Within 2 months of its discovery last spring, a novel influenza A (H1N1) virus, currently referred to as 2009 H1N1, caused the first influenza pandemic in decades. The virus has caused disproportionate disease among young people with early reports of virulence similar to that of seasonal influenza. This clinical review provides an update encompassing the virology, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of the 2009 H1N1 virus. Because information about this virus, its prevention, and treatment are rapidly evolving, readers are advised to seek additional information. We performed a literature search of PubMed using the following keywords: H1N1, influenza, vaccine, pregnancy, children, treatment, epidemiology, and review. Studies were selected for inclusion in this review on the basis of their relevance. Recent studies and articles were preferred.
On April 21, 2009, the Centers for Disease Control and Prevention (CDC) confirmed 2 cases (originally identified by the Department of Defense) of a febrile respiratory illness in children from southern California caused by infection with a novel influenza A (H1N1) virus. The 2 viral isolates were found to be genetically similar, to be resistant to amantadine and rimantadine, and to contain a novel genetic combination of segments from previous swine influenza viruses that have circulated in the United States since 1999, genes from swine viruses of the Eurasian lineage, and genes from avian influenza viruses. Neither of these children had exposure to swine or to each other, indicating that this virus was capable of human-to-human transmission. Several days later, the CDC reported that H1N1 viruses of the same strain had been confirmed among samples from patients in Mexico, where there was a cluster of 47 cases of rapidly progressive severe pneumonia that resulted in 12 known deaths.
In response to these cases, investigations and enhanced surveillance were implemented by the Mexican Ministry of Health with the assistance of the World Health Organization (WHO).
By June 11, 2009, nearly 30,000 cases of 2009 H1N1 virus had been confirmed across 74 countries, compelling the WHO to signal the phase 6 alert level, officially declaring the start of the 2009 influenza pandemic (Table 1).
This clinical review provides an update encompassing the virology, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of the 2009 H1N1 virus. To identify relevant literature, we searched PubMed using the following keywords: H1N1, influenza, vaccine, pregnancy, children, treatment, epidemiology, and review. Studies were selected for inclusion in this review on the basis of their relevance and currency.
The known historical roots of the influenza A H1N1 virus can be traced to 1918, when a virus currently thought to be of avian origin overcame the complex species barriers required to infect humans. Thus began an influenza pandemic that would result in an estimated 50 to 100 million deaths, more than any other influenza pandemic in history. During the second and more severe wave of human disease in 1918, herds of swine were reported to be infected with a respiratory illness of similar scope and severity. Shope, a veterinarian, determined that a virus was the causative agent of this swine illness and hypothesized that the human pandemic influenza strain of 1918 must be closely related. His work with mice and other subsequent studies have supported his hypothesis. Thereafter, the swine and human influenza viruses rapidly diverged antigenically, and H1N1 continued to infect humans in seasonal epidemics. In 1957, the H1N1 virus was replaced by a new strain, designated H2N2, that combined genetic material from its H1N1 predecessor and an avian influenza virus. However, influenza A/H1N1 reemerged in a 1976 outbreak among 230 Army soldiers at Fort Dix, NJ, resulting in 1 death. The virus did not extend to the civilian population. One year later, another A/H1N1 strain emerged in China, Hong Kong, and the former Soviet Union.11 This reemergence was thought to result from an unintended laboratory release and caused mild symptoms in predominantly young people. Since 1977, the H1N1 influenza virus has persistently contributed to seasonal epidemics alongside the often more dominant H3N2 subtype.
Like influenza B and C, influenza A belongs to the Orthomyxoviridae family. It contains a genome made up of 8 segments of negative-sense RNA that encodes 11 proteins (Figure 2). Standard influenza nomenclature includes the virus type (A, B, or C), geographical origin, strain number, year of isolation, and virus subtype. Thus, the influenza A/H1N1 virus isolated in California in 2009 is identified as influenza A/California/04/2009 (H1N1). Influenza A subtype classification is based on the antigenicity of the 2 major cell surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). To date, 16 HA (H1-H16) and 9 NA (N1-N9) subtypes have been identified.
The structure and function of the proteins encoded by the 8 genome segments have been defined. The HA protein facilitates binding of the virus to host cell receptors and subsequent endosomal fusion. Polymerase subunits (basic polymerase [PB] 1, PB2, and acidic polymerase) and nucleoprotein implement the replication and transcription of viral RNA. The nuclear export protein and the matrix protein export the viral ribonucleoprotein complexes from the nucleus into the cytoplasm for assembly into new virions at the plasma membrane. Viral release from the cells is facilitated by the NA protein.
Antigenic variation through drift and shift of HA and NA proteins enables the virus to escape host immune responses. Drift refers to frequent, minor changes on the HA and/or NA antigens. Antigenic drifts in the HA subtype are associated with seasonal epidemics and often reduce the effectiveness of the previous seasonal vaccines. Shift refers to the introduction of an influenza A virus subtype to which the population has no preexisting immunity. Although the precise mechanism is unknown, shifts are widely assumed to be facilitated by the virus’s segmented genome and the genetic diversity it achieves by infecting a varied reservoir of animals. Antigenic shifts in HA subtypes are associated with pandemics, 3 of which occurred in the past century. The most infamous was the “Spanish flu” pandemic of 1918 that resulted in between 50 and 100 million deaths worldwide. In 1957, the introduction of H2N2 resulted in the “Asian flu” pandemic and claimed about 70,000 lives in the United States and about 2 million worldwide. Eleven years later, a novel H3N2 virus caused the “Hong Kong flu” of 1968 and resulted in about 70,000 deaths in the United States and about 1 million worldwide.
The emergence of the 2009 H1N1 virus is an unprecedented event in modern virology. The 2009 H1N1 virus does not fit the classic definition of a new subtype for which most of the population has no previous infection experience. Since 1977, H1N1 viruses have been in continuous circulation, and most persons born before 1956 have previous infection experience with H1N1 strains in the pre-H2N2 era. The 2009 H1N1 virus also does not fit the classic definition of drift because it has no direct evolutionary relationship with recently circulating H1N1 viruses of human origin. However, all H1N1 strains share subtype antigens identified by immune-diffusion tests, which is the basis for influenza virus subtype classification. Immune recall exists within each subtype (all H1N1 strains). For example, populations born before 1957 (during the period of H1N1 circulation) responded well to 1 dose of swine influenza virus vaccine in 1976, despite low or no preexisting antibodies to the HA, just as persons currently 10 years or older have responded well to a single dose of the 2009 H1N1 vaccine.
The natural reservoir for all influenza A subtypes is waterfowl, with certain subtypes transmissible among humans, pigs, and 16 other mammals. Human influenza viruses bind to receptors composed of a sialic acid and galactose linked by an α 2,6 bond (SAα2,6Gal) on epithelial cells within the respiratory tract. Avian influenza viruses, however, preferentially bind to receptors composed of sialic acid and galactose linked by an ? 2,3 bond (SA?2,3Gal) on epithelial cells within the intestinal tract of waterfowl. The epithelial cells lining the trachea of swine express both receptors, making swine a “mixing vessel” for coinfection with influenza A subtypes and reassortment.
Once the virus binds to columnar epithelial cells of the respiratory tract, it interferes with host cell protein synthesis and, through unclear mechanisms, induces apoptosis of the host cell. Before cell death, new virions are produced and released to infect adjacent cells. Necrotizing bronchitis and intra-alveolar hemorrhage and edema result.