Steroid for Flu: Mechanisms, Classes, and Immune Effects

Steroids, particularly corticosteroids, have been explored as a potential treatment for severe flu cases due to their anti-inflammatory properties. While they help control excessive immune responses, their effects on viral infections remain complex and sometimes controversial. Understanding how steroids interact with the immune system in influenza cases is essential for evaluating their benefits and risks.

Mechanisms in Pulmonary Inflammation

Influenza infection triggers an inflammatory response in the lungs, primarily driven by the host’s reaction to viral replication. The virus targets epithelial cells lining the respiratory tract, causing cellular damage and releasing damage-associated molecular patterns (DAMPs). These molecules activate pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors, initiating signaling pathways that amplify inflammation. Nuclear factor kappa B (NF-κB) and interferon regulatory factors (IRFs) drive the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interferons, leading to immune cell recruitment and further tissue damage.

As inflammation progresses, neutrophils and monocytes infiltrate the lungs, releasing reactive oxygen species (ROS) and proteolytic enzymes that degrade the extracellular matrix. While these responses aim to eliminate the virus, excessive neutrophilic activity can disrupt the alveolar-capillary barrier, increasing vascular permeability and promoting pulmonary edema. This fluid buildup reduces oxygen diffusion, contributing to hypoxemia and respiratory distress. Severe influenza cases, such as those caused by H1N1 or H5N1 strains, often show heightened neutrophilic infiltration and elevated IL-1β and IL-8 levels, correlating with worse clinical outcomes (The Journal of Immunology, 2014).

Endothelial cells also play a role in pulmonary inflammation, as viral infection induces endothelial activation and upregulation of adhesion molecules like ICAM-1 and VCAM-1. This facilitates leukocyte adhesion and extravasation into lung tissue, perpetuating inflammation. Endothelial dysfunction can contribute to microvascular thrombosis, where fibrin deposition and platelet aggregation obstruct capillary blood flow. A study in The Lancet Respiratory Medicine (2017) found that patients with severe influenza pneumonia exhibited increased levels of circulating von Willebrand factor, a marker of endothelial injury, linking vascular dysfunction to disease severity.

Glucocorticoid Receptor Functions

Glucocorticoid receptors (GRs) mediate corticosteroids’ effects as ligand-activated transcription factors, regulating inflammation and immune responses. These receptors, part of the nuclear receptor superfamily, are highly concentrated in lung tissue, making them particularly relevant in influenza-induced pulmonary inflammation. When a glucocorticoid binds to its receptor in the cytoplasm, the receptor undergoes a conformational change, dissociating from heat shock proteins and immunophilins. This transformation exposes its nuclear localization signal, enabling its translocation into the nucleus to regulate gene expression.

Inside the nucleus, activated GRs bind to glucocorticoid response elements (GREs) in target gene promoters, upregulating anti-inflammatory proteins like annexin A1, which inhibits phospholipase A2, a key enzyme in pro-inflammatory mediator synthesis. GRs also suppress cytokine, chemokine, and adhesion molecule gene transcription by interfering with NF-κB and activator protein-1 (AP-1), reducing inflammation. This dual mechanism—activating anti-inflammatory pathways while suppressing pro-inflammatory signals—underlies corticosteroids’ immunomodulatory effects in respiratory diseases, including severe influenza.

Beyond transcriptional regulation, GRs exert rapid non-genomic effects, altering cellular activity within minutes of corticosteroid exposure. For example, glucocorticoids inhibit mitogen-activated protein kinase (MAPK) signaling, reducing phosphorylation of proteins involved in inflammatory cascades. They also enhance dual specificity phosphatase 1 (DUSP1) expression, which deactivates MAPKs, further dampening inflammation. These non-genomic mechanisms are particularly relevant in acute cases like severe influenza pneumonia, where rapid inflammation control may prevent respiratory failure.

Different Classes of Corticosteroids

Corticosteroids used in influenza-related complications vary based on their route of administration and systemic effects. The three primary classes—systemic, inhaled, and intranasal—differ in pharmacokinetics, bioavailability, and therapeutic applications.

Systemic

Systemic corticosteroids, such as prednisone, methylprednisolone, and dexamethasone, are administered orally or intravenously and exert widespread effects. They are often considered in severe influenza cases complicated by acute respiratory distress syndrome (ARDS) or cytokine storm, where excessive inflammation leads to lung injury and multi-organ dysfunction. A study in The Lancet (2020) found that dexamethasone reduced mortality in critically ill COVID-19 patients, suggesting potential benefits in severe influenza. However, systemic corticosteroids can suppress antiviral immune responses, potentially prolonging viral shedding. A meta-analysis in Clinical Infectious Diseases (2019) reported that influenza patients receiving systemic corticosteroids had a higher risk of secondary bacterial infections, highlighting the need for careful patient selection. Given these risks, systemic corticosteroids are typically reserved for cases with significant respiratory compromise rather than routine influenza treatment.

Inhaled

Inhaled corticosteroids (ICS), such as budesonide and fluticasone, are commonly used in chronic respiratory conditions like asthma and chronic obstructive pulmonary disease (COPD). These medications deliver corticosteroids directly to the airways, reducing systemic exposure and minimizing side effects. A study in The Journal of Allergy and Clinical Immunology (2021) suggested that ICS might reduce the severity of viral respiratory infections by dampening local inflammation without significantly impairing systemic immune responses. However, some research indicates that ICS use may increase susceptibility to viral infections by altering airway immune defenses. Unlike systemic corticosteroids, inhaled formulations are not typically used for acute influenza treatment but may benefit individuals with pre-existing lung conditions who experience virus-induced exacerbations.

Intranasal

Intranasal corticosteroids (INS), including fluticasone propionate and mometasone furoate, are primarily used for allergic rhinitis but may help manage upper respiratory symptoms of influenza. These medications target nasal inflammation, reducing congestion and mucus production without significant systemic absorption. While they do not directly influence lower respiratory tract inflammation, they may alleviate flu-related nasal symptoms and improve breathing comfort. A study in The American Journal of Rhinology & Allergy (2018) found that INS use in viral upper respiratory infections reduced nasal obstruction and postnasal drip, potentially enhancing patient comfort during influenza episodes. However, their impact on viral clearance and disease progression remains unclear. Given their localized effects, intranasal corticosteroids are generally considered adjunctive treatments rather than primary interventions for influenza-related complications.

Influence on Immune Cell Activity

Corticosteroids significantly alter immune cell populations, affecting their distribution, activation, and function. One immediate change following corticosteroid administration is a redistribution of circulating leukocytes. Neutrophils increase in peripheral blood due to reduced adhesion to endothelial surfaces, while lymphocytes, monocytes, and eosinophils are sequestered in lymphoid tissues, reducing their numbers in circulation. This shift impacts immune surveillance and may dampen antiviral responses in influenza-infected individuals.

Beyond redistribution, corticosteroids interfere with intracellular signaling pathways. In macrophages and dendritic cells, they suppress antigen presentation by downregulating major histocompatibility complex (MHC) class II expression, impairing T cell activation and reducing production of pro-inflammatory cytokines like interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Simultaneously, corticosteroids promote regulatory T cell (Treg) expansion, further suppressing inflammation through interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) release. While these mechanisms help control excessive immune activation, they may also delay viral clearance in influenza infections.

Changes in Gene Transcription Patterns

Corticosteroids exert their effects largely through modifications in gene transcription, altering the expression of genes involved in inflammation, metabolism, and cellular stress responses. These changes occur via the glucocorticoid receptor, which binds to glucocorticoid response elements (GREs) or interferes with transcription factors like NF-κB and AP-1.

One major consequence is the suppression of pro-inflammatory mediators. Genes encoding cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-beta (IFN-β) are downregulated, reducing lung inflammation in severe influenza cases. Corticosteroids also enhance transcription of anti-inflammatory proteins like annexin A1, which inhibits phospholipase A2, decreasing eicosanoid production. While this regulation mitigates excessive immune activation, it may also prolong viral shedding and increase susceptibility to secondary infections.

Additionally, corticosteroids influence genes involved in metabolism and stress resistance, promoting gluconeogenesis and increasing blood glucose levels. They also enhance the transcription of heat shock proteins and antioxidant enzymes, protecting cells from oxidative damage. These broad transcriptional effects highlight the balance between inflammation control and immune competency, underscoring the ongoing debate over corticosteroid use in influenza treatment.