Swine Flu :An Endemic and Pandemic Disease

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Review Article Kalavapudi.Vyshnavi et al. / Journal of Pharmacy Research 2010, 3(1),93-99 ISSN: 0974-6943 Available online through http://jprsolutions.info Swine Flu :an endemic and pandemic disease

Kalavapudi.Vyshnavi*,Dr.I.Sudheer babu, Sriman.Tirumala.Gudimella.Raviteja*, palaniyappan.Venkatesh, Kothandam.Hariprasath. *Sir.C.R.Reddy College of Pharmaceutical Sciences, Eluru-534007, Andhra Pradesh, India. Received on: 20-09-2009; Revised on: 16-10-2009; Accepted on:15-12-2009

ABSTRACT Swine flu is a highly contagious disease of pigs and infection by any one of several types of swine influenza virus. Swine influenza virus is any strain of influenza family of viruses that is endemic in pigs. It is estimated that 50 to 100 million people were killed worldwide. The direct transfer of the virus probably occurs either by pigs (touching noses, or through dried mucus) and close contact with infected people. People who work with poultry and swine, especially people with intense exposures, are at increased risk of zoonotic infection with influenza virus endemic in these animals, and constitute a population of human hosts in which zoonosis and reassortment can co-occur. Symptoms of swine flu are similar to most influenza infections: running nose, body aches, chills, fever (100°F or greater), cough, fatigue, and headache, myalgia, dyspnea with fatigue being reported in most infected individuals. The two major tests that are being used are the nasopharyngeal (or back of the throat) swab for viral culture, the gold standard, and the indirect evidence test by detection of antibodies to novel H1N1 with polymerase chain reaction(PCR) studies. Antiviral treatment with either zanamivir alone or with a combination of oseltamivir and either amantadine or rimantadine should be initiated as soon as possible after the onset of symptoms. There are two kinds of 2009 H1N1 vaccines being produced:- A 2009 H1N1 “flu shot”, The 2009 H1N1 nasal spray flu vaccine. In our review paper, we have detailed the transmission, classification of influenza virus, replication, symptoms, treatment and its preventive measures.

Keywords: Swine influenza virus, oseltamivir, amantadine.

INTRODUCTION

The Pandemic H1N1/09 virus is a swine-origin influenza A (H1N1) virus strain responsible for the 2009 flu pandemic. The ini- The word Influenza comes from the Italian language and re- tial outbreak was called the “H1N1 influenza.” In July 2009 WHO fers to the cause of the disease; initially, this ascribed illness to experts changed the name to “pandemic H1N1/09 virus” to distin- unfavorable astrological influences. Changes in medical thought led guish it from the current “seasonal H1N1 virus”. In the Netherlands it to its modification to influenza del freddo, meaning “influence of the was originally called “pig flu” but is now called “Mexican flu” by cold”. The word influenza was first used in English in 1743 when it the national health institute and in the media. Southwas adopted, with an anglicized pronunciation, during an outbreak of Korea and Israel briefly considered calling it the “Mexican virus”. the disease in Europe. The first convincing record of an influenza Later the South Korean press used “SI”, short for “swine pandemic was of an outbreak in 1580, which began in Russia and influenza”. Taiwan suggested the names “H1N1 flu” or “new flu”, spread to Europe via Africa. In Rome, over 8,000 people were killed, which most local media adopted. The World Organization for Animal and several Spanish cities were almost wiped out. Pandemics contin- Health proposed the name “North American influenza”. The European ued sporadically throughout the 17th and 18th centuries, with the Commission adopted the term “novel flu virus”. Swine flu is a highly pandemic of 1830–1833 being particularly widespread; it infected ap- contagious disease of pigs and infection by any one of several types proximately a quarter of the people exposed (Potter et al.,2001). The of swine influenza virus. Swine influenza virus is any strain of influ- most famous and lethal outbreak was the 1918 flu pandemic (Spanish enza family of viruses that is endemic in pigs flu pandemic) (type A influenza, H1N1 subtype), which lasted from 1918 to 1919. It is not known exactly how many it killed, but estimates HISTORY: range from 20 to 100 million people (Patterson et al., 1991). This pandemic has been described as “the greatest medical holocaust in history” and may have killed as many people as the Black Death. After *Corresponding author. 1930, for the following 60 years of swine influenza strains were Dr. Kalavapudi.Vyshnavi almost exclusively H1N1. Later flu pandemics were not so devastat- Sir.C.R.Reddy College of Pharmaceutical Sciences, Eluru-534007, Andhra ing. They included the 1957 Asian flu (type A, H2N2 strain) and the Pradesh, India. 1968 Hong Kong Flu (type A, H3N2 strain), but even these smaller Tel.: + 91-9441102235 outbreaks killed millions of people. In 1976, there was an outbreak of Telefax: +91- swine flu at Fort Dix. This virus is not the same as the 2009 outbreak, E-mail: [email protected];[email protected] but it was similar insofar as it was an influenza A virus that had simi- larities to the swine flu virus. There was one death at Fort Dix. The Journal of Pharmacy Research Vol.3.Issue 1.January 2010 93-99 Kalavapudi.Vyshnavi et al. / Journal of Pharmacy Research 2010, 3(1),93-99 government decided to produce a vaccine against this virus, but the virus can infect a pig respiratory cell at the same time as a swine vaccine was associated with neurological complications (Guillain-Barré influenza virus; some of the replicating RNA strands from the human syndrome) and was discontinued. Then between 1997 and 2002 new virus can get mistakenly enclosed inside the enveloped swine influ- strains of three different subtypes and five different enza virus. For example, one cell could contain eight swine flu and genotypes emerged as causes of influenza. During the mid-20th century, eight human flu RNA segments. The total number of RNA types in identification of influenza sub types became possible allowing accu- one cell would be 16; four swine and four human flu RNA segments rate diagnosis of transmission to humans. It is estimated could be incorporated into one particle, making a viable eight RNA that 500,000 people were killed worldwide. The etiological cause of segmented flu virus from the 16 available segment types. Various influenza, the Orthomyxoviridae family of viruses, was first discov- combinations of RNA segments can result in a new subtype of virus ered in pigs by Richard Shope in 1931. This discovery was shortly (known as antigenic shift) that may have the ability to preferentially followed by the isolation of the virus from humans by a group headed infect humans but still show characteristics unique to the swine influ- by Patrick Laidlaw at the Medical Research Council of the Unitedenza virus (Recker et al.,2007). It is even possible to include RNA Kingdom in 1933. strands from birds, swine, and human influenza viruses into one virus if a cell becomes infected with all three types of influenza (for example, TRANSMISSION: two bird flu, three swine flu, and three human flu RNA segments to produce a viable eight-segment new type of flu viral genome). Forma- Transmission between pigs tion of a new viral type is considered to be antigenic shift; small changes in an individual RNA segment in flu viruses are Influenza is quite common in pigs, with about half of breed- termed antigenic drift and result in minor changes in the virus. How- ing pigs having been exposed to the virus in the US. Antibodies to ever, these can accumulate over time to produce enough minor the virus are also common in pigs in other countries. The main route changes that cumulatively change the virus’ antigenic makeup over of transmission is through direct contact between infected and time (usually years). uninfected animals. These close contacts are particularly common during animal transport. Intensive farming may also increase the risk Second, pigs can play a unique role as an intermediary host of transmission, as the pigs are raised in very close proximity to each to new flu types because pig respiratory cells can be infected directly other. The direct transfer of the virus probably occurs either by pigs with bird, human, and other mammalian flu viruses. Consequently, pig touching noses, or through dried mucus. Airborne transmissions respiratory cells are able to be infected with many types of flu and can through the aerosols produced by pigs coughing or sneezing are also function as a “mixing pot” for flu RNA segments. Bird flu viruses, an important means of infection. The virus usually spreads quickly which usually infect the gastrointestinal cells of many bird species, through a herd, infecting all the pigs within just a few days. Transmis- are shed in bird feces. Pigs can pick these viruses up from the envi- sion may also occur through wild animals, such as wild boar, which ronment and seem to be the major way that bird flu virus RNA seg- can spread the disease between farms (Vicente et al., 2002). ments enter the mammalian flu virus population.

Transmission to humans

People who work with poultry and swine, especially people with intense exposures, are at increased risk of zoonotic infection with influenza virus endemic in these animals, and constitute a population of human hosts in which zoonosis and reassortment can co- occur (Gray et al., 2009). Vaccination of these workers against influenza and surveillance for new influenza strains among this population may therefore be an important public health measure. Transmis- sion of influenza from swine to humans who work with swine was documented in a small surveillance study performed in 2004 at the University of Iowa. This study among others forms the basis of a recommendation that people whose jobs involve handling poultry and swine be the focus of increased public health surveillance. Other professions at particular risk of infection are veterinarians and meat processing workers, although the risk of infection for both of these Structure of the influenza virion. The hemagglutinin (HA) groups is lower than that of farm workers. and neuraminidase (NA) proteins are shown on the surface of the particle. The viral RNAs that make up the genome are shown as red Infection to humans coils inside the particle and bound to Ribonuclear Proteins (RNPs).

Two main series of events can lead to swine flu becoming a major CLASSIFICATION: cause for influenza illness in humans: Types of influenza virus First, the influenza viruses (types A, B, C) are enveloped RNA viruses with a segmented genome; this means the viral RNA Influenza viruses A, B and C are very similar in overall struc- genetic code is not a single strand of RNA but exists as eight different ture. The virus particle is 80- 120 nanometres in diameter and usually RNA segments in the influenza viruses. A human (or bird) influenza

Journal of Pharmacy Research Vol.3.Issue 1.January 2010 93-99 Kalavapudi.Vyshnavi et al. / Journal of Pharmacy Research 2010, 3(1),93-99 roughly spherical, although filamentous forms can occur.

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the family Orthomyxoviridae:

· Influenza virus A · Influenza virus B · Influenza virus C

These viruses are only distantly related to the human parainfluenza viruses, which are RNA viruses belonging to the paramyxovirus family that are a common cause of respiratory infections in children such as croup (vainion et al,.1994), but can also

Hemagglutinin cause a disease similar to influenza in adults. (Hall et al, .2001) Neuraminidas

Influenza virus A

This genus has one species, influenza A virus. Wild aquatic Types of Nuclear Material q birds are the natural hosts for a large variety of influenza A. Occasion- q q ally; viruses are transmitted to other species and may then cause A / Fujian /411/ 2002( H3N2) devastating outbreaks in domestic poultry or give rise to human A / Fujian /411/ 2002 ( H3N2) influenza pandemics. The type A viruses are the most virulent human p p p p p pathogens among the three influenza types and cause the most severe disease. Hemagglutinin (HA) and neuraminidase (NA) are the Virus Geographical Strain Year of Isolation Virus subtype two large glycoproteins on the outside of the viral particles. HA is types origin number a lectin that mediates binding of the virus to target cells and entry of Diagram of influenza virus nomenclature (for a Fujian flu virus) the viral genome into the target cell, while NA is involved in the A. The only other animals known to be susceptible to influenza B release of progeny virus from infected cells, by cleaving sugars that infection are the seal and the ferret. This type of influenza mutates at bind the mature viral particles. Thus, these proteins are targets a rate 2–3 times lower than type A and consequently is less geneti- for antiviral drugs. Furthermore, they are antigens to cally diverse, with only one influenza B serotype. As a result of this which antibodies can be raised. Influenza A viruses are classified into lack of antigenic diversity, a degree of immunity to influenza B is usu- subtypes based on antibody responses to HA and NA. For example, ally acquired at an early age. However, influenza B mutates enough the influenza A genome contains 11 genes on eight pieces of RNA, that lasting immunity is not possible. This reduced rate of antigenic encoding for 11 proteins: hemagglutinin (HA), neuraminidase (NA), change, combined with its limited host range (inhibiting cross nucleoprotein (NP), M1, M2, NS1, NS2 or NEP (Nuclear export pro- species antigenic shift), ensures that pandemics of influenza B do not tein ), PA, PB1, PB1-F2 and PB2 (Ghedin et al.,2005). These different occur. types of HA and NA form the basis of the H and N distinctions in, for example, H5N1. There are 16 H and 9 N subtypes known, but only H Influenza virus C 1, 2 and 3, and N 1 and 2 are commonly found in humans. This genus has one species, influenza C virus, which infects The influenza A virus can be subdivided into humans, dogs and pigs, sometimes causing both severe illness and different serotypes based on the antibody response to these local epidemics (Taubenberger et al., 2008). Filamentous forms are viruses (Hay et al., 2001). The serotypes that have been confirmed in more common in influenza C, which can form cordlike structures up to humans, ordered by the number of known human pandemic deaths, 500 micrometers long on the surfaces of infected cells. However, in- are: fluenza C is less common than the other types and usually · H1N1, which caused Spanish flu in 1918, and the 2009 flu pandemic only cause’s mild disease in children. · H2N2, which caused Asian Flu in 1957 · H3N2, which caused Hong Kong Flu in 1968 virus life cycle: · H5N1, a current pandemic threat Replication · H7N7, which has unusual zoonotic potential · H1N2, endemic in humans and pigs Host cell invasion and replication by the influenza virus. Vi- · H9N2 ruses can only replicate in living cells. Influenza infection and replica- · H7N2 tion is a multi-step process: firstly the virus has to bind to and enter · H7N3 the cell, then deliver its genome to a site where it can produce new · H10N7 copies of viral proteins and RNA, assemble these components into Influenza virus B new viral particles and finally exit the host cell. This genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza Influenza viruses bind through hemagglutinin onto sialic

Journal of Pharmacy Research Vol.3.Issue 1.January 2010 93-99 Kalavapudi.Vyshnavi et al. / Journal of Pharmacy Research 2010, 3(1),93-99

acid sugars on the surfaces of epithelial cells; typically in the nose, surface (in the case of neuraminidase and hemagglutinin, (stage 5b) throat and lungs of mammals and intestines of birds (Stage 1). After or transported back into the nucleus to bind vRNA and form new the hemagglutinin is cleaved by a protease, the cell imports the virus viral genome particles (stage 5a). Other viral proteins have multiple by endocytosis. Once inside the cell, the acidic conditions in actions in the host cell, including degrading cellular mRNA and us- the endosome cause two events to happen: first part of the hemag- ing the released nucleotides for vRNA synthesis and also glutinin protein fuses the viral envelope with the vacuole’s membrane, inhibiting translation of host-cell mRNAs (Kash et al., 2006). then the M2 ion channel allows protons to move through the viral Negative-sense vRNAs that form the genomes of future viruses, RNA- envelope and acidify the core of the virus, which causes the core to dependent RNA polymerase, and other viral proteins are assembled dissemble and release the viral RNA and core proteins. The viral RNA into a virion. Hemagglutinin and neuraminidase molecules cluster (vRNA) molecules, accessory proteins and RNA-dependent RNA into a bulge in the cell membrane. The vRNA and viral core proteins polymerase are then released into the cytoplasm (Stage 2). leave the nucleus and enter this membrane protrusion (stage 6). The mature virus buds off from the cell in a sphere of host phospholipid These core proteins and vRNA form a complex that is trans- membrane, acquiring hemagglutinin and neuraminidase with this mem- ported into the cell nucleus, where the RNA-dependent RNA poly- brane coat (stage 7) (Nayak et al., 2004). As before, the viruses ad- merase begins transcribing complementary positive-sense vRNA here to the cell through hemagglutinin; the mature viruses detach (Stage 3a and b). The vRNA is either exported into the cytoplasm and once their neuraminidase has cleaved sialic acid residues from the translated (stage 4), or remains in the nucleus. Newly synthesized viral host cell. Drugs that inhibit neuraminidase, such as oseltamivir, there- proteins are either secreted through the Golgi apparatus onto the cell fore prevent the release of new infectious viruses and halt viral repli-

Journal of Pharmacy Research Vol.3.Issue 1.January 2010 93-99 Kalavapudi.Vyshnavi et al. / Journal of Pharmacy Research 2010, 3(1),93-99 cation. After the release of new influenza viruses, the host cell dies. DIAGNOSIS:- Because of the absence of RNA proofreading enzymes, the RNA- Swine flu is presumptively diagnosed clinically by the patient’s his- dependent RNA polymerase that copies the viral genome makes an tory of association with people known to have the disease and their error roughly every 10 thousand nucleotides, which is the approxi- symptoms. Usually, a quick test (for example, nasopharyngeal swab mate length of the influenza vRNA. Hence, the majority of newly sample) is done to see if the patient is infected with influenza A or B virus. Most of the tests can distinguish between A and B types. The manufactured influenza viruses are mutants, this cause ”antigenic test can be negative (no flu infection) or positive for type A and B. If drift”, which is a slow change in the antigens on the viral surface over the test is positive for type B, the flu is not likely to be swine flu time. The separation of the genome into eight separate segments of (H1N1). If it is positive for type A, the person could have a conven- vRNA allows mixing or reassortment of vRNAs if more than one type tional flu strain or swine flu (H1N1). Swine flu (H1N1) is definitively of influenza virus infects a single cell. The resulting rapid change in diagnosed by identifying the particular antigens associated with the viral genetics produces antigenic shifts, which are sudden changes virus type. In general, this test is done in a specialized laboratory and from one antigen to another. These sudden large changes allow the is not done by many doctors’ offices or hospital laboratories. How- virus to infect new host species and quickly overcome protective ever, doctors’ offices are able to send specimens to specialized labo- immunity. This is important in the emergence of pandemics, as dis- ratories if necessary. The two major tests that are being used are the cussed below in the section on Epidemiology. nasopharyngeal (or back of the throat) swab for viral culture, the gold standard, and the indirect evidence test by detection of antibodies to novel H1N1 with PCR studies. SYMPTOMS:

TREATMENT: Symptoms of swine flu are similar to most influenza infections: running nose, body aches, chills, fever (100F orAntiviral Treatment (medication) greater), cough, fatigue, and headache, myalgia, dyspnea with fatigue being reported in most infected individuals (Suzuki et al., 2007). Some Suspected Cases: patients also get nausea, vomiting, sore throat, diarrhea (less common) and loss of appetite. Some develop severe respiratory symp- Empiric antiviral treatment is recommended for any ill per- toms and need respiratory support (such as a ventilator to breathe for son suspected to have swine influenza A (H1N1) virus infection. the patient). Patients can get pneumonia (bacterial secondary infec- Antiviral treatment with either zanamivir alone or with a combination tion) and respiratory fatigue if the viral infection persists, and some of oseltamivir and either amantadine or rimantadine should be initi- can develop seizures. Death often occurs from secondary bacterial ated as soon as possible after the onset of symptoms. Recommended infection of the lungs. Conjunctivitis is rare but, has been reported. It duration of treatment is five days. can be difficult to distinguish between the common cold and swine flu in the early stages of these infections, but flu can be identified by Confirmed Cases: a high fever with a sudden onset and extreme fatigue. For antiviral treatment of a confirmed case of swine influenza A (H1N1) virus infection, either oseltamivir (Tami flu) Symptoms of Swine Flu or zanamivir (Relenza) may be administered. Recommended duration of treatment is five days. These same antiviral should be considered Psychological Systemic for treatment of cases that test positive for influenza A but test nega- lethargy tive for seasonal influenza viruses H3 and H1 by PCR. Fever Lack of appetite Pregnant Women:

Nasopharynx Oseltamivir, zanamivir, amantadine, and rimantadine are all Running nose Respiratory “Pregnancy Category C” medications, indicating that no clinical stud- Sore throat Coughing ies have been conducted to assess the safety of these medications for pregnant women.

Dosage:-oseltamivir (tamiflu) for adults 75mg- two times a day, for Gastric children 30mg-two times a day. Intestinal Nausea Route of administration- oral medication. Diarrhea Vomitting Dosage:-Zanamivir for adults 5mg-two times a day. For children 5mg- one time a day.

Route of administration- inhaled through a device similar to an asthma inhaler and should not be used by anyone with respiratory conditions such as asthma and lung diseases.

Journal of Pharmacy Research Vol.3.Issue 1.January 2010 93-99 Kalavapudi.Vyshnavi et al. / Journal of Pharmacy Research 2010, 3(1),93-99 VACCINATION: close contact with people who are sick. When you are sick, keep your distance from others to protect them from getting sick too.If possible, A flu vaccine is the single best way to protect against influ- stay home from work, school, and errands when you are sick. You will enza illness. There are two kinds of 2009 H1N1 vaccines being pro- help prevent others from catching your illness.Cover your mouth and duced: nose with a tissue when coughing or sneezing. It may prevent those around you from getting sick.Washing your hands often will help A 2009 H1N1 “flu shot”— an inactivated vaccine (containing killed protect you from germs.Germs are often spread when a person touches virus) that is given with a needle, usually in the arm. The indications something that is contaminated with germs and then touches his or for who can get the 2009 H1N1 flu shot are the same as for seasonal her eyes, nose, or mouth.Get plenty of sleep, be physically active, flu shots. The flu shot is approved for use in people 6 months of age manage your stress, drink plenty of fluids, and eat nutritious food. and older, including healthy people, people with chronic medical conditions and pregnant women. The same manufacturers who produce PREVENTION IN SWINE: seasonal flu shots are producing 2009 H1N1 flu shots for use in the United States this season. The 2009 H1N1 flu shot is being made in the same way that the seasonal flu shot is made. Methods of preventing the spread of influenza among swine include facility management, and vaccination. Vaccination stratagies The 2009 H1N1 nasal spray flu vaccine : for SIV control and prevention in swine farms typically include the use of one of several bivalent SIV vaccines commercially available. A vaccine made with live, weakened viruses that do not Facility management includes using disinfectants and ambient tem- cause the flu (sometimes called LAIV for “live attenuated influenza perature to control virus in the environment and it is readily inacti- vaccine”). The indications for who can get the 2009 H1N1 nasal spray vated by disinfectants. Herd management includes not adding pigs vaccine are the same as for seasonal nasal spray vaccine. LAIV is carrying influenza to herds that have not been exposed to the virus. approved for use in healthy* people 2 years to 49 years of age who Carrier pigs are usually responsible for the introduction of SIV into are not pregnant. The nasal spray vaccine for use in the United previously uninfected herds and countries, so new animals should be States is being made by Med Immune, the same company that makes quarantied. the seasonal nasal spray vaccine called “FluMist®.” The 2009 H1N1 nasal spray vaccine is being made in the same way as the seasonal nasal spray vaccine. PREVENTION IN HUMANS:

About 2 weeks after vaccination, antibodies that provide PREVENTION OF PIG TO HUMAN TRANSMISSION: protection against 2009 H1N1 influenza virus infection will develop in the body. The 2009 H1N1 vaccine will not protect against seasonal The transmission from swine to human is believed to occur influenza viruses. Vaccination against 2009 H1N1 should begin as mainly in swine farms where farmers are in close contact with live soon as vaccine is available and continue throughout the influenza pigs,so farmers and veterinarians are encouraged to use a face mask season, into December, January, and beyond. This is because the when dealing with infected animals. The use of vaccines on swine to timing and duration of flu activity can vary. Flu seasons can last as prevent their infection is a major method of limiting swine to human late as April or May. transmission. CDC’s Advisory Committee on Immunization Practices (ACIP), a panel made up of medical and public health experts, met July PREVENTION OF HUMAN TO HUMAN TRANSMISSION: 29, 2009, to make recommendations on who should receive the 2009 H1N1 vaccine when it becomes available. People in the following five Influenza spreads between humans through coughing or sneezing target groups: and people touching something with the virus on it and then touching their own nose or mouth.Recommendations to prevent spread of · pregnant women, the virus among humans include using standard infection control · people who live with or provide care for infants younger than 6 against influenza. This includes frequent washing of hands with soap months (e.g., parents, siblings, and day care providers), and water or with alcohol based hand sanitizers, especially being out · health care and emergency medical services personnel, in public. · people 6 months through 24 years of age, and, · People 25 years through 64 years of age who have certain medical conditions that put them at higher risk for influenza-related complications. ACKNOWLEDGEMENT:

PREVENTIVE MEASURES: We are thankful to our management Sir C.R.Reddy Educa- tional Institutions, Eluru, W.G District, Andhra Pradesh., for provid- The single best way to prevent seasonal flu is to ing necessary facilities. get vaccinated each year, but good health habits like covering your cough and washing your hands often can help stop the spread of REFERENCES: germs and prevent respiratory illnesses like the flu. There also are flu 1. Vicente J, Leon-vizcaino L, Gortazar C, Jose Cubero M, Gonzalez antiviral drugs that can be used to treat and prevent the flu.Avoid M, Martin-atance P. Antibodies to selected viral and bacterial patho-

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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.3.Issue 1.January 2010 93-99