Local Nasal Response Against COVID-19: Debate Regarding the Absence of Nasal Inflammatory Symptoms

Introduction

COVID-19 differs from other upper respiratory tract infections (URTIs) in its high degree of chemosensory involvement. ¹ However, this high level of chemosensory involvement in COVID-19 occurs in the absence of nasal obstruction/inflammatory symptoms. A review of 75 164 COVID-19 patients, 113 818 influenza type A patients, and 9266 influenza type B patients indicated that nasal inflammatory symptoms, such as runny nose (14%, 70%, and 74%, respectively), sore throat (15%, 45.5%, and 33%), and rhinorrhea (9.5%, 44.5%, and 49%), were less frequent in COVID-19. ² In addition to chemosensory involvement, it is also necessary to focus on the absence of nasal obstruction/inflammatory symptoms in COVID-19. This may also explain why some people exposed to SARS-CoV-2 get infected and just don’t manifest URTI symptoms.

Mechanism of Local Nasal Defense in URTI

URTIs are limited by the local defenses of the upper respiratory tract (URT). Nasal congestion and rhinorrhea are important mechanisms of local defense against URTI in the URT. Nasal congestion usually occurs within the first week of URTI after systemic responses, such as fever. This congestion is a result of a response to vasodilatory mediators, such as bradykinin. Nasal obstruction decreases the nasal airflow and blocks cooling of the nasal mucosa by outside air. With increases in the nasal blood flow, the intranasal mucosa temperature increases. Increased temperature is a main natural defense mechanism and has a long historical use in medicine. ³ In general, URTIs are associated with an increase in temperature of 3 °C to 5 °C in the nasal mucosa, while the body temperature increases by only 0.1 °C. ⁴ T-cell migration also increases with temperature, and this migration further facilitates chemotaxis.

The optimal growth temperature for coronaviruses is 32 °C to 33 °C, which is the normal temperature of the superficial layer of the nasal mucosa. However, the lungs are maintained at a temperature of 37 °C. Most viruses show inhibition of their effects at temperatures above 33 °C. This temperature difference may also be why the nasal mucosa acts as a reservoir for coronaviruses. A previous experimental study in mice also demonstrated that increasing the temperature from 33 °C to 37 °C increases antiviral defense protein expression (type I/III IFN genes and IFN-stimulated genes). ⁵ In another study, at pH 6.0, increasing the temperature from 33 °C to 37 °C decreased the infectivity and viability of coronaviruses. ⁶ Although there have been no reports of the reduction of coronavirus viral load with increasing temperature from 33 °C to 37 °C, the WHO guidelines indicate that exposure to temperatures >56 °C for 15 minutes results in a 4 log reduction of coronavirus viral load. ⁷ Yap et al reported that increasing environmental temperature adversely affects SARS-CoV-2 lifetime. At 30°C, 35°C, and 40°C, SARS-CoV-2 lifetimes were 22.5, 9.4, and 4.0 hours, respectively. ⁸

With rhinorrhea, trigeminal nerve stimulation results in the release of inflammatory mediators in the nasal system. Rhinorrhea produces an exudate containing important antimicrobial molecules, such as IgA, IgG, lactoferrin, and lysozyme. ⁹

Comment

Although COVID-19 research is currently focused on the symptoms of the disease, it is also necessary to examine the absence of symptoms commonly associated with other URTIs to better understand virus dynamics. The absence of nasal inflammatory signs indicates a local deficiency in the affected respiratory system or viral advantage over natural defense systems. In either conditions, COVID-19 escapes or hides from the defense systems of the URT. A better understanding of these phenomena will facilitate the development of new therapeutic modalities to support the URT defense mechanisms, such as intranasal interleukins, vaccines, and so forth. Improving local defenses in the URT may trigger immune mechanisms to work more effectively.

Influenza is the best-studied viral infection. Previous studies of influenza virus indicate that vaccination results in the production of serum levels of IgG antibodies. However, IgG may not be effective for mucosal surfaces and may not be sufficient to protect the nasal and tracheal mucosae against URTIs. Intranasal vaccines have been developed, and the application of intranasal H5 influenza vaccine has been shown to not only produce local secretory IgA but also to induce IgG in serum. ¹⁰

Nasal inflammatory symptoms may be more important than previously thought. The absence of nasal inflammation allows the virus to replicate effectively and rapidly in the URT. Some people exposed to SARS-CoV-2 get infected and just don’t manifest URTI symptoms. Bende et al inoculated human coronavirus 229E into 24 subjects after which 3 subjects remained uninfected, 13 subjects were clinically infected and 8 subjects had sub-clinical infection. ³ The local defenses may be able to overcome viral load with previous coronavirus infections, but this seems not to be the case for the novel coronavirus, SARS-CoV-2.