The 2009 global pandemic of influenza is
currently active in 207 countries including India(1). India’s central and
state governments have taken the pandemic very seriously and have made
several unprecedented and innovative interventions. In the past India had
neglected to monitor endemic/seasonal influenza, but the pandemic has
raised public awareness to a high level through print and electronic
media. This perspective offers a review of information on global evolution
of this pandemic.
India’s Preparedness: Anticipating Pandemic
For the first time in history, people were able to
watch the pandemic approach, evolve and grow, with ample time available to
prepare to face it(2,3). Human influenza viruses belong to 3 types, A, B
and C. Only type A causes pandemics. It was the ‘highly pathogenic avian
influenza A/H5N1 virus’ (HPAI-H5N1) that emerged as pan-zootic in 2003
that alerted the world of an impending pandemic(4,5). It infected humans
only rarely(6). In February 2006, it affected poultry farms in the
tri-junction region of Maharashtra, Gujarat and Madhya Pradesh. During
2008 and 2009, it infected farm and backyard chicken in several districts
in West Bengal, Assam, Tripura and Sikkim(7). Massive culling within 3
kilometers of infected birds and strict control of importation of chicks
and feeds halted the outbreak. No human infection occurred in India(7).
Globally, 442 human infections and 262 deaths (case-fatality 59%) were
reported in 15 countries(7). It does not transmit between humans; hence it
did not seed a pandemic. However, anticipating a pandemic, India’s
Ministry of Health and Family Welfare (MoHFW) drafted a Pandemic
Preparedness and Response Plan (PPRP) in 2004(8).
What emerged in 2009 was another virus, Pandemic
influenza A (H1N1) (P-09-H1N1), with opposite qualities – highly
transmissible but of low virulence(9). It appeared in March in western
coastal North America, and spread very rapidly in Mexico and California in
April and then to other countries through May and June(10,11). The WHO
formally declared the pandemic (Phase 6 on a scale of 1-6) on June 11(11).
Promptly India revised PPRP in anticipation of its arrival in India(12).
Antigenic Drift, Shift and Emergence of Pandemics
The host range of influenza A viruses include water
birds, domestic ducks, poultry, swine and humans. The protein spikes on
the viral surface – hemagglutinin (H, for viral attachment to host cell)
and neuraminidase (N, for viral release from cell after multiplication),
are used to classify subtypes. Birds get infected with viruses carrying H1
to 16 and N 1 to 9; humans are infected by viruses carrying H1, H2 and H3
and N1 and N2 – rarely with H5 and H7.
The virus genome contains 8 single-stranded RNA
molecules. During virus multiplication in host cells they may commonly
undergo point mutations causing antigenic variations in daughter viruses –
this is ‘antigenic drift’. A network of global laboratories conduct
continuous surveillance of influenza-like illness (ILI) and isolated
influenza viruses are analyzed to determine if any new drifted variants
have begun circulating; in that case vaccine for the next season would be
updated to include the new variant. Since influenza season is not
synchronous in the north and south hemispheres, vaccine definition may be
different for the two.
Simultaneous host infection with 2 subtypes can lead to
the emergence of ‘reassortant’ viruses with different gene configuration
from either parent virus. If the emergent virus carries surface antigens
not present in earlier circulating strains, the phenomenon is called as
‘antigenic shift’. Since wild birds and swine are frequently infected
with several H and N subtypes, antigenic shift is relatively frequent
among avian and swine influenza viruses. Host-specificity and transmission
efficiency are determined by cell-surface virus receptors. Swine’s
receptors accept swine, avian and human viruses and serve as ‘mixing
vessel’ for antigenic shift. If shifted virus is capable of efficient
human-to-human transmission, the stage is set for pandemic as humans would
be immuno-logically naïve to it. Only a rare antigenic variant may be fit
for human infection, thus seeding a pandemic.
The 20th century pandemics were in 1918 (H1N1), 1957
(H2N2) and 1968 (H3N2). The new virus tends to replace endemic/seasonal
influenza viruses and post-pandemic, it continues to circulate as the new
seasonal virus. Thereafter it would exhibit antigenic drift; thus more
than one drifted variant may co-circulate. H1N1 virus circulated globally
from 1918 till 1957 and was replaced by H2N2 virus; in 1968, H3N2 virus
replaced H2N2. The seasonal H3N2 viruses that continue to be isolated
globally are descendants of the 1968 pandemic virus. In 1977 a descendant
of the 1918 pandemic H1N1 virus reappeared in northern hemisphere; it
might have been accidentally released from a laboratory(13). It slowly
established circulation globally; subsequently endemic/seasonal viruses in
both hemi-spheres are H3N2 and H1N1.
The Virus of 2009 Pandemic
The P-09-H1N1 virus was unanticipated(14). Although by
definition H1N1, its antigens came from swine influenza viruses(14).
Interestingly, in 1976 another novel swine-origin H1N1 had emerged in the
United States but it did not easily transmit between humans(15). P-09-H1N1
is antigenically distinct from earlier human H1N1 viruses. Neither
seasonal H1N1 nor vaccine containing it induces cross-reacting
neutralizing antibodies against P-09-H1N1(16). It is a re-assortant with
gene segments from viruses of swine (European, North American and Asian; 5
segments), birds (two segments) and humans (one segment)(17). Although
swine-related, it has not been detected in nature in swine or birds(18).
When exposed to infected humans, swine and turkeys have been infected by
P-09-H1N1(19, 20). Under laboratory conditions turkeys do not develop
clinical disease and transmission between birds is very inefficient(21).
Once the pandemic settles down, the virus is most
likely to become the predominant agent of endemic/seasonal influenza.
Antigenic changes in seasonal H3N2 occur by mutations and genetic
recombination between co-circulating viruses of the same subtype (22). A
similar phenomenon is likely to occur with P-09-H1N1 also, resulting in
variants that escape natural or vaccine-induced immunity, to become future
seasonal influenza. Reassortment with co-circulating viruses of a
different subtype may also occur; the fear is that viruses with greater
pathogenicity and efficient transmissibility may thus emerge. Of greatest
concern is the possibility of re-assortment with HPAI-H5N1 in domestic
poultry/ducks. Continuous surveillance of influenza cases, particularly
severe or atypical, is essential for the early detection of such variants.
Pathogenesis of Influenza (P-09-H1N1)
Influenza virus enters host cells through specific
cell-surface virus receptors consisting of sialic acid (SA) linked to
galactose such as SAa(2,3)Gal (avian) or SAa(2,6)Gal (human). In birds
receptors are widely distributed in gastrointestinal and respiratory
tracts, but in humans are mostly in upper respiratory tract (URT, nasal
mucosa, paranasal sinuses, pharynx). Within this broad picture, specific
subtypes may use receptors distributed differentially(23,24). The
preferential binding leads to host specificity of viruses. Human viruses
replicate efficiently in URT, hence transmit between humans via droplets
of URT secretions. Virus replication in the lower respiratory tract
contributes to greater pathogenicity. The absence of HPAI-H5N1 receptors
in human URT is why it does not spread human-to-human. With heavy/repeated
exposure it may reach the bronchioles carrying receptors, leading to
severe disease with high case-fatality(2, 7). Since P-09-H1N1 binds to URT
receptors, it circulates among humans. Receptors have also been detected
in the lungs, offering an explanation why the pandemic influenza leads to
primary viral pneumonia and acute respiratory distress syndrome (ARDS)
with high case-fatality more frequently than endemic/seasonal
Pathology of influenza is due to direct cell/tissue
damage, inflammation and innate immunity. Respiratory symptoms are due to
cell death and inflammation. Innate immune responses lead to the release
of chemokines/cytokines, mostly pro-inflammatory IL-6 and IFN-a(26).
Viral damage is essentially confined to URT, trachea and bronchi. The
systemic symptoms (see below) are attributed to cytokine excess or
‘cytokine storm’(26). Primary viral pneumonia, pulmonary edema and ARDS
are due to bronchiolar/alveolar viral cytopathology and cytokine storm.
Secondary bacterial pneumonia is common. In severe cases, multi-organ
failure may occur. Rarely influenza causes encephalopathy or encephalitis
in children; the pathogenetic mechanism is unknown. Not unexpectedly they
have been observed even during the current pandemic(27).
Immune Responses to Influenza
Adaptive immunity results in humoral and cell-mediated
responses. Immunity offers long-term protection against disease when
exposed to the homologous or closely related virus subtype. Thus, when
H1N1 closely related to 1918 pandemic virus reappeared in 1977, persons
born prior to 1955 had lower attack rates than younger individuals – in
1957 H1N1 had been replaced by the pandemic H2N2(28). However, unlike in
the case of many other viral diseases, robust protection against
re-infection and disease may not happen in many. This is due to a complex
set of factors. Since the incubation period is very short and infection
and disease are due to local infection in URT, adaptive immunity may not
act fast enough to prevent symptoms. Antigenic drift results in virus
subtypes that escape from immunity.
Rich nations in the temperate zones promote influenza
vaccinations in selected population sections with high risk for severity.
Using the surrogate of antibody response for protection, P-09-H1N1
vaccines have been made and are in current use in many countries.
Epidemiology and Clinical Spectrum
In temperate climate countries, seasonal influenza
incidence reaches epidemic proportions during winter months – October to
December in the Northern and June to August in Southern Hemispheres. The
seasonal epidemics cause excess mortality — mostly in the elderly (>65 y)
and in the very young (<5 y). This pattern apparently results from complex
factors of epidemiology and immunity. The very young tend to be
immunity-naïve and the very old have co-morbidities, particularly chronic
lung or heart disease.
In India, endemic/seasonal influenza had been generally
ignored in public health and in healthcare. Etiology-specific diagnosis
requires laboratory tests that are not widely available. Therefore what we
know about epidemiology and clinical features are from research studies.
Both pandemic H2N2 (1957) and H3N2 (1968) circulated in India(29). The
National Institute of Virology (NIV) started influenza surveillance in
Pune in 1976, where annual rainy season outbreaks occur, mostly due to
H3N2 and B viruses(29). Seasonal H1N1 appeared in the 1990s(29). Since
1980s there were several studies on viruses in acute respiratory diseases
in children, in Vellore, Chennai, Lucknow, Kolkata, Delhi and Pune(30).
Influenza virus infection was documented in every study – with about 4-15%
positive nasopharyngeal specimens(30). Recently a network of influenza
virus surveillance laboratories have been established at Pune, Vellore,
Chennai, Kolkata, Dibrugarh, Mumbai, Nagpur and Delhi, for virus isolation
from Influenza like illness(ILI). Results are not yet available. India
does not have a vaccination policy for Influenza.
The ILI begins suddenly with any of the following, in
varying combination: fever, sore throat, cough, nasal congestion, malaise,
headache, myalgia and loss of appetite. Occasionally nausea, vomiting and
diarrhea may occur. The sensitivity and specificity of clinical diagnosis
are low. In the majority, the illness is self-limited with recovery within
The incubation period is 1-3 days (range 1-7 days). The
clinical picture of P-09-H1N1 is usually a mild ILI. Detailed
investigations in Peru showed that one-third infected persons were
asymptomatic; one-third had short febrile illness without seeking medical
care and one-third were ill enough to be hospitalized(31).
Some unexpected clinical features have been detected in
the 2009 pandemic, with relatively higher frequency of severe disease and
case-fatality in certain subjects – such as in otherwise healthy children
and pregnant women (particularly third trimester)(32). The experience in
other countries has shown higher risk of severe influenza
(endemic/seasonal) disease in children below 2 years, and persons above 65
years and those with chronic respiratory (asthma, chronic obstructive
pulmonary disease) and cardiac (congestive cardiac failure) diseases,
diabetes or immunosuppression (HIV infection, malignancy,
immunosuppressive medications). Obesity (BMI>30) is also associated with
severe disease. Attack rate has been lower in senior citizens than in
younger persons, possibly due to immune memory of H1N1 infection prior to
1957. About 10-30% of hospitalized persons during this pandemic have
required intensive care including ventilator support. Severe disease in
the healthy and young has caused much fear among the public(33).
Clinicians must be alert to secondary invasive bacterial infection and
Shortness of breath, low blood pressure, cyanosis and
labored breathing should alert the pediatrician of impending viral
pneumonia or ARDS. Persistent high grade fever beyond 3 days is another
signal of possible severe disease.
Two types of seasonal influenza vaccines are available
– live attenuated and inactivated(34). The inactivated vaccine is
‘trivalent’ containing 2 recent circulating virus A subtype
representatives and a B subtype(34). The vaccine formulation (of
representative subtypes) is prescribed by the World Health Organization
twice every year before the peak influenza season in the southern and
Some 30 different monovalent P-09-H1N1 vaccines have
been licensed recently in many countries – using virus grown in eggs or
cell culture(35-37). Inactivated vaccines may be whole virus or subunit
(split) and with or without adjuvant. Over 150 million doses have already
been administered. The current FDA-approved vaccine is non-adjuvanted(38).
For children (6 months-10 years), 2 doses and for all above 10, a single
dose has been recommended(38). Adjuvanted vaccines are in use in some
European countries. The Global Advisory Committee on Vaccine Safety is
currently reviewing safety data. In general the safety profile has been
excellent; anaphylaxis may occur and the vaccine-provider should be fully
prepared to detect early signs/symptoms and to treat immediately and
appropriately. Since seasonal virus and pandemic virus are co-circulating
in many countries, both vaccines are recommended for simultaneous
vaccination in a few countries(39). There are various recommendations for
prioritizing vaccination in different population groups(37, 39). The
P-09-H1N1 virus will replace seasonal H1N1 virus for southern hemisphere
winter of 2010(39).
In India, the processes for licensing pandemic vaccine
(for importation and for indigenous manufacture) are in progress(40).
Unless a national policy is articulated on the control of endemic/seasonal
influenza, including surveillance, labo-ratory diagnosis, case-reporting
and vaccination, the pandemic vaccine may be viewed as a tool for
crisis-management and not visionary.
Neuraminidase inhibitors (NAI) – oseltamivir, zanamavir
and peramivir can be used for treatment or prophylaxis. Detailed
information is available on the web sites of WHO and CDC(41,42).
Individuals with severe influenza or with high risk for the same, benefit
from therapy, particularly when initiated within 48 hours of onset of
symptoms – and may be beneficial even if delayed beyond 48 hours(43).
Persons on intensive care may benefit from doubling the dosage and
duration of treatment(43,44). Reports of resistance to oseltamivir are a
cause for concern; zanamavir (by inhalation) or peramavir (IV) should be
used in oseltamivir-resistant cases(43,44).
Laboratory diagnosis of infection with P-09-H1N1 is
ideally made by direct detection methods – real time reverse transcriptase
polymerase chain reaction (rRT-PCR), viral culture or antigen detection by
immunochromatography. Respiratory secretion sampling is made by
nasopharyngeal aspiration, deep nasal or throat swabbing, or a
combination. Viral culture provides viral strains for further
characterization, subtyping and genotyping. Serum antibody assays using
haemagglutination-inhibition or virus neutralization methods are not
useful for clinical care, but are excellent for epidemiology and for
India’s Response to the Pandemic
The interventions designed by the Government of India (GoI)
are to prevent entry of P-09-H1N1, to retard its circulation in urban
communities and to reduce case-fatality through diagnosis and antiviral
treatment in designated hospitals(40). Starting from mid-April, all
passengers arriving from overseas are screened at 18 international
airports and anyone with ILI tested for infection. Infection was first
detected on 16 May; by 4 December 9,735,765 have been screened, 28,150
individuals tested virologically for infection and 315 (1.2%) found
infected with P-09-H1N1(40). In the community, 91,945 symptomatic persons
were tested and 19,632 (22%) were diagnosed infected and treated(40). Once
infection is found spreading in the community, the usefulness of airport
screening is open to question.
Among the total of 19,947 persons confirmed infected,
627 have died – for an overall case-fatality of 3.14%. This includes
persons with and without co-morbidities and persons with primary viral and
secondary bacterial pneumonias. Considering that hospitalization and
testing would be skewed towards more severely ill, the case-fatality is
likely to be an overestimate of what it is among all infected persons or
ill persons. Highest case-fatality was in the age group 20-39 and next
highest in <5 children.
India began with all virological tests conducted in
just 2 national laboratories (in Delhi and Pune) and later expanded the
laboratory network to include one per state. Thus the pandemic has acted
as a spotlight on the paucity of diagnostic laboratories for the
nation(45). GoI designated selected hospitals for admitting persons with
P-09-H1N1 infection so that further transmission could be slowed. When
severely ill persons were hospitalized, the lack of intensive care
competence and equipment were found to be a serious problem in some of
them, again illustrating the questions of quality and equity of healthcare
in many hospitals(45).
There has been an earnest attempt by GoI to educate the
public about the need to cover the mouth when sneezing or coughing (to
prevent droplets in air) and for hand-washing after touching sick persons.
Unfortunately, the MoHFW does not have an efficient communication channel
to inform the medical personnel. Dedicated websites and
television/newspaper advertising have attempted to bridge this gap(40,46).
Contributors: TJJ conceived of the need and
structure of the paper and TJJ and MM wrote different sections of the
paper. Both approved the final version.
Competing interests: None stated.
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