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influenza

Etiology: 1) influenza A a) epidemic during winter months b) influenza A pneumonia is associated with underlying heart disease 2) influenza B a) more endemic than influenza A b) 20-30% of influenza infections 3) parainfluenza viruses 15% 4) risk factors for severe disease & complications a) COPD b) heart disease c) diabetes mellitus d) kidney disease e) chronic anemia or other hematologic disease f) debilitated condition g) > 64 years of age [19] h) immunocompromised patients i) premature birth [45] j) pregnancy or delivery within 2 weeks [19] k) very young children [19] l) morbid obesity (BMI > 40) [93] m) long-term aspirin therapy in patients < 19 years [93] Epidemiology: 1) annual winter outbreaks (October-April) 2) influenza A is most common & generally produces the most serious disease 3) infection is highly contagious spread via exhaled breath [73], aerosolized droplets of nasal secretions or contaminated hands a) an individual may be contagious 1 day prior to onset of symptoms to 5 days after resolution [9] - persons with influenza are likely most contagious during the first 3-4 days of illness [96] b) air samples yield small-particle viral RNA as far as 6 feet from infected patients [29] c) aerosolized infectious RNA is contained in particles small enough to elude standard surgical masks [29] d) children are the main sources of influenza transmission [56] e) vaccinating children provides the most effective method achieving disease control [56] 4) major pandemics have occurred when there has been a change in both neuraminidase & hemagglutinin antigens 5) estimated 290,000-650,000 seasonal influenza-associated respiratory deaths annually in 33 countries [71] - Sub-Saharan Africa, western Pacific, & southeast Asia with highest rates of flu-related respiratory deaths [71] 6) 2012-2013 season - influenza A (H3N2) > influenza B > pandemic A/H1N1 - 6.1% of outpatient visits during peak activity - among people >= 65 years of age, hospitalization rate was 2 per 1000 - death related to pneumonia & influenza peaked at 9.9% - 149 deaths among children; more than 1/2 associated with influenza B 7) 2013-2014 season - 2009 H1N1 influenza A is dominant strain - nearly all hospitalizations due to H1N1 - 47% of hospitalized patients obese [34] - 2013-2014 vs 2012-2013 - lower rates of death & outpatient visits for influenza- like illness [41] - higher hospitalization rates among patients aged 50-64 - nearly all viruses analyzed were antigenically similar to the components of the 2013-2014 influenza virus vaccine [41] 8) 2014-2015 season - 90% of cases in 2014 due to H3N2 virus - circulating H3N2 strains not well matched to the H3N2 strain included in 2014-2015 flu vaccine - all strains susceptible to neuraminidase inhibitors [CDC FluView] [68] 9) 2015-2016 season [61] - 60% of cases due to influenza A(H1N1)pdm09 - influenza A(H3N2), influenza B/Yamagata lineage, & influenza B/Victoria lineage in lesser frequencies - most circulating viruses matched the components of the seasonal influenza virus vaccine - 1% of influenza A(H1N1)pdm09 virus were resistant to oseltamivir & peramivir; all were susceptible to zanamivir - cumulative hospitalization rate for confirmed flu was 31.3 per 100,000 population [61] 10) 2016-2017 season - predominant circulating strain is influenza A H3 which is covered by the vaccine [CDC FluView] [68] 11) 2017-2018 season - predominant circulating strain is influenza A H3N2 [70] - all viruses tested sensitive to oseltamivir, zanamivir, & peramivir - Jan 12, 2018 widespread & intense but may be peaking [72] - 2017-2018 season as intense as 2009 pandemic [76] - influenza activity increasing again, all states but Hawaii reporting high flu activity (Jan 26, 2018) [75] - 63 deaths in children reported as of Feb 9, 2018 [76] - 3 of 4 children had not been vaccinated [77] - 43% of patients presenting with laboratory-confirmed influenza had been vaccinated [77] 12) 2018-2019 season [83] - influenza A(H1N1)pdm09 viruses predominant in most regions - influenza A(H3N2) viruses most common in the Southeast. - most circulating viruses are genetically similar to the reference viruses used for this year's flu vaccines. - all tested viruses susceptible to neuraminidase inhibitors (oseltamivir, zanamivir, peramivir & baloxavir) - all tested isolates have been susceptible to zanamivir - < 1% have shown reduced susceptibility to oseltamivir - late surge in H3N2 influenza March 2019 [85] - 28 influenza-related pediatrics deaths. 1/2 with underlying condition [84] 13) 2019-2020 season - earliest start in the U.S. in 15 years, South hit hardest - influenza B/Victoria more common early than influenza A - Influenza B/Victoria & A(H1N1)pdm09 most common [89] 14) 2022-2023 season - H3N3 is the predominant early circuating strain [95] 15) outbreaks may still occur despite vaccination [44] Pathology: 1) replication in ciliated columnar epithelial cells a) pharynx b) tracheobronchial tree 2) acute mucosal necrosis 3) major immunological antigens are neuraminidase & hemagglutinin 4) spontaneous resolution in 4-5 days is most common 5) protection after natural infection is primarily mediated by hemagluttin & neuraminidase-specific antibodies in serum (IgG) & mucosa (IgA), & possibly other conserved influenza proteins [33] 6) T-cell responses also play a role in immunity [33] Genetics: - point mutation in NS1 gene (glutamic acid at position 52) in fatal H5N1 flu virus in Hong Kong 1997 [5] Clinical manifestations: 1) incubation period 1-4 days [19] 2) fever*, generally abrupt onset 3) cough*, non-productive 4) nasal congestion without sneezing [13] 5) sore throat 7) parotitis 8) headache, frontal or retro-orbital [93]] 9) myalgias 10) weakness, fatigue, malaise, lethargy 11) increased risk of hallucinations, delirium, abnormal behavior early in the illness [47] 12) common symptoms may be absent in severely immunocompromised patients [35] 13) asymptomatic in most people (seasonal or pandemic) [37] 14) clinical diagnosis: sensitivity 36%, specificity 78% [53] * combination with 99% negative predictive value [24] * decision guide for laboratory testing based on - new or increased cough (2 points) - headache, subjective fever, & triage temperature >100.4 F (each 1 point) [85] - score >= 3 92% sensitive, 35% specific Laboratory: 1) during a confirmed local outbreak, diagnosis is clinical with laboratory testing reserved for patients at high risk for complication [19] 2) influenza virus antigen in tissue [66] a) antigens 1] hemagglutinin 2] neuraminidase b) assays 1] direct fluorescent antibody (DFA) 2] enzyme immunoassays (EIA) for influenza A antigen detection c) specificity = 98% but sensitivity = 54% in adults & 67% in children [26,66] 3) RT-PCR* for influenza A virus RNA [4,53, 27] - sensitivity 92% (best among tests), specificity 98% [66] 4) RT-PCR* for influenza B virus RNA - sensitivity 95% (best among tests), specificity 98% [66] 5) RT-PCR* able to identify influenza A virus RNA, influenza B virus RNA & SARS-CoV2 RNA [96] - this is a point-of-care test [97] 6) Influenza A & B Point of Care Test (Alere) [48] 7) influenza virus serology 8) influenza virus identified by culture a) 1st 2-3 days of illness when viral shedding is maximal b) 2-7 days for results of culture c) centrifugation-enhanced shell vial cultures with 1-2 day incubation times 9) specimens a) nasopharyngeal secretions b) throat swabs less sensitive c) if patient is hospitalized, tracheal aspirate or bronchoalveolar lavage specimen should also be obtained * RT-PCR recommended vs antigen testing by Infectious Disease Society of America for diagnosis if testing is likely to change management [19] Radiology: - chest X-ray - bronchiolitis & bronchopneumonia - interstitial infiltrate - presence of lobar consolidation suggests bacterial coinfection [98] Complications: 1) extension of viral-mediated necrosis to involve alveoli a) severe viral pneumonia (ARDS) b) potentially fatal 2) secondary bacterial pneumonia a) cause of most influenza-related deaths [12] b) oropharyngeal bacteria 1] Streptococcus pneumoniae* 2] Staphylococcus aureus* 3] Haemophilus influenzae c) vulnerable at greatest risk 3) severe influenza with admission to the ICU predicts risk for invasive pulmonary aspergillosis [79] 3) increased virulence of the flu & higher incidence of pneumonia in severely immunocompromised patients [35] 5) increased risk of bipolar disorder in offspring of pregnant women with influenza (RR=5) [36]: 6) children's medical visits for respiratory tract infection (within 3 days) confer 12-fold increase in risk for ischemic stroke [42] - editorialist not impressed - absolute risk is very low - no evidence that attempt to treat would mitigate risk [42] 7) cardiovascular events in adults with influenza - acute myocardial infarction can be triggered by influenza [74] - cardiovascular events are common among adults hospitalized with influenza [91] - antiviral treatment & vaccination lower risk [91] 8) risk factor: long-term aspirin therapy in patients < 19 years [93] * most common causes of secondary bacterial pneumonia [52,53] Differential diagnosis: - respiratory syncytial virus (RSV) [4] - over 200 viruses cause influenza-like illness [43] - influenza A & unfluenza B represent ~ 10% of all circulating viruses [43] - common cold vs influenza vs Covid-19 Management: 1) uncomplicated influenza a) bedrest b) cough suppressants c) antipyretic agents - acetaminophen may be of no benefit [57] d) antiviral agents - indications: - hospitalized patients - severe, complicated or progressive infection - high risk of influenza complications [19] - start within 2 days of symptom onset [19] - regardless of immunization status [82] - regardless of symptom duration in hospitalized patients [19] - neuraminidase inhibitors - of marginal benefit [38] - for 2014-2015 season high-risk patients should be given a neuraminidase inhibitor before confirmatory test results are in [49] - post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir probably decreases risk of symptomatic seasonal influenza in patients at high risk for severe disease & may reduce risk of symptomatic zoonotic influenza after exposure to novel influenza A viruses associated with severe disease [102] - zanamivir (Relenza) [30] - associated with bronchospasm [19] - contraindicated with pulmonary disease or cardiovascular disease - emergence of resistance [19] - early treatment for high-risk patients [23] - may provide a net benefit over no treatment [27] - oseltamivir (Tamiflu) [30] - early treatment for high-risk patients [23,27]; patients with underlying respiratory disease - may prevent hospitalization in elderly patients, both vaccinated & unvaccinated [7] - may improve survival in hospitalized elderly [16] - not associated with reduced risk of hospitalization [100] - may provide a net benefit over no treatment [27]; shortens duration of influenza symptoms (4 vs 5 days) [50]; lowers risk of hospitalization (0.6 vs 1.7%) [50] - older, sicker patients with flu-like syndrome may benefit from oseltamivir with or without confirmed influenza infection [90] - antiviral of choice for influenza outbreaks in long-term care facilities [6] - resistance of influenza A to oseltamivir is emerging [10] - may be used in children & infants < 1 year of age [23] - does not reduce viral shedding or transmission among household contacts [54] - zanamivir or oseltamivir may be continued for the entire influenza season for high-risk patients [82] - baloxavir marboxil is about as effective as oseltamivir [80] - consider if high-risk of complications [92] - CDC does not recommend use of baloxavir for treatment of influenza in pregnant women, breastfeeding mothers, or immunosuppressed persons [93] - combination therapy may be of benefit - oseltamivir, amantadine, & ribavirin [18] - associated with reduced viral load but no clinical improvement over oseltamivir monotherapy [67] - clarithromycin-naproxen-oseltamivir combination reduced mortality of patients hospitalized for Influenza A(H3N2) [65] - favipiravir + oseltamivir better than oseltamivir alone for treatment of severe influenza [86] - avoid combination antiviral therapy [82] - may reduce duration of symptoms & decrease risk of complications [19] - adamantanes - amantadine (Symmetrel) 100 mg PO BID for 5 days - not recommended due to high rate of resistance [19] - rimantadine (Flumadine) 100 mg PO BID for 5 days - not recommended due to high rate of resistance [19] - resistance to adamantanes in 2005-2006 season [14] - adamantanes active against influenza A only - not recommended by CDC due to resistance of circulating strains [23] - no longer considered useful [82] e) herbal/homeopathic remedies [8] - elderberry syrup (Sambucol) may be of benefit [21] - echinacea may modestly help some symptoms - NO evidence in support of oscillococcinum, vit C or zinc 2) complicated influenza a) primary viral pneumonia - hospitalization - oxygenation (see ARDS) - peramivir 300-600 mg IV (once) [82] b) secondary bacterial pneumonia - empiric antibiotic treatment directed at most common organisms (see above) - ceftriaxone + azithromycin - vancomycin for MRSA not recommended unless admitted to ICU or identified MRSA risk factors other than prior influenza infection [99] c) Reye's syndrome - intensive care support to manage hypoglycemia, increased blood ammonia & cerebral edema d) glucocorticoids not considered useful [82] e) coinfection with SARS-Cov2 - remdesivir may be safely coadministered with oseltamivir [96] 3) prophylaxis a) influenza vaccination - annual influenza vaccination recommended for all persons > 6 months of age - vaccination mid-October to mid-November [6] - for patients & health care workers [6] - consistently poor response in the elderly [28] - serious influenza can develop despite vaccination & can cause considerable mortality in the elderly [16] b) live attenuated influenza virus vaccine (FluMist) - not recommended for 2016-17 flu season [62] c) surgical mask as effective as N95 respirator in protecting healthcare workers from influenza [20] d) hand hygiene & surgical masks can reduce transmission of influenza in households & in healthcare systems [22,63] e) baloxavir marboxil (Xofluza) FDA-approved for post-exposure prophylaxis for adults & chilren >= 12 years within 48 hours of exposure Comparative biology: - genes for broadly neutralizing antibodies inserted into an adenoviral gene-therapy vector in mice & ferrets infected many respiratory tract cells & resulted in secretion of Ab that protected the animals from lethal inocula of several strains of influenza virus [19]

Interactions

disease interactions

Related

influenza A virus influenza antigen test influenza B virus influenza C virus influenza D virus influenza virus vaccine, inactivated (Fluogen, Fluzone, Fluvirin, Flushield, Fluarix, Flulaval, Agriflu, Afluria, Flublok Quadrivalent, FluCelVax, Fluad, RIV4)

Specific

avian influenza A; H5N1 influenza; H5 influenza swine flu

General

viral infection respiratory tract infection Orthomyxoviridae (influenza virus)

References

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