Kurt Weber, MD, Attending Physician/Faculty, Orlando Health EM Residency, Director, Corporate Office of Research Operations, Orlando, FL; Clinical Assistant Professor of Emergency Medicine, Florida State University College of Medicine, Tallahassee.
Kathryn Bondani, MD, Resident Physician, Orlando Health EM Residency, Orlando, FL.
Philip Giordano, MD, Attending Physician/Faculty, Orlando Health EM Residency, Chief of Research Operations, Orlando Health, Orlando, FL; Clinical Assistant Professor of Emergency Medicine, Florida State University College of Medicine, Tallahassee.
Charles L. Emerman, MD, Chairman, Department of Emergency Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH.
Influenza is possibly the most widespread and well known of infectious diseases. Seasonal epidemics can be found on all continents, and no age segment of the population is untouched. Among these groups, both symptoms and severity will vary. Definitive diagnosis in the emergency department (ED) is problematic, as rapid bedside tests vary in sensitivity and specificity and must be interpreted in the context of local disease prevalence. Initiation of antiviral treatment is an issue an emergency physician (EP) should consider. The following review will give the emergency physician information to manage these patients.
Influenza-like illnesses have been described since the time of Hippocrates, varying from mild upper respiratory symptoms to cases of fulminant hemorrhagic disease.1 The peak of the annual flu season can be classified as an "epidemic" the episodic pandemics are what history remembers.
A pandemic is "an epidemic occurring worldwide or over a very wide area, crossing international boundaries, and usually affecting a large number of people."2 Influenza pandemics occur about three times per century, with the most famous being the Spanish flu of 1918. The loss of human life in the 1918 flu pandemic was phenomenal. The mortality rate was 2-20%, contrasting with mortality rate of 0.1% for the seasonal flu.3 In total, 5% of the world's population died, with estimates of 25 million dead in 25 weeks. For comparison, HIV/AIDS has accounted for 25 million deaths in its first 25 years.3
The first pandemic of this century was the "swine flu" pandemic of 2009. While it ultimately was milder than previous pandemics, with a case fatality rate of 0.03%, the 2009 flu earned its designation by infecting 482,300 people in 199 countries.4
Influenza viruses are RNA viruses in the Orthomyxoviridae family known to cause disease in a variety of animal species. The family can be split into three genera (influenza A, B, and C), all of which cause infection in humans.5 Of the three, influenza A is both the most prevalent and most severe.6 It is responsible for the annual flu season as well as the pandemics seen throughout history. Influenza B circulates at lower levels and produces less severe disease.7 Influenza C is capable of producing severe disease, but is much less common and not routinely included in the rapid diagnostic testing kits.8
All three genera have a similar structure that includes a viral envelope surrounding a central RNA genome core. (See Figure 1.) The central genomic core is made up of eight single-stranded RNA.9 The envelope contains two large glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which serve as the targets for both antiviral agents and host antibodies. HA is responsible for binding the free-floating virus to target cells and introducing the viral genome. NA mediates the release of viral progeny from the infected cells.10
Figure 1: Structure of Influenza Virus
There are 17 different hemagglutinin antigens (H1-H17) and 10 different neuraminidase antigens (N1-N10) that form the basis of nomenclature in the subtypes of influenza A.11,12 For example, an influenza A virus with a type 5 hemagglutinin and type 1 neuraminidase encoded in its genome would be known as H5N1. Influenza A variants can also be grouped according to the host species to which the flu viruses are endemic (e.g., bird flu, human flu, swine flu, equine flu). Currently, N1H1, H1N2, and H3N2 are the only known influenza A subtypes circulating among humans.12 Sporadic cases of different variants may arise but do not result in sustained transmission.13
Antigenic Shift Versus Drift
Influenza evolves through two important mechanisms: antigenic drift and antigenic shift.14,15 (See Figure 2.) Antigenic drift occurs as random mutations create a variety of strains with small antigenic differences. Because of their similarities to the prior generations, it's likely humans will have immunity to most variants.16 However, a small antigenic change in the right place can provide a new strain with just the advantage it needs to infect and transmit itself successfully from human to human. This strain will move steadily through the population, causing a seasonal epidemic.16
Figure 2: Antigenic Drift and Antigenic Shift
Antigenic shift or reassortment occurs when an influenza virus acquires completely new surface antigens. Reassortment is when two different viruses infect the same host cell and exchange genetic material during replication.17 This most often occurs when strains endemic to different species mix. This can result in a unique strain not seen by humans previously. With lack of immunity, these novel strains can spread widely and quickly, causing a pandemic.18 The virus responsible for the 1918 pandemic, for example, incorporated genetic material from human, swine, and avian origins.19
Infected persons become contagious after a 1-3 day incubation period just before clinical symptoms manifest. The virus will shed for another 5-7 days, with the second or third day being the highest infectivity period.20
The influenza virus can spread person to person by direct transmission of respiratory secretions when a person sneezes or coughs, producing aerosolized virions.21 A sneeze will release tens of thousands of virus particles, most of which will quickly settle from the air; however, inhaling just one virus particle can result in active infection.21,24,25 People can also acquire the virus through picking up particles from contaminated surfaces.22 The virus can survive outside the body for variable lengths of time. On hard, non-porous surfaces, the virus may persist one to two days, but only five minutes on skin.25 Protected in mucus, the virus can survive up to 17 days, and indefinitely when frozen.26,27
Presentation. Consider influenza in anyone who presents with abrupt onset of cough and nasal congestion along with high fever and shaking chills. These symptoms have been reported as the most sensitive findings, yet their low specificities illustrate the overlap between influenza and other respiratory viral illnesses, particularly the common cold.28 (See Table 1.) In periods of local outbreaks when all three symptoms are present, the prevalence of the flu may top 70%.29
Table 1: Common Symptoms of Influenza
Influenza differentiates itself with extreme fatigue and myalgias throughout the body, particularly the back and legs. The myalgias can be severe and a major cause for the loss of work and school days. Less frequently, conjunctival injection and rashes are noted. While mild vomiting may be seen in adults, it is not a predominant symptom, and diarrhea is unusual in seasonal variants. Children commonly exhibit more gastrointestinal symptoms than adults during the illness.30 Because of the variance of symptoms, particularly among different age groups, and dependency on local disease prevalence, reliable clinical prediction rules for influenza infection have not been developed.30 To help guide the practicing clinician, the Infectious Disease Society of America (IDSA) has published guidance on when to consider influenza.31 (See Table 2.)
Table 2: Who Should Be Considered for Influenza Infection
While the overwhelming majority of influenza infections will be a mild, self-limiting process, certain cases evolve to a severe respiratory illness that requires hospitalization.32 What starts out as mild upper respiratory tract infection can quickly progress into a severe viral pneumonitis, usually by day 4 or 5 of illness.33 This pneumonitis is associated with severe hypoxemia, ARDS, and fulminant shock, characterized by diffuse infiltrates on chest radiography.34,35 (See Figure 3.)
Figure 3: Diffuse Infiltrates on Chest Radiography
The most lethal complication is bacterial pneumonia.36,37 The classic organism described is Staphylococcus, including methicillin-resistant Staphylococcus aureus (MRSA), but Streptococcus pneumoniae and Streptococcus pyogenes have been documented as well.38 Bacterial superinfection has been implicated in up to 38% of deaths during influenza outbreaks and can be seen early (2-3 days) in the illness.38,39
Preexisting medical comorbidities are also affected in influenza infections, particularly underlying lung disease. Both asthma and chronic obstructive pulmonary disease (COPD) exacerbations are prolonged during co-infection and highly correlated with the need for hospitalization and respiratory failure.36,37
Rarely, complications are seen in other body systems. Neurologic manifestations, including confusion, seizure, and encephalopathy, have been described.40
The recent introduction of new, more effective antiviral treatments has stimulated the development of diagnostic testing methods for influenza. (See Table 3.) These tests rely on either direct detection of the virus within respiratory samples or indirect identification via the patient's immune response.
Table 3: Diagnostic Testing
Types of Tests
Rapid Influenza Diagnostic Tests (RIDTs). RIDTs are testing kits for the rapid detection of the influenza virus through recognition of viral antigens and are the most commonly utilized tests in the emergency department setting. There are two broad categories of RIDTs:41 those that can detect both influenza A and B but cannot distinguish between the two types, and those that can detect both influenza A and B and can distinguish between the two types. There is currently no RIDT that can specifically distinguish between influenza A virus subtypes. Respiratory samples are provided via nasopharyngeal (NP) swab, nasopharyngeal aspirate, or, rarely, throat swabs.
Sensitivity varies widely among types of RIDTs and have been reported as anywhere between 10-71%, with specificities greater than 90%.42,43 Sensitivity varies greatly based on collection time in comparison to onset of illness, study population, type of specimen, and circulating subtypes of disease.44 Sensitivity has also been found to be much higher in pediatric populations, likely due in part to higher concentrations of viral shedding by children.45 Since viral shedding peaks within the first 48 hours after symptoms, optimal sensitivity is obtained when collected within this time period.46 Recently, the CDC in conjunction with the Biological Advanced Research and Development Authority and the Medical College of Wisconsin tested 11 commercially available, FDA-approved RIDTs using stock samples of circulating virus strains.47 While all tests were able to detect the virus at its highest concentrations, many struggled with detection at lower levels of viral dilution.
Immunofluorescence Microscopy. For detection of influenza virus by immunofluorescence microscopy, respiratory samples are incubated with fluorescent-stained viral monoclonal antibodies and then examined under a fluorescence microscope for dye uptake.46 Uptake of dye indicates the presence of infection. The sensitivity and specificity of this type of test relies heavily on the number of infected cells present in the respiratory sample and is technique- and technician-dependent.45,46 Benefits of this type of testing include the ability for respiratory samples to be incubated with a variety of different monoclonal antibodies, allowing for simultaneous detection of multiple and alternative respiratory viruses, as well as a relatively rapid result time of about two hours.45,46 Owing to its difficult technique and varying sensitivity, immunofluorescence is not routinely available in hospital and commercial laboratories.
Viral Culture. Viral culture has traditionally served as the "gold standard" for diagnosing influenza.45,46 Isolation of the influenza virus is complex and requires evaluation of samples for at least 7 to 14 days. A newer technique, known as shell viral culture, has the ability to shorten detection time to 48 hours; however, this shortened time is still too long to be useful for individual patient care.46,47 It has been estimated that viral culture may miss 3% to 46% of influenza-positive patients, as viral shedding is minimal later in disease course and extremely difficult to isolate via culture.45,47 Viral cultures are still routinely used in reference laboratories, as they are useful in providing information on antiviral susceptibility of circulating strains, as well as allowing collection of stock virus to be used in research.41,42
Reverse-Transcription Polymerase Chain Reaction Assays. RT-PCR is currently considered to be the most sensitive and specific test for the diagnosis of influenza and is rapidly replacing viral isolation as the gold standard.41,42,46,47 In multiple studies, RT-PCR has been shown to identify more samples as positive than other diagnostic methods, including viral culture.45,47 Currently, platforms for RT-PCR are available in large state public health institutions and reference laboratories but are not widely available in rural or small community hospitals.41 This lack of widely available laboratories, the long time period required for testing (4-6 hours), and the technical skill required makes RT-PCR not feasible for management of individual patients in the emergency department setting, but still useful for confirmatory testing and population surveillance.
Using Diagnostic Tests for Treatment Decisions. When making a decision to use influenza testing in patient care, the clinician has to take into account several variables. First, most initial testing will be completed by RIDTs, which, as previously discussed, can have variable sensitivity rates; false-negative findings may occur because of low quantities of viral shedding, inappropriately collected samples, or emergence of novel viral subtypes that are not recognized by current rapid tests.44
One should also take into account the prevalence of influenza in their population. (See Figure 4.) During times of high prevalence, the positive predictive value of RIDTs is highest, meaning that a positive result is likely a true positive and a negative result more likely to be a false negative.46,48 During times of low prevalence of disease, the positive predictive value of RIDTs is lowered, meaning that a positive test result is more likely to be a false positive and a negative result more likely a true negative.44,48 In high prevalence periods, all patients do not require testing, as clinical judgment can approach sensitivities of 79-87%.48 During periods of low prevalence, both the CDC and the WHO recommend confirmatory testing by viral culture or RT-PCR.44,48
Figure 4: Interpreting the RIDT
Clinicians should be aware of the cost vs. benefit aspects of influenza testing. The average cost of both a rapid influenza test and a course of antiviral treatment is approximately $50.43 When influenza prevalence and clinical suspicion are both high, it is more cost effective to treat empirically. The opposite is true when influenza prevalence is low.
Adamantanes. Adamantanes were initially approved for treatment of influenza A in 1966. These drugs interfere with viral uncoating inside the cell by inhibiting the M2 ion channel protein.49 These drugs have no effect against influenza B, as they lack this protein.49,50 The oral drug amantadine was the first drug in this class. Concerns about adamantadine's central nervous system side effects, including confusion, decreased seizure threshold, and insomnia,45,50 led to the research and development of the newer drug rimantadine, which has a less severe side-effect profile. Multiple studies done in the 1960s to 1970s showed that adamantanes were effective in shortening the duration and severity of influenza A illness.49,50 No studies have shown a decrease in the rate of influenza complications with adamantane treatment.49
Since the 2006 influenza season, resistance to adamantanes has grown to more than 90% in the United States, with more recent resistance rates approaching 100%.51,52,53 Due to this high level of resistance, routine use of adamantanes for influenza treatment or prophylaxis is not recommended.
Neuraminidase Inhibitors. Neuraminidase inhibitors are a newer class of antivirals that inhibit the neuraminidase, thus blocking the virus's ability to reproduce through inhibition of budding.52 It is believed that replication of influenza cells within the respiratory tract reaches its peak within 24 to 72 hours after onset of illness, and initiation of neuraminidase therapy is recommended as soon as possible to target the replication stage of the virus and halt further host cell infection.52 As opposed to the amantadanes, these drugs are active against both influenza A and B. Currently two drugs are available.
Zanamivir. Zanamivir is administered by inhalation through a diskus. The drug becomes highly concentrated in the respiratory tract with low systemic absorption; only 5-15% of the total dose being absorbed and excreted in the urine.54 As the drug is inhaled, there is potential for respiratory side effects. Studies of FEV during treatment of patients with underlying asthma or chronic lung disease have had mixed results,54,55 and there have been some case reports of serious, sometimes fatal, bronchospasm associated with use;54 thus, zanamivir is contraindicated in patients with asthma and other chronic respiratory diseases.54,55
Zanamivir is FDA approved for treatment of influenza in patients older than 7 years of age and the prophylaxis of influenza in patients older than 5 years of age. Treatment dose is 10 mg (or two inhalations) twice a day for five days, and the prophylaxis dose is 10 mg once a day for 10 days.54
Oseltamivir. Oseltamivir is an oral capsule or powder for liquid suspension that is readily absorbed from the gastrointestinal tract and converted into its active carboxylated form.56 It achieves high plasma concentration, thus facilitating its activity outside of the respiratory tract. The most common side effects are nausea and vomiting, which occur in 5-10% of patients and may be reduced when taken with food.51,53,56 Serious hypersensitivity reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been rarely reported and should lead to prompt discontinuation of the drug.56
Oseltamivir is FDA approved for treatment of influenza in patients older than 2 weeks of age who have been symptomatic for no greater than 48 hours and for influenza prophylaxis for those older than 1 year of age. (See Table 4.) The dosage should be adjusted for those with renal impairment.56
Table 4: Oseltamivir Dosing Guidelines
Efficacy in Treatment. Neuraminidase inhibitors initiated within 48 hours of symptoms onset decrease the severity and duration of influenza A and B illness. Multiple studies done in a wide range of geographical locations and patient populations have confirmed these findings.51,52,55,56
Early treatment seems to be the key to optimal neuraminidase inhibitor efficacy. The IMPACT trial done in 1999-2000 looked at the time between initiation of oseltamivir therapy and the duration and severity of influenza illness in more than 1400 patients 12 to 70 years of age.55 Results showed that initiation of therapy within 12 hours had the largest impact, and initiation at 48 hours the smallest impact on duration and severity of disease. Initiation of therapy at time intervals between 12 and 48 hours affected the disease duration and severity proportionally.
Data are limited on whether neuraminidase treatment can lower complication rates; however, several small-scale studies have shown that treatment with oseltamivir can lower incidence of lower respiratory tract complications, lower antibiotic usage, and decrease hospitalization rates.51,52,57,58
Resistance. In contrast to adamantanes, development of resistance to neuraminidase inhibitors is uncommon. Prior to 2007, annual surveillance identified a less than 1% resistance rate among circulating viral strains.59 During the 2007-2008 influenza season, the incidence of resistance increased to approximately 10% in the H1N1 viral strain in the United States.59 Despite this seasonal anomaly, current viral surveillance data indicate that approximately 99% of currently circulating influenza strains remain sensitive to neuraminidase inhibitors.52
A parenteral form of zanamivir is being investigated,60,61 and recent trials show that it may reduce viral shedding and prevent illness. Peramivir is another new neuraminidase inhibitor that is undergoing trials for IV and IM administration60,61,62 and also appears to be effective in reducing duration and severity of illness.62,63 Laninamivir, a long-acting, single-dose inhalational neuraminidase inhibitor, is also under investigation, and early studies show it to be non-inferior to oral oseltamivir.60,61,63
Whom To Treat
According to the CDC in their 2011 recommendations on the use of antivirals,53 clinicians should initiate prompt treatment of confirmed or suspected influenza in persons at high risk for influenza complications or those who require hospitalization. The CDC identifies the following groups as high risk:
- children younger than 5 years old (especially those younger than 2 years old);
- Adults older than 65 years;
- people with chronic pulmonary (including asthma), cardiovascular, renal, hepatic, hematologic (including sickle cell), metabolic disorders (including diabetes), or neurologic disorders (including spinal cord disorders, mental retardation, cerebral palsy, and seizures);
- people with immunosuppression via medications or HIV;
- people who are pregnant or within 2 weeks post-partum;
- people younger than 18 years of age on chronic aspirin therapy (due to increased risk of Reyes syndrome);
- American Indians/Alaskan Natives;
- people who are morbidly obese;
- residents of nursing homes and other chronic care facilities.
In addition, treatment should be considered in those with confirmed or suspected illness who are not at high risk as long as treatment can be initiated within 48 hours of symptom onset.53 These patients with low risk of complications do not require treatment, but may see some benefit of shortened duration and a decrease in lost work days.52
Patients with suspected or confirmed illness requiring hospitalization should be started on antiviral treatment even if outside of 48 hours from symptom onset,41,42 as recent observational studies show that treatment up to 96 hours from symptom onset can reduce risk of severe outcomes.
The secondary illness attack rates among close contacts of those with confirmed influenza (especially family members residing in the same household) have been reported as 10-40%.66,67 Several large, randomized, controlled trials have shown that chemoprophylaxis with oseltamivir or zanamivir is 70-80% effective in protecting close contacts when given within 48 hours of exposure.67-69 Persons who should be considered for antiviral chemoprophylaxis include family or other close contacts of a person with suspected or confirmed influenza who are at higher risk for influenza complications but are not protected by vaccination.53,70 Patients who receive chemoprophylaxis may still acquire the influenza virus and potentially be able to transmit the virus even if clinical illness is prevented.53,66,71 Chemoprophylaxis should only be considered if antivirals can be started within 48 hours of the most recent exposure.64,68,69 As previously discussed, zanamivir is approved for chemoprophylaxis in patients older than 5 years of age, and oseltamivir is approved for patients older than 1 year of age.
Some thought has been given to pre-exposure prophylaxis, especially in very high-risk populations such as nursing home residents and severely immunosuppressed patients.56 A six-week study of oseltamivir chemoprophylaxis among nursing home residents demonstrated a 92% reduction in influenza illness.56,77 Pre-exposure prophylaxis must be administered for the length of time that exposure may occur.56 This prolonged use of antivirals may lead to a higher incidence of viral resistance and should only be used in those who are very high risk who cannot be otherwise protected.53,71 Duration of pre-exposure prophylaxis is varied to anywhere from 28-42 days.53,71 There are no data on therapy for more than six weeks. Dosing remains identical to post-exposure prophylaxis.
The spread of influenza from person to person is primarily through large particle respiratory droplet transmission, i.e., when an infected person coughs or sneezes near an uninfected person.53 Emergency department waiting rooms and triage areas should remain vigilant about appropriate respiratory hygiene and cough etiquette during periods of high prevalence of influenza infection. Health care team members should actively ask all patients about respiratory symptoms and should attempt to isolate those with suspected respiratory illness.72 Posting visual alerts to provide patients as well as health care personnel with instructions on facemask use, cough etiquette, and hand hygiene is a reasonable step to aid in infection control.72
Once in the emergency department, droplet precautions should be implemented for patients with suspected influenza.72 These precautions require patients to be placed in single treatment areas whenever possible. Health care workers should wear facemasks when entering rooms, and these masks should be discarded after leaving the patient's room. While the CDC currently recommends N95 respirators, a recent randomized, controlled trial found that surgical masks appeared to be no worse than N95 respirators, and transmission rates leading to confirmed diagnosis were similar in the two populations.73 If the patient on droplet precautions must be moved for treatment or testing purposes, the patient should wear a facemask. Communication between departments about suspicions of influenza is important in helping decrease spread of the disease.72
For emergency department procedures that may cause increased infectious aerosols, such as intubation or cardiopulmonary resuscitation, the number of health care workers should be limited to only essential personnel and personal protective equipment, including a surgical mask, gown, and gloves, should be worn.72 Unprotected health care personnel and visitors should not be allowed in rooms for these procedures.
Special Considerations for Treatment and Prevention
Pregnancy. Pregnant women are especially susceptible to developing severe illness from influenza virus and are at an increased risk of hospitalization due to complications.74,75,76 During the recent H1N1 pandemic, pregnant women were four times more likely to be hospitalized, had higher rates of ICU admission, and had higher rates of death than the general population.74,77 Those women who have underlying conditions, including asthma, obesity, pregestational or gestational diabetes, and hypertension, appear to be at the greatest risk of hospitalization and death.74 Risk of influenza complications, including preterm labor and fetal death, appears to be highest in the second and third trimesters.74,76
Multiple studies have shown no increased risk in stillbirth or other birth complications with administration of vaccination or antiviral treatment.74-76 Current public health recommendations from the Advisory Committee on Immunization Practices and ACOG recommend influenza vaccination during the second and third trimesters as well as early treatment with antiviral medications without reliance on diagnostic testing.64,68 All currently available antivirals are pregnancy category C medications and dosing is identical to that for non-pregnant adults.64
Pediatrics. Children younger than the age of 2 years have high rates of hospitalization due to influenza, with the highest rates of both hospitalization and death occurring in those younger than 6 months.77,78
Infants younger than 6 months of age get some influenza protection from natural maternal influenza antibodies.77 Breastfeeding has also been shown to have some protective effects.77 Since 2003, influenza immunization has been recommended for infants ages 6 to 23 months and this was expanded to all children in 2010.
Efficacy of neuraminidase inhibitors in children has been shown in multiple large studies.51,54 In one large trial, oseltamivir treatment within 48 hours shortened the length of illness by 36 hours and decreased the incidence of otitis media by 44%.51
Elderly. Of the current estimated 36,000 influenza-related deaths in the United States each year, 90% occur in older adults and are most related to cardiovascular and pneumonia complications.79 In addition, almost two-thirds of all influenza-related hospitalizations for influenza are persons older than 65 years of age.72 Not surprisingly, severe influenza infection risk escalates with an increase in comorbidities, with the most vulnerable older adults experiencing 60 times the risk of hospitalization and death compared to that of healthy 65- to 75-year-olds.79 The highest risk factors include very advanced age, prior admission for influenza or pneumonia, chronic conditions including heart, lung, and renal disease, malignancy, previous stroke, and dementia.79
Prompt antiviral treatment of those with confirmed or suspected influenza68 is imperative, and post-exposure prophylaxis is indicated in any patient with known exposure. There is no change in treatment or prophylaxis dosing based on age alone.56,68
Immunocompromised. Despite the underlying cause of immunosuppression, all groups are higher risk for severe influenza infection resulting in hospitalization or death.82
In any patient who develops suspected or confirmed influenza, prompt treatment with antivirals should be initiated.56,91 Evidence is very limited, but oseltamivir post-exposure chemoprophylaxis has been shown to be effective for some immunocompromised patients and is strongly recommended for this patient group.91
Influenza is and will continue to be one of the most important infectious disease entities in emergency medicine. Influenza has classic mechanisms of evolution that make seasonal epidemics a certainty and historic pandemics a possibility.
Available medication for influenza includes an inhaled medication (zanamivir) and oral medication (oseltamivir). For most patients, these antivirals are not indicated unless they can be started within 48 hours. However, some patients at high risk for severe disease may benefit from treatment initiated after this timeframe.
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