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A Whereas there is only one type of influenza B virus, influenza A has multiple subtypes, characterized by a combination of the 16 known hemagglutinin (HA) and 9 neuraminidase (NA) genes that code for the viral envelope or surface proteins (205). The viral surface proteins (especially HA and NA) play a prominent role in viral entry and escape from the human respiratory epithelial cells within which the virus replicates.
Reassortment, which recombines genome segments from two influenza strains (when simultaneously infecting the same host cell) into a new progeny virus, is another important molecular mechanism driving the evolution and emergence of novel influenza viruses. Influenza types A and B cause frequent and occasionally severe diseases in man, with influenza type A being generally more common than type B. Traditional pandemic influenza surveillance has focused on monitoring antigenic shifts, i.e. This continued until the emergence of a new subtype, H2N2, in 1957, signaling the beginning of another influenza pandemic.
Historically, it seemed reasonable to expect that new pandemics would emerge from the reassortment between existing human influenza viruses and those of avian origin from Southeast Asia. Interestingly, ongoing surveillance has reported that each of these subtypes may be predominant in different geographical regions and that this situation is continually changing.
It is recognized that birds provide a diverse gene pool of influenza A virus from which novel genes may be introduced into human influenza viruses. Six mild cases of H9N2 avian influenza infection in children occurred in Hong Kong in 1999, 2003, 2008 and 2009 (22,23,192).
The most widely reported and widespread human avian influenza cases are those due to infection by the highly pathogenic avian influenza (HPAI) A(H5N1) virus. There have also been reports (though far fewer) of zoonotic influenza infections from swine. On this basis, future routine surveillance of potential zoonotic origins for the next pandemic influenza virus should be expanded to include swine and perhaps other animals (200). Clinically, influenza is generally a self-limiting disease starting with an abrupt onset of fever (with or without chills), accompanied by generalized myalgia, rhinorrhea, headache, sore throat and coughing.
The annual epidemics of seasonal influenza now have a well-defined, age-specific mortality pattern, with young infants and the elderly (>65 years old) being most at risk, most probably due to relatively little immunological experience with the virus (in infants) and a waning of specific immunological immunity (in the elderly). Surprisingly, there was a less significant excess mortality found amongst the elderly during the 1918 pandemic possibly because this population may have had previous exposures (and therefore a degree of pre-existing, cross-protective immunity) to an even older influenza virus that was antigenically similar to the 1918 A (H1N1) virus. The 1997 outbreak of avian influenza A(H5N1) virus in Hong Kong was the first confirmed example of a purely avian influenza virus crossing the species barrier into man a€“ apparently without any adaptation in an intermediate host (e.g. Subsequent studies into the nature of various influenza virus receptors in avian and human hosts have led to a greater understanding of the mechanisms by which such species-crossing events can happen (129,172,197), with the recent swine-origin 2009 influenza A(H1N1) pandemic (see below) further emphasizing the significance of this zoonotic transmission route. The incubation period for avian A(H5N1) influenza virus infection has been estimated to be up to 7 days, but in most cases it is around 2a€“5 days after the last known exposure to sick or dead poultry (104,190).
Analyses of human influenza A(H5N1) cases in Hong Kong, Vietnam, Thailand and Cambodia have revealed that fever and cough were the most common initial symptoms (46,220).
Common laboratory findings on admission have included leukopenia, lymphopenia, and mild-to-moderately decreased platelet counts (104,118,190).
So far, in the fatal cases of human influenza A(H5N1) infection, the median time from onset to death has been about 9 days (191). Most fatal cases of human A(H5N1) did not have any history of pre-existing disease, which contrasts with the usual pattern of predisposing factors leading to severe and fatal cases of seasonal influenza infection that occurs in annual epidemics during inter-pandemic periods.
Most illnesses caused by the 2009 A(H1N1) virus have been acute and self-limited, with the highest attack rates reported among children, young adults and pregnant women (160,161).
In contrast to seasonal influenza most of the serious illnesses caused by the pandemic virus occurred amongst children. Other pre-existing comorbidities on admission with the 2009 A(H1N1) infection that were associated with poor clinical outcomes included obesity and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD). In the United States, among patients who were hospitalized with pandemic influenza, 32-45% were under the age of 18 years, with approximately 9-31% requiring admission to an intensive care unit (ICU) (99).
It has been found that pandemic influenza A(H1N1) virus infections can be life-threatening for pregnant women, particularly for those in the third trimester (19). In one large US study, the most common presenting symptoms of patients admitted to intensive care with pandemic A(H1N1) included fever in 97%, cough in 93%, shortness of breath in 87%, fatigue in 46%, vomiting in 25%, and diarrhea in 24% (99).
Radiographic findings commonly include diffuse mixed interstitial and alveolar infiltrates (see case studies), although lobar and multilobar distributions occur, particularly in patients with bacterial coinfection. It is now well-accepted that seasonal and pandemic influenza are frequently complicated by bacterial infections (217).
Secondary bacterial pneumonia is a common cause of death in persons with seasonal influenza and co-infections have been found with about 25% of all influenza-related deaths. The US Centers for Disease Control and Prevention (CDC) examined post-mortem lung specimens from patients with fatal cases of pandemic influenza A(H1N1) for bacterial causes of pneumonia. In recent years, a variety of molecular approaches to direct detection of viral nucleic acids in clinical specimens have also been explored for rapid diagnosis, including nucleic acid hybridization as well as RT-PCR, though PCR is increasingly becoming the most widespread technique (Figure 4).
The converse of this is that RT-PCR testing, by itself cannot determine the viability of the virus even though its RNA is detectable.
With the recent pandemic influenza A(H1N1) pandemic virus, specifically designed PCR assays became the preferred method of detection as the pandemic virus was found to grow more slowly than seasonal influenza virus in conventional cell culture and it is less easily detected by the conventional immunofluorescence tests that are usually quite sensitive for seasonal influenza A. As a result of the massive numbers of individuals presenting to community and hospital healthcare services, annually, seasonally, with influenza-like illness (ILI) each year, there has been considerable interest in the application of rapid, point-of-care (POC) tests for influenza diagnosis for several years. Therefore, for most of these rapid POC tests for both seasonal and the novel pandemic influenza virus, the overall sensitivity is poor, ranging from as low as 20% to as high as 90%, depending on which study is cited (86).
Table 1A shows the currently recommended NAI doses for both treatment and post-exposure prophylaxis for different ages of patients.
The treatment of pregnant women infected with 2009 A(H1N1) is considered a priority as there appears to be an increased risk (though this is relative) of complications in this population (100).
The mechanism of the adamantanes drugs (amantidine, rimantidine) is to block the viral M2 matrix protein, which is an ion channel required to cause a pH change to allow the uncoating of the virus and the release of its RNA, once it has been taken inside a permissive host cell by endocytosis (102,202). Resistance to oseltamivir arising in patients treated with oseltamivir has been reported in a few cases so far. There is increasing evidence and conviction that a significant proportion (20-30%) of deaths due past influenza pandemics may have been a result of secondary bacterial infections. Influenza immunization (or vaccination) should be the main method of controlling this infection and is recommended for certain high-risk groups in a population (Box 1) that may suffer more severe consequences of influenza infection, e.g.
Each year the WHO Collaborating Laboratories from around the world gather a selection of influenza viruses isolated from clinical samples in order to identify which influenza subtypes and strains have been most recently circulating and which are most likely to persist in the population for some time.
In recent years, the most common vaccine was an inactivated trivalent vaccine composed of the HA antigens from seasonal influenzas A(H1N1) and A(H3N2) and seasonal influenza B. Prior to the incorporation of the pandemic virus into the seasonal influenza vaccine, many trials were performed with the pandemic virus antigen alone as a monovalent vaccine with generally reasonable efficacy and relatively few adverse effects being reported (79,125,139,141,194), despite concomitant and intensified adverse effect surveillance and reporting (13,39,40).
Such inactivated vaccines can take a variety of forms in the way the virus antigen is prepared, including inactivated whole or split virus or subunit virus antigens.
Live attenuated vaccines have never contained thiomersal and one such vaccine is available for influenza, though the age range for which these are licensed are more restrictive than for the more traditional inactivated vaccines. There has been interest in recent years to move towards developing a more universal influenza vaccine (i.e. Even before the emergence of the 2009 influenza A(H1N1) pandemic, in recent years there has been a greater emphasis on public health interventions to inhibit human-to-human transmission of influenza, which has led to a renewed interest in the study of the epidemiology and transmission of these viruses (78,97,117,133,189). After its emergence from Mexico in March 2009, it was soon found that because of its novelty and therefore the absence of any prior immunity in most of the population, the 2009 pandemic influenza A(H1N1) virus transmitted efficiently between individuals even outside the normal seasonal influenza period for a particular country. One of the first steps for public health teams in identifying and controlling the spread of the disease is to provide an accurate, yet easy-to-apply case definition. However, purely clinical case definitions may not be specific enough and include many cases that are unrelated to the specific pathogen under investigation. In a situation such as the current 2009 swine-origin influenza A(H1N1) pandemic, where most countries affected have abandoned testing (simply because the number of samples is far too high) and rely on clinical case definitions, a comparative evaluation of case definitions of influenza in subsets of patients would help inform optimal estimates of the disease burden associated with influenza epidemics.
Whereas public health tends to focus on limiting disease impact at a population level, infection control focuses more on limiting the transmission of infection between individuals, e.g. Infection control doctrines such as hand hygiene and respiratory etiquette are widely supported in the literature and universally accepted (101,148). Respiratory etiquette is another important means of preventing transmission in all pandemic phases.
Whilst there is no direct evidence on the usefulness of surveillance and case reporting in the context of influenza transmission, experts agree that influenza surveillance supports a range of necessary preparedness activities. A In most countries viral diagnosis of influenza is currently not routine practice, and is hampered by lack of resources, the need for expert technologists and expensive equipment.
Droplet transmission is thought to be the primary mode of transmission of the influenza virus. There is limited evidence from seasonal influenza to support and differentiate between the clinical importance of contact, droplet or droplet nuclei (airborne) transmission of influenza.
Current thinking recommends reserving surgical masks, N95 respirators and other personal protective equipment for hospital and ambulatory patients when the pandemic is widespread.
Interestingly, a recent study has shown that surgical and N95 masks may provide the same level of protection in healthcare workers, using the detection of influenza infection in participants by PCR or 4-fold rise in serological titers as the endpoint for the study (122).
In contrast, the use of masks and other personal protective equipment for the general public has even less evidence to support it with the exception of some evidence from the SARS outbreak, which may not be relevant as the behaviour of the SARS-coronavirus and influenza are quite different, i.e.
Social distancing measures such as office and school closures, cancellation of large gatherings at events, and travel restrictions have been implemented in many countries during SARS and more recently during the current swine-origin influenza A (H1N1) pandemic. A Recent modeling studies generally support school closure and confinement in the home as an effective means of reducing overall attack rates within communities when coupled with antiviral prophylaxis, however the reality remains that this does not account for the effect that this may have when individuals are displaced into other settings (8,73), though one recent questionnaire-based study has demonstrated the overall number of contacts does decrease for individual school children when schools are closed (98). One well-investigated example of this has been the effects of school closure on the subsequent progression of an influenza pandemic.
Consistent with the literature, widespread and sustained screening of travelers would ultimately be impractical and inefficient as long as detecting asymptomatic shedding is not feasible.
Many teams, worldwide are working on the better understanding of various aspects of the way influenza transmits in different situations and as our knowledge improves it is likely that these public health approaches will be modified. The continued variation and adaptation of the influenza virus to different hosts (both animal and human) in different environments will continue to challenge us. Patient A was a 41-year old Caucasian man with no underlying comorbidities and no history of influenza vaccination.
Figure A: Serial chest X-ray changes for Patient A in a fatal pandemic influenza A(H1N1) infection. Patient B was a 22-year old, pregnant (29 weeks gestation) Somalian woman with no underlying comorbidities and no history of influenza vaccination. Patient C was a 45-year old Caucasian man with no underlying comorbidities and no history of influenza vaccination. They are lipid-enveloped, single-stranded, negative-sense, segmented RNA viruses (Figure 1) that exist in three recognized serotypes: influenza (A, B and C). Of the 16 HA subtypes of influenza A virus, six have been found in a significant number of human infections (H1, H2, H3, H5, H7 and H9); however, so far only three subtypes of HA (H1, H2, H3) and two subtypes of NA (N1, N2) have caused pandemics in humans (Figure 2). Being the major targets of the human immune response, they are known to evolve rapidly under host immunological selection pressure.
Studies have shown that human influenza viruses frequently undergo gene reassortments (92,136), some of which might be advantageous to viral fitness. The very young (infants) and the elderly are more vulnerable to typical seasonal influenza infections because of their inexperienced or ageing immune system, respectively. Although its genome has been sequenced and analyzed thoroughly since 2000 (4,156,157,158,159,183), several hypotheses regarding the origin, particularly whether it had emerged from a pure avian or human influenza virus, or via an intermediate human-avian reassortment virus, still exist and remain controversial (75,76,216). Therefore, it was something of a surprise when the recent H1N1(2009) pandemic virus appeared to be a reassortant of two swine influenza viruses of distinct genotypes a€“ a Eurasian avian-like swine influenza virus and a triple reassortant swine influenza virus (137,155), emerging from Mexico (Figure 2) (70). Although it is now clear that bird-to-human transmission events have significantly contributed to the genesis of previous influenza pandemics affecting the global population, there have been numerous reports of other bird-to-human transmissions affecting individuals. From 1958-2005, there were 36 laboratory-confirmed cases of human infection by swine influenza viruses (i.e. Gastrointestinal symptoms such as loss of appetite, abdominal pain, vomiting and diarrhea are also commonly reported. Hence, the mortality curve typically appears U-shaped when age-specific excess mortality due to pneumonia and influenza is plotted (93). The spectrum of illness caused by these pandemic viruses was similar to other influenza virus infections, though certain individuals, such as those with underlying cardiovascular disease, tended to have severe complications. Retrospective analysis of 1918 A (H1N1) cases has revealed a fatal pathological triad of leukopenia, hemorrhagic diathesis and pulmonary edema that killed many healthy young adults during the 1918 pandemic. A similar scenario has been postulated with the more recent 2009 A (H1N1) influenza pandemic, during which the younger population were more affected than the elderly (85).
In cases for which limited human-to-human transmission may have occurred, the incubation period has been estimated to be 3-10 days (191).
Gastrointestinal symptoms including vomiting, diarrhea and abdominal pain were reported early in the course of illness in some cases (103,190,219).
However, for patients with a clinically mild illness, there was no decrease in the white blood cell count (104). The fatality rate amongst hospitalized patients was high and varied widely between countries (33a€“100%), although the overall rate is probably much lower because it has been difficult to estimate the number of mild or asymptomatic human A(H5N1) infections in the community (8). Yet, in A(H5N1) -infected patients who did have underlying cardiovascular, pulmonary and renal diseases, severe illness was also more common (8). This was soon shown to be caused by a novel swine-origin influenza A(H1N1) virus (S-OIV), initiating the first influenza pandemic of the 21st century (147). Adults older than 60 years of age were spared relative to the younger age groups presumably because of prior exposure to antigenically related influenza viruses earlier in life, resulting in the development of cross-protective antibodies (55,85,131). Interestingly, it was lowest for children aged 5-14 (11, range 3-36, per 100 000) and highest for those aged >or=65 (980, range 300-3200, per 100 000). In the UK 13% of hospitalized patients were admitted to a high dependency or intensive care unit and 5% died - 36% of these deaths were in patients under the age of 16 years. Approximately 25-50% of patients with 2009 A(H1N1) virus infection who were hospitalized or died had no reported coexisting medical conditions.


In pregnant women delivering before 37 weeks gestation, almost all had pneumonia and approximately 50% of the women in one case series did not have an additional risk factor other than being pregnant (89).
Patients usually become symptomatic within a week of exposure and are infectious for about 8 days thereafter (25,53).
Dyspnea, tachypnea in children, chest pain, hemoptysis or purulent sputum, prolonged or recurrent fever, altered mental status, dehydration, and reappearance of lower respiratory tract symptoms after improvement were all signs of progression to more severe disease or complications (112,204). Chest computed tomography has shown multiple areas of ground-glass opacities, air bronchograms, and alveolar consolidation, particularly in the lower lobes (99). Of laboratory-confirmed cases of community-acquired pneumonia, about 30% involve bacteriala€“viral co-infection.A Streptococcus pneumoniaeA is the most common cause of community-acquired pneumonia and bacterial co-infection with influenza A (83). In a retrospective, descriptive study of all reported influenza-associated pediatric deaths in the 2007a€“2008 influenza season in the United States, it was found thatA S. Of the 22 cases with histopathologic, immunohistochemical and molecular evidence of co-infection with identified bacteria, there were 10 cases withA S. After 1-10 days, the presence of any influenza virus can be confirmed with specific immunofluorescence testing with hemagglutination being a useful (but non-specific a€“ since other non-influenza viruses such as rubella may also cause hemagglutination) marker of virus growth. Since it may take several days for the culture to become positive, the results may not be ready early enough to inform the immediate clinical management of the patient.
Although viability is not unreasonably assumed if the viral RNA is detected in a clinical specimen recently obtained from a live patient, for environmental and infection control studies where the viability of the virus detected on surfaces is important, RT-PCR testing cannot help and viral culture is still required a€“ to demonstrate viability and the potential for onward transmission.
In fact, throughout the pandemic (June 2009- August 2010), PCR methods were the preferred method of detection of this novel virus mainly because these conventional methods were insufficiently sensitive to diagnose new human cases (33,77). Such test can offer almost instant results in busy community healthcare clinics, when sending samples to the nearest diagnostic laboratory can be time-consuming and costly, and may reduce the unnecessary prescription of broad-spectrum antibiotics for common respiratory virus infections.
Unfortunately, it soon became clear that these rapid test kits appeared to be even less sensitive for the novel pandemic influenza virus, with sensitivities as low as 20%-30%, though most ranged over 40%-60% (14,29,56,63,67,77,86,105,110,123,164,165,193,198,199).
Although they have been specifically designed to be easy to use (similar to an over-the-counter pregnancy test in complexity), their sensitivities vary according to many factors. Thus, for a symptomatic patient with a negative result on one of these POC tests, this may not necessarily exclude an influenza infection and the physician needs to decide whether additional, more sensitive laboratory tests are required and likely to change their clinical management of the patient (including whether just to send the patient to the nearest emergency room).
As well as the adamantane drugs (amantadine, rimantadine) that are only effective against influenza type A, there are the newer neuraminidase inhibitors (NAIs, zanamivir - RelenzaA®) and oseltamivir - TamifluA®).
For seasonal influenza A(H1N1), most of these viruses are resistant to oseltamivir (though zanamivir is still effective in most cases) and most are still susceptible to the adamantine drugs, though resistance seems to be increasing.
Treatment is recommended for 5 days, whereas prophylaxis is recommended for at least 2 weeks or at least for 7 days after contact and illness onset with the last infected individual. A recent study suggests that so far, oseltamivir treatment appears to be safe in pregnancy (179), and that on this basis, it should be commenced as soon as possible after the onset of symptoms (212), as well as being offered for post-exposure prophylaxis (35). Several amino acid substitutions in this viral M2 gene will prevent the binding of these adamantine drugs to the M2 protein, thus conferring resistance to these drugs. Since all influenza B, most H3N2 seasonal influenza and the A(H1N1) pandemic influenza viruses are resistant to adamantanes (since they possess the M2 protein drug resistance mutations), it is recommended to use the neuraminidase inhibitors oseltamivir and zanamivir instead of amantadine and rimantadine for the treatment of current circulating influenza (54).
The most commonly reported resistance mutation, H275Y (using the numbering for N2 viruses), occurs in the neuraminidase (NA) gene (36,37). Recent analyses of the 1918 pandemic mortality figures suggest that a significant number of deaths were due to secondary infection withA Hemophilus influenzae, S. This allows them to recommend the most protective antigenic (almost entirely hemagglutinin, HA) composition for that season’s approaching influenza epidemics in the northern and southern hemispheres. However, there have been more public adverse events reported in the world media, including some incidences of febrile seizures (seeA Table 2), occasional severe injection site lymphadenitis (82,169), and perhaps most unusual of all, narcolepsy in vaccine recipients in Sweden (132).
In recent years, there has been heightened concern regarding other components of vaccines, including the various types of manufacturers’ proprietary adjuvants and in particular, the mercury-containing preservative, thiomersal. The main risk is that of an allergic reaction in the form of a local delayed-type hypersensitivity reaction.
In addition, this vaccine is contraindicated in young children (aged 2-4 years) with or at risk of asthma (e.g.
Reinforcing this, there have been a number of public health threats related to various subtypes of animal influenza viruses infecting humans in recent years (e.g. Case definitions form the cornerstone of the investigation and management of outbreaks a€“ duties that form a significant component of the role of public health agencies. One interesting study evaluated the accuracy of clinical case definitions for different influenza subtypes during an outbreak in France during the 1995a€“1996 influenza season. However, in most outbreak situations, only one consensus case definition will be used and such retrospective analyses of its effectiveness can only be performed later a€“ usually once the outbreak is well underway, or even when it is over. The WHO's recommended pandemic influenza interventions include hand hygiene as routine (10). Respiratory hygiene and cough etiquette is generally interpreted to include covering the mouth and nose with a tissue or into the upper sleeve when coughing or sneezing, and refraining from spitting (38).
There are concerns, however, about resource constraints, especially in a large outbreak (2). A belief in the potential risk of airborne transmission has lent support for N95 respirators, which are designed to stop up to 95% of small airborne particles (18). It is noteworthy that N95 respirators need fit-testing and are expensive, further compromising their usefulness.
SARS was shown to be relatively uninfectious until the appearance of symptoms, whereas influenza does appear to have a short period of transmissibility prior to symptom onset (71). However, their effectiveness in an influenza outbreak has not yet been well-established (10,65).
Various mathematical modeling studies have suggested that whilst there maybe some delay in the spread of the pandemic from closing schools, this will only be effective if the subsequent behavior of children outside of school does not result in a similar number of contacts and that such relative isolation is prolonged during the pandemic period (107). Screening and quarantining entering travelers at international borders did not substantially delay virus introduction in past pandemics, except in some island countries, and will likely be even less effective in the modern era. Ongoing surveillance of influenza viral antigenic drift for the annual update of the antigenic composition of the seasonal influenza vaccine constitutes one of the most successful international public health collaborations in modern times. He was admitted to hospital with a 4-day history of a flu-like illness, including rhinorrhea, nausea, vomiting and diarrhea. She was seen after a 5-day history of flu-like illness (coryzal symptoms, blocked nose) which had worsened over the previous day with fever and dyspnea. In this recovering case, note the gradually resolution of the pulmonary infiltrates and consolidation. Basler CF, Reid AH, Dybing JK, Janczewski TA, Fanning TG, Zheng H, Salvatore M, Perdue ML, Swayne DE, Garcia-Sastre A, Palese P, Taubenberger JK. Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, Uyeki TM, Zaki SR, Hayden FG, Hui DS, Kettner JD, Kumar A, Lim M, Shindo N, Penn C, Nicholson KG. Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY.
Bhat N, Wright JG, Broder KR, Murray EL, Greenberg ME, Glover MJ, Likos AM, Posey DL, Klimov A, Lindstrom SE, Balish A, Medina MJ, Wallis TR, Guarner J, Paddock CD, Shieh WJ, Zaki SR, Sejvar JJ, Shay DK, Harper SA, Cox NJ, Fukuda K, Uyeki TM. Blachere FM, Lindsley WG, Pearce TA, Anderson SE, Fisher M, Khakoo R, Meade BJ, Lander O, Davis S, Thewlis RE, Celik I, Chen BT, Beezhold DH. Black S, Eskola J, Siegrist CA, Halsey N, Macdonald N, Law B, Miller E, Andrews N, Stowe J, Salmon D, Vannice K, Izurieta HS, Akhtar A, Gold M, Oselka G, Zuber P, Pfeifer D, Vellozzi C.
Whilst influenza B and C are only found in humans, influenza A virus infects various mammals (including pigs and horses, and more rarely, other animals such as dogs) and numerous species of birds (both aquatic and terrestrial).
In addition, both influenza A and B do exist as several genetically distinct lineages that co-circulate in humans, with the different influenza A strains, in particular, varying sufficiently in the HA component to require different HA antigens to be present in the seasonal influenza vaccine to ensure the induction of adequate specific immunity. This generates further novel antigenicity allowing the virus to continually escape from the existing host immunity developed from previous infections or vaccination (88). In contrast, pandemic influenza can cause mortality in the younger, fitter adult population, which may, paradoxically, result from an over-active immunological response to a completely new pathogen (182) or to a more virulent virus, per se. Following the end of the 1918 pandemic, the H1N1 influenza virus continued to circulate in the human population causing recurrent but less severe seasonal outbreaks. It has remained in the global population and has been co-circulating with the other seasonal influenza virus subtype, H3N2, ever since.
What may not have been so surprising for a zoonotic pathogen was that early infections may have been more serious with a lessening of morbidity and mortality as it gradually adapted to man as it spread across the USA then rapidly throughout the rest of the world in just a few months. These infections were more sporadic with relatively short transmission chains, usually limited to a single person or at most a small group between whom close contact was routine (e.g. The usual reason for admission to hospital is when the infection has spread to the lower respiratory tract, causing a range of pulmonary disease ranging from croup, bronchitis, bronchiolitis to frank pneumonia (203). Similar to seasonal influenza virus infections, the mortality curve during the 1957 and 1968 pandemics was U-shaped, with increased fatality rates, mainly due to various forms of pneumonia, in infants and the elderly (93).
In addition, extensive non-respiratory system involvement was a notable and unusual feature during the 1918 pandemic (93). The mortality was over 30% (6 deaths out of 18 confirmed cases) and dramatically alerted the influenza community to the very real possibility of direct zoonotic transfers of animal influenza viruses directly from their animal host to humans (44,220). In the 138 people in whom the confirmed cause of death was pandemic A(H1N1), the median age was 39 (interquartile range 17-57) (55).
Non-white and pregnant patients were over-represented and 45% of patients had at least one underlying condition, mainly asthma (138). Overall, of all inpatient deaths in this UK study, 59% occurred in previously healthy people (138,161).
Underlying conditions that were associated with complications from seasonal influenza were also risk factors for complications from 2009 A(H1N1) virus infection (160). Although pregnant women represent only 1 to 2% of the population, among patients with 2009 A(H1N1) virus infection, they accounted for up to 7-10% of hospitalized patients, 6-9% of ICU patients and 6-10% of patients who died.
Infection with the pandemic influenza A(H1N1) virus causes a broad spectrum of clinical syndromes, ranging from afebrile upper respiratory illness to fulminant viral pneumonia.
The principal clinical syndrome leading to hospitalization and the need for intensive care was a diffuse viral pneumonitis associated with severe hypoxemia, ARDS, or in some cases, sometimes shock and renal failure.
Yet notably, in children who generally shed higher levels of virus, the reported sensitivities seemed to be generally higher (50,87,166), similar to seasonal influenza viruses (151,169), though there is some variability in this (199).
These include the experience and skill of the operator, as well as other patient-related factors, such as age (they may be more sensitive in children who shed more virus), and the specific type of sample that is collected and tested.
Pediatric dosing is based on weight for those weighing less than 40 kg, above 1 year of age. However, as always, the actual application of these recommendations will be down to the individual decision and risk assessment of the patient and her doctor. The incidence and prevalence of oseltamivir-resistant 2009 A(H1N1) viruses is likely to increase, given the continued widespread use of the drug for treatment. Since these northern (Nov-Jan) and southern (Jun-Sep) influenza seasons are about 6 months apart, the vaccine manufacturers have, on average, just 6 months to produce enough vaccine for the northern and southern hemisphere populations, whilst still maintaining the high quality of the final product. Investigations into some of these adverse effects are being conducted, but in the vast majority of individuals, the inactivated trivalent seasonal influenza vaccine containing the 2009 pandemic influenza A(H1N1) virus (of swine origin) has so far been found to be just as safe as the previous seasonal influenza vaccines (196).
However, very few people exhibit any such reaction in response to the vaccine a€“ even those who display such a reaction to thiomersal in patch testing. H1, H3, H5, H7, H9, etc.), but these vaccines are still very much experimental (57,68,167,176), and the current WHO-led surveillance and updating of the antigenic components of the annual seasonal influenza vaccines for northern and southern hemispheres may well continue for many years to come. Secondary attack rates in the well-defined outbreak reported from the Mexican town of La Gloria, Veracruz, in mid-February of 2009 were estimated at 61% and 29% in those under and over the age of 15 years, respectively (70). Early on in the 2009 influenza A(H1N1) pandemic, the WHO developed case definitions for cases of this new infection (Box 3).
Unfortunately, a study of the literature to date indicates that the quality of evidence upon which disease mitigation can be planned is generally poor (9,10). Other controlled studies have shown a protective effect of hand hygiene in reducing upper respiratory infections, although not all of these are necessarily related to influenza infection (64,173).
Promotion of respiratory etiquette should be coupled with a strong emphasis on public education that includes all the relevant information about influenza.
This area is controversial and the evidence is limited (17,116,171,180,185,186,187), though more recent studies have certainly demonstrated that both influenza RNA and live virus can be found in air (12,120,177,218), so ignoring this potential route of airborne transmission may now be imprudent. Discomfort is also a problem when N95 masks have to be worn for long periods and several studies of compliance with N95 masks have found a general reluctance amongst healthcare workers to comply with these recommendations a€“ even in potentially hazardous situations (74,130,168). This single study suggested that use of surgical masks compared with an N95 respirator resulted in non-inferior rates of laboratory confirmed influenza (122). Most experts recommend against the use of masks or respirators by the public prior to the arrival of pandemic influenza and in the early localized phase (2). However, more recent studies report that when numbers are small, isolation in hospitals using appropriate infection control measures may be effective (8). Despite the current suggestion that influenza epidemics may be amplified in primary schools, data on the effectiveness of school closures for reducing community transmission are contradictory. In addition, the social and economic disruption for the working parents may be difficult to overcome as at least one parent will have to take time off work to look after young children at home (26,27). Instead, WHO recommends providing information to international travelers and possibly screening travelers departing countries with potentially transmissible human infections.
His initial presentation to the first hospital (duration of stay 5 days) was one of severe respiratory failure and septicemia after a week of flu-like symptoms. Non-pharmaceutical public health interventions for pandemic influenza: an evaluation of the evidence base. Neurological sequelae of 2009 influenza A (H1N1) in children: a case series observed during a pandemic.
Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines. First introduction of highly pathogenic H5N1 avian influenza A viruses in wild and domestic birds in Denmark, Northern Europe.
Sometimes there may be a combination of these effects, such as is seen with 1918 pandemic influenza-like viruses (109) or the more recent avian A(H5N1) influenza virus (144).


The subsequent 1957 and 1968 pandemics, which are now thought to have their origins in Asia (7), resulted in a lower morbidity and mortality, yet still had a significant impact on global health. Since then, this 1968 H3N2 human influenza virus has been circulating globally, and continually mutating, for more than forty years. An outbreak of highly pathogenic H7N7 avian influenza in the Netherlands in 2003 caused mostly mild illness in 83 people, but also the unfortunate death of one veterinarian (58). Ironically, due to advances in antibacterial therapy during these periods, fatal cases caused by primary influenza viral pneumonia in the absence of any secondary bacterial infections, increased. These were all features unique to the 1918 A (H1N1) pandemic which were not observed in the subsequent 1957 and 1968 pandemics, nor the more recent 2009 A (H1N1) pandemic. Patients with A(H5N1) virus infection were usually hospitalized 4a€“6 days after onset of illness (191). The severe human A(H5N1) infections in the 1997 Hong Kong outbreak were also noted to develop reactive hemophagocytic syndrome which was a unique pathologic feature in 3 of the 6 fatal cases, as were increased blood levels of interferon-I±, tumor necrosis factor- I± and other cytokines. Multiple organ failure with signs of renal dysfunction with or without cardiac compromise was often observed.
The Spanish experience also confirmed that pregnancy as well as obesity, and previously healthy individuals, were at risk of dying. A report by a consortium of Australian and New Zealand intensive care physicians stated that as many as one-third (n=68) of patients on their ICUs received extra-corporeal membrane oxygenation (ECMO). There appears to be a particularly increased risk of death among infected women during the third trimester, especially among those who have coinfection with the human immunodeficiency virus (HIV) (5).
Most patients typically present with fever (95%), cough (88%), shortness of breath or dyspnea (60%), fatigue (43%), runny nose (38%), sore throat (31%), headache (34%), and myalgia (36%) (99). This clinical syndrome accounted for approximately 49-72% of ICU admissions during the A(H1N1) pandemic (112,204).
Post-influenza pneumonia may, at least in part, be due to resolution of inflammation caused by the primary viral infection. There are many commercial kits available for such testing, but they can only be applied effectively in professional diagnostic laboratories with trained, skilled manpower and the required equipment. In these tests, a sample of respiratory secretions is treated with a mucolytic agent and then tested, either on a filter paper, in an optical device, or with a dip-stick in which reaction with specific antibody results in a color change. Although all types of respiratory samples can be used in such tests, the sensitivity appears to be better with nasopharyngeal swabs and aspirates than with throat swabs or gargles (48,163), which may contain more virus as it has been shown that the sensitivity of these rapid tests depend on the amount of virus in the sample (41,42,96,164,184).
This has an advantage over both oseltamivir (taken orally) and zanamivir (taken by inhaler) in that it can be given intravenously.
However, now, oseltamivir should only be used for treating severely ill cases of 2009 A(H1N1) infection (as per seasonal influenza use recommendations) and no longer used as post-exposure prophylaxis unless vulnerable groups have been exposed (212). More information on the use of thiomersal in vaccines is available at the US Food and Drug Administration (FDA) website (69).
One of these, avian influenza H5N1, had already raised concerns about the potential to cause a pandemic and many of the existing pandemic preparedness plans had been based on this threat from H5N1 (119,128,215).
Interestingly, they also included laboratory test results in these definitions, which was unusual a€“ most case definitions are made purely on clinical symptoms and signs (see Box 3). The recommendation therefore is that rigorous and routine hand hygiene using either soap and water or a suitable hand gel sanitizer is an important strategy for healthcare workers and the general public in all settings and at all phases of a pandemic (2). However, there are many potential confounders in this study (some of which are acknowledged by the authors themselves) and other teams should repeat this study before such counter-intuitive conclusions about the comparative efficiencies of surgical and N95 masks are widely accepted.
In spite of the lack of definitive evidence, voluntary self-isolation in the home was recommended for all phases of a US pandemic (2). Some studies suggest a decline in community transmission rates of respiratory infections with school closures (90), whereas others have noted a protective effect when schools remained open (10). In particular, school closure has to be part of an overall mitigation strategy, including the treatment and home isolation of infected individuals to reduce further contacts (178). The principal focus of interventions against pandemic influenza spread should be at national and community levels rather than international borders (9).
As was seen with the recent 2009 influenza A(H1N1) pandemic, the surveillance for such influenza viral reassortment or antigenic shift events is much more incomplete as it needs to involve various animal species that can also act as influenza virus reservoirs (145,200). She was admitted (Day 1) under the obstetric team and treated for community-acquired pneumonia (CAP) with oral amoxicillin 500 mg tds and clarithromycin 500 mg bd. Pandemic influenza A(H1N1) was detected and treatment was started with oseltamivir (75 mg bd orally). Importantly, these subsequent pandemics supported the hypothesis that pandemics are likely to recur and that there may be a benefit in preparing for them. It infected mostly children and young adults because the older population had already been exposed to a similar H1N1 strain that had been prevalent during 1947-1957, giving these older adults significant pre-existing immunity to this more recent H1N1 virus. As of 29 December 2010, there were 512 reported cases of human infection of A(H5N1), with 304 deaths (i.e. Other specific manifestations include myositis, which usually occurs 3 days (range, 0a€“18 days) after influenza onset (1,94) and myocarditis, though this is a rare complication.
This suggests that cytokine responses contribute significantly to the pathogenesis of human A(H5N1) infections (146,188). Whether the severity of illness varies by clade or subclade of A(H5N1) virus infection, by age, or by immunological, genetic, or other factors is as yet unconfirmed (191). 48 per 100,000), being highest in persons aged 18 years and older, and lowest in children aged 5-17 years (150).
They present with marked irritability, severe lethargy, poor oral intake, dehydration resulting in shock, and seizures (84,121).
These ECMO-treated patients were often young adults with severe hypoxemia and despite the use of ECMO still had a 21% mortality rate by the end of the study period (52). A proportion of affected patients may present with gastrointestinal symptoms such as diarrhea and vomiting.
It is important to note that currently available prognostic algorithms for community-acquired pneumonia, such as CURB-65 (a measure of confusion, urea nitrogen, respiratory rate, and blood pressure and an age of 65 years or older), may not apply (5). These mechanisms restore tissue homeostasis but greatly impair the host response against unrelated bacterial pathogens (195).
The simplicity of some of the tests allows them to be used in the clinic-office setting to which the majority of pandemic influenza-infected individuals with relatively mild illness are likely to present. This in turn depends on how soon the patient presents for a sample to be collected after the onset of acute infection, as well as how well the sample (whether nasal swab, nasopharyngeal swab or nasopharyngeal aspirate) is taken (127).
A high specificity means that a positive result on the test is almost certainly an indication of influenza infection, rather than this just being a false positive. Combination therapy with oseltamivir and rimantadine can be given empirically if the influenza subtype is unknown, and indeed some patients infected with 2009 A(H1N1) have been given this combination as initial empirical therapy (34). However, there has been one case of oseltamivir-resistance reported in an individual with no history of oseltamivir use (30). Hence, it was something of a surprise to many agencies, worldwide, when the novel swine-origin influenza A (H1N1) virus (S-OIV) emerged from Mexico leading to the WHO, in June 2009, declaring that its spread had reached pandemic proportions (43). In all 12 clinical case definitions were evaluated for their abilities to diagnose influenza virus infection. An additional factor to take into account is the lethality of the infection that is being controlled.
Various mathematical modeling tools have been used to assess the impact of restricting air travel on the spread of pandemic influenza. Such coverage is much more problematic as the numbers of such species, any one of which could be harbouring a unique reassortment, is vast and scattered in varying livestock holdings across the globe. His blood cultures grew a Group A Streptococcus, for which he was he was treated with intravenous benzylpenicillin 1.2 g qds.
This belief was reinforced most recently by the emergence of the 2009 A(H1N1) influenza virus a€“ deemed to be the first influenza pandemic of the 21st century. Perhaps most famously of all, an outbreak of an A(H1N1) swine influenza virus occurred at Fort Dix, New Jersey, resulting in one death and respiratory illness in up to 230 soldiers in early 1976 (72) a€“ which led to a controversial, and arguably unnecessary, US government-led, mass influenza vaccination campaign (170).
In infants, influenza can mimic sepsis more usually caused by various bacterial infections, which can add to the difficulty of a timely diagnosis (45). Complications of influenza included invasive bacterial coinfections, encephalopathy or encephalitis (sometimes necrotizing), and diabetic ketoacidosis (115,140). A small subset of patients have presented solely with gastrointestinal or neurological symptoms without fever or cough (53,99).
In addition, there have been sporadic cases of pandemic influenza A(H1N1) infections with neurologic manifestations, presenting as confusion, seizures, unconsciousness, acute or post-infectious encephalopathy, quadriparesis and encephalitis (140).
So for these rapid test kits, a positive result is more reliable (as an indicator of a true influenza infection) than a negative result (which may not necessarily indicate the absence of an influenza infection), in determining the patient’s influenza status.
The worrying issue then is whether such resistant viruses will eventually become fit enough to transmit efficiently in the population (perhaps displacing the wild-type susceptible virus), making the worldwide stockpiles of oseltamivir effectively useless. These findings suggest that both antibiotics and anti-bacterial vaccines may be an important component of the management of influenza infections (83). They were associated with positive predictive values of 27% to 40% and negative predictive values of 80% to 91% (24).
For a highly lethal and transmissible pathogen, such as smallpox, isolation of the sick and quarantining of those exposed is more acceptable to the general public and therefore probably more effective, as the consequences of not limiting the spread throughout the population are more devastating. However, the benefits may be fairly minor and may not be worth the inevitable and serious social and economic disruption this will cause (20,61,91).
This will require much closer and regular cooperation with the farming and veterinary community in order to comprehensively characterize and monitor these animal viral populations. Pandemic influenza A(H1N1) infection was confirmed by PCR testing on throat and nasal swabs the next day, by which time he had been switched to intravenous (IV) zanamivir as he was unable to absorb orally.
Respiratory transmission from a symptomatic mother to a newborn was reported and newborn infants manifest with apnea, tachypnea, cyanosis, and lethargy (5).
Particularly in children, this virus seems to have a propensity to cause neurologic complications (3,34,60). This will only become more essential as the world population increases and the demand for high quality meat, requiring more intensive farming methods of such animal hosts, only increases. Despite this, he rapidly deteriorated (see chest X-ray series below) and was admitted to intensive care (ICU) the next day, where he eventually died 6 days later.
She began to deteriorate overnight and was given non-invasive ventilation whilst awaiting transfer to ICU, where she was eventually intubated for worsening respiratory function and pulmonary edema. His respiratory failure required extracorporeal membrane oxygenation (ECMO) at the second hospital (duration of stay approximately 3 weeks). Gastrointestinal symptoms (including nausea, vomiting, and diarrhea) occur more commonly than in seasonal influenza, especially in adults (53).
Influenza is not one of the viruses traditionally considered as a cause of neurologic illness in children, but this particular pandemic A(H1N1) virus subtype may well become part of the routine differential diagnoses in such pediatric presentations, if this virus starts to co-circulate in human populations, long-term, as one of the seasonal influenza viruses. However, with sufficient support and funding from governments as well as those in the livestock industry, together with the ongoing dedication of the clinical and scientific influenza virus community, there is no reason why the level of animal influenza virus surveillance should not be able to at least match that which already exists for human influenza. The following day (Day 2), pandemic influenza A(H1N1) was detected in a respiratory sample and she was started on oseltamivir (dose 75 mg bd orally).
He was eventually transferred to the current hospital (Day 1 of admission) after coming off ECMO but still requiring ventilatory support on ICU and hemofiltration. No other respiratory virus out of: seasonal influenza A(H1N1) and B, respiratory syncytial virus (RSV), parainfluenza viruses, human metapneumonvirus or adenoviruses were detected.
No testing was performed for the detection of the viral oseltamivir-resistance mutation H275Y. No other coinfecting bacteria were found at this point, but she had been on empirical antibiotics. No other respiratory virus out of: influenza A (non-H1N1 pandemic) and B, respiratory syncytial virus (RSV), parainfluenza viruses, human metapneumovirus or adenoviruses were detected. On ICU during the same day, she desaturated to 47% during suctioning and large amounts of reddish fluid (possibly a sign of a viral hemorrhagic pneumonitis) was removed. His family, a wife and two young children (twins) were also infected with pandemic A(H1N1) but recovered without any serious illness. As she was obviously not ventilating adequately a decision was made to deliver the baby via emergency Caesarian section the same day. Treatment with oseltamivir continued and on Day 3 his pandemic influenza A(H1N1) PCR was still positive. In summary, this was a rapidly fatal case of pandemic A(H1N1) infection in a previously healthy man with no underlying comorbidities.
The baby was found to be negative for pandemic influenza A(H1N1) and was stable on neonatal ICU on continuous positive airways pressure (CPAP) ventilation.
Soon after, the mother had to be transferred to another hospital for respiratory monitoring for possible extracorporeal membrane oxygenation (ECMO). She was found to be improving after several days, and was eventually transferred back to the original hospital without undergoing ECMO (Day 9).
Interestingly, a repeat check showed a recurrence of a low level A(H1N1) positive PCR on Day 9.
She continued to improve on ICU and was extubated on day 13 and transferred to the obstetric unit. Eventually, he became PCR negative on two separate samples by Day 22 and 23, and was stable enough to have his tracheostomy decannulated and to move to a hospital ward by Day 23. Her treatment with oseltamivir ceased on Day 12 as two repeat pandemic influenza A(H1N1) PCRs were found to be negative.




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