Measurement of Inflammatory Markers in Trials of COVID-19
CCBYNCOpen access
Rapid response to:
Research
Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data
Measurement of Inflammatory Markers in Trials of COVID-19
Dear Editor
We read with great interest the recent observational studies of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19 pneumonia [1,2]. While these studies are impressive for their breadth and efforts to control statistically for confounders there remain serious concerns about observational bias and selection for treatment.
In particular, it is clear that prior work has noted a drop in inflammatory markers following the administration of HCQ in trials for the treatment of COVID-19 pneumonia [3]. Few observational trials to date have stratified results using LDH release, C-reactive protein (CRP), or lymphocyte counts following treatment.
LDH levels have been used to assess survival in the setting of cancer for many years, higher levels portending a much worse prognosis [4]. An LDH level greater than 365 U/Liter alone can also predict for death from COVID-19 disease 10-18 days in advance with 90% accuracy [5]. CRP level and percent lymphocytes add another 5% to accurate predictions of mortality. These relatively straightforward measurements can be easily applied to all randomized and observational trials of patients being treated for COVID-19 disease, to more accurately assess the efficacy of therapy in those patients at highest risk.
COVID-19 pathogenesis can be partially explained by infection of the dendritic cell (DC) and endothelial cells through engagement of the ACE2/DC-SIGN/CD209/CD147 receptor complex on these cells as well as infection of the type II pneumocyte through its comparable expression of the ACE2/L-SIGN/CD209/CD147 complex [6]. A critical primary target of viral infection with subsequent destruction and intussusceptive neoangiogenesis is the ACE2/DC-SIGN/CD209/CD147 complex on pulmonary endothelium [7] which can also lead to inflammation with an increased LDH and possibly other inflammatory markers.
HCQ is a modulator of the DC as well as autophagy pathways in these and other cells [8]. Such modulation could be expected to blunt the initial deleterious immune response, limit DC transmission of virus, and reduce levels of LDH and other inflammatory markers.
As the clinical trials data on treatments for COVID-19 mature, models that involve modulation of DCs as well as endothelial cells infected by SARS-CoV-2, guided by use of such inflammatory markers, should be taken into account with stratification of patients being evaluated. It should also be relatively straightforward to re-analyze existing observational trials and control for LDH levels as well as other inflammatory markers if available.
1 Mahévas M, Tran V-T, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020 May 14;369:m1844. doi: 10.1136/bmj.m1844
2 Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 May 24; doi: 10.1016/S0140-6736(20)31180-6
3 Yu B, Wang DW, Li C. Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19. medRxiv. 2020 Jan 1;2020.04.27.20073379. doi: 10.1101/2020.04.27.20073379
4 Petrelli F, Cabiddu M, Coinu A, et al. Prognostic role of lactate dehydrogenase in solid tumors: A systematic review and meta-analysis of 76 studies. Acta Oncol (Madr). 2015 Aug 9;54(7):961–70. doi: 10.3109/0284186X.2015.1043026
5 Yan L, Zhang H-T, Goncalves J, et al. An interpretable mortality prediction model for COVID-19 patients. Nat Mach Intell. 2020;2(5):283–8. doi: 10.1038/s42256-020-0180-7
6 Brufsky A, Lotze M. DC/L SIGNs of Hope in the COVID-19 Pandemic. J Med Virol. 2020; doi: 10.1002/jmv.25980
7 Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 May 21; doi: 10.1056/NEJMoa2015432
8 Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155–66. doi: 10.1038/s41584-020-0372-x
Competing interests:
No competing interests
24 May 2020
Adam M Brufsky
Professor of Medicine, Associate Chief, Division of Hematology-Oncology
Micheal T Lotze
UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine
300 Halket Street, Suite 4628, Pittsburgh, PA, USA 15213
Rapid Response:
Measurement of Inflammatory Markers in Trials of COVID-19
Dear Editor
We read with great interest the recent observational studies of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19 pneumonia [1,2]. While these studies are impressive for their breadth and efforts to control statistically for confounders there remain serious concerns about observational bias and selection for treatment.
In particular, it is clear that prior work has noted a drop in inflammatory markers following the administration of HCQ in trials for the treatment of COVID-19 pneumonia [3]. Few observational trials to date have stratified results using LDH release, C-reactive protein (CRP), or lymphocyte counts following treatment.
LDH levels have been used to assess survival in the setting of cancer for many years, higher levels portending a much worse prognosis [4]. An LDH level greater than 365 U/Liter alone can also predict for death from COVID-19 disease 10-18 days in advance with 90% accuracy [5]. CRP level and percent lymphocytes add another 5% to accurate predictions of mortality. These relatively straightforward measurements can be easily applied to all randomized and observational trials of patients being treated for COVID-19 disease, to more accurately assess the efficacy of therapy in those patients at highest risk.
COVID-19 pathogenesis can be partially explained by infection of the dendritic cell (DC) and endothelial cells through engagement of the ACE2/DC-SIGN/CD209/CD147 receptor complex on these cells as well as infection of the type II pneumocyte through its comparable expression of the ACE2/L-SIGN/CD209/CD147 complex [6]. A critical primary target of viral infection with subsequent destruction and intussusceptive neoangiogenesis is the ACE2/DC-SIGN/CD209/CD147 complex on pulmonary endothelium [7] which can also lead to inflammation with an increased LDH and possibly other inflammatory markers.
HCQ is a modulator of the DC as well as autophagy pathways in these and other cells [8]. Such modulation could be expected to blunt the initial deleterious immune response, limit DC transmission of virus, and reduce levels of LDH and other inflammatory markers.
As the clinical trials data on treatments for COVID-19 mature, models that involve modulation of DCs as well as endothelial cells infected by SARS-CoV-2, guided by use of such inflammatory markers, should be taken into account with stratification of patients being evaluated. It should also be relatively straightforward to re-analyze existing observational trials and control for LDH levels as well as other inflammatory markers if available.
Address correspondence to Adam Brufsky, MD, PhD at brufskyam@upmc.edu
1 Mahévas M, Tran V-T, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020 May 14;369:m1844. doi: 10.1136/bmj.m1844
2 Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 May 24; doi: 10.1016/S0140-6736(20)31180-6
3 Yu B, Wang DW, Li C. Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19. medRxiv. 2020 Jan 1;2020.04.27.20073379. doi: 10.1101/2020.04.27.20073379
4 Petrelli F, Cabiddu M, Coinu A, et al. Prognostic role of lactate dehydrogenase in solid tumors: A systematic review and meta-analysis of 76 studies. Acta Oncol (Madr). 2015 Aug 9;54(7):961–70. doi: 10.3109/0284186X.2015.1043026
5 Yan L, Zhang H-T, Goncalves J, et al. An interpretable mortality prediction model for COVID-19 patients. Nat Mach Intell. 2020;2(5):283–8. doi: 10.1038/s42256-020-0180-7
6 Brufsky A, Lotze M. DC/L SIGNs of Hope in the COVID-19 Pandemic. J Med Virol. 2020; doi: 10.1002/jmv.25980
7 Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 May 21; doi: 10.1056/NEJMoa2015432
8 Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155–66. doi: 10.1038/s41584-020-0372-x
Competing interests: No competing interests