The novel influenza A (H1N1) virus pandemic: An update

In the 4 months since it was first recognized, the pandemic strain of a novel influenza A (H1N1) virus has spread to all continents and, after documentation of human-to-human transmission of the virus in at least three countries in two separate World Health Organization (WHO) regions, the pandemic alert was raised to level 6. The agent responsible for this pandemic, a swine-origin influenza A (H1N1) virus (S-OIV), is characterized by a unique combination of gene segments that has not previously been identified among human or swine influenza A viruses. As of 31th July 2009, 168 countries and overseas territories/communities have each reported at least one laboratory-confirmed case of pandemic H1N1 infection. There have been a total of 162,380 reported cases and 1154 associated deaths. Influenza epidemics usually take off in autumn, and it is important to prepare for an earlier start this season. Estimates from Europe indicate that 230 millions Europe inhabitants will have clinical signs and symptoms of S-OIV this autumn, and 7–35% of the clinical cases will have a fatal outcome, which means that there will be 160,000–750,000 H1N1-related deaths. A vaccine against H1N1 is expected to be the most effective tool for controlling influenza A (H1N1) infection in terms of reducing morbidity and mortality and limiting diffusion. However, there are several issues with regard to vaccine manufacture and approval, as well as production capacity, that remain unsettled. We searched the literature indexed in PubMed as well as the websites of major international health agencies to obtain the material presented in this update on the current S-OIV pandemic.


Introduction
I n recent years, there has been much concern about the possibility of an infl uenza pandemic caused by a novel, highly virulent, strain to which the population has no immunity and which, therefore, may be associated with high mortality rates. Social and scientifi c reaction toward such an event has been, as demonstrated in the case of avian fl u (H5N1), institution of epidemiological surveillance and ensuring clinical preparedness. [1,2]

The Novel Epidemic: Etiology and Hypothesis on Its Origin
The infl uenza pandemic the world was waiting for may have arrived on April 2009, although to date its virulence appears to be no greater than that of seasonal infl uenza. Mexico was the fi rst country where there was a sharp increase in reports of patients requiring hospitalization for pneumonia and an unusual series of deaths, leading to the suspicion that a new infl uenza virus strain was in circulation. During the same period, offi cials at the Centres for Disease Control and Prevention (CDC), Atlanta, uncovered two cases of infl uenza, the so-called 'swine infl uenza,' that were clearly due to a novel strain; the two patients were children living in neighbouring disease occurred among soldiers in an army base in Fort Dix, New Jersey. Two hundred and thirty individuals had serological evidence of infection and there was one death. A novel virus H1N1 A/New Jersey/76 was identifi ed as the cause of the epidemic that, fortunately, did not extend outside the base. [8] In November 1977, another H1N1 strain re-emerged in the former Soviet Union, Hong Kong, and North-Eastern China. It caused a relatively mild disease, mostly in young people. [9,10] Genetic studies showed that the virus causing the 1977 epidemic was similar to the one isolated in the year 1950, but signifi cantly different from the infl uenza A (H1N1) strains isolated in 1947 and 1957. Thus, it is likely that the 1977 strain was one that had been preserved since 1950. [10] The cause of the re-emergence was hypothesized to be due to accidental release from a laboratory, in the face of a waning population immunity to H1N1. [11] The current S-OIV lineage carries three gene segments that share, with the human seasonal virus, a common descent from the 1918 H1N1 virus. Indeed, whereas 1918 infl uenza A (H1N1) virus likely emerged simultaneously from birds to humans and swine, S-OIV probably emerged from swine to humans. This was likely the result of a reassortment between two infl uenza A (H1N1) swine viruses. These two viruses were actually the products of at least four independent avian-to-mammalian cross-species transmission. During this process of evolution there were at least four reassortments of gene segments among avian, human and swine-adapted viruses. [12] It is not clear, however, whether this sharing of genes segments between human seasonal infl uenza A (H3N2) and current seasonal influenza A (H1N1) will allow S-OIV-infected individuals to develop effective immunity and clinical protection against S-OIV itself.
The aim of this review is to give an update of the global situation of the 2009 S-OIV pandemic. To obtain the material presented in this article, we searched the PubMed database using the following key words: H1N1, S-OIV, and swine fl u. We also visited the websites of the main international health agencies, namely the World Health Organization (WHO) and Centres for Disease Control (CDC), Atlanta, to search for relevant matter. The cut-off date for the search was August 10, 2009.

Global Epidemiology
According to the WHO, [13] all continents have been affected by the pandemic. As of 31 st July 2009, 168 countries and overseas territories/communities have each reported at least one laboratory-confi rmed case of pandemic (H1N1) infl uenza, with a total of 162,380 reported cases and 1154 associated deaths. However, the number of cases reported actually understates the real number of cases, given that countries are no longer required to test and report individual cases.

Estimates of the impact of the pandemic
In Europe a major wave of the S-OIV epidemic is expected this autumn; [14] this is also likely in other countries that experienced the fi rst wave in May-July. However, it is not possible at this point to make any prediction regarding the possible infection rates and the timing of the epidemic in the different countries.
Infl uenza epidemics usually take off in autumn, and it is important to prepare for an earlier start in this season. In the UK, which was one of the countries to suffer the fi rst wave of the S-OIV epidemic, the Department of Health estimates that 30% of the general population will develop clinical disease, with 15% suffering complications and 2% requiring hospitalization. The case fatality rate is expected to be 0.1-0.35% of the clinical cases. In the UK, the expected rate for sickness work absence is 12% of workforce at the peak level. [15] Europe has nearly 700 million inhabitants. If the estimates from UK apply in the rest of the continent, 230 millions European inhabitants will report clinical signs and symptoms of S-OIV infection this autumn, and there will be approximately 230,000-750,000 related deaths, i.e., about 33-107 deaths per 100,000 inhabitants. If the case fatality rate from the WHO S-OIV data (1154 deaths/162,380 cases, i.e., 0.07% of clinical cases) is applied the number of deaths could be lower, i.e., around 160,000.
During years 1972-1992, infl uenza-related mortality and hospitalization rates in the US were, respectively, 9.1 and 50 per 100,000 population. [16] A possible explanation for the difference between the 1972-1992 US rate and the UK estimates for autumn, 2009, could be the difference in age structure in the previous period and in the current one due to aging of the population. In fact, in the period 1972-92 during the inter-pandemic years, over 90% of influenza-related deaths occurred among persons 65 years of age or older; consequently, the incidence of infl uenza-related mortality was 100-fold higher for these age-groups than among younger persons. The higher UK fatality rate estimate can be explained by the fact that there has been a substantial increase in the number of persons aged ≥65 years and these persons are at increased risk for death from infl uenza complications. Indeed, though the rates of infection are highest among children and young adults, complications, hospitalizations, and deaths from infl uenza are higher among persons aged ≥65 years and those (of any age) who have medical conditions that place them at increased risk.

Transmission routes of S-OIV
From what has been documented in international public health reports, it is clear that human S-OIV infection spreads easily through different countries and continents. The emergence of S-OIV infection among humans represents the greatest pandemic threat ever observed since the emergence of an (H3N2) infl uenza virus in 1968. [5] Infl uenza due to a virus of swine origin has been previously reported only sporadically in humans, and generally affected young persons and their family members with recent exposure to pigs. [17] Some cases with no history of exposure to pigs have also been reported [18,19] and, although these reports are quiet scant, it gives credence to the hypothesis that human-to-human transmission is possible.
Since its fi rst recognition, the pandemic strain of S-OIV has spread worldwide within 3 months. After human-to-human transmission was documented in at least three countries of two WHO regions, the pandemic alert was raised to phase 6 on 11 th June, 2009.
The transmission routes and incubation period of S-OIV are similar to that of any other infl uenza virus. [20,21] The infl uenza virus belongs to the Orthomyxoviridae family, has an envelope, and has a size of 0.08-0.12 µm. The main route of transmission is respiratory, through inhalation of large droplets and, possibly, small droplet nuclei [22] expelled while coughing or sneezing. Transmission via respiratory droplets requires close contact between source and recipient because droplets do not remain suspended in air for long and generally travel only short distances (<6 ft). Transmission on the hands of patients and their caregivers has also been described as being potentially relevant. [23] Another potential transmission routes is contact with fomites [24] contaminated with respiratory or gastrointestinal fl uids. [25,26] Since many patients with S-OIV infection have complained of diarrhea, [27,28] feco-oral transmission should be considered a potential transmission route, [22] until further data are available.
In the early epidemic phase, most of the cases were imported, whereas currently the majority of cases are autochthonous. For instance, recent German surveillance reports for S-OIV notifi ed 105 domestic cases, i.e., 53% of the total cases reported from the country. For 96 out of 105 domestic cases (91%), the source of infection was known; moreover, 73 of the 96 cases (76%) were outbreak-related, while 23 cases were related to an imported case. [29] Schools represent the ideal environment for infl uenza virus transmission because of crowding and close contact between children, who usually share items and toys. Indeed, school clusters have been described everywhere. [29][30][31] All events involving crowds -like the case of the rock festival in Belgium [32] or private parties [29] -have the potential to cause the occurrence of infl uenza clusters. Table 1 shows some recommendations for minimizing the diffusion of S-OIV in community settings [33] .

Clinical Presentation Symptoms and signs
Influenza is the most frequent cause of acute respiratory illness requiring medical intervention. [34] It usually causes an acute, self-limiting, febrile illness but it can also lead to severe complications or death, particularly in patients with compromised immunity (e.g., pregnant women, elders, HIVinfected persons, etc.) or underlying medical conditions (e.g., cardiac or pulmonary disease). [35] The pandemic is still under study but, so far, the clinical presentation of the novel S-OIV A (H1N1) seems to resemble that of seasonal infl uenza, and the majority of patients infected with the pandemic virus experience mild symptoms and recover fully within a week, even without medical treatment.
In order to better defi ne the clinical features of this pandemic, we reviewed the descriptions of S-OIV cases in the literature from across the world [Tables 2 and 3]. According to this data, S-OIV patients complained mostly of the classical infl uenza symptoms; in addition, S-OIV patients also often have diarrhea and vomiting, which are not usually seen in seasonal infl uenza. [5] Fever was reported by a median of 87% (62-100%) of cases, cough by 82.5% (59-100%), sore throat by 57% (2-82%), diarrhea by 13.5% (2-50%), and vomiting by 12.5% (2-50%) [ Table 2]. Other symptoms reported by patients include myalgia, arthralgia, nasal congestion, headache, anorexia, sneezing, nausea, shortness of breath, and conjunctivitis.

Age
The younger age-groups appear to be much more susceptible than the elderly to S-OIV infection. This is concordant with the age-stratifi ed sero-epidemiological data, which suggests that persons >60 years of age are more likely to have neutralizing antibodies to the virus. [60] According to a report of 642 confi rmed cases in the US, with patients ranging in age from 3 months to 81 years, 60% of patients were ≤18 years old, 40% were 10-18 years old, and only 5% were ≥51 years of age. [5] The majority (>97%) of confi rmed cases of S-OIV infection in Mexico were also in those <60 years of age. [61] Hospitalization One of the more controversial issues is the question of hospitalization for S-OIV infection; hospitalization is often deemed necessary because of the need for isolation of these patients. During the influenza seasons of 1972-1992, the average seasonal burden due to infl uenza was estimated to be about 50 hospitalizations per 100,000 US inhabitants per season. [16] From March 28 to May 4, 35 out of 642 confi rmed cases (5%) in the US and 52 out of 949 cases (6%) in Mexico were hospitalized. [37] In Europe, the initial approach was different from that in North America, with some countries placing the emphasis on case fi nding and contact-tracing, with antiviral treatment of patients and chemoprophylaxis of contacts. Later, cases were isolated in hospitals and quarantine was practised in most European countries though not in the UK. [2] In this phase of the pandemic, most national and international guidelines recommend that individuals with suspected fl u be treated at home so as to avoid contact with other people. In case of any of the emergency warning signs, which includes diffi culty breathing, confusion, severe or persistent vomiting, and worsening of cough, urgent medical attention is required. Patients who present with fl u-like symptoms and then improve,

Table 1: Recommendations for minimizing the diffusion of S-OIV in the community-settings
Persons with infl uenza-like illness should be advised to stay home for 7 days after the onset of illness or at least 24 h after symptoms have resolved.
Persons who are at high risk of complications from S-OIV should consider the risk of exposure to S-OIV if they attend public gatherings where the virus is circulating and, possibly, should consider staying away from public gatherings. At public gatherings hand washing facilities (with soap and running water, hand sanitizer, and tissues) should be widely available. On-site medical assessment and care for persons with infl uenza-like illness should be provided. At public gatherings information on S-OIV transmission and on the ways to reduce the risk of acquiring infection should be widely provided.
In the case of hospital admission, patients who are confi rmed, probable, or suspected cases should be placed directly into individual rooms and the door should be kept closed. Healthcare personnel interacting with these patients should adhere to the guidelines for proper hand hygiene. Nonsterile gloves and gowns should be donned, and eye protection and respiratory protection ensured, before entering the patient's room. Isolation precautions should be continued for 7 days from symptom onset or until resolution of symptoms. [62] Complications Pneumonia is the most common complication of seasonal infl uenza. This complication is rare in interpandemic eras but becomes more frequent when a pandemic occurs. From March 24 to April 29, 2009, a total of 2155 cases of severe pneumonia were reported in Mexico. During this period, that represented the early phase of the S-OIV epidemic, a pronounced shift in morbidity was evident, with 71% of cases of severe pneumonia occurring in patients between the ages of 5 and 59 years, as compared with an average of 32% of cases in that age-group during previous periods. [63] Similarly, there was a marked change in the mortality pattern, with an increase in the mortality rate in the 5-59 year age-group as compared with the rates observed in this same age-groups during previous periods of epidemic infl uenza (87% vs 17%). [63] Data from the literature reported 79 cases of pneumonia [ Table 3]; however, rates of pneumonia complication varied according to the population on study. Out of 642 confi rmed cases of human S-OIV infection in the US, 36 (9%) required hospitalization. Of 22 hospitalized patients (on whom data was available), 11 (50%) had pneumonia, eight required admission to an intensive care unit, four had respiratory failure, and two died. [5] In Mexico, among 98 patients hospitalized for acute respiratory illness at the National Institute of Respiratory Diseases in Mexico City during the early stages of the infl uenza A (H1N1) outbreak, 18 cases of pneumonia and confi rmed S-OIV infection were identifi ed. All these patients had bilateral pneumonia and had complaints of fever, cough, and dyspnea. All of them had increased serum lactate dehydrogenase levels; creatinine kinase levels were increased in 62%, and lymphopenia was present in 61%. Twelve patients required mechanical ventilation and seven died. [47] All pneumonias were radiologically confi rmed, with 11 patients having bilateral patchy alveolar opacities (predominantly basal) affecting three or four quadrants. [47] Among non-pulmonary complications of infl uenza are various forms of central nervous system involvement, including encephalitis, transverse myelitis, aseptic meningitis, and the Guillan-Barré syndrome. [64][65][66][67][68] Four cases of neurological complications associated with S-OIV infection in children have been described in the literature. These patients were aged 7-17 years and were admitted with signs of infl uenza-like illness and seizures or altered mental status. Three of the four patients had abnormal electroencephalograms (EEGs). In all four patients, novel infl uenza A (H1N1) viral RNA was detected in nasopharyngeal specimens but not in cerebrospinal fl uid (CSF). All four patients recovered fully and had no neurologic sequelae at discharge. These fi ndings indicate that, as with seasonal infl uenza, neurologic complications can occur after respiratory tract infection with novel infl uenza A (H1N1). [69] Risk groups The risk of morbidity from seasonal infl uenza is higher among pregnant women. Pregnant women with underlying medical conditions such as asthma are at particularly high risk for infl uenza-related complications. [70,71] [57] WHO strongly recommends that in areas where S-OIV infection is widespread pregnant women, as well as the clinician treating them, be alert to symptoms of infl uenza-like illness. In addition to the increased risk for pregnant women, groups at increased risk of severe or fatal illness include people with underlying medical conditions, particularly chronic lung disease, cardiovascular disease, diabetes, and immunosuppression.
Some preliminary studies suggest that extreme obesity represents a risk factor for severe disease. [54,58] Obesity has not been identified previously as a risk factor for severe complications of seasonal infl uenza. In a report from Michigan on 10 ICU patients with S-OIV infection and ARDS, nine patients were obese, with seven being extremely obese (BMI ≥40); three of these patients died. [54] In another study from Colombia, seven patients died; of them, one was obese and one underweight. [58] Finally, HIV-infected people (especially those with AIDS or low CD4 cell counts) who acquire H1N1 infection may be at increased risk for more severe disease and complications. [44] In addition, they may be at increased risk for secondary bacterial infections, including pneumonia. [72][73][74] In immunocompromised hosts the illness may last longer than in immunocompetent ones and the virus may replicate for weeks to months, leading to more prolonged H1N1 virus shedding. [75,76] Antiviral treatment Two classes of antiviral drugs are available for the treatment of influenza: neuraminidase inhibitors, (zanamivir and oseltamivir) and adamantanes (amantadine and rimantadine). [5] Genetic analysis has shown that S-OIV is resistant to the adamantanes, whereas it is susceptible to oseltamivir and zanamivir. [77] At the beginning of the S-OIV pandemic, the use of neuraminidase inhibitors was encouraged because oseltamivir and zanamivir have been proven to be able to reduce the duration and the incidence of complications of seasonal infl uenza, [78] especially when treatment is started early (ideally, within 48 h of the onset of symptoms). [79] Indeed, data from our review evidenced an overuse of oseltamivir or zanamivir.
Clinical studies have shown that 88-100% patients received antiviral treatment, even though patients with complications or with underlying disease ranged from 2 to 11%. [44,46,50] As more data on antiviral effectiveness, clinical features of illness, adverse events from antiviral use, and antiviral susceptibility become available, recommendations on treatment are changing. Until the year 2007, resistance of infl uenza A (H1N1) virus to neuraminidase agents occurred only in a small proportion of cases. [80] More recently, a high rate of oseltamivir resistance in seasonal infl uenza virus A (H1N1) infection has been reported in Europe [81] and the US. [82] Moreover, two cases of oseltamivir-resistant S-OIV in immunosuppressed patients have already been reported. [83] Till date, the use of oseltamivir and zanamivir has been restricted to patients at relatively higher risk for infl uenza complications, [79] i.e., children <5 years old; adults ≥65 years; persons with conditions such as chronic pulmonary, cardiovascular, renal, hepatic, hematologic, neurologic, neuromuscular, or metabolic disorders; persons with immunosuppression due to any cause; pregnant women; residents of nursing homes and chronic-care facilities; persons (<19 years old) receiving long-term aspirin therapy.
The CDC suggest that antiviral chemoprophylaxis with either oseltamivir or zanamivir can be considered for the following [

Vaccine Against H1N1
A vaccine against H1N1 is expected to be the most effective tool for controlling infl uenza A (H1N1) infection in terms of reducing morbidity and mortality and limiting diffusion. However, several issues exist around vaccine manufacture and approval, as well as production capacity.
WHO conducted a survey in collaboration with all infl uenza vaccine manufacturers to review the current status of northern hemisphere seasonal vaccine production, and to assess the capabilities of the manufacturers for supplying the new infl uenza A(H1N1) vaccine over a 1-year period. The survey showed that by the time of the expected new epidemic wave most manufacturers will be technically ready to initiate largescale production of the pandemic infl uenza vaccine. [84] However, there are still many controversies regarding the number of vaccine doses required to achieve full immunological protection and the possible utility of adjuvants. [85,86] Another critical point is related to manufacturing capacity, which is likely to be inadequate to meet the entire demand of the large number of requesting countries.
There is also great concern related to the fast-track approval processes for the H1N1 vaccine set up by many regulatory agencies since this means that a vaccine might be licensed for use without satisfying the usual safety and efficacy requirements. For instance, the emergence of swine infl uenza at Fort Dix in 1976 led to the implementation of a mass vaccination program, with 40 million civilian vaccinations. Following the vaccination, there were 532 cases of the Guillain-Barré syndrome (a rare side effect of infl uenza vaccination) and 32 deaths. [87] The mass vaccination campaign was then stopped and the vaccine was withdrawn.
Another important query is who should be prescribed the H1N1 vaccine. Seasonal infl uenza vaccine is currently provided to all persons who wish to reduce the risk for becoming ill with infl uenza or of transmitting it to others. Routine annual vaccination is recommended for high-risk groups, including children aged 6 months to 18 years, all persons aged ≥50 years, and other adults at risk for medical complications from influenza. [88] Moreover, all persons who live with or care for persons at high risk for infl uenza-related complications, including contacts of children aged <6 months, should receive infl uenza vaccine annually.
Overall, it is estimated that around 85% population is eligible for infl uenza vaccination, which is likely to be above the production capacities for H1N1 vaccine, at least in the early phase of a pandemic. Countries need to determine their order of priority based on country-specifi c conditions, in order to deliver vaccination to priority groups and to groups with a social utility.
On July 29, 2009, the Advisory Committee on Immunization Practices (ACIP) -an advisory committee to CDCrecommended that novel H1N1 fl u vaccine be made available fi rst to the following fi ve groups in the US [89] : Combined, these groups would equal approximately 159 million individuals in the US.
In conclusion, as the S-OIV pandemic spreads worldwide, we can expect a signifi cant number of clinical cases this autumn, and there will be an obvious impact on morbidity and mortality rates. In order to minimize the public health impact and the associated social consequences, all countries should prepare their plans in time to face the epidemic appropriately in terms of clinical guidance, infection control, and hospital preparedness. To achieve satisfactory endpoints, national health organizations should provide recommendations to physicians, patients, and community settings and should also implement vaccination programmes, with a clear idea of where the priorities lie.