D-List Superbugs: Influenza

By Jeffrey De La Cruz, MD
Resident Physician, NYU/Bellevue Emergency Medicine

Edited by Adaira Landry, MD

 

Intro

Influenza is spread primarily through large respiratory droplets or contamination of surfaces. About 4 days after exposure patients will typically start to develop an abrupt onset of fever, headache, myalgias or dry cough—generally this presentation will be considered an uncomplicated influenza illness. Symptoms usually resolve after 3-7 days from onset. Patients can have a more complicated course if they have primary influenza pneumonia, exacerbation of underlying medical conditions like COPD, or secondary bacterial pneumonia (Strep pneumoniae, Staph aureus, community-acquired MRSA, Haemophilus influenza are the more common pathogens). There is not a validated and widely used decision rule to help distinguish influenza from other viral pathogens based on signs and symptoms. We do know that there is some seasonal variance with influenza being more common in winter months. We also have laboratory tests like respiratory panels to screen for influenza. However, the poor sensitivity and uncertain utility of these tests makes their value in the typical uncomplicated influenza presentation questionable. Treatment recommendations, supported by the CDC, IDSA, and WHO have come under recent scrutiny—we should ALL be familiar with the recent data on influenza treatment.

Recap Basics

Some things to remember about influenza:

  • Wear a mask and wash your hands. Influenza is primarily transmitted via respiratory secretions and contaminated surfaces. Protect yourself and patients.
  • Young patients or people with chronic underlying comorbidities may be sicker for longer. Fever, myalgias, malaise, dry cough and sore throat are common symptoms. The fever and myalgias usually lasts 3-5 days; but may last for up to 10 days or more in children, elderly, people with chronic illnesses, or immunocompromised patients.
  • Complaints are not specific to influenza. Abrupt fever, headache, myalgias, and malaise + URI symptoms (cough, sore throat, nasal discharge) can be associated with most viral infections. Sensitivity and predictive value of diagnostic tests vary based on prevalence and level of influenza activity. Per the CDC, the positive predictive value of influenza (in healthy persons living in area with confirmed influenza circulating) is 79-88% for acute onset fever and cough. Young children and elderly present atypically and are less likely to complain of fever and cough. Therefore providers must have some suspicion for influenza and decide when the decision to diagnose actually changes management.
  • Complications can vary in severity. Pneumonia is the most common complication and 90% of deaths will occur in patients 65 years and older. Other complications like bronchitis, sinus and ear infections can occur.
  • Certain groups at risk for complications. Think about impeding danger for patients with asthma, chronic pulmonary or cardiovascular disease, immunocompromised status, obesity, adults 65 and older or children 2 years or younger.

Work-up

When it comes to influenza one must ask if confirming a diagnosis of influenza will change management in your patient or other surrounding patients. Generally speaking, a clinical diagnosis will be sufficient to provide supportive care. However patients who are requiring contact with other patients or who are part of a large outbreak in a hospital, school, or nursing home should be tested for epidemiology and public health purposes. Providers should know what tests are available to order for standard workup.

Table 1 is from the CDC and lists the common tests available to make diagnosis:

Method Types Detected Acceptable Specimens Test Time
Viral cell culture (conventional) A and B2 NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum 3-10 days
Rapid cell culture (shell vials; cell mixtures) A and B2 As above 1-3 days
Immunofluorescence, Direct (DFA) or Indirect (IFA) Antibody Staining A and B2 NP swab or wash, bronchial wash, nasal or endotracheal aspirate 1-4 hours
RT-PCR4 (singleplex and multiplex; real-time and other RNA-based) and other molecular assays A and B2 NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum Varied (Generally 1-6 hours)
Rapid Influenza Diagnostic Tests A and B NP swab, (throat swab), nasal wash, nasal aspirate
Table 1: Influenza Virus Testing Methods
  • Viral diagnostic tests – rapid influenza diagnostic tests are most commonly used in the United States. These have limited sensitivity (generally 40-70%) and false negative results are common (accurate results depend on pretest probability, prevalence of influenza in patient population tested, time from illness onset to time of testing, and quality of test compared to PT-PCR). Other options are immunofluorescence assays and Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR)-based testing. RT-PCR is the gold standard.
  • Viral culture and serologic testing – Takes 48-72 hours before results come back and will not change management in ER setting.

Treatment

Tamiflu was developed in the 1990s and approved by FDA in 1999. Following that approval there were papers showing the benefits of Tamiflu. However along side these published endorsements from Roche, the FDA in 2000 grew cautious of the data and placed a warning and precautions label describing neuropsychiatric events, skin reactions, and inability to prevent bacterial infections with using Tamiflu. As it stands now, the current Tamiflu label has the following statement below:
Screen Shot 2014-10-07 at 9.06.18 AM
Despite this label, Tamiflu has continued to be used for treatment of influenza and prevention of complications. In 2002, the initiative for global stockpile began with encouragement from the WHO. In 2004-2005 the U.S. and WHO began to release plans for pandemic should it occur. And by 2009 the H1N1 pandemic outbreak caused countries all over the world to stockpile BILLIONS of dollars worth of the drug, as pictured below. This stockpiling continued despite papers that highlight that there is limited data on treatment of influenza. and that guidelines are not supported by evidence.
flu2
The debate on Tamiflu moved to a different level on April 10th 2014 when this paper was published. The Cochrane Group provided a systematic review looking for both safety and effectiveness of antivirals for influenza. One could safely argue most physicians were unaware that Roche had unpublished data unavailable to outsiders, however it appears the BMJ was well aware of this private data for years. After years of struggle for transparency, a total of 77 trials were released from Roche, but only 20 were included with 9,600 patients in this recent systematic review by Tom Jefferson et. al. The results found no evidence to support that the antivirals reduced pneumonia complications, hospitalization rates, or could stop the spread of a pandemic. There was also evidence of psychiatric, renal and endocrine complications from its use. This study stirred up waves that literally overnight changed the way Tamiflu could be viewed and used by physicians. Even the mainstream media changed opinions from a positive perspective to doubtful overnight.

Conclusion

As it currently stands on the CDCs website antivirals are still recommended for the treatment of influenza in certain populations. Use of antivirals for influenza is the biggest area of controversy surrounding influenza treatment. For an amazing audio update on this topic, check out this press conference. In short, the biggest debate regarding influenza has been on transparency with the unpublished data on oseltamivir (Tamiflu), which was developed by Roche. Now with this released information we have a different perspective that might eventually change our management. Something for us all to remember is that most commonly, influenza is a self-limiting infection without complications. We should be inspired to look at the primary literature ourselves and make an informed decision as to whether antivirals are needed. Ultimately, have a discussion with your patients and tell them your perspective on the data and how that has influenced your choices.

Reference

Prevention & Control of Influenza – Recommendations of the Advisory Committee on Immunization Practices (ACIP) 2008. MMWR 2008 Aug 8; 57(RR07);1-60.

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