sharma bring up an important point regarding the safety profile of subcutaneous tocilizumab in patients with COVID-19 at risk of concomitant bacterial infections.1 As already concisely described, in our case–control series, only relatively young patients with severe COVID-19 pneumonia, requiring oxygen support through nasal cannulas or masks, hyperinflammation (C-reactive protein >20 mg/dL) and no contraindications to tocilizumab, including suspected concomitant bacterial infection, were included.2 Well aware of the potential adverse effects of tocilizumab, our screening protocol to rule out concomitant bacterial infection was based on medical history, collected at the time of and during hospitalisation in advance of tocilizumab administration, absolute white blood cell, neutrophil and lymphocyte counts, serial procalcitonin (PCT) values, which were persistently <0.1 ng/mL in most patients, as well as imaging testing assessing for concomitant infection sites outside the lungs. Indeed, several patients were cautiously excluded due to suspicion of superimposed bacterial infection based on clinical input or PCT values above that threshold, and if immunodeficiency was clinically relevant or reasonably suspected. As reported, under these strict and cautious treatment criteria, the bacterial infection did not prove to revert the expected beneficial effects of tocilizumab administration.2 The point raised by our colleagues is of utmost importance and may contribute to explain the remarkable difference in outcomes observed in some retrospective series reporting on the early beneficial administration of subcutaneous tocilizumab,2–4 compared with other reports on intravenous tocilizumab in more severe and possibly intubated patients with COVID-19.5 6 As a consequence, comments on the risks of late bacterial infections related to the treatment with tocilizumab, possibly causing an excess of bacterial adverse events, even severe, are welcome. Indeed, in future reports, the incidence of such events should be appraised as a composite endpoint including death, as patients meeting lethal outcomes cannot experience late infections. Therefore, although we agree that the available data on early subcutaneous treatment with tocilizumab are definitely preliminary, existing data suggest a survival benefit in selected patients with COVID-19, an evidence that may be considered for possible therapeutic decisions in the ongoing scenario of the present pandemic and that should be explored in adequately powered randomised controlled trials (RCTs). RCTs are indeed eagerly awaited even in the course of the present case escalation rates around the world,7 provided an adequate setting to enrol such patients in an RCT. In the meantime, we agree once more that patients treated with subcutaneous tocilizumab for COVID-19 should be monitored for possible bacterial complications, as clearly stated in the prescribing information available to clinicians. Anyway, as our and other reports suggest, administration of subcutaneous tocilizumab early in the course of the disease, that is, before mechanical ventilation is required or resorted on, may result in greater clinical benefit compared with standard of care and infrequent occurrence of secondary infections, as mechanical ventilation is likely to represent a major risk factor for such complications in these prevalently young patients.2–4
As to the point of the possible need of screening for chronic underlying infections at risk of reactivation due to urgent tocilizumab exposure in patients with COVID-19, based on current evidence we feel that, under the strict exclusion/inclusion criteria recalled earlier, this possibility may be considered a minor issue, considering that patients with COVID-19 will be receiving one, or possibly two doses of subcutaneous tocilizumab, which is a therapeutic frame unlikely to induce enough immunosuppression and, in turn, cause reactivation of latent infection(s). As a consequence, empirical coprescription of isoniazid, even in countries with a high prevalence of active and latent tuberculosis, may be viewed at this stage as redundant, and possibly causing an excess of drug toxicity or drug–drug interaction issues in treated patients.
Finally, with regard to the possible IL-6-driven prescription of tocilizumab in patients with severe COVID-19 pneumonia, this may be interesting and possibly relevant, but at present beyond the purpose of our study.2 Despite having the possibility of assaying IL-6 at our centre since 6 April 2020, IL-6 values assays were not mandatorily performed in our patients in advance of subcutaneous tocilizumab administration, as the inclusion criteria were once more only those described in our letter. We find that, for the time being, those treatment criteria may actually help timely and appropriate prescription of subcutaneous tocilizumab to patients with early and severe deterioration of respiratory function due to COVID-19 pneumonia in settings where, as in ours, IL-6 assays may be limiting.
Handling editor Josef S Smolen
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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