32-06: Common Viral Respiratory Infections

General Considerations

Respiratory syncytial virus (RSV) is a paramyxovirus that causes annual outbreaks during the wintertime with usual onset of pulmonary symptoms between mid-October and early January in the continental United States (excluding Florida). Outside the United States, RSV usually peaks during wet months in areas with high annual precipitation and during cooler months in hot and dry areas. It occurs earlier in urban areas.

There are two major subtypes, A and B, and it appears that the A subtype is associated with disease severity. RSV is the leading cause of hospitalization in US children, with annual hospitalization rates of 6 per 1000 children younger than 5 years. Globally, the annual RSV hospitalization rates are 4 per 1000 children less than 5 years old, 19 among children less than 1 year old, 20 among children less than 6 months old, and 64 among premature children less than 1 year. Prematurity is a major risk factor for severe disease. Early RSV bronchiolitis in children, along with a family history of asthma, are associated with persistence of airway reactivity later in life.

RSV also causes upper and lower respiratory tract infection in adults, with the virus entering through contact with mucous membranes. RSV occurs with increasing severity in those with comorbid conditions, older adults (accounting for a rate of 4 per 1000 hospitalizations and 14,000 deaths annually), persons with severe combined immunodeficiency, and patients after lung or bone marrow transplantation (because CD8 T cells are not available for viral clearance). An interleukin-1 receptor polymorphism is shown to be associated with more severe bronchiolitis. Recurrences occur throughout life. The average incubation period is 5 days. Up to 10% of disease classified as invasive pneumococcal disease is thought to be RSV or influenza.

In immunocompromised patients, such as bone marrow transplant recipients, serious pneumonia can occur, and outbreaks with a high mortality rate (greater than 70%) are reported.

Other paramyxoviruses important in human disease include human metapneumovirus, parainfluenza virus, and Nipah virus.

Human metapneumovirus is a ubiquitous seasonal virus circulating during late winter to early spring. It is divided into subgroups A and B. Metapneumovirus accounted for 7.3% of childhood (younger than 16 years old) pneumonia in a Norwegian series of 3650 patients in which RSV accounted for 28.7%. Clinical presentations range from mild upper respiratory tract infections to severe lower respiratory tract infections (eg, bronchiolitis, croup, and pneumonia). Lower respiratory tract (sometimes severe) infections have been observed among immunocompromised and elderly adults, especially residents of nursing homes. In lung transplant recipients, human metapneumovirus is a common cause of respiratory illness and is thought to increase the risk of acute and chronic graft rejection. Ribavirin appears to be well tolerated in lung transplant recipients with metapneumovirus infection.

Human parainfluenza viruses (HPIVs) are commonly seen in children and are the most common cause of laryngotracheitis (croup). Four different serotypes are described, and they differ in their clinical presentations as well as epidemiology. HPIV-1 and HPIV-2 are responsible for croup. HPIV-3 is associated with bronchiolitis and pneumonia. HPIV-4 is a less frequently reported pathogen. Reinfections are common throughout life. HPIVs can also cause severe disease in older individuals, immunocompromised persons, and patients with chronic illnesses.

Nipah virus is a highly virulent paramyxovirus first described in 1999. Cases are concentrated mainly in Southeast Asia (Malaysia, Singapore, Bangladesh, and India). Fruit bats are identified as the natural host of the virus. An outbreak of 14 cases, 8 fatal, occurred in Bangladesh associated with drinking date palm sap between 2010 and 2014. Direct pig-human, cow-human, human-human, and nosocomial transmission are reported. Nipah virus causes acute encephalitis with a high fatality rate (67–92%), although respiratory symptoms are also described. Cranial nerve palsies, encephalopathy, and dystonia are among neurologic sequelae (15–32%) seen in infected individuals. Relapses occurring weeks and months after initial infection are described (3.4–7.5%).

Clinical Findings

A. Symptoms and Signs

In RSV bronchiolitis, proliferation and necrosis of bronchiolar epithelium develop, producing obstruction from sloughed epithelium and increased mucus secretion. Signs of infection include low-grade fever, tachypnea, and wheezes. Apnea is a common presenting symptom. Hyperinflated lungs, decreased gas exchange, and increased work of breathing are present. Pulmonary hemorrhage is reported. In children, RSV is globally the most common cause of acute lower respiratory infection and also a common cause of acute and recurrent otitis media. In patients with Down syndrome, RSV develops at a later age and is associated with more protracted hospitalizations.

B. Laboratory Findings

A rapid diagnosis of RSV infection is made by viral antigen identification of nasal washings using an ELISA or immunofluorescent assay, but PCR-based rapid tests are increasingly used. Coinfection with bacteria is relatively uncommon in industrialized countries although Clostridioides (formerly Clostridium) difficile–associated diarrhea is documented to occur after RSV infections in a Canadian study. Coinfection with Bordetella pertussis and other viruses occurs in a subset of patients hospitalized for RSV infection. Multiplex assays in conjunction with influenza A and B tests are available commercially. RSV viral load assay values at day 3 of infection may correlate with requirement of intensive care and respiratory failure in children.

Human metapneumovirus is best diagnosed by PCR. Tests for rapid detection of viral antigens with immunofluorescence or ELISA, and PCR techniques are also widely available for detection of HPIV. Culture may also be used. ELISA (serum and CSF) and PCR (urine and respiratory secretions but not blood) are both used for Nipah virus infection diagnosis.

Treatment & Prevention

Treatment of RSV consists of supportive care, including hydration, humidification of inspired air, antibiotic therapy (to reduce other respiratory morbidity), and ventilatory support as needed. Neither bronchodilating agents nor corticosteroids have demonstrated efficacy in bronchiolitis although individual patients with significant bronchospasm or history of asthma might respond to them. Oral antiviral agents remain under study.

The use of aerosolized ribavirin or RSV-enriched IVIG, or both, can be considered in high-risk patients, such as those with a history of bone marrow transplantation, and appears to lessen mortality. Pregnant women, including hospital staff, should avoid ribavirin exposure. Therapy with surfactant lacks evidence to make recommendations on its use. The prophylactic monoclonal antibody palivizumab, while recommended for and effective in high-risk infants (premature infants less than 32 weeks’ gestational age, as well as infants with congenital heart and lung diseases and Down syndrome), is not of proven efficacy among adults with RSV.

A 2017 clinical trial studied the administration of palivizumab to preterm infants to prevent long-term sequelae; palivizumab did not suppress the onset of atopic asthma but did result in a significantly lower incidence of recurrent wheezing. Azithromycin therapy during RSV infection has been shown to reduce the probability of recurrent wheezing during the subsequent year by approximately 50%. MEDI8897 is a recombinant human RSV monoclonal antibody that is being developed as RSV prophylaxis for infants (NCT02114268).

No RSV vaccine is currently commercially available. A vaccine composed of the RSV postfusion F protein with glucopyranosyl lipid adjuvant was found to be immunogenic but not to protect older adults from RSV. It is currently being evaluated in pregnant women in their third trimester, with the goal of passively protecting infants through transfer of RSV-specific maternal antibodies (NCT01960686). Other vaccines under development include a variety of live, attenuated vaccines and a variety of subunit vaccines for adults and infants. The use of RNA interference therapy in lung transplant patients may have some beneficial effects.

Prevention in hospitals entails rapid diagnosis, hand washing contact isolation, and perhaps passive immunization. (Passive immunization is costly but is associated with improved antiviral titers in hematologic stem cell transplant recipients). The use of conjugated pneumococcal vaccination appears to decrease the incidence of concomitant pneumonia associated with viral infections in children in some countries. Viral shedding averages 11 days and correlates inversely with age and directly with severity of infection.

Therapeutic modalities for human metapneumovirus and parainfluenza virus infections under investigation include intravenous ribavirin administration. Vaccines for human metapneumovirus and parainfluenza virus are in early stages of development. During the initial Nipah virus outbreak, ribavirin was used empirically, although its efficacy remains questionable.

General Considerations

Influenza (an orthomyxovirus) is a highly contagious disease transmitted by the respiratory route in humans. Transmission occurs primarily by droplet nuclei rather than fomites or direct contact. There are three types of influenza viruses that infect humans. While type A can infect a variety of mammals (humans, swine, horses, etc) and birds, types B and C almost exclusively infect humans. Type A viruses are further divided into subtypes based on the hemagglutinin (H) and the neuraminidase (N) expressed on their surface. There are 18 subtypes of hemagglutinin and 11 subtypes of neuraminidase.

Annual epidemics usually appear in the fall or winter in temperate climates, although sporadic cases occur as summer outbreaks in northern areas such as Alaska or the southern hemisphere. Up to 5 million cases of severe influenza are estimated by the WHO to occur annually, with up to 0.5 million annual deaths. Influenza epidemics affect 10–20% of the global population on average each year and are typically the result of minor antigenic variations of the virus, or antigenic drift, which occur often in influenza A virus. On the other hand, pandemics—associated with higher mortality—appear at longer and varying intervals (decades) as a consequence of major genetic reassortment of the virus (antigenic shift) or adaptation of an avian or swine virus to humans (as with the pandemic H1N1 virus of 1918). (https://www.who.int/influenza/surveillance_monitoring/updates/latest_update_GIP_surveillance/en/).

The highly pathogenic avian influenza subtypes are discussed in the next section. The novel swine-origin influenza A (pandemic H1N1) virus emerged in Mexico in 2009 and quickly spread throughout North America and the world causing a pandemic. This virus originated from triple-reassortment of North American swine, human, and avian virus lineages and Eurasian swine virus lineages and replaced the previous H1N1 seasonal virus.

Clinical Findings

A. Symptoms and Signs

Type A and B seasonal influenza viruses produce clinically indistinguishable infections, whereas type C usually causes mild illness. The incubation period is 1–4 days. In unvaccinated persons, uncomplicated influenza often begins abruptly. Symptoms range widely from nearly asymptomatic to a constellation of systemic symptoms (including fever, chills, headache, malaise, and myalgias) and respiratory symptoms (including rhinorrhea, congestion, pharyngitis, hoarseness, nonproductive cough, and substernal soreness). Gastrointestinal symptoms and signs may occur, particularly among young children with influenza B virus infections. Fever lasts 1–7 days (usually 3–5). Elderly patients especially may present with lassitude and confusion, often without fever or respiratory symptoms. Signs include mild pharyngeal injection, flushed face, and conjunctival redness. Moderate enlargement of the cervical lymph nodes and tracheal tenderness may be observed. The presence of fever (higher than 38.2°C) and cough during influenza season is highly predictive of influenza infection in those older than 4 years.

B. Laboratory Findings

Rapid influenza diagnostic tests for detection of influenza antigens from nasal or throat swabs are widely available, highly specific, and produce fast results but have low sensitivity leading to high false-negative results. Not all commercial rapid influenza diagnostic tests can differentiate between influenza A and influenza B, and none of the available rapid influenza diagnostic tests can provide information on influenza A subtypes. Newer digital immunoassays and rapid nucleic acid amplification tests are more sensitive than traditional rapid influenza diagnostic tests; however, the sensitivity of newer PCR techniques is compromised early in the season during low prevalence periods. A nasopharyngeal swab, nasal aspirate, combined nasopharyngeal swab with oropharyngeal swab, or material from a bronchoalveolar lavage can be tested for any influenza strain. When influenza pneumonia is suspected, lower respiratory tract specimens should be collected and tested for influenza viruses by RT-PCR or the above assays.

Differential Diagnosis

The differential diagnoses for influenza-like infections include a variety of viral respiratory infections (parainfluenza, RSV, atypical dengue, adenovirus, enterovirus, coronavirus) or other viral infections (flavivirus, CMV, EBV, acute HIV infection), as well as bacterial infections such as mycobacterial infection (atypical pneumonia), pertussis, and Legionnaire disease. Epidemiologic factors can suggest Legionnaire (elderly smokers). Chronicity of cough may suggest adenovirus, mycobacterial, or pertussis infection. Leukocytosis and lymphadenopathy are more often seen with CMV and EBV. Distinguishing influenza from dengue requires attention to rhinitis (influenza) and thrombocytopenia (dengue).

Complications

Hospitalization or ICU admission for influenza is often a consequence of diffuse viral pneumonitis with severe hypoxemia and sometimes shock. Patients with asthma, residents of nursing homes and long-term care facilities, adults aged 65 years or older, persons who are morbidly obese, and persons with underlying medical conditions (pulmonary, renal, cardiovascular, hepatic, hematologic, neurologic and neurodevelopmental conditions; and immune-deficient conditions, such as HIV, diabetes, and cirrhosis) are at high risk for complications. Infection during pregnancy increases the risk for hospitalization and may be associated with severe illness, sepsis, pneumothorax and respiratory failure, spontaneous abortion, preterm labor, and fetal distress.

Influenza causes necrosis of the respiratory epithelium, increased adherence of bacteria to infected cells, and ciliary dysfunction, which predispose to secondary bacterial infections due to pneumococci, staphylococci, or Haemophilus spp. In turn, bacterial enzymes (eg, proteases, trypsin-like compounds, and streptokinase) activate influenza viruses. Frequent complications are acute sinusitis, otitis media, purulent bronchitis, and pneumonia.

Cardiovascular diseases are a complication of influenza infection, in particular among older adults, and influenza is postulated to be a significant trigger for myocardial infarction, cerebrovascular disease, and sudden death. Several studies suggest that influenza vaccination has protective effect against major adverse cardiovascular events. Neurologic complications, including seizures and encephalopathy, may occur. Encephalopathic complications of influenza are uncommon.

Reye syndrome (fatty liver with encephalopathy) is a rare and severe complication of influenza (usually B type) and other viral diseases (especially varicella), particularly in young children. It consists of rapidly progressive hepatic failure and encephalopathy, and there is a 30% mortality rate. The pathogenesis is unknown, but the syndrome is associated with aspirin use in the management of viral infections.

Treatment

Treatment is supportive. Antiviral therapy should be considered for all persons with acute illness, in particular those at high risk for developing complications who have a suggestive clinical presentation or with laboratory-confirmed influenza. Clinical trials show a reduction in the duration of symptoms, hospital admissions, as well as secondary complications, such as otitis, sinusitis, or pneumonia, but not mortality when using these agents. Maximum benefit is expected with the earliest initiation of therapy. Although the benefit of antiviral therapy after 48 hours of illness is reduced, it should be initiated if the patient is hospitalized or critically ill. Benefit has been noted up to 4–5 days into illness.

The antiviral treatment of choice should be based on the susceptibility of the circulating virus. Currently, since high levels of resistance to the adamantanes (amantadine and rimantadine) persist among seasonal H1N1 and H3N2 influenza A viruses and these agents are not effective against influenza B viruses, amantadine and rimantadine are not recommended for treatment.

Three neuraminidase inhibitors are FDA approved for treatment of influenza A and B: oral oseltamivir, inhaled zanamivir, and intravenous peramivir. The CDC recommends treatment with oral oseltamivir (75 mg twice daily for 5 days) as the drug of choice for patients of any age, pregnant women, and patients who are hospitalized or have complicated infection. Absorption of oral oseltamivir is considered reliable, except in patients with impaired gastric motility or gastrointestinal bleeding.

Inhaled zanamivir (10 mg, 2 inhalations twice daily for 5 days) is indicated for uncomplicated acute influenza in patients 7 years and older, is relatively contraindicated among persons with asthma because of the risk of bronchospasm, and is not formulated for use in mechanically ventilated patients. Inhaled zanamivir lacks efficacy in pneumonia, probably due to poor bioavailability in the peripheral lungs.

Intravenous peramivir (600 mg in single dose) is used for outpatient treatment of uncomplicated infection in patients 18 years and older and is recommended when there is a concern about inadequate oral absorption of oseltamivir. The efficacy of peramivir in patients with severe illness and in patients with influenza B is not well established. Some studies demonstrated that repeated doses for up to 5 days of intravenous peramivir is safe, effective and shorten the duration of influenza illness.

Resistance to neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir) can occur during or after prolonged use in immunocompromised patients, particularly in persons who have undergone hematopoietic stem cell transplant. Intravenous zanamivir is an investigational drug that could be requested for clinical use if there is a concern for oseltamivir-resistant influenza strain. Depending on the mutation conferring the resistance, the virus might develop resistance to oseltamivir but remain susceptible to zanamivir. Laninamivir is a long-acting inhaled neuraminidase inhibitor used for the treatment of seasonal influenza, including infection caused by oseltamivir-resistant virus. It is licensed in Japan and South Korea and is currently in phase III clinical trials in the United States.

Baloxavir (a selective inhibitor of influenza cap-dependent endonuclease that is given as a single oral dose) was approved by the FDA in 2018 for treatment of uncomplicated influenza A and B infections. Baloxavir is given as 40 mg or 80 mg orally once daily depending on weight (the higher dose for persons 80 kg or more) and should be given within the first 48 hours of infection. Its side effects include diarrhea and bronchitis, and to date, its effects in patients older than 65 years or younger than 12 years are not established. Baloxavir’s unique mechanism of action will likely make it useful as part of multidrug therapy for resistant disease. For complicated disease, especially in immunosuppressed patients, the combination of oseltamivir, amantadine, and ribavirin appears to produce faster viral clearance but no definite clinical improvement. Other drugs are being tested in vitro showing potent antiviral activity against multidrug-resistant influenza viruses.

The first class of organosilanes have potent antiviral activity against influenza A viruses that are resistant to amantadine and oseltamivir. Dapivirine, an FDA-approved HIV nonnucleoside reverse transcriptase inhibitor, has broad-spectrum antiviral against multiple strains of influenza A and B viruses. Iminosugars are also under study. Updated advice is available at http://www.cdc.gov/flu/index.htm.

Prognosis

The duration of the uncomplicated illness is 1–7 days, and the prognosis is excellent in healthy, nonelderly adults. Hospitalization typically occurs in those with underlying medical disease, at the extremes of age, and in pregnant women. Most fatalities are due to bacterial pneumonia although exacerbations of other disease processes, in particular cardiac diseases, occur. Pneumonia resulting from influenza has a high mortality rate among pregnant women and persons with a history of rheumatic heart disease. Mortality among adults hospitalized with influenza ranges from 4% to 8%, although higher mortality (greater than 10–15%) may be seen during pandemics and among immunocompromised individuals. At least 64% of pneumonia and influenza deaths occurred among elderly persons in the United States, who comprised only 15% of the population.

If the fever recurs or persists for more than 4 days with productive cough and white cell count over 10,000/mcL, secondary bacterial infection should be suspected. Pneumococcal pneumonia is the most common secondary infection, and staphylococcal pneumonia is the most serious. Major complications include viral myocarditis and viral encephalitis.

Prevention

Annual administration of influenza vaccine is the most effective measure for preventing influenza and its complications. Seasonal influenza vaccines can reduce influenza hospitalizations by an estimated 61%. Vaccination of healthcare workers is associated with decreased mortality among hospitalized patients and those in long-term care facilities. Vaccination prevents influenza illness among pregnant women and their infants during the first months of life.

The ACIP and the American College of Obstetricians and Gynecologists’ Committee recommend annual influenza vaccination for all persons over 6 months of age with no contraindications. Vaccination is emphasized for high-risk groups and their contacts and caregivers.

Several Cochrane database analyses have analyzed the efficacy of the influenza vaccines in select populations. The studied groups include patients with COPD (a documented reduction in exacerbations with inactivated vaccine), the elderly (where vaccination shows some efficacy), adults with cancer (weak evidence, some lower mortality and influenza-related outcomes), healthy adults (established efficacy with inactivated vaccine, but only modest effects in pregnant women and newborns), and healthy children (where both live and inactivated vaccines lower the rate of influenza infections).

Other reviews establish the efficacy and safety of influenza vaccination in patients with rheumatoid arthritis, asthma, or myasthenia gravis, and elderly nursing home patients. The obese have an impaired response to the influenza vaccine.

Multiple influenza vaccine products are licensed in the United States and available from different manufacturers. These include inactivated influenza vaccines (standard- or high-dose, trivalent [IIV3] or quadrivalent [IIV4], adjuvanted or unadjuvanted), recombinant vaccines (trivalent [RIV3] or quadrivalent [RIV4]), and live attenuated influenza vaccine (LAIV4). All trivalent vaccines contain antigens from one strain each of influenza A (H1N1), influenza A (H3N2), and influenza B. Quadrivalent vaccines include an additional influenza B strain. The CDC does not endorse one influenza vaccine product over another, although each influenza vaccine product has different age indications and contraindications. The CDC publishes its annual influenza recommendations in the late summer (www.cdc.gov/mmwr).

LAIV4 use, not recommended by the CDC for the last two seasons due to concerns about its effectiveness against influenza viruses in prior years, is currently considered an acceptable option for groups in whom it is indicated. The efficacy of including the fourth A/Slovenian strain is as yet unknown.

Adults over the age of 18 years, including pregnant women, can receive any influenza vaccine, with few exceptions. Patients 65 years or older should receive a high-dose trivalent inactivated influenza vaccine containing four times more hemagglutinin than standard dose, or Fluad, a trivalent inactivated influenza vaccine that contains an adjuvant (MF59), which enhances the immune response to the vaccine. Fluzone intradermal inactivated quadrivalent vaccine is equally immunogenic and safe but more expensive than the intramuscular vaccine and is not recommended for persons older than 65 years. Adults older than 65 years can use any IIV or RIV intramuscular vaccine; in a large randomized trial, high-dose IIV3 showed superior efficacy over standard-dose IIV3 and may provide better protection. Some data suggest intradermal vaccination is more effective than intramuscular vaccination in the elderly. The herpes zoster vaccine can be safely coadministered with the seasonal influenza vaccines in patients over 50 years of age, with similar immunogenicity.

For patients with cancer, chemotherapeutic regimens containing rituximab show persistent perturbations of B-cell and Ig synthesis, and these modifications decrease humoral responses to the influenza vaccine. Adjuvanted vaccine is efficacious but has resulted in brief disease exacerbation in persons with psoriatic arthritis taking TNF-alpha inhibitors.

Vaccination is contraindicated for persons with a history of severe allergic reaction to influenza. Precautions should be taken if patients report a history of Guillain-Barré syndrome 6 weeks following an influenza vaccine and if patients have a moderate to severe acute illness with or without fever until clinical improvement. Persons with a history of egg allergy with hives only may receive any recommended influenza vaccine. Those with more severe allergic reactions to eggs may receive any recommended vaccine under close observation in a health care facility under the supervision of a provider with experience treating severe allergic reactions. Only the recombinant vaccine is completely egg-free.

Additional vaccine information can be found at http://www.cdc.gov/flu/professionals/vaccination/index.htm.

When antiviral chemoprophylaxis is used, it prevents 70–90% of influenza infections. Chemoprophylaxis is not routinely recommended and is not recommended prior to exposure to prevent development of resistance. Chemoprophylaxis may be considered for persons at increased risk for complications from infection who are exposed to an infected patient within 2 weeks of vaccination, for persons unlikely to respond to vaccination because of immunosuppression after exposure to an infected person, for persons for whom vaccination is contraindicated and who are at high risk for complications after exposure to an infected person, and for prevention of infection in residents of institutions during an outbreak. Alternatively, a person can be monitored closely, and antiviral therapy initiated at the first onset of symptoms after exposure. Initiation of chemoprophylaxis is not recommended more than 48 hours after exposure. Patients taking chemoprophylaxis should seek urgent medical care if an influenza-like illness develops.

Chemoprophylaxis against influenza A and B is accomplished with daily administration of the neuraminidase inhibitors oseltamivir (75 mg/day, oral) or zanamivir (10 mg/day, inhaled) to continue through 7 days after last known exposure. For outbreak control in long-term care facilities and hospitals, a minimum of 2 weeks is recommended, including in vaccinated persons if the seasonal vaccine is not well matched to the circulating strain, to continue until 1 week after identification of the last known case. Zanamivir should not be given as chemoprophylaxis to asthmatic persons, nursing home residents, or children younger than 5 years.

Breakthrough infections with influenza occur with neuraminidase inhibitors (in a study with zanamivir) and with vaccination. The efficacy of chemoprophylaxis is proven for individuals and households but not community settings.

Hand hygiene and surgical facemasks appear to prevent household transmission of influenza virus isolates when implemented within 36 hours of recognition of symptoms in an index patient. Such nonpharmaceutical interventions assist in mitigating the spread of pandemic and interpandemic influenza to nonvaccinated persons. In one study, patients with seasonal H1N1 influenza infection were infectious from 1 day before to about 7 days following illness onset. Children and immunosuppressed persons exhibit prolonged viral shedding and may be infectious longer. Winter school breaks during periods of high influenza transmission appear to decrease rates of visits to primary care practitioners for influenza illness among children and adults.

The data are not currently sufficient to modify statin usage for influenza vaccination. There may be, however, some impaired effectiveness against the H3N2 influenza A component of vaccines from the immunomodulatory effects of statins.

Any hospital patient in whom the infection is suspected should be isolated in an individual room with standard and droplet precautions. CDC guidelines recommend the equivalent of N95 masks for aerosol generating procedures (eg, bronchoscopy, elective intubation, suctioning, administering nebulized medications). For such procedures, an airborne infection isolation room can be used, with air exhausted directly outside or recirculated after filtration by a high efficiency particulate air (HEPA) filter. Strict adherence to hand hygiene with soap and water or an alcohol-based hand sanitizer and immediate removal of gloves and other equipment after contact with respiratory secretions is essential. Precautions should be maintained until 7 days from symptom onset or until 24 hours after symptom resolution, whichever is longer. Postexposure prophylaxis or close monitoring and early treatment should be considered for close contacts of patients who are at high risk for complications of influenza and may be considered for health care personnel, public health workers, or first responders who experienced a recognized, unprotected close contact exposure to a person with influenza virus infection during that person’s infectious period.

A regimen of dose sparing vaccination (to 3.5 mcg) is advocated by some providers to address the extreme shortage of influenza vaccine, particularly in developing world countries, with adequate vaccination against all components except H3N2, where there is reduced seroconversion.

When to Admit

• Limited availability of supporting services.

• Pneumonia or decreased oxygen saturation.

• Changes in mental status.

• Consider with pregnancy.

General Considerations

Zoonotic influenza viruses are distinct from human seasonal influenza viruses and do not easily transmit between humans. In addition, a number of viral genetic changes are required for adaptation to humans. For avian influenza viruses, birds are the natural hosts. Around the world and in North America, avian influenza A outbreaks occur in poultry from time to time (including a 2016 outbreak in Dubois County, Indiana, with avian but no human cases), and the virus has become endemic in poultry in some countries, mostly in Southeast Asia and Egypt. Occasionally, avian influenza viruses may infect humans or other mammals, including domestic cats and dogs. Illness in humans ranges from mild disease to rapid progressive severe disease and death depending on the subtype.

The primary risk factor for human infection is direct or indirect exposure to infected live or dead poultry or contaminated environments, such as live bird markets. Slaughtering and handling carcasses of infected poultry are also risk factors.

The emergence of H5, H7, and H9 avian influenza virus subtypes in humans raises concern that the virus may undergo genetic reassortment or mutations in some of the genes and develop greater human-to-human transmissibility with the potential to produce a global pandemic. All fatal avian influenza virus infections acquire their internal gene segments from H9N2 viruses, the most widespread avian influenza subtype.

Human infections with H5N1 viruses have been reported to WHO from 16 countries, the first report in the Americas was in Canada in 2014, and approximately 60% of the cases have died. Infection with H7N9 avian influenza virus was first reported in China in 2013. Since then, many cases have been reported around the world with an average case fatality rate of 40%. Infections with other H7 avian influenza viruses (H7N2, H7N3, and H7N7) have occurred sporadically around the world. Rare human cases of influenza H9N2 are also reported.

Clinical Findings

A. Symptoms and Signs

Distinguishing avian influenza from regular influenza is difficult. History of exposure to dead or ill birds or live poultry markets in the prior 10 days, recent travel to Southeast Asia or Egypt, or contact with known cases should be investigated. Patients infected by H5N1 or H7N9 avian influenza A viruses have an aggressive clinical course. The symptoms and signs include fever followed by lower respiratory symptoms (cough, dyspnea). Upper respiratory tract symptoms are less common. Gastrointestinal symptoms are reported more frequently in H5N1 infections. Conjunctivitis is reported in influenza H7 infections. Other systems can also be involved leading to neurologic manifestations (encephalopathy, seizure) and liver impairment. Prolonged febrile states and generalized malaise are common. Respiratory failure, multiorgan dysfunction, and septic shock are the usual cause of death. Bacterial superinfections are reported.

For human infections with H7N7 and N9B2 avian influenza virus infections, most cases have been mild with a few cases hospitalized and very few reports of deaths resulting from infection.

B. Laboratory Findings

Current commercial rapid antigen tests are not optimally sensitive or specific for detection of H5N1 influenza and should not be the definitive test for influenza. More sensitive RT-PCR assays are available through many hospitals and state health departments. Diagnostic yield can be improved by early collection of samples, preferably within 7 days of illness onset. Throat swabs or lower respiratory specimens (such as tracheal aspirate or bronchoalveolar lavage fluid) may provide higher yield of detection than nasal swabs. When highly pathogenic strains, such as H5N1 influenza virus infections, are suspected, extreme care in the handling of these samples must be observed during preliminary testing. Positive samples must then be forwarded to the appropriate public health authorities for further investigation (eg, culture) in laboratories with the adequate level of biosafety (level 3).

Treatment

Persons with severe illness and confirmed and probable cases with mild disease should receive treatment as soon as possible. The current first-line recommendation is to use the neuraminidase inhibitor oseltamivir, 75 mg orally twice daily for 5 days administered within 48 hours from onset of illness. Longer courses of therapy (eg, 10 days) should be considered in hospitalized patients with severe illness and persistent viral shedding. Data are lacking for use of inhaled zanamivir or peramivir for severe avian influenza. Overall oseltamivir, by modeling, is associated with a 49% reduction in mortality from H5N1 avian influenza virus infections. As with seasonal influenza, enteric oseltamivir is well absorbed in critically ill persons without gastric stasis, known malabsorption, or gastrointestinal bleeding. Daily intravenous peramivir (600 mg, reduced to 200 mg for kidney dysfunction) for a minimum of 5 days and a maximum of 10 or more days (depending on severity of illness) or zanamivir (10 mg inhaled daily for 10 days) may be considered in such patients. Combination therapy with amantadine or rimantadine (in countries where H5N1 influenza virus A strains are likely to be susceptible to adamantanes) may be considered in patients with pneumonia or progressive disease. Resistance of avian H5N1 influenza strains to amantadine and rimantadine is present in most geographic areas. Resistance to neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir) can occur with H5NA and H7N9 avian–infected patients. Successful treatment with administration of convalescent plasma is reported.

Prevention

The most effective method of prevention is avoidance of exposure. Persons who work with poultry should practice good hand hygiene and use appropriate personal protective equipment. These workers should also be vaccinated against seasonal influenza, since this can reduce the likelihood of coinfection with avian and seasonal influenza. Persons should avoid visiting live poultry markets when able and should avoid contact with ill birds. No risk exists for acquiring avian influenza through the consumption of well-cooked poultry products. The US government bans the importation of poultry from infected areas. Culling of animals has been effective in ending outbreaks of highly pathogenic avian influenza but is difficult with H7-infected poultry because most are asymptomatic. Policies regarding closure of live poultry markets during avian epidemics are controversial.

Persons with exposure should monitor themselves for 10 days after the last known exposure and should seek prompt medical attention if new fever or respiratory symptoms develop. Postexposure prophylaxis is not recommended in persons working with noninfected birds or who used appropriate personal protective equipment while working with infected birds. For persons with exposure to infected persons, postexposure prophylaxis is recommended for household and family members and may be considered for health care personnel with close unprotected contact. Postexposure prophylaxis regimens include 75 mg of oseltamivir orally or 10 mg inhaled zanamivir twice daily for 5 or 10 days from the last known exposure, depending on the length of the exposure. Careful surveillance for human cases and prudent stockpiling of medications with establishment of an infrastructure for dissemination are essential modalities of control. Nonpharmacologic means of control include masks, social distancing, quarantine, travel limitations, and infrastructure development, particularly for emergency departments.

Current vaccines do not provide cross-protection against strains of the H5, H7, and H9 influenza viruses. The United States government has prepandemic stockpiles of adjuvanted H5N1 vaccines and H7N9 vaccines that are not available to the public. The highly diverse genetic nature and the rapid evolution of the avian influenza viruses has resulted in the emergence of viruses that are distinct from stockpiled vaccines. New vaccine development is ongoing to generate vaccines against H7N9 and H5N1 with broadened protection against unmatched strains. Some of these vaccines are under study in preclinical and clinical trials; however, no vaccines are currently commercially available for humans.

Control of infection among the poultry population is key to prevention of human disease. Vaccination of poultry as a sole means of control is ineffective. Closing live poultry markets can interrupt outbreaks. Additional adjunctive measures, such as days where live markets are closed temporarily for disinfection (which can decrease viral loads in surrounding ground water) or separation of land-based poultry from waterfowl, are needed for improved control.

Because the potential for pandemic influenza for many of the new reassortment viruses is not fully known, continued surveillance is essential, and stockpiling of vaccines, adjuvant, and medications (oseltamivir and zanamivir) is warranted at the public health level.

General Considerations

SARS is a respiratory syndrome caused by a unique coronavirus, transmitted through direct or indirect contact of mucous membranes with infectious respiratory droplets. The virus is shed in stools, but the role of fecal-oral transmission is unknown. The natural reservoir appears to be the horseshoe bat (which eats and drops fruits ingested by civets, the earlier presumed reservoir and a likely amplifying host), which can carry a variety of different coronavirus strains.

The earliest cases were traced to a health care worker in Guangdong Province in China in late 2002, with rapid spread thereafter throughout Asia and Canada, considered a consequence of spread through travel. The last cases were reported in 2004. The 2003 outbreak involved 8098 probable cases from 29 countries, with 774 fatalities. Nine additional cases associated with a research laboratory were reported in China in 2004 with no further cases reported since then.

Clinical Findings

A. Symptoms and Signs

SARS is an atypical pneumonia that affects persons in all age groups. Severity ranges from asymptomatic disease to severe respiratory illness. Many subclinical cases probably go undiagnosed. Seasonality, as with influenza, is not established. The incubation period is 2–7 days, and it can be spread to contacts of affected patients for 10 days. The mean time from onset of clinical symptoms to hospital admission is 3–5 days. In all clinical cases, persistent fever is present; chills or rigors (or both), cough, shortness of breath, rales, and rhonchi are the rule. Headache, myalgias, and sore throat are common with watery diarrhea occurring in a subset of patients. Elderly patients may report malaise and delirium, without the typical febrile response.

B. Laboratory Findings and Imaging

Leukopenia (particularly lymphopenia) and low-grade disseminated intravascular coagulation are common. Modest elevations of ALT and creatine kinase are frequently seen. Arterial oxygen saturation less than 95% with associated nonspecific pulmonary infiltrates is evident in 80% of affected individuals. A high-resolution CT scan is abnormal in 67% of patients with initially normal chest radiographs.

Serum serologies, including enzyme immunoassays and fluorescent antibody assays, are available through public health departments at the state level, although seroconversion may not occur until 3 weeks after the onset of symptoms. The detection rates for the virus using conventional RT-PCR are generally low during the first week of illness. Urine, nasopharyngeal aspirate, and stool specimens are positive in 42%, 68%, and 97%, respectively, on day 14 of illness. Viral isolation is technically laborious and time-consuming.

Complications

ARDS, with extensive bilateral consolidation, occurs in about 16% of patients, and about 20–30% of patients require intubation and mechanical ventilation.

Treatment

Severe cases require intensive supportive management. Different agents including, lopinavir/ritonavir, ribavirin, interferon, IVIG, and systemic corticosteroids were used during the 2003 epidemic, but the treatment efficacy of these agents remains inconclusive. In vitro studies with ribavirin show no activity against the virus, and a retrospective analysis of the epidemic in Toronto suggests worse outcomes in patients who received the drug. A 2017 study of alisporivir, a nonimmunosuppressive cyclosporine A analog, alone and in combination with ribavirin, initially showed efficacy in vitro but then did not improve outcomes in a mouse model. A meta-analysis studying the use of Chinese herbs failed to show any efficacy in treating SARS. Studies using monoclonal antibodies are underway based on the response of some patients to immune convalescent sera of convalescent patients.

Prognosis

The overall mortality rate of identified cases is about 14%. Poor prognostic factors include advanced age (mortality rate greater than 50% in those over 65 years of age compared with less than 1% for those under 2 years of age), chronic hepatitis B infection treated with lamivudine, high initial or high peak lactate dehydrogenase concentration, high neutrophil count on presentation, diabetes mellitus, acute kidney disease, and low counts of CD4 and CD8 on presentation.

Prevention

Health care workers engaged in procedures that involve contact with respiratory droplets are at risk. Isolation of high-risk patients is essential, and simple hygienic measures may help reduce transmission.

Control measures include quarantining in the home for high-risk exposed persons and the use of facemasks for preventing hospital-acquired infections. The validity of using such masks in the community remains unsubstantiated. Continual reporting of suspected cases is crucial, as is awareness of restrictions on international travel. The most cautious modalities include monitoring for 10 days after the last potential exposure and confinement of recovering patients for a similar interval. Currently, there are two vaccine candidates in early stages of development. One is the 218-amino acid residue receptor-binding domain of SARS, expressed in yeast, and it is called RBD219-N1. The other is a single-plasmid DNA vaccine encoding the spike (S) glycoprotein of SARS; it has been shown to be safe in a phase I clinical trial (NCT00099463).

General Considerations

Middle East respiratory syndrome (MERS) is a syndrome associated with a coronavirus similar to the cause of severe acute respiratory syndrome (SARS). Patients with MERS have had a history of residence or travel in the Middle East, in particular Saudi Arabia, or contact with such patients. The virus is probably transmitted through direct or indirect contact of mucous membranes with infectious respiratory droplets. The virus is shed in stool, but the role of fecal-oral transmission is unknown. The earliest cases were identified in 2012 in the Kingdom of Saudi Arabia, and 75% of all cases have occurred there. Additional cases have occurred throughout the Middle East, Africa, and Europe, with a reported death rate of 36% (http://www.who.int/emergencies/mers-cov/en/). So-called super-spreaders are often responsible for propagating the pathogen in the early stages of an outbreak.

Person-to-person transmission can occur within families; hospital-associated cases comprise 25% of cases. The median incubation period is 5 days (range, 2–14) with the mean age of 50 (range 9 months to 99 years) and 65% occurring among men. Over 90% of patients have an underlying medical condition, including diabetes mellitus (68%), hypertension (34%), or chronic heart or kidney disease. Those with diabetes, kidney disease, chronic lung disease, or other immunocompromising conditions likely are at highest risk for severe disease.

Camels appear to be the principal reservoir, and several studies show that contact with dromedary herds of camels is greater among cases than controls. Raw camel milk is considered a potential source. Persons who work with camels are more likely to have antibody evidence of past infection.

Clinical Findings

A. Symptoms and Signs

MERS is an acute respiratory syndrome, with the most common symptoms being fever (98%), cough (83%), and dyspnea (72%). Chills and rigors are common (87%). Gastrointestinal symptoms may occur, with diarrhea being most common (26%), followed by nausea and abdominal pain, and may precede respiratory symptoms. Mild and asymptomatic cases are reported.

B. Laboratory Findings and Imaging

Hematologic findings in the largest series to date include thrombocytopenia (36%), lymphopenia (34%), and lymphocytosis (11%). Moderate elevations in lactate dehydrogenase (49%), AST (15%), and ALT (11%) are recognized. Chest radiograph abnormalities are nearly universal and include increased bronchovascular markings, patchy infiltrates or consolidations, interstitial changes, opacities (reticular and nodular) and pleural effusions, and total lung opacification. Ground-glass opacities and consolidation are most commonly seen. The findings mimic those of many other causes of pneumonia.

Serum serologies and RT-PCR are available through CDC (contact information below, on MMWR reference site). Highest viral loads are found in lower respiratory tract specimens, including bronchoalveolar lavage fluid, sputum, and tracheal aspirates. These samples are preferred for diagnosis. The CDC recommends sending lower respiratory tract specimens, nasopharyngeal and oropharyngeal swabs, and serum for testing. In confirmed cases, serial sample collection (perhaps every 2–4 days) from multiple sites is recommended to increase understanding of virus shedding kinetics. In cases in which symptom onset occurred more than 14 days prior and symptoms are ongoing, serum should be sent to the CDC for serologic testing and the above specimens should be sent for RT-PCR.

C. Case Definition

A patient with severe illness shows the following characteristics: fever (38°C, 100.4°F or higher) and pneumonia or ARDS (based on clinical or radiologic evidence); and either history of travel in or near the Arabian Peninsula within 14 days before symptom onset; or close contact with a symptomatic traveler in whom fever and acute respiratory illness (not necessarily pneumonia) developed within 14 days after traveling in or near the Arabian Peninsula (above); or is a member of a cluster of patients with severe acute respiratory illness (eg, fever and pneumonia requiring hospitalization) of unknown etiology in which MERS-CoV is being evaluated, in consultation with state and local health departments.

In milder illness, patients have fever and symptoms of respiratory illness (not necessarily pneumonia; eg, cough, shortness of breath) and history of having close contact with a confirmed MERS case as well as a history of being in a health care facility (as a patient, worker, or visitor) within 14 days of symptom onset in a country or territory within the Arabian Peninsula in which recent health care–associated cases of MERS have been identified.

Of note, fever may not be present in certain patients, including the very young, elderly persons, immunosuppressed individuals, or those taking certain medications.

Complications

Respiratory failure is such a common complication that in a series from Saudi Arabia, 89% of patients required intensive care and mechanical ventilation. Patients with MERS-CoV appear to advance faster to respiratory failure than do those with SARS.

Treatment

Respiratory support is essential. No vaccine or known antiviral therapy exists to combat MERS. Current therapies are adapted from SARS treatments, which include broad-spectrum antibiotics, corticosteroids, interferons, ribavirin, lopinavir-ritonavir, or mycophenolate mofetil. A small retrospective study found improved survival at 14 days with ribavirin and interferon-alpha but not at 28 days. A novel study is underway to investigate the safety of SAB-301, a fully human polyclonal anti-MERS IgG collected from transchromosomic cattle (cattle that produce fully human polyclonal IgG; NCT02788188). Further studies are necessary to evaluate the efficacy of these treatments.

Prognosis

The overall mortality rate of identified cases is about 36%. Advanced age is associated with a poor prognosis.

Prevention

Isolation and quarantine of cases is authorized by CDC. Strict infection control measures are essential as well as care and management of household contacts and hospital workers engaged in the care of patients. Travelers to Saudi Arabia (including the many pilgrims to the holy sites) should practice frequent hand washing and avoid contact with those who have respiratory symptoms. Evaluation of patients with suspect symptoms within 14 days of return from Saudi Arabia is essential. Because healthcare workers engaged in procedures that involve contact with respiratory droplets are at risk, isolation of high-risk patients is essential, as are simple hygienic measures. Control measures, including quarantining in the home for high-risk exposed persons and the use of facemasks for preventing hospital-acquired infections, are important. Assisting public health authorities with case reporting and surveillance is essential.

Camel workers including slaughterhouse and market workers, veterinarians, and racing personnel should wear facial protection and protective clothing and practice good personal hygiene, including frequent hand washing after touching animals. Family members of such personnel should not be exposed to work paraphernalia including clothing and shoes and workers should shower at the site of employment rather than the home. Avoid direct contact with camels (who may be asymptomatic but who can transmit the virus though nasal or ocular discharge, milk, urine, and feces). All infected animals should be kept off the market, including their meat products, and buried or destroyed.

Several MERS vaccines are under development, and most of these are based on MERS-CoV “spike” glycoprotein (NCT03615911). The most recent vaccine to enter phase I clinical trials is a biologic vaccine called ChAdOx1 (NCT03399578).

The world is responding to a new outbreak of respiratory disease caused by a novel coronavirus that emerged in late 2019 in China and quickly spread across the globe. The viral strain was given an initial name of 2019-nCoV, accounting for the year of discovery, its status as a “novel” virus, and its family name (CoV). The official CDC-recommended terminology for the virus is SARS-CoV-2, and the illness caused by this virus is called “Coronavirus Disease 2019” or COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/summary.html).

Coronaviruses are a large family of viruses commonly found in people and many species of animals including bats, camels, cattle, and cats. Animal coronaviruses can rarely infect people and then spread person-to-person such as with MERS-CoV, SARS-CoV, and now with SARS-CoV-2. Like MERS-CoV and SARS-CoV, the SARS-CoV-2 virus is a betacoronavirus, which is one of the four genera of coronaviruses; all three of these betacoronaviruses have their origins in bats.

COVID-19 was declared a pandemic by the WHO on March 11, 2020. SARS-CoV-2 appears to have first developed in a seafood market in Wuhan, China. As of March 11, 2020, 114 countries had reported COVID-19 cases, and the number of global cases surpassed 110,000 including over 4000 deaths. While more than 90% of the global fatalities have been reported from the Chinese province of Hubei and its capital, Wuhan, the numbers outside of China are growing faster than inside China. As of March 2020, the CDC continued to recommend that travelers avoid all nonessential travel to China, Iran, South Korea, and Italy (Level 3 Travel Health Notice) and that older adults or those who have chronic medical conditions consider postponing travel to Japan (Level 2 Travel Health Notice).

Most infected individuals are asymptomatic. Those who develop symptoms usually have fever, respiratory symptoms, and, on occasion, abdominal symptoms. COVID-19 is particularly serious in the elderly and in those with immunocompromising conditions. It does not seem to cause serious disease in children. The infection shows a predilection for pulmonary tissues, and, in fulminant cases, it produces a pneumonia. Some patients progress to an adult respiratory distress syndrome akin to the coronavirus infections that cause SARS and MERS (but unlike the far more common “common cold” coronavirus infections).

SARS-CoV-2 shows a higher rate of person-to-person spread than the 2003 SARS-CoV virus. The principal mode of transmission is likely respiratory droplets, which can be propelled up to six feet by sneezing or coughing. SARS-CoV-2 is not believed to be significantly aerosolized but airborne precautions are currently recommended in healthcare settings until the virus’ exact modes of transmission have been fully characterized. While the case-fatality was higher with the 2003 SARS-CoV, the number of infected cases, a consequence of the disease dynamics, is already higher with SARS-CoV-2 than with either the SARS or MERS agents. The incubation period ranges from about 2-24 days with an average of about 5.2 days.

The reservoir is not fully known. Like all coronavirus infections, bats are an ultimate reservoir and perhaps amplified by pangolins, an Asian anteater whose scales are traded on black markets for circulatory problems.

Prevention and treatment recommendations are evolving. The usual cautions include handwashing with soap and water for at least 20 seconds, wearing a mask for exposure to patients with cough (using impermeable masks, e.g. N95 masks), and isolating cases (and, in particular, removing infected patients from incubating transportation structures such as airplanes or cruise ships). Several antiviral agents are under study, including boosted protease inhibitors (both lopinavir/ritonavir and darunavir/cobicistat used in HIV therapy). A new antiviral agent under study named remdesivir (a nucleic acid analogue with known activity against the Ebola and Marburg agents, as well as RSV, Lassa virus, and Nipah virus) is available from the manufacturer Gilead on a compassionate usage basis. It was used for Chinese cases and for an American patient quarantined in Washington State. A combination of neutralizing monoclonal antibodies (REGN3048 and REGN3051) produced by Regeneron is being studied in a first-in-human clinical trial sponsored by the National Institute of Allergy and Infectious Diseases. Additional agents under investigation include CytoDyn’s leronlimab (PRO 140; a CCR5 antagonist) and Galidesivir (BCX4430; a nucleoside RNA polymerase inhibitor). Several candidate vaccines are under development.

Three factors that are complicating the control of this epidemic viral agent are 1) its known infectivity of health care workers, 2) its spread by infected individuals during an early asymptomatic phase of illness, and 3) difficulty accessing testing. In the US, nucleic acid testing is currently being offered by the CDC, local and state health departments, and two commercial testing companies (LabCorp and Quest).

A case tally and other current information are available through the WHO website (https://www.who.int/emergencies/diseases/novel-coronavirus-2019) and, with a map, through The Johns Hopkins University Wuhan Coronavirus website (https://systems.jhu.edu/research/public-health/ncov/).