Clinical Characterization

Though not the primary focus of this (biochemical) project, clinical characterization set an important precedent to the molecular study of the influenza virus. Influenza is thought to have first appeared in the late 1500’s, though possibly earlier, and was responsible for many prominent epidemics prior to its more scientific study in the early nineteenth century.3 Much available literature through the nineteenth and early twentieth century appears to be focused on characterizing the clinical presentation of influenza, and distinguishing it from other infectious conditions.

Influenza is a common, typically mild infection of the upper respiratory tract caused by the influenzavirus. While there are many types of influenza viruses, the most common and dangerous to human health is Influenza A.1 Influenza A H1N1 is one of the most historically relevant and dangerous flu subtypes, responsible for both the 1918 Spanish Flu4 and the 2009 Swine Flu epidemics.2 Human influenza viruses typically target respiratory epithelial cells. Like all viruses, influenza cannot self-replicate, and instead relies on the molecular machinery of its host to perform necessary processes for replication. Infection provides the virus access to cellular components such as ribosomes and polymerases, coercing the host cell into expending energy and resources to its replication.6 Eventually, these processes take a toll on the host cells, and mount an immune response, collectively producing the common symptoms associated with mild influenza infection such as fever, fatigue, headache, sore throat and cough.1,7 Though many cases of the flu are characterized by clinical symptoms, influenza can be more definitively diagnosed by both antibody reactivity, RT-PCR tests (rapid), or serological tests.8,9,10

While influenza is an infectious condition, some individuals are more greatly affected than others. If influenza infection migrates to the lower respiratory tract, more serious symptoms and secondary, sometimes fatal, pneumonia ensues.1 Acute respiratory distress syndrome (ARDS) can also occur is severe cases.1 Lower respiratory tract infection (LRTI), caused by influenza and numerous other pathogens, is a prominent cause of death worldwide,10 but relatively little is known about why the virus sometimes spreads to the lower respiratory tract. Studies focusing on the etiology of LRTIs seem to have more commonly focused on the causative microbes,12 rather than a mechanism of migration.

When influenza does infect the lower respiratory tract, it can lead to cytonecrosis in the bronchioles (Fig. 1), bronchi, and alveoli. Particularly in the alveoli, areas of necrosis are often associated with local hemorrhage. Hemorrhage and influx of immune cells in response to these processes can lead to significant pulmonary edema, consistent with symptoms such as dyspnea and cyanosis in individuals with severe infection.10 Viral pneumonias can also present with hemoptysis, particularly with frothy sputum production.10

Figure 1. Sections of stained lung tissue from an individual infected with the 1918 H1N1 influenza at 40x magnification (left) and 200x magnification (right) showing necrotizing bronchiolitis from Tauenberger and Morens 2008.10

Individuals with weakened or underdeveloped immune systems such as adolescents and the elderly are more likely to develop severe infection.1 Those with pre-existing health conditions such as chronic pulmonary disease, heart disease, or diabetes are at greater risk of developing complications such as hemorrhagic bronchitis and pneumonias.10

The following pages will explore the biochemical and molecular mechanisms underlying influenza infection and immunity which lead to the symptoms associated with the typical clinical presentation described above, as well as current understanding of effective treatments and preventative measures.

Note: This is not one of my core theme pages.

Works Cited

  1. Krammer, F.; Smith, G. J. D.; Fouchier, R. A. M.; Peiris, M.; Kedzierska, K.; Doherty, P. C.; Palese, P.; Shaw, M. L.; Treanor, J.; Webster, R. G.; et al. Influenza. Nat. Rev. Dis. Primer 2018, 4 (1), 1–21. https://doi.org/10.1038/s41572-018-0002-y.
  2. CDC. Types of Influenza Viruses https://www.cdc.gov/flu/about/viruses/types.html (Accessed Feb 13, 2020). 
  3. Brief History of the Influenza Virus http://www.mypediatriccenter.com/brief-history-influenza-virus/. (Accessed 27 March 2020).
  4. CDC. Flu Symptoms & Complications https://www.cdc.gov/flu/symptoms/testing.htm (Accessed Mar 12, 2020) 
  5. CDC. Influenza (Flu) https://www.cdc.gov/flu (Accessed Apr 14, 2020)
  6. Cohen, F.S. How Viruses Invade Cells. Biophys J 2016 110(5): 1028-1032. 10.1016/j.bpj.2016.02.006
  7. KEGG. Influenza A pathway.  https://www.kegg.jp/kegg-bin/show_pathway?hsa05164+H00398 
  8. Kaul, K.L.; Mangold, K.A.; Du, H.; Pesavento, K.M.; Nawrocki, J. and Nowak J.A. Influenza A Subtyping. J Mol Diagn 2010 12(5):664-669. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928431/ 
  9. CDC. Diagnosing Flu https://www.cdc.gov/flu/symptoms/testing.htm (accessed Mar 12, 2020)
  10. Taubenberger, J.K. and Morens, D.M. The Pathology of Influenza Virus Infections. Annu Rev Pathol 2008 3:499-522. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504709/
  11. Malosh, R.E.; Martin, E.T.; Ortiz, J.R.; and Monto, A.S. The risk of lower respiratory tract infection following influenza virus infection: A systematic and narrative review. Vaccine 2018 36(1):141-147.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736984/
  12. Benet, T. et al. Microorganisms Associated With Pneumonia in Children <5 Years of Age in Developing and Emerging Countries: The GABRIEL Pneumonia Multicenter, Prospective, Case-Control Study. Clin Infect Dis 2017 65(4):604-612.  https://www.ncbi.nlm.nih.gov/pubmed/28605562

For more information and resources, see Annotated Bibliography.

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