Exploring the Viral Paradigm — Acute Cold Respiratory Syndrome: A Comparative Pathophysiological Analysis and Rationale for Nosological Differentiation in ICD-11 in Accordance with WHO Classification Reform

Abstract

Background. Acute respiratory illnesses, collectively referred to as the "common cold," represent one of the most prevalent conditions worldwide, affecting billions of individuals annually and imposing an enormous socioeconomic burden estimated at over $40 billion per year in the United States alone. Despite their ubiquity, the etiopathogenesis of these conditions remains insufficiently understood and scientifically contested. Contemporary medicine attributes all common cold episodes exclusively to viral infections — predominantly rhinoviruses (30–50%), coronaviruses (10–15%), and other respiratory viruses. However, this monocausal viral paradigm fails to explain several well-documented clinical and epidemiological inconsistencies: the onset of symptoms within minutes of cold exposure (far preceding any possible viral incubation period), the reversibility of symptoms upon rewarming, the absence of fever in a substantial proportion of cases, and the paradoxical age-related pattern of incidence in which elderly individuals — despite progressive immunosenescence — suffer fewer episodes than children or young adults. These unresolved contradictions call for a fundamental reassessment of the pathogenesis of cold-associated respiratory disease. The present review builds upon and extends the pathophysiological framework systematically introduced by Gozhenko et al. (2025, 2026), who first proposed a paradigmatic shift from a pathogen-centric to a host-response model of the common cold, and who first described the five interconnected pathophysiological mechanisms forming a self-sufficient symptom cascade independent of any viral agent.

Objective. This narrative review critically examines the role of cold exposure and cold stress in the pathogenesis of acute upper respiratory tract disorders and proposes a novel conceptual framework distinguishing two fundamentally different clinical entities: Acute Cold Respiratory Syndrome (ACRS) and Acute Viral Respiratory Syndrome (AVRS). The review introduces a three-phase model of ACRS in which cold-induced vascular dysfunction opens a "gateway" for endogenous microbiome activation, followed by neutrophilic inflammation as a second phase — a mechanism analogous to the ancient folk tradition of steam inhalation therapy (potato steam, warm dry air inhalation documented by British researchers approximately 20 years ago). The review further presents evidence supporting a paradigmatic shift from a pathogen-centric to a host-response model, as proposed by Gozhenko et al. (2025, 2026), and provides formal justification for WHO ICD-11 nosological reform.

Methods. A comprehensive narrative literature review was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases, covering publications from 1946 to 2026 in English, Ukrainian, and Polish. Search terms included: cold stress, thermoregulation, upper respiratory tract, mucosal immunity, vasoconstriction, common cold pathophysiology, mucociliary clearance, cold air inhalation, HPA axis immune suppression, TRPM8, TRPA1, nasal mucosa cold, respiratory microbiome, neutrophilic inflammation, warm air inhalation therapy, geomagnetic disturbances immune, aromatherapy nasal. Artificial intelligence tools (large language models) were used exclusively for auxiliary tasks — initial literature sorting, grammatical proofreading, and reference formatting — with all scientific content, analyses, and conclusions being the sole intellectual product of the authors. Original thermodynamic calculations of metabolic energy expenditure during cold air breathing were performed and are presented in full within the manuscript.

Results. Convergent evidence from physiology, immunology, neuroscience, thermodynamics, and microbiology reveals a three-phase pathophysiological model of ACRS fundamentally distinct from AVRS. Phase I (Initiation, 0–30 min): Cold air activates TRPM8 (threshold <25–28°C) and TRPA1 (threshold <17°C) thermosensory receptors, triggering rapid sympathetically mediated vasoconstriction within seconds to minutes, followed by reactive vasodilation with ischemia–reperfusion injury, release of histamine, bradykinin, prostaglandins (PGE₂, PGD₂), leukotrienes (LTC₄, LTD₄), and substance P — producing the clinical triad of rhinorrhea, nasal congestion, and sneezing independently of any viral agent. Phase II (Microbiome Activation and Bacterial Phase, 2–24 h): Cold-induced vascular dysfunction, mucociliary paralysis, and local immunosuppression open a "gateway" for the resident upper respiratory tract microbiome. The shift from protective commensals (Lactobacillus spp., Dolosigranulum pigrum) toward opportunistic pathogens (Staphylococcus aureus, Streptococcus pneumoniae) triggers neutrophilic recruitment and the classical inflammatory response — explaining why "pure" ACRS, if untreated, progresses to purulent rhinitis and sinusitis without any external viral agent. Phase III (Resolution or Viral Superinfection, 6 h – 3 days): Upon rewarming, pure ACRS resolves spontaneously. However, cold-induced mucociliary dysfunction, reduced sIgA, and suppressed interferon signaling create a "window of vulnerability" (2–4 h) that maximally favors viral invasion — explaining the clinical phenomenon of "severe cold after chilling." The comparative analysis of ACRS versus AVRS (Gozhenko et al., 2025, 2026) demonstrates that these two entities differ fundamentally in trigger (cold stress vs. external viral agent), incubation period (absent vs. obligatory 12–72 h), pathogenetic mechanism (thermoregulatory vasospasm → microbiome activation → neutrophilic inflammation vs. viral cytopathic effect → interferon response → adaptive immunity), seasonality (strictly temperature-dependent vs. year-round, as demonstrated by the COVID-19 pandemic), and therapeutic target (rewarming, steam inhalation, saline rinses vs. antiviral agents, vaccines). Original thermodynamic calculations demonstrate that conditioning cold air (0°C) to tracheobronchial conditions (37°C, 100% relative humidity) requires approximately 14.2 W — equivalent to ~18% of basal metabolic rate at rest, rising to 40–50% under extreme cold (−20°C). Neuro-ecological modulation by geomagnetic disturbances and therapeutic neuromodulation by aromatherapy (menthol, eucalyptol, camphor as natural TRPM8/TRPA1 agonists) are identified as novel dimensions of ACRS pathophysiology and treatment not previously integrated into a unified clinical concept.

Conclusions. The "common cold" is not a purely infectious disease but a complex syndrome in which cold stress plays an independent and fundamental pathogenetic role through a three-phase cascade: neurogenic vascular dysfunction → microbiome-mediated bacterial activation → neutrophilic inflammation. The term Acute Cold Respiratory Syndrome (ACRS), as systematically described by Gozhenko et al. (2026), more accurately reflects this multifactorial etiology. The current ICD-10/ICD-11 classification leads to massive overdiagnosis of viral infections, irrational antibiotic and antiviral prescribing, and neglect of evidence-based preventive strategies. Formal recognition of ACRS as an independent nosological entity in ICD-11 is scientifically justified, clinically necessary, and economically imperative — with potential annual savings of $20–44 billion globally.