Time to re-define ‘normal’ in the context of Post-Acute COVID-19 biomarkers in the assessment of patient outcomes?

Introduction: Post-acute COVID-19 or Long COVID (LC) is a threat to health and well-being, and 1 in 10 infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop persistent symptoms. LC is associated with >200 symptoms that impact quality of life and functional status. Many LC patients are being dismissed from care due to returning ‘normal’ results on ‘routine’ clinical investigations. Accordingly, the objective of the study was to explore the relationship between potential diagnostic biomarkers, symptom profile severity and functional status.

Method: Participants with a confirmed history of COVID-19 were recruited from Long COVID clinics in the United Kingdom, as part of a 16-week cohort observation study. Venous blood samples were taken from 35 individuals [24 female] and assessed for standard clinical chemistry markers of inflammatory and metabolic status, including full blood count (white blood cells [WBC], red blood cells [RBC], platelets, haemoglobin, hematocrit, ferritin, mean corpuscular volume [MCV] mean corpuscular haemoglobin [MCH], mean corpuscular haemoglobin concentration [MCHC], red cell distribution width [RDW], basophils, neutrophils, lymphocytes, eosinophils, monocytes), CRP, d dimers, interleukin 6 (IL-6), and lactate dehydrogenase [LDH]. Patient-reported outcomes and symptoms were assessed by validated self-report methods including fatigue, dyspnoea, cognitive deficit, quality of life and symptom frequency and severity. Functional status was assessed via 6-Minute-Walk (6MWT).

Results: Sixty-three percent of participants [17 female] had one or more values outside of expected reference ranges (WBC n=3, RBC n=6, haemoglobin n=3, haematocrit n=2, MCV n=3, MCH n=3, MCHC n= 1, RDW n=4, neutrophils n=3, lymphocytes n=5, monocytes n=1, basophils n=2, CRP n=3, ferritin n=3, d-dimer n=9). These changes were not linked to changes in function status or patient-reported outcomes during the first three visits (p=>0.05), there was a significant between-group difference with those outside of expected reference ranges completing less on the 6MWT (p=<0.05).

Discussion: The pathophysiology of LC is complex and patients report broad symptoms across multiple organ systems, such as respiratory, gastrointestinal, cardiovascular, and the autonomic nervous system. Routine clinical investigations of biomarkers are vital, but assessments often return results within a pre-determined ‘normal’ range. Whilst routine testing is important, condition-specific investigations should also be explored. Further inspection of the data in reference to the symptom profile and reduced functional status demonstrates a need for more holistic approaches.
Conclusion: The complex pathophysiology of LC requires further understanding and development of investigative approaches to LC diagnoses and treatment. Routine investigations of people with LC demonstrate abnormal responses which and even those that return ‘normal’ results experience debilitating symptom profiles and reduced quality of life. Due to the complex underlying mechanistic issues of LC, more specific biochemical profiling is required during clinical investigations.