# Type I Interferon-Related Gene Expression and Laboratory Abnormalities in Acute Infection Are Associated with Long COVID Symptom Burden

## TL;DR

This study finds that immune system markers during acute SARS-CoV-2 infection are linked to the severity of long COVID symptoms months later.

## Contribution

The study identifies specific immune and hematologic factors in acute infection associated with long-term symptom burden in long COVID patients.

## Key findings

- Higher white blood cell and neutrophil counts during acute infection correlate with severe long COVID symptoms.
- Lower MX-1 gene expression during acute infection is associated with a higher symptom burden in long COVID.
- Absolute monocyte count independently correlates with long COVID symptom severity.

## Abstract

Background: Long COVID—defined as the persistence of symptoms or the development of new symptoms beyond four weeks after acute SARS-CoV-2 infection—affects an estimated 10–30% of individuals recovering from COVID-19, posing a significant public health burden. Emerging evidence suggests that type I interferons (IFNs) (a critical group of cytokines in the antiviral defense) and hematologic alterations, such as lymphopenia and elevated inflammatory markers, are linked to both the severity of acute COVID-19 and the likelihood of developing long-term symptoms. The aim of this study is to explore the association between type I IFN signatures and long COVID. A second aim is to examine the relationship between laboratory findings during acute infection and long COVID. Methods: The study included 61 patients investigated for the presence of long COVID symptoms 16.5 ±1.5 months after acute infection. Patients were divided into two groups of higher symptom burden of long COVID and those with milder symptoms based on demographic, laboratory, and clinical data as well as type I IFN-inducible gene expression (MX-1, IFIT-1, and IFI-44) measured in peripheral blood by real-time PCR. Data collected during acute infection were recorded. Peripheral blood samples were collected during the acute phase of infection, within the first 48 h of hospital admission. IFN-inducible gene expression was measured prospectively at that time, and RNA was extracted immediately for subsequent analysis. Results: History of intubation emerged as a significant associated factor of severe long COVID, with 75% of intubated patients reporting >8 persistent symptoms approximately 16 months post-infection. Higher white blood cell (WBC) and neutrophil counts but lower eosinophil and monocyte counts in acute infection were found to be associated with a high burden of long COVID symptoms. Interestingly, absolute monocyte count was found to independently correlate with higher long COVID symptom burden. Lactate dehydrogenase (LDH) and serum glutamic-oxaloacetic transaminase (SGOT) also differed significantly between groups, with higher levels correlating with a high burden of long COVID symptoms. Notably, MX-1 transcript levels in peripheral blood at the time of acute infection were reduced in patients with a high burden of long COVID symptoms, suggesting that dysregulated immune responses during the acute phase may contribute to persistent symptoms. Conclusions: These findings suggest the potential association of hematological and immune markers with long COVID severity, as well as the importance of monitoring these parameters to identify at-risk patients for early interventions.