Identifying and Treating Non-COVID Viral Respiratory Infections

Executive Summary

• Viral respiratory infections range from asymptomatic to life-threatening illness with multi-organ failure. They are common in all age groups, but mortality is highest at both extremes of age.
• Viral respiratory infections play an important role as a trigger for exacerbations of chronic respiratory conditions, such as asthma and chronic obstructive pulmonary disease.
• The more common viral causes of respiratory tract infection include rhinovirus, human adenovirus, influenza virus types A and B, human metapneumovirus, parainfluenza virus, respiratory syncytial virus, and coronavirus.
• A variety of responses involving interferon and cytotoxic T-cell responses with release of cytokines and chemokines are associated with elimination of the virus and subsequent recovery.
• Antibiotic resistance in the U.S. healthcare setting is a growing threat to public health, with 2.8 million people becoming infected and 35,000 people dying each year from antibiotic-resistant infections.

Definition

These days, it is easy to think every patient with a cough or a runny nose has COVID-19. But it is important to remember that all of the viral respiratory diseases are still circulating and causing significant disease and discomfort. Respiratory viruses can cause a variety of clinical manifestations, from asymptomatic infections to life-threatening illnesses with multi-organ failure.¹ Viruses affect individuals across all age groups, posing a significant symptom burden. They also are responsible for high societal financial burden because of lost productivity, healthcare costs, and school absenteeism.² In addition, they are a leading cause of mortality in children younger than 5 years of age in low- and middle-income countries.³

Because of recent advances in diagnostic testing with enhanced capability to detect pathogens, viruses have been proven to be significant causes of respiratory tract infection even among immunocompetent patients. The morbidity and mortality burden of viral respiratory tract infections likely will continue to grow as the percentage of elderly adults and those with chronic medical conditions increases.⁴

In addition, viral respiratory infections are recognized as key triggering factors in exacerbations of chronic respiratory diseases, such as bronchiectasis, asthma, and chronic obstructive pulmonary disease (COPD).²

Epidemiology

About 13 million patients presented to an emergency department (ED) in 2018 (pre-pandemic) with respiratory symptoms.⁵ As a result, in part, of the aging of the U.S. population and of the success of childhood vaccination programs, the epidemiology of respiratory tract infection is changing.⁴

The incidence and morbidity of these viral infections is greatest at the extremes of life — in infants and in the older population. As many as 70% of children and 30% of adults with a viral respiratory infection may develop lower respiratory symptoms, with the virus often the sole pathogen identified.⁶ In addition, the respiratory viral infection may be the initial insult in a cascade of events that leads ultimately to bacterial respiratory infection.¹ Most respiratory virus infections occur in the fall and winter months, but some, such as human adenovirus infection, do not show a specific seasonal variation.⁷

On average, young children have six to eight colds per year and adults have two to four colds per year. Day care attendance is a major risk factor for respiratory illnesses in children, and the frequency of colds increases with the number of children in the group. However, frequent infections in the preschool years may lower the frequency of the common cold during school-age years.

Etiology

Viruses responsible for the highest number of respiratory tract infections include rhinovirus, human adenovirus, influenza virus types A and B, human metapneumovirus, parainfluenza virus, respiratory syncytial virus (RSV), and coronavirus.^8,9 With the exception of adenovirus, which is a deoxyribonucleic acid (DNA) virus, all of these are ribonucleic acid (RNA) viruses.

Pathophysiology

Respiratory viruses are transmitted readily from person to person via direct contact, aerosolization of infective droplets during coughing or sneezing, or indirectly by hand transfer from contaminated objects or surfaces to the nasal or conjunctival epithelium of susceptible individuals. Table 1 outlines some common routes of transmission.^10,11

After transmission, the pathogenesis of viral respiratory tract infections is not fully understood but appears to involve a delicate balance between virus infection and clearance by the host. Viral inoculation occurs chiefly through the eyes and nose, following which most viruses replicate locally in the respiratory epithelium of the large and small airways without triggering systemic infection.

This viral replication within the airways may, depending on viral and host factors, result in inflammation, increased mucosal secretions, and leukocyte infiltration, as well as changes in ciliary and mucus-producing functions. Both upper and lower ciliated airway cells may be destroyed, causing epithelial denudation, which can lead to compromise of phagocytic cell function and clearance mechanisms, thus increasing susceptibility to bacterial superinfection.

The pathogenesis of infection of the respiratory tract by viral pathogens also is dependent on host immune responses. Certain viruses, for example, may interact with the immune systems in ways that activate immediate hypersensitivity reactions, leading to virus-induced airway constriction.

The host immune system employs a range of responses, including cytotoxic T-cell release of cytokines and chemokines leading to elimination of the virus and subsequent recovery. Illustrating the body’s contribution to the (sometimes) fine line between recovery and worsening illness, excessive cytokine release can occur, with the most severe representing the clinical entity known as “cytokine storm, a systemic inflammatory condition associated with significant morbidity and mortality.”¹⁰

Clinical Features

Common Cold

The common cold is a conventional term for a mild upper respiratory illness caused by rhinovirus. Symptoms often start with a sore throat, soon thereafter accompanied by nasal congestion, rhinorrhea, sneezing, and cough.¹² The initial sore throat usually resolves rapidly, while the initial watery nasal discharge becomes progressively thicker and more purulent. This purulence of the nasal discharge generally is not associated with changes in the nasopharyngeal bacterial flora and does not necessarily indicate a simultaneous nasal mucosal bacterial infection.

While fever is a common finding among children with upper respiratory infection of any cause, it is an uncommon finding in adults. Additional symptoms associated with the common cold syndrome include hoarseness, headache, malaise, and lethargy. Muscle aches are an occasional complaint in patients with colds, although they are a more characteristic feature of influenza infection. Table 2 shows the signs and symptoms of a cold vs. influenza.

The designation of a particular upper respiratory infection as a common cold, sinusitis, acute otitis media, pharyngitis, or bronchitis often is arbitrary, since upper respiratory tract infections can affect any part of the mucosa. Indeed, multiple areas (simultaneously or at different times) often are affected during the course of the same illness.¹³

Common colds typically are short-lived, lasting a few days, with occasional lingering symptoms lasting longer. Symptoms peak within one to three days and generally clear by one week, although a lingering cough often persists.

Although they are unlikely to cause mortality or serious morbidity in immunocompetent patients, common colds are responsible for considerable discomfort, lost work, and medical costs. They also are sometimes accompanied by a bacterial complication, the most common of which is acute otitis media, which occurs in about 20% of children with viral upper respiratory infections. Sinusitis and pneumonia are other common bacterial complications, with sinusitis estimated to complicate about 0.5% to 2% of colds. Pneumonia associated with a viral upper respiratory infection may be an extension of the viral infection to the lung but may commonly be a bacterial complication of the predisposing viral illness.^12,13

Acute viral respiratory infections also often are implicated in acute exacerbations of asthma and COPD. Although RSV is the most common cause of severe viral respiratory illness, rhinovirus infection also has been associated with severe and even fatal lower respiratory tract disease.

Laryngitis

Laryngitis is defined as infectious or non-infectious inflammation of the larynx. Acute laryngitis most frequently is caused by the same viruses as the common cold, and its clinical course most often lasts fewer than three to four weeks. Symptoms typically include dysphonia and/or pain in the anterior neck in concert with other symptoms of an upper respiratory infection.¹⁴

Influenza

The influenza virus is a single-stranded RNA virus from the Orthomyxoviridae family that causes an acute respiratory illness. Human epidemics of influenza are caused by the human influenza subtypes A and B, while influenza virus type C causes a mild respiratory illness similar to the common cold.

Genetic properties of influenza viruses can lead “antigenic shifts,” with the potential to cause pandemics of human illness because of a lack of preexisting immunity.¹⁵ Seasonal epidemics occur in temperate climates annually during the fall and winter season, while in tropical regions, cases of influenza are reported intermittently throughout the year. Worldwide, the annual mortality as the result of influenza is estimated at 290,000 to 650,000.¹⁶

Respiratory tract infection by influenza virus commonly causes headache, sore throat, fever, nasal congestion, generalized muscle aches, and malaise. Abdominal symptoms, such as vomiting and/or diarrhea, may occur, particularly in children.

Severe infection may lead to lower respiratory tract disease, central nervous system involvement (encephalopathy and encephalitis), and severe dehydration. Further complications may lead to organ failure and septic shock.¹⁷ Typically, abrupt onset of symptoms follows a one- to four-day incubation period, and the illness typically lasts about three to seven days, although cough and fatigue may persist beyond two weeks.¹⁸

Influenza infection also may lead to exacerbations of underlying chronic diseases, such as asthma, COPD, and congestive heart failure.

Acute Bronchitis

Acute bronchitis presents as productive or non-productive cough in the setting of a self-limited infection of the epithelial cells of the bronchi. More than 90% of cases of uncomplicated acute bronchitis are caused by a viral infection, although a minority may be caused by nonviral organisms, including Moraxella catarrhalis, Mycoplasma pneumoniae, Bordetella pertussis, Chlamydia pneumoniae, Haemophilus influenzae, Legionella, or even Streptococcus pneumoniae.¹⁹ Inhalation of respiratory irritants, such as cigarette smoke, also may cause acute bronchitis.²⁰

Symptoms of acute bronchitis include those found in other clinical syndromes of upper and lower respiratory tract infections and characteristically include cough for at least five days, low-grade fever, headache, dyspnea, wheezing, rhonchi, or other signs of obstruction. Symptoms last two to three weeks, but in some cases, cough may persist for as long as eight weeks.²¹

Diagnostic Studies

Identification of a specific viral cause is not necessary, and most respiratory viral infections are diagnosed clinically.²² Testing may be indicated for influenza when antiviral medications would be considered or in cases where the diagnosis needs to be confirmed. There are a variety of rapid influenza tests available that identify the presence of viral nucleoprotein antigens in the sample. Confirmation is by reverse transcription-polymerase chain reaction (RT-PCR) or viral culture. While the rapid tests are available in about 15 minutes, they have a lower sensitivity compared to the RT-PCR or culture. Sensitivity is around 50% to 70% for rapid tests, with a specificity of 90% to 95%. Therefore, a negative test in a patient with classic symptoms, especially during a flu surge, should be interpreted with caution. However, a positive test is very likely to be influenza. The highest amount of viral shedding occurs around day 3-4, and the testing has the highest sensitivity around that time. Nasopharyngeal specimens often are used most commonly in routine clinical practice and in many epidemiologic studies.²³

In the absence of abnormal vital signs, history, or physical examination findings suggestive of pneumonia, imaging with chest radiograph is not necessary in most cases.

Some common testing methods are summarized in Table 3.¹⁰

Differential Diagnosis

The differential diagnosis for viral upper respiratory infections depends on the symptom presentation but includes bacterial pneumonia, COVID-19, allergic rhinitis, medication side effects, fungal infection, acid reflux, voice misuse or overuse, toxic inhalation, postnasal drainage, and trauma. A careful history and physical examination usually are sufficient to distinguish among these.

Management

Common Cold

Because the symptoms of the common cold are universally self-limited, treatment is aimed at reducing the severity of symptoms. Educating patients about the natural progression of symptoms of the common cold can help manage their expectations, limit pointless antibiotic use, and prevent unnecessary use of over-the-counter products.²³

Antibiotics are of no benefit in the treatment of acute viral upper respiratory infections in adults and children, and physicians should avoid prescribing them.^24,25

Treatments proven to be ineffective, effective, and even harmful are summarized in Table 4.

The U.S. Food and Drug Administration (FDA) has issued an advisory that over-the-counter cold formulations containing decongestant or antihistamine products should not be marketed for the treatment of children younger than age 4 years because of lack of benefit coupled with low but significant mortality rates associated with their use in this population.^26,27 The only safe and effective treatments for children are analgesics (acetaminophen or nonsteroidal anti-inflammatory drugs), acetylcysteine, honey (only for children older than 12 months of age), nasal saline irrigation, intranasal ipratropium, and menthol rub.²³

Laryngitis

There are no evidence-based criteria to help distinguish between laryngitis caused by bacterial or viral infection. Furthermore, routine prescription of antibiotics in the treatment of acute laryngitis has not been shown to improve clinical outcomes.²⁸

Treatment is supportive and includes voice rest, adequate systemic hydration humidification, local lubrication, and avoidance of irritants. Although they are used widely, corticosteroids are not recommended in patients with hoarseness, except in children with croup.³⁰ For hoarseness lasting longer than three weeks, as well as for individuals with recent surgery, endotracheal intubation, weight loss, or a history of radiation therapy to the neck, referral to an otolaryngologist for direct visualization of the vocal cords by laryngoscopy should be considered.

Influenza

Management for influenza also is largely supportive, with the same principles for management of the common cold described earlier also applying to influenza. Antivirals have been shown to reduce symptom duration by one-half day to one day in adults. They also may reduce mortality, particularly in high-risk individuals, such as those who develop severe respiratory illness, the very young (age < 2 years) or elderly (age > 65 years), pregnant patients, those with chronic medical conditions or immunosuppression, and residents of long-term care facilities.

For previously healthy symptomatic outpatients, treatment can be considered if it can be started within 48 hours after symptom onset. Treatment with antivirals should be started in the ED in patients who are to be admitted when influenza is confirmed or strongly suspected, to reduce morbidity and mortality.³¹

There are three categories of antiviral medications approved by the FDA for the treatment of influenza. These include neuraminidase inhibitors, cap-dependent endonuclease inhibitors, and adamantanes. (See Table 5.) The neuraminidase inhibitors and the novel cap-dependent endonuclease inhibitors are active against circulating influenza A and B strains. The adamantanes are not recommended for treatment of influenza because they are only active against influenza type A, compounded by the fact that currently circulating influenza A strains exhibit excessively high rates of resistance to these drugs.³¹

Annual vaccination is a major component of the effort to prevent and control influenza outbreaks, in tandem with basic infection mitigation measures for infections of the respiratory tract. The World Health Organization (WHO) coordinates the adjustments to vaccine composition every year based on the predicted strains for the upcoming flu season. ED-based vaccine programs can facilitate patients receiving their vaccines and overcome hesitancy.^32,33

Current recommendations call for annual vaccinations in all patients 6 months of age and older with any of the licensed, age-appropriate vaccines, including the inactivated influenza vaccine, recombinant vaccine, or live attenuated vaccine.³⁴ The accuracy of the “match” between the vaccine and the eventual circulating strain(s) determines the number needed to vaccinate to prevent one case of influenza. Australia, whose flu season occurs about six months earlier than ours, reports that this year’s vaccine (FluCAN) has an efficacy of around 45% to 50% against the disease and its complications.³⁵ The most common adverse effect of vaccine administration is fever, which occurs in less than 1% of recipients. Other adverse effects are much less common.³⁶ The benefit of vaccination outweighs potential harm. Universal annual vaccination is strongly encouraged to enhance herd immunity, thus protecting the most high-risk individuals from exposure to the virus. Annual vaccination is preferred over chemoprophylaxis as the primary method of prevention because of increasing antiviral resistance.

Oral oseltamivir or inhaled zanamivir may be prescribed for chemoprophylaxis within 48 hours after exposure in patients at high risk of influenza complications, those with severe immune deficiencies who may not mount an appropriate immune response, or as part of an institutional outbreak control strategy.³¹ They also can be considered for those who have been exposed to a person with influenza in the first two weeks following vaccination or for those in whom influenza vaccination is contraindicated.³¹

Acute Bronchitis

Routine antibiotic use in acute, uncomplicated bronchitis has limited efficacy and is associated with significant adverse effects and, therefore, is not recommended. Treatment should be directed at symptom reduction and carefully balanced against potential adverse effects. Routine use of antibiotics is not recommended for uncomplicated acute bronchitis since they have limited efficacy and significant adverse effects.

Bronchodilator therapy with inhaled albuterol may be useful in individuals with asthma or COPD but may not significantly reduce cough in children or adults without preexisting lung disease.^37,38

An Additional Aspect: Antibiotic Resistance

Antibiotic resistance is a significant public health threat, with 2.8 million people becoming infected and 35,000 people dying each year from antibiotic-resistant infections as of 2019.³⁹

Antibiotic-resistant infections stem in part from unnecessary prescribing of antibiotics, such as for viral respiratory tract infections. (See Table 6.)

Many strategies exist to help reduce the inappropriate use of antibiotics, including patient education through written materials and verbal information aimed at helping frame the patient’s expectations relating to duration of symptoms. Additional strategies include the use of laboratory markers that may predict bacterial infection, such as procalcitonin and point-of-care C-reactive protein testing, clinical decision support tools, delayed antibiotic prescriptions, and the use of diagnostic terms that reinforce the benign nature of the condition (e.g., “chest cold”).⁴⁰

Better physician-patient communication is needed to address this mounting threat. By empathizing with the patient and not downplaying the discomfort caused by viral infections, the physician serves as a therapeutic dyad partner with the patient, proactively addressing symptoms and offering support without exposing them to further risk through unnecessary antibiotic use.

Summary

Viral upper respiratory tract infections are common and, in most cases, self-limited but uncomfortable conditions. Diagnosis is clinical and treatment is supportive. Still, it is important to have a good understanding of the expected clinical course and know when to suspect a complication, such as exacerbation of COPD or a secondary bacterial infection. Antibiotics are not indicated in viral upper respiratory infections and their inappropriate prescription is a contributor to antibiotic resistance, a growing public health concern.

Although pharmacotherapy exists for the management of symptoms and prevention of severe illness, prevention via proper cough hygiene, handwashing, appropriate use of personal protective equipment, and vaccination when possible is useful for the protection of oneself and others.

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