Influenza in the ED: The Basics and Why is my patient so sick?

Authors: Carolina Mendoza, MD (Emergency Medicine Resident at McGovern Medical School) and Hilary Fairbrother, MD, MPH (Director of Undergraduate Education at McGovern Medical School) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case

A 40-year-old male with no past medical history presents from home with cough, congestion, shortness of breath, and fever for the past six days. His fever is subjective, and the shortness of breath is progressively worsening. He has been taking over the counter cold medicine and NSAIDs with little relief. Initial vital signs show a temperature of 103 degrees Fahrenheit, pulse of 120 beats per minute, blood pressure of 128/70 mm Hg, respiratory rate of 28, and an oxygen saturation of 89% on room air. On exam, patient appears diaphoretic with an increased work of breathing. He is placed on a non-rebreather mask, and O2 saturation improves to 100%.

Background

Influenza is an acute upper respiratory infection that typically occurs during the winter months (November to March) caused by the influenza A and B viruses. The Centers for Disease Control and Prevention (CDC) defines influenza as an illness with a fever of greater than 100°F and either a sore throat or cough in the absence of other known causes (1). However, a patient’s clinical presentation can vary by age, and there are a wide variety of symptoms associated with influenza infection. Studies have attempted to distinguish the clinical presentations of patients with influenza, but there has been no clinical finding with a sensitive or specific enough positive likelihood ratio to rule out or rule in influenza (2-4). Among those with influenza fever, cough, sore throat, headache, myalgia, and rhinitis appear to be the most common symptoms (1). Cough and fever within 48 hours of symptoms onset has the best positive predictive value (79%) of influenza (4). Vomiting and diarrhea are more frequently seen in the pediatric population, but these symptoms are far less likely than the typical upper respiratory symptoms (5). Additionally, numerous complications can occur after an infectious with influenza including acute bronchitis, secondary bacterial pneumonia, otitis media, myocarditis, pericarditis, myoglobinuria, renal failure, encephalitis, and toxic shock syndrome (3).

In the United States, about 20% of the population is infected with the influenza virus during the winter season (1). Transmission of the virus occurs through large droplets and direct contact with small particle aerosols (3). A higher prevalence occurs in school children given close proximity in confined spaces. Viral shedding occurs 24 to 48 hours before onset of illness and ceases 6 to 7 days later. Periods of shedding are longer in children and elderly with studies showing up to a mean of 19 days after start of symptoms (3). Those at higher risk for complications include children and adults with pre-existing respiratory diseases like asthma and chronic obstructive pulmonary disease, morbid obesity, children under 2 years of age, and elderly patients (particularly those > 75 years old) (7). Studies have shown that children younger than 6 months of age and children with chronic medical conditions also have a high risk of mortality related to influenza (1, 5). In the adult population, about 90% of the deaths occur in people greater than 65 years of age (6, 8).

Evaluation

Upon evaluating patients who present with influenza like illness, it is important to first stabilize the patient and manage his/her respiratory status. As stated before, the signs and symptoms of influenza will vary depending on a patient’s age and medical problems. Additionally, it is important to understand the local prevalence of influenza to better guide your evaluation and management of the patient. While influenza is typically seasonal, it can occur throughout the year. The CDC issues a weekly report regarding the region-based frequency of influenza that can help inform the prevalence of influenza in your area (https://www.cdc.gov/flu/weekly/fluactivitysurv.htm).

The risk stratification of patients is important to better manage those who are at higher risk for complications. Populations at high risk for severe course of influenza infection include (1, 13):

  • Age <2 and > 65
  • Chronic pulmonary disease (asthma, COPD, etc.)
  • Chronic cardiovascular, renal, or hepatic disease
  • Hematologic disease
  • Diabetic patients
  • Immunocompromised patients
  • Conditions that increase risk of aspiration or compromise respiratory function
  • Morbid obesity
  • Pregnancy

Diagnosis

Diagnostic tests available include viral culture, immunofluorescence, reverse transcriptase polymerase chain reaction (RT-PCR) assay, and rapid antigen testing. RT-PCR and viral culture are considered the “gold standard” but require more time and specialized laboratory testing (9). There are many approved RT-PCR testing types available, and they are highly sensitive and specific. Time to result can be from 1 – 8 hours. Depending on where you practice, RT-PCR samples may need to be sent to an outside laboratory, considerably increasing the reporting time. Viral cultures are also highly sensitive and specific but take anywhere from 3-10 days for final result reporting (10). Rapid antigen testing is commercially available, and this is the typical test used in the emergency department. Kits will detect both influenza A and B; however, they do not distinguish between the two (1). Rapid influenza diagnostic testing (RIDT) has a sensitivity of 50-70% with ranges of 10-80% reported and a specificity of 90-95% with a range of 85-100% (11). The low sensitivity and high specificity lead to many false negatives. A negative result cannot guarantee that a patient does not have the influenza virus, especially during high prevalence season. In the emergency department, we focus on ruling out diseases; therefore, a test with low sensitivity is not as useful. When there is a high prevalence of influenza, diagnosis based on clinical presentation is reasonable given the high prevalence of the disease (6, 19). A study completed by Stein et al. in 2004 showed there was no difference between clinical judgment and rapid antigen testing when diagnosing influenza during high prevalence season (12). Specific testing through PCR or culture should be saved for critically ill patients or patients being admitted to avoid exposing other patients in the hospital who are not infected with influenza (9).

Other contributory lab testing

Other laboratory testing is often non-specific, but can be helpful in specific situations. Matsuno et al. noted that while elderly patients with pneumonia caused by influenza were less likely to have a fever, they were likely to have higher C-Reactive Protein (CRP) levels on presentation to the ED (2). CBC is often nonspecific, though a WBC above 15,000 is often indicative of concomitant bacterial infection (3). Liver function and renal function tests may demonstrate end organ damage in severe disease.

Management

Mild to Moderate Influenza without risk factors:

Patients with no risk factors and mild to moderate disease can be discharged home with supportive treatment even during high influenza season. Antiviral treatment can be considered if the patient is within 48 hours of illness onset based on clinical judgement (1). The greatest clinical benefit is seen when antiviral treatment is administered within 48 hours of illness onset in both healthy and high-risk patients (13). Randomized controlled trials and meta-analyses have shown initiation of treatment within 48 hours of onset reduces duration illness and fever in healthy children and adults (18). According to a large 2014 randomized clinical trial in an urban hospital in Bangladesh even treatment initiated after the recommended 48 hours did not statistically reduce clinical symptoms. but it did reduce viral shedding (14).

Baloxavir marboxil is a new antiviral drug approved by the FDA in 2018 for the treatment of uncomplicated influenza in patients 12 years and older (13). It is not recommended for pregnant women, breast feeding mothers, patients with complicated disease, or hospitalized patients. It is an oral medication (pill) and is weight based (20 mg or 40 mg tabs available). The typical adult dose is 40 mg, PO, for a single dose. It should not be consumed with dairy products.

Outpatient management of uncomplicated influenza (13):

  • Oral oseltamivir, inhaled zanamivir, or oral baloxavir
  • Oseltamivir: oral, BID dosing x 5 days
    • Oseltamivir is the preferred treatment for pregnant women
  • Inhaled zanamivir is not recommended for those with severe or complicated illness
    • Zanamivir has been associated with bronchospasm and is not recommended for those with underlying reactive airway disease (i.e. asthma, COPD)
  • Oral baloxavir, 40 mg, single dose
    • Not recommended for complicated cases, hospitalized patients, breast feeding or pregnant women
  • Alternative treatment includes IV peramivir x 1 day

Mild to Moderate Influenza with risk factor(s):

Those at risk for complications or with previous pre-existing medical conditions benefit from initiation of antiviral therapy even if presenting after 48 hours from onset of symptoms. Studies have shown reduced rates of complications anddeath in hospitalized adult patients when treated for influenza (13). Some of these patients may be able to be discharged if they have adequate follow up and are able to manage the symptoms of their infection. You should not wait for laboratory confirmation in order to start antiviral therapy in high risk patients or the acutely ill (1). You also do not need to order or wait for confirmatory testing before initiating antiviral therapy in a patient with a high suspicion of influenza infection (13).

Disposition of patients depends on several factors (1):

  • Respiratory status and work of breathing
  • Oxygen saturation
  • Age
  • Comorbidities
  • Reliability of outpatient follow up

Consider inpatient admission for any patient who is at high risk for complications that may arise as result of primary influenza infection. For those who can be safely discharged, close follow up with a primary care doctor is recommended. Additionally, return precautions should be discussed with patients prior to discharge especially those with comorbidities.

Severe infection with or without risk factors:

Severe ill patients should be admitted to the appropriate level of care matching their disease findings. Antiviral treatment along with ventilatory support, fluid resuscitation, anti-bacterial treatment, and pressor medications may all necessary.

Patients with severe or complicated illness with suspected or confirmed influenza that require hospitalization (13):

  • Effect of specific antiviral medications has not been established
  • There does seem to be a benefit of neuraminidase inhibitor treatment when compared to no treatment in hospitalized patients
  • Duration and dosing of treatment has not been established for complicated influenza illness. Treatments must be altered based on clinical judgement.

Why is my patient so sick?

It is clear which patients are at the high risk for serious influenza infection, morbidity, and mortality from an epidemiological perspective. However, most of the pediatric hospitalization and half of the pediatric influenza related mortalities are in previously healthy children. This is at least partially due to the fact that the “attack rate” of influenza is 10-40% in children and symptomatic disease is around 9% (5, 15). Most of the adult influenza morbidity and mortality is due to age (patients older than 75) and chronic disease. This highlights the importance of influenza vaccination, particularly for any person coming into contact with children under the age of 6 months old and the elderly. It is important to remember that children are not eligible to get the influenza vaccine until they are 6 months old.

When patients with influenza become very ill, it is likely due to the secondary complications of the viral infection and other concomitant bacterial infections. The most common and serious complication of influenza is pneumonia. Secondary bacterial pneumonia is the most common complication in elderly patients. Patients will appear to be improving from their initial influenza infection followed by a relapse of fever/cough/sputum production (3). Novel or worsening infiltrates will likely appear on chest x-ray. There is some data that shows that elderly patients are less likely to have an elevated body temperature associated with their pneumonia and one study showed a correlation between CRP elevations and disease severity in patients over 65 years old (2).

When a young, otherwise healthy adolescent or adult becomes severe ill community associated methicillin-resistant S. aureusshould be suspected. The mortality rate is approximately 50%, and often patients were not started on antibiotics to cover CA-MRSA from the onset of infection, which is associated with increased mortality (16).

The virus itself can also directly attack the lungs, resulting in the rare but deadly complication of viral pneumonia. This is noted on chest x-ray as bilateral, reticular/nodular opacities. Predisposing factors for viral pneumonia include increased left atrial pressure and chronic pulmonary disease (3).

Pediatric specific complications include myositis and rhabdomyolysis, and a CK level should be for pediatric and adult influenza patients with severe muscle tenderness (3). Patients with pre-existing neurological conditions are at increased risk for the rare but serious CNS complications of influenza including seizures, meningitis, transverse myelitis, encephalitis, or Guillain-Barre syndrome (4 per 100,000 person years). Out of this list, seizures are the most common CNS complication of influenza (5).

CNS complications are possible in adults as well, though who is at risk and the mechanisms behind why influenza crosses the blood/brain barrier are not well understood.  Complications include encephalopathy, transverse myelitis, and Guillain-Barre syndrome. MRI imaging with T2 weighted images helps make these difficult diagnoses (3).

Finally, concomitant myocardial infarction is also possible both during an acute influenza illness and after an infection. A retrospective study in Maryland found an association between influenza A/H3N2 and MI. Older patients with known cardiac risk factors are at particular risk. A screening ECG and serum troponin level is recommended for patients over the age of 50 with chest pain or known cardiac risk factors (17).

Conditions that can mimic an influenza-like illness include endocarditis, myocarditis, and spinal epidural abscess. Consider these diagnoses in patients with risk factors and history/examination findings. The key is to keep these on your differential in the patient with symptoms resembling influenza. For more, see this emDocs post.

 Case Conclusion

The patient undergoes rapid antigen testing that is reported as negative. You decide to start antiviral therapy in addition to broad spectrum antibiotics given the time of year and the high prevalence of influenza. The patient is admitted to the hospital for further management given his new oxygen requirement and respiratory distress. The patient’s clinical diagnosis is confirmed with PCR positive for influenza B.

Summary

  • Influenza can present with wide variety of symptoms and can lead to multiple complications.
  • Be aware of your local seasonal prevalence of influenza and specific strains, as it will help limit inappropriate testing and lead to timely therapy (https://www.cdc.gov/flu/weekly/fluactivitysurv.htm)
  • Risk stratify patients depending on their comorbidities and previous medical problems
  • A negative rapid antigen test does not rule out influenza, particularly when prevalence is high
  • A purely clinical diagnosis of influenza (i.e. no confirmatory testing) during high influenza season is reasonable for low-risk patients who are likely to be discharged.
  • For low risk patients with mild to moderate illness, treat as outpatients with oral antiviral if presenting within 48 hours of illness onset, otherwise supportive treatment is recommended.
  • Hospital admission should be based on patient’s risk factors, age, respiratory status, clinical presentation, comorbidities, and access to outpatient follow up.
  • Treatment with antiviral medications is recommended for all patients who are severely ill, have complicated illness, are at high risk for complications, or are hospitalized.
  • Be aware that pneumonia (bacterial, CA-MRSA, viral), pediatric myositis/rhabdomyolysis, and MI in elderly patients are possible contributors to why your influenza patient may be so sick.

References/Further Reading:

  1. Murphy Influenza: Challenges In Diagnosis And Management In The Emergency Department. Emergency Medicine Practice. 2009;11(11):1-26. https://www.ebmedicine.net/topics.php?paction=showTopic&topic_id=205
  2. Matsuno O, et. al. Influence of age on symptoms and laboratory findings at presentation in patients with influenza-associated pneumonia. Arch Gerontol Geriatr.2009 Sep-Oct;49(2):322-5. doi: 10.1016/j.archger.2008.11.015. Epub 2009 Jan 15.
  3. Dolin R. Clinical manifestations of seasonal influenza in adults. UpToDate. https://www.uptodate.com/contents/clinical-manifestations-of-seasonal-influenza-in-adults?search=influenza&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2#H1. Published February 2, 2018. Accessed December 2, 2018.
  4. Monto AS, Gravenstein S, Elliott M, Colopy M, Schweinle J. Clinical signs and symptoms predicting influenza infection. Arch Intern Med. 2000;160(21):3243.
  5. Munoz, F. Seasonal influenza in children: Clinical features and diagnosis. UpToDate. https://www.uptodate.com/contents/seasonal-influenza-in-children-clinical-features-and-diagnosis?search=symptoms%20of%20influenza&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2. Accessed April 18th, 2019.
  6. Harper SA, Bradley JS, Englund JA, et al. Seasonal Influenza in Adults and Children—Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clinical Infectious Diseases. 2009;48(8):1003-1032. doi:10.1086/598513. Influenza (Flu): Estimated Influenza Illness, Medical visits, Hospitalizations, and Deaths in the United States – 2017-2018 influenza season. https://www.cdc.gov/flu/about/burden/2017-2018.htm. Published December 18, 2018. Accessed January 2, 2018.
  7. Glezen WP. Impact of Respiratory Virus Infections on Persons With Chronic Underlying Conditions. JAMA. 2000; 283(4):499. doi:10.1001/jama.283.4.499.
  8. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179.
  9. Influenza (Flu): Information on Rapid Molecular Assays, RT-PCR, and other Molecular Assays for Diagnosis of Influenza Virus Infection. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm. Published February 20, 2018. Accessed December 2, 2018.
  10. Uyeki, T. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. Clinical Infectious Diseases, Volume 68, Issue 6, 15 March 2019, Pages e1–e47, https://doi.org/10.1093/cid/ciy866. December 2018. https://academic.oup.com/cid/article/68/6/e1/5251935. Accessed April 18th, 2019.
  11. Influenza (Flu): Rapid Influenza Diagnostic Tests. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm. Published January 18, 2017. Accessed December 2, 2018
  12. Stein JC. Performance Characteristics of Clinical Diagnosis and a Rapid Influenza Test in the Detection of Influenza Infection in a Community Sample of Adults. Academic Emergency Medicine. 2004;11(5):566-566. doi:10.1197/j.aem.2004.02.235.
  13. Influenza (Flu): Influenza Antiviral Medications Summary for Clinicians. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Published November 28, 2018. Accessed December 2, 2018.
  14. Fry AM, Goswami D, Nahar K, Sharmin AT, Rahman M, Gubareva L, Azim T, Bresee J, Luby SP, Brooks WA. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomized placebo-controlled trial. Lancet Infectious Diseases. 2014; 14(2): 109-18. doi: 10.1016/S1473-3099(13)70267-6.
  15. Chaves SS, Perez A, Farley MM, Miller L, Schaffner W, Lindegren ML, Sharangpani R, Meek J, Yousey-Hindes K, Thomas A, Boulton R, Baumbach J, Hancock EB, Bandyopadhyay AS, Lynfield R, Morin C, Zansky SM, Reingold A, Bennett NM, Ryan P, Fowler B, Fry A, Finelli L, Influenza Hospitalization Surveillance Network. The burden of influenza hospitalizations in infants from 2003 to 2012, United States. Pediatr Infect Dis J. 2014;33(9):912.
  16. Kallen AJ, Brunkard J, Moore Z, Budge P, Arnold KE, Fosheim G, Finelli L, Beekmann SE, Polgreen PM, Gorwitz R, Hageman J. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Ann Emerg Med. 2009;53(3):358.
  17. Lichenstein R, Magder LS, King RE, King JC Jr. The relationship between influenza outbreaks and acute ischemic heart disease in Maryland residents over a 7-year period. J Infect Dis. 2012;206(6):821.
  18. Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenzain healthy adults: systematic review. 2006 Jan 28;367(9507):303-13.
  19. Influenza (Flu): Estimated Influenza Illness, Medical visits, Hospitalizations, and Deaths in the United States – 2017-2018 influenza season. https://www.cdc.gov/flu/about/burden/2017-2018.htm. Published December 18, 2018. Accessed January 2, 2018.

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