Influenza treatment

Influenza treatment
Mechanisms of inhibition of virus entry by peptides (viral entry can be blocked via interaction of peptide with hemagglutinin, commonly interacting with residue of sialic acid)[1]
SpecialtyInfectious disease

Treatments for influenza include a range of medications and therapies that are used in response to disease influenza. Treatments may either directly target the influenza virus itself; or instead they may just offer relief to symptoms of the disease, while the body's own immune system works to recover from infection.[2]

The main classes of antiviral drugs used against influenza are neuraminidase inhibitors, such as zanamivir and oseltamivir, polymerase acidic endonuclease inhibitors such as baloxavir marboxil, or inhibitors of the viral M2 protein, such as amantadine and rimantadine. These drugs can reduce the severity of symptoms if taken soon after infection and can also be taken to decrease the risk of infection. However, virus strains have emerged that show drug resistance to some classes of drug.[3][4][5]

Symptomatic

Influenza (Flu)
H1N1 virus
Types
Vaccines
Treatment
Pandemics
Outbreaks
See also

The US Centers for Disease Control and Prevention (CDC), recommends that people with influenza:[6][7]

  • Stay at home
  • Get plenty of rest
  • Drink a lot of liquids
  • Do not smoke or drink alcohol
  • Consider over-the-counter medications for symptoms
  • Consult a physician early on
  • Watch for emergency warning signs

Warning signs indicate that the disease is becoming serious and needs immediate medical attention. These include:[8][9]

In children other warning signs include irritability, failing to wake up and interact, rapid breathing, and a blueish skin color. Another warning sign in children is if the flu symptoms appear to resolve, but then reappear with fever and a bad cough.[6]

Over-the-counter medication

Antiviral drugs are prescription-only medication in the United States. Readily available over-the-counter medications do not directly affect the disease, but they do provide relief from influenza symptoms, as illustrated in the table below:

OTC medicines provide relief for flu symptoms[10]
Symptom(s) OTC Medicine
fever, aches, pains, sinus pressure, sore throat analgesics
nasal congestion, sinus pressure decongestants
sinus pressure, runny nose, watery eyes, cough antihistamines
cough cough suppressant
sore throat local anesthetics

Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin as taking aspirin in the presence of influenza infection (especially Influenzavirus B) can lead to Reye syndrome, a rare but potentially fatal disease of the brain.[11]

Antivirals

Antiviral drugs directly target the viruses responsible for influenza infections. Generally, anti-viral drugs work optimally when taken within a few days of the onset of symptoms.[12] Certain drugs are used prophylactically, that is they are used in uninfected individuals to guard against infection.[13]

Four licensed influenza antiviral agents are available in the United States: zanamivir, oseltamivir phosphate, peramivir, and baloxavir marboxil.[14] They are available through prescription only.[14]

Antivirals to treat influenza[14]
ClassEffective againstDrug name (INN)Brand nameYear approvedManufacturer
Neuraminidase inhibitors Influenza A & B zanamivir Relenza 1999 GlaxoSmithKline
oseltamivir Tamiflu 1999 Hoffmann-La Roche
peramivir Rapivab 2014 BioCryst Pharmaceuticals
Cap-dependent endonuclease inhibitor Influenza A & B baloxavir marboxil Xofluza 2018 Shionogi Pharma Co., Ltd.

In Russia and China a drug called arbidol is also used as a treatment. Testing of the drug has predominantly occurred in these countries and, although no clinical trials have been published demonstrating this is an effective drug, some data suggest that this could be a useful treatment for influenza.[15][16]

Interferons

The molecular structure of human interferon-alpha

Interferons are cellular signalling factors produced in response to viral infection. Research into the use of interferons to combat influenza began in the 1960s in the Soviet Union, culminating in a trial of 14,000 subjects at the height of the Hong Kong Flu of 1969, in which those treated prophylactically with interferon were more than 50% less likely to suffer symptoms, though evidence of latent infection was present.[17] In these early studies leukocytes were collected from donated blood and exposed to a high dose of Newcastle disease, causing them to release interferons. Although interferon therapies became widespread in the Soviet Union, the method was doubted in the United States after high doses of interferon proved ineffective in trials. Though the 1969 study used 256 units of interferon, subsequent studies used up to 8.4 million units. It has since been proposed that activity of interferon is highest at low concentrations.[18] Phase III trials in Australia are planned for 2010, and initial trials are planned in the U.S. for late 2009.[19]

Interferons have also been investigated as adjuvants to enhance to effectiveness of influenza vaccines. This work was based on experiments in mice that suggested that type I interferons could enhance the effectiveness of influenza vaccines in mice.[20] However, a clinical trial in 2008 found that oral dosing of elderly patients with interferon-alpha actually reduced their immune response to an influenza vaccine.[21]

Viferon is a suppository of (non-pegylated[22]) interferon alpha-2b, ascorbic acid (vitamin C), and tocopherol (vitamin E) which was reported in two small studies to be as effective as arbidol.[23][24] Another interferon alfa-2b medicine, "Grippferon", nasal drops, is used for treatment and emergency prevention of Influenza and cold.[25] Its manufacturers have appealed to the WHO to consider its use against avian influenza and H1N1 Influenza 09 (Human Swine Flu), stating that it was used successfully in Russia for eight years, but that "the medical profession in Europe and the USA is not informed about this medicine".[26]

Resistance

Influenza viruses can show resistance to anti-viral drugs. Like the development of bacterial antibiotic resistance, this can result from over-use of these drugs. For example, a study published in the June 2009 Issue of Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir (Tamiflu) stockpiles with additional antiviral drugs including zanamivir (Relenza) based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the tamiflu-resistance (His274Tyr) mutation which is currently widespread in seasonal H1N1 strains.[27] Yet another example is in the case of the amantadines treatment may lead to the rapid production of resistant viruses, and over-use of these drugs has probably contributed to the spread of resistance.[28] In particular, this high-level of resistance may be due to the easy availability of amantadines as part of over-the-counter cold remedies in countries such as China and Russia,[29] and their use to prevent outbreaks of influenza in farmed poultry.[30][31]

On the other hand, a few strains resistant to neuraminidase inhibitors have emerged and circulated in the absence of much use of the drugs involved, and the frequency with which drug resistant strains appears shows little correlation with the level of use of these drugs.[32] However, laboratory studies have shown that it is possible for the use of sub-optimal doses of these drugs as a prophylactic measure might contribute to the development of drug resistance.[32]

During the United States 2005–2006 influenza season, increasing incidence of drug resistance by strain H3N2 to amantadine and rimantadine led the CDC to recommend oseltamivir as a prophylactic drug, and the use of either oseltamivir or zanamivir as treatment.[33][34]

Research

Several generic prescription medications might prove useful to treat a potential H5N1 avian flu outbreak, including statins, fibrates, and chloroquine.[35][36][37]

Peptides

a)Most common interactions between antiviral peptides with an influenza virus lipid bilayer b)image shows polymerase assembly in virus replication cycle; antiviral peptides may bind to PB2 subunit and prevent the assembly of influenza polymerase complex[1]

Peptides are composed of an amino acid chain, with a M.W. between 400 and 5000 Da . More than a century ago, insulin was created as the first peptide drug to manage diabetes. With newly available synthetic technologies an increase in the development of peptides has occurred[38][39]

Viral RNA-dependent RNA polymerase is made-up of 3 polymerase subunits which are PB1, PB2 and PA, each in turn has its own function or respondsibility. In the end, Viral RNA-dependent RNA polymerase is bond together via noncovalent interactions, a disruption of RdRp in the interaction between PB1 and PA/PB2 is a logical target for a anti-influenza drug, because such a disruption would stop the enzyme task and hence viral replication[1]

Transfused antibodies

An alternative to vaccination used in the 1918 flu pandemic was the direct transfusion of blood, plasma, or serum from recovered patients. Though medical experiments of the era lacked some procedural refinements, eight publications from 1918 to 1925 reported that the treatment could approximately halve the mortality in hospitalized severe cases with an average case-fatality rate of 37% when untreated.[40][41]

Bovine colostrum might also serve as a source of antibodies for some applications.[42]

Ex vivo culture of T lymphocytes

Human T lymphocytes can be expanded in vitro using beads holding specific antigens to activate the cells and stimulate growth. Clonal populations of CD8+ cytotoxic T cells have been grown which carry T cell receptors specific to influenza. These work much like antibodies but are permanently bound to these cells. (See cellular immunity). High concentrations of N-acetylcysteine have been used to enhance growth of these cells. This method is still in early research.[43][44]

Supplements

Malnutrition can reduce the ability of the body to resist infections and is a common cause of immunodeficiency in the developing world.[45] Seasonal variation in sunlight exposure, which is required for vitamin D synthesis within the body, has been proposed as one of the factors accounting for the seasonality of influenza.[46] A meta-analysis indicated some support for adjunctive vitamin D therapy for influenza, but called for more rigorous clinical trials to settle the issue conclusively.[47]

A review of alternative medicines in influenza treatment details evidence suggesting that N-acetylcysteine, elderberry, or a combination of Eleutherococcus senticosus and Andrographis paniculata may help to shorten the course of influenza infection.[48] Another review concluded that there was "no compelling evidence" that any of these treatments were effective and that the available data on these products is particularly weak, with trials in this area suffering from many shortcomings, such as being small and poorly-designed and not testing for adverse effects.[49] One trial found that long term N-acetylcysteine (NAC) may decrease the severity of influenza symptoms.[50]

Elderberry

Elderberry(Sambucus nigra)

Elderberry (Sambucus nigra) extract has been used by some in influenza.[51] The preparation has been reported to reduce the duration of influenza symptoms by raising levels of cytokines.[52]

However, use has been described as "imprudent" when an influenza strain causes death in healthy adults by cytokine storm leading to primary viral pneumonia.[53] The manufacturer cites a lack of evidence for cytokine-related risks, but labels the product only as an antioxidant and food supplement.[54]

Green tea

High dietary intake of green tea (specifically, catechins and theanine that is found in tea products) has been correlated with reduced risk of influenza, as well as having an antiviral effect upon types A and B.[55][56][57]

References

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  5. ↑ Li, Guangdi; Jing, Xixi; Zhang, Pan; De Clercq, Erik (2021). "Antiviral Classification". Encyclopedia of Virology: 121–130. doi:10.1016/B978-0-12-814515-9.00126-0. Archived from the original on 20 October 2023. Retrieved 12 October 2023.
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  40. ↑ Thomas C. Luke, MD, MTMH; Edward M. Kilbane, MD, MPH; Jeffrey L. Jackson, MD, MPH; and Stephen L. Hoffman, MD, DTMH (2006-10-17). "Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment?". Annals of Internal Medicine. 145 (8): 599–609. doi:10.7326/0003-4819-145-8-200610170-00139. PMID 16940336. S2CID 2929898.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  55. ↑ Matsumoto, K; Yamada, H; Takuma, N; Niino, H; Sagesaka, YM (2005). "Effects of green tea catechins and theanine on preventing influenza infection among healthcare workers: a randomized controlled trial". BMC Complement Altern Med. 11: 15. doi:10.1186/1472-6882-11-15. PMC 3049752. PMID 21338496.
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  57. ↑ Imanishi, N; Tuji, Y; Katada, Y; Maruhashi, M; Konosu, S; Mantani, N; Terasawa, K; Ochiai, H (2002). "Additional inhibitory effect of tea extract on the growth of influenza A and B viruses in MDCK cells". Microbiol. Immunol. 46 (7): 491–4. doi:10.1111/j.1348-0421.2002.tb02724.x. PMID 12222936. S2CID 24102910.

Further reading

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