Cytokine release syndrome and the prospects for immunotherapy with COVID-19. Part 2: The role of interleukin 1

RATIONALE FOR TARGETING IL-1

IL-1 includes 2 distinct cytokines, IL-1 alpha and IL-1 beta. Along with IL-1 receptor antagonist (IL-1RA) and IL-18, these molecules play important roles in the acute inflammatory response. Interest in IL-1 in COVID-19 stems from the utility of targeting it in a variety of immune-mediated disorders; drugs of this class have approved indications for treating rheumatoid arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, and familial Mediterranean fever (Table 1), in which IL-1 is similarly elevated (as are other cytokines such as IL-6 and IL-18).⁵

Of even greater interest is the utility of targeting IL-1 in the nonapproved indications of secondary hemophagocytic lymphohistiocytosis and macrophage activation syndrome, which display many immunologic and clinical features similar to the cytokine release phase of COVID-19.⁶

IL-1 is a product of the activated inflammasome, a cytosolic multiprotein oligomer that can be activated by a variety of triggers, including infectious agents and endogenous danger signals generated by dying cells and activated platelets. IL-1 is produced primarily by macrophages and monocytes, cells that have been incriminated in the pathogenesis of the inflammatory phase of COVID-19 after being detected in the lung by single-cell RNA sequencing accompanied by the detection of elevated IL-1 in bronchial alveolar lavage fluid.⁷ It is postulated that in COVID-19, pulmonary macrophages are hyperactivated either directly by the virus or indirectly by the products of damaged tissues, or both. Of note, pulmonary macrophages and their elaborated cytokines are also considered central in the pathogenesis of acute respiratory distress syndrome, which can occur with COVID-19 infection.⁸

With several approved IL-1-targeting agents available, as of this writing, more than 10 trials in COVID-19 have been registered and 3 studies have recently been completed.^9–11 One of the completed studies is an open-label, noncontrolled series of 9 cases in which the recombinant IL-1 receptor antagonist anakinra was used at a dose of 100 mg every 12 hours. The patients were described as having advancing disease and responded with clinical defervescence documented by the halting of progression on chest radiographs. There were no deaths.⁹

In a second and larger, albeit retrospective trial,¹⁰ anakinra was used in a higher dose (5 mg/kg twice a day intravenously or 100 mg twice a day subcutaneously) for a variable time period guided by response, combined with a regimen of hydroxychloroquine and ritonavir-lopinavir. Outcomes at day 21 were compared with those of a similar group treated with the same drug regimen without anakinra. At 21 days, the anakinra group had lower levels of inflammatory markers and milder clinical courses than the control group, with a 10% mortality rate in the active treatment group vs 44% in the control group. Of note, 7 patients treated initially with a lower-dose regimen of anakinra were later given the higher dose because of minimal effects on laboratory and clinical parameters after 7 days; all had favorable responses. Overall, safety was good, with clinical improvement in 72%.

The third trial¹¹ is of particular interest because of its size (with 52 patients receiving anakinra and 44 historical controls) and the degree by which it reduced (by 48%) either the need for mechanical ventilation or death. While this relative risk reduction is impressive, the design limits the strength of any conclusions, as the comparator group was retrospectively derived and unmatched in certain clinical features. Both groups also received numerous other therapies, including hydroxychloroquine and azithromycin. Large prospective trials are now underway and should provide meaningful data on the potential merit of IL-1 inhibition for advanced disease.

Collectively, this experience, while small and uncontrolled, has been encouraging enough to support larger and more robust efforts moving ahead.

DESPITE CONCERNS, SAFETY PROFILE IS GOOD

Targeting of IL-1 carries several warnings and safety concerns, including risk of serious infection. Overall however, the incidence of serious infection associated with IL-1 inhibitors has been very low, which makes this targeted therapy particularly attractive in the setting of active infection. Isolated cases of atypical infections including fungal and mycobacterial have been reported, however.¹²

Anakinra is used off-label to treat acute gout in the inpatient setting, at a dose of 100 mg subcutaneously daily for 3 to 5 days. The largest observational study of anakinra in this setting found no serious infectious complications in a high-risk cohort of 100 patients that included solid organ transplant recipients and patients with active infection.¹³

Of all the approved IL-1 inhibitors, only canakinumab comes with a recommendation in its package insert to screen for latent tuberculosis before initiating therapy.¹² Concomitant use of IL-1 inhibitors with TNF inhibitors has been associated with an increased risk for serious infections, so these agents should not be combined.¹⁴

OPTIMAL DOSING UNKNOWN

Despite the lack of evidence of efficacy of targeting IL-1 in COVID-19 from randomized controlled trials, the preliminary reports noted above have been encouraging, and robust trials are underway. Currently registered trials of IL-1-targeting agents are using either anakinra or canakinumab at various doses, as single agents or in combination with other targeted therapies.

Moving ahead, an area of considerable uncertainty is the appropriate dosages and routes of drug administration. This particularly important for anakinra, for which the adequacy of the approved dose of 100 mg by subcutaneous injection once daily for approved indications (Table 1) has come under question for treatment of other cytokine release syndromes such as secondary hemophagocytic lymphohistiocytosis and macrophage activation syndrome.⁶ The largest study of anakinra in COVID-19 concluded that higher doses may be needed, but this conclusion was based on retrospective data.¹⁰

Currently, most of the registered trials of anakinra for COVID-19 are using higher doses than are generally used for approved indications. Fortunately safety data from large randomized controlled trials of this agent in the setting of sepsis have demonstrated that even very high doses (3,500 mg daily) can be well tolerated without evidence of infectious complications.¹⁶ Notably, dosage reduction recommendations for anakinra in the setting of reduced renal function are driven by pharmacokinetic data, not adverse events.

Similarly for canakinumab, the optimal dose for treating cytokine release in COVID-19 is unknown. The approved dosage of 300 mg subcutaneously for periodic fever syndromes and familial Mediterranean fever may not be optimal, and doses up to 600 mg subcutaneously been safely tolerated.¹⁷ Despite the large experience of targeting IL-1 in other cytokine storm settings, many questions remain unanswered regarding the optimal timing of therapy, in particular regarding how this will be determined, whether on the basis of clinical parameters, biomarkers, or both.

Ideally, treatment and response will be guided by a biomarker, but at present we don’t have one. Serum IL-1 levels have been unreliable for monitoring disease activity in hemophagocytic lymphohistiocytosis, and there are as yet no data in COVID-19. A biomarker to predict clinical course is desperately needed. A recently proposed simple algorithm incorporating lactate dehydrogenase, C-reactive protein, and lymphocyte count appears promising but has yet to be applied in prospective trials.¹⁸