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H1N1 transmission mode: H1N1 Influenza – StatPearls – NCBI Bookshelf

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h2N1 Influenza – StatPearls – NCBI Bookshelf

Continuing Education Activity

h2N1 influenza is a subtype of influenza A virus, a communicable viral illness which causes upper and in some cases lower respiratory tract infections in its host. This results in symptoms such as nasal secretions, chills, fever, decreased appetite, and in some cases, lower respiratory tract disease. This activity reviews the presentation, evaluation, and management of h2N1 influenza and stresses the role of an interprofessional team approach to the care of affected patients.

Objectives:

  • Identify the global, historical impact of h2N1 influenza.

  • Summarize the transmission of h2N1 influenza.

  • Describe the common symptoms associated with h2N1 influenza.

  • Explain the importance of improving care coordination, with particular emphasis on communication between interprofessional medical teams, to enhance prompt and thorough delivery of care to patients with h2N1 influenza and prevent further disease spread.

Access free multiple choice questions on this topic.

Introduction

h2N1 Swine flu is a subtype of influenza A virus (a communicable viral disease), which causes upper, and potentially, lower respiratory tract infections in the host it infects, resulting in symptoms such as nasal secretions, chills, fever, decreased appetite, and possibly lower respiratory tract disease. h2N1 swine influenza is a common infection in pigs worldwide, and that is why it is also known as swine flu. h2N1 swine flu leads to respiratory disease that can potentially infect the respiratory tract of pigs. Sometimes, people who are closely associated with pigs or in the proximity of pigs have developed swine flu (zoonotic swine flu). Swine influenza viruses can potentially cause infections in humans if antigenic characteristics of the virus change through reassortment. When this happens, transmission from person-to-person is usually inefficient. Influenza A pandemics such as the ones in 1918 and 2009 can occur if the transmission from person-to-person becomes efficient.  [1]

In 1918, a deadly influenza pandemic caused by h2N1 influenza virus, also known as the Spanish flu, infected approximately 500 million people around the world and resulted in the deaths of 50 to 100 million people (3% to 5% of the world population) worldwide, distinguishing it as one of the most deadly pandemics in human history. In 2009, a new strain h2N1 swine flu spread fast around the world among humans, and the World Health Organization (WHO) labeled it a pandemic. However, the 2009 h2N1 virus was not zoonotic swine flu because it was not transferred from pigs to humans. Instead, it spread through airborne droplets from human to human, and potentially, through human contact with inanimate objects contaminated with the virus and transferred to the eyes or nose. This virus caused similar symptoms to those seen in swine, possibly due to reassortment of the viral RNA structure, which allowed human-to-human transfer. [2][3]

Despite the name, an individual cannot acquire swine flu from eating pig products such as bacon, ham, and other pig products.  

Etiology

The h2N1 influenza virus is an orthomyxovirus and produces virions that are 80 to 120 nm in diameter, with an RNA genome size of approximately 13.5 kb. The swine influenza genome has 8 different regions which are segmented and encode 11 different proteins:

  • Envelope proteins hemagglutinin (HA) and neuraminidase (NA)

  • Viral RNA polymerases which include PB2, PB1, PB1-F2, PA, and PB

  • Matrix proteins M1 and M2

  • Nonstructural proteins NS1 and NS2 (NEP), which are crucial for efficient pathogenesis and viral replication

The surface glycoproteins HA and NA are how the h2N1-strain is differentiated from other strains of influenza A (h2N1, h2N2) depending on the type of HA or NA antigens expressed with metabolic synergy. The function of hemagglutinin is to cause red blood cells to cluster together, and it attaches the virus to the infected cell. Neuraminidase helps move the virus particles through the infected cell and assists in budding from host cells.

The h2N1 swine influenza viruses can potentially cause infections in humans if antigenic characteristics of the virus change. In 2009, the pandemic which started in Mexico with the h2N1 strain displayed a combination of segments of 4 different influenza viruses (quadruple genetic reassortment): pig-origin flu North American avian (comprising 34.4%), bird-origin flu of the human influenza strain (comprising 17.5%), North American swine (comprising 30.6%), and Eurasian swine (comprising 17.5%). Due to this coinfection with influenza virus from diverse animal species, the viruses were able to interact, mutate, and form new strains that had variable immunity. Although it had originated in pigs, it was able to spread from human to human. When the flu spreads from human-to-human, instead of from animals to humans, there can be further mutations, making it harder to treat because people have no natural immunity. [4][5][6]

Epidemiology

Swine flu was first isolated from pigs in the 1930s by researchers in the United States and was subsequently recognized by pork producers and veterinarians as a cause of flu infections in pigs worldwide, and for the next 60 years, h2N1 was the predominant swine influenza strain. People who are closely associated with pigs have been known to develop an infection, and pigs have also been infected with human flu from these handlers. In the vast majority of cases, cross-species transmission of the virus had remained confined to the specific area and not caused national or global infections in either pigs or humans. Unfortunately, due to the potential for genetic variation in the swine flu virus, there is always a possibility for cross-species transmission with the influenza viruses to occur. Investigators concluded that the “2009 swine flu” strain, which originated in Mexico, was termed novel h2N1 flu since it was mainly found infecting humans and exhibits 2 main surface antigens, hemagglutinin type 1 and neuraminidase type 1. The 8 RNA strands in novel h2N1 flu have 1 strand from human flu strains, 2 derived from avian (bird) strains, and 5 that were derived from swine strains. During the 2009 pandemic, the Centers for Disease and Control and Prevention (CDC) estimated that there were 43 to 89 million cases of swine flu reported during a 1-year span, with 1799 deaths in 178 countries worldwide.  [7][8]

The 1918 deadly influenza pandemic caused by h2N1 influenza virus, infected approximately 500 million people around the world and caused the death of roughly fifty to a hundred million people. The h2N1 variant of swine flu is the progeny of the strain that caused the 1918 swine flu pandemic. Although persisting in pigs, the descendant variants of the 1918 virus have also known to infect humans, contributing to the yearly seasonal epidemics of influenza. Direct transmission of the virus from pigs to humans is a rare occurrence, with only 12 documented cases in the United States since 2005. The potential retention of influenza virus strains in swine after these strains have disappeared in the human population, essentially make pigs a reservoir where swine influenza viruses could persist, and later emerge to reinfect humans once their immunity to these strains has waned. [1][9]

More recently in 2015, a mutant strain of h2N1 which caused the global pandemic in 2009, spread across India with over 10,000 reported cases and 774 deaths.

People who have a higher risk of becoming seriously ill if infected include:

  • Children younger than 5 years old

  • Adults older than age 65, younger adults, and children under age 19 who are on long-term aspirin therapy

  • People with compromised immune systems due to diseases such as AIDS

  • Currently gestating females

  • People suffering from chronic diseases such as asthma, heart disease, diabetes mellitus, or neuromuscular disease

Pathophysiology

h2N1 swine flu is an acute disease that infects the upper respiratory tract and can cause inflammation of the upper respiratory passages, trachea, and possibly the lower respiratory tract. The known incubation period for h2N1 swine flu ranges from 1 to 4 days, with the average around 2 days in most individuals, but some individuals, it may be as long as 7 days. The contagious period for adults starts about 1 day before symptoms develop and lasts around 5 to 7 days after the person develops symptoms. The contagious period may be longer in individuals with weakened immune systems and children (e.g., 10 to 14 days).

The acute symptoms of uncomplicated infections persist for three to seven days, and the disease is mostly self-limited in healthy individuals, but malaise and cough can persist for up to 2 weeks in some patients. Patients with more severe disease may require hospitalization, and this may increase the time of infection to around 9 to 10 days. The body’s immune reaction to the virus and the interferon response are the causes of the viral syndrome which includes high fever, coryza, and myalgia. Patients with chronic lung diseases, cardiac disease and who are currently pregnant are at higher risk of severe complications such as viral pneumonia, superimposed bacterial pneumonia, hemorrhagic bronchitis, and possibly death. These complications can potentially develop within 48 hours from the onset of symptoms. The replication of the virus occurs primarily in the upper and lower respiratory tract passages from the time of inoculation and peaks around 48 hours in most patients. The recommended time of isolation of the infected patient is around 5 days. [10]

Histopathology

Swine flu causes most symptoms in upper and lower respiratory tracts. Mild cases usually show a few pathologic changes in the respiratory tract, but severe cases can show clear pathologic changes of pneumonia. The pathological findings associated with swine flu include multifocal destruction and potential desquamation of the pseudo columnar and columnar epithelial cells, and possibly prominent hyperemia and edema in the submucosa. There may also be thrombus formation at the bronchiolar level. Sometimes, the acute inflammation could be severe and indicated by hemorrhagic tracheobronchitis and desquamative bronchiolitis, which could cause necrosis of the bronchiolar wall. Once necrosis occurs, polymorphs and mononuclear cells infiltrate into the affected area.

Histological changes in swine influenza pneumonia include: interstitial edema with possible inflammatory infiltrate, alveolar proteinaceous exudation associated with membrane formation, thrombosis of capillaries, necrosis of the alveolar septae, intra-alveolar hemorrhage, dislocation of desquamated pneumocytes with pyknotic nuclei into the surrounding alveolar spaces, diffuse alveolar damage with infiltration by the lymphocytes and histiocytes into the interstitium. During the late stage, the following changes have been reported in patients: diffuse alveolar damage, fibrosis, hyperplasia of the type II pneumocyte, epithelial regeneration, and squamous metaplasia have been found. These changes are characteristic of the fibroproliferative stage of acute respiratory distress syndrome and diffuse alveolar destruction. Bacterial coinfections were also identified in some autopsy cases. The most common bacteria isolated included Streptococcus pneumoniaeStreptococcus pyogenes, Staphylococcus aureus, community-acquired, methicillin-resistant Staphylococcus aureus, and Haemophilus influenzae.

History and Physical

The history and clinical presentations of h2N1 swine influenza have ranged from mild flu symptoms to severe respiratory symptoms (and possibly death) depending on the age of the patient, co-morbidities, vaccination status, and natural immunity in patients to the virus. According to the CDC, the signs and symptoms in humans infected with the 2009 h2N1 swine flu were similar to those of influenza. These include a fever and chills, cough, sore throat, congested eyes, myalgia, shortness of breath, weight loss, chills, sneezing, headache,  rhinorrhea, coughing, dizziness, abdominal pain, decreased appetite, and fatigue. The 2009 h2N1 strain also showed an increased number of people reporting vomiting and diarrhea as well. Because most of these symptoms are not exclusive to swine flu, a detailed history must also be taken to take into account the differential diagnosis of swine flu if the patient has directly contacted someone with confirmed swine flu or has been in an area that had documented cases of swine flu. Respiratory failure was the most common cause of death in severe cases. Other causes included high fever (causing neurological problems), pneumonia (causing sepsis), dehydration and severe hypotension (from vomiting and diarrhea), electrolyte imbalance associated complications, and kidney failure. More severe cases and fatalities were more likely observed in children younger than 5 years of age and elderly patients older than 60 years.

Other risk factors for severe disease include lung disorders such as chronic obstructive pulmonary disease (COPD), bronchial asthma, pneumonia, currently pregnant women, obesity, patients undergoing immunosuppressive therapy due to cancer or autoimmune disease, and underlying medical issues such as diabetes. Pregnant women acquired the infection during their third trimester were at greater risk for complications.

Evaluation

Influenza A (h2N1) virus infection could be encountered in a wide range of clinical settings and may result in variable pathologic findings. h2N1 should be one of the differential diagnosis in patients who present with unexplained flu-like symptoms or acute pneumonia in an area with known swine flu cases. Routine investigations should be performed for the patient who presents with these symptoms. These usually include hematological, microbiological, biochemical and radiologic tests. A respiratory sample (simple nose or throat swab) is required for a confirmed diagnosis of swine flu. In humans, these tests include the Reverse transcriptase-polymerase chain reaction test (RT-PCR), virus isolation test, and assays to detect a 4-fold increase in influenza virus antigens. The routine tests done to detect human influenza viruses, including the rapid test kits, do not always detect zoonotic viruses.

An indication that a novel, possibly zoonotic swine influenza virus could be present, is a detection of the influenza A virus, but not of the hemagglutinins in the seasonal human influenza viruses. The zoonotic influenza virus infections can sometimes be diagnosed retrospectively by serology, but potential cross-reactivity with human influenza viruses can complicate this diagnosis. Another concern is that the neuraminidase (NA) and hemagglutinin (HA) of some swine influenza viruses (the main target of the antibodies) originated from human influenza viruses, to which people could have already been exposed.

State, regional, and national public health laboratories do generally test for the novel influenza viruses.

Treatment / Management

The initial and best step in management should be to prevent swine flu. Specifically, with the prevention of swine flu in swine, prevention of transmission of swine flu from swine-to-humans, and prevention of human-to-human spread.

  1. Prevention of swine flu in swine: Main methods to prevent swine flu in pigs involve facility management (using disinfectants and regulated temperature to control viruses in the environment), herd management (not adding pigs possibly carrying influenza to the herds that have not yet been exposed to the virus), and vaccination. As much of the morbidity and mortality observed with swine flu is due to secondary infection by other pathogens, strategies that solely rely on vaccination may be insufficient.

  2. Prevention of swine to human viral transmission: Because swine can be infected with avian and human strains of h2N1 influenza, they are the primary hosts where antigenic shifts occur that can cause new strains of swine flu. Transmission of the influenza virus from swine to humans is usually seen in people who have a close association with pigs, such as farmers, pork handlers, and veterinarians. These individuals are strongly encouraged to wear face-masks when dealing with the animals to prevent transmission through respiratory droplets. The most important step of prevention is vaccination of the swine. Individuals with increased risk of acquiring swine flu through pigs are those who smoke and do not wear gloves or masks when dealing with infected animals, increasing the risk of possible hand-to-nose, hand-to-eye, or hand-to-mouth transmission.

  3. Prevention of human to human transmission: The main route of swine flu virus spread between humans is exposure to the virus when someone infected sneezes or coughs, and the virus enters one of the potential mucous surfaces, or when a person touched something infected with the virus and subsequently touch their nose, mouth, and surrounding areas. Swine flu is most contagious in the first 5 days of illness in most people, although this may increase in children and the elderly. Current CDC recommendations to prevent the spread of the virus include frequent handwashing with soap and water or alcohol-based sanitizers, and also disinfecting household, hospital and public settings by cleaning with a diluted bleach solution. Anyone who resides in an area where the disease is prevalent and suspects an infection or presents with flu-like symptoms, should stay away from work and public transportation and immediately see a doctor.

The best-known prevention method against swine flu is getting the h2N1 swine flu vaccine. In September 2009, the FDA permitted the new swine flu vaccine, and various studies by the National Institute of Health (NIH) showed that a single dose was enough to create sufficient antibodies to protect against the virus within 10 days. The vaccination is contraindicated in people who had a previous severe allergic reaction to the influenza vaccination. Those who are moderate to severely ill, including those with or without a fever, should take the vaccination when they recover or are asymptomatic.

The management for infected patients depends on the severity of symptoms of influenza, mild to moderate influenza can be treated at home with rest, oral hydration and symptomatic treatment with antipyretics like paracetamol, antihistaminic for nasal congestion and rhinitis and NSAIDS or Paracetamol for headaches and body aches. Patients with progressive or severe symptoms should be admitted to hospitals and preferably in intensive care units (ICU) if there are signs suggestive of impending respiratory failure or sepsis or multiorgan dysfunction. Aggressive supportive measures like intravenous (IV) hydration, correction of electrolyte imbalances, antibiotics for concomitant bacterial infections. Patients developing acute respiratory distress syndrome (ARDS) secondary to influenza should be treated with noninvasive or invasive mechanical ventilation. Severe cases of h2N1-induced ARDS have required the use of extracorporeal membrane oxygenation (ECMO).

The antiviral medications: zanamivir, oseltamivir, and peramivir have been documented to help reduce, or possibly prevent, the effects of swine flu if the medication is taken within 48 hours of the onset of symptoms. Known side effects of oseltamivir comprise skin conditions that are occasionally severe and sporadic transient neuropsychiatric events. These possible side effects are the reason the use of oseltamivir is cautioned in the elderly and individuals that have a higher risk of developing these side effects. An allergy to eggs is the only contraindication to zanamivir. Beginning October 1, 2008, the CDC tested 1146 seasonal influenza A (h2N1) collected viruses for resistance to the drugs oseltamivir and zanamivir. It concluded that 99.6% of the samples showed resistance to oseltamivir while none showed resistance to zanamivir. Of the 853 collected samples of the 2009 influenza A (h2N1) virus, only 4% demonstrated resistance to oseltamivir, while none of the 376 samples collected showed resistance to zanamivir.

Pregnant women who contract the h2N1, are at a greater risk of complications because of the body’s hormonal changes, physical changes and changes to their immune system to accommodate the growing fetus. For these reasons, the CDC recommends that all pregnant women get vaccinated to prevent the swine influenza virus. Swine influenza in pregnant women can be treated using antiviral medications: oseltamivir and zanamivir (neuraminidase inhibitors). It has been demonstrated that these 2 drugs are most effective when taken within 2 days of becoming sick. [11][12][13]

Prognosis

Evaluation of data reveals that some patients admitted with swine flu are at risk for sepsis, ARDS and death. Predictors of death include chronic lung disease, obesity, underlying neurological diseases, delayed admission, and other co-morbidity.

Enhancing Healthcare Team Outcomes

Swine flu is very contagious and is easily spread from humans after contact with pigs. The infection rapidly leads to moderate to severe symptoms and deaths are not rare. The key is to prevent the infection in the first place.

For best results, an interprofessional team should provide for the evaluation and care of patients with Swine flu. The team should be aware of patients at a high risk of becoming seriously ill if infected including you children, the elderly, those immunocompromized, gestating females, and those suffering from chronic debilitating diseases.

Today, the primary care provider, pharmacist and nurse practitioner should recommend the h2N1 vaccine to children and adults at risk. In addition, all pregnant women should be urged to get vaccinated to prevent the high mortality of the infection. The school nurse should encourage closure of the school even if only one case of h2N1 is identified. Parents should be encouraged to get the children vaccinated and prevent them from interacting with others; pharmacists are empowered to perform this function in many US states. In the hospital, the nurses should ensure that the patient is in a single isolation room with airborne precautions in place. Appropriate precautions have to be undertaken to prevent contact with body fluids and aerosols released in the air while coughing. Hand washing should be enforced and only a limited number of healthcare personnel should be allowed to come into contact with the infected person. Only through open communication among members of the interprofessional team can the morbidity and mortality of swine flu be reduced. [14][Level 5]

Figure

Digitally-colorized transmission electron microscopic (TEM),h2N1 influenza virus particles. Contributed by the Public Health Image Library (PHIL)

References

1.
Kshatriya RM, Khara NV, Ganjiwale J, Lote SD, Patel SN, Paliwal RP. Lessons learnt from the Indian h2N1 (swine flu) epidemic: Predictors of outcome based on epidemiological and clinical profile. J Family Med Prim Care. 2018 Nov-Dec;7(6):1506-1509. [PMC free article: PMC6293944] [PubMed: 30613550]
2.
Rewar S, Mirdha D, Rewar P. Treatment and Prevention of Pandemic h2N1 Influenza. Ann Glob Health. 2015 Sep-Oct;81(5):645-53. [PubMed: 27036721]
3.
Keenliside J. Pandemic influenza A h2N1 in Swine and other animals. Curr Top Microbiol Immunol. 2013;370:259-71. [PubMed: 23254339]
4.
Nogales A, Martinez-Sobrido L, Chiem K, Topham DJ, DeDiego ML. Functional Evolution of the 2009 Pandemic h2N1 Influenza Virus NS1 and PA in Humans. J Virol. 2018 Oct 01;92(19) [PMC free article: PMC6146824] [PubMed: 30021892]
5.
Baudon E, Chu DKW, Tung DD, Thi Nga P, Vu Mai Phuong H, Le Khanh Hang N, Thanh LT, Thuy NT, Khanh NC, Mai LQ, Khong NV, Cowling BJ, Peyre M, Peiris M. Swine influenza viruses in Northern Vietnam in 2013-2014. Emerg Microbes Infect. 2018 Jul 02;7(1):123. [PMC free article: PMC6028489] [PubMed: 29967457]
6.
Tapia R, García V, Mena J, Bucarey S, Medina RA, Neira V. Infection of novel reassortant h2N2 and h4N2 swine influenza A viruses in the guinea pig model. Vet Res. 2018 Jul 27;49(1):73. [PMC free article: PMC6062863] [PubMed: 30053826]
7.
Hasan F, Khan MO, Ali M. Swine Flu: Knowledge, Attitude, and Practices Survey of Medical and Dental Students of Karachi. Cureus. 2018 Jan 09;10(1):e2048. [PMC free article: PMC5844644] [PubMed: 29541569]
8.
Nelson MI, Souza CK, Trovão NS, Diaz A, Mena I, Rovira A, Vincent AL, Torremorell M, Marthaler D, Culhane MR. Human-Origin Influenza A(h4N2) Reassortant Viruses in Swine, Southeast Mexico. Emerg Infect Dis. 2019 Apr;25(4):691-700. [PMC free article: PMC6433011] [PubMed: 30730827]
9.
Nickol ME, Kindrachuk J. A year of terror and a century of reflection: perspectives on the great influenza pandemic of 1918-1919. BMC Infect Dis. 2019 Feb 06;19(1):117. [PMC free article: PMC6364422] [PubMed: 30727970]
10.
Calore EE, Uip DE, Perez NM. Pathology of the swine-origin influenza A (h2N1) flu. Pathol Res Pract. 2011 Feb 15;207(2):86-90. [PubMed: 21176866]
11.
Somerville LK, Basile K, Dwyer DE, Kok J. The impact of influenza virus infection in pregnancy. Future Microbiol. 2018 Feb;13:263-274. [PubMed: 29320882]
12.
Myers KP, Olsen CW, Gray GC. Cases of swine influenza in humans: a review of the literature. Clin Infect Dis. 2007 Apr 15;44(8):1084-8. [PMC free article: PMC1973337] [PubMed: 17366454]
13.
Littauer EQ, Esser ES, Antao OQ, Vassilieva EV, Compans RW, Skountzou I. h2N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation. PLoS Pathog. 2017 Nov;13(11):e1006757. [PMC free article: PMC5720832] [PubMed: 29176767]
14.
Cauchemez S, Ferguson NM, Wachtel C, Tegnell A, Saour G, Duncan B, Nicoll A. Closure of schools during an influenza pandemic. Lancet Infect Dis. 2009 Aug;9(8):473-81. [PMC free article: PMC7106429] [PubMed: 19628172]

h2N1 Influenza – StatPearls – NCBI Bookshelf

Continuing Education Activity

h2N1 influenza is a subtype of influenza A virus, a communicable viral illness which causes upper and in some cases lower respiratory tract infections in its host. This results in symptoms such as nasal secretions, chills, fever, decreased appetite, and in some cases, lower respiratory tract disease. This activity reviews the presentation, evaluation, and management of h2N1 influenza and stresses the role of an interprofessional team approach to the care of affected patients.

Objectives:

  • Identify the global, historical impact of h2N1 influenza.

  • Summarize the transmission of h2N1 influenza.

  • Describe the common symptoms associated with h2N1 influenza.

  • Explain the importance of improving care coordination, with particular emphasis on communication between interprofessional medical teams, to enhance prompt and thorough delivery of care to patients with h2N1 influenza and prevent further disease spread.

Access free multiple choice questions on this topic.

Introduction

h2N1 Swine flu is a subtype of influenza A virus (a communicable viral disease), which causes upper, and potentially, lower respiratory tract infections in the host it infects, resulting in symptoms such as nasal secretions, chills, fever, decreased appetite, and possibly lower respiratory tract disease. h2N1 swine influenza is a common infection in pigs worldwide, and that is why it is also known as swine flu. h2N1 swine flu leads to respiratory disease that can potentially infect the respiratory tract of pigs. Sometimes, people who are closely associated with pigs or in the proximity of pigs have developed swine flu (zoonotic swine flu). Swine influenza viruses can potentially cause infections in humans if antigenic characteristics of the virus change through reassortment. When this happens, transmission from person-to-person is usually inefficient. Influenza A pandemics such as the ones in 1918 and 2009 can occur if the transmission from person-to-person becomes efficient. [1]

In 1918, a deadly influenza pandemic caused by h2N1 influenza virus, also known as the Spanish flu, infected approximately 500 million people around the world and resulted in the deaths of 50 to 100 million people (3% to 5% of the world population) worldwide, distinguishing it as one of the most deadly pandemics in human history. In 2009, a new strain h2N1 swine flu spread fast around the world among humans, and the World Health Organization (WHO) labeled it a pandemic. However, the 2009 h2N1 virus was not zoonotic swine flu because it was not transferred from pigs to humans. Instead, it spread through airborne droplets from human to human, and potentially, through human contact with inanimate objects contaminated with the virus and transferred to the eyes or nose. This virus caused similar symptoms to those seen in swine, possibly due to reassortment of the viral RNA structure, which allowed human-to-human transfer. [2][3]

Despite the name, an individual cannot acquire swine flu from eating pig products such as bacon, ham, and other pig products. 

Etiology

The h2N1 influenza virus is an orthomyxovirus and produces virions that are 80 to 120 nm in diameter, with an RNA genome size of approximately 13.5 kb. The swine influenza genome has 8 different regions which are segmented and encode 11 different proteins:

  • Envelope proteins hemagglutinin (HA) and neuraminidase (NA)

  • Viral RNA polymerases which include PB2, PB1, PB1-F2, PA, and PB

  • Matrix proteins M1 and M2

  • Nonstructural proteins NS1 and NS2 (NEP), which are crucial for efficient pathogenesis and viral replication

The surface glycoproteins HA and NA are how the h2N1-strain is differentiated from other strains of influenza A (h2N1, h2N2) depending on the type of HA or NA antigens expressed with metabolic synergy. The function of hemagglutinin is to cause red blood cells to cluster together, and it attaches the virus to the infected cell. Neuraminidase helps move the virus particles through the infected cell and assists in budding from host cells.

The h2N1 swine influenza viruses can potentially cause infections in humans if antigenic characteristics of the virus change. In 2009, the pandemic which started in Mexico with the h2N1 strain displayed a combination of segments of 4 different influenza viruses (quadruple genetic reassortment): pig-origin flu North American avian (comprising 34.4%), bird-origin flu of the human influenza strain (comprising 17.5%), North American swine (comprising 30.6%), and Eurasian swine (comprising 17.5%). Due to this coinfection with influenza virus from diverse animal species, the viruses were able to interact, mutate, and form new strains that had variable immunity. Although it had originated in pigs, it was able to spread from human to human. When the flu spreads from human-to-human, instead of from animals to humans, there can be further mutations, making it harder to treat because people have no natural immunity.  [4][5][6]

Epidemiology

Swine flu was first isolated from pigs in the 1930s by researchers in the United States and was subsequently recognized by pork producers and veterinarians as a cause of flu infections in pigs worldwide, and for the next 60 years, h2N1 was the predominant swine influenza strain. People who are closely associated with pigs have been known to develop an infection, and pigs have also been infected with human flu from these handlers. In the vast majority of cases, cross-species transmission of the virus had remained confined to the specific area and not caused national or global infections in either pigs or humans. Unfortunately, due to the potential for genetic variation in the swine flu virus, there is always a possibility for cross-species transmission with the influenza viruses to occur. Investigators concluded that the “2009 swine flu” strain, which originated in Mexico, was termed novel h2N1 flu since it was mainly found infecting humans and exhibits 2 main surface antigens, hemagglutinin type 1 and neuraminidase type 1. The 8 RNA strands in novel h2N1 flu have 1 strand from human flu strains, 2 derived from avian (bird) strains, and 5 that were derived from swine strains. During the 2009 pandemic, the Centers for Disease and Control and Prevention (CDC) estimated that there were 43 to 89 million cases of swine flu reported during a 1-year span, with 1799 deaths in 178 countries worldwide. [7][8]

The 1918 deadly influenza pandemic caused by h2N1 influenza virus, infected approximately 500 million people around the world and caused the death of roughly fifty to a hundred million people. The h2N1 variant of swine flu is the progeny of the strain that caused the 1918 swine flu pandemic. Although persisting in pigs, the descendant variants of the 1918 virus have also known to infect humans, contributing to the yearly seasonal epidemics of influenza. Direct transmission of the virus from pigs to humans is a rare occurrence, with only 12 documented cases in the United States since 2005. The potential retention of influenza virus strains in swine after these strains have disappeared in the human population, essentially make pigs a reservoir where swine influenza viruses could persist, and later emerge to reinfect humans once their immunity to these strains has waned.  [1][9]

More recently in 2015, a mutant strain of h2N1 which caused the global pandemic in 2009, spread across India with over 10,000 reported cases and 774 deaths.

People who have a higher risk of becoming seriously ill if infected include:

  • Children younger than 5 years old

  • Adults older than age 65, younger adults, and children under age 19 who are on long-term aspirin therapy

  • People with compromised immune systems due to diseases such as AIDS

  • Currently gestating females

  • People suffering from chronic diseases such as asthma, heart disease, diabetes mellitus, or neuromuscular disease

Pathophysiology

h2N1 swine flu is an acute disease that infects the upper respiratory tract and can cause inflammation of the upper respiratory passages, trachea, and possibly the lower respiratory tract. The known incubation period for h2N1 swine flu ranges from 1 to 4 days, with the average around 2 days in most individuals, but some individuals, it may be as long as 7 days. The contagious period for adults starts about 1 day before symptoms develop and lasts around 5 to 7 days after the person develops symptoms. The contagious period may be longer in individuals with weakened immune systems and children (e.g., 10 to 14 days).

The acute symptoms of uncomplicated infections persist for three to seven days, and the disease is mostly self-limited in healthy individuals, but malaise and cough can persist for up to 2 weeks in some patients. Patients with more severe disease may require hospitalization, and this may increase the time of infection to around 9 to 10 days. The body’s immune reaction to the virus and the interferon response are the causes of the viral syndrome which includes high fever, coryza, and myalgia. Patients with chronic lung diseases, cardiac disease and who are currently pregnant are at higher risk of severe complications such as viral pneumonia, superimposed bacterial pneumonia, hemorrhagic bronchitis, and possibly death. These complications can potentially develop within 48 hours from the onset of symptoms. The replication of the virus occurs primarily in the upper and lower respiratory tract passages from the time of inoculation and peaks around 48 hours in most patients. The recommended time of isolation of the infected patient is around 5 days. [10]

Histopathology

Swine flu causes most symptoms in upper and lower respiratory tracts. Mild cases usually show a few pathologic changes in the respiratory tract, but severe cases can show clear pathologic changes of pneumonia. The pathological findings associated with swine flu include multifocal destruction and potential desquamation of the pseudo columnar and columnar epithelial cells, and possibly prominent hyperemia and edema in the submucosa. There may also be thrombus formation at the bronchiolar level. Sometimes, the acute inflammation could be severe and indicated by hemorrhagic tracheobronchitis and desquamative bronchiolitis, which could cause necrosis of the bronchiolar wall. Once necrosis occurs, polymorphs and mononuclear cells infiltrate into the affected area.

Histological changes in swine influenza pneumonia include: interstitial edema with possible inflammatory infiltrate, alveolar proteinaceous exudation associated with membrane formation, thrombosis of capillaries, necrosis of the alveolar septae, intra-alveolar hemorrhage, dislocation of desquamated pneumocytes with pyknotic nuclei into the surrounding alveolar spaces, diffuse alveolar damage with infiltration by the lymphocytes and histiocytes into the interstitium. During the late stage, the following changes have been reported in patients: diffuse alveolar damage, fibrosis, hyperplasia of the type II pneumocyte, epithelial regeneration, and squamous metaplasia have been found. These changes are characteristic of the fibroproliferative stage of acute respiratory distress syndrome and diffuse alveolar destruction. Bacterial coinfections were also identified in some autopsy cases. The most common bacteria isolated included Streptococcus pneumoniaeStreptococcus pyogenes, Staphylococcus aureus, community-acquired, methicillin-resistant Staphylococcus aureus, and Haemophilus influenzae.

History and Physical

The history and clinical presentations of h2N1 swine influenza have ranged from mild flu symptoms to severe respiratory symptoms (and possibly death) depending on the age of the patient, co-morbidities, vaccination status, and natural immunity in patients to the virus. According to the CDC, the signs and symptoms in humans infected with the 2009 h2N1 swine flu were similar to those of influenza. These include a fever and chills, cough, sore throat, congested eyes, myalgia, shortness of breath, weight loss, chills, sneezing, headache,  rhinorrhea, coughing, dizziness, abdominal pain, decreased appetite, and fatigue. The 2009 h2N1 strain also showed an increased number of people reporting vomiting and diarrhea as well. Because most of these symptoms are not exclusive to swine flu, a detailed history must also be taken to take into account the differential diagnosis of swine flu if the patient has directly contacted someone with confirmed swine flu or has been in an area that had documented cases of swine flu. Respiratory failure was the most common cause of death in severe cases. Other causes included high fever (causing neurological problems), pneumonia (causing sepsis), dehydration and severe hypotension (from vomiting and diarrhea), electrolyte imbalance associated complications, and kidney failure. More severe cases and fatalities were more likely observed in children younger than 5 years of age and elderly patients older than 60 years.

Other risk factors for severe disease include lung disorders such as chronic obstructive pulmonary disease (COPD), bronchial asthma, pneumonia, currently pregnant women, obesity, patients undergoing immunosuppressive therapy due to cancer or autoimmune disease, and underlying medical issues such as diabetes. Pregnant women acquired the infection during their third trimester were at greater risk for complications.

Evaluation

Influenza A (h2N1) virus infection could be encountered in a wide range of clinical settings and may result in variable pathologic findings. h2N1 should be one of the differential diagnosis in patients who present with unexplained flu-like symptoms or acute pneumonia in an area with known swine flu cases. Routine investigations should be performed for the patient who presents with these symptoms. These usually include hematological, microbiological, biochemical and radiologic tests. A respiratory sample (simple nose or throat swab) is required for a confirmed diagnosis of swine flu. In humans, these tests include the Reverse transcriptase-polymerase chain reaction test (RT-PCR), virus isolation test, and assays to detect a 4-fold increase in influenza virus antigens. The routine tests done to detect human influenza viruses, including the rapid test kits, do not always detect zoonotic viruses.

An indication that a novel, possibly zoonotic swine influenza virus could be present, is a detection of the influenza A virus, but not of the hemagglutinins in the seasonal human influenza viruses. The zoonotic influenza virus infections can sometimes be diagnosed retrospectively by serology, but potential cross-reactivity with human influenza viruses can complicate this diagnosis. Another concern is that the neuraminidase (NA) and hemagglutinin (HA) of some swine influenza viruses (the main target of the antibodies) originated from human influenza viruses, to which people could have already been exposed.

State, regional, and national public health laboratories do generally test for the novel influenza viruses.

Treatment / Management

The initial and best step in management should be to prevent swine flu. Specifically, with the prevention of swine flu in swine, prevention of transmission of swine flu from swine-to-humans, and prevention of human-to-human spread.

  1. Prevention of swine flu in swine: Main methods to prevent swine flu in pigs involve facility management (using disinfectants and regulated temperature to control viruses in the environment), herd management (not adding pigs possibly carrying influenza to the herds that have not yet been exposed to the virus), and vaccination. As much of the morbidity and mortality observed with swine flu is due to secondary infection by other pathogens, strategies that solely rely on vaccination may be insufficient.

  2. Prevention of swine to human viral transmission: Because swine can be infected with avian and human strains of h2N1 influenza, they are the primary hosts where antigenic shifts occur that can cause new strains of swine flu. Transmission of the influenza virus from swine to humans is usually seen in people who have a close association with pigs, such as farmers, pork handlers, and veterinarians. These individuals are strongly encouraged to wear face-masks when dealing with the animals to prevent transmission through respiratory droplets. The most important step of prevention is vaccination of the swine. Individuals with increased risk of acquiring swine flu through pigs are those who smoke and do not wear gloves or masks when dealing with infected animals, increasing the risk of possible hand-to-nose, hand-to-eye, or hand-to-mouth transmission.

  3. Prevention of human to human transmission: The main route of swine flu virus spread between humans is exposure to the virus when someone infected sneezes or coughs, and the virus enters one of the potential mucous surfaces, or when a person touched something infected with the virus and subsequently touch their nose, mouth, and surrounding areas. Swine flu is most contagious in the first 5 days of illness in most people, although this may increase in children and the elderly. Current CDC recommendations to prevent the spread of the virus include frequent handwashing with soap and water or alcohol-based sanitizers, and also disinfecting household, hospital and public settings by cleaning with a diluted bleach solution. Anyone who resides in an area where the disease is prevalent and suspects an infection or presents with flu-like symptoms, should stay away from work and public transportation and immediately see a doctor.

The best-known prevention method against swine flu is getting the h2N1 swine flu vaccine. In September 2009, the FDA permitted the new swine flu vaccine, and various studies by the National Institute of Health (NIH) showed that a single dose was enough to create sufficient antibodies to protect against the virus within 10 days. The vaccination is contraindicated in people who had a previous severe allergic reaction to the influenza vaccination. Those who are moderate to severely ill, including those with or without a fever, should take the vaccination when they recover or are asymptomatic.

The management for infected patients depends on the severity of symptoms of influenza, mild to moderate influenza can be treated at home with rest, oral hydration and symptomatic treatment with antipyretics like paracetamol, antihistaminic for nasal congestion and rhinitis and NSAIDS or Paracetamol for headaches and body aches. Patients with progressive or severe symptoms should be admitted to hospitals and preferably in intensive care units (ICU) if there are signs suggestive of impending respiratory failure or sepsis or multiorgan dysfunction. Aggressive supportive measures like intravenous (IV) hydration, correction of electrolyte imbalances, antibiotics for concomitant bacterial infections. Patients developing acute respiratory distress syndrome (ARDS) secondary to influenza should be treated with noninvasive or invasive mechanical ventilation. Severe cases of h2N1-induced ARDS have required the use of extracorporeal membrane oxygenation (ECMO).

The antiviral medications: zanamivir, oseltamivir, and peramivir have been documented to help reduce, or possibly prevent, the effects of swine flu if the medication is taken within 48 hours of the onset of symptoms. Known side effects of oseltamivir comprise skin conditions that are occasionally severe and sporadic transient neuropsychiatric events. These possible side effects are the reason the use of oseltamivir is cautioned in the elderly and individuals that have a higher risk of developing these side effects. An allergy to eggs is the only contraindication to zanamivir. Beginning October 1, 2008, the CDC tested 1146 seasonal influenza A (h2N1) collected viruses for resistance to the drugs oseltamivir and zanamivir. It concluded that 99.6% of the samples showed resistance to oseltamivir while none showed resistance to zanamivir. Of the 853 collected samples of the 2009 influenza A (h2N1) virus, only 4% demonstrated resistance to oseltamivir, while none of the 376 samples collected showed resistance to zanamivir.

Pregnant women who contract the h2N1, are at a greater risk of complications because of the body’s hormonal changes, physical changes and changes to their immune system to accommodate the growing fetus. For these reasons, the CDC recommends that all pregnant women get vaccinated to prevent the swine influenza virus. Swine influenza in pregnant women can be treated using antiviral medications: oseltamivir and zanamivir (neuraminidase inhibitors). It has been demonstrated that these 2 drugs are most effective when taken within 2 days of becoming sick. [11][12][13]

Prognosis

Evaluation of data reveals that some patients admitted with swine flu are at risk for sepsis, ARDS and death. Predictors of death include chronic lung disease, obesity, underlying neurological diseases, delayed admission, and other co-morbidity.

Enhancing Healthcare Team Outcomes

Swine flu is very contagious and is easily spread from humans after contact with pigs. The infection rapidly leads to moderate to severe symptoms and deaths are not rare. The key is to prevent the infection in the first place.

For best results, an interprofessional team should provide for the evaluation and care of patients with Swine flu. The team should be aware of patients at a high risk of becoming seriously ill if infected including you children, the elderly, those immunocompromized, gestating females, and those suffering from chronic debilitating diseases.

Today, the primary care provider, pharmacist and nurse practitioner should recommend the h2N1 vaccine to children and adults at risk. In addition, all pregnant women should be urged to get vaccinated to prevent the high mortality of the infection. The school nurse should encourage closure of the school even if only one case of h2N1 is identified. Parents should be encouraged to get the children vaccinated and prevent them from interacting with others; pharmacists are empowered to perform this function in many US states. In the hospital, the nurses should ensure that the patient is in a single isolation room with airborne precautions in place. Appropriate precautions have to be undertaken to prevent contact with body fluids and aerosols released in the air while coughing. Hand washing should be enforced and only a limited number of healthcare personnel should be allowed to come into contact with the infected person. Only through open communication among members of the interprofessional team can the morbidity and mortality of swine flu be reduced. [14][Level 5]

Figure

Digitally-colorized transmission electron microscopic (TEM),h2N1 influenza virus particles. Contributed by the Public Health Image Library (PHIL)

References

1.
Kshatriya RM, Khara NV, Ganjiwale J, Lote SD, Patel SN, Paliwal RP. Lessons learnt from the Indian h2N1 (swine flu) epidemic: Predictors of outcome based on epidemiological and clinical profile. J Family Med Prim Care. 2018 Nov-Dec;7(6):1506-1509. [PMC free article: PMC6293944] [PubMed: 30613550]
2.
Rewar S, Mirdha D, Rewar P. Treatment and Prevention of Pandemic h2N1 Influenza. Ann Glob Health. 2015 Sep-Oct;81(5):645-53. [PubMed: 27036721]
3.
Keenliside J. Pandemic influenza A h2N1 in Swine and other animals. Curr Top Microbiol Immunol. 2013;370:259-71. [PubMed: 23254339]
4.
Nogales A, Martinez-Sobrido L, Chiem K, Topham DJ, DeDiego ML. Functional Evolution of the 2009 Pandemic h2N1 Influenza Virus NS1 and PA in Humans. J Virol. 2018 Oct 01;92(19) [PMC free article: PMC6146824] [PubMed: 30021892]
5.
Baudon E, Chu DKW, Tung DD, Thi Nga P, Vu Mai Phuong H, Le Khanh Hang N, Thanh LT, Thuy NT, Khanh NC, Mai LQ, Khong NV, Cowling BJ, Peyre M, Peiris M. Swine influenza viruses in Northern Vietnam in 2013-2014. Emerg Microbes Infect. 2018 Jul 02;7(1):123. [PMC free article: PMC6028489] [PubMed: 29967457]
6.
Tapia R, García V, Mena J, Bucarey S, Medina RA, Neira V. Infection of novel reassortant h2N2 and h4N2 swine influenza A viruses in the guinea pig model. Vet Res. 2018 Jul 27;49(1):73. [PMC free article: PMC6062863] [PubMed: 30053826]
7.
Hasan F, Khan MO, Ali M. Swine Flu: Knowledge, Attitude, and Practices Survey of Medical and Dental Students of Karachi. Cureus. 2018 Jan 09;10(1):e2048. [PMC free article: PMC5844644] [PubMed: 29541569]
8.
Nelson MI, Souza CK, Trovão NS, Diaz A, Mena I, Rovira A, Vincent AL, Torremorell M, Marthaler D, Culhane MR. Human-Origin Influenza A(h4N2) Reassortant Viruses in Swine, Southeast Mexico. Emerg Infect Dis. 2019 Apr;25(4):691-700. [PMC free article: PMC6433011] [PubMed: 30730827]
9.
Nickol ME, Kindrachuk J. A year of terror and a century of reflection: perspectives on the great influenza pandemic of 1918-1919. BMC Infect Dis. 2019 Feb 06;19(1):117. [PMC free article: PMC6364422] [PubMed: 30727970]
10.
Calore EE, Uip DE, Perez NM. Pathology of the swine-origin influenza A (h2N1) flu. Pathol Res Pract. 2011 Feb 15;207(2):86-90. [PubMed: 21176866]
11.
Somerville LK, Basile K, Dwyer DE, Kok J. The impact of influenza virus infection in pregnancy. Future Microbiol. 2018 Feb;13:263-274. [PubMed: 29320882]
12.
Myers KP, Olsen CW, Gray GC. Cases of swine influenza in humans: a review of the literature. Clin Infect Dis. 2007 Apr 15;44(8):1084-8. [PMC free article: PMC1973337] [PubMed: 17366454]
13.
Littauer EQ, Esser ES, Antao OQ, Vassilieva EV, Compans RW, Skountzou I. h2N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation. PLoS Pathog. 2017 Nov;13(11):e1006757. [PMC free article: PMC5720832] [PubMed: 29176767]
14.
Cauchemez S, Ferguson NM, Wachtel C, Tegnell A, Saour G, Duncan B, Nicoll A. Closure of schools during an influenza pandemic. Lancet Infect Dis. 2009 Aug;9(8):473-81. [PMC free article: PMC7106429] [PubMed: 19628172]

h2N1 Influenza – StatPearls – NCBI Bookshelf

Continuing Education Activity

h2N1 influenza is a subtype of influenza A virus, a communicable viral illness which causes upper and in some cases lower respiratory tract infections in its host. This results in symptoms such as nasal secretions, chills, fever, decreased appetite, and in some cases, lower respiratory tract disease. This activity reviews the presentation, evaluation, and management of h2N1 influenza and stresses the role of an interprofessional team approach to the care of affected patients.

Objectives:

  • Identify the global, historical impact of h2N1 influenza.

  • Summarize the transmission of h2N1 influenza.

  • Describe the common symptoms associated with h2N1 influenza.

  • Explain the importance of improving care coordination, with particular emphasis on communication between interprofessional medical teams, to enhance prompt and thorough delivery of care to patients with h2N1 influenza and prevent further disease spread.

Access free multiple choice questions on this topic.

Introduction

h2N1 Swine flu is a subtype of influenza A virus (a communicable viral disease), which causes upper, and potentially, lower respiratory tract infections in the host it infects, resulting in symptoms such as nasal secretions, chills, fever, decreased appetite, and possibly lower respiratory tract disease. h2N1 swine influenza is a common infection in pigs worldwide, and that is why it is also known as swine flu. h2N1 swine flu leads to respiratory disease that can potentially infect the respiratory tract of pigs. Sometimes, people who are closely associated with pigs or in the proximity of pigs have developed swine flu (zoonotic swine flu). Swine influenza viruses can potentially cause infections in humans if antigenic characteristics of the virus change through reassortment. When this happens, transmission from person-to-person is usually inefficient. Influenza A pandemics such as the ones in 1918 and 2009 can occur if the transmission from person-to-person becomes efficient. [1]

In 1918, a deadly influenza pandemic caused by h2N1 influenza virus, also known as the Spanish flu, infected approximately 500 million people around the world and resulted in the deaths of 50 to 100 million people (3% to 5% of the world population) worldwide, distinguishing it as one of the most deadly pandemics in human history. In 2009, a new strain h2N1 swine flu spread fast around the world among humans, and the World Health Organization (WHO) labeled it a pandemic. However, the 2009 h2N1 virus was not zoonotic swine flu because it was not transferred from pigs to humans. Instead, it spread through airborne droplets from human to human, and potentially, through human contact with inanimate objects contaminated with the virus and transferred to the eyes or nose. This virus caused similar symptoms to those seen in swine, possibly due to reassortment of the viral RNA structure, which allowed human-to-human transfer. [2][3]

Despite the name, an individual cannot acquire swine flu from eating pig products such as bacon, ham, and other pig products. 

Etiology

The h2N1 influenza virus is an orthomyxovirus and produces virions that are 80 to 120 nm in diameter, with an RNA genome size of approximately 13.5 kb. The swine influenza genome has 8 different regions which are segmented and encode 11 different proteins:

  • Envelope proteins hemagglutinin (HA) and neuraminidase (NA)

  • Viral RNA polymerases which include PB2, PB1, PB1-F2, PA, and PB

  • Matrix proteins M1 and M2

  • Nonstructural proteins NS1 and NS2 (NEP), which are crucial for efficient pathogenesis and viral replication

The surface glycoproteins HA and NA are how the h2N1-strain is differentiated from other strains of influenza A (h2N1, h2N2) depending on the type of HA or NA antigens expressed with metabolic synergy. The function of hemagglutinin is to cause red blood cells to cluster together, and it attaches the virus to the infected cell. Neuraminidase helps move the virus particles through the infected cell and assists in budding from host cells.

The h2N1 swine influenza viruses can potentially cause infections in humans if antigenic characteristics of the virus change. In 2009, the pandemic which started in Mexico with the h2N1 strain displayed a combination of segments of 4 different influenza viruses (quadruple genetic reassortment): pig-origin flu North American avian (comprising 34.4%), bird-origin flu of the human influenza strain (comprising 17.5%), North American swine (comprising 30.6%), and Eurasian swine (comprising 17.5%). Due to this coinfection with influenza virus from diverse animal species, the viruses were able to interact, mutate, and form new strains that had variable immunity. Although it had originated in pigs, it was able to spread from human to human. When the flu spreads from human-to-human, instead of from animals to humans, there can be further mutations, making it harder to treat because people have no natural immunity. [4][5][6]

Epidemiology

Swine flu was first isolated from pigs in the 1930s by researchers in the United States and was subsequently recognized by pork producers and veterinarians as a cause of flu infections in pigs worldwide, and for the next 60 years, h2N1 was the predominant swine influenza strain. People who are closely associated with pigs have been known to develop an infection, and pigs have also been infected with human flu from these handlers. In the vast majority of cases, cross-species transmission of the virus had remained confined to the specific area and not caused national or global infections in either pigs or humans. Unfortunately, due to the potential for genetic variation in the swine flu virus, there is always a possibility for cross-species transmission with the influenza viruses to occur. Investigators concluded that the “2009 swine flu” strain, which originated in Mexico, was termed novel h2N1 flu since it was mainly found infecting humans and exhibits 2 main surface antigens, hemagglutinin type 1 and neuraminidase type 1. The 8 RNA strands in novel h2N1 flu have 1 strand from human flu strains, 2 derived from avian (bird) strains, and 5 that were derived from swine strains. During the 2009 pandemic, the Centers for Disease and Control and Prevention (CDC) estimated that there were 43 to 89 million cases of swine flu reported during a 1-year span, with 1799 deaths in 178 countries worldwide. [7][8]

The 1918 deadly influenza pandemic caused by h2N1 influenza virus, infected approximately 500 million people around the world and caused the death of roughly fifty to a hundred million people. The h2N1 variant of swine flu is the progeny of the strain that caused the 1918 swine flu pandemic. Although persisting in pigs, the descendant variants of the 1918 virus have also known to infect humans, contributing to the yearly seasonal epidemics of influenza. Direct transmission of the virus from pigs to humans is a rare occurrence, with only 12 documented cases in the United States since 2005. The potential retention of influenza virus strains in swine after these strains have disappeared in the human population, essentially make pigs a reservoir where swine influenza viruses could persist, and later emerge to reinfect humans once their immunity to these strains has waned. [1][9]

More recently in 2015, a mutant strain of h2N1 which caused the global pandemic in 2009, spread across India with over 10,000 reported cases and 774 deaths.

People who have a higher risk of becoming seriously ill if infected include:

  • Children younger than 5 years old

  • Adults older than age 65, younger adults, and children under age 19 who are on long-term aspirin therapy

  • People with compromised immune systems due to diseases such as AIDS

  • Currently gestating females

  • People suffering from chronic diseases such as asthma, heart disease, diabetes mellitus, or neuromuscular disease

Pathophysiology

h2N1 swine flu is an acute disease that infects the upper respiratory tract and can cause inflammation of the upper respiratory passages, trachea, and possibly the lower respiratory tract. The known incubation period for h2N1 swine flu ranges from 1 to 4 days, with the average around 2 days in most individuals, but some individuals, it may be as long as 7 days. The contagious period for adults starts about 1 day before symptoms develop and lasts around 5 to 7 days after the person develops symptoms. The contagious period may be longer in individuals with weakened immune systems and children (e.g., 10 to 14 days).

The acute symptoms of uncomplicated infections persist for three to seven days, and the disease is mostly self-limited in healthy individuals, but malaise and cough can persist for up to 2 weeks in some patients. Patients with more severe disease may require hospitalization, and this may increase the time of infection to around 9 to 10 days. The body’s immune reaction to the virus and the interferon response are the causes of the viral syndrome which includes high fever, coryza, and myalgia. Patients with chronic lung diseases, cardiac disease and who are currently pregnant are at higher risk of severe complications such as viral pneumonia, superimposed bacterial pneumonia, hemorrhagic bronchitis, and possibly death. These complications can potentially develop within 48 hours from the onset of symptoms. The replication of the virus occurs primarily in the upper and lower respiratory tract passages from the time of inoculation and peaks around 48 hours in most patients. The recommended time of isolation of the infected patient is around 5 days. [10]

Histopathology

Swine flu causes most symptoms in upper and lower respiratory tracts. Mild cases usually show a few pathologic changes in the respiratory tract, but severe cases can show clear pathologic changes of pneumonia. The pathological findings associated with swine flu include multifocal destruction and potential desquamation of the pseudo columnar and columnar epithelial cells, and possibly prominent hyperemia and edema in the submucosa. There may also be thrombus formation at the bronchiolar level. Sometimes, the acute inflammation could be severe and indicated by hemorrhagic tracheobronchitis and desquamative bronchiolitis, which could cause necrosis of the bronchiolar wall. Once necrosis occurs, polymorphs and mononuclear cells infiltrate into the affected area.

Histological changes in swine influenza pneumonia include: interstitial edema with possible inflammatory infiltrate, alveolar proteinaceous exudation associated with membrane formation, thrombosis of capillaries, necrosis of the alveolar septae, intra-alveolar hemorrhage, dislocation of desquamated pneumocytes with pyknotic nuclei into the surrounding alveolar spaces, diffuse alveolar damage with infiltration by the lymphocytes and histiocytes into the interstitium. During the late stage, the following changes have been reported in patients: diffuse alveolar damage, fibrosis, hyperplasia of the type II pneumocyte, epithelial regeneration, and squamous metaplasia have been found. These changes are characteristic of the fibroproliferative stage of acute respiratory distress syndrome and diffuse alveolar destruction. Bacterial coinfections were also identified in some autopsy cases. The most common bacteria isolated included Streptococcus pneumoniaeStreptococcus pyogenes, Staphylococcus aureus, community-acquired, methicillin-resistant Staphylococcus aureus, and Haemophilus influenzae.

History and Physical

The history and clinical presentations of h2N1 swine influenza have ranged from mild flu symptoms to severe respiratory symptoms (and possibly death) depending on the age of the patient, co-morbidities, vaccination status, and natural immunity in patients to the virus. According to the CDC, the signs and symptoms in humans infected with the 2009 h2N1 swine flu were similar to those of influenza. These include a fever and chills, cough, sore throat, congested eyes, myalgia, shortness of breath, weight loss, chills, sneezing, headache,  rhinorrhea, coughing, dizziness, abdominal pain, decreased appetite, and fatigue. The 2009 h2N1 strain also showed an increased number of people reporting vomiting and diarrhea as well. Because most of these symptoms are not exclusive to swine flu, a detailed history must also be taken to take into account the differential diagnosis of swine flu if the patient has directly contacted someone with confirmed swine flu or has been in an area that had documented cases of swine flu. Respiratory failure was the most common cause of death in severe cases. Other causes included high fever (causing neurological problems), pneumonia (causing sepsis), dehydration and severe hypotension (from vomiting and diarrhea), electrolyte imbalance associated complications, and kidney failure. More severe cases and fatalities were more likely observed in children younger than 5 years of age and elderly patients older than 60 years.

Other risk factors for severe disease include lung disorders such as chronic obstructive pulmonary disease (COPD), bronchial asthma, pneumonia, currently pregnant women, obesity, patients undergoing immunosuppressive therapy due to cancer or autoimmune disease, and underlying medical issues such as diabetes. Pregnant women acquired the infection during their third trimester were at greater risk for complications.

Evaluation

Influenza A (h2N1) virus infection could be encountered in a wide range of clinical settings and may result in variable pathologic findings. h2N1 should be one of the differential diagnosis in patients who present with unexplained flu-like symptoms or acute pneumonia in an area with known swine flu cases. Routine investigations should be performed for the patient who presents with these symptoms. These usually include hematological, microbiological, biochemical and radiologic tests. A respiratory sample (simple nose or throat swab) is required for a confirmed diagnosis of swine flu. In humans, these tests include the Reverse transcriptase-polymerase chain reaction test (RT-PCR), virus isolation test, and assays to detect a 4-fold increase in influenza virus antigens. The routine tests done to detect human influenza viruses, including the rapid test kits, do not always detect zoonotic viruses.

An indication that a novel, possibly zoonotic swine influenza virus could be present, is a detection of the influenza A virus, but not of the hemagglutinins in the seasonal human influenza viruses. The zoonotic influenza virus infections can sometimes be diagnosed retrospectively by serology, but potential cross-reactivity with human influenza viruses can complicate this diagnosis. Another concern is that the neuraminidase (NA) and hemagglutinin (HA) of some swine influenza viruses (the main target of the antibodies) originated from human influenza viruses, to which people could have already been exposed.

State, regional, and national public health laboratories do generally test for the novel influenza viruses.

Treatment / Management

The initial and best step in management should be to prevent swine flu. Specifically, with the prevention of swine flu in swine, prevention of transmission of swine flu from swine-to-humans, and prevention of human-to-human spread.

  1. Prevention of swine flu in swine: Main methods to prevent swine flu in pigs involve facility management (using disinfectants and regulated temperature to control viruses in the environment), herd management (not adding pigs possibly carrying influenza to the herds that have not yet been exposed to the virus), and vaccination. As much of the morbidity and mortality observed with swine flu is due to secondary infection by other pathogens, strategies that solely rely on vaccination may be insufficient.

  2. Prevention of swine to human viral transmission: Because swine can be infected with avian and human strains of h2N1 influenza, they are the primary hosts where antigenic shifts occur that can cause new strains of swine flu. Transmission of the influenza virus from swine to humans is usually seen in people who have a close association with pigs, such as farmers, pork handlers, and veterinarians. These individuals are strongly encouraged to wear face-masks when dealing with the animals to prevent transmission through respiratory droplets. The most important step of prevention is vaccination of the swine. Individuals with increased risk of acquiring swine flu through pigs are those who smoke and do not wear gloves or masks when dealing with infected animals, increasing the risk of possible hand-to-nose, hand-to-eye, or hand-to-mouth transmission.

  3. Prevention of human to human transmission: The main route of swine flu virus spread between humans is exposure to the virus when someone infected sneezes or coughs, and the virus enters one of the potential mucous surfaces, or when a person touched something infected with the virus and subsequently touch their nose, mouth, and surrounding areas. Swine flu is most contagious in the first 5 days of illness in most people, although this may increase in children and the elderly. Current CDC recommendations to prevent the spread of the virus include frequent handwashing with soap and water or alcohol-based sanitizers, and also disinfecting household, hospital and public settings by cleaning with a diluted bleach solution. Anyone who resides in an area where the disease is prevalent and suspects an infection or presents with flu-like symptoms, should stay away from work and public transportation and immediately see a doctor.

The best-known prevention method against swine flu is getting the h2N1 swine flu vaccine. In September 2009, the FDA permitted the new swine flu vaccine, and various studies by the National Institute of Health (NIH) showed that a single dose was enough to create sufficient antibodies to protect against the virus within 10 days. The vaccination is contraindicated in people who had a previous severe allergic reaction to the influenza vaccination. Those who are moderate to severely ill, including those with or without a fever, should take the vaccination when they recover or are asymptomatic.

The management for infected patients depends on the severity of symptoms of influenza, mild to moderate influenza can be treated at home with rest, oral hydration and symptomatic treatment with antipyretics like paracetamol, antihistaminic for nasal congestion and rhinitis and NSAIDS or Paracetamol for headaches and body aches. Patients with progressive or severe symptoms should be admitted to hospitals and preferably in intensive care units (ICU) if there are signs suggestive of impending respiratory failure or sepsis or multiorgan dysfunction. Aggressive supportive measures like intravenous (IV) hydration, correction of electrolyte imbalances, antibiotics for concomitant bacterial infections. Patients developing acute respiratory distress syndrome (ARDS) secondary to influenza should be treated with noninvasive or invasive mechanical ventilation. Severe cases of h2N1-induced ARDS have required the use of extracorporeal membrane oxygenation (ECMO).

The antiviral medications: zanamivir, oseltamivir, and peramivir have been documented to help reduce, or possibly prevent, the effects of swine flu if the medication is taken within 48 hours of the onset of symptoms. Known side effects of oseltamivir comprise skin conditions that are occasionally severe and sporadic transient neuropsychiatric events. These possible side effects are the reason the use of oseltamivir is cautioned in the elderly and individuals that have a higher risk of developing these side effects. An allergy to eggs is the only contraindication to zanamivir. Beginning October 1, 2008, the CDC tested 1146 seasonal influenza A (h2N1) collected viruses for resistance to the drugs oseltamivir and zanamivir. It concluded that 99.6% of the samples showed resistance to oseltamivir while none showed resistance to zanamivir. Of the 853 collected samples of the 2009 influenza A (h2N1) virus, only 4% demonstrated resistance to oseltamivir, while none of the 376 samples collected showed resistance to zanamivir.

Pregnant women who contract the h2N1, are at a greater risk of complications because of the body’s hormonal changes, physical changes and changes to their immune system to accommodate the growing fetus. For these reasons, the CDC recommends that all pregnant women get vaccinated to prevent the swine influenza virus. Swine influenza in pregnant women can be treated using antiviral medications: oseltamivir and zanamivir (neuraminidase inhibitors). It has been demonstrated that these 2 drugs are most effective when taken within 2 days of becoming sick. [11][12][13]

Prognosis

Evaluation of data reveals that some patients admitted with swine flu are at risk for sepsis, ARDS and death. Predictors of death include chronic lung disease, obesity, underlying neurological diseases, delayed admission, and other co-morbidity.

Enhancing Healthcare Team Outcomes

Swine flu is very contagious and is easily spread from humans after contact with pigs. The infection rapidly leads to moderate to severe symptoms and deaths are not rare. The key is to prevent the infection in the first place.

For best results, an interprofessional team should provide for the evaluation and care of patients with Swine flu. The team should be aware of patients at a high risk of becoming seriously ill if infected including you children, the elderly, those immunocompromized, gestating females, and those suffering from chronic debilitating diseases.

Today, the primary care provider, pharmacist and nurse practitioner should recommend the h2N1 vaccine to children and adults at risk. In addition, all pregnant women should be urged to get vaccinated to prevent the high mortality of the infection. The school nurse should encourage closure of the school even if only one case of h2N1 is identified. Parents should be encouraged to get the children vaccinated and prevent them from interacting with others; pharmacists are empowered to perform this function in many US states. In the hospital, the nurses should ensure that the patient is in a single isolation room with airborne precautions in place. Appropriate precautions have to be undertaken to prevent contact with body fluids and aerosols released in the air while coughing. Hand washing should be enforced and only a limited number of healthcare personnel should be allowed to come into contact with the infected person. Only through open communication among members of the interprofessional team can the morbidity and mortality of swine flu be reduced. [14][Level 5]

Figure

Digitally-colorized transmission electron microscopic (TEM),h2N1 influenza virus particles. Contributed by the Public Health Image Library (PHIL)

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    Frontiers | Comparative Review of SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza A Respiratory Viruses

    Introduction

    The 2019 novel coronavirus (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and influenza A viruses are major pathogens that primarily target the human respiratory system. Diseases associated with their infections vary from mild respiratory illness to acute pneumonia and even respiratory failure. Since 1918, the influenza A viruses have caused four pandemics. The first and most severe pandemic in recent history, known as “Spanish influenza,” occurred in 1918 and was caused by an h2N1 influenza A virus (IAV) strain (1). Approximately 500 million people were infected, and 50 million people died during this pandemic. The second pandemic, known as “Asian influenza,” occurred in 1957, was caused by an h3N2 IAV strain, and resulted in ~1.1 million deaths worldwide (2). The third pandemic, known as “Hong Kong flu,” occurred in 1968 and was caused by an h4N2 IAV strain, resulting in ~1 million deaths worldwide (3). The fourth pandemic was caused by the influenza A (h2N1) pdm09 virus, also known as the “novel influenza A virus,” and resulted in 151,700–575,400 deaths worldwide from 2009 to 2010 (4, 5). Since that time, the novel influenza A virus has continued to spread as a seasonal flu virus. From September 2019 to February 2020, this virus caused at least 34 million flu illnesses and 20,000 deaths. In November 2002, before the fourth influenza A pandemic, an epidemic caused by a betacoronavirus (SARS-CoV) and known as severe acute respiratory syndrome (SARS) began in South China and spread to 29 countries. The SARS outbreak caused ~8,000 infections and 774 deaths before it was contained in July 2003, with a case fatality rate (CFR) of 9.6% (the CFR was ~50% among patients 65 or older) (6). However, since 2004, there have not been any SARS cases reported anywhere in the world. In September 2012, Saudi Arabia reported the first case of Middle East respiratory syndrome (MERS), which was caused by another type of betacoronavirus (MERS-CoV). MERS-CoV spread to 27 countries and caused 2,519 infections and 866 deaths by January 2020, with a CFR of 34.4% (7).

    In December 2019, cases of the new coronavirus disease 2019 (COVID-19), caused by a new betacoronavirus (SARS-CoV-2), were first reported in Wuhan, China (8). These cases were characterized by acute pneumonia-associated symptoms, such as fever, dry cough, chills, shortness of breath, and muscle pain (9). The SARS-CoV-2 outbreak rapidly spread worldwide. It has infected more than 14 million individuals and resulted in more than 500,000 deaths as of 20 July 2020. In comparison with the other two coronaviruses, SARS-CoV-2 appears to be much more contagious and infectious; it has rapidly resulted in a pandemic constituting a global health emergency (Figures 1A–C).

    Figure 1. General characteristics of SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A viruses. (A) Epidemics of SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A viruses. The timeline, natural reservoirs, total number of deaths, and symptoms of the patients infected with these viruses. (B) Cumulative numbers of cases and deaths caused by SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A (during the last seasonal flu 2019–2020) viruses. Influenza A virus infected the most people, while SARS-CoV-2 caused the most deaths. (C) Case-fatality rate (CFR) of patients infected with SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A (the last seasonal flu 2019–2020) viruses stratified by age.

    To better understand the current COVID-19 pandemic caused by SARS-CoV-2, we have performed a comparative study between SARS-CoV-2 and past epidemic/pandemic viral infections that primarily affect the respiratory system: the influenza A viruses (h4N2 and h2N1 strains) and the two coronaviruses SARS-CoV and MERS-CoV. We have explored the genomic characteristics, transmission, reservoirs, and pathogenesis of these four pathogens. We have also considered the preventive and control measures conducted by the World Health Organization (WHO) against the spread of these pathogens. Additionally, we have elucidated how these viruses attack the immune system and the associated host immune system response. This comparative study will aid in informing public health administrators and medical experts on how to adequately distinguish between these viruses and identify the preventive and control measures recommended by the WHO against the spread of SARS-CoV-2.

    A brief comparison between the four pathogenic viruses, including their characteristics, pathogenesis, and transmission, is summarized in Table 1.

    Table 1. General characteristics of SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A viruses.

    Taxonomy, Structure, and Genomic Properties of the Viruses

    Influenza A

    Influenza A viruses that infect humans mainly consist of two strains (h2N1 and h4N2). Both strains are characterized as enveloped, negative-sense, single-stranded RNA viruses with a total genome size of ~13.5 kb (18, 19). The influenza A virus genome consists of eight different segments, with each segment containing a region that encodes one or two proteins with specific functions, including hemagglutinin (HA), polymerase basic protein 2 (PB2), nucleoprotein (NP), polymerase basic protein 1 (PB1), neuraminidase (NA), matrix (M), nonstructural protein (NS1), and polymerase acidic protein (PA) (20, 21).

    The HA protein of influenza A viruses binds to the glycoprotein terminal sialic acid and glycolipid receptors, which contain α-2,6 and α-2,3 sialic acid groups attached to galactose. Although HA is considered to be a more crucial antigenic determinant than NA, both proteins are potentially restrictive factors for viral evolution (20, 22). In addition, there are three viral polymerase proteins, PB1, PB2, and PA, encoded on segments 1, 2, and 3, respectively; these polymerase proteins form an enzyme complex that plays a role in transcription and replication. Finally, the NP protein encoded on segment 5 is used as a model to generate additional copies (23, 24).

    Influenza A viruses exhibit antigenic drift/shift properties, allowing them to avoid the host immune response. The Centers for Disease Control and Prevention (CDC) defines antigenic drift as genetic variation that occurs in antigen structures owing to point mutations in the HA and NA genes over time, whereas antigenic shift is the result of a sudden genetic reassortment between two or more closely related influenza viral strains (23, 24). A well-known example of the antigenic shift phenomenon is the triple reassortment that occurred in the influenza A pdm09 virus and caused the 2009 pandemic as a result of the replacement of the hemagglutinin h3 and polymerase PB1 genes of the avian h3N2 virus with two new avian h4 and PB1 genes (25, 26) (Figure 2A). These antigenic drift/shift properties can potentially reduce the effectiveness of vaccines and become a considerable challenge in antiviral therapy (27, 28).

    Figure 2. Influenza A evolution. (A) Triple reassortment influenza A viruses of the h2N1 subtype containing avian, swine, and human gene segments. The colored solid genes represent the gene segments as follows: yellow, classical swine A (h2N1) virus; green, North American avian virus; blue, human A (h4N2) virus; gray, Eurasian avian-like swine A(h2N1). (B) Reservoirs and interspecies transmission events of the pathogenic influenza A viruses. Wild birds, domestic birds, pigs, horses, and humans maintain their influenza A viruses. Spillover events occasionally occur, most frequently from wild birds (arrows in green).

    SARS-CoV

    The coronavirus family is so named because of the large spike protein molecules that are present on the virus surface and gives the virions a crown-like shape; coronavirus genomes are the largest among RNA viruses (29). This family has been classified into at least three primary genera (alpha, beta, and gamma). Within this family, seven viruses are currently known to infect humans, namely, NL63 and 229E from the alpha genus and OC43, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2 from the beta genus. SARS-CoV is a positive-stranded RNA virus belonging to the family Coronaviridae (30), order Nidovirales, genus Betacoronavirus, lineage B (from the International Committee on Taxonomy of Viruses). It was characterized as a giant, enveloped, positive-stranded RNA virus with a genome comprising 29,727 nucleotides (~30 kb), 41% of which are guanine or cytosine. The genomic body of this virus has the original gene order of 5′-replicase (rep), which makes up approximately two-thirds of the genome and consists of the large genes ORF1a and ORF1b. ORF1a and ORF1b of the rep gene encode two large polyproteins known as pp1a (486 kDa) and pp1ab (790 kDa). In addition, the 3′ structural spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins are encoded by four open reading frames (ORFs) downstream of the rep gene (31). The rep gene products are translated from genomic RNA, whereas the remaining viral proteins are translated from subgenomic mRNAs. In addition to the original genes, the SARS-CoV genome encodes another eight putative accessory proteins, known as ORFs 3a, 3b, 6, 7a, 7b, 8a, 8b, and 9b, which vary in length from 39 to 274 amino acids. Although the SARS-CoV rep gene and structural proteins have some sequence homology with other coronaviruses, the accessory proteins do not show substantial homology to the viral proteins of other coronaviruses at the amino acid level (31).

    MERS-CoV

    Although MERS-CoV belongs to the same family, order, and genus as SARS-CoV, it was the first betacoronavirus lineage C member identified as a “novel coronavirus” with a genome size of 30,119 nucleotides. The genome of MERS-CoV encodes 10 proteins. These 10 proteins comprise two replicase polyproteins (ORF1ab and ORF1a), four structural proteins (E, N, S, and M), and four nonstructural proteins (ORFs 3, 4a, 4b, and 5) (32). In addition to the rep and structural genes, there are accessory protein genes interspersed between the structural protein genes that may interfere with the host innate immune response in infected animals (7).

    SARS-CoV-2

    Although SARS-CoV-2 belongs to the same family and genus as SARS-CoV and MERS-CoV, genomic analysis revealed greater similarity between SARS-CoV-2 and SARS-CoV. Thus, researchers classified it as a member of lineage B (from the International Committee on Taxonomy of Viruses). Initially, the Coronaviridae Study Group of the International Committee on Taxonomy of Viruses identified this virus as a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus. Later, it was labeled as SARS-CoV-2 (33). The RNA genome size of SARS-CoV-2 is 30,000 bases in length. Among other betacoronaviruses, this virus is characterized by a unique combination of polybasic cleavage sites, a distinctive feature known to increase pathogenicity and transmissibility in other viruses (34).

    Genomic analysis of SARS-CoV-2 revealed that the genome consists of six major ORFs and shares less than an 80% nucleotide sequence identity with SARS-CoV. However, the seven conserved replicase domains in the ORF1ab amino acid sequence share a 94.4% identity with those in SARS-CoV (35). Genomic analysis also revealed that the SARS-CoV-2 genome is highly similar to that of the bat coronavirus (Bat CoV RaTG13), with a sequence identity of 96.2%. Furthermore, the receptor-binding spike protein shares a 93.1% similarity to Bat CoV RaTG13 (35). Meanwhile, relative to SARS-CoV, significant differences were observed in the sequence of the S gene of SARS-CoV-2, including three short insertions in the N-terminal domain, changes in four out of five of the crucial residues in the receptor-binding motif, and the presence of an unexpected furin cleavage site at the S1/S2 boundary of the SARS-CoV-2 spike glycoprotein. This insertion is a novel feature that differentiates SARS-CoV-2 from SARS-CoV and several SARS-related coronaviruses (SARSr-CoVs) (36).

    Viral Origin and Evolution

    Influenza A

    Influenza A h2N1 and h4N2 subtype viruses are two of the three combinations known to have circulated widely in humans and to currently cause seasonal influenza; these strains originated from birds and swine. Before 1979, the only lineage detected in swine herds from Europe was the classical swine influenza virus A h2N1 lineage 1A (25). This strain shares a mutual ancestor with the virus that caused the 1918 human influenza A pandemic. However, in the early 1980s, the classical swine h2N1 strain was displaced by a new European enzootic swine influenza A viral strain: the Eurasian, avian-like h2N1 (h2avN1) lineage 1C (26). After its rapid transmission from birds to mammals, the h2avN1 virus underwent rapid and sustained adaptation in mammals. Furthermore, this virus has also undergone rapid reassortment, resulting in the appearance of multiple genotypes. The two primary enzootic subtypes are h2N2 (h2huN2) lineage IB and h4N2, which occurred through the acquisition of HA or NA gene segments originating from seasonal human influenza viruses (Figure 2B) (37).

    As previously mentioned, influenza A exhibits antigenic drift/shift phenomena resulting from the HA protein’s ability to undergo rapid evolution because of the plasticity of the viral RNA-dependent RNA polymerase. It is believed that mutations occurring in the HA protein, including reassortments and mutations among animals and humans, were the drivers of previous pandemics (38).

    Adaptive mutations can lead to a number of phenotypic changes, including variations in antigenicity, increased diversity in viral protein sequences, the ability to avoid antibody pressure, receptor preference, virulence, altered fusion functionality, and evasion of the immune response. Rapid modifications can give rise to new strains with features that are different from any viruses that have previously been confronted, potentially causing another epidemic/pandemic (38).

    SARS-CoV

    In the early stages of the SARS outbreak, most of the new patient cases had animal exposure before developing the disease. Wide-ranging investigations revealed that SARS-CoV strains were transmitted to palm civets from other animals (39–41). Later, two studies reported the discovery of coronaviruses related to human SARS-CoV, which were named SARS-like coronaviruses or SARSr-CoVs, in horseshoe bats (genus Rhinolophus) (42, 43). Another study revealed that the viral strains of the SARS-like coronaviruses contain all of the genetic elements that are needed to form SARS-CoV. In particular, the bat strain WIV16, the closest relative to SARS-CoV, likely occurred through recombination of two other prevalent bat SARSr-CoV strains. These results suggest that bats may be the natural reservoirs for the virus and that palm civets are only intermediate hosts (Supplementary Figure 1) (44, 45).

    Thus, the hypothesis formed was that the direct ancestor of SARS-CoV was produced by recombination within bats and then transmitted to palm civets or other mammals via fecal–oral transmission. When virus-infected civets were transported to Guangdong market, the virus spread among the civets in the market and underwent further mutations before transmission to humans (46).

    MERS-CoV

    Unlike the SARS cases, most of the MERS cases had previous contact with dromedary camels. The MERS-CoV strains isolated from camels were almost identical to those isolated from humans (47, 48), and the MERS-CoV isolates were found to be highly prevalent in camels from the Middle East, Africa, and Asia (49, 50). Genomic sequence analysis indicated that the Tylonycteris bat coronaviruses HKU4 and HKU5 are phylogenetically related to MERS-CoV (they are all representatives of betacoronavirus lineage C) (51). Generally, all of the related MERS-CoVs isolated from bats support the hypothesis that MERS-CoV originated from bats (Supplementary Figure 1) (46).

    SARS-CoV-2

    Before the epidemic outbreak of COVID-19 in late January 2020, several patients had been exposed to different animals (from wild animals to poultry) at the Huanan seafood wholesale market. When the CDC declared the situation to be an epidemic, several studies identified potential reservoirs, but at present, the origin and evolution of SARS-CoV-2 remain debatable. The earliest genomic sequence analysis of SARS-CoV-2 indicated that it is a member of the genus Betacoronavirus and falls within the subgenus Sarbecovirus, which also includes SARS-CoV (9, 35, 52–54). As mentioned above, preliminary comparisons revealed that SARS-CoV-2 has an almost 79% similarity with SARS-CoV at the nucleotide sequence level and a 96% similarity with horseshoe bat RaTG13 (55–57). Correspondingly, a comparative study between the RmYN02 virus from Rhinolophus bats in Yunan Province, China, and SARS-CoV-2 indicated that RmYN02 was the closest relative to the long replicase gene of SARS-CoV-2 (~97% nucleotide sequence similarity) (35, 36).

    Even though bats are likely to be the reservoir host for this virus, their general biological differences from humans make it feasible that other mammalian species acted as intermediate hosts, in which SARS-CoV-2 obtained some or all of the mutations needed for effective human transmission. One of the suspected intermediate hosts, the Malayan pangolin, harbors coronaviruses showing high similarity to SARS-CoV-2 in the receptor-binding domain, which contains mutations believed to promote binding to the angiotensin-converting enzyme 2 (ACE2) receptor and demonstrates a 97% amino acid sequence similarity. By contrast, the genomic similarity was more divergent from SARS-CoV-2 (~91%) at the whole genome level (Supplementary Figure 1) (58, 59).

    Coronaviruses have lower mutation rates than other RNA viruses, especially influenza A viruses, and high rates of viral replication within hosts because of the 3′-to-5′ exoribonuclease activity associated with the nonstructural protein nsp.14 (36, 60). This protein has an RNA proofreading function and is responsible for coronaviruses’ resistance to RNA mutagens (60, 61).

    Receptor Binding of Viruses

    The high unpredictability among influenza A viral strains and their HAs relates to the significant discrepancy among host cells in showing different vulnerabilities to viral infection. HA plays a role in mediating the binding of influenza A viruses to sialic acid host cell receptors (62). The receptor-binding site lies at the top of the R domain of HA and contains exceptionally variable antigenic binding loops (63). Once the virus is bound to the host receptor, endocytosis of the virus element occurs. Additionally, a pH-dependent membrane fusion process is significant in controlling the viral genome’s release into the host cell. Influenza A viral strains and their HAs are very variable, which contributes to the significantly different vulnerabilities of host cells to viral infection (64).

    Influenza A viruses have demonstrated dominant genomic mutations, such as those within the HA 220 loop (Q223) and the D222G and D222N mutations, in which aspartic acid (D) is replaced by glycine (G) or asparagine (N), respectively. The D222G mutation is responsible for a change in receptor-binding affinity that enables the virus to bind to α-2,6 and α-2,3 sialic acid receptors on the epithelial cells of the upper respiratory tract and ciliated epithelial cells in the lower respiratory tract, respectively (65, 66).

    Although HA plays a crucial role in receptor binding and concurrent mutation capabilities, NA also has a key role in removing sialic acids from cellular receptors and from the new HA and NA on budding virions, which are sialylated as part of the glycosylation processes within the host cell (67). A balance between HA and NA is essential for viral fitness. Any mutations in HA or environmental changes, such as low pH conditions, can affect NA’s activity against sialoglycans (68, 69).

    The SARS-CoV trimeric spike protein facilitates coronavirus entry into host cells by binding to the host receptor and subsequently fusing the viral and host membranes. The spike protein consists of three segments, one of which is the ectodomain (70). The ectodomain is composed of two subunits: S1 and S2. The S1 subunit contains two individual domains, an N-terminal domain (NTD) and a C-domain, and each NTD or C-domain (sometimes both) binds to the host receptor to function as the receptor-binding domain (RBD). ACE2 is the host cell receptor of SARS-CoV and the primary target of deactivating antibodies. Several studies have shown that the binding affinity between the RBD of each SARS-CoV strain and ACE2 positively correlates with the contagion of different SARS-CoV strains in host cells (Supplementary Figure 2) (71, 72).

    The MERS-CoV spike protein subunit S1 C-domain has also been identified as the RBD (73). However, unlike SARS-CoV, MERS-CoV uses a dipeptidyl peptidase 4 (DPP4) β-propeller as its receptor. Likewise, the RBD of MERS-CoV contains an accessory subdomain that functions as the receptor-binding motif (RBM). Although the RBD core structures are remarkably analogous between MERS-CoV and SARS-CoV, their RBMs are distinct and may result in the recognition of different receptors (Supplementary Figure 2) (73).

    Since the outbreak of SARS-CoV-2, several studies have analyzed its genome and compared it with other coronaviruses, such as MERS-CoV and SARS-CoV (74, 75). The results of these studies have shown that SARS-CoV-2 has a similar RBD structure to that of SARS-CoV, despite amino acid variations at some key residues (9). Genomic comparison of SARS-CoV-2 with SARS-CoV and bat SARS-like coronaviruses revealed that the S1 subunits of the spike proteins have a sequence identity of ~75%, and recent experimental studies confirmed that ACE2 is the human receptor of SARS-CoV-2 (34). Therefore, it is essential to characterize the human receptor-binding capacity of SARS-CoV-2 to evaluate its human–human transmissibility. A recent study used the protein–protein docking method to measure the interaction between the SARS-CoV-2 spike RBD and ACE2; it was revealed that the SARS-CoV-2 human receptor-binding affinity was 73% of that of SARS-CoV, which suggests that SARS-CoV-2 binds to ACE2 with intermediate affinity (76) (Supplementary Figure 2).

    Host Factors, Disease Severity, and Pathogenesis

    Influenza, SARS, and MERS have caused major global health threats, and now the COVID-19 pandemic is rapidly spreading worldwide and is having a widespread and profound impact. Both viral and host factors determine the severity and clinical outcomes of the diseases caused by these viruses. Host factors include host immunity, age, sex, morbidities, and genetic variations.

    Influenza infections can cause high morbidity and mortality rates in the elderly (65 or older) and young populations with comorbidities (Figure 1C). Pathogenesis following influenza A infection occurs in two stages. The first stage is defined by the peak viral titer, along with the peak amount of inflammation associated with the infection, and lasts ~1 to 3 days. In the second stage, the infection progresses in some patients, and in severe cases, it may be associated with acute respiratory distress syndrome and sometimes death (77). Once a patient is infected with an influenza A virus, the humoral immune response will release neutralizing antibodies to target the influenza HA protein by blocking the binding of HA to sialic acids, thereby preventing viral fusion, inhibiting the release of offspring virions, and delaying proteolytic cleavage of HA by host receptors (78).

    Once a patient is infected with SARS-CoV, MERS-CoV, or SARS-CoV-2, the host innate immune system will identify the virus by using pattern recognition receptors, such as a toll-like receptor, NOD-like receptor, or RIG-I-like receptor, to recognize pathogen-associated molecular patterns. The adaptive immune response also plays a significant antiviral role by stabilizing the host defense mechanism against pathogens and minimizing the risk of developing an autoimmune reflex response or inflammation (9, 79). In general, human coronaviruses can be classified into two types: lowly pathogenic and highly pathogenic. Viruses with low pathogenicity, including HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU, can cause mild upper respiratory tract infections. In contrast, highly pathogenic viruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2, can cause lower respiratory tract infections, severe pneumonia, and sometimes fatal acute lung injury or acute respiratory distress syndrome, especially in older individuals (≥65 years old) (Figure 1C) (80).

    In addition to the lungs, coronavirus infection may damage other organs or tissues, including the gastrointestinal tract (81), spleen, lymph nodes, brain, skeletal muscles, thyroid, and heart (82, 83). The destruction of lung cells prompts a local immune response, engaging macrophages and monocytes that respond to the infection, release cytokines, and enhance adaptive T and B cell immune responses. In some cases, a dysfunctional immune response occurs, which can cause severe lung and systemic pathology. The invading coronavirus may incite host immune responses, and an excessive immune response may cause immunopathological damage (known as a cytokine storm) in patients with coronavirus infections (9, 84). Cytokine storms may enhance the infiltration of non-neutralizing antiviral proteins that facilitate viral entry into host cells, leading to increased viral infectivity (82, 85). Therefore, cytokine storms play a key role in the pathogenesis and clinical outcomes of patients with coronavirus infection.

    Transmissibility and Virulence

    The initiation of a pandemic requires the rise of a virus in a human population in which there is little or no pre-existing immunity, and the virus must be able to persist through human-to-human transmission (86, 87). The ability of influenza A viruses to adapt to various hosts and undergo reassortment events ensures the constant generation of new strains. These strains have variable degrees of pathogenicity, pandemic transmissibility, and reproduction numbers (R0) (Table 1) (88). However, only three subtypes of influenza A (h2–h4) have acquired the properties to cause pandemics in the last two centuries. Thus, an understanding of the capability of a virus to attain a contagious phenotype is a critical factor in evaluating the pandemic potential of novel subtypes (89, 90). The use of animal models has facilitated detailed studies of influenza A virus transmission by the contact and respiratory droplet routes. The presence of a single sick individual in a small space, such as an airplane or room, has been shown to be adequate for an outbreak among healthy individuals (Supplementary Figure 3) (91). Although infection and case fatality rates vary from one pandemic to another, the rates of influenza A virus infections in the pandemics were high, especially among people with little to no pre-existing immunity. When pandemic viruses become established in humans, their effective seasonal spread among healthy individuals eventually provides an enduring and even more significant public health issue in terms of hospitalizations and, in some cases, fatalities. Particle size (92), the distance of spread (92), disposition (92, 93), temperature (94), and relative humidity (95) are all considered to be factors that influence the rate of transmissibility of influenza A viruses. In addition, sialic acid receptors (α-2,3 and α-2,6) can affect the general species-specific cellular tropism of influenza A viruses (63).

    Contaminated surfaces also play an essential role in transmission. A respiratory pathogen can survive on surfaces, be transferred to hands or other equipment, and initiate infection through contact with the eyes, nose, or mouth (Supplementary Figure 3) (96). Influenza A has been shown to survive for 24–48 h on stainless steel and plastic surfaces. Inversely, the strains survived for <8–12 h on cloth, paper, and tissues. Quantifiable amounts of influenza A viruses were observed to be transmitted from stainless steel surfaces to hands after 24 h and from tissues to hands for up to 15 min. Viruses also survive on hands for up to 5 min after transfer from environmental surfaces. These results indicate a high transmission rate for influenza A viruses (97).

    SARS-CoV, MERS-CoV, and SARS-CoV-2 can survive on surfaces for extended periods, sometimes up to months. Like the influenza A viruses, the factors affecting the survival of these viruses on surfaces include the strain variation, titer, surface type, mode of deposition, temperature, humidity, and method used to determine the viability of the virus (98, 99). Several studies have indicated that SARS-CoV, MERS-CoV, and SARS-CoV-2 can survive on dry surfaces for a sufficient duration to accelerate onward transmission. Viable MERS-CoV was detected on steel and plastic surfaces after 48 h at 20°C with 40% relative humidity, with a decreased viability of about 8 h at 30°C with 80% relative humidity and of about 24 h at 30°C with 30% relative humidity. The estimated half-life of MERS-CoV ranges from ~0.5 to 1 h (98). On the other hand, another study conducted on the viability of SARS-CoVs detected on plastic surfaces and on polystyrene Petri dishes revealed that the virus survived for more than 5 days and more than 20 days, respectively, at room temperature. The viral viability was constant at lower temperatures (28°C) and lower humidity (80–89%) (100), whereas survival times ranged from 5 min to 2 days on paper, disposable gowns, and cotton gowns (99).

    Since the SARS-CoV-2 outbreak began, several researchers have attempted to analyze the survival time of this virus on different surfaces. One study published in the middle of March 2020 analyzed the aerosol and surface stabilities of SARS-CoV-2 and SARS-CoV. The study utilized five different environments (aerosols, plastic, stainless steel, copper, and cardboard). The results showed that the half-lives of SARS-CoV-2 and SARS-CoV were similar in aerosols and on copper. However, on cardboard surfaces, the half-life of SARS-CoV-2 was longer than that of SARS-CoV, and the highest levels of viability for both viruses were observed on stainless steel and plastic (~5.6 h on stainless steel and 6.8 h on plastic). The researchers concluded that the differences in the epidemiological characteristics of these viruses could result from other factors and that aerosol and fomite transmission of SARS-CoV-2 is probable because the virus can remain viable and infectious in aerosols and on surfaces for hours and hours to days, respectively (101).

    The effective management and control of such infections are increasingly performed with extensive contributions from mathematical modeling, which not only provides information on the nature of the infection itself but also makes predictions about the likely outcome of alternative courses of action (102). One useful mathematical model is the reproductive number R0, which is defined as the average number of secondary cases generated per typical infectious case (103). A value of R0 > 1 indicates that the infection may persist or grow in the population, whereas a value of R0 < 1 indicates that this infection will decrease in the population, although exceptions occur (103). The majority of seasonal influenza R0 values have been calculated for different populations and different continents, such as Europe and North America, with a median point estimate of R0 = 1.27 (IQR: 1.19–1.37) (104). The initial estimations of the reproduction numbers of SARS-CoV and MERS-CoV were calculated for China and the Middle East with R0 median = 0.58 (IQR: 0.24–1.18) (105) and R0 mean = 0.69 (95% CI: 0.50–0.92) (106), respectively. However, among the four viruses, SARS-CoV-2 has been calculated to be the most contagious, such as the R0 value associated with the Italian outbreak with a median point estimate of R0 = 3.1 (coefficient of determination, r2 = 0.99) (107).

    Prevention, Control, and Treatment of Virus Infection

    Strategies for preventing and controlling pandemic/epidemic viruses can be improved by being well-prepared. Preparedness strategies, which primarily include the quarantine of infected persons, self-protection (wearing facemasks, using disinfectants, washing hands, and disinfecting surfaces with bleach or alcohols), and social distancing are all considered to be important for a comprehensive plan that can be tested and promoted by conducting exercises to engage the whole of society.

    An influenza pandemic can be catastrophic, and in a typical year of seasonal outbreaks, influenza A viruses cause as many as 5 million cases of severe illness in humans and over 500,000 deaths. After the first confirmed cases of h2N1 influenza appeared in Mexico in February 2009, cases began to spread to the United States, and by the end of April 2009, cases had been reported in several United States cities and other countries on various continents, such as Canada, the United Kingdom, and New Zealand (108). During the last pandemic, the first activation of the International Health Regulations (IHR) provisions was prompted. The discussions that led to the IHR implementation were based on the SARS outbreak experience in 2003. These regulations describe the responsibilities of individual countries and the leadership role of the WHO in declaring and managing a public health emergency of international concern, establishing systematic approaches to surveillance, promoting technical cooperation, and sharing logistic support (108). However, because of the significant diversity of influenza viruses in animal hosts, extensive experimental testing and the development of pandemic preparedness measures against all viruses is unachievable (109).

    In this regard, the WHO periodically updates the influenza risk management and preparedness plan, and the latest guidance document, Pandemic Influenza Risk Management (PIRM), was released in May 2017 (110). This updated document supports national and global pandemic preparedness and risk management and utilizes lessons learned at the country, regional, and global levels (110). Furthermore, several WHO preparedness documents have been released since PIRM, such as Essential steps for developing or updating a national pandemic influenza preparedness plan (released in March 2018) and A practical guide for developing and conducting simulation exercises to test and validate pandemic influenza preparedness plans (published in September 2018) (111).

    During the SARS epidemic, more than 8,000 people were infected, and 774 deaths occurred between November 2002 and December 2003. SARS is highly contagious and is transmitted primarily by respiratory droplets; the highest transmission rates of SARS occurred in healthcare facilities (112). At the end of the SARS outbreak, the cases of over 1,700 healthcare workers who had been affected were reported to the WHO, from China (19% of total cases), Canada (43%), France (29%), and Hong Kong (22%). During this epidemic, insufficient or inappropriate infection control measures, such as inconsistent use of personal protective equipment, reuse of N95 masks, and lack of adequate infection control, were related to the high risk of infection among healthcare workers (113). Thus, in 2004, after the epidemic was contained, the WHO released a framework that was prepared according to the six phases of an epidemic, moving from preparedness, planning, and routine surveillance for cases, through to the prevention of the consequent international spread, to the disruption of global transmission (114).

    Since 2012, 27 countries have reported cases of MERS; Saudi Arabia has reported ~80% of human cases, and more than 50% of the cases in healthcare workers were nurses (115). The WHO, in collaboration with the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and national governments, have been working with healthcare workers and scientists in affected countries to gather and share scientific evidence based on the previous coronavirus epidemic. This information gathering process has been beneficial for better understanding of the virus and the disease it causes and for the regulation of outbreak response priorities, treatment approaches, and clinical management tactics (113).

    Although accumulated knowledge and risk preparedness from the influenza pandemics and SARS/MERS epidemics allowed researchers to examine the effectiveness of strategic plans in dealing with the ongoing pandemic of COVID-19, several challenges have been raised in preventing the spread of COVID-19, such as the lack of medical supplies and laboratory facilities for the assessment of the disease and the presentation of a high number of asymptomatic cases. In response to the announcement of the emergency, governments were bound by the IHR to disclose vital information regarding the identification and detection of COVID-19, regardless of the causative agent. Within the context of the Global Humanitarian Response Plan, a Health Cluster platform has been created to assess the response to the COVID-19 pandemic worldwide. This framework has adopted the following strategies: contain the spread of the COVID-19 pandemic and decrease morbidity and mortality; decrease the deterioration of human assets and rights, social cohesion, and livelihoods; and protect, assist, and advocate for refugees, internally displaced people, migrants, and host communities who are particularly vulnerable to the pandemic (source: WHO). The primary goal of the Health Cluster is to coordinate and support partners to fulfill essential health services to achieve the framework strategies. This goal is achieved by different roles and tasks, such as by raising awareness, alertness, and response planning at the country level and by conducting training and simulation exercises. The WHO Health Cluster framework is a gateway to useful resources to support COVID-19 preparedness and response (116).

    Generally, each pandemic/epidemic has presented a public health emergency of uncertain scope and effect; thus, essential elements of current approaches to pandemic preparedness and extenuation, such as the development of vaccines and stockpiling of antiviral drugs, necessitate detailed virological and immunological data on viruses with apparent pandemic potential. However, the development of vaccines against new strains is challenging. Therefore, physicians and health workers have found themselves facing the massive challenge of preventing infections or stabilizing patients’ conditions. Thus, several promising attempts have been made to utilize different antiviral treatments that have already been approved by the U.S. Food and Drug Administration (FDA) for the treatment of viral pneumonia infections. A list of antiviral drugs and vaccine approaches for influenza viruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 that have been used in clinics or are undergoing clinical trials are summarized in Table 2.

    Table 2. List of antiviral drugs and vaccine approaches for SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza viruses.

    Discussion and Conclusion

    Although the mode of transmission for SARS-CoV-2 is still somewhat unclear, all four viruses are thought to be transmitted by the same mechanism. Infection via respiratory droplets or secretions of infected individuals is the primary mode of transmission between humans. The spread of infection is occurring more rapidly for the current outbreak than in the SARS and MERS epidemics, although rates of human-to-human transmission were generally lower for MERS.

    The CFRs across the four viruses range from 0.1 to 35% (Table 1), with the highest rate for MERS cases and the lowest for seasonal influenza; however, it is essential to note that the CFR for COVID-19 should be interpreted carefully because the outbreak is still ongoing.

    With the exception of the influenza A viruses, the other viruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) are similar in zoonotic transmission. The MERS-CoV reservoir hosts are dromedary camels, and the SARS-CoV reservoir hosts are likely bats. It is still unclear whether SARS-CoV-2 was zoonotically transmitted from an infected palm civet, snake, or other animal at the Chinese seafood market.

    Regarding the origin of the virus, SARS-CoV and SARS-CoV-2 originate from China and share a high degree of similarity, including exposure to wild animals, whereas MERS-CoV and SARS-CoV-2 have shared similarities in that cases can remain asymptomatic while still spreading the disease. Furthermore, influenza A viruses and SARS-CoV-2 also have a similar characteristic when it comes to transmissibility (127).

    In the setting of extensive SARS-CoV-2 transmissions, the possibility of SARS-CoV-2 should be considered in all persons with a fever or lower respiratory infection, because it is challenging to straightforwardly distinguish between seasonal influenza and COVID-19, even if an epidemiologic link cannot be readily established. Furthermore, the timely reporting of cases, updates on clinical status and disposition of patients, the real-time analysis of data, and the appropriate dissemination of information are essential for outbreak-managing decisions.

    Author Contributions

    ZA: conceptualization, methodology, investigation, writing—original draft, and visualization. ML: visualization. XW: conceptualization, methodology, project administration, funding acquisition, writing—review and editing, and supervision. All authors contributed to the article and approved the submitted version.

    Funding

    This work was supported by the China Pharmaceutical University (grant number 3150120001 to XW).

    Conflict of Interest

    The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

    Acknowledgments

    We thank China Pharmaceutical University for its support and funding.

    Supplementary Material

    The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.552909/full#supplementary-material

    Supplementary Figure 1. The origins and intermediate hosts of SARS-CoV-2, SARS-CoV, and MERS-CoV.

    Supplementary Figure 2. Virus-host interaction. Th2, T helper 1; Th27, T helper 17; ACE2, angiotensin-converting enzyme 2; INF-1, interferon 1; INFγ, interferon gamma; DPP4, dipeptidyl peptidase-4; HA, hemagglutinin; NA, neuraminidase; M2e, Matrix 2 protein; MHC-1, major histocompatibility complex class 1.

    Supplementary Figure 3. Potential transmission routes of respiratory infection between infected and susceptible individuals (128). Respiratory infections with a droplet nuclei size ≤ 5 μm can travel to a distance ≥1 m. In contrast, respiratory infections with a droplet nuclei size ≥5 μm cannot travel to a distance ≥1 m. Large droplets may fall on different surfaces and infect healthy individuals through direct or indirect contact.

    Abbreviations

    SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SARS-CoV, severe acute respiratory syndrome coronavirus; MERS-CoV, the Middle East respiratory syndrome coronavirus; WHO, world health organization; CDC, center of disease control and prevention; nt, nucleotide; kb, kilobase; KDa, kilodalton molecular weight unit.

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    Exhaled Aerosol Transmission of Pandemic and Seasonal h2N1 Influenza Viruses in the Ferret

    Abstract

    Person-to-person transmission of influenza viruses occurs by contact (direct and fomites) and non-contact (droplet and small particle aerosol) routes, but the quantitative dynamics and relative contributions of these routes are incompletely understood. The transmissibility of influenza strains estimated from secondary attack rates in closed human populations is confounded by large variations in population susceptibilities. An experimental method to phenotype strains for transmissibility in an animal model could provide relative efficiencies of transmission. We developed an experimental method to detect exhaled viral aerosol transmission between unanesthetized infected and susceptible ferrets, measured aerosol particle size and number, and quantified the viral genomic RNA in the exhaled aerosol. During brief 3-hour exposures to exhaled viral aerosols in airflow-controlled chambers, three strains of pandemic 2009 h2N1 strains were frequently transmitted to susceptible ferrets. In contrast one seasonal h2N1 strain was not transmitted in spite of higher levels of viral RNA in the exhaled aerosol. Among three pandemic strains, the two strains causing weight loss and illness in the intranasally infected ‘donor’ ferrets were transmitted less efficiently from the donor than the strain causing no detectable illness, suggesting that the mucosal inflammatory response may attenuate viable exhaled virus. Although exhaled viral RNA remained constant, transmission efficiency diminished from day 1 to day 5 after donor infection. Thus, aerosol transmission between ferrets may be dependent on at least four characteristics of virus-host relationships including the level of exhaled virus, infectious particle size, mucosal inflammation, and viral replication efficiency in susceptible mucosa.

    Citation: Koster F, Gouveia K, Zhou Y, Lowery K, Russell R, MacInnes H, et al. (2012) Exhaled Aerosol Transmission of Pandemic and Seasonal h2N1 Influenza Viruses in the Ferret. PLoS ONE 7(4):
    e33118.

    https://doi.org/10.1371/journal.pone.0033118

    Editor: Yi Guan, The University of Hong Kong, China

    Received: October 20, 2011; Accepted: February 4, 2012; Published: April 3, 2012

    Copyright: © 2012 Koster et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Funding: This project was funded by the NIAID grant 1U01 AI074561 and NIAID contract HHSN2662004000951. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Competing interests: KL, JC, RS and SH are employees of Ibis Biosciences, An Abbott Company, which developed the technology of the T5000 platform. The current generation of this platform, the Abbott PLEX-ID is a commercially available platform and is protected by various patents including, but not limited to, US Patent Nos. 7,217,510 (issued May 15, 2007), 7,255,992 (issued August 14, 2007), 7,714,275 (issued May 11, 2010), 7,964,343 (issued June 21, 2011), 7,226,739 (issued June 5, 2007), 7,666,592 (issued February 23, 2010), 7,718,354 (issued May 18, 2010), and 7,781,162 (issued August 14, 2010). Ibis Biosciences has developed an Influenza assay for commercial sale which is not for use in diagnostics procedures. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.

    Introduction

    Seasonal influenza virus is a highly contagious respiratory pathogen that causes over one million infections and is associated with approximately 3000 up to 49,000 deaths each year in the United States [1]. Infections due to the 2009 h2N1 pandemic influenza virus were primarily self-limited with the highest attack rates among children and young adults [2]. Future pandemics could theoretically duplicate the high virulence of the 1918 pandemic [3], [4]. In addition to pre-pandemic vaccination, non-pharmaceutical interventions such as social distancing may have important roles in reducing transmission. The current poor quantitative understanding of influenza transmission could impair the development of evidence-based interventions [5], [6].

    Transmission is classified as three modes, by direct contact with infected persons or indirect contact with contaminated fomites, by inhaling large droplets (droplet spray) within a meter of the source, or by small particle aerosols exhaled during talking, coughing or breathing [7], [8]. Reviews of influenza transmission among human populations have concluded that transmission is by contact and droplet spray [9], [10] while others conclude that aerosol transmission contributes significantly to spread of infection [11], [12]. Transmissibility is currently estimated from the spread of influenza in relatively closed populations and is expressed as the number of secondary infections derived from one contagious person (basic reproductive number R0). The R0 for the 2009 h2N1 pandemic strain has been estimated to range from 1.4 to 1.8 [13]–[16], values that overlap with the R0 of seasonal strains of 1.7–2.1 [17] and 1.3–4.9 for the 1918 pandemic [18]. The epidemiological R0, however, is complicated by unmeasured human variables including contact behavior and pre-existing immunity [19].

    A quantitative measure of strain transmissibility independent of human variables would be useful in predicting epidemic potential. Transmissibility in an animal model is the combination of four serial components, first a threshold viral load in the respiratory mucosa of the contagious host, then exhalation of virus, survival of airborne virus, and finally replication kinetics of inhaled virus in susceptible mucosa [20]. Ferrets have served as a transmission model mimicking many features of human transmission [21], [22]. Key viral genotypic features in the hemagglutinin and PB2 segments related to relative transmissibility have been described in multiple subtypes [23]–[27]. Studies of non-contact droplet (aerosol) transmission between ferrets have utilized continuous exposures in a side-by-side cage design to identify relative differences in transmissibility between strains. Under these conditions H5N1 avian-origin viruses were not transmitted [28], whereas seasonal strains were readily transmitted, and pandemic strains were transmitted as readily [29] or less readily [30] than seasonal strains. Recently, the aerosol ID50 has been measured for two seasonal influenza strains in the ferret model [31], [32].

    Our goals in this study included measuring the viral load in the exhaled aerosol under controlled airflow conditions and exposing susceptible ferrets to exhaled aerosols for only 3 hours to approximate the duration of typical human exposures. We examined ferret-to-ferret exhaled viral aerosol transmission for one seasonal and three pandemic h2N1 strains. Ferrets infected with the seasonal virus exhaled higher levels of virus than those infected with the pandemic strains, yet transmission of the pandemic strains was significantly more efficient than the seasonal strain.

    Methods

    Virus

    Three strains of swine-origin pandemic 2009 h2N1 viruses A/California/04/2009 (Cal/04), A/Mexico/4482/2009 (Mex/4482) and A/California/07/2009 (Cal/07), and one seasonal h2N1 strain A/New Caledonia/20/99 (NC/99) were plaque-purified stocks obtained from the Influenza Division, Centers for Disease Control, with a history of two passages in embryonated eggs, and two passages in MDCK cells. Working stocks were prepared from two passages in embryonated eggs, aliquoted, and stored at −80°C up to four months until needed. The 2009 h2N1 viruses (Cal/04:FJ966079; Cal/07:FJ984387; Mex/4482:CY098505) were sequenced after passage to assure preservation of the consensus sequences according to the NIH Influenza Database.

    Virus inocula were titered before inoculation by the focus neutralization assay (FFU) and embryonated egg infection (EID50 or 50% egg infectious dose) and after each inoculation for FFU. Aliquots were thawed at 4°C and diluted in PBS to 106 FFU/mL for ferret inoculation. The titer of 106 FFU was approximately equivalent to 1.2–1×106 EID50 depending on the experiment. Donor ferrets were inoculated intranasally (i.n.) with 106 FFU/mL, 0.5 mL in each naris. In one experiment donor ferrets were inoculated by both the i.n. and intratracheal (i.t.) routes with a combined total dose of 106 FFU/mL. In one experiment donor ferrets were infected by nebulized virus as previously described [32]. Estimated delivered dose was calculated from viral RNA measured in the nebulized aerosol as described in the text.

    Animals

    Outbred castrated male ferrets (Mustela putorius furo) were obtained from Triple F Farms (Sayre, PA) at 12−18 weeks old, were quarantined for 14 days and weighed 1.0–1.2 kg when exposed to the viruses. Ferrets were uniquely identified by ear tags and subcutaneous transponders (IPTT-300; Bio Medic Data Systems Inc, Seaford, Delaware). Ferrets were pair- or triple-housed in plastic cages with perforated plastic bottoms (Model RB 272718UP6 Rabbit cage modified to hold ferrets; Allentown Cage Inc, Allentown, NJ) during the quarantine period but singly housed after viral exposure in ventilated cages to prevent cross infection by isolating the air entering and leaving each cage. Excreta pans under the cages, cage flooring, and room floors were cleaned daily. All procedures were conducted under protocols approved by the Institutional Animal Care and Use Committee (IACUC) at Lovelace Respiratory Research Institute (permit #08-011), all facilities were accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). Guidelines for ferret housing and environment described in the Guide for the Care and Use of Laboratory Animals, Seventh Edition, National Research Council, were strictly adhered to.

    Aerosol Exposure Apparatus

    Two exposure apparatuses were fabricated each consisting of a donor (infected ferret) chamber and a recipient (susceptible ferret) chamber with wire screens between the chambers to prevent direct contact (Figure 1A, B). The slightly smaller apparatus had a 7×7×15 cm long tunnel between the chambers and the larger apparatus had a screened 2 cm passage between the chambers. Air-flow was left-to-right, drawn into the left (donor) chamber at 12 L/min by controlled vacuum. In the tunnel or space between the donor and recipient chambers, three air sampling ports for polytetrafluoroethylene (PTFE) filters (Teflon, 37-mm, 2-m pore-size, Pall Life Sciences, NY) each withdrew 2 L/min, and a fourth port drew 1 L/min into a laser particle counter (Grimm). Air at 6 L/min entered the right (recipient ferret) chamber, was mixed by a fan and was removed through two HEPA filters in the right-side wall. Humidity (RH) and temperature were controlled by ambient laboratory air at approximately 45% (range 41–48) RH and 22°C respectively. After exposure, filters were put in 1ml serum-free media and vigorously vortexed for 20 seconds, the filter removed, a 500µl aliquot placed into 500µl of RNABee (Amsbio, Lake Forest, CA)and frozen at −80°C for RNA extraction, and the remaining fluid was frozen at −80°C for viral culture. After each exposure the chambers were washed with 1% bleach solution followed by repeated isopropyl alcohol rinses to remove all traces of viable virus and viral RNA. For the experiments infecting donor ferrets by nebulized virus, a six-jet Collison generator was loaded with 20 mL Eagles Minimal Essential Media and antifoam (Sigma) as previously described [32].

    Figure 1. Exposure chambers. A

    . Photograph of tunnel exposure chamber occupied by two sleeping ferrets in the left donor chamber and two active ferrets in the right ‘recipient’ chamber. Note that experiments are described with two ferrets in the donor chamber but no experiments were performed with two ferrets in the recipient chamber. A line diagram of this exposure chamber appears in reference 32. Air is drawn through HEPA filters in the left wall of the donor chamber (left side of photograph) passes through the tunnel where particle size and PTFE filter ports are located, and is withdrawn through the recipient chamber (right side) and exits through two ports into HEPA filters (not visible in photograph). B. Exploded view of exposure chamber without tunnel between donor and recipient ferret, designed to more closely approximate conditions of side-by-side cage exposures in published ferret-model aerosol transmission studies.

    https://doi.org/10.1371/journal.pone.0033118.g001

    Clinical Observations

    Following aerosol challenge, ferrets were observed twice daily for symptoms including sneezing, cough, nasal discharge, respiratory distress, reduction in activity, neurologic signs, or abnormal behavior. Activity was scored using standard criteria (0 = alert and playful, 1 = alert but playful only when stimulated, 2 = alert but not playful when stimulated, and 3 = neither alert nor playful when stimulated). Temperature was measured by transponder from two subcutaneous microchips (IPTT-300 Implantable Programmable Temperature and Identification Transponder; Bio Medic Data Systems, Inc, (BMDS) Seaford, DE 19973) implanted over the shoulder and hip regions and recorded by BMDS electronic proximity reader wand (WRS-6007; BMDS) as the average of the two readings twice daily.

    Pathology

    Ferrets were necropsied at protocol-determined intervals after exposure in order to image the gross lung pathology, measure viral load in upper respiratory tract, trachea and lung tissue, and assess the histological extent of infection. Lung lobe samples, trachea, nasal turbinates, liver, spleen, tracheobronchial lymph nodes, brain, and olfactory bulbs were processed for viral load and histopathology; results of extrapulmonary tissues will be reported elsewhere. Tissues for histopathology were fixed in 4% paraformaldehyde, embedded in paraffin, sectioned at 4 to 6 µm, stained with hematoxylin and eosin, and read by a veterinary pathologist without knowledge of the infection history. Selected lung tissue was fixed in methanol prior to incubation with anti-nucleoprotein antibody (Clontech) to correlate location of influenza antigen with histological characteristics of epithelial cell infection.

    Viral Load

    Sample collection, viral culture, RNA isolation, RT-qPCR and T5000™ assays were performed as previously described [32]. Viral load was determined by standard tissue culture on MDCK cells reported as focus-forming units (FFU) and also by real-time quantitative RT-qPCR. For aerosol samples collected from PTFE filters, viral genomic RNA was measured by two PCR-based assays, a standard RT-qPCR detecting nucleocapsid gene RNA (Lovelace Respiratory Research Institute [LRRI]), and a more sensitive experimental RT-PCR-based system using time-of-flight mass spectroscopy analysis of amplimers to detect six influenza A segments (T5000TM Biosensor System, Ibis Biosciences, Abbott Molecular) [33], [34]. Since recipient nasal washes were not cultured daily, but recipients had persistently positive viral RNA assays in daily throat swabs, infection was defined either by positive culture or by positive viral RNA levels >107 genome equivalents (Geq) for three or more consecutive days [32]. Data on viral RNA in aerosol samples are reported only for the more sensitive T5000 assay unless noted as a comparison of the two assays.

    Calculation of Inhaled Virus

    The viral RNA collected from the aerosol and analyzed by the T5000 assay was used to calculate the infectious virus dose inhaled by the exposed recipient ferret according to the formula:

    Virus inhaled = (Geq vRNA/h)*(FFU/Geq ratio)*(MV/filter sample flow rate).

    The FFU/Geq ratio was derived from 4 Teflon filter collections of high levels of aerosolized virus with positive culture and viral RNA data. The fraction of air inhaled was calculated from the minute ventilation (MV) divided by the airflow/min entering the recipient chamber (6 L/min). Minute ventilation was estimated from unpublished data and literature reports, adjusted for ferret weight and sedation status. For anesthetized ferrets weighing 280 g and 560 g, tidal volumes (TV) have been reported as 4.0 and 6.0 mL, respectively [35], [36]. TV for our ferrets weighing between 1.0 and 1.2 kg was calculated as 9.0 mL according to the ¾-power relationship between body weight and lung volume. The breathing rate (RR) was observed to be a mean of 35/min (range 28–43), and the lack of sedation was adjusted by multiplying the TV by 1.5 (J Mauderly, personal communication), yielding a calculated MV (TV*RR*1.5) of 472 mL/min.

    The aerosol ID50 was estimated using Proc Probit in SAS 9.1 (Cary, NC) employing data from Figure 7 on calculated inhaled virus and whether or not the recipient ferret was infected according to criteria described in Methods, viral load.

    Results

    Aerosol Characteristics

    Sampling of aerosol particles entering the recipient chambers showed similar particle size profiles for the two exposure chambers (Figure 2) except for the largest particles. The fraction of airborne particles >5 µm reaching the recipient chamber was 0% in the side-by-side exposure apparatus and 1% in the tunnel exposure apparatus. Total number of aerosolized particles per minute passing through the tunnel varied markedly during the typical 3-hour exposure, depending in part on the observed activity of the donor ferret (Figure 3).

    Figure 2. Distribution of particle dimensions delivered to recipient chamber.

    Particle diameter measured by laser light scattering plotted as log10 particles per liter of air divided into 24 diameter cohorts ranging from 0.25 microns to 12.5 microns. Particles sampled during 10 min. intervals with sampling airflow at 1.0 Lt/min and with one resting ferret infected with Cal/04 virus in donor chamber. Top graph: In side-by-side chamber sampling collected during the middle (green) and end (blue) of the same exposure period, and during an interval of no directed airflow when vacuum is off (control, red) particle numbers of all size cohorts decreased more than 100-fold. Bottom graph: In tunnel exposure chamber samples collected during first hour (blue), second hour (red) and third hour (green) of continuous 3 hour exposure.

    https://doi.org/10.1371/journal.pone.0033118.g002

    Figure 3. Particle Concentration variation during chamber exposure.

    Airborne particles were measured continuously by Grimm spectrometer and recorded as particles per liter of air in this typical exposure. Particle numbers per second vary over two orders of magnitude.

    https://doi.org/10.1371/journal.pone.0033118.g003

    Exhaled Aerosol Transmission Required a Donor Threshold Viral Load

    Pairs of donor ferrets were infected i.n. with 106 FFU of Cal/04 and 3 recipients were exposed in the tunneled chambers to the donor pair for 3 h approximately 24 h after donor infection. Exposures to ferrets with low viral loads in nasal wash (Figure 4, left graph) did not result in transmission indicated by negative cultures in the recipients, whereas exposure to culture-positive ferrets resulted in transmission and positive nasal wash cultures (right graph). Positive cultures in the donors and recipients correlated with levels of viral RNA >107 GEq in these experiments reported here and for a seasonal h2N1 virus [32]. Thus the level of mucosal viral load in the donor determined in part donor contagion under these experimental conditions.

    Figure 4. Exhaled aerosol transmission requires a donor threshold viral load.

    Two pairs (designated A and B) of donor ferrets (designated donor1 and donor2 of pair A, donor3 and donor4 of pair B) were infected i.n. and i.t. with a total dose of 106 FFU of Cal/04. Three recipients (R1, R2, R3 exposed to pair A; R4, R5, R6 exposed to pair B) were exposed individually to one of the donor pairs for 3 h approximately 24 h after donor infection. Exposures to donor ferrets Donor1 and Donor2 with low viral loads in nasal wash (green and red, left graph) did not result in transmission indicated by negative cultures (yellow squares) in each of the 3 recipients, whereas exposure to ferrets with higher titers of nasal wash virus (red bar) resulted in transmission and positive nasal wash cultures (yellow bars, right graph). Viral RNA (‘PCR’) is expressed as genome equivalents/mL nasal wash; Viral culture (‘virus’) is expressed as FFU/mL nasal wash.

    https://doi.org/10.1371/journal.pone.0033118.g004

    Comparison of Transmission after Exposures for 3 or 20 Hours

    To compare previously published continuous exposures (>24h) in side-by-side cages [26]–[31] with 3 h exposures in similar cages, donor ferrets were infected i.n. with 106 FFU of Cal/04, and one day later susceptible ferrets were exposed to donor exhaled viral aerosols. Infection was monitored by nasal washes twice and throat swabs daily for 5-days post-exposure (dpe) (Figure 5). The two recipients exposed for 20 hours lost weight and had high levels of viral RNA for 5 days. In contrast, recipients exposed for only 3 hours had lower levels of viral RNA in the throat below the threshold of infection.

    Figure 5. Aerosol transmission is more efficient after 20 h- than 3 h- exposures.

    Viral RNA (log10 genome equivalents (GEq) in total sample) in throat swabs from four donors (Do, red) infected intranasally 24 hours previously with Cal/04, and in four recipients (R, blue) each exposed to exhaled aerosols of one of the donors for either 3 hours (A and B) or 20 hours (C and D).

    https://doi.org/10.1371/journal.pone.0033118.g005

    Contagion Induced by Nebulized Virus

    Infection of donor ferrets by the intranasal route versus inhalation of nebulized virus could possibly induce differing efficiencies of contagion. Two donor ferrets were infected during a 1-hour exposure to nebulized Cal/04 virus, calculated to deliver a dose of 106 FFU approximating the intranasal doses used above. In contrast to intranasal inoculation donors infected by nebulized virus had decreased activity 2−6 days post-inhalation (dpi), sneezing 2−7 dpi, diarrhea 2−8 dpi, elevated temperature >2.5°C above baseline at 5 dpi and loss of 6% and 11% of body weight, respectively. Each ferret exposed to one donor in the chamber continuously for four days had temperature elevations >2.0°C on dpi 3−7 and 5, respectively, and loss of 5.6% and 7.7% body weight, respectively, but without sneezing or diminished activity. Donors had high viral load in the throat at 1 dpi after nebulized virus exposure, whereas the recipient ferrets had high viral load delayed until 4 days post-exposure (dpe) after exhaled aerosol exposure (Figure 6A). Donor-exhaled viral RNA aerosol levels were highest at 1 dpi and were quantitatively similar to the nebulized viral RNA levels delivered to the donors during the 1-hour exposure at 0 dpi (Figure 6B). Thus, contagion induced by nebulized virus appeared to be at least as potent as that induced by intranasal inoculation, and continuous exposure resulted in symptomatic recipients. Additional head-to-head comparisons are needed, however, to identify any significant differences in infections transmitted by inhaled aerosol from nebulized virus inhalation versus liquid droplet inoculation.

    Figure 6. Aerosol Transmission from donors infected by aerosolized virus.

    Transmission of Cal/04 between donors infected by nebulized virus and recipients exposed continuously for 4 days. A. Serial viral RNA titers from throat swabs of donors and recipients, and samples of aerosols collected during continuous exposures, measured by single-target RT-qPCR. B. Viral RNA captured on PTFE filters during a 1 hour interval each day after donor ferret infection, and measured by T5000 assay.

    https://doi.org/10.1371/journal.pone.0033118.g006

    Aerosol Transmission During Early and Late Donor Infection

    Observations in human infections have indicated that optimum contagion occurs during early infection prior to symptom appearance. To test for more efficient transmission in early infection, recipients were exposed to single donors 1, 3, or 5 days after the donors’ intranasal instillation. Donor viral loads in the upper respiratory tract were comparable among the three pandemic h2N1 strains by both culturable virus (approximately 104 FFU/mL) and levels of viral RNA (6–9 log10 genome equivalents/mL) for most donors of each strain (Figure 7). The exhaled viral RNA levels from each donor also were not significantly different among the three strains. No correlation between level of airborne viral RNA and subsequent transmission could be drawn, however, as six exposures resulted in transmission in the absence of detectable viral RNA in the aerosol. One day and 3 days after donor instillation of Cal/04, all exposed recipients were infected by viral RNA criteria and half by culture-positive criteria. None of the 3 ferrets exposed to culture-positive day 5 Cal/04-infected donors were infected. When results from all three strains are combined, donors on their fifth day of infection were significantly less likely to infect recipients by the viral RNA criteria (5/11 vs 11/11 on dpi 1, p = 0.006, Fisher’s exact test). Transmission from Mex/4482- and Cal/07-infected donors was reduced 3 and 5 days after inoculation likely due to fewer culture-positive nasal washes or throat swabs in the donors.

    Figure 7. Comparison of Transmission efficiency of pandemic 2009 h2N1 strains during early and later phases of donor infection.

    Single donor-single recipient exposures in which the interval between donor instillation and recipient exposure was varied from 1, 3, or 5 donor dpi. Viral culture (hatched bar) is expressed as FFU/mL (total sample) of nasal wash collected on day of exposure (donors) or the greatest value found on day 1−3 post-exposure (recipients). Aerosol data are expressed as genome equivalents/1-hour filter collection; each of three filters was measured in triplicate, and the mean of the three filters reported. For each virus: Cal/04 (green), Cal/07 (blue) and Mex/4482 (red), the donor-recipient pair are aligned horizontally across the figure.

    https://doi.org/10.1371/journal.pone.0033118.g007

    Comparison of Transmission Efficiency between 1 Seasonal and 3 Pandemic h2N1 Strains

    Nebulized seasonal virus NC/99 was infectious to ferrets with a low aerosol ID50, although culturable virus was rarely present in the upper airways [32]. To test whether this strain could be transmitted by exhaled aerosol, donor ferrets were infected i.n. with 106 FFU of NC/99, or one of the three pandemic 2009 h2N1 strains as described above, and susceptible ferrets were exposed to their exhaled aerosols 1 day later (summarized in Figure 8A). Using the criterion of viral load either by culture or by viral RNA, there was no evidence that NC/99 was transmitted in any of 10 exposures using either a pair of infected donors (double dose) or a single infected donor. In contrast, all 12 exposures to single Cal/04-infected ferrets resulted in infections, half detected by culture and the remainder by RT-qPCR and the T5000 assay. Almost all of the ferrets infected with the other two 2009 h2N1 pandemic strains had evidence of infection by viral RNA in the throat and nasal wash, but only 1 of 16 had positive cultures, as noted in Figure 7. No Cal/07-exposed ferrets developed culture-positive infections, significantly fewer than those in Cal/04 infections (Fisher exact test, p = 0.006).

    Figure 8. Efficiency of transmission success is inversely correlated with level of illness in the ferret aerosol-donor. A

    . Comparison of percent transmissions detected by positive culture or positive RT-qPCR of nasal washes or throat swabs of recipients tested 1−3 days post-exposure, for each strain of pandemic h2N1 2009 influenza A virus. Lack of transmission of NC/99 is shown as left-hand column for comparison. B. Group mean weight change in the donors following intranasal infection with the three pandemic h2N1 strains. C. Photographs of whole lung tissue at necropsy (day 5) of donor ferrets infected with Cal/04 (C2, middle photo) or Cal/07 (C1 and C3). Cal/07-infected lungs display multiple regions of firm, dusky tissue representing pneumonitis confirmed by histology, not seen in Cal/04-infected lungs.

    https://doi.org/10.1371/journal.pone.0033118.g008

    Intranasal inoculation of the donor ferrets induced varying degrees of illness depending on the pandemic h2N1 strain. Donors infected with Cal/04 transmitted more culture-positive infections, yet exhibited the least weight loss (Figure 8B), no gross lung pathology (Figure 8C) and the fewest respiratory symptoms (Table 1). In contrast, Cal/07 donors experienced the most weight loss, the most apparent pulmonary inflammation at necropsy (Figure 8C) and the most respiratory symptoms (Table 1), yet failed to transmit culture-positive infection (Figure 7). The Mex/4482 virus was intermediate between the two other strains in these measures of illness. This apparent inverse relationship between less disease and more efficient transmission requires more comparative investigations to extend these observations, but suggests an effect of the inflammatory response on aerosol transmission.

    Relationship of Exhaled Viral RNA Levels to Transmission

    A higher viral load in upper airway mucosa might be expected to result in more efficient aerosol transmission. Higher donor viral load in Cal/04 infection was associated with transmission in Figure 4, and in all experiments donor ferrets with less than 3 log10 FFU/nasal wash cultures never transmitted culture-positive infection, consistent with a donor threshold. On the other hand, donors with high levels of culturable pandemic h2N1 virus in nasal wash failed to transmit infection. Levels of virus in exhaled aerosols might be a more direct measure of contagion but measured viral RNA in exhaled aerosols was not clearly related to transmission of the pandemic h2N1 strains (Figure 7). Levels of viral RNA in exhaled aerosols were compared between the nasal-wash culture-positive NC/99-infected donors and the NW culture-positive Cal/04-infected donors. Under identical exposure conditions the NC/99 virus was not transmitted, compared to frequent transmission of Cal/04, yet NC/99-infected donors exhaled significantly higher levels of viral RNA measured by either assay than Cal04-infected donors (Figure 9). Transmission of Cal/04 occurred in spite of viral RNA-negative 1 h filter collections, likely attributable to highly variable levels of exhaled virus during the 3 h exposure.

    Figure 9. Exhaled viral RNA from donors infected with either NC/99 (A and B) or Cal/04 (C and D) virus.

    RNA was measured in each filter sample by two RT-qPCR-based assays, detecting a single genomic RNA segment (LRRI assay, solid bar) or six segments (Ibis T5000 assay, checkered bar), and expressed as genome equivalents/1-hour filter collection. Donors were infected intranasally with 106 FFU of either virus 24 hours prior to recipient exposure at a time when all donor nasal washes contained 104–105 FFU/mL. Each donor exposed three recipient ferrets and each of their corresponding collections (F1, F2, and F3) were the mean RNA levels from three filters each collecting airborne particles for 1 hour during the 3-hour exposure period.

    https://doi.org/10.1371/journal.pone.0033118.g009

    Source of Exhaled Virus

    Exhaled virus from contagious ferrets may be derived from both upper airway mucosa and small airways within the lung, and thus upper airway cultures may not reflect the total source of the exhaled viral aerosol. Viral load for each of the four influenza viruses was graphed according to both the upper airway viral RNA load and viral RNA levels in the lung of donor ferrets assessed on the day of exposure (Figure 10). Cal/07- and Mex/4482-infected ferrets had significantly higher viral loads measured by viral RNA levels in lung tissue than Cal/04-infected ferrets (p = 0.007), but these higher viral loads were associated with lower rates of transmission. The NC/99-infected donors did not have viral RNA in lung tissue nor transmitted infection by exhaled aerosol. Thus higher lung viral RNA titers were not associated with higher aerosol transmission efficiency among pandemic h2N1 strains, but a threshold level of virus required for transmission was not established. Imaginative experimental designs will be needed to determine the tissue source of exhaled virus.

    Figure 10. Viral loads (RNA genome equivalents per mL nasal wash or per g lung tissue) for each donor ferret on dpi 1 or dpi 3.

    Necropsy of donor was performed 2 h after exposing recipient ferrets. Data combined from 3 experiments indicated by circles, triangles and diamonds. Lung tissue viral RNA levels for Cal/04 were mean (SD) = 5.94 (2.72) compared to Cal/07+Mex/4482 lung RNA mean (SD) = 8.84 (1.42), significant by t test at p = 0.007. Aerosol transmission success for each virus is exhibited in Figures 4 and 7. The NC/99-infected donors did not have viral RNA in lung tissue nor transmitted infection by exhaled aerosol.

    https://doi.org/10.1371/journal.pone.0033118.g010

    Airway Culture-negative Lung Infection in Aerosol-exposed Ferrets

    Detection of culture-negative viral RNA in the recipient ferret airways raised the possibility of either a low level of infection that was not contagious or that no infection had been established. Recipient ferrets were necropsied at intervals after exposure for histological analysis (Table 2) and a sample of 15 lungs containing typical histologic characteristics of influenza infection were stained for viral antigen by immunohistochemistry (IHC). All ferrets with viral RNA in lung tissue after exposure to the pandemic h2N1 viruses had evidence of infection although it was graded as either minimal or mild in most cases. No recipient exposed to the NC/99 virus had histologic evidence of infection, consistent with the absence of viral RNA in the lung (Figure 10). Histological evidence of infection included epithelial karyomegaly and necrosis in terminal bronchioles with peribronchiolitis, and acute inflammation in the nasal turbinates (Figure 11 A, C, D, E).

    Figure 11. Histology of lung and turbinates from exhaled aerosol-exposed recipient ferrets infected with Cal/04. a,d:

    Mild focal bronchiolitis with epithelial cell karyomegaly and desquamated epithelium and neutrophil inflammatory cells in the lumen of small airways (solid arrows). b. Immunohistochemical detection of influenza nucleoprotein antigen in airway epithelial cells. c,d,e. Intramucosal and submucosal inflammatory cells in the turbinate (c) and peribronchial tissue (d,e).

    https://doi.org/10.1371/journal.pone.0033118.g011

    Among 9 recipient lungs infected with Cal/04 according to viral RNA criteria alone, 7 were positive by IHC (Figure 11B). Of 14 recipient lungs that were viral RNA negative, 9 were IHC-negative, but 5 were IF-positive. This discrepancy suggests that in low-level infections the extent of tissue sampling will impact interpretation. Thus aerosol exposures may result in culture-negative lung and turbinate infections manifest only by viral RNA and viral antigen to indicate established but weak viral replication.

    Calculation of the Aerosol Infectious Dose of Pandemic h2N1 Influenza A

    To calculate the aerosol ID50 of Cal/04 for recipients on days 1 and 3 post-exposure, the data were grouped according to the following criteria: For log10 dose <1 is group one, 2<log10 dose< = 3 is group two, 3<log10 dose<4 is group three, log10 dose >4 is the group four. For each group, the mean is used as the log10 dose for each group. The Proc Probit procedure in SAS (version 9.0 Cary NC) was used to calculate the infectious dose causing 50 percent of animals to be infected. The log10 dose causing the 50 percent of animals infected is 2.16 (145 genome equivalents). The 95% confidence levels are -1.69 and 2.913 (0.02 and 819 genome equivalents) (Figure 12). Using the aerosol viral RNA levels and the viral RNA:viable virus ratio developed previously [32], the aID50 was estimated at 1 virus particle (95% confidence limits: 0.1–3.0).

    Figure 12. Calculation of the infectious dose for exhaled aerosol Cal04.

    The Proc Probit procedure was used to calculate the infectious dose causing 50 percent of ferrets to be infected, as log10 dose = 2.16 (145 genome equivalents). The 95% confidence levels are –1.69 and 2.913 (0.02 and 819 genome equivalents).

    https://doi.org/10.1371/journal.pone.0033118.g012

    Discussion

    Our calculation of the minimal infectious dose of exhaled airborne Cal/04 pandemic virus as approximately 1 FFU is consistent with studies in ferrets and humans using nebulized virus. Using the same exposure chambers in this study, we reported the aerosol ID50 of the h2N1 NC/99 seasonal virus to be 4 pfu [32], although this NC/99 transmitted infection was detected only by seroconversion and viral RNA, and not by symptoms or viral culture. The minimal nebulized h4N2 seasonal virus dose inducing symptomatic infection in ferrets was 2 pfu by the aerosol route [31] compared to 1 pfu by the intranasal route. The minimal aerosol dose by nose-only exposure in ferrets was 1 pfu for a virulent avian H5N1 strain [37]. Intranasal minimal infectious dose of an H5N1 strain in mice was 4 pfu [38], and an h4N2 strain in guinea pigs was 5 pfu [39]. Human volunteers exposed to a nebulized seasonal h4N2 virus developed symptomatic infection from a calculated mean infectious aerosol dose of 0.3 to 6 TCID50[40], in contrast to substantially higher minimal doses by intranasal drops [41]. Although aerosol ID50 measurements for nebulized versus exhaled virus may not be exactly comparable, infectious doses transmitted by aerosol appear to be very low. If influenza transmission among ferrets is comparable to inter-human transmission, low aerosol infectious doses may have implications for designing public health interventions.

    Measuring aerosol transmissibility in animal models is dependent on the limitations imposed by the experimental conditions. Brief whole-body exposure between unrestrained, non-anaethetized ferrets was chosen for this study to approximate the conditions of transmission among humans in their daily activities. The advantages of this design include natural respiration patterns, expected dilution of airborne virus by deposition on the inanimate environment, and exposure to low concentrations of virus in the aerosol. The disadvantages include inability to exclude exposure by the non-inhalation routes, loss of aerosolized virus on the surfaces of the origin chamber, and the need for more surface decontamination between exposures. These disadvantages are advantages of the nose-only exposure systems [37], [42], but the reduced minute ventilation of the ferret sleeping in the conical restraint may alter the mucosal distribution of inhaled virus. Airborne virus has a low death rate constant if the humidity is low [43], experimentally confirmed in the guinea pig model by highest transmission at 20% relative humidity [39], [44]–[46]. Exposures in this study were conducted at relative humidity of approximately 45%, possibly reducing the efficiency of transmission.

    Our chamber designs intentionally limited the exposure to small-particle exhaled virus, less than 10 µm in the tunneled chamber and less than 5 µm in the un-tunneled chamber. We observed no marked difference in transmission efficiency between the two chambers. In a study of ferrets exposed to exhaled h4N2 virus with a size profile similar to ours [31], the cascade impactor captured more of the airborne infectious particles in the 4.7 µm diameter cohort in the two ferrets analyzed. It is possible that our chambers excluded significant numbers of infectious particles from reaching the susceptible ferrets, thus reducing culture-positive infections. Humans exhale droplets of widely varying sizes and quantity during normal breathing and talking [7], [47]. Exhaled infectious particle size needs further investigation, since virus in aerosol particles less than 3 µm diameter remain suspended in the air for an hour or more thus increasing opportunities for aerosol transmission.

    Quantifying aerosol transmissibility in animal models is dependent on the sensitivity of assays detecting airborne virus. The PTFE filter used in this study has been shown to be more efficient than the AGI impinger in capturing viral RNA but less efficient in capturing infectious particles [48]. During short collection intervals of 10 min or less both filters [32] and liquid impingers [31], [32] are efficient collectors. However, the marked variability of exhalation of particles, and presumably virus, over time is apparent in our data (figures 3, 7, 9) and in others (figure 1, [31]), suggesting that short periods of collection may not be reliable to capture total exhaled virus levels. In this study PTFE filter collections for 1 h were rarely culture-positive for virus and only for the Cal/04 virus, so we elected to use viral RNA collected during the entire exposure to estimate airborne virus inhalation. Influenza RNA, but not cultured virus, was detected in aerosols exhaled from three of five individuals infected with influenza A [49]. In cough specimens from subjects with acute influenza A, 81% had viral RNA detected by M segment RT-qPCR but only 2 of 21 had cultured virus [47]. We derived the ratio of total viral RNA to infectious particles from filters exposed to nebulized virus for only 20 minutes [32]. The lower ratio calculated using cascade impactors [32] may be due to destruction of intact genomic RNA [48]. Ratios of RNA genome equivalents to infectious virions have been subject to wide experimental variation. Viral particles secreted into tissue culture media consists primarily of non-infectious (defective interfering) particles among only 1% infectious particles [50]–[52]. Future work must address these technical limitations of quantifying low levels of aerosol infectious particles.

    Continuous exposures to exhaled aerosols with seasonal and pandemic strains have resulted in culture-positive infections and seroconversions [23]–[30]. In this study, however, neither symptoms nor culture-positive airways were commonly documented. Seroconversion was not used in this study because lung histopathology and viral load was examined during the first week after exposures. Many exposed ferrets with negative airway cultures had viral RNA-positive airways for 5 days after exposure. This observation was interpreted to indicate established mucosal infection, since UV-inactivated viral RNA deposited on ferret mucosa is cleared and undetectable within 24h [32]. We documented established lung infection with the pandemic h2N1, but not seasonal h2N1, viruses by immunohistochemical detection of viral antigen in culture-negative, viral RNA-positive ferrets. Nonetheless the culture-negative infections likely indicate that the viruses studied were significantly less virulent than that reported for the h4N2 strain [31]. Whether 3 h exposures to less virulent strains are contagious and provide immunologically relevant exposure should be tested.

    We compared three closely related pandemic 2009 h2N1 viruses for aerosol transmissibility and virulence. Intranasal infection with Cal/07 and Mex/4482 clearly induced greater morbidity, fever, weight loss, sneezing, and decreased activity, which were all absent in the ferrets infected with Cal/04. The greater morbidity of Cal/07 has been observed previously [53] as has the mild morbidity in ferret Cal/04 infections [29]. The genomic basis for this virulence heterogeneity is unknown, as only four nucleotide differences among the eight RNA segments were found between the Cal/04 and Cal/07 stocks we used (P Gao, unpublished data). Single nucleotide mutations in the hemagglutinin, neuraminidase, and PB2 segments have been shown to alter transmissibility [21], [23]–[27], but these mutations were not present in the strain isolates studied here.

    The two more virulent strains were less efficiently transmitted using the criteria of few culture-positive recipients, yet upper airway donor viral loads were similar among the three pandemic viruses. Moreover the levels of viral RNA in exhaled aerosols were also comparable. We speculate that either the donor’s mucosal inflammatory response diminished exhalation of viable virus, not distinguished by a viral RNA assay, or that aerosol-derived infection was a function of the relative replication efficiency of virulent virus strains in susceptible respiratory mucosa. In a recent study [54] we used computational modeling of viral kinetics in human tracheal epithelial cells to derive estimates of strain-specific viral productivity per infected cell and the spread of virus from a primary to secondarily infected cells (basic reproductive number R0). The replication efficiency of the pandemic Cal/04 strain was 5−10-fold greater than the seasonal NC/99 strain [54]. Similar differences between replication rates have been documented in ferret tracheal epithelial cells (unpublished data). Thus, successful transmission from contagious to susceptible ferret may depend as much on the replication efficiency of the virus strain as on the inhaled dose of viable virus and other virus-host relationships.

    Acknowledgments

    We thank Carol Emerson and Andrew Matchett for veterinary care, Alexander Klimov (Centers for Disease Control) for providing the stocks of viral strains, Wendy Piper and Thomas Gagliano for illustrations, and the Animal Care Team of LRRI for the care and maintenance of the ferret colony. We appreciate the advice and support of Rachelle Salomon and Martin Crumrine of the NIAID.

    Author Contributions

    Conceived and designed the experiments: FK YZ RCL SH PG YSC. Performed the experiments: KG YZ HM ZP RCL MZ. Analyzed the data: FK KG YZ KL RR HM ZP JC DT JP MZ YL YSC. Contributed reagents/materials/analysis tools: KH RS SH YL. Wrote the paper: FK YSC.

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      Steel J, Palese P, Lowen AC (2011) Transmission of a 2009 pandemic influenza virus shows a sensitivity to temperature and humidity similar to that of an h4N2 seasonal strain. J Virol 85: 1400–1402.
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      Lindsley WG, Blachere FM, Thewlis RE, Vishnu A, Davis KA, et al. (2010) Measurements of airborne influenza virus in aerosol particles from human coughs. PLoS ONE 5: e15100.
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      Fabian P, McDevitt JJ, Houseman EA, Milton DK (2009) Airborne influenza virus detection with four aerosol samplers using molecular and infectivity assays: considerations for a new infectious virus aerosol sampler. Indoor Air 19: 433–441.
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      Ngunjiri JM, Sekellick MJ, Marcus PI (2008) Clonogenic assay of type A influenza viruses reveals noninfectious cell-killing (apoptosis-inducing) particles. J Virol 82: 2673–2680.
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      Marcus PI, Ngunjiri JM, Sekellick MJ (2009) Dynamics of biologically active subpopulations of influenza virus: Plaque-forming, non-infectious cell-killing, and defective-interfering particles. J Virol 83: 8122–8130.
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      Mitchell H, Levin D, Forrest S, Beauchemin C, Tipper J, et al. (2011) Higher replication efficiency of 2009 (h2N1) pandemic influenza than those of seasonal and avian strains: kinetics from epithelial cell culture and computational modeling. J Virol 85: 1125–1135.

    90,000 China detected the first case of human infection with a new type of avian influenza :: Society :: RBK

    The world’s first case of human infection with a strain of avian influenza h20N3 virus was detected in Jiangsu province, we are talking about a 41-year-old man.According to the PRC authorities, this virus has no “effective ability” to infect people

    Photo: Lam Yik Fei / Getty Images

    China has revealed the world’s first case of human infection with avian influenza h20N3, according to the National Health Commission of the People’s Republic of China.

    According to the department, the disease was confirmed in a 41-year-old man from the city of Zhenjiang (Jiangsu province). On April 23, he was hospitalized with a fever and other symptoms (which are not specified), on April 28, experts studied the patient’s analyzes and came to the conclusion that he was sick with avian influenza h20N3. How exactly the man could become infected is not reported.

    According to the commission, the man is now in a stable condition and ready to be discharged. Among those with whom he was in contact, no cases of infection have been identified.

    h20N3 is a low pathogenic virus that is transmitted between birds. As stated in the commission, he “does not have an effective ability to infect a person.” Experts recommended avoiding contact with live birds, as well as those who died from the disease.

    Video
    90,000 What is avian influenza (“bird flu”).Memo for the population.

    What is avian influenza (avian influenza)?

    HIGHLY PATHOGENIC BIRD INFLUENZA is an acute contagious viral infection of domestic and wild birds, characterized by general depression, edema, multiple hemorrhages and lesions of internal organs, brain and skin. The birds are suffocating, the comb and beard turn blue, egg production drops to 100%. The causative agent of the disease is an RNA-containing virus with a segmented genome of the Orthomyxoviridae family, the genus Influenzaevirus, type A.
    All types of birds are susceptible to highly pathogenic influenza, including chickens, turkeys, ducks, pheasants, guinea fowls, quails, wood grouses, storks, gulls and almost all species of synanthropic birds (pigeons, sparrows, crows, gulls, ducks, jackdaws, etc.) ), wild, exotic and decorative birds, as well as pigs, horses, ferrets, mice, cats, dogs, other vertebrates and humans.
    The incidence of influenza in birds ranges from 80 to 100%, and mortality can reach up to 100%, depending on the degree of virulence of the virus strains and the housing conditions of the susceptible livestock.Chickens and turkeys are most susceptible to the virus. In chickens, disease caused by a highly pathogenic strain of the virus is often lightning-fast, asymptomatic and 100% fatal.
    This disease is characterized by a potentially high risk of the pathogen to humans.

    Sources of avian influenza viruses in nature

    The main source of the virus in nature is wild birds, mainly waterfowl, which carry the virus in the intestines and excrete it into the environment with saliva and droppings and from which poultry, primarily domestic waterfowl – ducks and geese, can become infected.In wild ducks, the influenza virus multiplies mainly in the cells lining the gastric tract, while the virus does not cause any visible signs of disease in the birds themselves and is released into the environment in high concentrations. The asymptomatic course of influenza in ducks and wading birds may be the result of adaptation to a given host over several hundred years. Thus, a “reservoir” is created that provides biological “immortality” to influenza viruses. With the help of migratory birds, this disease spreads over long distances.
    The main routes of transmission of the causative agent of the disease are through feed or water, when consumed, the body is infected (alimentary transmission), as well as through direct contact of a susceptible livestock with an infected bird – airborne transmission.

    Is avian influenza dangerous for humans?

    According to the World Health Organization, over the past eight years, strains of the avian influenza virus have become much more aggressive, are not limited to infection of birds and animals, and have begun to pose a threat in infecting humans.Human infection occurs through close contact with infected wild or poultry. In some cases, human infection is possible when eating meat and eggs of sick birds without sufficient heat treatment.
    The secretions of infected birds, getting on plants, in the air, in water, can infect humans and healthy birds through water when drinking and bathing, as well as by airborne droplets, airborne dust and through dirty hands.

    Resistance of avian influenza viruses to physical and chemical influences

    The virus is highly resistant in neutral humid environments, including water, and frozen, but highly sensitive to heat and disinfectants.

    1. Inactivated (dies) at 56 ° C for 3 hours, at 60 ° C for 30 minutes, and at a temperature of 75 ° C for several minutes;
    2. Inactivated in an acidic environment;
    3. Inactivated by oxidants, lipid solvents;
    4. Inactivated by formalin and iodine-containing preparations;
    5. The avian influenza virus, unlike human, is very stable in the external environment – in the carcasses of dead birds, it can live up to one year;
    6. It is stored for a long time in muscle tissues, faeces and water.

    Avian influenza symptoms in poultry

    Typical clinical signs of disease symptoms in all types of domestic and wild waterfowl are: increased body temperature, discoordination of movements, throwing the head back, rotating head movement with shaking, neck curvature, lack of response to external stimuli, refusal to feed and water, depression, sinusitis, nasal discharge, conjunctivitis, corneal opacity and blindness, diarrhea.Swelling and blackening of the ridge, cyanosis of the earrings, swelling of the subcutaneous tissue of the head and neck are noted.
    Infection among poultry can be asymptomatic or cause a decrease in egg production and respiratory system diseases, as well as proceed in a fulminant form, causing rapid death of the bird from systemic damage without any preliminary symptoms (highly pathogenic avian influenza). The death of a bird occurs within 24-72 hours.

    Symptoms of avian influenza in humans

    Classic signs of influenza:

    • acute deterioration of health with high fever (starting from 38 degrees),
    • headache, sore muscles and throat,
    • cough and runny nose, difficulty breathing,
    • inflammation of the mucous membrane eyes.
    • The most severe complication of the disease is pneumonia, which can cause shortness of breath, but it can also damage the heart, muscles and central nervous system.

    Prevention of avian influenza

    In order to prevent the occurrence and spread of avian influenza, owners who care for, keep, breed and sell poultry are obliged to:
    1. Carry out economic and veterinary measures to prevent the occurrence of bird disease;
    2.Provide to specialists in the field of veterinary medicine, upon their request, birds for inspection;
    3. Follow the instructions of specialists in the field of veterinary medicine on the implementation of measures for the prevention and control of avian influenza;
    4. Inform specialists in the field of veterinary medicine about all cases of sudden death or simultaneous mass illness of birds, as well as about their unusual behavior;
    5. Prior to the arrival of specialists, take measures to isolate birds suspected of the disease;
    6. Do not allow poultry to walk (exit) outside the yard area, exclude contact of poultry with wild birds, especially waterfowl.
    7. To carry out the sale and purchase of only poultry and ornamental poultry vaccinated against influenza in the presence of accompanying veterinary documents characterizing the territorial and species origin of the bird, the epizootic state of the place of its exit and allowing the identification of the bird.
    8. Keep territories and structures for keeping animals and poultry clean, carry out mechanical cleaning and disinfection of all rooms and territories: periodically (2-3 times a week) process the previously cleaned room and equipment (scoops, brooms, buckets) 3 percentage hot solution of caustic soda or 3% solution of bleach (chloramine).After disinfection of the poultry house, the perch and nests must be whitewashed twice (at an hourly interval) with freshly slaked lime.
    9. Protect the poultry house and feed storage rooms from the penetration of wild and synanthropic birds (notching of windows and doors).
    10. Store feed for poultry and ornamental poultry in tightly closed watertight containers out of the reach of wild birds. Boil food waste before feeding.
    11. Slaughter of poultry intended for sale shall be carried out at specialized enterprises.

    During the period of the threat of the emergence and spread of avian influenza:

    1. To prevent infection of poultry with influenza in individual households of citizens, it is necessary to transfer all poultry to a closed keeping regime.
    2. Install mechanical moving structures (silhouettes of birds of prey), mirror-mechanical devices (shiny ribbons, mirrors, which, swinging under the influence of the wind, give light glare, frightening birds) and other means to scare away wild birds on the territory of personal farmsteads, poultry farms birds.
    3. To take care of the bird, cleaning the premises and the territory in the work clothes allocated for this (dressing gown, apron, mittens, rubber shoes).
    4. Periodically (2-3 times a week) after mechanical cleaning of premises and equipment, disinfect with 3% hot caustic soda solution or 3% bleach solution (chloramine).
    5. After disinfection of the premises of the poultry house, the perch and nests must be whitewashed twice (at an hourly interval) with fresh lime.
    6. Subject to disinfection (soaking in a 3% solution of chloramine B for 30 minutes, boiling in a 2% solution of soda ash) and subsequent washing of work clothes.
    7. All new poultry entering the household should be vaccinated against avian influenza and allowed into the general herd not earlier than 28 days after vaccination.
    8. If carcasses of birds are found or a sick bird is found on the street, in private courtyards of citizens, it is necessary to immediately inform the state veterinary service of the region at the place of detection or keeping of birds in order to carry out the necessary measures for the study of corpses and sick birds in order to exclude avian influenza.

    Prevention of avian influenza in humans

    1. Observe the rules of personal hygiene, food storage conditions (joint storage of raw food with ready-made food is not allowed), use separate kitchen tools (knives, cutting boards) for processing raw food.
    2. Avoid contact with suspected or dead birds.
    3. To take care of the bird, cleaning the premises and the territory in the work clothes allocated for this (dressing gown, apron, mittens, rubber shoes).During cleaning, you should not drink, eat or smoke.
    4. Purchase for food poultry meat, eggs and other poultry products in places of authorized trade, demand from the seller accompanying documents confirming the quality and safety of products (veterinary certificate form No. 2 or veterinary certificate form No. 4, certificate of conformity, certificate of quality) …
    5. Eat poultry and eggs after heat treatment: boil the egg for at least 10 minutes, meat – for at least 30 minutes at a temperature of 100 ° C.
    6. Avoid contact with waterfowl and synanthropic birds (pigeons, sparrows, crows, seagulls, ducks, jackdaws, etc.).
    7. Do not visit regions affected by avian influenza unless absolutely necessary.

    In case of finding a dead or sick wild bird, as well as in all cases of illness or death of poultry
    , report to the following phone numbers:

    State Veterinary Institutions of the Moscow Region

    1.GUVMO “Balashikhinskaya regional station for the fight against animal diseases” (hereinafter – raySBBZh) _ Address: 143930, Mosk. region, Balashikha district, Balashikha, md. Saltykovka, apt. Akatovo, 48, t. 8 (495) 524-12-22, E-mail: [email protected]
    2. GUVMO “Volokolamskaya SBBZh” Address: 143604, Moscow region, Volokolamsk district, Volokolamsk , st. Akademicheskaya, 24, t. 8 (496) 362-83-54; 8 (496) 362-83-46, E-mail: [email protected]
    3. GUV MO “Voskresenskaya rayonSBBZh” Address: 140225, MO, Voskresensky district,Chemodurovo, st. Centralnaya, 16, t. 8 (496) 445-37-82; 8 (496) 445-38-44; E-mail: [email protected]
    4. GUV MO “Dmitrovskaya SBBZH” Address: 141800, Moscow region, Dmitrov, st. Komsomolskaya, 5, t. 8 (495) 993-91-54; 8 (496) 223-18-00; E-mail: [email protected]
    5. GUV MO “Domodedovskaya rayonSBBZh” Address: 142000, MO, Domodedovo, microdistrict Central, Promyshlennaya st., 15, t. 8 (496) 793- 02-13; 8 (496) 793-16-85; E-mail: [email protected]
    6. GUV MO “Egorievskaya rayonSBBZh” Address: 140300, MO, Yegoryevsk, Kolomenskoe shosse, d.9, t. 8 (496) 402-13-27; E-mail: [email protected]
    7. GUV MO “Zaraiskaya rayonSBBZh” Address: 140600, MO, Zaraysk, st. Field, 17, t. 8 (496) 662-41-91; Email: [email protected]
    8. GUV MO “Istra SBBZH” Address: 143500, MO, Istra, st. Sovetskaya, 49, t. 8 (495) 994-57-12; Email: [email protected]
    9. GUV MO “Kashirskaya rayonSBBZh” Address: 142900, MO, Kashira, st. Pushkinskaya, 9, t. 8 (496) 693-18-25; 8 (496) 693-11-58; E-mail: [email protected]
    10. GUV MO “Klinskaya SBBZh” Address: 141600, M.O., Klinsky district, Klin, st. Durymanova, 20, t. 8 (496) 242-25-98; E-mail: [email protected]
    11. GUV MO “Kolomenskaya rayonSBBZh” Address: 140405, MO, Kolomna, Kolychevsky proezd, 2, t. 8 (496) 615-71-11; 8 (496) 615-72-03; E-mail: [email protected]
    12. GUV MO “Krasnogorskaya SBBZh” Address: 143406, MO, Krasnogorsk, st. Georgy Dimitrov, 11, t. 8 (498) 568-43-95; E-mail: [email protected]
    13. GUV MO “Leninskaya rayonSBBZh” Address: 142701 MO, Leninsky district, Vidnoye, Leninsky Komsomol ave.1 bldg. B, t. 8 (495) 541-52-12; 8 (498) 547-10-92; E-mail: [email protected]
    14. GUV MO “Lotoshinskaya rayon SBBZh” Address: 143800, MO, pos. Lotoshino, st. Kalinina, 59, t. 8 (496)
    287-16-58; E-mail: [email protected]
    15. GUV MO “Lukhovitskaya rayon SBBZh” Address: 140500, MO, Lukhovitsy, street 50 years of the VLKSM, 15, t. 8 (496) 632-15 -04; E-mail: [email protected]
    16. GUV MO “Lyubertsy rayon SBBZh” Actual and legal Address: 140009, MO, Lyubertsy, st. Initiative, d. 46, t. 8 (498) 553-90-45; E-mail: vetlub @ mail.ru
    17. GUV MO “Mozhaiskaya rayonSBBZh” Address: 143200, MO, Mozhaisk, st. Lugovaya, 22, t. 8 (496) 382-12-63; 8 (496) 382-76-71; E-mail: [email protected]
    18. GUV MO “Mytishchinskaya SBBZH” Address: 141006, MO, Mytishchi, pos. Kombiferma, 4, t. 8 (495) 583-72-01; E-mail: [email protected]
    19. GUV MO “Naro-Fominsk rayon SBBZh” Address: 143300, MO, Naro-Fominsk, st. Marshal Zhukov, 170, t. 8 (496) 343-51-21; E-mail: [email protected]
    20. GUV MO “Noginsk SBBZh” Address: 142400, M.O., Noginsk, st. Nikanorova, 17; 8 (496) 514-31-25; 8 (496) 514-26-25; E-mail: [email protected]
    21. GUV MO “Odintsovskaya rayonSBBZh” Address: 143021, M.O., Odintsovsky district, p / o Nazaryevo, Matveykovo village, 2, t. 8 (495 ) 598-06-79; 8 (495) 598-06-80; E-mail: [email protected]
    22. GUV MO “Ozerskaya rayonSBBZh” Address: 140560, MO, Ozyory, st. Yuri Sergeev, 33, t. 8 (496) 702-14-02; 8 (496) 702-39-41; E-mail: [email protected]
    23. GUV MO “Orekhovo-Zuevskaya rayon SBBZh” Address: 142660, MO, Orekhovo-Zuevsky area,Drezna, st. Sovetskaya, 17, t. 8 (496) 418-38-07; E-mail: [email protected]
    24. GUV MO “Pavlovo-Posad Veterinary Station for Combating Animal Diseases” Address: 142500, MO, Pavlovsky-Posad, Mishutinskoe shosse, 68, t. 8 (496) 432-41-56; 8 (496) 433-16-13; E-mail: [email protected]
    25. GUV MO “Podolskaya rayonSBBZh” Address: 142108, MO, pos. Railway, st. Bolshaya – Serpukhovskaya, 199 “B”, t. 8 (496) 753-20-97; E-mail: [email protected]
    26. GUV MO “Pushkinskaya rayonSBBZh” Address: 141202, g.Pushkino, Yaroslavl highway, 182, t. 8 (495) 993-31-56; 8 (495) 993-52-30; E-mail: [email protected]
    27. GUV MO “Ramenskaya rayon SBBZh” Address: 140104, MO, Ramenskoe, st. Landing, 12, t. 8 (496) 461-90-21; 8 (496) 461-51-68; E-mail: [email protected]
    28. GUV MO “Ruzskaya rayonSBBZh” Address: 143100, MO, Ruza, st. Socialist, house 74-a, t. 8 (496) 272-30-60; E-mail: [email protected]
    29. GUV MO “Sergiev Posad rayon SBBZh” Address: 141300, MO, Sergiev Posad, avenue of the Red Army, d.255-B, t. 8 (496) 542-82-35; 8 (496) 542-45-56; E-mail: [email protected]
    30. GUV MO “Serebryano-Prudskaya rayon SBBZh” Address: 142970, MO. Serebryano-Prudsky district, p. Serebryanye Prudy, st. Michurina, 7, t. 8 (496) 673-15-86; 8 (496) 673-22-38; E-mail: [email protected]
    31. GUV MO “Serpukhov district SBBZh” Address: 142206, MO, Serpukhov, st. 2nd Moscow, 82, t. 8 (496) 772-09-24; E-mail: [email protected]
    32. GUV MO “Solnechnogorskaya SBBZh” Address: 141500, MO, g. Solnechnogorsk. st.Obukhovskaya, 45, t. 8 (495) 994-13-50; E-mail: [email protected]
    33. GUV MO “Stupinskaya rayonSBBZh” Address: 142800, Moscow region, Stupino, Sadovaya st., 3, t. 8 (496) 644-10-18 ; E-mail: [email protected]
    34. GUV MO “Taldomskaya rayonSBBZh” Address: 141900, MO, g. Taldom, st. Sovetskaya, 12, t. 8 (496) 206-01-17; 8 (496) 206-37-11; E-mail: [email protected]
    35. GUV MO “Chekhovskaya rayonSBBZh” Address: 142300 M.O. Chekhov, st. October, 2, t. 8 (496) 726-68-70; Email: [email protected]
    36.GUV MO “Shaturskaya rayonSBBZh” Address: 140700, MO, Shatura, street 1 Maya, 13, t. 8 (496) 452-32-42; Email: [email protected]
    37. GUV MO “Shakhovskaya rayonSBBZh” Address: 143700, MO, pos. Shakhovskaya, st. Partizanskaya, 40a, t. 8 (496) 373-38-42; E-mail: [email protected]
    38. GUV MO “Schelkovskaya rayonSBBZh” Actual and legal Address: 141100, MO, Shchelkovo, Zarechnaya st., 105-a, t. 8 (496) 566-48-37; E-mail: [email protected]
    39. GUV MO “Dzerzhinsk city station for combating animal diseases” (hereinafter – city SBBZh) Address: 140090, g.Dzerzhinsky, st. Dzerzhinskaya, 13, t. 8 (495) 551-56-90; 550-13-55; E-mail: [email protected]
    40. GBUV MO “Dolgoprudnenskaya city SBBZH” Address: 141700, MO Dolgoprudny, Mendeleev st., 1; 8 (495) 506-60-42; E- mail: [email protected]
    41. GUV MO “Railway city SBBZh” Address: 143980, Zheleznodorozhny, st. Novaya, d. 16, t. 8 (495) 522-42-98; E-mail: [email protected]
    42. GUV MO “Zhukovskaya GorSBBZh” Address: 140180, Zhukovsky, Kirov lane, 7, t. 8 (495) 556-89-10; Email: vetgykovsk @ mail.ru
    43. GUV MO “Korolevskaya GorSBBZh” Address: 141060, Korolev, Gagarina street, 5, t. 8 (495) 516-77-99; Email: [email protected]
    44. GUV MO “Orekhovo-Zuevskaya GorSBBZh” Address: 142605, g. Orekhovo-Zuevo, 1st Lugovoy proezd, 5a, t. 8 (496) 423-43-70; E-mail: [email protected]
    45. GUV MO “Podolskaya GorSBBZh” Address: 142118, Podolsk, Talalikhina st., 19, t. 8 (496) 754-78-61; Email: [email protected]
    46. GUV MO “Ramenskaya GorSBBZh” Address: 140104, Ramenskoe, st. Serov, d.21, t. 8 (496) 467-95-77; E-mail: [email protected]
    47. GUV MO “Reutov city SBBZh” Address: 143969, Reutov, st. October, 36, t. 8 (495) 791-37-62; 8 (498) 661-93-14; E-mail: [email protected]
    48. GBUV MO “Khimki city SBBZh” Address: 141407 MO, Khimki, st. Nagornoye Highway, 9, t. 8 (495) 571-65-93; E-mail: [email protected]
    49. GUV MO “Elektrostal city SBBZh” Address: 144009, Elektrostal, 1st Communal pr-d. 10/12 T. 8 (496) 575-59-49; E-mail: [email protected]
    50.GUV MO “MosoblVSS” Address: 140009, MO, Lyubertsy, st. Initiative, d. 46, t. 8 (495) 565-40-40; Email: [email protected]
    51. GUV MO “Mosoblvetlaboratoriya” Address: 140225 MO, Voskresensky district, pos. Chemodurovo, st. Centralnaya, 16 tel. 8 (496) 445-37-92; E-mail: [email protected]

    Rospotrebnadzor spoke about the differences between the symptoms of coronavirus and influenza

    Influenza and COVID-19 viruses have a similar disease pattern – they cause respiratory illness and are transmitted by contact.However, the important difference between the two is the transmission speed. This was reported on the Rospotrebnadzor website.

    According to the department, influenza and COVID-19 viruses cause respiratory illness, which is a wide range of disease variants – from asymptomatic or mild to severe illness and death.

    They are both transmitted by contact, by airborne droplets and through fomites. In this regard, the Russians were reminded of the need to adhere to simple rules of prevention, namely, use a mask, observe hand hygiene and social distance.

    However, the important difference between the two viruses is the transmission speed. Influenza has a shorter average incubation period and a shorter serial interval (time between successive cases) than coronavirus. For COVID-19, the serial interval is estimated at 5-6 days, while for the influenza virus it is three days. This shows that the flu can spread faster than the coronavirus.

    Rospotrebnadzor noted that transmission in the first 3-5 days of illness or potentially pre-symptomatic transmission is the main cause of influenza transmission.In turn, there are people who can spread COVID-19 24-48 hours before the first symptoms appear. However, this is probably not the main cause of transmission at this time.

    “It is estimated that the reproductive rate – the number of secondary infections caused by one infected person – for the COVID-19 virus is between 2 and 2.5, which is higher than for influenza. However, the estimates made for COVID-19 and influenza are very contextual and time-dependent, making direct comparisons difficult, ”the agency’s website said.

    Influenza and COVID-19 viruses have a similar spectrum of symptoms, but the proportion of severe cases is different. Coronavirus data show that about 80 percent of infections are mild or asymptomatic, 15 percent are severe and only five percent are critical and require ventilation. For influenza, the proportion of severe and critical cases is higher.

    If we talk about the risk group, then, according to the press service of the department, the greatest risk of contracting the flu exists in children, pregnant women, the elderly, as well as citizens with chronic diseases and immunodeficiency.With regard to COVID-19, it is now known that older age and underlying medical conditions increase the risk of severe infection.

    According to State Duma deputy and former sanitary doctor of Russia Gennady Onishchenko, the damage to all people from influenza is even higher than from coronavirus, but only because the total incidence is much higher.

    Over the past day in Russia, another 17,717 people have contracted coronavirus – this is the maximum figure for a pandemic. The leaders among the regions in terms of the number of daily growth were Moscow – 4906, Petersburg – 758, Moscow region – 514.In total, 1,581,693 cases of infection were recorded in Russia. For all the time, 27,301 people have died, and 1,186,041 recovered.

    Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor Mikhail Paltsev in an interview with the Parliamentary Gazette said that the incidence of COVID-19, which increased in the fall, will decline, when the frosts hit. In turn, in the spring the number of infected people will increase again, but the new wave will be less intense.

    As Professor Viktor Zuev said in an interview with Parlamentskaya Gazeta, vaccination and strengthening of the mask regime will help stabilize the epidemiological situation.

    90,000 “One virus has crowded out another”: should Russia expect a flu epidemic | Articles

    There will be no flu epidemic in Russia if the preventive measures introduced to combat the coronavirus are observed. However, to fully protect yourself and your loved ones, it is better to be vaccinated against both diseases, doctors say . The doctors explained to Izvestia when to vaccinate, how to combine them and how to take care of their immunity.

    Will there be a flu epidemic in Russia?

    An influenza epidemic can bypass Russia, subject to the preventive measures introduced to combat coronavirus, said specialist in especially dangerous infections, immunologist Vladislav Zhemchugov.

    According to him, such anti-epidemic measures as during the COVID-19 pandemic were not in any flu epidemic. For this reason, there was no outbreak of the disease last year.

    – Epidemics of both influenza and coronavirus are mainly formed due to the transmission of the virus by airborne droplets, so the measures that are taken against both diseases are equally effective, – explains the director of Lifetime + Kirill Yuvchenko to Izvestia. – Today, some of the people who could carry the flu work from home.Those who still travel to work and, accordingly, visit public places more often, but wear masks, spread viruses less.

    Photo: RIA Novosti / Alexander Kondratyuk

    However, to fully protect yourself and your loved ones , doctors recommend vaccinating against both diseases . The specialists explained to Izvestia how to combine vaccinations and take care of their immunity.

    Who is influenza dangerous for?

    According to Kirill Yuvchenko, there will be cases of influenza in Russia in any scenario.Its epidemic is a seasonal phenomenon, which is supported by the variability of the virus, which does not allow “once and for all” to create a vaccine.

    – Few people know about the true extent of the flu at normal times. There are laboratory tests that can reveal which virus is causing the disease, but they are rarely used, except in case of hospitalization. The patient rarely finds out whether he was ill with any of the viruses that cause ARVI (and there are, according to various sources, from 800 to 1000), or the flu – this is not so important, when the disease goes away by itself in a week, ” says Yuvchenko.

    According to the expert, flu is especially dangerous for children and the elderly. In some years, diseases were pronounced and associated with large losses. And if statistics on the number of infected were published daily at this time, it would be disappointing.

    In turn, sanitary doctor Nikolai Dubinin notes that influenza can aggravate the course of coronavirus infection and mask its course.

    Photo: Izvestia / Sergey Konkov

    – A situation may arise that a person will think: he has ARVI or flu, but in fact – a coronavirus.However, the latter is now unlikely, since all patients with acute respiratory viral infections are treated as potentially infected with coronavirus, says Dubinin.

    However, This year, as in the past, the incidence of influenza may be significantly lower than usual. Compliance with preventive measures and vaccination will greatly contribute to this.

    Strengthening prevention measures

    According to general practitioner Regina Shaydullina, last year in Russia did without an outbreak of influenza.This was due to the coronavirus pandemic, or rather, with the strengthening of preventive measures against its background.

    – Self-isolation, wearing masks and gloves, keeping distance, using antiseptics and vaccination positively influenced the epidemiological situation, including influenza, the expert says.

    Compliance with similar measures and participation of the state will affect the development of the situation this year – how strictly it will monitor compliance with the mask regime and whether it will impose restrictions.In such conditions, the epidemic will take place on an insignificant scale, says Kirill Yuvchenko.

    Photo: RIA Novosti / Maxim Bogodvid

    – Wearing PPE (Personal Protective Equipment) on public transport could save many lives. As for, for example, employees of retail enterprises, there is nothing new in mask mode, there were such recommendations even before the spread of the coronavirus, they simply preferred not to follow them, – says the source of Izvestia.

    On the other hand, today’s favorable flu situation may have negative consequences , notes Elena Rusakova, a neonatologist at the Polyclinic.ru network of medical centers. Russians will not develop collective immunity to SARS and influenza, which may lead to a serious outbreak of respiratory infections in the epidemiological season of 2021–2022.

    The influenza virus has not disappeared anywhere, it is still circulating, it was just conditionally supplanted by COVID-19 , adds Maria Menshikova, senior medical consultant of the Teledoktor24 service.This means that next fall, the flu may return in an enhanced version.

    – Virologists fear that due to the low incidence, the overall population immunity to this disease will be severely affected: fewer infections can lead to an increase in the population susceptible to infection and a larger outbreak of influenza next winter, says Menshikova.

    Do I need a flu shot?

    In order to protect themselves and loved ones, doctors recommend that Russians get vaccinated against both coronavirus and flu.Of course, in compliance with the rules of vaccination.

    Photo: RIA Novosti / Alexey Malgavko

    – In Russia, the coverage of influenza vaccination before the start of the coronavirus pandemic was surprisingly large – 60%, says Kirill Yuvchenko. – According to the results, the incidence rate decreased slightly, but the mortality rate decreased significantly. As with the coronavirus, the vaccine protects against severe disease, not infection as such.

    According to Regina Shaydullina, need to be vaccinated against both diseases, the main thing is to observe the interval between procedures.So, it is recommended to get a flu shot two to three weeks before the onset of the seasonal rise in incidence, so that the body has time to develop antibodies. It is best to schedule vaccinations for September – early October.

    – If we talk about combining vaccinations against coronavirus and influenza, the time difference between them must be at least 30 days. It is better to first get vaccinated against coronavirus and count down the indicated time after the introduction of the second component. Between the first and second components of the coronavirus vaccine, should not be vaccinated against influenza, the expert notes.

    Also, do not forget about other preventive measures: wearing masks, keeping a distance in crowded places, washing hands, using antiseptics and disposable wipes for a runny nose and cough, notes Elena Rusakova. A balanced diet, adequate sleep, walking in the fresh air and exercising will help strengthen the immune system.

    – Stay home at the first sign of illness. Eat all the vegetables and fruits available. Keep the body in good shape and in a good mood – this way you will protect yourself from illness, sums up Maria Menshikova.

    Photo: TASS / Sergey Savostyanov

    Rospotrebnadzor has already announced plans to vaccinate against influenza at least 60% of the Russian population and at least 75% of citizens at risk this year in the new epidemiological season of 2021–2022.

    Hygiene for influenza, coronavirus infection and other acute respiratory viral infections

    Hygiene for influenza, coronavirus infection and other acute respiratory viral infections
    What should you do during the active circulation of influenza pathogens, coronavirus infection and other pathogens of acute respiratory viral infections (SARS) in order to prevent your own infection and protect others if you get sick?
    The causative agents of all these diseases are highly contagious and are transmitted mainly by airborne droplets.
    When sneezing and coughing in the air around a sick person, microdroplets of his saliva, sputum and respiratory secretions, which contain viruses, are spread. Larger droplets settle on surrounding objects and surfaces, small ones stay in the air for a long time and are transported to distances of up to several hundred meters, while viruses retain the ability to infect from several hours to several days. The main measures of hygienic prevention are aimed at preventing healthy people from contact with particles of a sick person’s secretions containing viruses.
    Compliance with the following hygienic rules will significantly reduce the risk of infection or further spread of influenza, coronavirus infection and other SARS.

    How not to get infected
    · Wash hands after visiting any public places, transport, touching doorknobs, money, public office equipment in the workplace, before eating and preparing food. Pay special attention to thoroughly soaping (at least 20 seconds), and then completely drying your hands.
    · After returning home from the street – wash your hands and face with soap, rinse your nose with isotonic salt solution.
    · Touch the face and eyes with freshly washed hands. If water and soap are not available, use alcohol-based hand sanitizers to clean your hands. Or use a disposable napkin, if necessary, touching the eyes or nose
    · Wear a disposable medical mask in crowded places and transport. It is necessary to change the mask to a new one every 2-3 hours; the mask cannot be reused.
    · Give preference to sleek hairstyles when you are in crowded places, loose hair, often in contact with your face, increases the risk of infection.
    · Avoid close contact and stay in the same room with people with visible signs of SARS (coughing, sneezing, nasal discharge).
    · Do not touch door handles, handrails, other objects or surfaces in public spaces with bare hands.
    · Limit welcome handshakes, kisses, and hugs.
    · Ventilate the premises more often.
    · Do not use shared towels.
    How not to infect others
    · Minimize contact with healthy people (welcome handshakes, kisses).
    · If you feel unwell, but have to communicate with other people or use public transport – use a disposable mask, be sure to change it to a new one every hour.
    · When coughing or sneezing, be sure to cover your mouth, if possible – with a disposable handkerchief, if not – with your palms or elbows.
    · Use only personal or disposable tableware.
    · Isolate your personal hygiene items from household members: toothbrush, washcloth, towels.
    · Carry out wet cleaning of the house every day, including the treatment of door handles, switches, office equipment control panels.


    Influenza, coronavirus infection and other acute respiratory viral infections (ARVI)
    Influenza, coronavirus infection and other acute respiratory viral infections (ARVI) are in first place in terms of the number of people who become ill each year 90,025
    Despite constant efforts to combat the causative agents of influenza, coronavirus infection and other acute respiratory viral infections, they still have not been defeated.
    Thousands of people die from complications of influenza every year.
    This is due to the fact that viruses, primarily influenza viruses and coronaviruses, have the ability to change their structure and a mutated virus is capable of infecting a person again. So, a person who has had the flu has a good immune barrier, but nevertheless a new modified virus is able to easily penetrate through it, since the body has not yet developed immunity against this type of virus.
    For whom is the most dangerous encounter with the virus?
    Children and the elderly are especially hard to tolerate the infection; complications that can develop during the illness are very dangerous for these age groups.Children get sick more seriously due to the fact that their immune systems have not yet met this virus, and for the elderly, as well as for people with chronic diseases, the virus is dangerous due to a weakened immune system.
    Risk groups
    • Children
    • People over 60 years old 90,025
    • People with chronic lung diseases (bronchial asthma, chronic obstructive pulmonary disease)
    • People with chronic diseases of the cardiovascular system (congenital heart defects, coronary heart disease, heart failure)
    • Pregnant women 90,025
    • Medical professionals
    • Workers of public transport, catering establishments
    How does the infection occur?
    The infection is transmitted from a sick person to a healthy person through the smallest droplets of saliva or mucus that are released during sneezing, coughing, talking.Contact transmission is also possible.
    Symptoms
    Depending on the specific type of pathogen, symptoms can vary significantly, both in severity and in combination.
    • Temperature rise
    • Chills, general malaise, weakness, headache, muscle pain
    • Decreased appetite, possible nausea and vomiting
    • Conjunctivitis (possibly)
    • Diarrhea (possibly)
    On average, the illness lasts about 5 days. If the temperature lasts longer, complications may have arisen.
    Complications
    • Pneumonia
    • Encephalitis, meningitis
    • Complications of pregnancy, development of fetal pathology
    • Exacerbation of chronic diseases
    Treatment of the disease is carried out under the supervision of a physician who, only after examining the patient, prescribes a treatment regimen and gives other recommendations. The sick person must comply with bed rest, eat well and drink more fluids.
    Antibiotics
    Taking antibiotics in the early days of the disease is a big mistake.Antibiotics are not able to cope with the virus, in addition, they adversely affect the normal microflora. Antibiotics are prescribed only by a doctor, only in case of complications caused by the addition of a bacterial infection. Taking antibacterial drugs as a preventive measure for the development of complications is dangerous and useless.
    A sick person should stay at home and not pose a threat of infection to others.
    Prevention
    The most effective way to prevent influenza is to get vaccinated annually.The composition of the influenza vaccine changes annually. First of all, it is recommended to get vaccinated for those who are at risk. The optimal time for vaccination is October-November. Infants can be vaccinated against influenza from 6 months of age.
    Vaccines against most pathogens of acute respiratory viral infections have not been developed.
    Universal prevention measures
    • Wash your hands often and thoroughly
    • Avoid contact with people coughing
    • Follow a healthy lifestyle (sleep, healthy food, physical activity)
    • Drink plenty of fluids
    • Regularly ventilate and humidify the air in the room where you are
    • Be in public places less often
    • Use a mask when in transport or in public places
    • Avoid hugging, kissing and shaking hands when meeting
    • Do not touch your face, eyes, nose with unwashed hands
    At the first sign of a viral infection – consult a doctor!


    Influenza, coronavirus, other acute respiratory viral infections – a mask will help!
    During the period of active circulation of pathogens of influenza, coronavirus infection, and other pathogens of acute respiratory viral infections, we recall the advisability of using a disposable medical mask as an effective measure to prevent infection and limit the spread of infection.
    These viruses are transmitted from person to person mainly by airborne droplets, through microdroplets of respiratory secretions that are formed when infected people speak, sneeze or cough.
    With air, these droplets can get onto the surface of the mucous membrane of the upper respiratory tract of healthy people who are next to an infected person.
    Infection can also occur as a result of direct or indirect contact of a healthy person with the respiratory secretions of an infected person.
    Using a disposable medical mask prevents droplets of respiratory secretions, which may contain viruses, from entering the body of a healthy person through the nose and mouth.
    • Wear a mask when caring for a family member with symptoms of a viral respiratory illness.
    • If you are sick or have symptoms of a viral respiratory illness, wear a mask before approaching other people.
    • If you have symptoms of a viral respiratory illness and need to see a doctor, wear a mask well in advance to protect those around you in the waiting area.
    • Wear a mask when in crowded places.
    • Use the mask once; reuse of the mask is not allowed.
    • Change the mask every 2-3 hours or more often.
    • If the mask is wet, it should be replaced with a new one.
    • After using the mask, discard it and wash your hands.
    Disposable medical mask, if used correctly, is a reliable and effective method of reducing the risk of infection and preventing the spread of influenza, coronavirus and other ARVI pathogens


    Memo: Prevention of influenza and coronavirus infection
    Influenza and coronavirus viruses cause respiratory diseases of varying severity in humans.Symptoms are similar to those of regular (seasonal) flu. The severity of the disease depends on a number of factors, including the general condition of the body and age.
    Predisposed to the disease: the elderly, small children, pregnant women and people with chronic diseases (asthma, diabetes, cardiovascular diseases), and with weakened immunity.

    RULE 1. WASH HANDS OFTEN WITH SOAP
    Clean and disinfect surfaces using household detergents.
    Hand hygiene is an important measure to prevent the spread of influenza and coronavirus infection. Washing with soap removes viruses. If you cannot wash your hands with soap and water, use alcohol or disinfectant wipes.
    Cleaning and regular disinfection of surfaces (tables, doorknobs, chairs, gadgets, etc.) removes viruses.

    RULE 2. OBSERVE THE DISTANCE AND ETIQUETTE
    Viruses are transmitted from a sick person to a healthy person by airborne droplets (when sneezing, coughing), therefore, you must maintain a distance of at least 1 meter from patients.
    Avoid touching your eyes, nose, or mouth with your hands. The flu virus and coronavirus are spread by these routes.
    Wear a mask or other available protective equipment to reduce the risk of illness.
    When coughing, sneezing, cover your mouth and nose with disposable tissues, which should be discarded after use.
    Avoiding unnecessary travel and visits to crowded places can reduce the risk of illness.

    RULE 3. LEAD A HEALTHY LIFESTYLE
    A healthy lifestyle increases the body’s resistance to infection.Maintain a healthy schedule, including adequate sleep, eating foods rich in protein, vitamins and minerals, and being physically active.

    RULE 4. PROTECT THE RESPIRATORY ORGANS WITH A MEDICAL MASK
    Among other means of prevention, wearing masks occupies a special place, thanks to which the spread of the virus is limited.
    Medical masks for respiratory protection are used:
    – when visiting crowded places, traveling by public transport during a period of increasing incidence of acute respiratory viral infections;
    – when caring for patients with acute respiratory viral infections;
    – when communicating with persons with signs of an acute respiratory viral infection;
    – with the risk of infection with other infections transmitted by airborne droplets.

    HOW TO WEAR THE MASK CORRECTLY?
    Masks can be of different designs. They can be one-time use or they can be applied multiple times. There are masks that last 2, 4, 6 hours. The cost of these masks is different due to the different impregnation. But you can’t wear the same mask all the time, so you can infect yourself twice. Which side to wear a medical mask inward is not a matter of principle.
    To protect yourself from infection, it is extremely important to wear it correctly:
    – the mask must be carefully fixed, tightly covering the mouth and nose, leaving no gaps;
    – try not to touch the surfaces of the mask when removing it, if you touched it, wash your hands thoroughly with soap or alcohol;
    – a wet or damp mask should be changed to a new, dry one;
    – do not reuse the disposable mask;
    – A used disposable mask should be discarded immediately.
    When caring for a patient, after the end of contact with a sick person, the mask should be removed immediately. After removing the mask, wash your hands immediately and thoroughly.
    The mask is appropriate if you are in a crowded place, on public transport, as well as when caring for the sick, but it is not advisable in the open air.
    It is good to breathe fresh air while you are outdoors and you should not wear a mask.
    At the same time, doctors remind that this single measure does not provide complete protection against the disease.In addition to wearing a mask, other preventive measures must be followed.

    RULE 5. WHAT TO DO IN CASE OF INFLUENZA, CORONAVIRUS INFECTION?
    Stay at home and see a doctor urgently.
    Follow your doctor’s instructions, stay in bed and drink as much fluids as possible.

    WHAT ARE THE SYMPTOMS OF FLU / CORONAVIRUS INFECTION
    High body temperature, chills, headache, weakness, nasal congestion, cough, shortness of breath, muscle pain, conjunctivitis.
    In some cases, there may be symptoms of gastrointestinal disorders: nausea, vomiting, diarrhea.

    WHAT ARE THE COMPLICATIONS
    Viral pneumonia is the leading complication. Deterioration in viral pneumonia is rapid, and many patients develop respiratory failure within 24 hours, requiring immediate respiratory support with mechanical ventilation.
    Promptly initiated treatment helps to alleviate the severity of the disease.

    WHAT TO DO IF SOMEONE HAS A FLU / CORONAVIRUS INFECTION IN THE FAMILY?
    – Call a doctor.
    – Give the patient a separate room in the house. If this is not possible, keep a distance of at least 1 meter from the patient.
    – Minimize contact between sick and loved ones, especially children, the elderly and people with chronic diseases.
    – Ventilate the area frequently.
    – Keep clean and wash and disinfect surfaces with household detergents as often as possible.
    – Wash your hands often with soap and water.
    – When caring for a sick person, cover your mouth and nose with a mask or other protective equipment (handkerchief, scarf, etc.).
    – Only one family member should take care of the sick person.

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    90,000 WHO Information: Similarities and Differences – COVID-19 and Influenza

    An outbreak of an infectious disease caused by a new coronavirus infection (COVID-19) continues to develop, and against this background, this disease is compared with the flu.

    Both diseases are respiratory diseases, but there are important differences between the two viruses and how they spread. This is important in terms of what public health measures can be taken to respond to each virus.

    Q: How are COVID-19 and influenza viruses similar?

    First, COVID-19 and influenza viruses have a similar disease pattern. That is, they both cause respiratory illness, which is a wide range of disease variants, from asymptomatic or mild to severe illness and death.

    Secondly, both viruses are transmitted by contact, by airborne droplets and through fomites. As such, the important health care measures that everyone can take to prevent infection are the same, such as hand hygiene and respiratory etiquette (coughing into the elbow or into a tissue and discard immediately).

    Q: What is the difference between COVID-19 and influenza viruses?

    An important difference between the two viruses is the transmission speed.

    Influenza has a shorter average incubation period (time from infection to onset of symptoms) and a shorter serial interval (time between successive cases) than COVID-19 virus. The serial interval for the COVID-19 virus is estimated at 5-6 days, while for the influenza virus, the serial interval is 3 days. This means the flu can spread faster than COVID-19.

    In addition, transmission in the first 3-5 days of illness, or potentially presymptomatic transmission – transmission of the virus before symptoms appear – is the main cause of influenza transmission.In contrast, while we know that there are people who can spread the COVID-19 virus 24-48 hours before symptoms appear, this does not appear to be the main cause of transmission at this time.

    The reproductive rate – the number of secondary infections caused by one infected person – is estimated to be between 2 and 2.5 for the COVID-19 virus, which is higher than for influenza. However, estimates made for COVID-19 and influenza are highly contextual and time-dependent, making direct comparisons difficult.

    Children are an important contributor to the transmission of the influenza virus in society. For the COVID-19 virus, initial data show that children are less affected by the disease than adults, and the incidence of symptomatic disease in the 0-19 age group is low. Additional preliminary data from households in China show that children are infected by adults, not the other way around.

    While the two viruses have a similar spectrum of symptoms, the proportion of severe cases appears to be different.For COVID-19, data to date suggest that 80% of infections are mild or asymptomatic, 15% are severe, requiring oxygenation, and 5% are critical, requiring ventilation. The proportions of severe and critical cases are higher than those seen for influenza.

    Children, pregnant women, the elderly, people with chronic diseases and immunodeficiency are most at risk of severe influenza infection. With regard to COVID-19, we now know that older age and underlying medical conditions increase the risk of severe infection.

    Deaths from COVID-19 appear to be higher than from influenza, especially seasonal flu. While it will take some time to fully understand the true extent of COVID-19 mortality, the data we have shows that the crude death rate (the number of reported deaths divided by the number of reported cases) is 3-4%, the infectious mortality rate (the number of reported deaths divided by the number of infections) will be lower. For seasonal flu, mortality is usually well below 0.1%.However, mortality is largely determined by access to and quality of care.

    Q: What medical supplies are available for COVID-19 and influenza viruses?

    Although China is currently conducting clinical trials of a number of drugs and more than 20 vaccines for COVID-19 are being developed worldwide, there are currently no licensed vaccines or therapeutic agents. At the same time, antiviral drugs and flu vaccines exist.Although the flu vaccine is not effective against the COVID-19 virus, it is highly recommended to get vaccinated every year to prevent getting the flu.

    Based on WHO material at https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200307-sitrep-47-covid-19.pdf?sfvrsn = 27c364a4_2

    GBPOU “Volgograd College of Mechanical Engineering and Communications”

    Information on measures of personal and public prevention of influenza, ARVI and coronavirus infection (2019-nCov)

    Information from Rospotrebnadzor of the Russian Federation of 30.10.2020
    “Five rules of protection against coronavirus and SARS”

    RULE 1. WASH HANDS WITH SOAP FREQUENTLY
    Clean and disinfect surfaces using household detergents.
    Hand hygiene is an important measure to prevent the spread of influenza and coronavirus infection. Washing with soap removes viruses. If you cannot wash your hands with soap and water, use alcohol or disinfectant wipes.
    Cleaning and regular disinfection of surfaces (tables, doorknobs, chairs, gadgets, etc.)) removes viruses.

    RULE 2. OBSERVE THE DISTANCE AND ETIQUETTE
    Viruses are transmitted from a sick person to a healthy person by airborne droplets (when sneezing, coughing), so you must maintain a distance of at least 1.5 meters from each other.
    Avoid touching your eyes, nose, or mouth with your hands. The coronavirus, like other respiratory diseases, is spread by these routes.
    Wear a mask or other available protective equipment to reduce the risk of illness.
    When coughing, sneezing, cover your mouth and nose with disposable tissues, which should be discarded after use.
    Try to reduce travel and visits to crowded places to help reduce your risk of illness.

    RULE 3. LEAD A HEALTHY LIFESTYLE
    A healthy lifestyle increases the body’s resistance to infection . Maintain a healthy schedule, including adequate sleep, eating foods rich in protein, vitamins and minerals, and being physically active.

    RULE 4. PROTECT THE RESPIRATORY ORGANS WITH A MEDICAL MASK
    Among other means of prevention, wearing masks occupies a special place, thanks to which the spread of the virus is limited.
    Medical masks for respiratory protection are used:
    – when visiting crowded places, traveling by public transport during a period of increasing incidence of acute respiratory viral infections;
    – when caring for patients with acute respiratory viral infections;
    – when communicating with persons with signs of an acute respiratory viral infection;
    – with the risk of infection with other infections transmitted by airborne droplets.

    HOW TO WEAR THE MASK CORRECTLY?
    Masks can be of different designs.They can be one-time use or they can be applied multiple times. Which side to wear a medical mask inward is not a matter of principle.
    To protect yourself from infection, it is extremely important to wear it correctly:
    – the mask must be carefully fixed, tightly covering the mouth and nose, leaving no gaps;
    – try not to touch the surfaces of the mask when removing it, if you touched it, wash your hands thoroughly with soap or alcohol;
    – a wet or damp mask should be changed to a new, dry one;
    – do not reuse the disposable mask;
    – A used disposable mask should be discarded immediately.
    When caring for a patient, after the end of contact with a sick person, the mask should be removed immediately. After removing the mask, wash your hands thoroughly immediately.
    The mask is necessary if you are in a crowded place, in public transport, a store, a pharmacy, in an elevator, or when caring for a sick person.

    RULE 5. WHAT TO DO IN CASE OF ARVI, FLU, CORONAVIRUS INFECTION?
    Stay home and see a doctor.
    Follow your doctor’s orders and stay in bed.

    How are COVID-19 and influenza viruses similar?

    COVID-19 and influenza viruses have a similar disease pattern. They both cause respiratory illness, which is a wide range of disease variants, from asymptomatic or mild to severe illness and death.

    Both viruses are transmitted by contact, airborne droplets and through fomites. Therefore, do not forget about the simple rules of prevention: use a mask, observe hand hygiene and social distance.

    How are COVID-19 and influenza viruses different?

    An important difference between the two viruses is the transmission speed. Influenza has a shorter average incubation period (time from infection to onset of symptoms) and a shorter serial interval (time between successive cases) than COVID-19 virus. The serial interval for the COVID-19 virus is estimated at 5-6 days, while for the influenza virus, the serial interval is 3 days. This means the flu can spread faster than COVID-19.

    In addition, transmission in the first 3-5 days of illness, or potentially presymptomatic transmission – transmission of the virus before symptoms appear – is the main cause of influenza transmission. In contrast, it is known that there are people who can spread the COVID-19 virus 24-48 hours before the onset of symptoms, this does not appear to be the main cause of transmission at this time.

    The reproductive rate – the number of secondary infections caused by one infected person – is estimated to be between 2 and 2.5 for the COVID-19 virus, which is higher than for influenza.However, estimates made for COVID-19 and influenza are highly contextual and time-dependent, making direct comparisons difficult.

    The two viruses have a similar spectrum of symptoms, with the proportion of severe cases likely to differ. For COVID-19, data to date suggest that 80% of infections are mild or asymptomatic, 15% are severe, requiring oxygenation, and 5% are critical, requiring ventilation.