COVID-19 Sequelae and the Host Proinflammatory Response: An Analysis From the OnCovid Registry

Abstract

Background: Fifteen percent of patients with cancer experience symptomatic sequelae, which impair post-COVID-19 outcomes. In this study, we investigated whether a proinflammatory status is associated with the development of COVID-19 sequelae.

Methods: OnCovid recruited 2795 consecutive patients who were diagnosed with Severe Acute Respiratory Syndrome Coronavirus 2 infection between February 27, 2020, and February 14, 2021. This analysis focused on COVID-19 survivors who underwent a clinical reassessment after the exclusion of patients with hematological malignancies. We evaluated the association of inflammatory markers collected at COVID-19 diagnosis with sequelae, considering the impact of previous systemic anticancer therapy. All statistical tests were 2-sided.

Results: Of 1339 eligible patients, 203 experienced at least 1 sequela (15.2%). Median baseline C-reactive protein (CRP; 77.5 mg/L vs 22.2 mg/L, P < .001), lactate dehydrogenase (310 UI/L vs 274 UI/L, P = .03), and the neutrophil to lymphocyte ratio (NLR; 6.0 vs 4.3, P = .001) were statistically significantly higher among patients who experienced sequelae, whereas no association was reported for the platelet to lymphocyte ratio and the OnCovid Inflammatory Score, which includes albumin and lymphocytes. The widest area under the ROC curve (AUC) was reported for baseline CRP (AUC = 0.66, 95% confidence interval [CI]: 0.63 to 0.69), followed by the NLR (AUC = 0.58, 95% CI: 0.55 to 0.61) and lactate dehydrogenase (AUC = 0.57, 95% CI: 0.52 to 0.61). Using a fixed categorical multivariable analysis, high CRP (odds ratio [OR] = 2.56, 95% CI: 1.67 to 3.91) and NLR (OR = 1.45, 95% CI: 1.01 to 2.10) were confirmed to be statistically significantly associated with an increased risk of sequelae. Exposure to chemotherapy was associated with a decreased risk of sequelae (OR = 0.57, 95% CI: 0.36 to 0.91), whereas no associations with immune checkpoint inhibitors, endocrine therapy, and other types of systemic anticancer therapy were found.

Conclusions: Although the association between inflammatory status, recent chemotherapy and sequelae warrants further investigation, our findings suggest that a deranged proinflammatory reaction at COVID-19 diagnosis may predict for sequelae development.

Figure 1.

Study flow diagram. CRP = C-reactive protein; LDH = lactate dehydrogenase; NLR = neutrophil to lymphocyte ratio; OIS = OnCovid Inflammatory Score; PLR = platelet to lymphocyte ratio; ROC = receiver operating characteristics; SACT = systemic anticancer therapy.

Figure 2.

Fixed multivariable analysis according to categorized baseline inflammatory markers or indices for COVID-19 sequelae. A) COVID-19 sequelae overall, B) respiratory sequelae, and C) post–COVID-19 fatigue. Adjusting covariates for each analysis were sex (male vs female), age (≥65 vs <65 years), number of comorbidities (0-1 vs ≥2), primary tumor (clustered as breast, gastrointestinal, gynecological or genitourinary, thoracic, and others), receipt of systemic anticancer therapy within 4 weeks of COVID-19 diagnosis (yes vs no), tumor stage (defined as advanced vs nonadvanced), tumor status (presence of active vs nonactive disease), experience of at least 1 COVID-19 complication (yes vs no), receipt of any COVID-19–specific therapy (yes vs no), hospitalization (preexisting for whatever cause, including cancer vs due to COVID-19 vs not required), and country (United Kingdom; Spain; Italy; and France, Belgium, or Germany). CI = confidence interval; CRP = C-reactive protein; LDH = lactate dehydrogenase; NLR = neutrophil to lymphocyte ratio; OIS = OnCovid Inflammatory Score; OR = odds ratio; PLR = platelet to lymphocyte ratio.

Figure 3.

Fixed multivariable analysis including different type of systemic anticancer therapy (SACT) as covariate (1237 patients) for COVID-19 sequelae. A) COVID-19 sequelae overall, B) respiratory sequelae, and C) post–COVID-19 fatigue. CDKi = cyclin dependent kinase inhibitors; CI = confidence interval; GI = gastrointestinal; GU = genitourinary; GY = gynecological; ICIs = immune checkpoint inhibitors; MABs = monoclonal antibodies; OR = odds ratio; PARPi = poly adenosine diphosphate-ribose polymerase inhibitors; TKIs = tyrosine kinase inhibitors; UK = United Kingdom.

Figure 4.

Median baseline inflammatory markers or indices according to different types of systemic anticancer therapy (SACT) regimens at COVID-19 diagnosis. A) C-reactive protein (CRP); no SACT: 33.0 mg/L (interquartile range [IQR] = 8.5-101.7 mg/L), chemotherapy = 18.8 mg/L (IQR = 6.1-68.8 mg/L), immune checkpoint inhibitors (ICIs) = 42.0 mg/L (IQR = 0.8-101.1 mg/L), endocrine therapy = 23.5 mg/L (IQR = 3.9-90 mg/L), tyrosine kinase inhibitors (TKIs) or monoclonal antibodies (MABs) = 12.0 mg/L (IQR = 4.6-53.5 mg/L), poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) or cyclin dependent kinase inhibitors (CDKi) = 6.8 mg/L (IQR = 2.9-29.1 mg/L). B) Neutrophil to lymphocyte ratio (NLR); no SACT = 4.8 (IQR = 2.6-9.2), chemotherapy = 3.5 (IQR = 2.0-8.8), ICIs = 3.6 (IQR = 1.9-7.1), endocrine therapy = 5.4 (IQR = 1.8-11.3), TKIs or MABs = 4.2 (IQR = 2.2-6.9), PARPi or CDKi = 4.0 (IQR = 1.0-8.4). Median values are presented as Log₁₀. Two-sided P values calculated with the Kruskal–Wallis test.