# Influenza and Respiratory Viruses

## Influenza

### Virology

Influenza viruses belong to the Orthomyxoviridae family and possess a negative-sense, single-stranded RNA genome organized into eight segments, a feature that has profound implications for viral evolution and pandemic potential. Influenza A is the most clinically significant type and is further classified into subtypes based on two surface glycoproteins: hemagglutinin (HA, of which 18 subtypes are known) and neuraminidase (NA, with 11 subtypes). The maintenance of influenza A in avian and swine reservoirs creates the conditions for the emergence of novel strains with pandemic potential. Influenza B is divided into two lineages, Yamagata and Victoria. It lacks a significant animal reservoir and causes seasonal epidemics but not pandemics. Notably, the Yamagata lineage may have become extinct following the public health measures implemented during the COVID-19 pandemic. Influenza C causes only mild illness and is not epidemiologically significant.

Two mechanisms of genetic change drive influenza evolution. Antigenic drift refers to the accumulation of point mutations in the genes encoding HA and NA, producing the gradual variation that necessitates annual vaccine reformulation. Antigenic shift is a more dramatic process involving the reassortment of genome segments between human and animal influenza strains, generating novel HA and NA combinations to which the human population has no pre-existing immunity. Antigenic shift is the mechanism underlying influenza pandemics, including the 1918 H1N1 and 2009 H1N1 events.

### Epidemiology

Seasonal influenza epidemics cause an estimated 9 to 45 million illnesses, 140,000 to 810,000 hospitalizations, and 12,000 to 61,000 deaths annually in the United States. The influenza season in the Northern Hemisphere spans October through May, with peak activity typically in January and February. Populations at highest risk for severe disease and complications include adults aged 65 and older, children under 5 years (particularly those under 2), pregnant women, individuals with chronic medical conditions including pulmonary, cardiovascular, renal, hepatic, and metabolic diseases, immunosuppressed patients, individuals with morbid obesity defined as a body mass index of 40 or greater, and residents of nursing homes and long-term care facilities.

### Clinical Presentation

The typical clinical presentation of influenza is characterized by the abrupt onset of fever ranging from 38 to 40 degrees Celsius, myalgia, headache, dry cough, sore throat, and rhinorrhea. Gastrointestinal symptoms are more common in children than adults. Complications of influenza include primary viral pneumonia, secondary bacterial pneumonia most commonly caused by Staphylococcus aureus (including MRSA), Streptococcus pneumoniae, and Haemophilus influenzae, myocarditis, rhabdomyolysis, encephalitis, acute respiratory distress syndrome, and exacerbation of underlying chronic conditions such as asthma, COPD, and heart failure.

### Diagnosis

Rapid molecular assays using nucleic acid amplification testing represent the preferred diagnostic modality for influenza, offering sensitivity exceeding 95 percent, specificity greater than 99 percent, and results within 15 to 60 minutes. Rapid antigen tests provide point-of-care results but have substantially lower sensitivity, in the range of 50 to 70 percent, with particular limitations for influenza B detection. A negative rapid antigen test does not exclude influenza, and molecular confirmation should be pursued when clinical suspicion is high. Reverse transcription PCR remains the reference standard for sensitivity and is the primary tool for surveillance and outbreak investigation. Multiplex respiratory viral panels, such as FilmArray and GenMark platforms, can simultaneously detect influenza and other respiratory viruses from a single specimen. Testing is recommended for all hospitalized patients with respiratory illness during influenza season.

### Treatment

| Agent | Dose | Route | Duration | Mechanism | Key Notes |
|---|---|---|---|---|---|
| Oseltamivir (Tamiflu) | 75mg BID | Oral | 5 days | Neuraminidase inhibitor | First-line; start even if >48h in hospitalized patients |
| Baloxavir (Xofluza) | 40-80mg × 1 | Oral | Single dose | Cap-dependent endonuclease inhibitor | ~10% resistance emergence (PA/I38T mutation) |
| Peramivir | 600mg × 1 | IV | Single dose | Neuraminidase inhibitor | For patients unable to take oral medications |
| Zanamivir (Relenza) | 10mg BID (inhaled) | Inhaled | 5 days | Neuraminidase inhibitor | Contraindicated in asthma/COPD (bronchospasm) |

Oseltamivir (Tamiflu), administered at 75 milligrams orally twice daily for five days, is the most widely used antiviral agent for influenza. The greatest benefit is achieved when treatment is initiated within 48 hours of symptom onset, but oseltamivir is still recommended for hospitalized patients even beyond this window, as late treatment has been shown to reduce complications and mortality in severe disease.

Baloxavir marboxil (Xofluza) is a cap-dependent endonuclease inhibitor administered as a single oral dose of 40 milligrams for patients weighing 40 to less than 80 kilograms or 80 milligrams for those weighing 80 kilograms or more. The CAPSTONE-2 trial demonstrated benefit in high-risk patients. However, a clinically relevant concern is the approximately 10 percent rate of resistance emergence during treatment due to the PA/I38T mutation, which may limit its utility in some settings.

Peramivir, administered as a 600 milligram intravenous single dose, is reserved for patients who cannot take oral medications. Zanamivir (Relenza) is an inhaled neuraminidase inhibitor that is contraindicated in patients with asthma or COPD due to the risk of bronchospasm.

For hospitalized and critically ill patients, oseltamivir 75 milligrams twice daily for five days remains the standard, though the duration may be extended beyond five days in critically ill or immunocompromised patients. Higher doses of 150 milligrams twice daily have been considered in immunocompromised patients, though the evidence for this approach is limited. Current circulating H1N1 and H3N2 strains remain susceptible to both oseltamivir and baloxavir, though the H275Y mutation in H1N1 confers oseltamivir resistance and is subject to ongoing surveillance.

### Prevention

Annual influenza vaccination is recommended for all persons aged six months and older. Vaccine composition has evolved from quadrivalent formulations containing two influenza A and two influenza B strains to trivalent formulations containing one A H1N1, one A H3N2, and one B Victoria strain, reflecting the apparent disappearance of the Yamagata lineage.

For adults aged 65 and older, high-dose (Fluzone HD) or adjuvanted (Fluad) formulations are preferentially recommended due to superior immunogenicity compared to standard-dose vaccines. Recombinant influenza vaccine (Flublok) is produced without eggs and is available for patients with egg allergy, with emerging data suggesting superior efficacy. The live attenuated influenza vaccine (FluMist) is administered intranasally and is approved for healthy, non-pregnant individuals aged 2 to 49 years. Optimal timing for vaccination is September through October, though vaccination can and should be administered throughout the season.

Chemoprophylaxis with oseltamivir 75 milligrams daily is indicated for post-exposure prophylaxis in high-risk individuals and for institutional outbreak control in long-term care facilities.

<image>A comprehensive influenza management algorithm. Start with "Suspected influenza (acute onset fever, cough, myalgia during flu season)." First step: "Rapid molecular testing (NAAT preferred over antigen test)." If positive: branch into "Outpatient (mild)" and "Hospitalized/severe/high-risk." Outpatient pathway: "Oseltamivir 75mg BID x 5 days if within 48h of symptom onset; consider baloxavir marboxil single dose as alternative." Hospitalized pathway: "Oseltamivir 75mg BID x 5 days (start regardless of symptom duration); droplet precautions; monitor for bacterial superinfection (S. aureus, S. pneumoniae) -- add antibiotics if bacterial pneumonia suspected." High-risk features box: "Age ≥65, pregnancy, chronic lung/heart/renal/liver disease, immunosuppressed, BMI ≥40, children <5." Include a prevention sidebar: "Annual vaccination (high-dose/adjuvanted for ≥65), post-exposure chemoprophylaxis." Use a clinical decision tree format.</image>

## SARS-CoV-2 (COVID-19)

### Current Landscape (Post-Pandemic)

SARS-CoV-2 has transitioned from a pandemic pathogen to an endemic respiratory virus with seasonal circulation patterns. The ongoing evolution of viral variants continues to shape the epidemiology and clinical manifestations of disease. Widespread immunity from both vaccination and natural infection has fundamentally altered the risk profile, with severe disease now concentrated primarily in unvaccinated individuals, the elderly, and immunocompromised patients. The therapeutic approach has correspondingly evolved from the acute pandemic protocols emphasizing broad-scale intervention to targeted therapy for populations at highest risk for severe outcomes.

### Treatment (High-Risk Outpatients)

Nirmatrelvir/ritonavir (Paxlovid), administered as 300 milligrams of nirmatrelvir with 100 milligrams of ritonavir orally twice daily for five days, is the preferred oral antiviral for high-risk outpatients within five days of symptom onset. In unvaccinated populations, it demonstrated approximately 89 percent reduction in hospitalization, though this benefit is attenuated in vaccinated individuals with hybrid immunity. The ritonavir component, included as a pharmacokinetic booster, is a potent CYP3A4 inhibitor, creating critical drug interactions with medications including tacrolimus, calcineurin inhibitors, statins, and many anticoagulants. A thorough medication reconciliation is mandatory before prescribing.

Remdesivir, administered as a three-day intravenous course with 200 milligrams on day one followed by 100 milligrams on days two and three, is an option for high-risk outpatients within seven days of symptom onset. The PINETREE trial demonstrated an 87 percent reduction in hospitalization. Molnupiravir, 800 milligrams orally twice daily for five days, offers lesser efficacy with approximately 30 percent reduction in hospitalization and carries theoretical concerns about mutagenesis. It is reserved for situations in which Paxlovid and remdesivir are unavailable.

### Treatment (Hospitalized)

The treatment of hospitalized COVID-19 is stratified by disease severity. Remdesivir as a five-day course is indicated for patients requiring supplemental oxygen but not mechanical ventilation, based on the ACTT-1 trial, which demonstrated a five-day reduction in time to recovery. Dexamethasone 6 milligrams daily for ten days provides a mortality benefit in patients requiring supplemental oxygen or mechanical ventilation, as demonstrated by the landmark RECOVERY trial. Critically, dexamethasone provides no benefit and may cause harm in patients who are not hypoxic, and it should not be administered to this population.

For patients on high-flow oxygen or mechanical ventilation, baricitinib, a JAK inhibitor, can be added to dexamethasone and remdesivir based on the COV-BARRIER trial. Tocilizumab, an IL-6 receptor inhibitor, is indicated for patients with rapid respiratory deterioration and elevated C-reactive protein despite dexamethasone, supported by the REMAP-CAP and RECOVERY trials. Convalescent plasma is no longer routinely recommended.

## Respiratory Syncytial Virus (RSV)

### Clinical Significance

Respiratory syncytial virus has emerged as a pathogen of major clinical importance across the age spectrum. It is the leading cause of lower respiratory tract infection in infants under one year of age and is increasingly recognized as a serious cause of respiratory illness in adults aged 65 and older, causing an estimated 60,000 to 160,000 hospitalizations and 6,000 to 10,000 deaths annually in the United States in this age group. RSV carries particularly high mortality in immunocompromised patients, with RSV pneumonia mortality reaching 30 to 50 percent in some series of hematopoietic stem cell transplant and solid organ transplant recipients.

### Diagnosis

Diagnosis of RSV relies on PCR-based testing, which provides the highest sensitivity. Rapid antigen tests are available but have substantially lower sensitivity in adults compared to children. Multiplex respiratory viral panels routinely include RSV alongside influenza and other respiratory pathogens.

### Treatment

Treatment of RSV is primarily supportive for most patients. Ribavirin, available in both aerosolized and oral formulations, has been used in some HSCT and SOT patients with RSV lower respiratory tract infection, though efficacy data are limited and practical challenges with aerosolized delivery are considerable. Nirsevimab (Beyfortus), a long-acting monoclonal antibody targeting the RSV F protein, provides passive immunization for neonates and infants entering their first RSV season through a single intramuscular injection that confers approximately five months of protection. Nirsevimab has largely replaced palivizumab, which required monthly injections and was limited to high-risk infants including those born before 29 weeks gestation and those with chronic lung disease or hemodynamically significant heart disease.

### RSV Vaccines (2023)

The approval of RSV vaccines in 2023 represented a landmark achievement after decades of development efforts. Two vaccines are available for adults aged 60 and older: Arexvy (GSK), an adjuvanted protein-based vaccine, and Abrysvo (Pfizer), a bivalent prefusion F protein vaccine. Both are recommended through shared clinical decision-making between the patient and provider. Additionally, Abrysvo is approved as a maternal vaccine administered at 32 to 36 weeks of gestation during September through January, providing protection to infants through passive transfer of maternal antibodies. This maternal vaccination strategy serves as an alternative to nirsevimab for infant protection.

## Other Respiratory Viruses

### Parainfluenza Viruses (PIV)

The parainfluenza viruses, types 1 through 4, are important respiratory pathogens with particular significance in immunocompromised populations. Type 3 is the most common cause of parainfluenza infection in immunocompromised adults, particularly HSCT recipients, in whom it can cause severe pneumonia. In children, parainfluenza viruses are the classic cause of croup. No specific antiviral therapy is available, though aerosolized ribavirin has been used in HSCT patients with lower respiratory tract involvement. Diagnosis is accomplished through multiplex PCR panels.

### Human Metapneumovirus (hMPV)

Human metapneumovirus is a paramyxovirus that produces a clinical syndrome similar to RSV. It can cause severe lower respiratory tract infection in elderly and immunocompromised patients and is an important cause of community-acquired pneumonia in adults. No specific antiviral therapy exists, and management is supportive.

### Adenovirus

Adenovirus is a non-enveloped DNA virus with more than 50 recognized serotypes. The clinical spectrum is broad and includes pharyngitis, pneumonia, keratoconjunctivitis, hemorrhagic cystitis (particularly common in HSCT recipients), hepatitis, and encephalitis. Disseminated adenovirus disease in HSCT and SOT recipients can be devastating and carries high mortality. Treatment options include cidofovir administered intravenously, which carries significant nephrotoxicity requiring concurrent probenecid and aggressive hydration, and brincidofovir, an oral prodrug of cidofovir with reduced nephrotoxic potential that was originally approved for smallpox treatment. Diagnosis relies on PCR from blood, with quantitative viral load monitoring used to guide treatment in HSCT recipients, and from clinically affected sites.

### Rhinovirus

Rhinovirus, with more than 100 serotypes, is the most common cause of the common cold. While traditionally considered a relatively benign upper respiratory pathogen, rhinovirus is increasingly recognized as a cause of severe lower respiratory tract infection in immunocompromised patients and is a major trigger for COPD exacerbations. No specific antiviral therapy is available, and management remains supportive.

<image>A comparison chart of the major respiratory viruses relevant to ID fellowship practice. Create a grid with columns for: Influenza A/B, SARS-CoV-2, RSV, Parainfluenza, hMPV, and Adenovirus. Rows should include: viral family, genome type, seasonality (show a month bar chart), high-risk populations, key clinical features, diagnostic method of choice, specific antiviral treatment (list drug names), and available vaccines/prophylaxis. Use color coding by viral family: blue for orthomyxovirus, red for coronavirus, green for paramyxovirus, purple for adenovirus. Highlight cells where specific antiviral therapy is available in green and where no specific therapy exists in gray. Include a note about multiplex PCR panels detecting all these pathogens simultaneously. Professional medical reference table format.</image>

## Key Clinical Pearls

- Oseltamivir should be started in ALL hospitalized influenza patients regardless of symptom duration -- even late treatment reduces mortality in severe disease
- Baloxavir (Xofluza) is a convenient single-dose option but carries a ~10% risk of resistance emergence during treatment
- Paxlovid (nirmatrelvir/ritonavir) has critical drug interactions through CYP3A4 inhibition -- ritonavir interacts with tacrolimus, statins, anticoagulants, and many other medications; always check
- Dexamethasone for COVID-19 is only beneficial in patients requiring oxygen -- do NOT give to patients who are not hypoxic (RECOVERY trial)
- RSV vaccines for adults ≥60 and maternal vaccination represent a major 2023 breakthrough -- first RSV vaccines after decades of development
- Adenovirus in HSCT recipients can be devastating -- monitor quantitative viral loads and consider cidofovir early for rising viremia
- Influenza vaccination with high-dose or adjuvanted formulations is preferentially recommended for adults ≥65 -- standard-dose vaccines are less immunogenic in this population
- A negative rapid influenza antigen test does NOT exclude influenza -- molecular testing (NAAT) is the preferred diagnostic modality

## References
1. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the IDSA: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. *Clin Infect Dis*. 2019;68(6):e1-e47.
2. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. *N Engl J Med*. 2021;384(8):693-704.
3. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19 (EPIC-HR). *N Engl J Med*. 2022;386(15):1397-1408.
4. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents (CAPSTONE-1). *N Engl J Med*. 2018;379(10):913-923.
5. Fleming-Dutra KE, Jones JM, Roper LE, et al. Use of the Pfizer respiratory syncytial virus vaccine during pregnancy for the prevention of respiratory syncytial virus-associated lower respiratory tract disease in infants. *MMWR Morb Mortal Wkly Rep*. 2023;72(41):1115-1122.