|Year : 2019 | Volume
| Issue : 1 | Page : 1-8
Influenza A viruses: Current perspectives on swine flu virus
Martin E Ohanu1, Daniel B Olusina2, Anthony O Eni2, Emmanuel N Aguwa3, Chinwe J Chukwuka4
1 Department of Medical Microbiology, University of Nigeria Enugu Campus, Enugu, Nigeria
2 Department of Morbid Anatomy, University of Nigeria Enugu Campus, Enugu, Nigeria
3 Department of Community Medicine, University of Nigeria Enugu Campus, Enugu, Nigeria
4 Department of Medicine, University of Nigeria Enugu Campus, Enugu, Nigeria
|Date of Web Publication||1-Aug-2019|
Dr. Daniel B Olusina
Department of Morbid Anatomy, University of Nigeria Enugu Campus, Enugu
Source of Support: None, Conflict of Interest: None
Swine influenza, a genetic reassortment of swine, avian, and human influenza viruses, is a respiratory disease of pigs that recently caused a pandemic. It contains deoxyribonucleic acid that is typical to avian, swine, and human viruses, including elements from European and Asian swine viruses. The main targets of the influenza virus are the columnar epithelial cells of the respiratory tract. The aim of this review was to present updates on influenza A viruses with particular attention to recent developments on swine flu H1N1. In-depth interest is on current historical accounts, pathogenesis, clinical features, diagnosis, treatment, and prevention. The review shows that there is tremendous improvement on the knowledge and understanding of the mechanisms of influenza disease and outcomes of management. There is an increasing diagnostic facility and emphasis on advanced infection control measures, encouraging frequent, adequate hand washing, use of alcohol-based hand sanitizers, and use of quarantine facility for treating serious cases and vaccination of people at risk.
Keywords: Flu pathology, influenza virus, swine flu
|How to cite this article:|
Ohanu ME, Olusina DB, Eni AO, Aguwa EN, Chukwuka CJ. Influenza A viruses: Current perspectives on swine flu virus. Int J Med Health Dev 2019;24:1-8
|How to cite this URL:|
Ohanu ME, Olusina DB, Eni AO, Aguwa EN, Chukwuka CJ. Influenza A viruses: Current perspectives on swine flu virus. Int J Med Health Dev [serial online] 2019 [cited 2020 Aug 15];24:1-8. Available from: http://www.ijmhdev.com/text.asp?2019/24/1/1/263549
| Introduction|| |
Influenza, a respiratory illness also known as flu, is caused by viruses of the family Orthomyxoviridae. There are four genera in the family and these are Influenzavirus A, Influenzavirus B, Influenzavirus C, and Influenzavirus D. The classification of the members of the family into genera is based on their glycoproteins, nucleoprotein (NP), and matrix (M) differential composition. Influenza A viruses have 18 hemagglutinin activity (HA) (H1–H18) and 11 neuraminidase activity (NA) (N1–N11) subtypes, which potentially form 144 HA and NA combinations. The natural reservoir hosts of influenza A viruses are aquatic birds. Each year, both influenza A and B viruses are responsible for seasonal epidemics accounting for over 200,000 hospitalizations and 30,000–50,000 deaths. As per the World Health Organization (WHO) estimates, over billion cases of influenza virus infections occur yearly with three to five million cases being severe and resulting in 290,000–650,000 deaths, making it the leading cause of mortality after acquired immune deficiency syndrome (AIDS).
Swine influenza (swine flu) is a highly contagious respiratory disease of pigs caused by type A influenza virus that regularly causes outbreaks of influenza in pigs. New pandemic flu virus evolves when different flu viruses infect a pig, a person, or a bird, after mingling with their genetic material. The resulting hybrid could spread quickly because people would have no herd immunity defenses against it. The feared swine flu pandemic virus contains deoxyribonucleic acid (DNA) that is typical to avian, swine, and human viruses, including elements from European and Asian swine viruses.
| History of Influenza Pandemics|| |
Throughout history, the world has faced devastating epidemics and pandemics of influenza. This includes the Spanish flu in 1918, the Asian flu in 1958, the Hong Kong flu in 1968, and the more recent 2009 H1N1 pandemic. Since 1997, human infections with a novel H5N1 subtype of highly pathogenic avian influenza have been reported. In addition, H9N2, H7N7, and recently H7N9 detected in China in 2011 caused human infections.
In 1918–1919, at least 20 million persons worldwide died from this virus (H1N1). In 1957 and 1968, two other less deadly flu pandemics occurred. On June 11, 2009, another H1N1 pandemic (the first pandemic of the twenty-first century) started in Mexico, but did not kill as many people as that of 1918.
By June 2009, the WHO reported that there were 15,510 cases in 53 countries and that swine flu, or H1N1 influenza, had reached a pandemic level, and alert level was raised to phase 6, indicating widespread human infections (affecting Australia, the United Kingdom, Japan, and Chile). This marks the first time it has been called a global flu epidemic in 41 years and in the new millennium.
In terms of mortality, the first person confirmed to die from this swine flu lived in Oaxaca State, Mexico, who developed symptoms and died on April 4, 2009. By July 16, 2009, 684 confirmed deaths had been reported worldwide for a total of 126,168 reported cases. This gave an overall “computed case fatality rate” of 0.54%. This value varied from 0.1% to 5.1% depending on the country (and the accurate quantification of deaths and overall case counts). As of December 11, 2009, there were 10,567 confirmed deaths worldwide. However, it was suggested that total mortality (including deaths unconfirmed or unreported) from the new H1N1 strain was “unquestionably higher” than this. On October 28, 2009, the Federal Ministry of Health of Nigeria announced that the first case of swine flu had been reported in a 9-year-old American girl residing in Lagos, one of the major cities in Nigeria. The girl recovered fully with symptomatic treatment after 5 days of illness. Subsequently, Nigeria enhanced surveillance in Murtala Mohammed International Airport, Seme, and Idiroko borders with the Republic of Benin to monitor all entries into the country.
The Federal Ministry of Health also supplied adequate quantities of Tamiflu, the antiviral drug, for treatment and other medical supplies for containment of cases of the influenza in all the 36 states and federal capital territory (Abuja, Nigeria).
| Transmission|| |
Swine flu viruses do not normally infect humans. However, sporadic human infections with swine flu have occurred in persons with direct exposure to pigs or other wild life.
The impact of passive immunity on the transmission of swine influenza A virus (swIAV) was evaluated. There was an efficient and extended spread of swIAV at population scale in the presence of maternally derived antibodies and could contribute to swIAV persistence on farms.
Swine influenza viruses are not transmitted by cooked food, including pork or pork products, and with an internal temperature of 160°F, this kills the swine flu virus, other viruses, and bacteria.
| Microbiology|| |
Swine flu virus (H1N1) was first isolated from a pig in 1930 and it belongs to the family Orthomyxoviridae. At the virion center lies eight segments of negative–stranded ribonucleic acid (RNA) put together with a nucleocapsid protein into a helical symmetry capsid. Surrounding the nucleocapsid lies an outer membrane studded with two long distinct glycoprotein spikes. One has HA and the other has NA. HA is a sialic acid receptor–binding molecule, which mediates entry of the virus into the target cells. Neuraminidase cleaves neuraminic acid and disrupts the mucin barrier, exposing the sialic acid–binding sites beneath. Thus, NA cleaves the cell mucin barrier, whereas HA fuses to the cells sialic acid residue, enabling viral adsorption and penetration.
When influenza viruses from different species infect pigs, they can reassort (i.e., swap genes), and new viruses that are a mix of swine, human, and/or avian (triple reassortment) influenza viruses can emerge. Over the years, different variations of swine flu viruses have emerged including H1N1, H1N2, H3N2, and H3N1. Infection by H1N1 and H1N2 was associated with porcine reproduction and respiratory syndrome virus seropositive status in pigs. However, most of the recently isolated influenza viruses from pigs have been H1N1 viruses.
| Pathology|| |
Viral entry into cells: The main targets of the influenza virus are the columnar epithelial cells of the respiratory tract of the immunologically susceptible individuals acquired through aerosol shed from coughing or sneezing. Influenza virus, if not neutralized by secretory antibodies, replicates in the epithelial cells throughout the respiratory tree of infected people. The receptor-binding site of viral hemagglutinin (HA) is required for binding to galactose-bound sialic acid on the surface of host cells. The cleavage from the binding site at the host cell is the functional role of viral neuraminidase. The virulence of the influenza virus depends on the compatibility of neuraminidase with hemagglutinin. Once the cell membrane and the virus have been closely juxtaposed by virus–receptor interaction, the complex is endocytosed. This is followed by fusion of the viral and endosomal membranes with the release of viral RNA into the cytoplasm; the viral RNA is then imported into the nucleus for transcription and translation.
Once influenza has efficiently infected respiratory epithelial cells, replication occurs within hours and numerous virions and toxic proteins are produced. Through the process of budding, infectious particles are released mostly from the apical plasma membrane of epithelial cells into the airways and this is accompanied by local and systemic inflammation.
Mechanism of cell death, apart from apoptosis, will also include T cell–mediated cell death as the immune system targets virus-infected cells.
The histologic alterations for nonfatal influenza viral infections predominantly involve the upper respiratory tract and trachea, but fatal cases of influenza usually show evidence of pneumonia.
Trachea and bronchi: H1N1 virus attaches more readily to ciliated epithelial cells and goblet cells throughout the upper respiratory tract than the H5N1 virus. The sloughing of the epithelium can be so severe that in some areas only the basal layer of the epithelium remains. Later stages show mononuclear inflammatory cell infiltrates in the walls.
Smaller airways: Changes in the smaller airways are similar to those described for larger airways, with hyperemia and edema followed later by necrosis and loss of epithelium. Desquamative bronchiolitis, often accompanied by ulceration, has been observed. In severe cases, the wall thickness can be focally necrotic.
Pathology of influenza virus pneumonia
Severe infections and mortalities associated with influenza are related with the development of viral pneumonia. These can be, however, severe enough to cause extensive consolidations and to give bronchopneumonic changes and are often indeed complicated by bacterial infections leading to bacterial bronchopneumonia.
The changes seen in the lungs of the patients dying from influenza pneumonia include capillary and small vessel thromboses, interstitial edema, and inflammatory infiltrates in addition to necrotizing bronchitis and bronchiolitis.
The diffuse alveolar damage (leading clinically to the syndrome of adult respiratory distress) is due partly to viral production, diffuse alveolar damage, induction of apoptosis, vascular thrombosis–induced necrosis, and T cell–mediated damage.
Secondary or coincident bacterial pneumonias frequently occur and complicate the pathologic picture.
| Clinical Features of Swine Flu|| |
Influenza is mainly a mild self-limiting disease. The incubation period is 1–4 days and the clinical features of swine flu include chills, fever, headache, sore throat, cough, and fatigue. These symptoms admittedly can occur in patients with malaria, upper respiratory tract infections, and/or pneumonia.
Those at risk of a more severe infection include subjects that are asthmatics, elderly, diabetics, obese, with heart disease, immunocompromised, and pregnant.
| Diagnosis|| |
To confirm the diagnosis of swine influenza A infection, a respiratory specimen generally needs to be collected within the first 4–5 days of illness (when an infected person is most likely to be shedding virus, i.e., period of infectivity). However, some persons, especially children, may shed virus for 10 days or longer and a serological test can be used to screen for influenza A., There are various approaches currently available or under development for the diagnosis of influenza infections in humans.
The diagnostic techniques include virus isolation by viral culture in mammalian cells or embryonated eggs (considered one of the gold standards for the diagnosis of viral infections), or shell viral culture, which involves propagation of viruses in mammalian cells grown in small 1-dram vials or shell vials; direct fluorescent antibody test also known as immunofluorescent antibody test, an antigen-based test; serological assays used to detect influenza virus–specific antibody responses, which include hemagglutination inhibition assay, microneutralization or virus neutralization assay, enzyme-linked immunosorbent assay, and Western blotting; rapid influenza diagnostic test for rapid diagnosis of influenza virus infections in point of care (POC) settings, which uses monoclonal antibodies; and lab-on-a-chip/microchip devices, which provide a new route to develop a new generation of POC influenza test that originates from microelectromechanical system technology. Others are nucleic acid–based tests that are based on polymerase chain reaction (PCR) and detect virus-specific DNA or RNA sequences/genetic materials rather than viral antigens or antibodies and these include reverse transcriptase PCR, loop-mediated isothermal amplification–based assay, simple amplification–based assay, nucleic acid sequence–based amplification, microarray-based approaches, and nucleic acid sequencing approaches (Sanger sequencing and next-generation sequencing).
Culture, isolation, and identification of swine flu influenza A virus may require sending the specimen to recognized special diagnostic centers.
| Treatment|| |
Treatment is effective if started less than 48h after the onset of symptoms. Early suspicion and even earlier diagnosis are paramount. Confirmed severe cases, suspected cases at high risk of complications, the very young (<2 years), and the elderly (>65 years) should be treated.
Pregnant women and immunocompromised patients make the priority list for treatment.
Adamantanes interfere with viral uncoating inside the cells but viruses easily develop resistance to them. Examples are amantadine and rimantadine. The neuraminidase inhibitors interfere with the release of progeny influenza viruses from infected cells. They are effective against both influenza A and B and the risk of resistance is lower than that for the adamantanes. Examples are oseltamivir or “Tamiflu” available as color-coded capsules and oral suspension and zanamivir “Relenza” available as diskhaler. In the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria, Tamiflu is used for the treatment of swine flu. A worrisome adverse effect of oseltamivir is neuropsychiatric events, especially in children who may cause self-inflicted injury and become confused soon after ingesting the medication.
| Recommendations for Healthy People against Swine Flu|| |
Healthy individuals are advised to reduce the time spent in close contact with people with influenza-like illness, keep windows in their house or room open as much as possible, wash their hands often with soap and water, and ensure standard precautions at all times in a hospital setting.
| For People with Influenza-like Illness|| |
It is recommended that they stay home once they notice the symptoms for at least 2 days after the symptoms have stopped, cover their mouth and nose with tissue when coughing/sneezing, and dispose of the tissue immediately after in the trash. It is important they avoid reusing masks and change when they are wet. When in close contact with others, they should wear a face mask to reduce spread to people, wash their hands often with soap and water or use alcohol-based hand cleaners.
It also recommend that in the setting of influenza-like illness they should go to the hospital if they develop chest pain, become breathless, are not passing enough urine, and are dehydrated.
| Complications|| |
The most frequent complication of influenza is pneumonia, with secondary bacterial pneumonia being the most common form and primary influenza pneumonia the most severe. Secondary bacterial pneumonia is most commonly caused by Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Other complications include exacerbation of chronic pulmonary disease, croup (a typical complication of influenza infection in children), myocarditis (a rare event), Reye’s syndrome, and possibly systemic lupus erythematosus.
Causes of death: H1N1 influenza (swine flu) tends to cause high morbidity but low mortality. Death occurs because of severe pneumonic changes in the lungs and the clinical syndrome of adult respiratory distress.
| Prevention|| |
Prevention may be primary or secondary. Primary prevention involves all those actions aimed at reducing the spread of the infection when already present or suspected. These include health education on the spread of the disease and improving personal hygiene and personal protective measures. There should be reduced person-to-person contact. Indeed, avoid shaking hands or other hand-to-hand contact whenever possible. Also avoid kissing on the cheek or other face-to-face contact as a greeting method. Instead, use other methods of greeting such as waving hand, smiling, and bowing, depending on the culture.
Use of antibacterial soap to wash hand or alcohol-based hand sanitizer to wipe hand after touching public facility or after shaking hand will give extra protection. Wearing flu face mask will help avoid infection spread in enclosed spaces. Transferring any flu, including swine flu, is most likely in close quarters such as air-conditioned cars and airplanes. If you are in such environment, identify air vent closest to you and direct the vent to blow air away from your face. When suspects stay at home, they should remain so until they are afebrile for 24h without the need for antipyretics.
Secondary prevention involves vaccination. The H1N1 swine flu viruses are antigenically very different from human H1N1 viruses, and therefore, vaccines for human seasonal flu would not provide protection from H1N1 swine flu virus. For the recent H1N1 swine flu pandemic, two types of vaccines were available: “live attenuated” and “dead virus.” The live attenuated vaccine was available as a nasal spray. This became available early in October 2009 and was appropriate for persons aged 2–49 years. A live attenuated virus vaccine is contraindicated in pregnant women and people with reduced immunity. Other contraindications to the use of nasal vaccine include hypersensitivity to aspirin, gentamicin, and egg protein.
The second vaccine was an injectable, appropriate for persons aged 6 months to 60 years.
Who should be vaccinated?: During periods of epidemic, the general public is encouraged to get vaccinated against the H1N1 virus but the following people are at more risk and necessarily need to be vaccinated: pregnant women, elderly patients >65 years, children (6 months to 5 years), health-care personnel, patients with chronic ill health such as asthma, chronic obstructive lung disease, diabetes, neurological, and cardiovascular diseases. Persons with weak immune system, including patients with HIV/AIDS, or on chronic steroid therapy also need to be vaccinated. Caregivers to young infants also need to be vaccinated., Though the WHO by the second quarter of 2010 considers the current swine flu pandemic ended, it advises countries to be vigilant for possible outbreaks.
| Discussion|| |
In August 2010, the WHO declared that swine flu (H1N1) pandemic was over, affecting 15,413 people, but the H1N1 swine flu virus continues to circulate as part of seasonal flu. So H1N1 has not gone away. Research data suggest initial emotional concerns about infection are also significant predictors of behavioral responses to pandemic threat. It was also observed that children and patients with neurotic and somatoform disorders were overrepresented among those expressing moderate/severe swine flu concerns.
Vaccination (including the intranasal form) offers the best protection for those at high risk from flu. The H1N1 vaccine is now a part of the seasonal flu jab, which also protects against other circulating strains. Pregnant women are being offered the seasonal vaccine for the first time because as a group, they are affected more during the pandemic and are at greater risk of serious complication. Also, there is the advantage of the women passing protective antibodies to their offsprings through the placenta or breast milk. Recently, a novel swine influenza virus dubbed A (H3N2) emerged in January 2012, carrying gene from the human pandemic strain, which affects mainly children, and with serine at position 228 in the HA critical for its transmissibility. In pigs, tracheal epithelial cells preinfected with swH1N1 showed Streptococcus suis bacterial adhesion and invasion levels that were increased more than 100-fold compared to those of normal cells. Again a replicon particle vaccine expressing an H3N2-derived NP gene was able to decrease nasal shedding and viral load, following heterosubtypic 2009 pH1N1 challenge in pigs.
Viruslike particles (VLPs), which resemble infectious virus particles in structure and morphology, have been used to develop vaccines for veterinary use, after being successfully evaluated in swine, canine, duck, and chicken models. Results from other studies provided support for continued development of the VLP for animal vaccine against influenza virus.
Radiologic features though diagnostically contributory have no significance as a prognostic indicator. Chronic obstructive pulmonary disease (COPD) or COPD by malignity in patients with H1N1 infection was a potential risk factor in terms of increased morbidity.
Influenza update indicates that in North America, the influenza season has started. The predominant subtype of influenza viruses detected was A (H1N1). In countries of tropical areas, variable influenza activity was reported. In Africa, overall influenza activity reported from Western middle and Eastern Africa was at low levels with the exception of Cameroon and Kenya.
The use of reverse genetics technology has made it substantially easier to generate reassortant viruses and to evaluate the contribution of individual virus gene on virus transmissibility in animal models such as ferrets and guinea pigs. H5, H7, and H9 avian influenza viruses represent the top three subtypes that are candidates to cause the next human influenza pandemic. Avian influenza (H5N1) is rare in humans (in developed countries). Though a vaccine is available for it, it is only available now to government agencies and for stockpiles. Meanwhile, avian influenza is common to wild migratory waterfowl but does not usually harm them. However, the H5N2 strain is deadly when it spreads to commercial poultry and can wipe out a flock of tens of thousands of birds in a few days. Though China and United States have large swine populations, the global ecologic migration of influenza A viruses in swine is complex.
If not neutralized by secretory antibodies, the virus invades airway and respiratory tract cells. Diagnosis of influenza is based on clinical criteria, use of rapid diagnosis, viral culture of nasopharyngeal or throat samples, and possibly a chest radiography. The present epidemic of influenza in India and other countries has led to fear, panic, and confusion because there was no effective preparedness for this flu. There are many factors that contribute to the high annual incidence of influenza virus, including shortage of medicines and lack of reliable diagnostic labs. A study in Thailand showed that pandemic H1N1 was widespread and was commonly found in the Thai pig population, increasing the risk of novel reassortant viruses and should be added as a reference virus for H1 test as well as monitoring the zoonotic potential. Besides, extensive research is essential to find ways to fight the emergence of new strains, which will continue to haunt the public health and the scientific communities. Prevention of clinical influenza is the most effective management strategy, and vaccination is one of the most efficient tools. Vaccination (including high dose) in addition to enhanced surveillance, prompt reporting, isolation through home medical leave, and segregation of smaller groups decreases the spread of influenza. There is a need to determine how well flu vaccine is effective, which will depend on design, population, and season of study. In many countries, there are significant gaps between knowledge and actual practice of the health-care providers, regarding swine flu. If such gaps exist in the health sector, one can then imagine the pitiable conditions among the poor and underprivileged sections of the society in low-income countries. The people spit on the roads and the sick instead of staying at home attend religious activities with huge gatherings and cannot practice healthy and hygienic attitudes. The situation is worse in countries fighting civil or terror wars that lead to huge refugee and migration crisis, providing conditions for exporting influenza A and other diseases to stable countries. Countries should stock up vaccines, antiviral drugs, and include poultry and swine workers in preparedness for the next outbreak. The influenza vaccine for the 2015–2016 seasons is available in both trivalent and quadrivalent influenza formulations. Trivalent vaccine contains an A/California/7/2009 (H1N1) pdm09-like virus, an A/Switzerland/9715293/2013 (H3N2)-like virus, and a B/Phuket/3073/2013-like virus (B/Yamagata lineage), whereas quadrivalent vaccine contains an additional B virus (B/Brisbane/60/2008-like virus [B/Victoria lineage]). Some new recommendations include the use of attenuated influenza vaccine and inactivated vaccine, vaccination of those with a history of egg allergy, and consideration for immunocompromised persons.
| Conclusion and Recommendation|| |
Pandemics of influenza are unpredictable. Unfortunately early diagnosis is still a challenge because of similar clinical symptoms it shares with several other diseases and lack of diagnostic facilities. Control measures will therefore depend strongly on having high index of suspicion, maintaining good personal hygiene, standard precaution in health facilities, immunization with appropriate vaccine, and stocking drugs for treating both humans and animals. Further studies on genomic epidemiology, with advanced mathematical modeling, on this unpredictable infectious pathogen are needed.
Financial support and sponsorship
All authors contributed privately.
Conflicts of interest
There are no conflicts of interest.
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