Influenza is a single-stranded negative-sense RNA virus. There are 4 types (A, B, C, and D), with influenza A and influenza B of clinical significance to humans. Of the 2, influenza B is of relative less importance resulting in milder disease, and it has never been the cause of a pandemic as it only infects humans and is less prone to antigenic shift via reassortment. Influenza virus is notable for 2 surface proteins: Hemagglutinin (H), which binds sialic acid receptors of respiratory epithelial cells (the soft palate, in particular), and Neuraminidase (N), which functions to cleave sialic acid residues allowing the release of virions from an infected host cell whereby these virus particles can infect another cell. Subtypes of influenza A are defined by H and N proteins (ie, H1N1is a subtype of influenza A and a frequent cause of seasonal flu). Because of its limited host range, Influenza B undergoes only minor genetic changes over time. Instead of subtypes, Influenza B is divided into 2 main lineages : Victoria and Yamagata. Influenza Strains are an even more specific version of either a subtype or a lineage (ie, A/Croatia/10136RV/2023 (H3N2)-like virus); however, sometimes, this term is used colloquially to denote a subtype. Transmission occurs primarily via respiratory droplets produced when an infected person—most contagious during the first 3 days of illness—coughs, sneezes, or even talks. ^, The severity of influenza pathogenesis is a function of viral damage to host tissue, the host inflammatory response that can be deleterious if too robust and—in some cases—the development of a secondary bacterial infection. Direct viral damage to the host occurs in the form of epithelial cell death. The degree to which the infection spreads beyond the upper respiratory tract to involve alveolar epithelial cells leading to disruption in gas exchange is a key determinant of disease severity. Epithelial cell death leads to further viral antigen exposure, spurring proinflammatory cytokine release, leading to further airway, and alveolar epithelial denudation and extracellular matrix degradation potentially culminating in the clinical diagnosis of acute respiratory distress syndrome (ARDS). Bacterial coinfection (either occurring simultaneously with influenza infection or as post-influenza bacterial pneumonia) occurs in approximately 10% of hospitalized patients diagnosed with influenza and is associated with an increased mortality risk. Based largely on animal models, mechanisms leading to simultaneous coinfection include damage to respiratory epithelial cells leading to impaired mucociliary clearance and increased colonization and binding of bacteria to the underlying basal membrane. Post-influenza bacterial pneumonia, on the other hand, is hypothesized to largely be a function of immune system impairment including neutrophil dysfunction.

The global burden of influenza is substantial with the World Health Organization (WHO) estimating between 290,00 and 650,00 attributable deaths annually. Influenza activity is seasonal in both the Northern and Southern Hemispheres with the peak incidence in the United States occurring between December and March. Risk factors for severe influenza pneumonia include but are not limited to age greater than 65 years, comorbidities, immunosuppression, and pregnancy.

Influenza cannot be definitively diagnosed on clinical presentation. The most reported symptoms are: cough, fever and coryza, none of which can be used to distinguish influenza from other upper respiratory viral illnesses that commonly occur during the winter months. While sudden onset of fever and body aches are frequently described on bedside rounds as being suggestive of influenza, these symptoms can also be seen in cases of COVID-19 or RSV infection. There are no radiographic features of RSV lower respiratory tract infection that distinguish.

Reverse transcription polymerase chain reaction (RT-PCR) is the gold standard for the diagnosis of influenza. Multiplex RT-PCR has the additional advantage of simultaneously detecting the presence of other viruses including RSV and SARS-CoV-2. RT-PCR testing can be performed on nasopharyngeal (NP) or lower respiratory samples with the latter being more sensitive in cases of influenza pneumonia. If clinical suspicion for influenza remains high despite a negative NP test, then RT-PCR testing should be performed on a lower respiratory sample.

Thomas Francis and Jonas Salk, working with the support of the United Army, created the first inactivated influenza vaccine more than 80 years ago. Modern flu vaccines are either trivalent or quadrivalent—containing either 3 or 4 viral strains. Each year, the strains included in the vaccine are chosen based on prior global monitoring of influenza viruses performed by both the WHO and the CDC. While the ultimate effectiveness of the vaccine is dependent on how well the included strains match the circulating virus during any given season, the influenza vaccine is an exemplar in the history of public health initiatives. In just the 2023–24 season, the CDC estimates that the flu vaccine prevented more than 100,000 patient hospitalizations and nearly 8000 deaths in the United States. The influenza vaccine is recommended for all adults and should be administered in September or October in the Northern Hemisphere. Of note, egg allergy is no longer a contraindication to receiving the vaccine. Clinicians should also be aware that a phase 3 clinical trial comparing a messenger RNA (mRNA) influenza vaccine versus a traditional quadrivalent inactivated influenza vaccine was recently completed. This observer-blind trial, enrolling more than 40,000 patients ≥50 years of age across 11 countries, showed the mRNA vaccine to have 26.6% higher relative efficacy against laboratory-confirmed influenza illness at 6 month follow-up compared with the traditional influenza vaccine. Considering the many advantages of mRNA vaccine technology compared with inactivated virus-based vaccines, peer review of this trial, along with careful consideration by both the WHO and CDC, is urgently needed.

The ATS/IDSA community-acquired pneumonia guidelines recommend neuraminidase inhibitor treatment of all hospitalized patients with influenza. Neuraminidase inhibitors competitively bind to the active site of the viral enzyme inhibiting cleavage of sialic acid and then ultimately preventing the release and spread of newly formed virions from infected epithelial cells. For hospitalized patients with influenza pneumonia oseltamivir is the first-line choice with peramivir being reserved for hospitalized patient for whom oral administration is not feasible. The evidence for benefit of antiviral therapy for influenza is strongest when therapy is instituted early; therefore, therapy should be started empirically in patients suspected of influenza pneumonia while awaiting RT-PCR testing results. ^, Nonetheless, oseltamivir, even when initiated greater than 48 hours after admission, is associated with a mortality benefit. There is also evidence to suggest that among critically ill patients with influenza oseltamivir therapy duration should be extended for longer than the standard 5 day course.

The most common bacterial coinfections among patients with influenza pneumonia are methicillin susceptible Staphylococcus aureus and Staphylococcus pneumoniae . Accordingly, the recent ATS/IDSA guidelines recommend that empirical antibiotic treatment of community-acquired pneumonia be initiated for all patients who test positive for influenza with MRSA coverage reserved for patients with risk factors.

Unfortunately, there are no recommended immunomodulatory therapies for the treatment of influenza. Quite the opposite, meta-analysis on non-randomized controlled studies has shown steroids to increase the risk of secondary infections, lengthen intensive care unit stay and are ultimately associated with increased mortality when used to treat patients with influenza pneumonia.

Patients with suspected or known influenza infection should be placed in private rooms. Standard (handwashing) and droplet (eye protection and surgical masks for either 7 days past illness onset or greater than or equals to 24 hours after resolution of fever with improvement in respiratory symptoms) precautions are recommended for clinicians caring for patients with influenza. Contact precautions (gown and gloves), in general, are not standard of care as transmission of influenza via contaminated surfaces is estimated to be a rare occurrence. However, gowns, gloves, eye protection and N95 masks are required during all aerosol-generating procedures (bronchoscopy, intubation, etc.).

SARS-CoV-2, the causative agent of COVID-19, is a single-stranded positive-sense RNA virus, and 1 of 7 coronaviruses known to infect humans. Historically, human coronaviruses were of little consequence as the causative agents of the common cold. Beginning this century, 4 coronaviruses emerged with dire clinical ramifications: severe acute respiratory virus-1 (2002), Middle east respiratory syndrome (2012) and SARS-CoV-2 (2019). As a corona virus, SARS-CoV-2 is notable for its spike proteins that project from its cellular membrane. When looked at under an electron microscope the virion resembles a crown, hence its name (corona is Latin for crown). Transmission of SARS-CoV-2 is via respiratory droplets; fomites serving as an infectious source is highly unlikely. And unlike other respiratory viral illness, patients with COVID-19 can be infectious 1 to 2 days before they develop symptoms and then remain potentially contagious for several days post-symptom onset. The spike protein binds to its obligate receptor, angiotensin-converting enzyme 2 (ACE2), leading to fusion of the viral and host cell membranes and subsequent release of the viral genome into the host cell. ACE2 is highly expressed in epithelial cells of the nasal mucosa and in the nasopharynx and oropharynx. Interestingly, ACE2 expression is greater among peripheral alveolar macrophages compared with hilar alveolar macrophages possibly explaining propensity for COVID to present with peripheral infiltrates on chest radiography. Because of its crucial role in SARS-CoV-2 pathogenesis, the spike protein has been a therapeutic target for both vaccine and monoclonal antibody development although not without challenges. SARS-CoV-2, being an RNA virus, has a high mutation rate with many of the genome changes involving the spike protein. A new variant is identified when there are genetic changes resulting in a virion that differs from its ancestor strain in terms of: transmissibility, pathogenicity and immune escape potential or its impact on vaccine efficacy. SARS-CoV-2 variants are known both by a scientific, alphanumeric designation (ie, B.1.1.529) and by a WHO naming system that uses letters of the Greek alphabet (ie, Omicron). Bacterial coinfection has also been described with COVID-19, although its incidence is significantly less when compared with bacterial coinfection and influenza. Fungal coinfections with Aspergillus or Mucorales were also described during the pandemic and were associated with increased mortality. In the case of Aspergillosis, the incidence remains unclear with rates ranging from 0% to 33% of critically ill patients being coinfected and autopsy studies noting histopathologic evidence of invasive mold infection in only 2% of cases. Mucormycosis coinfection is comparatively less common. Initially described in India and later in other parts of the world, analysis of a large US COVID-19 database placed the incidence of Mucormycosis coinfection at 0.08% (n = 53/68,383). Immunomodulation was the common risk factor for both fungal coinfections with steroid use being associated with mucormycosis and IL-6 pathway inhibition and steroid use being associated with aspergillosis. ^,

Since December 31, 2019, 7.1 million people have died from COVID-19, with the United States having the most deaths of any country at more than 1.2 million. No longer a notifiable disease in the United States, between October 1, 2024 and September 20, 2025 the CDC estimates that 44,000 and 63,000 Americans died from COVID-19. While case fatality rates are dependent upon several factors (year, location, available treatments and supportive care etc.) on a population level, vaccinations have reduced the risk of death from COVID-19. COVID-19 infections occur year-round although there is seasonal variation with peaks in both the summer and winter months. Older adults are at the highest risk for severe COVID-19 with more the 80% of COVID-19 deaths occurring in individuals over age 65. Underlying medical conditions including but not limited to chronic heart or kidney disease, chronic obstructive pulmonary disease and obesity are associated with an increased risk of severe COVID-19.

Patients with COVID-19 share many of the symptoms seen with other upper respiratory viral illnesses including cough, fever, headache and myalgias. With the evolution of different variants since 2020, there have been subtle changes in clinical presentation; loss of taste (ageusia) or smell (anosmia) were unique features the Alpha and Delta variants. More recently, infection with Omicron subvariants (referred to in the popular press as Stratus and Nimbus variants) is often heralded by a sore throat described as “razor blade throat.”

RT-PCR is the gold standard laboratory platform for diagnosing COVID-19 typically performed using NP swab specimens. Testing performed using lower respiratory samples is more sensitive and can be especially helpful in cases in which the NP sample was negative despite a high suspicion for COVID-19.

COVID-19 vaccines, particularly mRNA-based vaccines saved an estimated 14.4 to 19.8 million lives during the first year of use. Seasonal COVID-19 vaccination is now available. Like the yearly influenza vaccine, these vaccines are designed to be protective against the most current variants. The WHO, The European Union and The Canadian National Advisory Committee on Immunization recommend yearly COVID-19 vaccinations for all or select patient populations, while the CDC suggests that the choice of whether to vaccinate be made by “shared decision-making” between the clinician and the patient. ^,,,

All patients hospitalized because of COVID-19 should receive the antiviral remdesivir as treatment has been shown to increase survival regardless of disease severity (ranging from no oxygen requirement to invasive mechanical ventilation). Remdesivir is a prodrug that is metabolized into its active form, a nucleoside analog resembling adenosine triphosphate, and effectively terminates viral RNA synthesis. Based on an open-label trial of a patient not requiring mechanical ventilation, it is reasonable to treat for 5 days if the patient demonstrates clinical improvement. For all other critically ill patients or hospitalized patients who are slow to improve, the 10-day course tested in the seminal randomized clinical trial is recommended.

For patients who are initially diagnosed with COVID-19 and are critically ill, especially those receiving mechanical ventilation, empirical antibiotics should be carefully considered in addition to remdesivir. In light of the infrequency of bacterial coinfection, the potential for adverse side effects, empirical antibiotics should be discontinued promptly once a bacterial infection is ruled out.

The use of immunomodulating therapies for hospitalized patients with COVID-19 has been extensively studied. Dexamethasone treatment of critically ill patients with SARS-CoV-2 is recommended by guidelines, including those put forth by IDSA, NIH, and WHO; however, there is uncertainty regarding its benefit for the treatment of COVID-19. Dexamethasone treatment was adopted early during the pandemic after the release of the RECOVERY trial, and these results largely formed the basis for guidelines supporting the use of glucocorticoid treatment. In this large trial, compared with usual care, dexamethasone treatment resulted in an overall 3% absolute mortality benefit and a 9% mortality benefit among the subset of patients receiving mechanical ventilation. Despite its size ( N = 11,303), certain aspects of the RECOVERY trial design and execution raise concerns regarding the fidelity of these results: open-label design (risk of detection and performance bias); overall 43% of recruited patients were not enrolled with 18% excluded because dexamethasone was not available, or the attending physician considered the patient not suitable to receive the drug (risk of major selection bias); 21% of screened patients were excluded because dexamethasone was not available or the attending physician considered the patient unsuitable; 11% of patients did not have confirmed SARS-CoV-2 infection (information bias); and safety monitoring of adverse events and superinfections or long-term outcomes data were not collected. Most notably, the mortality rate in the usual care arm was unexpectedly high compared with all other trials conducted during the same period. For example, among patients receiving mechanical ventilation at baseline, the mortality rate in the RECOVERY trial was 41.4%, while in ACTT-1, the mortality rate was 19.3%. ^, Surprisingly, placebo-controlled trials evaluating steroids for the treatment of COVID-19 are relatively few ( N = 571), and most were stopped early; nonetheless, when studied in this format, less prone to biases, steroids have not demonstrated a mortality benefit (RR 0.91 [95% CI, 0.49, 1.69]).

IL-6 pathway inhibition for the treatment of COVID-19, using tocilizumab, sarilumab, or siltuximab has also not consistently shown meaningful clinical benefit. Despite IDSA, NIH, and WHO-sponsored guidelines recommending its use for the treatment of hospitalized patients with COVID-19 requiring oxygen therapy, placebo-controlled trials evaluating IL-6 pathway inhibitors do not reveal a mortality benefit.

Baricitinib is the only immunomodulator to be shown to improve survival when tested in both open-label and placebo-controlled trials. ^, An oral Janus kinase 1 and 2 inhibitor, Baricitinib inhibits several intracellular cytokine signaling pathways; moreover, baricitinib has been shown in vitro to reduce viral infectivity presumably via its binding affinity to AP2-associated protein kinase 1 and cyclin G-associated kinase, thereby reducing clathrin-mediated endocytosis. ^, Baricitinib therapy should be administered to all patients hospitalized for COVID-19 receiving oxygen support, including patients receiving other immunosuppressants such as steroids without any apparent increased risk of secondary infections.

Patients with suspected or confirmed COVID-19 should be placed in a private room if possible or cohorted with other patients similarly infected. CDC infection prevention guidelines for clinicians providing direct care to hospitalized patients with COVID-19 recommend that standard and contact precautions be employed along with N-95 respirators and eye protection. These guidelines are largely unchanged since February, 2020 and fail to account for more recent data showing that COVID is transmitted via aerosols and large droplets, that fomites transmission is likely exceeding rare, and the surgical masks are non-inferior to N-95 respirators for preventing transmission. ^,,, Since there are no studies addressing safety during aerosol-generating procedures, the use of N-95 and contact precautions should be employed when a high-risk procedure such as bronchoscopy and endotracheal intubation is being performed.