Influenza Abstracts 1

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Boneset in Dyspesia and Febrile Infections
            (Brinker, 2010)  Download
The bitters in boneset have tonic effects on the alimentary tract and digestion. Increases in both secretions and motility are common physiologic responses to bitter botanical compounds. The prevalent use of boneset by native Americans and pioneers for common febrile conditions such as malaria could be explained by its diaphoretic effect of controlling fever through sweating. This does not, however, explain its ability to dramatically relieve the associated body aches in these conditions. ts ability to protect against viral diseases such as influenza may be attributed at least partially to an enhancement of nonspecific immune resistance. The tea provides a proper extract for the polysaccharides that have been shown to actively improve phagocytosis. However, the tinctures that have been popularly used and tested are also known to be effective in these conditions, possibly due to the sesquiterpene lactone eufoliatin that contributes to an immune-enhancing ffect. It may be other sesquiterpene lactones or undiscovered phytochemical components that make this plant a special contributor to the management of common viral complaints. Inhibition of Gram-positive bacteria by water and ethanolic extracts is an additional feature that could contribute to treating or preventing secondary infections caused by these organisms.

Vitamins A and D in the treatment of colds
            (Crampton, 1944)  Download
112 patients with colds received a cod-liver oil concentrate. The dosage contained 150,000 units of vitamin A and 15,000 units of vitamin D on the first day and one-third of these amounts on the second day. If symptoms remained, two-thirds of the original dose was given on the third day. After the first 24 hours, 30.3% of the patients were symptom-free and an additional 51.8% were almost symptom-free, for a total of 82.1% cured or almost cured. Using this treatment, many patients have avoided colds by stopping them in their prodromal stage. No adverse effects of the treatment were seen.


 

Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment
            (De Flora et al., 1997) Download
N-acetylcysteine (NAC), an analogue and precursor of reduced glutathione, has been in clinical use for more than 30 yrs as a mucolytic drug. It has also been proposed for and/or used in the therapy and/or prevention of several respiratory diseases and of diseases involving an oxidative stress, in general. The objective of the present study was to evaluate the effect of long-term treatment with NAC on influenza and influenza-like episodes. A total of 262 subjects of both sexes (78% > or = 65 yrs, and 62% suffering from nonrespiratory chronic degenerative diseases) were enrolled in a randomized, double-blind trial involving 20 Italian Centres. They were randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 months. Patients suffering from chronic respiratory diseases were not eligible, to avoid possible confounding by an effect of NAC on respiratory symptoms. NAC treatment was well tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. Frequency of seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected subjects under NAC treatment developed a symptomatic form, versus 79% in the placebo group. Evaluation of cell-mediated immunity showed a progressive, significant shift from anergy to normoergy following NAC treatment. Administration of N-acetylcysteine during the winter, thus, appears to provide a significant attenuation of influenza and influenza-like episodes, especially in elderly high-risk individuals. N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clinically apparent disease.

The effect of DHEAS on influenza vaccination in aging adults
            (Degelau et al., 1997) Download
OBJECTIVE: To determine whether simultaneous administration of dehydroepiandrosterone sulfate (DHEAS) exhibits adjuvant activity in the immune response of aging humans by supplementing influenza vaccination with the maximum single dose of DHEAS that could be practically injected subcutaneously (approximately 7.5 mg). DESIGN: A randomized, double-blind, placebo-controlled trial of DHEAS injection with 1993-94 and 1994-95 influenza vaccine in older subjects. In addition, initial safety, tolerability, and control testing with 1993-94 influenza vaccine was conducted in young subjects. SETTING: An urban primary care geriatrics clinic. PARTICIPANTS: Seventy-eight older adult volunteers (mean age 78.61 +/- 3.43 years, range 73-90 years) and 20 younger controls (< 40 years, means age 32.76 +/- 5.39 years) were recruited from clinic and community advertising. Subjects were free of disease or medication known to affect immune function. MEASUREMENTS: Immune responses to vaccine at 0, 2, and 4 weeks were measured by vaccine antigen-induced lymphoproliferation in peripheral blood mononuclear cells (PBMC) and serum antibody response by hemagglutination inhibition (HI). RESULTS: The maximum DHEAS dose that could be practically administered subcutaneously was 7.5 mg. Baseline DHEAS levels were significantly lower in older adults (52.1 vs 236.4 micrograms/dL, P < .001). The 1993 old adult DHEAS group HI response tended to be higher for the H3N2 Beijing antigen but not for the H1N1 or B antigen. In subjects with HI titers less then 1:40 for the H3N2 Beijing antigen (n = 29), the post-vaccination titer response tended to be higher among the 16 subjects who received DHEAS (P = .06). The peak response for the H3N2 antigen was associated with the initial DHEAS serum concentration in the DHEAS and placebo groups (R2 = .22, P = .04 and R2 = .21, P = .06, respectively). No significant differences were found for antibody responses to the H1N1 and B antigens or vaccine-antigen induced lymphoproliferation. CONCLUSION: A one-time supplemental dose of DHEAS with influenza vaccination appeared to enhance the specific HI antibody response to the 1993-94 H3N2 antigen in a small group of older adults. These findings were limited to those with lower prevaccination titers and lower DHEAS concentrations. Although clinical implications of these findings for influenza vaccine are uncertain, these results suggest additional detailed immunologic investigations on the role of DHEAS in the aging human immune response are warranted.

Impact of Vitamin D Supplementation on Influenza Vaccine Response and Immune Functions in Deficient Elderly Persons: A Randomized Placebo-Controlled Trial.
            (Goncalves-Mendes et al., 2019) Download
Background: Immunosenescence contributes to reduced vaccine response in elderly persons, and is worsened by deficiencies in nutrients such as Vitamin (Vit-D). The immune system is a well-known target of Vit-D, which can both potentiate the innate immune response and inhibit the adaptive system, and so modulate vaccination response. Objective: This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in deficient elderly persons could improve influenza seroprotection and immune response. Design: Deficient volunteers (Vit-D serum <30 ng/mL) were assigned (V1) to receive either 100,000 IU/15 days of cholecalciferol (D, n = 19), or a placebo (P, n = 19), over a 3 month period. Influenza vaccination was performed at the end of this period (V2), and the vaccine response was evaluated 28 days later (V3). At each visit, serum cathelicidin, immune response to vaccination, plasma cytokines, lymphocyte phenotyping, and phagocyte ROS production were assessed. Results: Levels of serum 25-(OH)D increased after supplementation (D group, V1 vs. V2: 20.7 ± 5.7 vs. 44.3 ± 8.6 ng/mL, p < 0.001). No difference was observed for serum cathelicidin levels, antibody titers, and ROS production in D vs. P groups at V3. Lower plasma levels of TNFα (p = 0.040) and IL-6 (p = 0.046), and higher ones for TFGβ (p = 0.0028) were observed at V3. The Th1/Th2 ratio was lower in the D group at V2 (D: 0.12 ± 0.05 vs. P: 0.18 ± 0.05, p = 0.039). Conclusions: Vit-D supplementation promotes a higher TGFβ plasma level in response to influenza vaccination without improving antibody production. This supplementation seems to direct the lymphocyte polarization toward a tolerogenic immune response. A deeper characterization of metabolic and molecular pathways of these observations will aid in the understanding of Vit-D's effects on cell-mediated immunity in aging. This clinical trial was registered at clinicaltrials.gov as NCT01893385.

Influenza virus-induced glucocorticoids compromise innate host defense against a secondary bacterial infection.
            (Jamieson et al., 2010)  Download
Multicellular organisms are continuously exposed to many different pathogens. Because different classes of pathogens require different types of immune responses, understanding how an ongoing immune response to one type of infection affects the host's ability to respond to another pathogen is essential for a complete understanding of host-pathogen interactions. Here, we used a mouse model of coinfection to gain insight into the effect of respiratory influenza virus infection on a subsequent systemic bacterial infection. We found that influenza infection triggered a generalized stress response leading to a sustained increase in serum glucocorticoid levels, resulting in a systemic suppression of immune responses. However, virus-induced glucocorticoid production was necessary to control the inflammatory response and prevent lethal immunopathology during coinfection. This study demonstrates that activation of the hypothalamic-pituitary-adrenal axis controls the balance between immune defense and immunopathology and is an important component of the host response to coinfection.

Low plasma levels of adrenocorticotropic hormone in patients with acute influenza.
            (Jefferies et al., 1998)  Download
Plasma levels of adrenocorticotropic hormone (ACTH) and cortisol were measured in young adults with influenza virus type A (H3N2) infection for whom cultures were positive and in comparable controls without symptoms or other evidence of illness. The mean plasma ACTH level +/- SE in 19 patients with acute influenza was 13.5 +/- 2.1 pg/mL compared with 23 +/- 3.2 pg/mL in 11 controls (P = .02). Mean plasma ACTH levels +/- SE had risen to 21 +/- 4.1 pg/mL in specimens obtained from patients during convalescence. The mean plasma cortisol level +/- SE in patients with acute influenza was 13.7 +/- 1.4 micrograms/dL compared with 10.8 +/- 1.0 micrograms/dL in controls (P = not significant). ACTH levels in individual controls were relatively higher than their cortisol levels, but ACTH levels in patients tended to be lower than cortisol levels in paired specimens. These findings suggest that influenza virus type A infection may have an inhibitory effect on the production or release of ACTH.


 

Anti-influenza virus effects of cocoa.
            (Kamei et al., 2016)  Download
BACKGROUND:  Cocoa contains biologically active ingredients that have broad-spectrum antimicrobial activity, which includes an inhibitory effect on influenza virus infection. RESULTS:  A cocoa extract (CE) was prepared by treating defatted cocoa powder with boiling water. The extract demonstrated dose-dependent inhibition of infection in Madin-Darby canine kidney (MDCK) cells infected with human influenza virus A (H1N1, H3N2), human influenza virus B and avian influenza viruses (H5N1, H5N9). CE inhibited viral adsorption to MDCK cells. Animal experiments showed that CE significantly improved survival in mice after intra-nasal administration of a lethal dose of influenza virus. In human intervention trials, participants were allocated to two groups, one in which the participants ingested cocoa for 3 weeks before and after vaccination against A(H1N1)pdm2009 influenza virus and another in which the participants did not ingest cocoa. Neutralizing antibody titers against A(H1N1)pdm2009 influenza virus increased significantly in both groups; however, the extent of the increase was not significantly different between the two groups. Although natural killer cell activity was also elevated in both groups, the increase was more substantial in the cocoa intake group. CONCLUSION:  Drinking cocoa activates natural immunity and enhances vaccination-induced immune response, providing stronger protection against influenza virus infection and disease onset.

Pathologic anatomy and bacteriology of influenza: epidemic of autumn, 1918
            (Lucke et al., 1919) Download (54MB file)
In this paper the results of our studies on the pathologic anatomy and bacteriology of influenza during the epidemic of the fall of 1918 at Camp Zachary Taylor and Camp Knox, Kentucky, are prescnted. Necropsies, with routine bacteriologic cultures, were performed throughout the entire epidemic, so that a fairly definite picture of its various stages could be formed. The present investigation has been limited to 126 definitely proven fatal cases of influenza. These were selected from a considerably larger number by ruling out all patients who clinically gave evidence of preexisting disease, such as tuberculosis, measles, etc., or where such evidence was found at the ṇecropsies. Thus the morbid changes encountered may be looked on as primarily representing the end-results of the virus of influenza and its commensals.


 

Effects of green tea catechins and theanine on preventing influenza infection among healthcare workers: a randomized controlled trial
            (Matsumoto et al., 2011)  Download
BACKGROUND: Experimental studies have revealed that green tea catechins and theanine prevent influenza infection, while the clinical evidence has been inconclusive. This study was conducted to determine whether taking green tea catechins and theanine can clinically prevent influenza infection. METHODS: DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial of 200 healthcare workers conducted for 5 months from November 9, 2009 to April 8, 2010 in three healthcare facilities for the elderly in Higashimurayama, Japan. INTERVENTIONS: The catechin/theanine group received capsules including green tea catechins (378 mg/day) and theanine (210 mg/day). The control group received placebo. MAIN OUTCOME MEASURES: The primary outcome was the incidence of clinically defined influenza infection. Secondary outcomes were (1) laboratory-confirmed influenza with viral antigen measured by immunochromatographic assay and (2) the time for which the patient was free from clinically defined influenza infection, i.e., the period between the start of intervention and the first diagnosis of influenza infection, based on clinically defined influenza infection. RESULTS: Eligible healthcare workers (n = 197) were enrolled and randomly assigned to an intervention; 98 were allocated to receive catechin/theanine capsules and 99 to placebo. The incidence of clinically defined influenza infection was significantly lower in the catechin/theanine group (4 participants; 4.1%) compared with the placebo group (13 participants; 13.1%) (adjusted OR, 0.25; 95% CI, 0.07 to 0.76, P = 0.022). The incidence of laboratory-confirmed influenza infection was also lower in the catechin/theanine group (1 participant; 1.0%) than in the placebo group (5 participants; 5.1%), but this difference was not significant (adjusted OR, 0.17; 95% CI, 0.01 to 1.10; P = 0.112). The time for which the patient was free from clinically defined influenza infection was significantly different between the two groups (adjusted HR, 0.27; 95% CI, 0.09 to 0.84; P = 0.023). CONCLUSIONS: Among healthcare workers for the elderly, taking green tea catechins and theanine may be effective prophylaxis for influenza infection. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT01008020.


 

Role of Fat-Soluble Vitamins A and D in the Pathogenesis of Influenza: A New Perspective
            (Mawson, 2013)  Download
Reduced exposure to solar radiation, leading to a deficiency of vitamin D and hence impaired innate immunity, has been suggested as a trigger for influenza viral replication and as an explanation of seasonal influenza. Although this hypothesis accounts for many unexplained facts about the epidemiology of influenza, gaps remain in understanding the pathogenesis and manifestations of the disease. Several observations suggest a role for vitamin A compounds (retinoids) in the disease. This paper presents a new model of the …

A randomized, controlled trial comparing traditional herbal medicine and neuraminidase inhibitors in the treatment of seasonal influenza.
            (Nabeshima et al., 2012) Download
The herbal medicine, maoto, has been traditionally prescribed to patients with influenza in Japan. To better understand the efficacy of maoto for the treatment of influenza, a randomized trial was conducted for comparison with oseltamivir or zanamivir. Adult patients with influenza symptoms, including fever, positive for quick diagnostic kit for influenza within 48 h of fever onset were assessed for enrollment. The data of 28 patients randomly assigned to maoto (n = 10), oseltamivir (n = 8), or zanamivir (n = 10) were analyzed for the duration of fever (>37.5°C) and total symptom score from symptom cards recorded by the patient. Viral isolation and serum cytokine measurements were also done on days 1, 3, and 5. Maoto granules, a commercial medical dosage form, are made from four plants: Ephedra Herb, Apricot Kernel, Cinnamon Bark, and Glycyrrhiza Root. Median durations of fever of patients assigned maoto, oseltamivir, or zanamivir were 29, 46, or 27 h, respectively, significantly different for maoto and oseltamivir. No significant between-group differences were found in total symptom score among three groups. Viral persistent rates and serum cytokine levels (IFN-α, IL-6, IL-8, IL-10, and TNF-α) during the study period showed no differences among three groups. The administration of oral maoto granules to healthy adults with seasonal influenza was well tolerated and associated with equivalent clinical and virological efficacy to neuraminidase inhibitors.


 

Effect of an Echinacea-Based Hot Drink Versus Oseltamivir in Influenza Treatment: A Randomized, Double-Blind, Double-Dummy, Multicenter, Noninferiority Clinical Trial.
            (Rauš et al., 2015)  Download
BACKGROUND:  Echinacea has antiviral activity against influenza viruses in vitro and has traditionally been used for treatment of colds and flu. OBJECTIVES:  This randomized, double-blind, double-dummy, multicenter, controlled clinical trial compared a new echinacea formulation with the neuraminidase inhibitor oseltamivir, the gold standard treatment for influenza. METHODS:  Following informed consent, 473 patients with early influenza symptoms (≤48 hours) were recruited in primary care in the Czech Republic and randomized to either 5 days of oseltamivir followed by 5 days of placebo, or 10 days of an Echinacea purpurea-based formulation called Echinaforce Hotdrink (A. Vogel Bioforce AG, Roggwil, Switzerland). The proportion of recovered patients (influenza symptoms rated as absent or mild in the evening) was analyzed for noninferiority between treatment groups using a generalized Wilcoxon test with significance level α = 0.05 (2-sided) and using a CI approach in the per-protocol sample. RESULTS:  Recovery from illness was comparable in the 2 treatment groups at 1.5% versus 4.1% after 1 day, 50.2% versus 48.8% after 5 days, and 90.1% versus 84.8% after 10 days of treatment with Echinaforce Hotdrink and oseltamivir, respectively. Noninferiority was demonstrated for each day and overall (95% CI, 0.487-0.5265 by generalized Wilcoxon test). Very similar results were obtained in the group with virologically confirmed influenza virus infections and in a retrospective analysis during the peak influenza period. The incidence of complications was lower with Echinaforce Hotdrink than with oseltamivir (2.46% vs 6.45%; P = 0.076) and fewer adverse events (particularly nausea and vomiting) were observed with Echinaforce Hotdrink. CONCLUSIONS:  Echinaforce Hotdrink is as effective as oseltamivir in the early treatment of clinically diagnosed and virologically confirmed influenza virus infections with a reduced risk of complications and adverse events. It appears to be an attractive treatment option, particularly suitable for self-care. Clinical trial identifier: Eudra-CT: 2010-021571-88. (Curr Ther Res Clin Exp. 2015; 77:66-72).

Salicylates and pandemic influenza mortality, 1918-1919 pharmacology, pathology, and historic evidence.
            (Starko, 2009)  Download
The high case-fatality rate--especially among young adults--during the 1918-1919 influenza pandemic is incompletely understood. Although late deaths showed bacterial pneumonia, early deaths exhibited extremely "wet," sometimes hemorrhagic lungs. The hypothesis presented herein is that aspirin contributed to the incidence and severity of viral pathology, bacterial infection, and death, because physicians of the day were unaware that the regimens (8.0-31.2 g per day) produce levels associated with hyperventilation and pulmonary edema in 33% and 3% of recipients, respectively. Recently, pulmonary edema was found at autopsy in 46% of 26 salicylate-intoxicated adults. Experimentally, salicylates increase lung fluid and protein levels and impair mucociliary clearance. In 1918, the US Surgeon General, the US Navy, and the Journal of the American Medical Association recommended use of aspirin just before the October death spike. If these recommendations were followed, and if pulmonary edema occurred in 3% of persons, a significant proportion of the deaths may be attributable to aspirin.

Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren.
            (Urashima et al., 2010) Download
BACKGROUND:  To our knowledge, no rigorously designed clinical trials have evaluated the relation between vitamin D and physician-diagnosed seasonal influenza. OBJECTIVE:  We investigated the effect of vitamin D supplements on the incidence of seasonal influenza A in schoolchildren. DESIGN:  From December 2008 through March 2009, we conducted a randomized, double-blind, placebo-controlled trial comparing vitamin D(3) supplements (1200 IU/d) with placebo in schoolchildren. The primary outcome was the incidence of influenza A, diagnosed with influenza antigen testing with a nasopharyngeal swab specimen. RESULTS:  Influenza A occurred in 18 of 167 (10.8%) children in the vitamin D(3) group compared with 31 of 167 (18.6%) children in the placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; P = 0.04]. The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements (RR: 0.36; 95% CI: 0.17, 0.79; P = 0.006) and who started nursery school after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; P = 0.005). In children with a previous diagnosis of asthma, asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D(3) compared with 12 children receiving placebo (RR: 0.17; 95% CI: 0.04, 0.73; P = 0.006). CONCLUSION:  This study suggests that vitamin D(3) supplementation during the winter may reduce the incidence of influenza A, especially in specific subgroups of schoolchildren. This trial was registered at https://center.umin.ac.jp as UMIN000001373.

Effects of vitamin D supplements on influenza A illness during the 2009 H1N1 pandemic: a randomized controlled trial.
            (Urashima et al., 2014) Download
In a prior randomized trial, we found that the incidence of influenza A was less in the vitamin D3 group than among those on placebo, but the total incidence of either influenza A or B did not differ between groups. In this trial, the incidence of influenza A or B was less in the vitamin D3 group than in the placebo group only during the first half of the study. To elucidate whether vitamin D3 has preventive actions against influenza A, we conducted another trial during the 2009 pandemic of the H1N1 subtype of influenza A. Students (n = 247) of a Japanese high school were randomly assigned to receive vitamin D3 supplements (n = 148; 2000 IU per day) or a placebo (n = 99) in a double-blind study for 2 months. The primary outcome was incidence of influenza A diagnosed by a rapid influenza diagnostic test by medical doctors. Influenza A was equally likely in the vitamin D3 group (20/148: 13.5%) compared with the placebo group (12/99: 12.1%). By post hoc analysis, influenza A occurred significantly less in the vitamin D3 group (2/148: 1.4%) compared with the placebo group (8/99: 8.1%) (risk ratio, 0.17; 95% confidence interval, 0.04 to 0.77; P = 0.009) in the first month. However, during the second month, the vitamin D3 group experienced more events and effectively caught up with the placebo group. Vitamin D3 supplementation did not lower the overall incidence of influenza A during the 2009 H1N1 pandemic. A post hoc analysis suggests that the initial benefit during the first month of treatment was lost during the second month.

 


References

Brinker, F (2010), ‘Boneset in Dyspesia and Febrile Infections’, J Am Herbalists Guild, 9 (1), 13. PubMed:
Crampton, CW (1944), ‘Vitamins A and D in the treatment of colds’, NY State J Med, 44 162-66. PubMed:
De Flora, S., C. Grassi, and L. Carati (1997), ‘Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment’, Eur Respir J, 10 (7), 1535-41. PubMed: 9230243
Degelau, J., D. Guay, and H. Hallgren (1997), ‘The effect of DHEAS on influenza vaccination in aging adults’, J Am Geriatr Soc, 45 (6), 747-51. PubMed: 9180672
Goncalves-Mendes, N, et al. (2019), ‘Impact of Vitamin D Supplementation on Influenza Vaccine Response and Immune Functions in Deficient Elderly Persons: A Randomized Placebo-Controlled Trial.’, Front Immunol, 10 65. PubMed: 30800121
Jamieson, AM, et al. (2010), ‘Influenza virus-induced glucocorticoids compromise innate host defense against a secondary bacterial infection.’, Cell Host Microbe, 7 (2), 103-14. PubMed: 20159617
Jefferies, WM, et al. (1998), ‘Low plasma levels of adrenocorticotropic hormone in patients with acute influenza.’, Clin Infect Dis, 26 (3), 708-10. PubMed: 9524849
Kamei, M, et al. (2016), ‘Anti-influenza virus effects of cocoa.’, J Sci Food Agric, 96 (4), 1150-58. PubMed: 25847473
Lucke, B, T Wight, and E Kime (1919), ‘Pathologic anatomy and bacteriology of influenza: epidemic of autumn, 1918’, Archives of Internal Medicine, 24 (2), 154-237. PubMed:
Matsumoto, K., et al. (2011), ‘Effects of green tea catechins and theanine on preventing influenza infection among healthcare workers: a randomized controlled trial’, BMC Complement Altern Med, 11 15. PubMed: 21338496
Mawson, AR (2013), ‘Role of Fat-Soluble Vitamins A and D in the Pathogenesis of Influenza: A New Perspective’, ISRN Infectious Diseases, PubMed:
Nabeshima, S, et al. (2012), ‘A randomized, controlled trial comparing traditional herbal medicine and neuraminidase inhibitors in the treatment of seasonal influenza.’, J Infect Chemother, 18 (4), 534-43. PubMed: 22350323
Rauš, K, et al. (2015), ‘Effect of an Echinacea-Based Hot Drink Versus Oseltamivir in Influenza Treatment: A Randomized, Double-Blind, Double-Dummy, Multicenter, Noninferiority Clinical Trial.’, Curr Ther Res Clin Exp, 77 66-72. PubMed: 26265958
Starko, KM (2009), ‘Salicylates and pandemic influenza mortality, 1918-1919 pharmacology, pathology, and historic evidence.’, Clin Infect Dis, 49 (9), 1405-10. PubMed: 19788357
Urashima, M, et al. (2010), ‘Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren.’, Am J Clin Nutr, 91 (5), 1255-60. PubMed: 20219962
Urashima, M, et al. (2014), ‘Effects of vitamin D supplements on influenza A illness during the 2009 H1N1 pandemic: a randomized controlled trial.’, Food Funct, 5 (9), 2365-70. PubMed: 25088394