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Systematic Review

The efficacy of azithromycin in the treatment of influenza A infection: A systematic review

[version 1; peer review: awaiting peer review]
PUBLISHED 01 Oct 2024
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS AWAITING PEER REVIEW

Abstract

Background

The WHO recommendation against the use of macrolides reflects the little low-quality evidence about the effect of azithromycin (AZ) on influenza A infection. Considering recent reports about AZ use despite the WHO’s unfavorable recommendations, we aimed to test the evidence for the usage of AZ in the treatment of influenza A infection.

Methods

Various online databases were searched till August 2023 and thorough text and evidence evaluation resulted in selecting 7 studies.

Results

The selected reports included randomized control trials (two), cohort (three), case/control (one) studies, and one case report. Pooling of the results was unattainable due to the variability among studies in patient criteria, study outcomes, and study designs. Based on the limited reports with insufficient evidence, a recommendation for the use of AZ in the treatment regimen was not possible despite the associated reduction in inflammatory cytokines by AZ administration and the absence of significant adverse effects or mortality in hospital-admitted or ICU patients. While these findings support the current guidelines for the treatment of influenza A infection, the evidence behind these guidelines and treatment characteristics were illustrated.

Conclusion

AZ shows a potential symptom improvement and pro-inflammatory laboratory indices in influenza A patients. Another positive aspect is the absence of complications associated with AZ administration to critically ill patients and acceptable prognosis. However, it is crucial to have more quality research on this matter that focuses on the indication of the use of AZ, and the timing of initiation, dosage, and duration of treatment while monitoring adverse events.

Keywords

Azithromycin, influenza A, guidelines, influenza pandemic, macrolides

1. Introduction

Influenza is a communicable respiratory viral infection affecting the upper respiratory tract and occasionally the lower tract, causing pneumonia (Boktor, Hafner et al. 2023, Moghadami 2017). In addition, Influenza is highly infectious with an incubation period of 1 – 3 days and, in healthy individuals, is usually a self-limiting disease with recovery usually within 2 to 7 days (Bhatt, Singh et al. 2021). The enveloped Influenza viruses are four distinct strains that are composed of single-stranded RNA chains and have high mutation rates and antigenic variances. Annually, Influenza types A and B infect individuals throughout the winter season, also known as the epidemic season (Boktor, Hafner et al. 2023). Four influenza pandemics have arisen since the early 1900s, namely in 1918 (Spanish Influenza H1N1), 1957 (Asian Influenza H2N2), 1968 (Hong Kong Influenza H3N2), and 2009 (H1N1) (Harrington, Kackos et al. 2021).

Influenza virus infections persistently lead to high levels of morbidity and mortality and impose a financial strain on healthcare systems and societies. The World Health Organization (WHO) estimated the annual occurrence of Influenza A infections to be about 3-5 million cases, with a death toll of 290,000-650,000 individuals globally (Mostafa 2023). While the influenza virus can potentially infect all age groups, a higher risk of contracting the infection is reported in adults aged 18-64 years. Moreover, life-threatening cases of illness are more evident among pregnant women associated with perinatal mortality, prematurity, smaller neonatal size and lower birth weight (Pierce, Kurinczuk et al. 2011), young children under 5 years of age, elderly patients aged 65 years and above (de Courville, Cadarette et al. 2022), and those with underlying health conditions such as respiratory or cardiac disease, chronic neurological conditions, and immunosuppression (Pebody, Andrews et al. 2013). According to the Centers for Disease Control and Prevention (CDC), fatalities within the elderly population accounted for 70% - 85% of the total Influenza-related mortality (Centers for Disease Control and Prevention 2024). Additionally, a study published in 2017 stated that influenza-related lower respiratory tract infection (LRTI) accounted for an estimated 145,000 deaths, 9,459,000 hospitalizations, and 81,536,000 days of hospitalization (Troeger, Blacker et al. 2019). Also, an earlier study reported that 65% of the economic impact attributed to vaccine-preventable illnesses is caused by Influenza infection (Ozawa, Portnoy et al. 2016).

The manifestations of seasonal Influenza can be noticed across a spectrum, ranging from asymptomatic infection or moderate upper respiratory symptoms (dry cough and nasal congestion for 3-7 days), with or without fever, to more significant complications, including but not limited to secondary bacterial infections, pneumonia, bronchiolitis, croup, myocarditis, myositis, rhabdomyolysis, encephalopathy, encephalitis, renal failure, respiratory failure, acute respiratory distress syndrome, and septic shock (Tyrrell, Allen et al. 2021). Intensive care unit (ICU) admission among influenza patients is correlated with pre-existing illnesses such as obstructive/central sleep apnoea syndrome, myocardial infarction, and body mass index (BMI) > 30, where a higher incidence of pulmonary co-infection is described (Beumer, Koch et al. 2019).

The development of influenza complications and the mortality rates are contributed by the infection-associated immune reactions. According to Jiang and Zhang (2023), overactivation of the innate immune system due to the influenza virus could yield a state of excessive cytokines release and aggressive proinflammatory effects that are responsible for mortality and morbidity (Jiang, Zhang 2023). Additionally, it was found that increased systemic levels of pro-inflammatory cytokines constituted a hallmark in severe cases of pandemic (H1N1) 2009” (Bermejo-Martin, Ortiz de Lejarazu et al. 2009, To, Hung et al. 2010). This serves as a potential target in the management of Influenza by medications that show immunomodulatory effects such as Macrolides (Viasus, Paño-Pardo et al. 2011).

As stated in the latest World Health Organization (WHO) recommendations, the current guidelines for the treatment of influenza A include antivirals and vaccination (World Health Organization 2021). Antiviral medications, specifically neuraminidase inhibitors such as oseltamivir, zanamivir, and peramivir, reduce the symptoms’ duration and severity, decrease the risk of complications, and enhance the treatment outcomes. Given that influenza is a vaccine-preventable disease, influenza vaccines stand as the most efficient approach to managing the symptoms of seasonal influenza, particularly among vulnerable groups and healthcare workers. It is mandatory to regularly update the vaccines to align with the repetitive evolution of circulating viruses (de Courville, Cadarette et al. 2022). Additionally, other alternatives for influenza treatment, such as corticosteroids, macrolides, and passive immunotherapy, are not favoured according to WHO due to lack of evidence (World Health Organization 2021).

The recent viral pandemics repositioned macrolides for their potential use as anti-influenza agents. Macrolides is a group of naturally derived compounds consisting of a lactone ring with attached deoxy sugars. Some of the macrolides, such as azithromycin (AZ), possess antibiotic activity through binding to the bacterial 50S ribosomal subunit, which results in the interruption of bacterial protein synthesis (Arsic, Barber et al. 2018). This action is mainly bacteriostatic, and it can also become bactericidal at high concentrations (Zarogoulidis, Papanas et al. 2012). Various animal studies proposed a potential positive effect of AZ against viral infections. Dat Huu Tran et al. (2019) showed that a single administration of AZ intranasally to mice infected with A(H1N1)pdm09 virus had effectively minimized viral load in the lungs and alleviated the infection-induced hypothermia (Tran, Sugamata et al. 2019). Other macrolides showed a favourable impact on preventing lung disease and viral proliferation in mice by their ability to control the release of neutrophil myeloperoxidase (which has been implicated in the pathogenesis of severe influenza-induced pneumonia), pro-inflammatory cytokines, and interferon-α production in the lung (Sugamata, Sugawara et al. 2014).

The WHO-based recommendation against the use of macrolides reflects the scattered few studies on human subjects or clinical trials about the effect of macrolides on viral infections, especially influenza. Furthermore, the WHO guidelines were generally based on a study with very low-quality evidence randomized control trial (World Health Organization 2021). Here, we aim to test the evidence for the recommendation of the usage of AZ in the treatment of influenza, particularly in light of recent observations that the use of AZ was reported despite the WHO’s unfavourable recommendations.

2. Methods

This systematic review is reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to test the evidence of AZ use in the treatment regimen of Influenza A infections (Figure 1). The PRISMA checklist is also included in the extended data depository. The systematic review was not registered. To compile a comprehensive dataset, a thorough search strategy was implemented across multiple electronic databases, including PubMed, ProQuest, Scopus, and Embase (August 2023). The chosen databases provided a broad scope, allowing us to capture a diverse range of studies relevant to our review topic.

4233a20a-5ff9-49cf-a0f4-0abee17e68bc_figure1.gif

Figure 1. PRISMA chart outlining the review process.

The search strategy employed a combination of keywords, including “azithromycin”, and “influenza A”. Only studies about the Influenza “A” strain were included, and all studies focused on other strains were excluded. We deliberately imposed no limitations on participant age or recruitment location, encompassing community, outpatient, and hospital settings. To enhance precision, additional filters such as “full-text”, “research article”, “scholarly journals”, and “peer-reviewed” were applied. We restricted results to publications between 2007 and 2023 and set the language criterion to English publications specifically. The deliberate choice aimed to eliminate potential language barriers and ensure a uniform screening process.

The systematic review methodology involved a two-stage deduplication process, excluding 1544 redundant entries out of 6145 obtained titles. The initial phase of deduplication utilized Excel and yielded an initial pool of 5141 articles (1004 deduplicated automatically). Subsequently, manual deduplication was performed which reduced this pool to 4601 articles. This meticulous approach ensured the dataset’s integrity and reliability for comprehensive analysis.

To manage the extensive dataset, a systematic approach to screening was adopted. The six co-authors were organized into three pairs; each assigned the responsibility of independently screening titles and abstracts for all the search-returned publications. This is to determine the eligibility of studies for data retrieval by checking if they met our study criteria. Any conflicts or disagreements during the screening phase were resolved through consultation with a third opinion. After excluding 4549 articles by title and abstract review, 52 reports were sought for retrieval and full-text review. The same pairs reviewed the full text of the included studies, and the required data was extracted from each. The full-text review resulted in the further exclusion of 47 studies and 5 records for further steps. The manual search in the excluded review resulted in another 2 articles qualified for the next step of data extraction and evidence testing bringing the total included studies to 7.

Data Extraction: A structured data extraction form (Google form) was used to collect data elements of each study and extracted them into a Microsoft Excel (Microsoft® Excel® for Microsoft 365 MSO (Version 2210 Build 16.0.15726.20188) 64-bit) worksheet (the worksheet is provided in an alternative free format; Google Sheets, refer to the Data availability statement). This form encompassed key elements such as study design (i.e., prospective, retrospective, case-control, cohort study, etc …), country of conduct, sample size, publication year, study duration, primary outcomes and measurement method, secondary outcomes (if any), research question, and the journal of publication. Each divided pair independently extracted study data from included publications, and the results were then compared. Two studies were excluded after full-text review as they failed to report AZ specifically in the treatment. A third party resolved differences. Data sources were carefully reviewed, and the extracted data was used in our analysis.

Assessment of bias: After completing data extraction, we noticed that all our included articles lay under the study design of either randomized controlled trials, cohort studies, or case-report series. Thus, an Evidence Appraisal Tool called “LEGEND” (Let Evidence Guide Every New Decision), which was developed by Cincinnati Children’s Hospital, and was used to assess the quality of the data. The authors of the forms have made these forms available for use given proper referencing is followed: “refer to data repository documents for permission” (Cincinnati Children’s Organization 2019). The authors have contacted the authors and obtained permission to use them. This tool was selected for its suitability in accommodating varied study designs. It facilitated the evaluation of validity, reliability, and applicability, culminating in the determination of Evidence Levels for each study.

Themes were generated based on the selected studies’ patient criteria, treatment regimens, and clinical outcomes. Table 1 summarizes the included studies and evidence evaluations.

Table 1. Summary of the included studies in the systematic review and the evidence evaluation scores.

No.Title of the articleYear and Country of publicationStudy type and durationWhat is the research question?Study populationSample sizeWhat is the primary outcome of the study? How was it measured?Main resultsWhat are the secondary outcomes? if anyEvidence level
1Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia2011, SpainCohort study, 5 monthsWhat is the effect of immunomodulatory therapies on the development of severe disease in hospitalized adults with laboratory-confirmed pandemic influenza A (H1N1) 2009 complicated by pneumonia?68/197 Hospitalized adults with laboratory-confirmed influenza A (H1N1) 2009 complicated by pneumonia68/197ICU admission or death after 1 day of hospital admission, ObservationImmunomodulatory therapies were not Associated with a lower risk of developing severe disease (OR 0.64; 95% CI 0.22-1.86)NA3b
2Macrolide-based regimens in absence of bacterial co-infection in critically ill H1N1 patients with primary viral pneumonia2013, SpainCohort study, 2009-2011Is macrolide-based treatment associated with mortality in critically ill H1N1 patients with primary viral pneumonia?H1N1 Patients of ICU with primary viral pneumonia in 148 intensive care units (ICU)190/733The mortality rate, by observation and recording ICU deathsLength of ICU Stay in survivors was not significantly Different in Macrolides-based treatment compared to patients who Did not, and they Had lower ICU Mortality in the univariate analysis, but no significant effect in the propensity multivariate analysis.NA3a
3Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial2017, ChinaRCT, 4 yearsWhat are the effects of adjunctive macrolide treatment (specifically azithromycin) on inflammation, viral clearance, and symptom resolution in adults with severe influenza infections?50 hospitalized adults for laboratory-confirmed influenza.50Change in plasma cytokine/chemokine concentrations over time (Day 0 to Day 10), Laboratory analysis of blood samplesPro-inflammatory cytokines IL-6, CXCL8/IL-8, IL-17, CXCL9/MIG, stnfr-1, IL-18, and CRP declined faster in the oseltamivir-azithromycin Group.Viral load changes, and Symptom score changes.2a.
4Assessment of efficacy of oseltamivir-azithromycin combination therapy in prevention of influenza- a (H1N1) infection complications and rapidity of symptom relief2020, KSACohort study, three years (2016-2019)What is the efficacy of oseltamivir-azithromycin combination therapy (102/329) vs oseltamivir alone (227/329) in preventing complications of influenza A (H1N1) infection and rapid symptom relief?Hospitalized patients who were reported to be diagnosed with Influenza A (H1)pdm09 infection329/589Improvement of influenza symptom severity using Acute Symptom Severity Score (ARI) score which includes 8 common symptomsSignificantly less secondary bacterial infection, shorter hospitalization, less respiratory support, and influenza symptom score in the combination groupIncidence of (a) secondary bacterial infections (b) multi-organ failure (c) requirement of mechanical respiratory support during hospitalization (d) acute kidney injury (e) length of hospital stay (f) requirement of vasopressor use (g) ICU admission4a
5Clinical manifestation, symptoms and outcome of pandemic influenza A (H1N1) 2009 in hospitalized patients2011, SerbiaCase/controlTo investigate clinical symptoms, risk factors for severe forms of influenza, treatment, and outcome in patients with novel influenza A (H1N1) hospitalized in the Clinic for Infectious and Tropical Diseases MMA.98/1288 hospitalized patients with flu-like illness98Hospital death, observationFatal outcome was noted in 2.0% of the patients (2 of 98 patients) and in 33.3% of the patients treated in the ICU.
Patients seem to have benefited from antiviral therapy, especially in the first 48 hours.
Assessment of comorbidities, ICU admission, lab investigations4b
6Efficacy of Combination Therapy with Oseltamivir Phosphate and Azithromycin for Influenza: A Multicenter, Open-Label, Randomized Study2014, JapanRCT, December 2010-March 2011To evaluate the effects of combination therapy with an anti-influenza agent, oseltamivir, and a single-dose formulation of azithromycin (AZM),Patients with influenza from the Nagasaki University Hospital and 13 of its affiliated hospitals and clinics107The change in the inflammatory cytokines levels, the cytokine bead arrayStatistically significant differences were not observed in the expression levels of inflammatory cytokines and chemokines between the 2 groups. The maximum temperature in the combo-group was lower than that in the mono-group on day 3 through day 5 (p=0.048), particularly on day 4 (p=0.037).The time required for resolution of influenza-related symptoms, incidence of complications, and adverse reactions.2a
7Personal, Occupational, and Public Health Perspectives on Dealing with the First Case of Influenza A (H1N1) in the United Arab Emirates2011, UAECase report, two weeksDescribe the personal experience and the management of the first case of H1N1 in the UAEA 48-year-old male1NAIssues related to workplace considerations and general public health, including preventive measures, the need for isolation of the patient, dealing with contacts, return to work, and communication with the workforce.NA5a

3. Results

3.1 Literature search and selection

A total of 6,145 studies were identified through the initial online database search. After excluding duplicates (n=1,544), 4601 studies remained, out of which 4592 were removed after reviewing the titles and the abstracts by applying the inclusion and exclusion criteria. Our inclusion criteria comprised original articles written in English, published between 2007 and 2023, and studies reporting the effectiveness of AZ in the treatment of influenza A (H1N1) viruses. Following the full-text review of the remaining 52 studies, 47 studies were excluded for various reasons; 15 reviews and the rest did not align with the aim and scope of our study and were considered irrelevant (diagnostic rather than therapeutic reports, animal studies, outcomes were not correlated to AZ use, case-report with no specific mention of azithromycin, conference abstract). Five studies qualified for the next step of evidence testing. The references of the 15 reviews underwent a secondary manual title search, resulting in the inclusion of 2 additional studies. The final 7 studies underwent evidence testing using the “LEGEND” evidence testing form (Cincinnati Children’s Organization 2019). After a thorough analysis of the remaining studies, four themes were generated. Table 1 summarizes the main findings of the reviewed studies with the evidence level (Table 1, Supplementary Data). Pooling of the results was impossible due to the variability among studies in patient criteria, study outcomes, and study designs.

3.2 Results of data analysis

3.2.1 AZ effect in reducing cytokines

Two studies (Kakeya, Seki et al. 2014, Lee, N., Wong et al. 2017) investigated the effect of AZ on cytokine levels, both studies received a “2a” rating during the evidence testing phase indicating a good quality randomized controlled trial. This suggests that the methodologies used in both studies were robust and reliable for drawing conclusions, similarities emerge in the baseline setup of these studies. In both trials, patients were randomized to different treatment groups, ensuring a balanced distribution of individuals. Additionally, the baseline characteristics and severity of influenza infections were comparable across the groups, enhancing the reliability of the subsequent analyses. Nevertheless, the studies did diverge regarding their specific methodologies and outcomes.

The study by Lee, Wong, et al. (2017) involved 50 hospitalized patients with influenza A/H3N2 infections and complications, randomly assigned to two equal groups: oseltamivir-AZ and oseltamivir alone groups (25 patients each). The groups were meticulously matched for baseline characteristics and infection severity. Notably, the oseltamivir-AZ group demonstrated a more rapid decline in key cytokines—IL-6, CXCL8/IL-8, IL-17, and CXCL9/MIG—compared to the oseltamivir-alone group. Similarly, percentage reductions in cytokine levels were higher in the combination therapy group compared to the monotherapy group: IL-6 (−83.4% vs. −59.5%), CXCL8/IL-8 (−80.5% vs. −58.0%), IL-17 (−74.0% vs. −34.3%), and CXCL9/MIG (−71.3% vs. −56.0%) (Lee, N., Wong et al. 2017).

On the other hand, Kakeya, Seki et al. (2014) included 107 influenza A-infected patients in their study and divided them into two treatment groups: the mono-group (oseltamivir, 56 patients) and the combo-group (oseltamivir plus extended-release azithromycin: 51 patients). The baseline levels of inflammatory markers, including IL-6, IL-8, IL-12, TNF-a, IL-1b, TGF-b1, PCT, and HMGB1, showed no significant differences between the two groups initially despite early resolution of symptoms in the combination group. However, TNF-α levels were notably higher in the combination group on day 0 (p = 0.03). Subsequent analyses on days 2 and 5 revealed no significant differences in cytokine expression, although TNF-α levels were different on day 5, ultimately decreasing below measurable limits in both groups (Kakeya, Seki et al. 2014).

While both studies maintained a high-quality evidence rating, their methodologies and outcomes diverge. Lee, Wong et al.’s study suggested the potential benefit of adjunctive AZ in hastening the decline of key cytokines, which was supported by specific percentage reductions and mechanistic insights. In contrast, findings from the second study pointed towards a convergence in overall cytokine responses between mono and combo treatment groups, despite an initial difference in TNF-α levels. Therefore, a significant effect of AZ on the inflammatory markers level in influenza infection can not be determined based on the reviewed reports.

3.2.2 AZ effect on influenza symptom control

Four different studies investigated the impact of AZ on the management of influenza symptoms (Ishaqui, Khan et al. 2020, Kakeya, Seki et al. 2014, Lee, N., Wong et al. 2017, Shah, Tar-Ching et al. 2011). These symptoms included fever, general discomfort, muscle pain, joint pain, headaches, sore throat, nasal symptoms, coughing, wheezing, dyspnea, and chest discomfort.

In one study by Ishaqui et al. (2020), a cohort study was conducted with an evidence level of 4a. Two groups were formed: Group-AV with 227 patients, who were treated solely with antiviral (AV) Oseltamivir without antibiotics, and Group-AV+AZ with 102 patients, who received a combination therapy of Oseltamivir and AZ for at least 3-5 days. Their progress was assessed using the Acute Symptom Severity Score (ARI score), and it was discovered that Group-AV+AZ patients had significantly lower symptom severity scores on both day 3 (16.6 vs 15.08; P<0.001) and day 5 (12.7 vs 10.7; P≤0.0001) (Ishaqui, Khan et al. 2020).

The randomized controlled trial by Kakeya, Saki et al. (2014) showed a positive outcome in the symptoms in the combo group (Oseltamivir plus an extended-release AZ) 107 compared to the mono-group (Oseltamivir alone). Patients recorded their influenza symptoms, maximal temperature, and activities of daily living using a 7-symptom Influenza Symptom Severity scale (ISS) and a visual analogue scale (Influenza Impact Well-Being Score [IIWS]). The combo group showed a significant decrease in maximum temperature on day 4 (p=0.037) and lower maximum temperatures from day 3 to day 5 (p=0.048) compared to the mono group. Improvement in sore throat was also more frequent on day 2 in the combo group (p>0.05). The combo group also showed a trend toward earlier resolution of fever compared to the mono-group (p=0.05 on day 2 and p=0.06 on day 5). However, other influenza-related symptoms showed no significant differences between the groups (Kakeya, Seki et al. 2014).

Symptom improvement with AZ was also reported in a case report by Shah et al. (2011) with an evidence level of 5a and no comparison. A comprehensive analysis was conducted on a 48-year-old patient diagnosed with H1N1 influenza. The therapeutic regimen employed for this individual encompassed the administration of Oseltamivir along with AZ and paracetamol. Remarkably, the patient exhibited rapid improvement in fever and sore throat upon the initiation of this treatment protocol (Shah, Tar-Ching et al. 2011).

On the other side, the randomized controlled trial by Lee, Wong et al. (2017) also compared the symptom improvement among the two treatment groups: oseltamivir-AZ and oseltamivir alone groups using a 4-point scale. Unlike the previous study, there was a trend towards symptom score reduction in the combination group (b 0.463, 95%CI-1.297,0.371, P = 0.277; percentage reduction from baseline: 79.0% and 70.4% respectively), but the improvement did not reach statistical significance (Lee, N., Wong et al. 2017).

Together, these studies demonstrated that using AZ as an adjunct treatment has notable positive effects, particularly in reducing the severity of influenza-related symptoms.

3.2.3 Effect in critically ill patients/ICU: complication, mortality

The use of AZ in critically ill or ICU-admitted patients was shown in five studies (Lee, N., Wong et al. 2017, Ishaqui, Khan et al. 2020, Viasus, Paño-Pardo et al. 2011, Martin-Loeches, Bermejo-Martin et al. 2013, Mikić, Nožić et al. 2011). As previously mentioned, Lee, Wong et al. (2017) showed a trend toward symptom improvement without obtaining a statistical difference between antiviral treatment alone vs antiviral and AZ combination. It is worth mentioning here that, in this study, the two groups developed “potentially serious complications” or suffered other cardiovascular and respiratory illnesses before hospital admission, and the two groups had similar baseline characteristics before randomization. Despite the significant reduction of inflammatory cytokines in the combination group, other clinical parameters did not show a difference between the two groups, such as the development of complications, use of supplemental oxygen, requirement of assisted ventilation, duration of hospitalization, need for extended care, adverse events, and death. The treatment was generally well-tolerated, with one patient discontinuing AZ after three days due to dizziness, which subsided spontaneously (Lee, N., Wong et al. 2017).

In the retrospective cohort study Ishaqui, Khan et al. (2020) on 309 hospitalized influenza A patients due to severe illness. the combination therapy (AV+AZ) was associated with fewer complications, including a statistically significant reduction in secondary bacterial infections related to Influenza-A (H1) pdm09 in group AV+AZ patients (102 patients) (23.4% vs. 10.4% in the 227 patients in the group-AV; P=0.019). Additionally, patients in Group-AV+AZ had shorter hospital stays (6.58 days vs 5.09 days; P≤0.0001), fewer ICU admissions (28.2% vs 10.8%; P=0.0004), less need for mechanical respiratory support (38.3% vs 17.6%; P≤0.0001), lower incidences of multi-organ failure (17.4% vs 5.9%; P=0.0081) (Ishaqui, Khan et al. 2020).

Another cohort study from 13 tertiary hospitals on 197 patients with pandemic influenza A (H1N1) complicated by pneumonia was reviewed as it specifically examined the effect of immunomodulatory medications on the disease severity (defined as ICU admission or death after 1 day of admission) (Viasus, Paño-Pardo et al. 2011). One-third of the patients (68 patients) received additional anti-inflammatory therapy early after admission in the form of corticosteroids (37 patients), macrolides (31 patients), and statins (12 patients) as part of their treatment regimen. Notably, patients who received macrolides were less likely to develop severe illness as in Ishaqui, Khan et al. (2020), and none of them died. A multivariate analysis was performed given the variability of the patient’s criteria and the higher prevalence of comorbidity in the immunomodulatory therapy groups. It showed that none of these therapies was associated with a lower risk of developing severe disease. At the same time, the presence of comorbidities and high-risk classes (based on the Pneumonia Severity Index, IPS) are significant factors associated with the development of severe disease (Viasus, Paño-Pardo et al. 2011).

One study with 3a evidence level assessed prospectively AZ use and the mortality in 733 ICU patients from 148 ICU units diagnosed with primary viral pneumonia during the H1N1 virus influenza A pandemic with severe respiratory failure (Martin-Loeches, Bermejo-Martin et al. 2013). 190 patients (25.9%) received macrolide-based combination treatment. These patients had different characteristics from other treatment groups such as a higher prevalence of chronic obstructive pulmonary disease, statistically significant lower severity on ICU admission, and less often multiple organ dysfunction syndrome. Among the macrolide-based treatment groups, 90 patients received AZ. Multiorgan dysfunction syndrome developed less frequently in the macrolide-based treatment group (23.4 vs 30.1%, p <0.05) while the length of ICU stay for survivors did not significantly differ between the macrolide and non-macrolide groups (10 (IQR 4–20) vs. 10 (IQR 5–20), p=0.9). Total ICU mortality was 24.1% (n=177), with a lower mortality rate observed in the univariate analysis among patients receiving macrolides (19.2 vs. 28.1 %, p=0.02), but logistic regression analysis and propensity score analysis showed no significant effect of macrolide-based treatment on ICU mortality (OR = 0.87; 95 % CI 0.55–1.37, p=0.5) (Martin-Loeches, Bermejo-Martin et al. 2013).

The report by Mikić, Nožić et al. (2011) described 98 hospitalized patients with flu-like illness accompanied by complications such as pulmonary infiltrates, hypoxemia, acute lung injury, or respiratory failure plus other systemic illnesses, with 4b evidence level. No evidence about the AZ benefit can be inferred from this study as the authors did not specify which outcomes were related to the treatment groups which were vaguely reported. The patients received antiviral (oseltamivir) alone or with antibiotics (either AZ alone or ceftriaxone or both), or only symptomatic treatment. The study observed that 2 patients (2.0%) experienced a fatal outcome, which amounted to 33.3% of the patients treated in the Intensive Care Unit (ICU) (Mikić, Nožić et al. 2011).

Collectively, except for one retrospective observational study (Ishaqui, Khan et al. 2020), AZ did not show a superior benefit for critically ill or ICU-admitted influenza patients. Furthermore, the decision to administer AZ in these critically ill patients was not explained (except for the randomized control trial (Lee, N., Wong et al. 2017)) or AZ was administered in more ill patients, which could have affected the course of therapy and unsupported an inference.

3.2.4 AZ use in influenza: safety and adverse effects

The final theme was to evaluate the safety and adverse effects of prescribing AZ for viral Influenza A (H1N1) patients. Among the 3 articles that explored the adverse effects of AZ in Influenza A patients, no severe adverse effects were noted (Ishaqui, Khan et al. 2020, Lee, N., Wong et al. 2017, Kakeya, Seki et al. 2014, Mikić, Nožić et al. 2011). In the randomized controlled trial by Lee, Wong et al. (2017), it was evident that there was no difference between the combination group of AZ and oseltamivir and standalone therapy of oseltamivir regarding mechanical ventilation need (p=0.149) and supplemental oxygen therapy (p=0.544). However, it is noteworthy to mention that one patient had to stop AZ after 3 days due to dizziness. Furthermore, a similar incidence of adverse effects was seen in both groups (2 severe adverse effects in the combination group and 1 severe adverse effect in the standalone group, p>0.99) with no cardiovascular events noted. Finally, all events were transient and reversible as well as all adverse effects were considered unrelated to the treatment (Lee, N., Wong et al. 2017).

Similarly, Kakeya, Seki et al. (2014) did not report a significant difference in the adverse effects between the combination and the stand-alone therapy in their randomized controlled trial, where 11 out of 56 (19.6%) from the combination group and 9 out of 51 (17.6%) experienced adverse effects. In addition, no severe adverse effects occurred or patients were discontinued due to an adverse effect and it was noteworthy to mention that the most common adverse effects noticed were diarrhoea (n=3 in the combination group) and a decrease in the number of white blood cells (n=5 in combination group and n=3 in standalone therapy) and only one patient developed secondary pneumonia in the standalone therapy group. Finally, a decrease in serum albumin and total protein levels on day 2 happened due to AZ addition in the combination group. On the other hand, red blood cell count, haemoglobin, and haematocrit values on days 2 and 5 showed a statistically significant increase in the combination group which can indicate a better clinical prognosis, but no conclusions can be drawn here. Likewise, no adverse events were reported by Ishaqui, Khan et al. (2020), and the length of hospital stay was significantly less (p<0.0001) which indicates faster recovery and better disease progression.

To conclude our results, no significant events were found regarding safety and adverse effects when AZ was introduced to the treatment regimen of influenza A-infected patients compared to antiviral agents alone. In most instances, the adverse effects were reversible and transient.

4. Discussion

In this systematic review, we provided further evidence about the use of AZ in the treatment of influenza A viral infection in hospitalized or critically ill patients. Based on the limited reports with insufficient evidence, a recommendation for the use of AZ in the treatment regimen was not possible despite the associated reduction in inflammatory cytokines by AZ administration and the absence of significant adverse effects or mortality in hospital-admitted or ICU patients. While these findings support the current guidelines for the treatment of influenza A viral infection, the evidence behind these guidelines and treatment characteristics were provided in this report.

The use of AZ in Influenza A is mechanistically well grounded and indirectly supported by prior experiences with other viral pneumonia, chronic pulmonary diseases (COPD, Asthma, Chronic Cough, and Bronchiectasis), and inflammatory disorders (Bronchiolitis obliterans) (Smith, Du Rand et al. 2020). Yet, the empirical practice of AZ treatment for Influenza A has not been substantiated by good-quality clinical data. In addition, the current guidelines recommend not administering a macrolide antibiotic for the treatment of influenza and justify that by the “insufficient evidence for benefit rather than evidence for harm”, denoting low-quality evidence. The guidelines were based on a few studies (1 RCT and 1 observational study) (World Health Organization 2021). Despite, maybe even because of, these limitations, new articles have been published recently. A critical appraisal of the currently available evidence is valuable especially since the guidelines do not provide evidence about the macrolides’ safety and complications except for the nosocomial infection (World Health Organization 2021). Moreover, the guidelines do not focus on AZ only and include clarithromycin and other macrolides which necessitates contextualizing the ongoing trials and improving the set-up of future trials (Kanoh, Rubin 2010, Zimmermann, Ziesenitz et al. 2018).

Despite the pleiotropic effects of azithromycin, it is certainly not a monotherapy for influenza nor the most potent molecule. Targeted antiviral drugs will likely have a more robust effect on the viral load and they should be started as soon as possible (Muthuri, Venkatesan et al. 2016). However, the anti-inflammatory effects of AZ at targeted anti-IL1, anti-IL6, or steroids are stronger than anti-viral medications (Kanoh, Rubin 2010, Zimmermann, Ziesenitz et al. 2018). AZ is not a standalone therapy as highlighted in all the reviewed studies, but rather an adjunctive therapy for antiviral, anti-inflammatory, and in selected cases, antibiotic drugs. The combination of these medications depends on the patient’s presentation, immune status, and disease stage as it can help the disease prognosis and help prevent secondary bacterial complications (Ishaqui, Khan et al. 2020, Kakeya, Seki et al. 2014, Lee, N., Wong et al. 2017, Martin-Loeches, Bermejo-Martin et al. 2013, Viasus, Paño-Pardo et al. 2011). However, the decision to use drug combinations was not justified or explicitly detailed in these studies, which makes suggesting personalized recommendations for AZ use difficult.

The safety of AZ has always been in limbo as it has shown cardiovascular effects such as acute heart failure, specifically for what was seen recently in a COVID-19 cohort of patients where acute heart failure developed in patients with pre-existing cardiovascular diseases (Bergami, Manfrini et al. 2023, Juurlink 2014). Despite that, as seen in our results, the risk of cardiovascular adverse effects was low in patients who took AZ in combination therapy. In addition, the adverse effects noted were diarrhea (Kakeya, Seki et al. 2014) and dizziness (Lee, N., Wong et al. 2017), while other adverse effects were not significantly different from other treatment options devoid of AZ.

Furthermore, as proven in studies regarding acute respiratory distress syndrome, mechanical respiratory need improves significantly in patients who take AZ and even leads to quicker discontinuation of mechanical ventilation (Kawamura, Ichikado et al. 2018). This confirms our findings as we have concluded that the mechanical respiratory need was improved leading to a lesser hospital stay and faster disease resolution (Lee, N., Wong et al. 2017, Ishaqui, Khan et al. 2020).

Regarding viral load, AZ has direct and indirect antiviral activity in bronchial epithelial cells and other host cells (Gielen, Johnston et al. 2010). In addition to SARS-CoV-2, this has also been shown for influenza, rhinovirus, dengue, ebolavirus, parainfluenza virus, zika virus and enterovirus (Gyselinck, Janssens et al. 2021, Zeng, Meng et al. 2019, Damle, Vourvahis et al. 2020). Data collected here was suggestive of a decrease in the viral load yet inconclusive as only 2 out of the 7 articles mentioned a positive decrease in viral load and 1 of the articles mentioned a neutral relation where there was no change in viral load which highly indicates future focus on this matter. In connection to the anti-inflammatory role of AZ, it has a golden history of having a benefit in reducing cytokines released as evident in multiple COVID researches and animal models of viral infections (Fernandez, Elmore et al. 2004, Stellari, Sala et al. 2014, Zimmermann, Ziesenitz et al. 2018). These findings match our review results (Lee, N., Wong et al. 2017).

Influenza A infection symptom control with AZ-combination therapy has generally shown a positive effect and there are no incidence reports as far as the evidence reviewed that AZ caused a deterioration of an influenza A patient. However, failure to reach a significant relationship between AZ and symptom improvement in some reports prevented us from concluding this positive effect (Ishaqui, Khan et al. 2020, Kakeya, Seki et al. 2014, Lee, N., Wong et al. 2017, Shah, Tar-Ching et al. 2011). In related studies about COVID-19 infection, the time of initiation of the drugs had a significant effect on the resolution of symptoms (Siddiqi, Mehra 2020). This is unlike the studies under review where AZ was initiated for patients requiring hospital admission or critically ill patients requiring ICU. This strongly suggests that further studies are warranted to help guide the appropriate timing of initiation of macrolide therapy in influenza A to better observe its potential benefits.

The findings of this systematic review must be seen in light of some limitations. First, and most importantly, the number and the evidence quality of the published data about AZ in influenza A treatment are restricted to infer an evidence-based recommendation. The available studies, in addition to being few, did not follow the same methodology for sampling, study design, disease severity, treatment regimen, and primary and secondary outcomes. This renders data pooling and comparison for our review question impossible. Finally, it is important to isolate the use of AZ from other macrolides, which is not considered in the current guidelines (World Health Organization 2021). Most other macrolides such as clarithromycin have a variety of findings that either support or go against their use (Snow, Longobardo et al. 2022, Ishii, Komiya et al. 2012, Lee, C., Tai et al. 2021) while AZ generally has stronger molecular and clinical supportive evidence.

In conclusion, AZ shows a potential symptom improvement in influenza A patients, as well as pro-inflammatory laboratory indices such as cytokine release. Another positive aspect of AZ usage is the absence of complications associated with its administration to critically ill patients and acceptable prognosis. However, it is crucial to have more quality research on this matter that focuses on the indication of the use of AZ, and the timing of initiation, dosage, and duration of treatment while monitoring adverse events.

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Amer Abd Alsamad Y, Abdul Muin Daas O, Talal Allababidi M et al. The efficacy of azithromycin in the treatment of influenza A infection: A systematic review [version 1; peer review: awaiting peer review]. F1000Research 2024, 13:1111 (https://doi.org/10.12688/f1000research.152870.1)
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