Background

Influenza is an infectious airborne disease occurring seasonally which causes acute illness with systemic symptoms of varying intensity. It is responsible for huge losses in terms of working days, human misery, and mortality. More virulent strains of influenza have made their appearance and there been three pandemics during the last century including the Spanish flu in 1918, which is a huge loss. Influenza also infects several animal species and some of these strains transmit from animals to human beings. 

Influenza viruses are divided into four types: A, B, C, and D. Of these two main types like influenza A and B viruses cause seasonal diseases. 

Influenza A viruse are broken down into different subtypes depending on combination of two proteins on viral surface, hemagglutinin (H), and neuraminidase (N). All currently circulating human influenza viruses are found to share these two subtypes: influenza A(H1N1) and A(H3N2). Where as A(H1N1) viruses and A(H1N1) pdm09 viruses are different. A(H1N1) pdm09 caused pandemic in 2009 the virus was different earlier than 2009.  

Some variants are assigned to lineages for example the influenza B viruses which are not subdivided into subtypes but further to lineages Influenza type B viruses are classified into either B/Victoria or B/ Yamagata lineage. 

Influenza C virus is detected much less frequently and most often causes only mild infections. Hence, it has little or no public health importance. 

Influenza D viruses infect mainly cows and do not usually infect people. 

The symptoms of influenza are identical to a few other viral infections that affect upper respiratory tract. Influenza can be ascertained through rapid diagnostic test but this test only provides limited sensitivity and predictive values. The mainstay in confirming influenza virus infection is  identification of influenza virus ribonucleic acid (RNA) through the use of reverse transcription-polymerase chain reaction or by viral culture of nasopharyngeal or throat secretions. 

The best policy is, of course, prevention. The vaccines produced annually in the United States contain antigens from the strains judged most likely to cause infection during the winter flu season. 

Hemophilus influenza type-B 

Haemophilus influenzae is a coccobacillus negative gram that infects the upper respiratory tract of the children, most commonly through inhalation of the nasal secretions. More severe infections result from its polysaccharide capsule or coat. Hib is the most common cause of more than 90 % of systemic infections. This organism causes pneumonia and meningitis in young children and is a considerable health problem to the world with up to 3 million severe cases presenting each year. These have gained significance for global vaccination because of increasing antibiotic resistance in Hib, the only public health tool by which rapid declines in the incidence of Hib disease in the world can be achieved. 

H1N1 influenza 

H1N1 influenza is a influenza A virus subgroup illness on respiratory area, including both the upper and lower tracts of its host. Swine influenza is a recombination of swine, avian, and human strains of influenza which achieved global attention with the 2009 outbreak. The virus only affects the respiratory tracts of pigs, and humans usually expose themselves while they are among infected pigs. Reassortment of strains of influenza enhances replication and, hence, transmission, causing pandemics such as 1918 and 2009. Influenza 2009 transmission of H1N1 was aerial through droplets, and possibly through the transfer of the virus found on fomite contaminate surfaces. Consuming pig products caused huge commercial losses to the food and tourism industry because of the misconceptions concerning swine flu. 

Avian H5N1 influenza 

In most cases, patients contract avian influenza (H5) through direct contact with live poultry. In fact, since hemagglutinin type 5 molecules avidly bind to avian respiratory cells this virus easily transmitted among species but attachment to human cells is difficult. Avian viruses Favour sialic acid alpha (2-3) galactose that is seen in the alveoli and terminal bronchi while human viruses choose sialic acid alpha (2-6) galactose found on epithelial cells in the upper respiratory tract. Yet, very few human-to-human transmissions have been reported. Although, most deaths in humans resulted from bird flu found in Indonesia and sporadic outbreaks have still been noted in China, Egypt, Thailand, and Cambodia. Theoretically, mutation of the hemagglutinin by antigenic drift might lead to a virus that easily transfers from humans to humans which in turn might cause a global pandemic. 

Epidemiology

Influenza is a tropical viral infection that occurs every year usually starting from late summer to early fall in the Northern Hemisphere. WHO, estimates that about 1 billion cases of influenza occur in each year leading to 3–5 million severe cases or 290,000 to 650,000 influenza-related respiratory deaths annually. On average, flu-associated deaths in the United States were between 3,000 and 49,000 annually for the period between 1976 to 2006. The Centers for Disease Control and Prevention estimated 35 million influenza-associated illnesses, 16 million influenza-related medical visits, 380,000 flu-associated hospitalizations, and 20,000 influenza-related deaths were reported for the 2019-2020 influenza season.

The H1N1 influenza pandemic was responsible for an estimated 500,000-700,000 deaths in the United States and an estimated 30-40 million deaths worldwide. It is therefore worth noting that 2009-2010 influenza season was characterized by circulation of an epidemic strain, H1N1 “swine flu,” more severe with disease among persons < 65 years, and higher rates of hospitalizations among children and young adults. By 2021, from the World Health Organization a consideration of 862 cases of avian influenza had resulted in 455 deaths. Most cases have been in eastern Asia, with some in cases of Eastern Europe and North Africa. 

Anatomy

Pathophysiology

Influenza viruses are single-stranded RNA viruses classified under the family Orthomyxoviridae and having three types: A, B, and C. Influenza A viruses cause most human and avian influenza infections. The most abundant surface proteins, hemagglutinin (H) and neuraminidase (N), are key to virulence and consequently, neutralizing antibodies of acquired immunity to influenza.

Typing of Influenza A is done by identifying both the H and N proteins, and 17 H and nine N types are recognized. The most common prevailing influenza A subtypes infecting humans are H3N2 and H1N1, and the trivalent vaccine contains strains from H1N1 and H3N2 in addition to an influenza B strain. Influenza A is genetically labile and mutation rates are as high as 300 times that of other microbes.

Antigenetic drift and antigenetic shift cause the changes observed in its major functional and antigenic proteins. The latter is less frequent and may result in a virulent strain of influenza that has the triad of infectivity, lethality, and transmissibility leading to a possible pandemic. 

Etiology

There are four types of influenza viruses A, B, C, and D. Influenza A and B viruses are known to infect humans every year during the epidemic season. In the recent past, there have been reports of outbreaks of influenza C, especially in children. Influenza viruses belong to the family Orthomyxoviridae. During 2021- 2022, the predominant type of influenza circulating in the US has been influenza A (H3N2).  

Transmissibility of the avian influenza (i.e., human H5N1 influenza virus) is primarily through direct contact with infected or dead ill birds with the virus. Other mechanisms of the infection involve coming into close contact with excreta from infected birds or with contaminated surfaces or water. Close and prolonged contact of a caregiver with an infected person is supposed to have resulted in at least one case.  

Genetics

Prognostic Factors

Influenza causes morbidity that requires individuals to take time off work and school. In children and seniors, the infection can be fatal, with higher mortality rates seen in those with pre-existing lung diseases and diabetes. Overall, influenza can severely impact the quality of life for 1-2 weeks each session. 

Clinical History

Influenza with a spectrum of severity influenced by factors like age, underlying health conditions, vaccination status, and natural immunity. Vaccinated individuals generally experience a milder symptoms and lower complication rates. 

Mild cases: Symptoms include cough, fever, sore throat, myalogia, headache, runny nose, and congested eyes. Ocular symptoms like photophobia and ocular pain can occur due to viral tropism. 

Severe cases: Progression may include rapid onset of shortness of breath, tachycardia, hypotension, necessitating respiratory support within 48 hours. 

Physical Examination

The presentation of influenza varies widely among patients. Some may appear acutely ill, exhibiting weakness and respiratory symptoms, while others may show only mild signs of illness. 

Patients may show the following: 

Fever with temperature of 100 to 104⁰F. This will be milder in elderly people than young individuals. 

Pharyngitis 

Severely sore throat 

Eyes may be watery and red 

Tachycardia that occurs due to fever, hypoxia or both 

Skin could be warm to hot based on the temperature condition 

Absence of nasal discharge   

Fatigued appearance 

Pulmonary findings include rhonchi or dry cough with lungs in clear condition along with focal wheezing. 

Influenza A virus shows up acute encephalopathy. 

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Adenovirus 

Dengue 

Cytomegalovirus  

ARDS (acute respiratory distress syndrome) 

Arenaviruses 

Echovirus infection 

Legionnaires disease 

Hantavirus pulmonary syndrome 

HPIV (human parainfluenza viruses) 

Other parainfluenza viruses 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Approach considerations: 

The Advisory Committee on Immunization Practices advises that all persons aged 6 months and older should receive an annual seasonal inactivated influenza vaccine that should be administered before onset of influenza community activity. The ACIP Adult Immunization Schedule designates the recombinant and inactivated influenza vaccines. Public health strategies like enhanced surveillance, isolation, and segregation will helps to control the transmission of influenza in closed facilities.  Patients with influenza may be hospitalized if the severity of underlying chronic diseases is increased or if patients are too debilitated to care for themselves at home.

The influenza vaccine provides protection against the strains it targets and becomes effective within 0-4 days of administration. Specific recommendations are provided by CDC for different groups. Historically, it has shown 50-60% efficacy against influenza A viruses and 70% efficacy against influenza B viruses. Recommendations for influenza vaccine components are informed by global surveillance, genetic, antigenic characterization, antiviral susceptibility, and the availability of candidate vaccine viruses. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Pre-hospital care: 

Prehospital care focuses on supportive measures, including providing supplemental oxygenation, ventilation support, establishing intravenous access, and administering a crystalloid bolus for hemodynamic stability. Providers should utilize proper personal protective equipment (PPE) and inform hospitals about potential needs for respiratory isolation of patients. In low-risk areas, patients with fever and respiratory complaints should wear a standard mask to reduce airborne droplet transmission. Advance notification to the hospital regarding the requirement for patient respiratory isolation is recommended. 

Use of influenza antivirals

Oseltamivir:  

It inhibits neuraminidase responsible for breaking the bond between host cell membrane and newly formed virions. Neuraminidase is a glycoprotein present on the surface of influenza virus facilitates the release of virion into host cell by cleaving the attachment between sialic acid receptor on host cell membrane and hemagglutinin on viral surface. 

Zanamivir:  

It blocks the enzyme neuraminidase responsible for breaking the bond between host cell membrane and newly formed virions. 

Baloxavir marboxil:  

This is a prodrug which metabolizes to baloxavir. It suppresses the activity of cap-dependent endonuclease specific to influenza that results in blocking of replication of virus. 

Use of inactivated viral vaccines

Influenza virus vaccine quadrivalent:  

This vaccine consists of two strains of each of influenza A and influenza B. The vaccine produces antibodies that are specific to the specific virus strains contained within the vaccine. 

Influenza virus vaccine quadrivalent (recombinant):  

This is used as an active immunization against influenza due to influenza viruses A and B in adults > 69 years of age. 

Cell-cultured influenza virus vaccine quadrivalent:  

This vaccine is derived from cells i.e., egg-free and in adults and children of age six months and older. 

Use of live viral vaccines

Intranasal influenza virus vaccine quadrivalent: This is used as an active immunization for preventing influenza due to influenza viruses A and B in patients of age 2 to 49 years. 

Use of uricosuric agents

Probenecid:  

It suppresses tubular secretion of active metabolite oseltamivir by reducing its clearance 50%. 

Use of H1N1 vaccines

Adjuvanted influenza virus vaccine:  

This vaccine consists of AS03 adjuvant. Clinical studies suggest that this vaccine stimulates the immune response necessary. This is indicated for immunization against the disease due to influenza virus A H5N1 subtype. 

Influenza virus vaccine (H5N1): This is an inactivated virus vaccine that induces antibodies against viral hemagglutinin which causes the breakdown of attachment of virions to epithelial cells of human respiratory tract. 

use-of-phases-of-management-in-treating-influenza

There are millions of affected cases every year with various people and it ends up costing much in terms of healthcare. Patient education in reference to vaccination and how to perform handwashing is recommended. Vaccinations offered by schools and pharmacists as practiced will reduce healthcare cost.  

Surveillance programs pick up epidemics and flu vaccines put a lid on symptoms in people with lung disease, diabetes, chronic illnesses, the elderly, and children. The flu vaccine safeguards against hospital admissions and will avert some deaths. 

Medication

Future Trends

Media Gallary

References

Influenza – StatPearls – NCBI Bookshelf (nih.gov)