Acute Cold Respiratory Syndrome: A Narrative Review of Pathophysiological Mechanisms Beyond Viral Etiology

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. 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 — Acute Cold Respiratory Syndrome (ACRS) — as an independent nosological entity with clearly defined pathophysiological mechanisms, distinct diagnostic criteria, and specific clinical implications. The review further presents a paradigmatic shift from a pathogen-centric to a host-response model of the common cold, as proposed by Gozhenko et al. (2025). Methods A comprehensive narrative literature review was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases, covering publications from 1946 to 2025 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. 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, and thermodynamics reveals five interconnected pathophysiological mechanisms underlying ACRS: Vascular dysfunction: Inhalation of cold air activates TRPM8 (threshold < 25–28°C) and TRPA1 (threshold < 17°C) thermosensory receptors in the nasal mucosa, triggering rapid sympathetically mediated vasoconstriction within seconds to minutes. This is followed by reactive vasodilation with ischemia–reperfusion injury, increased capillary permeability, and release of histamine, bradykinin, prostaglandins (PGE₂, PGD₂), leukotrienes (LTC₄, LTD₄), and substance P — collectively producing the clinical triad of rhinorrhea, nasal congestion, and sneezing independently of any viral agent. Mucociliary dysfunction: Cold air reduces nasal mucosal temperature to 15–20°C, decreasing ciliary beat frequency (CBF) by approximately 50% — from 12–15 Hz to 6–8 Hz at 20°C, with near-complete arrest below 10°C. Simultaneously, dehydration of inhaled cold air increases mucus viscosity and reduces elasticity, impairing mucociliary transport. Mucociliary clearance time increases from a normal 10–20 minutes to over 60 minutes, significantly compromising pathogen elimination and epithelial barrier integrity. Metabolic and thermodynamic stress: 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. During physical exertion (minute ventilation 30–60 L/min) this proportion rises to 25–35%, and under extreme cold (−20°C) may reach 40–50% of basal metabolism. This substantial energetic burden induces local ATP depletion in ciliated epithelial cells, impairs ion pump function (Na⁺/K⁺-ATPase), reduces synthesis of protective proteins (mucins, defensins, lysozyme), and activates pro-inflammatory signaling pathways (NF-κB, MAPK). Neuroendocrine immunosuppression: Cold stress activates the hypothalamic–pituitary–adrenal (HPA) axis, elevating corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol. Concurrently, sympathetic activation releases noradrenaline and adrenaline, producing a biphasic immunomodulatory effect: transient stimulation followed by sustained suppression of mucosal immunity. Secretory IgA (sIgA) production is reduced through direct suppression of plasma cell function, decreased mucosal blood flow, and HPA-mediated immunosuppression — collectively increasing susceptibility to secondary viral infection. Resolution of the age paradox: The counterintuitive age-related incidence pattern (children > adults > elderly) is explained not by differences in immune competence but by quantitative differences in cold exposure: children spend more time outdoors in cold weather, dress less adequately, have a higher relative minute ventilation per kilogram of body weight, and possess less developed thermoregulatory mechanisms. This host-response model, proposed by Gozhenko et al. (2025), provides a more parsimonious and evidence-consistent explanation than the traditional "accumulated immunity" hypothesis. The synergistic interaction between ACRS and viral infection is also characterized: cold-induced mucociliary dysfunction prolongs viral contact time with the mucosa, epithelial barrier compromise facilitates viral invasion, and neuroendocrine immunosuppression reduces interferon-based antiviral defense — collectively creating conditions that maximally favor viral replication and symptomatic disease. Ten original research problems and ten testable research hypotheses are formulated, including: the TRPM8-mediated vasoconstriction hypothesis (pharmacological blockade as prevention), the metabolic depletion hypothesis (ATP deficit as a measurable biomarker of ACRS), the thermoacclimatization hypothesis (systematic cold hardening as an evidence-based preventive strategy), the microbiome disruption hypothesis, and the neurogenic inflammation hypothesis (substance P and CGRP as primary mediators of symptom onset). 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. The term Acute Cold Respiratory Syndrome (ACRS) more accurately reflects the multifactorial etiology of acute upper respiratory tract disorders, encompassing thermal stress, vascular dysfunction, metabolic burden, and immune modulation — with or without concomitant viral infection. The paradigmatic shift from a pathogen-centric to a host-response model, as proposed by Gozhenko et al. (2025), is scientifically justified and supported by convergent evidence from multiple biomedical disciplines. ACRS and viral upper respiratory tract infection are not mutually exclusive but synergistic processes: ACRS acts as a "gateway" that enhances viral susceptibility, while viral infection potentiates the cold-initiated inflammatory response. Recognition of ACRS as an independent nosological entity has significant practical implications: it reframes prevention (active cold protection as a standalone strategy), diagnosis (differentiation of ACRS from viral cold using proposed major and minor criteria), and treatment (warming and mucociliary restoration without antiviral agents in pure ACRS), with the potential to substantially reduce the global socioeconomic burden of one of humanity's most common diseases. Актуальність Гострі респіраторні захворювання, що колективно позначаються терміном «застуда», є одними з найпоширеніших патологій у світі: вони вражають мільярди людей щорічно та спричиняють колосальний соціально-економічний тягар, що перевищує 40 мільярдів доларів на рік лише у США. Попри їх повсюдність, етіопатогенез цих захворювань залишається недостатньо вивченим і науково дискусійним. Сучасна медицина пояснює всі прості простудні епізоди виключно вірусними інфекціями — переважно риновірусами (30–50%), коронавірусами (10–15%) та іншими респіраторними вірусами. Однак ця моноказуальна вірусна парадигма не пояснює низки добре задокументованих клінічних та епідеміологічних невідповідностей: розвиток симптомів протягом хвилин після холодового впливу (задовго до будь-якого можливого інкубаційного періоду), оборотність симптомів після зігрівання, відсутність лихоманки у значній частині випадків та парадоксальна вікова закономірність захворюваності, за якої літні люди — попри прогресивну імуносенесценцію — хворіють рідше, ніж діти та молоді дорослі. Ці невирішені суперечності потребують фундаментального переосмислення патогенезу холодо-асоційованих респіраторних захворювань. Мета Цей наративний огляд критично аналізує роль холодового впливу та холодового стресу в патогенезі гострих захворювань верхніх дихальних шляхів і пропонує нову концептуальну модель — Гострий холодовий респіраторний синдром (ГХРС) — як самостійну нозологічну одиницю з чітко визначеними патофізіологічними механізмами, специфічними діагностичними критеріями та конкретними клінічними імплікаціями. Огляд також обґрунтовує парадигматичний зсув від патоген-центричної до хост-відповідної моделі «застуди», запропонований Gozhenko et al. (2025). Методи Проведено комплексний нара