Acute respiratory tract infection (ARI) is the most common reason for primary care visits worldwide.1 Approximately 1 billion cases of ARI occur per year in the US.2 The most frequent ARIs are of viral origin and include the common cold and influenza (flu). Flu activity was unusually low throughout the 2020-2021 flu season in part because of COVID-19 mitigation measures.2 Rates of many other respiratory pathogens also remained decreased in early 2020, with rates starting to rise in Spring 2021.2

With the reopening of schools and offices this fall, the number of visits for ARI is expected to increase in both primary care and urgent care settings. The Centers for Disease Control and Prevention (CDC) has warned that clinicians should be aware of increases in some respiratory virus activity and remain vigilant for off-season increases.2

Figure. Number of specimens tested and the percentage of positive tests for influenza viruses and respiratory syncytial virus by year — United States, 2016–2021. Source: CDCa,2

The common cold is a term for a heterogeneous group of mild, self-limited upper respiratory illnesses caused by more than 100 different viruses such as rhinoviruses, adenoviruses, and coronaviruses. Acute respiratory tract infections peak in childhood at 6 to 8 episodes per year and decline to about 1 per year after age 603; these infections are the primary reason that children miss school and adults miss work. Children are particularly susceptible to these infections due to poor personal hygiene, lack of acquired immunity to the most common viruses, and difficulty adhering to social distancing rules. A lack of long-standing immunity to respiratory syncytial virus (RSV), parainfluenza virus, and human coronavirus can lead to repeated infection with these viruses in adulthood.4


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Influenza can be caused by a number of different circulating influenza strains in any given flu season. While there are 4 types of influenza viruses, types A and B tend to be the most virulent; type A viruses are responsible for most influenza pandemics.5 Symptoms of flu can range from mild to severe or even fatal (Figure).6

Source: CDC.a,6

Symptoms of Colds vs Influenza

Acute respiratory tract infection is characterized by overproduction of mucus by airway mucosa. This leads to accumulation of mucus causing the most bothersome symptoms such as cough and dyspnea. Understanding the role of mucus in these conditions may lead to improved treatment of these symptoms for more patients.

The classic symptoms of flu are sudden onset of fever, chills, myalgia, and other upper respiratory complaints. The common cold follows a more gradual onset and is characterized by stuffy/runny nose, sore throat, sneezing, and low-grade to no fever.  Less severe cases of influenza may easily be mistaken for the common cold (Table 1).7 In the clinic, rapid flu tests can assist in differentiating between colds and influenza and determining which patients might benefit from antiviral therapies in addition to symptomatic treatment.

Table 1. Differences in Flu and Cold Clinical Symptoms

SymptomFluCommon Cold
OnsetSuddenGradual
Runny NoseYes (less common)Yes (very common)
Stuffy NoseSometimesCommon
Sore ThroatYes (less common)Yes (very common)
SneezingSometimesYes
Chest discomfortYesMild-moderate
High FeverYesRare (low-grade fever)
ChillsYesUncommon
HeadacheYesRare
MyalgiaYesRare
Fatigue/weaknessYesRare
Adapted from CDC.7

Mechanisms Underlying Cold and Influenza Symptoms

In nonasthmatic individuals, symptoms of the common cold and influenza are generally limited to the upper respiratory tract. The most prominent symptoms, rhinorrhea and nasal obstruction, are associated with a neutrophilic inflammatory response resulting in increased vascular permeability and stimulation of mucus hypersecretion.8 A growing body of data suggest that the host response to these viral infections is the primary driver of the clinical and pathologic changes observed during these illnesses rather than direct viral injury of respiratory cells.9

Viral replication begins in the nasopharyngeal epithelium leading to a cascade of local and systemic immune responses through various mechanisms.10 Viral replication triggers cytokine-mediated local inflammatory reactions, which in turn generate systemic symptoms.10 Bradykinin, an inflammatory mediator, is believed to have a major role in generating local symptoms such as sore throat and nasal congestion by increasing blood vessel permeability.10 Sneezing, an inflammatory response in the nose and nasopharynx, may be mediated via histamine receptors on the trigeminal nerves.10 Parasympathetic neural pathways activate and coordinate local responses such as blood vessel dilation and capillary leakage, which leads to edema and accumulation of transudates in the nasal passages.11,12 Airway hyper-responsiveness and mucus secretion is induced by the tachykinin peptides neurokinin A and B and substance P, resulting in mild to copious exudative discharge.13,14