Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Introduction:  Influenza is described as an acute respiratory infection due to influenza viruses.² 

    • Transmission Electron Micrograph of Negatively Stained Influenza Virions (100,000X)⁸

      "This negatively stained transmission electron micrograph (TEM) shows recreated 1918 influenza virions that were collectred from supernatants of 1918-infected Madin-Darby Canine Kidney (MDCK) cells cultures 18 hours after infection."8

    • The upper and/or lower respiratory tract is affected with systemic presentations including fever, myalgia (muscle aches), headache and weakness.

      • Influenza Symptoms⁷

        Haggstom M Main Symptoms of Influenza.7

    • Outbreaks are often yearly and may result in both notable morbidity and even mortality rates in certain high-risk individuals.² 

    • Influenza viruses belong to the Orthomyxoviridae family.²

      • Influenza Virus Overview

        Influenza A, B, and C viruses describe three separate groups.2  Distinguishing between the groups depends on antigenic properties of the nucleoprotein and matrix protein antigens. Furthermore, influenza A viruses are additionally subtyped based on surface hemagglutinin and neuraminidase antigens. Individual strains descriptions include site of origin, isolate number, your of isolation and subtype. Using the following is example "influenza A/California/07/2009 (H1N1), the influenza A in question  exhibits 16 different hemagglutinin antigen subtypes (H subtypes) and 9 distinct neuraminidase antigen subtypes (N subtypes). Only H1, H2 and H3 along with N1 and N2 subtypes are related to disease epidemics in humans. Influenza B and C viruses use comparable designations yet H and N antigens are not described using subtype designations.2

    •  Often the term "flu" is used in reference to a relatively mild upper respiratory infection, perhaps the "common cold". ² 

      • This illness is not due to influenza virus but rather other upper respiratory viruses, such as rhinoviruses.

      • Influenza is notably a severe, acute disease across age groups with symptoms as noted below.

        • The acute initial stage of influenza last about three days although cough and other symptoms may endure for several weeks.² 

    • Influenza virus initially infects upper respiratory tract epithelial cells, causing a loss of ciliated epithelium.² 

       

      • Ciliated Epithelium⁵

        Blaus B Ciliated Epithelium http://commons.wikimedia.org/wiki/File:Blausen_0750_PseudostratifiedCiliatedColumnar.png

      •  

        Ciliated Respiratory Epithelia (Viewed from Above)⁶

        Attribution:  CiliaScientist:  "Overhead view of ciliated respiratory epithelia."  https://www.youtube.com/watch?v=VfSeRI2nMhA (6/2014) Cilia Scientist YouTube Channel:  https://www.youtube.com/channel/UCVdTukbG9Zfy7U9TfS7QWow

      • Loss of ciliated epithelium in turn prevents the respiratory tract from clearing viruses or bacteria by the process of mucociliary flow.² 

        • Production of interferons, cytokines and other response factors promotes both local and systemic inflammatory reactions.² 

          • Systemic inflammatory effects form the basis of many "flu" symptoms that comprises syndrome (fever, chills, headache, malaise and muscle aches).

          • In addition absence of ciliated epithelium allows bacteria to more readily enter the lower respiratory tract.

            • Many deaths thought to result from influenza virus infection may be due to secondary bacterial pneumonias.² 

  • Complications of Influenza

    • Complications due to influenza are more likely to occur in patients older than 65 and in those individuals who also have chronic health issues.⁸ 

      • These health issues include:⁸ 

        •  Cardiac disease

          • Congestive heart failure, as an example

        • Pulmonary disease

          • Chronic obstructive pulmonary disease (COPD)

          • Coronaviruses and rhinoviruses are the pathogens is most responsible for worsening of chronic lung disease.¹¹ 

            • However, influenza might account for as much as 25%.^11,12 

            • Influenza virus and other respiratory viruses may worsen chronic respiratory diseases, by mechanisms likely associated with inflammatory mediators such as interleukins and cytokines and as a result of changes in the ratio of T-cell subsets, a change that may increase sensitivity to other allergens.^11,13

        • Diabetes mellitus

        • Hemoglobinopathies

        • Renal disease

        • Immunosuppression.

      • Possible complications of influenza include myositis, sometimes with myoblobinemia and renal failure, myocariditis and pericarditis.¹⁰  

        • Additional complications: 

          • Encephalopathy

          • Transverse myelitis

          • Guillain-Barré syndrome and

          • Reye's syndrome (made more likely in children who have been administered aspiring have been noted.)

            •  Reye's syndrome is a noninflammatory encephalopathy that develops acutely and is described by the:¹¹

              • Clinical presentation overall and the finding that cerebrospinal fluid (CSF) contains < 8 m leukocyte/mm3 or by

              • Histological brain sections showing cerebral edema without perivascular meningeal inflammation associated with either fatty liver or a 3-fold increase in transaminases or serum ammonia.^11,14 

              •  

                Liver Histopathology in Reye's Syndrome¹⁵

                Ewing EP Jr (CDC) Histopathology of Reye's syndrome, liver. "Histopathology of autopsy liver from child who died of Reye's syndrome Hepatocytes are pale-staining due to intracellular fat droplets."

              • The correlation of Reye's syndrome with influenza has been suggested for several decades with more than 90% of cases occurring in white children less than 14 years of age.

              • Adult cases are typically associated with influenza A and appear fatal.¹¹

        • Following severe viral pneumonia, some patients may experience additional, respiratory-related health issues including reactive airway disease, respiratory insufficiency and/or pulmonary fibrosis.¹⁰

      • The likelihood of influenza complications appears increased in second or third trimester pregnancy.

      • Another group at higher risk for influenza complications is children less than five years old, particularly infants.⁸  

    • The most important influenza complication is pneumonia including:

      • "Primary" influenza viral pneumonia

         

        • Chest x-ray vs. CT scan showing primary influenza pneumonia in the same patient²²

          Chest x-ray showing primary influenza pneumonia (H1N1) may be difficult to distinguish from pulmonary edema, in view of the presence of perihiliar congestion with hazy opacification (lower lobes) (left)22 This X-ray is from a patient with primary H1N1 (swine-origin influenza A) on day 1 of hospitalization.22  CT scans (computed tomography) may provide additional diagnostic information useful in differentiating primary viral pneumonia from bronchiolitis and interstitial pneumonia. (right) This CT scan is from the same patient. 22 Attribution: These images correspond to Fig 1A and Fig 2 from reference 22.

      • Secondary bacterial pneumonia^8,11

        • Viral influenza complicated by bacterial pneumonia was noted during the 1918 influenza pandemic as well as during subsequent epidemic and inter-epidemic periods.^11,16 

          • During the 1918 pandemic, S. aureus pneumonia was described.^11,17 

            • Features includeed:

              • Fulminant course with an "cherry-red indigo-blue" unusual cyanosis

              • Lack of consolidation

              • "Dirty salmon-pink purulent sputum"

              • Leukopenia

              • Multiple micro-abscesses described in autopsy

              • Near total fatality.

            • More recently, during the 2003-2004 and 2006-2007 influenza seasons, severe cases of community-acquired pneumonia caused by methicillin-resistant S aureus (MRSA) was associated with 33% mortality.^11,18

        • In this circumstance the typical viral influenza infection proceeds to near resolution of symptoms only to be then complicated 4-14 days later by fever recurrence, dyspnea and pulmonary consolidation.

        • Typically pathogens responsible for this effect include Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae along with some other Gram-negative bacilli.¹¹

          • Streptococcus pneumoniae is likely the most notable pathogen responsible for secondary bacterial infection.

          • These bacteria colonize the nasopharynx and cause infection, given changes in bronchopulmonary defenses.⁸ 

            • The infection may be specified by Gram's staining along with culture of a sputum sample.

            • Secondary bacterial pneumonia is more likely to occur in high-risk patients with chronic pulmonary and cardiac disease and in elderly individuals.

              • Secondary bacterial pneumonia often responds to antibiotic therapy when treatment is begun promptly.⁸

        • Some mechanisms have been proposed that describe how bacteria act synergistically with influenza virus.^11,19 

          • These mechanisms include:

            • Increased binding and bacterial invasion

            • Enhanced viral replication

            • Changes in host-inflammatory response.

          • Interactions between influenza virus and bacteria have been described most thoroughly with Streptococcus pneumoniae.

            • In that instance, as viral neuraminidase cleaves sialic acid to release new virions from host cells, epithelial layer damage of the airways occurs which exposes binding sites required for pneumococcus adherence.^11,19 

      • Combination of viral and bacterial pneumonia.⁸ 

        • Viral Pneumonia:  Pulmonary complications¹¹

          "The most frequent serious complications of influenza are pulmonary and fall into 4 primary categories: influenza pneumonia, secondary bacterial pneumonia, pneumonia due to unusual pathogens or in immunocompromised hosts, and exacerbations of chronic pulmonary diseases."11

        • The most common pneumonia-related complication during influenza outbreaks suggests mixed features of both bacterial and viral pneumonia.⁸ 

          • Beginning with an acute illness, bacterial pneumonia manifestations become the prominent clinical presentation.⁸  

          • Accordingly, sputum cultures during the viral/bacterial pneumonia timeframe contain both influenza A virus and a bacterial pathogen.

            • Physical examination and x-ray may reveal areas of consolidation or regions of infiltrates.

            • Mixed viral and bacterial pneumonia tend to have less widespread lung involvement compared to primary viral pneumonia.

              • As noted earlier, bacterial infections typically respond to antibacterial drugs.⁸