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H1N1 Influenza
Introduction
H1N1 influenza, a subtype of influenza A virus, is an infectious viral illness that causes both upper and, in some cases, lower respiratory tract infections in its host. H1N1 influenza infections can cause symptoms such as rhinorrhea, cough, decreased appetite, fever, rigors, myalgia, headache, and, possibly, lower respiratory tract disease and gastrointestinal disease.[1][2][3] Although other influenza strains exist, influenza A and B viruses predominantly impact human health.
Three subtypes of swine influenza circulate globally—H3N2, H1N2, and H1N1. The H1N1 influenza gained worldwide attention as "swine flu" during the 2009 pandemic after swine influenza viruses were reassorted with preexisting H1N1 strains.[4] Swine flu emerged from the recombination of various prior swine, avian, and human influenza strains, causing a global pandemic affecting millions of people and impacting industries, including food and tourism.
H1N1 influenza leads to a respiratory disease that can infect pigs' respiratory tract. Humans susceptible to swine influenza are typically exposed through close association with infected pigs, a condition known as zoonotic "swine flu." Swine influenza viruses can potentially infect humans if the antigenic characteristics of the virus change through the reassortment of different influenza strains.[5] This process can enhance replication and transmission, facilitating efficient transfer to human hosts. Such reassortments have led to pandemics, as seen in 1918 and 2009, when the virus acquired efficient person-to-person transmission capabilities.[6]
In 1918, the H1N1 influenza virus, commonly known as the Spanish flu, sparked a devastating pandemic that infected roughly 500 million individuals worldwide and led to the deaths of an estimated 50 to 100 million people, accounting for 3% to 5% of the global population at the time. This made it one of the deadliest pandemics in human history.[7] Similarly, the H1N1 influenza strain in 2009 was classified as a pandemic by the World Health Organization (WHO).[8] The 2009 H1N1 virus spread through airborne droplets from human to human, possibly via fomites contaminated with the virus, and subsequently transferred to the mucosa or upper respiratory tract.[9] Notably, similarities in symptoms of H1N1 in both humans and pigs arose, potentially due to the viral reassortment of preexisting strains. This similarity in symptoms suggested a commonality in viral pathogenesis across multiple hosts, likely facilitated by reassortment, thus enhancing efficient transmission.[4][10] During the pandemic, a common misconception was that individuals could contract swine flu from consuming pig products such as bacon, ham, and other pork items. However, the virus is isolated to the respiratory system and does not involve plasma, making transmission through food unlikely.[11] This misunderstanding resulted in substantial commercial losses in the food and tourism industries.[12]
Etiology
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Etiology
The H1N1 influenza virus belongs to the orthomyxovirus family and has a single-stranded negative-sense ribonucleic acid (RNA) genome. Its virions typically measure between 80 and 120 nm in diameter, with an RNA genome size of around 13.5 kb. The influenza genome comprises 8 segmented regions that encode a total of 11 different proteins, as mentioned below.
- Envelope proteins: Hemagglutinin (HA) and neuraminidase (NA).[13]
- Viral RNA polymerases: PB2, PB1, PB1-F2, PA, and PB.
- Matrix proteins: M1 and M2.[14]
- Nonstructural proteins: NS1 and NS2 (NEP), which are crucial for efficient pathogenesis and viral replication.
The H1N1 strain of influenza A is distinguished from other strains, such as H1N2, based on the surface glycoproteins hemagglutinin and neuraminidase, which exhibit metabolic synergy.[15] Hemagglutinin triggers erythrocyte aggregation by binding to sialic acid and facilitates virus attachment to infected cells, enabling endocytosis.[16] Subsequent fusion with the endosome, mediated by matrix proteins, allows viral RNA-dependent polymerase to initiate viral replication.[17] Neuraminidase is crucial during viral budding by cleaving sialic receptors and promoting virus spread to neighboring cells.[18]
Epidemiology
H1N1 influenza was first isolated from pigs in the 1930s by researchers in the United States and was subsequently recognized by pork producers and veterinarians as a cause of influenza infections in pigs worldwide.[19] People closely associated with pigs have been known to develop a disease, and pigs have also been infected with human influenza from these handlers.[20] The virus can potentially cause cross-species transmission through viral reassortment. Selection pressure from human populations immune to established strains of influenza can result in changes in antigenic structure over time to evade host immune responses, also known as antigenic drift.[21]
Significant shifts in the envelope proteins, known as antigenic shifts, can lead to the emergence of new influenza strains capable of evading the host immune response and facilitating human-to-human transmission in previously susceptible populations. For instance, the 2009 H1N1 pandemic, originating in Mexico, resulted from the combination of multiple strains, including Eurasian avian-like H1N1, avian H1N1, and a previously reassorted lineage consisting of avian H1N1, human H3N2, and swine influenza viruses.
Revised estimates from the 2009 H1N1 influenza pandemic indicated 151,700 to 575,500 respiratory and cardiac deaths occurred during the first 12 months of the pandemic, with up to 24% of the global population estimated to have been infected based on seroprevalence studies.[22][23] The 1918 deadly influenza pandemic caused by the H1N1 influenza virus infected approximately 500 million people around the world and caused the death of roughly 50 to 100 million people.[24] The 2009 H1N1 "swine flu" variant is the progeny of the strain that caused the 1918 influenza pandemic.[25] Although variants persist in pigs, the viral descendants of the 1918 virus are also known to infect humans, contributing to the seasonal epidemics of influenza from strains including H2N2 and H3N2.[26]
Influenza strains, including H1N1, are known to transmit between pigs and humans frequently, but human-to-human transmission is uncommon.[27] The 2009 H1N1 strain was easily transmitted between pigs and humans.[28] The potential retention of influenza virus strains in swine after these strains disappear in the human population essentially makes pigs a reservoir where swine influenza viruses can persist.[29] These strains can later emerge to reinfect human populations following reassortment, waned immunity, or a combination of both. As a result, new variants can continue to develop with increased genetic diversity, resulting in new threats to susceptible human populations.[3][30]
Pathophysiology
H1N1 influenza is an acute disease that infects the upper respiratory tract and can cause inflammation of the upper passages, trachea, and, possibly, the lower respiratory tract.[2][31] The known incubation period for the 2009 H1N1 influenza strains has a median duration of 2 days but ranges from 1 to 7 days. The virus replication occurs primarily in the upper and lower respiratory tract passages from the time of inoculation and peaks around 48 hours in most patients.[32] The infectious period begins a day before symptoms develop and lasts approximately 5 to 7 days after the person develops symptoms.[33][34] The period of viral shedding, which correlates with the infectious period, may be up to 15 days in children and last weeks to months in immunocompromised individuals.[35][36] The recommended time of isolation of the infected patient is approximately 7 days.[34]
The acute symptoms of uncomplicated infections persist for 3 days but can range from 1 to 11 days.[2] The disease is mostly self-limited in healthy individuals, but malaise and cough can persist for up to 2 weeks in some patients. Patients with more severe disease may require hospitalization, and this may manifest within 4 to 5 days.[37] The body's immune reaction to the virus and the interferon response are the causes of the viral syndrome, which includes high fever, coryza, and myalgia.[38] Individuals with chronic lung diseases, cardiac conditions, and those who are pregnant face a heightened risk of severe complications, including viral pneumonia, superimposed bacterial pneumonia, hemorrhagic bronchitis, and potentially fatal outcomes. These complications may manifest within 48 hours from the onset of symptoms.[39]
Histopathology
The main area of H1N1 influenza pathogenesis is the upper and lower respiratory tracts. Mild cases usually show a few pathologic changes in the respiratory tract, but severe cases can show clear pathological pneumonia changes. The pathological findings associated with H1N1 influenza include multifocal destruction, potential desquamation of the pseudo-columnar and columnar epithelial cells, and possibly prominent hyperemia and edema in the submucosa.[32] Thrombus formation at the bronchiolar level is also expected. Sometimes, the acute inflammation is severe and is indicated by hemorrhagic tracheobronchitis and desquamative bronchiolitis. This may cause necrosis of the bronchiolar wall. After necrosis occurs, polymorphs and mononuclear cells infiltrate into the affected area.
Although the virus can be observed using electron microscopy, histopathological changes are nonspecific and necessitate additional diagnostic methods for confirmation. These methods include virus isolation through culture, serology, molecular detection via polymerase chain reaction (PCR), or immunohistochemistry (see Image. Electron Microscopic View of H1N1 Influenza Virus Particles).[40] Histological changes in H1N1 influenza pneumonia include interstitial edema with possible inflammatory infiltrate, alveolar proteinaceous exudation associated with membrane formation, thrombosis of capillaries, necrosis of the alveolar septae, intra-alveolar hemorrhage, dislocation of desquamated pneumocytes with pyknotic nuclei into the surrounding alveolar spaces, diffuse alveolar damage with infiltration by the lymphocytes and histiocytes into the interstitium.[41]
In the late stage, patients may exhibit various changes, including diffuse alveolar damage, fibrosis, hyperplasia of type II pneumocytes, epithelial regeneration, and squamous metaplasia. These alterations are indicative of the fibroproliferative stage of acute respiratory distress syndrome (ARDS) and diffuse alveolar destruction. Additionally, bacterial coinfections may be present, with Streptococcus pneumoniae, S pyogenes, Staphylococcus aureus (including community-acquired and methicillin-resistant strains), and Haemophilus influenza being among the most commonly isolated bacteria.[42]
History and Physical
The history and clinical presentations of H1N1 swine influenza can vary widely, ranging from mild upper respiratory tract symptoms to severe respiratory complications, including death. These outcomes depend on factors such as the patient's age, underlying health conditions, influenza vaccination status, and natural immunity to the virus.[2] The signs and symptoms of H1N1 influenza closely resemble those of seasonal influenza, including fevers, chills, cough, runny nose, sore throat, conjunctivitis, muscle pain, difficulty breathing, weight loss, headache, nasal congestion, near-fainting, abdominal discomfort, decreased appetite, and fatigue. However, compared to seasonal influenza, H1N1 tends to present with more frequent episodes of cough, muscle pain, and pleural chest pain.[43] Additionally, the 2009 H1N1 strain was associated with increased vomiting and diarrhea.[44] Given that many symptoms overlap with other conditions, a detailed patient history is essential to differentiate H1N1 influenza, particularly in cases exposed to confirmed H1N1 cases or recent travel to high-prevalence areas.
In severe cases of the 2009 H1N1 pandemic influenza, respiratory failure and shock were the leading causes of death.[37] Other sequelae included encephalopathy, delirium, stroke, gastrointestinal bleeding, secondary bacterial sepsis, myocardial infarction, decompensated cardiac failure, myocarditis, and renal impairment requiring renal replacement therapy.[45] Unlike seasonal influenza strains, the 2009 H1N1 virus was associated with more severe cases and fatalities in children and adults aged 60 and younger.[46]
Additional risk factors for severe disease during the 2009 pandemic included pregnancy, particularly during the second and third trimesters, a body mass index equal to or greater than 35 kg/m2, the presence of chronic medical conditions, and delayed initiation of oseltamivir treatment (≥5 days after symptom onset).[39][47] Chronic medical conditions include chronic obstructive pulmonary disease, bronchial asthma, immunosuppression, chronic liver disease, neurological disorders, and diabetes mellitus.
Evaluation
Influenza A (H1N1) virus infection can manifest across different clinical settings, leading to diverse presentations. It is essential to consider H1N1 as a potential differential diagnosis in patients exhibiting unexplained flu-like symptoms or acute pneumonia, especially in regions with confirmed influenza cases. Initial evaluations should include routine investigations such as hematological, microbiological, biochemical, and radiological tests to establish a diagnosis.
Diagnostic confirmation of influenza A (H1N1) virus infection necessitates obtaining a respiratory sample, such as a nasopharyngeal swab, aspirate, or wash. Various tests can be conducted on these samples, including reverse transcriptase-PCR (RT-PCR), viral isolation by culture, complement fixation testing, haemagglutination assays, and antibody detection via immunofluorescence. Further serological assays during convalescence may be performed to detect seroconversion from immunoglobulin M (IgM) to IgG or a four-fold increase in influenza virus IgG antibody levels.[48][49] In addition to rapid point-of-care tests, these tests are specific for human influenza viruses, including the rapid point-of-care tests, and do not always detect zoonotic variants.[50]
An indication of a novel swine influenza virus may arise if an influenza A virus is detected lacking specific proteins typically found in human influenza viruses, such as hemagglutinins. Diagnosis of zoonotic influenza virus infections may sometimes be achieved retrospectively through serological testing. However, the potential for cross-reactivity with human influenza viruses can complicate this diagnostic process.[51] Another concern is that the neuraminidase (NA) and hemagglutinin (HA) envelope proteins of certain swine influenza viruses, which are the primary targets of host immune-mediated responses, may originate from ancestral human influenza viruses. This could indicate viruses that have previously circulated in human populations. Depending on the jurisdiction, state, regional, or national public health laboratories may be able to conduct genomic analysis and test for novel influenza viruses.[52]
Treatment / Management
Many management strategies applicable to influenza are also relevant to H1N1, except in cases involving variants of zoonotic origin. In such instances, prevention is the most effective approach to managing H1N1 influenza. This involves preventing and controlling swine influenza outbreaks in pigs, minimizing transmission of swine influenza variants from pigs to humans, and ultimately, halting human-to-human transmission.
Prevention of swine influenza in pigs: Prevention of swine influenza in pigs primarily relies on three key methods: facility management, herd management, and vaccination. Facility management involves implementing measures such as disinfection and regulated temperature controls to minimize viral replication in the environment. Herd management strategies include preventing overcrowding and quarantining pigs with influenza-like illnesses away from unexposed pig groups. Additionally, vaccination plays a crucial role.[53][54][55][56] Without complementary prevention and mitigation measures, vaccinations alone may not effectively limit swine influenza spillover events.(B3)
Prevention of swine-to-human viral transmission: Preventing swine-to-human viral transmission is crucial in mitigating the risk of H1N1 transmission to humans. While reducing influenza incidence in swine populations is essential, addressing swine-to-human transmission events is equally important in minimizing outbreak potential. Swine are susceptible to both avian and human strains of H1N1 influenza, earning them the nickname "mixing vessels." In these animals, viral reassortment can occur, leading to the emergence of new strains of swine influenza through antigenic shifts.[57]
Transmission of the influenza virus from swine to humans is usually seen in people closely associated with pigs, such as farmers, pork handlers, and veterinarians.[58] These individuals are strongly encouraged to wear face masks when dealing with infected animals to prevent transmission through respiratory droplets, given their efficacy in preventing influenza transmission.[59] Individuals with an increased risk of acquiring H1N1 influenza through pigs are also advised to employ similar strategies to prevent transmission in humans, emphasizing hand hygiene.(B2)
Prevention of human-to-human transmission: The main routes of zoonotic swine influenza virus spread between humans are most likely via inhalation of respiratory droplets or aerosols, mucosal contact, and fomite exposure, such as when a susceptible individual contacts a contaminated surface and then makes contact with their mucosal membranes in the nose, mouth or eyes.[60] Addressing these potential transmission points is critical during the infectious period of influenza. Documented strategies to prevent the spread of the virus include frequent handwashing with soap and water or alcohol-based sanitizers and disinfecting household, hospital, and public settings by cleaning with a diluted bleach solution.[61] Anyone who resides where the disease is prevalent suspects an infection or presents with flu-like symptoms should stay away from work and public transportation and immediately see a doctor.
During the 2009 H1N1 influenza pandemic, a viable vaccine was approved by the Food and Drug Administration (FDA) in the United States of America following studies by the National Institute of Health (NIH) indicating a single dose within 10 days of illness was sufficient to create protective antibodies against the virus.[62][63] The vaccination is contraindicated in people with a previous severe allergic reaction to the influenza vaccination. Those who are moderate to severely ill, including those with or without a fever, should take the vaccination when they recover or are asymptomatic.(B2)
The treatment of infected patients depends on the severity of symptoms of H1N1 influenza. Mild-to-moderate influenza is usually self-limiting and can be treated at home with rest and oral hydration. Symptomatic treatment for H1N1 influenza may include antipyretics such as paracetamol/acetaminophen, antihistamines for nasal congestion and rhinitis, and simple analgesia like non-steroidal anti-inflammatories or paracetamol/acetaminophen for headaches, myalgias, and arthralgias. Patients experiencing progressive or severe symptoms should be managed in an inpatient setting to monitor for potential intensive care unit (ICU) intervention, especially if signs indicate impending respiratory failure, sepsis, or multiorgan dysfunction. Aggressive supportive measures may include intravenous (IV) hydration, the correction of electrolyte imbalances, and antibiotics for concurrent bacterial infections. Patients developing acute respiratory distress syndrome (ARDS) secondary to influenza should be treated with non-invasive or invasive mechanical ventilation. Severe cases of H1N1-induced ARDS have required extracorporeal membrane oxygenation (ECMO).[64](A1)
Clinicians managing this condition should be aware that early antiviral treatment within 72 hours of symptom onset may decrease severe disease and mortality. Additionally, they should understand which antiviral treatments are effective in this window. Vaccines and other preventative measures are critical in reducing H1N1 influenza transmission during outbreaks. The antiviral medications, oral oseltamivir, IV zanamivir, and IV peramivir, have each been documented to help reduce, or possibly prevent, the effects of H1N1 influenza if the medication is taken within 48 hours of the onset of symptoms.[65][66][67] (A1)
Oseltamivir, a neuraminidase inhibitor, has effectively reduced inpatient readmission rates and mortality associated with influenza, making it a recommended chemoprophylaxis agent during H1N1 influenza outbreaks.[68][69] Common adverse effects of oseltamivir include nausea, vomiting, headache, and skin reactions such as atopic dermatitis and urticaria. Rare but serious adverse reactions may include Steven Johnson syndrome, hepatobiliary enzyme derangement, sporadic transient neuropsychiatric events, and gastrointestinal bleeding.[70][71][72]. Caution should be exercised when prescribing oseltamivir to individuals at higher risk of experiencing these adverse effects.(B2)
Zanamivir is another neuraminidase inhibitor, administered via IV route, that has clinical efficacy in hospitalized influenza patients unable to tolerate oral oseltamivir.[73][74] Individuals treated with zanamivir most commonly experience headaches, but it has been rarely associated with bronchospasm.[75] Zanamivir is contraindicated in individuals with an allergy to its components and in severe milk protein allergy.[76] However, zanamivir and oseltamivir may be used in influenza prophylaxis among older or immunocompromised patients, where vaccination is contraindicated.[66][77](A1)
Peramivir, developed in 2010, is another IV neuraminidase inhibitor alternative to oseltamivir in high-risk patients with influenza, demonstrating fever alleviation comparable to oseltamivir.[78][79] Post-marking experiences revealed mild adverse effects of diarrhea and abnormal behavior were commonly reported, with neutropenia and leukopenia observed rarely.[80] A systemic review of influenza resistance to neuraminidase inhibitors pooled analyses indicated approximately 2.6% of influenza samples were resistant to oseltamivir, 0% were resistant to zanamivir, and 0% to peramivir.[81] Individuals who remain symptomatic after 10 days of treatment should be assessed for secondary infections and potentially screened for antiviral resistance.[61](A1)
Pregnant women who contract the H1N1 are at a greater risk of complications because of hormonal and inflammatory response dysregulation, as well as systemic changes to their cell-mediated immunity to accommodate the growing fetus.[82][83] Neonates born to pregnant patients with H1N1 have higher frequencies of pre-term birth and intrauterine growth restriction.[69] For these reasons, during the 2009 H1N1 pandemic, the United States Centers for Disease Control and Prevention and the WHO recommended all pregnant women be vaccinated to prevent infection. Oseltamivir has been used frequently in pregnancy and has shown efficacy in reducing severe illness with H1N1 influenza in pregnant women within 48 hours of symptom onset.[84] Zanamivir also has demonstrated safety data for H1N1 influenza.[85](B2)
Differential Diagnosis
The conditions included in the differential diagnosis are infections such as HIV, COVID-19, adenovirus, arenavirus, cytomegalovirus, dengue, and echovirus infection, acute respiratory distress syndrome, hantavirus pulmonary syndrome, human parainfluenza virus and other parainfluenza virus infections, Legionnaires disease, Pneumocystis jirovecii pneumonia infection, cryptococcal pneumonia infection, and Mycoplasma pneumoniae and Chlamydia pneumoniae infections.
Among these, the viral infections most closely resembling H1N1 influenza in presentation include COVID-19, seasonal influenza strain, and parainfluenza virus infections.
Prognosis
Pandemic 2009 H1N1 influenza infection was associated with a mortality of approximately 1%.[86] Individuals aged 50 and older had a lower risk of infection compared to younger age groups, while hospitalization rates were higher among those aged 5 or younger and between the ages of 5 and 14. Severe disease was more prevalent in individuals with chronic comorbidities. Key laboratory findings in severe cases included elevated levels of lactate dehydrogenase, creatinine phosphokinase, C-reactive protein, and lymphopenia.[87][88]
Prognostic variables associated with death or ICU admission in H1N1 influenza include diabetes, corticosteroid therapy, histamine-2 receptor use, and morbid obesity, as well as secondary cardiovascular and bacterial complications.[89] Additionally, a study involving 1651 patients during the 2009 pandemic revealed that delaying oseltamivir administration for more than 5 days independently correlated with hospitalization, ICU admission, and heightened odds of mortality.[90]
Complications
The 2009 H1N1 influenza pandemic strain primarily led to respiratory complications, such as pneumonia, exacerbation of chronic pulmonary disease, and, to a lesser extent, ARDS.[91] Cardiovascular complications and secondary bacterial infections could exacerbate outcomes.[88] Neurological complications varied and included seizures, focal neurological deficits, Guillain-Barré syndrome, and myositis.[92] Long-term sequelae from H1N1 influenza-related ARDS have also been observed. One year post-H1N1 influenza, individuals experienced increased exertional dyspnea scores, reduced frequencies of returning to work, and higher rates of anxiety and depression compared to those without H1N1-related ARDS.[93] These potential outcomes emphasize the importance of ensuring appropriate and timely treatment to prevent acute and long-term complications.
Deterrence and Patient Education
The H1N1 influenza virus, as a respiratory pathogen, can be prevented through proper personal hygiene and environmental control measures. Encouraging the distribution and use of masks, along with practicing regular hand hygiene using soap and water, antiseptic hand wash, or alcohol-based hand rubs, is essential. These practices are essential before engaging in activities that involve contact between the hands and face.[61] Education on proper cough and sneeze etiquette, along with social distancing measures, should be provided to minimize exposure to respiratory secretions.[94] Disinfecting contaminated surfaces with agents like alcohol, sodium hypochlorite, or quaternary ammonia compounds is also recommended.[95]
Enhancing Healthcare Team Outcomes
H1N1 influenza is highly infectious and can spread easily and quickly from infected humans or through contact with pigs carrying the virus. The infection can quickly progress to moderate-to-severe symptoms and, in some cases, fatalities. For optimal outcomes, patients with H1N1 influenza should be evaluated and cared for by an interprofessional healthcare team. This team should be aware of high-risk patients, including children, older and immunocompromised individuals, pregnant women, and those suffering from chronic conditions.[96]
The treating clinician, whether primary care physician, pharmacist, or nurse practitioner, should advocate for administering the H1N1 influenza vaccine to both children and adults at risk. Furthermore, it is crucial to encourage vaccination for all pregnant women to mitigate morbidity, mortality, and fetal complications.[96] In emergency situations, the school nurse, in collaboration with school authorities, should assess the need for school closure in the event of H1N1 cases.[97]
Parents should be encouraged to have their children vaccinated against H1N1 influenza and advised to self-isolate if infected to minimize exposure to others. Pharmacists are authorized to administer vaccines in many states within the United States and other countries. In hospital settings, nurses should ensure that infected patients are placed in single isolation rooms with airborne precautions. Notably, taking appropriate measures to prevent contact with bodily fluids and aerosols generated during coughing is essential. Strict adherence to hand hygiene protocols is crucial, and only a limited number of healthcare personnel should have contact with infected patients. Open communication among interprofessional healthcare team members is essential for reducing the morbidity and mortality associated with H1N1 influenza.[98]
Media
(Click Image to Enlarge)
Electron Microscopic View of H1N1 Influenza Virus Particles. Digitally colorized transmission electron microscopic view of H1N1 influenza virus particles.
Public Health Image Library, Public Domain, Centers for Disease Control and Prevention
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