Pathogenesis and Clinical Findings of Infection in Humans by Influenza virus

Influenza is the most common and severe human respiratory infection. According to WHO data, seasonal influenza epidemics affect 5-10% of adult population and 20-30% of children. They result in 3-5 million of severe disease cases annually followed by 250,000-500,000 deaths.

Global pandemics of influenza involve up to 30-40% of human population with millions death cases.

During influenza outbreak the source of infection is human (patient with the disease). The airborne (aerosol) mechanism of transmission is predominant for influenza virus. Occasionally the disease can be transmitted by direct contact.

Incubation period depends on virus inoculation dose and lasts 1-3 days. Respiratory epithelium is the primary target for viral infection.

Short replication cycle of influenza virus provides the rapid spread of the infection within the epithelium of airways. Neuraminidase degrades the mucous layer of the respiratory tract, promoting viral dissemination. Subsequently the trachea, bronchi, bronchioli, and alveolar epithelial cells become involved into the process. Propagating viruses cause deep cellular destruction with subsequent epithelium desquamation. Also influenza viruses may affect endothelial cells resulting in damage of microcirculation blood vessels.

Influenza is characterized by sudden onset with the headache, dry cough, high fever and muscular aches. Uncomplicated cases of illness are finished within 5-7 days. Children usually display more severe forms of the disease.

Most frequent complication of influenza is pneumonia development. It can be primary viral, secondary bacterial, or combined. Secondary immunodeficiency, resulting in the defects of secretory IgA synthesis and phagocyte dysfunction, and the impairment of the ciliary clearance elevates the probability of bacterial complications. The combined viral-bacterial pneumonia occurs in 7-10 days of the disease onset and can increase greatly the influenza mortality rate especially in case of S. aureus infection.

Rare but severe complication of influenza virus infection is virus-induced encephalitis.

Specific antibodies and cytotoxic cells appear in 12-15 days after the disease onset. After the disease the strong long-active subtype-specific immunity is formed. Antibodies to hemagglutinin and neuraminidase possess protective activity. Anti-ribonucleoprotein antibodies are type- specific. They are used for virus typing. Host interferon activity can inhibit influenza virus replication and accelerates the recovery.

Passive immunity is maintained in newborns and infants for 6-8 months after birth.

Pathogenesis of avian flu caused by H5N1 or H7N9 virus is dramatically different from typical seasonal influenza A disease.

Avian flu viruses, e.g. H5N1 strain, actively circulate in Southeast Asia amongst the aquatic birds (e.g., ducks, which are the natural reservoirs of infection). Periodically they cause devastating epizootics in poultry (primarily, chickens) resulting in destruction of most of their population.

Humans become infected only after the long close contact with infected birds (e.g., the poultry workers or villagers working with infected flocks) or by alimentary route. Aerosol transmission or human-to-human transmission of avian influenza is not registered.

Avian H5N1 pathogen is different from human influenza A viruses by the number of substantial traits.

First, it reacts mainly with epithelial cells bearing the sialic receptors with α-2-3-glycosidic bonds; in humans these receptors are somewhere present only in the lower respiratory tract. As the result, airways of humans are poorly susceptible to H5N1 virus. However, if entered into deep airways, H5N1 ultimately causes viral pneumonia with damage of lung tissue.

Second, hemagglutinin of H5N1 is activated by the vast number of non-specific proteases present in all human tissues that predisposes to systemic viral disease.

And third, H5N1 infection triggers a massive production of proinfllammatory cytokines with cell death and tissue damage (systemic inflammatory response syndrome or SIRS).

Hence, if started, H5N1 infection in humans manifests as severe pneumonia, followed by respiratory distress syndrome (RDS) and systemic virus infection with endothelial damage and multiorgan failure that often leads to patient’s death.

From 1997 to 2016 WHO registered 854 human H5N1 infection cases with 450 deaths (about 50% fatality).

If after the putative reassortment with seasonal influenza A virus H5N1 agent becomes capable of infecting humans by aerosol route with human-to-human transmission, H5N1 infection will pose a tremendous pandemic threat for human population.