key: cord-301281-yur5hs2h
authors: Zelek, Wioleta M.; Cole, Jade; Ponsford, Mark J.; Harrison, Richard A.; Schroeder, Ben E.; Webb, Nicholas; Jolles, Stephen; Fegan, Christopher; Morgan, Matt; Wise, Matt P.; Morgan, B. Paul
title: Complement Inhibition with the C5 Blocker LFG316 in Severe COVID-19
date: 2020-11-01
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202007-2778le
sha: 
doc_id: 301281
cord_uid: yur5hs2h

nan

To the Editor:

In critically ill patients with coronavirus disease (COVID-19), a hyperinflammatory host response contributes to organ dysfunction and death. The role of complement in these events is unclear. Complement activation yields powerful proinflammatory effectors, notably C5a and membrane attack complex, and triggers coagulation (1); it has been implicated in bacterial sepsis and septic shock, sepsis-like syndromes associated with coronavirus infections, and COVID-19-associated microvascular injury and thrombosis (2) (3) (4) . Recently, the C5a/C5aR1 axis was implicated in COVID-19 lung pathology (5) . We here report the contribution of complement activation and impact of complement blockade in severe COVID-19, defined as marked respiratory impairment requiring intensive care and ventilation support. Drugs were administered under the Novartis Managed Access Program and permission to undertake this case series study was granted by the director of research and development at Cardiff and Vale University Health Board. Complement dysregulation was identified in critically ill patients with RT-PCR-confirmed COVID-19; terminal complement complex (TCC) and C5a levels were measured in mechanically ventilated patients in the Critical Care Unit at a single center if the clinician considered that the clinical trajectory was not improving ( Figure 1A ). Five patients were selected, based on high levels of TCC (above the mean 1 2 SD for controls; 7.14 mg/L) and either treatment failure (patients 1-3) or failure to improve (patients 4 and 5) where death was not considered imminent (clinical judgement), for inclusion in a compassionate use study of complement blockade using LFG316 (tesidolumab; Novartis Managed Access Program), a C5-blocking monoclonal antibody (mAb) that prevents generation of the proinflammatory effectors C5a and membrane attack complex (6) . As patients were unable to provide written informed consent, assent from relatives was obtained. Pretreatment disease course is summarized in Table 1 . All five patients selected were paralyzed and proned while receiving mechanical ventilation. High-frequency oscillatory ventilation and nitric oxide were used alone or in combination in the first three patients. Duration of ventilation before LFG316 is shown in Table 1 . Each patient received a single 1,500-mg dose of LFG316 by intravenous infusion, anticipated from unpublished Novartis data to fully inhibit C5 for .7 days, preceded by chlorpheniramine (4 mg) and hydrocortisone (100 mg). Antibiotic prophylaxis (phenoxymethylpenicillin or clarithromycin) was provided to mitigate risk of encapsulated bacterial infections. In all patients, CH50 was completely suppressed up to Day 4 after treatment with partial recovery at Day 7; TCC and C5a levels fell to within the normal range and remained low through Day 7; CRP (C-reactive protein) levels were elevated before dosing and, except for patient 5, fell after dosing (.80%) and remained reduced through Day 7 (Table 1) . Patients 1, 2, and 4 showed rapid resolution of CRP and improved oxygenation and CO 2 ; recovery in patient 3 was much slower, but all four showed improved ventilation after dosing ( Figure 1B ). Patient 5 failed to respond to LFG316 despite complete complement blockade, developed a sudden pulseless electrical activity cardiac arrest, and died 9 days after treatment; uniquely, CRP levels did not fall after treatment in this patient, suggesting that there was another driver of inflammation, likely the identified occult Klebsiella infection. Among our severe COVID-19 cohort who did not receive LFG316, 67 of 71 were mechanically ventilated and paralyzed, and 28 of these were proned. Mean duration of ventilation in this subgroup was 19.5 days. Death occurred in 13 (46.4%).

Currently, there are no proven effective therapies for critically ill patients with COVID-19 requiring mechanical ventilation (7) . The potential efficacy of anticomplement drug therapy in COVID-19 has been tested in a handful of patients to date and was recently reviewed (8) . Diurno and colleagues treated four patients with COVID-19 with the C5-blocking mAb eculizumab, weekly 34 (9). All were self-ventilating with moderately elevated CRP that fell after treatment; all recovered over 14 days. Mastaglio and colleagues treated a single nonventilated patient with the C3 blocker AMY-101 continuously infused over 14 days with favorable outcome (10) . In each of these reports, patients selected had relatively mild disease and no measurements of complement parameters to assess dysregulation before or in response to drug were reported.

We describe a preliminary evaluation of the potential benefit of C5 blockade in severe COVID-19; we show that the C5-blocking mAb LFG316 could be administered in critically ill mechanically ventilated patients with COVID-19; a single dose of LFG316 blocked C5 activity and complement activation for at least 4 days in all treated patients. In four of five patients, there was sustained improvement in clinical state persisting beyond C5 blockade. Four days after dosing, an occult Klebsiella infection was found in the nonresponding patient 5; given the known impact of complement blockade on risk of infection with gram-negative bacteria, it is possible that LFG316 treatment exacerbated the infection. No other adverse effects of therapy were seen in any of the treated patients. Our results suggest that transient blockade of C5 is sufficient to interrupt the hyperinflammatory cycle in severe COVID-19 and permit recovery even in the most extreme clinical situations. This finding differs from previous case reports of complement inhibition in COVID-19 where patients were less severely ill and treated for extended periods (8) (9) (10) . Our data are supportive of ongoing clinical trials of C5 blockade in severe COVID-19 and may inform design of current and future trials of anticomplement drugs where repeated or prolonged complement blockade are proposed; indeed, prolonged complement blockade may not only be unnecessary for patient benefit but also be harmful by increasing infection risk, a known consequence of complement blockade, over weeks or months in recovering patients, likely on other immune suppressants and with residual lung damage.

Study limitations include small cohort size and lack of a randomized control group. Although our data identify complement dysregulation and support clinical benefit of complement blockade in severe COVID-19, these limitations make it impossible to demonstrate proof of efficacy. Further studies are warranted to confirm impact of complement blockade on hyperinflammatory and/or thrombotic components of COVID-19 disease and to establish optimal timing and dosing. n Author disclosures are available with the text of this letter at www.atsjournals.org.

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Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome

Respiratory pathophysiology of mechanically ventilated patients with COVID-19: a cohort study

Electrical impedance tomography for positive end-expiratory pressure titration in COVID-19-related acute respiratory distress syndrome

Respiratory mechanics of COVID-19-versus non-COVID-19-associated acute respiratory distress syndrome

Recruitability and effect of PEEP in SARS-Cov-2-associated acute respiratory distress syndrome

Lung recruitability in COVID-19-associated acute respiratory distress syndrome: a single-center observational study

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a longitudinal study

Complement, a target for therapy in inflammatory and degenerative diseases

Targeting complement pathways in polytrauma-and sepsis-induced multiple-organ dysfunction

Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Explore COVID-19 IPH group; Explore COVID-19 Marseille Immunopole group. Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis

Generation and characterization of LFG316, a fully-human anti-C5 antibody for the treatment of age-related macular degeneration

ACTT-1 Study Group Members. Remdesivir for the treatment of COVID-19 -preliminary report

Complement as a target in COVID-19?

Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience

The first case of COVID-19 treated with the complement C3 inhibitor AMY-101

The authors thank all patients who participated in this study and gratefully acknowledge the support of Intensive Care and Clinical Immunology Laboratory staff for assistance in the routine care of these individuals. They also thank Dr. Manish Pandey for providing comparative audit data on Critical Care deaths. LFG316 was a gift from the Novartis Managed Access Program.

The Effect of Hypopnea Scoring on the Arousal Threshold in Patients with Obstructive Sleep Apnea A low respiratory arousal threshold (ArTH Resp ) is one of several endotypes that contribute to the pathogenesis of obstructive sleep apnea (OSA). Accordingly, it has emerged as a potential "drugable" target to treat OSA (1). Notably, Edwards and colleagues (2) developed a clinical screening tool to identify OSA patients with low ArTH Resp based on three predictive variables obtained from standard overnight sleep studies (i.e., polysomnograms [PSGs]): 1) nadir oxygen saturation .82.5%, 2) apnea-hypopnea index (AHI) ,30 events/hour, and 3) percentage of respiratory events that are hypopneas (%hypopnea) .58.3% that correctly predicted the presence of a low ArTH Resp in 84% of patients.However, a key limitation of this tool is that it was developed using hypopnea scoring rules from the older "Chicago" (AASM 1999 ) criteria (3), which have since been updated to the current American Academy of Sleep Medicine (AASM) "Recommended" (AASM 2012Rec ) and "Acceptable" (AASM 2012Acc ) criteria. The AASM 2012Rec -defined hypopneas are associated with a >3% oxygen desaturation or EEG arousal, whereas AASM 2012Acc requires a stricter >4% oxygen desaturation and does not consider arousals (4). Though it is established that differing scoring criteria impact the AHI and %hypopnea (5-7) , we recently demonstrated that scoring criteria also influence the measurement of another key OSA endotype (8) , the sensitivity of the ventilatory control system. However, the extent to which changes in scoring criteria impact the predictive utility of the ArTH Resp score is unknown. Accordingly, we aimed to determine the influence that the 2012 scoring criteria has on the tool's performance.