Influenza Mimics: Pearls & Pitfalls

Author: Laurel Barr, MD (Assistant Professor of Emergency Medicine, The Ohio State University; Consultant to the Professional Staff in the Center for Regional Emergency Medicine, The Medicine Institute at the Cleveland Clinic) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)


Have you ever been in the ED just minding your own business when the bus arrives and 10 people check in? You blink at the board, utter a few exclamatory words to yourself, drop your pizza and give up hope that you might have time for a meal when the food is still hot. You then go to see the family of 4 who checked in with “flu-like” symptoms. Unfortunately many symptoms can be described as “flu-like” and keeping a broad differential is important to avoid missing a serious illness. Consider these patients all checking in with “flu-like” illness.


Case 1: 16 year-old male with fever, sore throat, and headache. No significant past medical history. Exam reveals a sick appearing male who is in no acute distress. Temp 37.8, otherwise within normal limits. Oropharynx has mild swelling and erythema without exudates. Neck is stiff. Neurological exam is nonfocal.

Case 2: 22 year-old female G2P1 at approximately 18 weeks with cough, fever, malaise, and shortness of breath.   PMH: Asthma. Exam reveals a gravid female in no acute distress. Afebrile with normal vital signs. ENT exam is normal except for rhinorrhea and cough. Breath sounds are diminished in the left lower lobe, with faint expiratory wheezes bilaterally.

Case 3: 66 yo M with cough, fever, and shortness of breath. The patient is a smoker with a history of MI, DM, and hepatitis. Exam reveals mild respiratory distress. Vital signs Temp 38.3, HR 120, RR 26, O2 sat 90%. CXR shows right lower lobe opacities (clinical correlation advised).


Flu season is off to a slow start this year, however this does not mean that those on the front lines of healthcare are seeing a shortage of patients with “flu-like” symptoms. It is our job to identify those in need of medical treatment from those in need of some chicken soup. Keeping a broad differential and systematically evaluating each possibility will help to identify those in need of further testing and care.


Differential Diagnosis

Typical influenza symptoms include fever, headache, myalgias, malaise, cough, and rhinorrhea. Patients may also have GI symptoms such as abdominal pain and vomiting. You should have a broad differential diagnosis that can be narrowed by the patient’s specific symptoms. Organize your differential into infectious diseases vs. non-infectious diseases and stable vs. unstable.   Unstable vital signs may indicate severe illness and helps identify those in need of resuscitation. Keep in mind the critical diagnoses in every patient. You won’t find it if you don’t think about it.

Influenza differential diagnosis

Unstable Sepsis Thyroid storm, Drug reaction, Neuroleptic Malignant Syndrome, Serotonin Syndrome, Malignant Hyperthermia
Shortness of breath/chest pain Pneumonia, Acute Respiratory Distress Syndrome, Respiratory failure, Endocarditis, Pericarditis Pulmonary Embolism, Myocardial Infarction
Headache/myalgias Meningitis, Encephalitis, Malaria, Novel viruses, Acute Retroviral Infection Intracranial Hemorrhage, Stroke , Cavernous sinus thrombosis
Sore throat/dysphagia Peritonsillar Abscess, Retropharyngeal Abscess, Epiglottitis, Dental infections
Nausea, vomiting, and diarrhea Appendicitis, Tubo-ovarian Abscess Crohn’s Disease, Peritonitis

Critical Diagnoses



Many patients will meet systemic inflammatory response (SIRS) criteria on presentation for fever and tachycardia. Keep a broad differential and search for other sources of infection. Consider further testing in these patients and admission in patients who do not respond to antipyretics and intravenous fluids.


Pneumonia, Acute Respiratory Distress Syndrome (ARDS), or Respiratory Failure

Patients may suffer from influenza pneumonia or a secondary bacterial pneumonia. Risk factors for severe influenza and influenza pneumonia include age >65 or <2 years, pregnancy, obesity, chronic pulmonary disease such as asthma and COPD, chronic cardiovascular / renal / hepatic / hematologic disease including sickle cell disease, neuromuscular disorders, and immunosuppressed patients such as those as with diabetes, cancer, or HIV.[i] Female sex and influenza vaccination are protective against severe illness.[ii],[iii],[iv] While this information may not be available to us, the virus subtype also contributes to severity. The predominant virus circulating this flu season is influenza A (H1N1)pdm09[v] which is the strain responsible for the 2009/2010 pandemic and is associated with higher mortality among the young (age <65) and pregnant. Also keep in mind post-influenza staph pneumonia classically affects the young and healthy and can have high mortality.[ii] It is important to instruct all patients to return to the ED with worsening disease. Procalcitonin level may be considered to help exclude bacterial coinfection,[vi] but results are not always readily available in the ED.



Always consider with headache and fever. Especially consider in those with petechial rash, focal neurological findings, or altered mental status.


Cavernous sinus thrombosis

Consider in any patient with risk factors for the disease. Females are affected more than men. Other risk factors are cancer, pregnancy, local infection, hypercoagulability (think other DVT risk factors), oral contraceptive pills (OCPs), or local tumor. Closely examine for cranial nerve deficits. Cranial nerve 6 floats in the cavernous sinus and will be first affected, presenting with lateral gaze palsy.



Other infections can often present with “flu-like” symptoms. Consider peritonsillar abscess (PTA), retropharyngeal abscess (RPA), dental infection, or epiglottitis in any patient with a sore throat or dysphagia. Epiglottitis, once considered a pediatric diagnosis, now occurs more often in adults but can also occur in unvaccinated children. In those with predominant chest pain consider endocarditis and pericarditis. Encephalitis can present with or without focal neurological deficit and should be considered in any patient with altered mental status or abrupt change in behavior such as new onset psychosis especially with flu like symptoms. In any patient with recent travel or exposure to mosquitoes consider encephalitis, malaria, tick or mosquito borne illnesses, and other viruses such as Zika, chikungunya, or dengue virus. Think about HIV. Acute retroviral infection can present as “flu-like” illness. AIDS should heighten suspicion for severe illness, fungal infections, pneumonia, and meningitis.



Consider non-infectious etiologies based on symptoms. In patients with predominant chest pain or dyspnea myocardial infarction (MI) and pulmonary embolism (PE) can occur concurrently with a cold and can rarely cause hyperpyrexia. Don’t miss intracranial hemorrhage (ICH) or stroke in those with cardiac risk factors or trauma. Neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), malignant hyperthermia (MH), and thyroid storm can all present with fever and tachycardia. In any patient with recent medication changes consider NMS, SS, MH, other drug reaction, or toxidrome. If multiple presentations of flu-like symptoms are presenting from the same household, consider carbon monoxide. Malignant hyperthermia is rare but can be treated with dantrolene in addition to supportive care and therefore should be considered.


Clinical Approach

Narrow your differential by the patient’s symptoms, history, and focused physical exam. Order testing as appropriate.


Sore throat/Dysphagia:

Ddx: PTA, RPA, epiglottitis, dental infection.

History and Exam: Throat for exudates, asymmetrical swelling, drooling, stridor, cervical adenopathy. Dentition for abscess or other dental infection. Neck for meningismus. Ears for AOM.

Consider: Imaging such as CT or Xray.



Ddx: Meningitis/encephalitis, Cavernous venous thrombosis, ICH, stroke, malaria, acute retroviral infection, other viruses. Toxins such as carbon monoxide (especially with multiple presentations from the same household).

History and Exam: Neck for meningismus. Thorough cranial nerve exam especially CN 6 for lateral gaze palsy. Fundoscopic exam for papilledema. Neuro exam for focal deficits or AMS. Skin for rash. Illicit history of trauma, travel, possible tick or mosquito exposure, recent sexual exposure, headache red flags.

Consider: spinal fluid analysis, CT or CTA head, MRI or MRA head, CT or MRI venogram. Carboxyhemoglobin measurement.



Ddx: ARDS, pneumonia, PE, MI, endocarditis, pericarditis.

History and Exam: Pulmonary exam for consolidation and pulse oximetry. Cardiovascular exam for murmurs, tachycardia, arrhythmias. Consider PE/DVT risk factors. Medical history for comorbidities, cardiovascular risk factors, and IV drug abuse.

Consider: CXR, EKG, troponin, CT chest, procalcitonin.


Nausea, vomiting:

Ddx: Meningitis, appendicitis, TOA, Crohn’s disease, peritonitis, UTI.

History and Exam: Neck for meningismus. Thorough abdominal exam for peritonitis, masses, RLQ or RUQ tenderness. In female consider pelvic exam for discharge and adnexal tenderness.

Consider: spinal fluid analysis, CBC, BMP, UA, cervical cultures, abdominal CT or pelvic ultrasound.


Fever, Tachycardia and unstable vital signs:

Ddx: Sepsis, Pneumonia/ARDS/Resp failure, encephalitis, malignant hyperthermia, thyroid storm, drug reaction, neuroleptic malignant syndrome, serotonin syndrome, Cavernous venous thrombosis, PE, intracranial hemorrhage, stroke, MI.

ABCs and supportive care simultaneous with evaluation if needed. Pulmonary exam for consolidation and pulse oximetry. Cardiovascular exam for murmurs, tachycardia, arrhythmias. Neurological exam for altered mental status or focal deficits. Examine skin for rashes, infection, diaphoresis, dryness, jaundice. Elicit history of new medications and drug use. If considering NMS and SS check reflexes to differentiate.

Consider: CBC, lactate, liver enzymes, BMP, troponin, TSH, Urinalysis, drug screen, CXR.


Treatment of Influenza

Treatment of influenza is largely supportive care. The CDC recommends empiric treatment with neuraminidase inhibitors within 48 hours of symptom onset or up to 5 days from symptom onset in severe cases; although even the CDC admits their efficacy is questionable. A summary of the evidence supporting antivirals for influenza is available on the CDC website.[vii] It is not required to test for influenza prior to treatment. Tamiflu (oseltamivir) is available orally. Relenza (zanamivir) is inhaled and contraindicated in those with respiratory comorbidities. Rapivab (peramivir) is intravenous. Rimantadine and amantadine are discouraged due to high resistance in influenza A and inactivity against influenza B. Consider admission for any patient suspected of having influenza with unstable vital signs after treatment, an oxygen requirement, poor follow up, extremes of age, significant comorbidities, or if unable to exclude other serious diagnoses.


References / Further Reading


[ii] Euro Surveill. 2015 Nov 19;20(46). doi: 10.2807/1560-7917.ES.2015.20.46.30066. Intensive care unit surveillance of influenza infection in France: the 2009/10 pandemic and the three subsequent seasons. Bonmarin I1, Belchior E, Bergounioux J, Brun-Buisson C, Mégarbane B, Chappert JL, Hubert B, Le Strat Y, Lévy-Bruhl D.

[iii] Enferm Infecc Microbiol Clin. 2014 Feb;32(2):70-5. doi: 10.1016/j.eimc.2013.02.009. Epub 2013 Apr 11. [Effectiveness of influenza vaccination in preventing hospital admission due to exacerbations of chronic obstructive pulmonary disease]. [Article in Spanish] Montserrat-Capdevila J, Godoy P, Marsal JR, Cruz I, Solanes M.

[iv] Hum Vaccin Immunother. 2014;10(2):423-7. doi: 10.4161/hv.26858. Epub 2013 Oct 25. Effectiveness of the influenza vaccine at preventing hospitalization due to acute exacerbation of cardiopulmonary disease in Korea from 2011 to 2012. Seo YB, Choi WS, Baek JH, Lee J, Song JY, Lee JS, Cheong HJ, Kim WJ.


[vi] J Infect. 2015 Dec 15. pii: S0163-4453(15)00372-2. doi: 10.1016/j.jinf.2015.11.007. [Epub ahead of print] Procalcitonin (PCT) levels for ruling-out bacterial coinfection in ICU patients with influenza: A CHAID decision-tree analysis. Rodríguez AH, Avilés-Jurado FX, Díaz E, Schuetz P, Trefler SI, Solé-Violán J, Cordero L, Vidaur L, Estella Á, Pozo Laderas JC, Socias L, Vergara JC, Zaragoza R, Bonastre J, Guerrero JE, Suberviola B, Cilloniz C, Restrepo MI, Martín-Loeches I; SEMICYUC/GETGAG Working Group.



4 thoughts on “Influenza Mimics: Pearls & Pitfalls”

  1. Equally important is to not be satisfied with a diagnosis. Superimposed pneumonia or, even worse – influenza myocarditis is easy to miss and easy to die from. Also, bacteremia will look like a non-specific (viral) illness, so consider blood cultures where appropriate.

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