Why is temperature sensitivity important for the success of common respiratory viruses?

This review explores the idea that temperature sensitivity is an important factor in determining the success of respiratory viruses as human parasites. The review discusses several questions. What is viral temperature sensitivity? At what range of temperatures are common respiratory viruses sensitive? What is the mechanism for their temperature sensitivity? What is the range of temperature along the human airway? What is it that makes respiratory viruses such successful parasites of the human airway? What is the role of temperature sensitivity in respiratory zoonoses? A definition of temperature sensitivity is proposed, as "the property of a virus to replicate poorly or not at all, at the normal body temperature of the host (restrictive temperature), but to replicate well at the lower temperatures found in the upper airway of the host (permissive temperature)." Temperature sensitivity may influence the success of a respiratory virus in several ways. Firstly; by restricting the infection to the upper airways and reducing the chance of systemic infection that may reduce host mobility and increase mortality, and thus limit the spread of the virus. Secondly; by causing a mild upper airway illness with a limited immune response compared to systemic infection, which means that persistent herd immunity does not develop to the same extent as with systemic infections, and re-infection may occur later. Thirdly; infection of the upper airway triggers local reflex rhinorrhea, coughing and sneezing which aid the exit of the virus from the host and the spread of infection in the community.

Placebo and Side Effects Confound Clinical Trials on New Antitussives.

This review discusses how the placebo effect related to treatment side effects may confound clinical trials on antitussives and specifically looks at the implications for trials on ATP antagonists. These new antitussives have distinctive side effects on the sensation of taste, and investigators have expressed concerns that this may unblind the clinical trials. Blinding is an essential component of trial design, but the degree of blinding in trials is rarely assessed. The assumptions of additivity and balance in clinical trials are discussed as important factors that allow assessment of the pharmacological activity of an antitussive. How side effects unbalance a clinical trial by amplifying the placebo effect of active treatments is discussed. The point is made that unblinding of trials invalidates any assessment of efficacy but that there is little interest or discussion about this fundamental aspect of trials. Proposals are discussed which may improve the blinding of trials and control placebo effects by changes to participant information, trial design, patient selection and use of active placebos. The issue of unblinding of clinical trials is not a new issue, but if real progress is to be made in developing new antitussives, then it is an issue that needs to be urgently addressed.

The role of nasal congestion as a defence against respiratory viruses.

INTRODUCTION: This review discusses how nasal congestion may have benefits as a mechanism of defence against respiratory viruses. METHODS: A literature research was conducted on respiratory viruses and nasal congestion, following a recently published review on how temperature sensitivity is important for the success of common respiratory viruses. RESULTS: The literature reported that common respiratory viruses are temperature sensitive and replicate well at the cooler temperatures of the upper airways (32°C), but replication is restricted at body temperature (37°C). The amplitude of the phases of congestion and decongestion associated with the nasal cycle was increased on infection with respiratory viruses and this caused unilateral nasal congestion and obstruction. Nasal congestion and obstruction increase nasal mucosal temperature towards 37°C and therefore restricted the replication of respiratory viruses. CONCLUSION: Nasal congestion associated with the nasal cycle may act as a mechanism of respiratory defence against infection with respiratory viruses.

What is the Role of Over 100 Excipients in Over the Counter (OTC) Cough Medicines?

Most medicines are white bitter powders that are formulated as tablets and capsules but cough medicines are an exception where the taste and appearance of the medicine are more important to the patient than the pharmacology of the active ingredient. Excipients are generally defined as any ingredient in a medicine other than the active ingredient. In most medicines excipients play a supportive role in delivering the medicine, but in the case of cough medicines, excipients have more important and complex roles and they can also be the main active ingredient of the cough medicine as menthol, glycerol, and sugars, which are declared as active ingredients. This review searched the United Kingdom electronic medicines compendium (emc) and found over 100 excipients in 60 different liquid formulations of over the counter cough medicines. The excipients were divided into functional groups: sweeteners, thickeners, flavors, colors, antimicrobials, and buffers, and the incidence and function of the different excipients is discussed. When considering the efficacy of a cough medicine, clinicians and pharmacists tend to think of the pharmacology of antitussives such as dextromethorphan or expectorants such as guaifenesin, and they rarely consider the role of excipients in the efficacy of the medicine. This review discusses the functions and importance of excipients in cough medicines and provides some new information for clinicians, pharmacists, and all interested in the treatment of cough when considering the composition and efficacy of a cough medicine.

Treatment of Acute Cough Due to the Common Cold: Multi-component, Multi-symptom Therapy is Preferable to Single-Component, Single-Symptom Therapy--A Pro/Con Debate.

Acute viral upper respiratory tract infection, or, the common cold, affects essentially every human being, and cough is reported as its most frequent associated symptom. Billions of dollars are spent worldwide annually by individuals seeking relief from this multi-symptom syndrome. Thousands of non-prescription, over-the-counter products are available worldwide, aimed at relieving the various bothersome symptoms induced by the common cold. Differences of opinion exist as to whether optimal therapy for cough associated with the common cold consists of multi-component, multi-symptom cough/cold preparations, or, whether single-component medications, aimed at relief of specific symptoms, represent the optimal therapeutic approach. The 5th American Cough Conference, held in Washington, D.C. in June, 2015, provided an ideal forum for discussion and debate of this issue between two internationally recognized experts in the field of the common cold and its treatment.

Common cold.

The common cold is a unique human disease, as it is arguably the most common disease and because of the large number of respiratory viruses causing colds it is one of the most complex of human diseases. This review discusses the respiratory viruses and notes that all these viruses may cause the illness complex recognised as the common cold. The common cold is discussed as part of the "iceberg concept" of disease which ranges from asymptomatic infection to severe illness and death. The factors influencing the incidence of colds are discussed: crowding and sociability, stress, smoking and alcohol, immune status, sex, age, sleep, season, chilling, nutrition and exercise. The mechanism of symptoms related to the innate immune response is explained and symptomatic treatments are tabulated. Morbidity associated with common cold is discussed and possible vaccines.

Treatment of COVID-19 symptoms with over the counter (OTC) medicines used for treatment of common cold and flu.

Persons suffering from acute upper respiratory tract viral infections (URTI) commonly use over the counter (OTC) medicines to relieve symptoms such as fever, muscle aches, cough, runny nose, sore throat and nasal congestion. At present OTC medicines are only licensed for treatment of common cold and flu symptoms and not for treatment of the same symptoms associated with COVID-19. The innate immune response responsible for the mechanisms of the symptoms of URTI is the same for all respiratory viruses including SARS-CoV-2 and these symptoms can be relieved by treatment with the same OTC medicines as available for treatment of colds and flu. This review provides scientific information that OTC treatments for common cold and flu-like illness caused by respiratory viruses are safe and effective treatments for the same symptoms associated with COVID-19.

Management of acute upper respiratory tract infection: the role of early intervention.

INTRODUCTION: Upper respiratory tract infection (URTI) is an illness caused by an acute infection by viruses or bacteria of the nose, sinuses, pharynx, and larynx. Most URTIs are short, mild, and self-limiting, but some can lead to serious complications, resulting in heavy social and economic burden on individuals and society. AREAS COVERED: This article presents the management guidelines and consensus established through the Delphi method during an expert roundtable conducted in November 2020 and results of a targeted literature review. EXPERT OPINION: The current acute URTI management strategies aim toward symptom alleviation and prevention of URTI virus transmission. The effectiveness of these strategies is highly increased with early intervention, administered prior to the peaking of viral shedding. This reduces the chances of developing a full-blown acute URTI, decreases symptom severity, and reduces viral transmission. Mucoadhesive gel nasal sprays have shown promising results for early intervention of acute URTI. They act by creating a barrier that can trap virus particles, thereby preventing invasion of the mucosa by the virus. Additionally, they deliver broad spectrum activity that is effective against a wide variety of pathogens that cause acute URTI. Acute URTI warrants greater attention and proactive management in reducing its burden.

Race and ethnicity in nasal plastic surgery: a need for science.

Race and ethnicity have no scientific or anthropologic validity, yet nasal plastic surgeons continue to categorize patient demographic variables according to racial and ethnic lines. The aim of this article is to discuss the problems of using race and ethnicity as demographic variables in nasal surgery. It is important to define the population demographics in any surgical study, but race and ethnicity are categories without any scientific basis. The nasal index or other anthropometric objective measures of the external nose may be used as discriminators of variation for studies in rhinology, but more studies are required to define their clinical relevance and usefulness in plastic surgery. The article critically examines the use of racial/ethnic categories and anthropometric measurements in nasal plastic surgery.

Observational study of the effects of upper respiratory tract infection on hydration status.

BACKGROUND: A frequent treatment recommendation during acute respiratory infection is to increase fluid intake. This is the first study to investigate whether upper respiratory tract infections (URTIs) such as common cold can lead to dehydration, as commonly believed by the public. METHODS: This was an exploratory, noninterventional, observational, single-center study. Subjects made 2 visits to a UK study center for assessments of dehydration, once during URTI and then 2-3 weeks later when fully recovered. The primary endpoint was a comparison of serum osmolality during vs after URTI. Complete blood count, serum urea, serum electrolytes, urine parameters (eg, osmolality, specific gravity, color), body weight/BMI, subjective assessment of thirst, and physician assessment of dehydration were additional outcomes. Only descriptive statistics and shift tables were used. RESULTS: Fifty-five otherwise healthy adults with moderate to severe URTI of < 120 h in duration were enrolled (63.6% female, 94.5% white, mean [SD] age 21.0 [6.8] years). There was no evidence of dehydration based on serum osmolality (mean [SD] 287.63 [4.83] mosm/kg during URTI; 288.60 [5.99] mosm/kg after recovery). With only a few exceptions, complete blood count, serum urea, serum electrolytes, urine specific gravity, urine color, and physician ratings of hydration remained stable. Body weight decreased > 1% in 34.0% of subjects and increased > 1% in 17.0% between visits, with similar changes in BMI. Urine osmolality varied: 14 subjects showed a decrease and 5 showed an increase, resulting in a higher mean [SD] urine osmolality during URTI (700.50 [231.59] vs 618.47 [320.29] mosm/kg). Subjects perceived greater thirst during URTI. CONCLUSIONS: In this pilot observational study, we found no evidence that URTIs such as common cold are associated with dehydration, contrary to popular belief.

Soothing Properties of Glycerol in Cough Syrups for Acute Cough Due to Common Cold.

The treatment and management of acute cough due to common cold costs billions of dollars of healthcare expenditure and there is a growing opinion that a simple linctus containing glycerol with flavourings such as honey and lemon is a safe and effective treatment for acute cough in children and adults. Glycerol is a component of most cough syrups, and although it is often thought of only as a solvent or thickening agent in cough syrups, it may be a major component for the efficacy of cough syrups due to its special properties of lubrication, demulcency, sweetness, and acting as a humectant. The major benefit of cough syrups in soothing cough is likely due to the properties of the syrup rather than the active ingredients and this review discusses the special properties of glycerol in relation to the treatment of acute cough.

Mechanisms of the placebo effect of sweet cough syrups.

The review discusses the large placebo effect associated with cough medicines and speculates on the observation that most cough medicines are formulated as sweet syrups rather than capsules or tablets. The review proposes that the major benefit of cough medicines for treatment of cough associated with common cold is related to the placebo effect rather than the pharmacological effect of an active ingredient. The placebo effect is discussed in terms of physiological effects of cough syrups associated with the taste of the medicine and true placebo effects associated with belief in the therapy. The idea is developed that a sweet taste may modulate cough at the level of the nucleus tractus solitarius, possibly by influencing the production of endogenous opioids.

Paradoxical sensation of nasal airflow in patients with common cold. Are we measuring the correct modality?

CONCLUSIONS: A paradoxical relationship between objective and subjective measures of nasal obstruction exists in participants not exposed to any treatment. The sensation of nasal obstruction may be due to the amalgamation of many different nasal sensations. Improved methods for measuring nasal sensations are required to further investigate the relationship between objective and subjective measures of nasal obstruction. OBJECTIVES: In a recent study it was shown that the subjective sensation of nasal patency increased as the nasal passages became objectively more obstructed in patients who received a placebo compared to those who received an oral decongestant. This paradoxical response may be explained as a placebo effect, i.e. patients who received a placebo may have expected to feel less obstructed. The aim of the present study was to investigate this interesting paradox by determining objective and subjective measures of nasal obstruction over time in participants not exposed to any treatment. MATERIAL AND METHODS: A total of 60 healthy participants with common cold were recruited. Objective and subjective measures of nasal obstruction were recorded at baseline and at 1 and 2 h using posterior rhinomanometry and a visual analogue scale. RESULTS: Objective measures demonstrated an increase in nasal obstruction over time for both nasal passages considered together and for individual nasal passages. Subjective measures demonstrated a sensation of decreased nasal obstruction over time for both nasal passages considered together and for individual nasal passages.

The nasal cycle and age.

CONCLUSION: The reciprocal nature of the nasal cycle declined with age in keeping with other published data, suggesting that studies of the nasal cycle may be a useful measure of central nervous system (CNS) disease and aging. OBJECTIVES: The aim of this study was to investigate changes in the nasal cycle with age. METHODS: In one male subject changes in nasal airflow were measured by anterior rhinomanometry to determine the reciprocal nature of the 'nasal cycle' at age 28 and again at age 66 years. RESULTS: Significant reciprocity was demonstrated in the historical study (age 28 years) with correlation coefficients for the 3 study days of -0.81, -0.83 and -0.79. compared with the current study (age 66 years) where non-significant correlation coefficients of 0.02 and -0.43 were obtained.

Cough induced by mechanical stimulation of the upper airway in humans.

OBJECTIVES: Cough has previously been induced in animals by means of mechanical stimulation of the upper airway but this method has not previously been applied to humans. The aims of this study were to determine if cough could be induced in humans on mechanical stimulation of the upper airway and to see if this mechanically induced cough was reproducible. We also wished to investigate if there was any difference in cough sensitivity between healthy subjects and those with acute upper respiratory tract infection (URTI). MATERIAL AND METHODS: In the first investigation, 2 groups were studied: 15 healthy subjects and 30 subjects with URTI with a mean age of 20 years. Cough was induced by vibration of the airway at the level of the trachea using a modified men's shaver. In the second investigation to determine the reproducibility of this mechanically induced cough, two groups from a different population were studied: 15 healthy subjects and 29 subjects with URTI with a mean age of 20.3 years. Cough was induced by airway vibration before and after a 90-min rest period. RESULTS: In the first investigation it was demonstrated that cough can be induced within 2 s of vibration; subjects with URTI are more sensitive to cough induction and cough approximately five times more than healthy subjects; cough increases with repeated stimulation and reaches a maximum after three periods of vibration; the cough response may be mediated by rapidly adapting airway sensory receptors. In the second investigation there was no significant difference in mean cough counts before and after a 90-min rest period in both groups, which demonstrates that the mechanically induced cough is reproducible. CONCLUSION: This is the first study to elicit cough in humans by mechanical stimulation of the upper airway. This new method of inducing cough in subjects with URTI may be useful for studying both the mechanism of cough and the effects of antitussive medicines.

Analgesic and Decongestant Efficacy of the Combination of Aspirin with Pseudoephedrine in Patients With Symptoms of Upper Respiratory Tract Infection.

The study investigated the efficacy and safety of a combination therapy of 1,000 mg aspirin (ASA) and 60 mg pseudoephedrine (PSE) on the symptoms of pain (combined score for headache and sore throat) and nasal congestion in 833 patients with acute upper respiratory tract viral infection (URTI), over 4 hours after a single dose in the clinic and over 3 days with multiple doses at home. The study demonstrated that over 4 hours in the clinic the combination ASA plus PSE was superior to PSE or placebo for relief of pain symptoms measured subjectively with pain scores, and was superior to ASA or placebo for relief of nasal congestion as measured objectively with rhinomanometry and subjectively with congestion scores. After 3 days of treatment, ASA plus PSE was superior to PSE but not to placebo or ASA for global pain assessments, and ASA plus PSE was superior to ASA and placebo but not to PSE for congestion assessments. No unexpected adverse events occurred and no serious adverse events were attributed to study medicines. This study demonstrates that a combination therapy of ASA plus PSE provides safe and effective relief of both common cold pain related symptoms and nasal congestion.

Mechanical induction of cough in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) frequently develop a dry, irritating cough which often proves refractory to anti-tussive therapies. The precise pathogenetic mechanisms responsible for this cough are unknown. We hypothesised that changes in nerves modulating mechanical sensitivity in areas of interstitial fibrosis might lead to enhanced cough response to mechanical stimulation of the chest in IPF. METHODS: We studied 27 non-smoking subjects with IPF (63% male), mean (SD) age 71.7 (7) years and 30 healthy non-smokers. Quality of life (Leicester Cough Questionnaire), cough symptom scores and cough severity scores (visual analog scales) were recorded. Percussion stimulation was applied over the posterior lung base, upper anterior chest and manubrium sternum at sequential frequencies (20 Hertz (Hz), 40 Hz and 60 Hz) for up to 60 seconds and repeated twice at two minute intervals. The number of subjects achieving two and five-cough responses, total cough counts and cough latency were recorded. In separate experiments, the effect of mechanical stimulation on the pattern of breathing was determined in eight IPF subjects and five control subjects. RESULTS: In patients with IPF, we demonstrated strong correlations between subjective cough measurements, particularly the cough symptom score and Leicester Cough Questionnaire (r = -0.86; p < 0.001). Mechanical percussion induced a true cough reflex in 23/27 (85%) IPF subjects, but only 5/30 (17%) controls (p < 0.001). More patients with IPF reached the two-cough response at a lower frequency (20 Hz) posteriorly than at other positions. Highest mean cough totals were seen with stimulation at or above 40 Hz. Mechanical stimulation had no effect on respiratory rate but increased tidal volume in four (50%) subjects with IPF, particularly at higher frequencies. It was associated with increased urge to cough followed by a true cough reflex. CONCLUSIONS: This study demonstrates that patients with IPF show enhanced cough reflex sensitivity to mechanical stimulation of the chest wall whilst normal individuals show little or no response. The observation that low frequency stimulation over the lung base, where fibrosis is most extensive, induces cough in more patients than at other sites supports the hypothesis that lung distortion contributes to the pathogenesis of cough in IPF.