Neurofilament Light Chain in Patients with COVID‐19 and Bacterial Pneumonia

Abstract

We read with great interest the recent article by Sutter and colleagues reporting increased serum neurofilament light chain (NfL) levels in COVID-19 patients compared to non-COVID-19 intensive care unit (ICU) patients without infectious disease. 1 They postulated that infection with SARS-CoV-2 leads to neuronal injury in ICU-patients and that NfL might be used to identify patients at risk for neurological complications.We evaluated these findings in the broader context of infectious disorders by comparing the plasma NfL levels of critically ill patients with similar disease severity and pneumonia induced by SARS-CoV-2 versus bacterial pathogens. We excluded patients with neurological comorbidities or trauma and matched the study population investigated by Sutter et al for sex, age, and disease severity (COVID-19 pneumonia vs bacterial pneumonia: mean age = 65 years, range = 42-89, 78% male, Sequential Organ Failure Assessment [SOFA] score = 4, range = 2-11 vs mean age = 67 years, range = 50-89, 90% male, SOFA score = 3, range = 0-5). Most notably, we observed that patients with COVID-19 pneumonia had considerably lower NfL levels compared to patients with bacterial pneumonia at day 3 AE 1 after onset of sepsis (defined as infection-related acute change in total SOFA score ≥ 2 points), which did not significantly increase over time (Fig A). Consistently with previous reports, we found a positive correlation between NfL levels and age as well as SOFA score in COVID-19 patients (see Fig B , C).FIGURE: Neurofilament light chain (NfL) assay by Quanterix (Billerica, MA) HD-X was used to measure NfL levels according to manufacturer's instructions. (A) Comparison of NfL levels in patients with COVID-19 pneumonia at day 3 AE 1 and day 7 AE 1 (n = 18) and bacterial pneumonia at day 3 AE 1 (scatter dot blot with mean; n = 10) after onset of sepsis (analysis of variance on ranks, p < 0.001; Dunn multiple comparison test, ***p < 0.001). (B, C) Pearson correlation was used to assess correlations between neurofilaments and Sequential Organ Failure Assessment (SOFA) score (n = 36; day 3 AE 1 and 7 AE 1) or age (n = 18; day 3 AE 1) in COVID-19 patients.

Plasma Biomarkers of Neuropathogenesis in Hospitalized Patients With COVID-19 and Those With Postacute Sequelae of SARS-CoV-2 Infection

“…Our results confirm previously published findings that patients hospitalized with severe COVID-19 have elevated biomarkers of CNS injury in their blood. 6 , 21 - 25 This finding therefore supports the body of literature showing that COVID-19 neurologic sequelae in the acute phase are accompanied by damage to the CNS despite the fact that direct SARS-CoV-2 infection of the brain parenchyma remains a matter of debate. 26 In severely ill patients, the possible causes of CNS injury include hypoxemia, vasculopathy, coagulopathy, or systemic inflammation leading to blood-brain barrier disruption.…”

Prognostic value of serum/plasma neurofilament light chain for COVID‐19‐associated mortality

“…An increase in serum or CSF NfL has been previously associated with increased ICU mortality due to sepsis‐associated encephalopathy 8 . This study expands these data to COVID‐19 ICU admissions: First, we validated reports linking high serum/plasma NfL levels to COVID‐19 severity 9–13,22,23 . Our longitudinal measurements demonstrated that rise in NfL generally occurs during hospitalizations of critically ill patients and trails other transient laboratory abnormalities such as decreased ALC and increased LDH by 5–20 days.…”

“…8 This study expands these data to COVID-19 ICU admissions: First, we validated reports linking high serum/plasma NfL levels to COVID-19 severity. [9][10][11][12][13]22,23 Our longitudinal measurements demonstrated that rise in NfL generally occurs during hospitalizations of critically ill patients and trails other transient laboratory abnormalities such as decreased ALC and increased LDH by 5-20 days. The degree of LDH increase is a strong determinant of the subsequent magnitude of NfL rise, suggesting that COVID-19-associated CNS injury is secondary to damage of other critical organs, such as liver, kidneys, and lungs.…”

“…This conclusion aligns with pathology studies ruling out strong primary infiltration of CNS tissue by the SARS-CoV-2 or by the immune system; those studies instead attribute COVID-19-associated CNS damage to processes such as hypoxia or intravascular coagulation. 24 Compared to previous studies of NfL in COVID-19, [9][10][11][12][13]22,23 we studied a cohort of patients in which a high proportion eventually died (133/338 = 39.3%). This allowed us to unequivocally link high serum/plasma NfL levels with COVID-19 mortality, something that remained ambiguous in the previous studies.…”

Concerns Regarding Therapeutic Implications of Very Low‐Level Dystrophin

“…By not making the distinction of biochemically normal versus biochemically abnormal dystrophin, the authors may inadvertently heighten the expectations of patients, families, physicians, and regulatory agencies regarding anticipated clinical benefit from very low levels of semifunctional dystrophin. 1…”