In this study, five tools were applied to draw bibliometric maps and visualization images for 2,176 articles. The current state of research and emerging trends of influenza inflammatory responses were systematically assessed through quantitative, qualitative, and comprehensive research methods. Notably, this is the first bibliometric study in this research field.

The volume of articles in the research field has gradually increased, with explosive growth detected after 2009 and 2019. The number of articles published yearly since 2015 has exceeded 110 (R2 = 0.8707), indicating that the study of inflammatory response in influenza has significant research value. The United States ranks first in publications (928 articles), mainly due to the high productivity of St. Jude Children’s Research Hospital (52 articles) in this field. China and the United Kingdom rank second and third with 450 and 158 articles, respectively. The United States showed close collaborations with several countries/regions, such as China and Canada. Additionally, most countries and researchers cooperated with China, Australia and Canada. However, many countries have little or no collaboration in this field (Fig. 3A − 3B). Professor Ross Vlahos published the most related literature (22 articles). Most articles are published in the PLoS One (95 articles). Furthermore, 6 of 10 most highly cited periodicals had impact factors higher than 10, indicating high research quality in this field.

Influenza virus is a part of the Orthomyxoviridae family. This family is characterized by viral glycoproteins including hemagglutinin (HA) and neuraminidase (NA), which determine the virus subtypes [32]. The influenza virus is effectively prevented by the robust defense mechanism of the innate immune system. Pattern recognition receptors (PRRs) identify pathogen-associated molecular patterns (PAMPs) [33], leading to the secretion of interferons (IFNs), pro-inflammatory cytokines, eicosanoid, and chemokines [34, 35], thus detecting viral infections. Studies have shown that the 1918 influenza virus also exhibits high pathogenicity in mice. Studies have also verified the multi-genic origin of this virulence phenotype [36]. Darwyn Kobasa showed that the 1918 influenza virus can cause severe respiratory infections in primate cynomolgus macaque models, thereby leading to acute respiratory distress or even death [37]. Additionally, infection dysregulates antiviral response in animals, suggesting that an atypical host innate immune response may accelerate mortality [38]. Influenza virus can modulate host immune responses, a common feature of pathogenic influenza viruses.

Severe complications caused by pandemic influenza or high pathogenic (HP) H5N1 avian influenza virus are associated with rapid and massive infiltration of inflammatory cells [39]. Menno D de Jong et al. conducted virological and immunological studies on 18 H5N1 patients and eight individuals with human influenza virus subtypes to assess the correlation between high viral replication and virus-induced cytokine dysregulation with disease severity in humans. The research findings revealed that individuals infected with human H5N1 influenza exhibit elevated viral loads within the throat region, while viral RNA is present in the rectum and bloodstream. Furthermore, a decrease in peripheral blood T lymphocyte counts is observed in these cases, alongside high concentrations of chemokines and cytokines. Notably, this elevation is more pronounced in deceased patients, which correlates with the viral load detected in their throat samples [30]. This study suggests that the primary cause of H5N1 influenza lies in the high viral loads and subsequent intense inflammatory response. The severe damage caused by the excessive inflammatory response during IAV infection is able to cause life-threatening lung diseases. Both HP virus and H5N1 avian influenza viruses can induce a cytokine storm characterized by dysregulation and overproduction of inflammatory cytokines. The aforementioned consequences are linked to the occurrence of severe pulmonary edema, both primary and secondary pneumonia, as well as alveolar hemorrhage in cases of acute bronchopneumonia [40, 41]. Researchers have employed flow cytometry to assess the cellular immune response in mouse lung infections caused by HP H1N1 and H5N1 influenza viruses. The results indicate a substantial rise in the quantity of macrophages and neutrophils present in the infected lungs. Macrophages and neutrophils can rapidly accumulate in the lungs due to HP influenza viruses. The HP influenza virus infection is linked to acute pulmonary inflammation, and these cells are essential in this process [42].

Macrophages and neutrophils are capable of releasing chemokines and cytokines, which act in an autocrine manner. The production of chemokines at the site of infection leads to the recruitment of additional immune cells, such as neutrophils, monocytes, and natural killer (NK) cells, to the airways. These recruited immune cells target virus-infected epithelial cells for NK cell-mediated virus clearance [43]. Influenza virus-infected lungs recruit monocytes and neutrophils quickly to eliminate infected and dying cells [44]. Monocytes/macrophages infected with viruses can generate pro-inflammatory cytokines such as interleukin-1, tumor necrosis factor-alpha, and interferon-alpha (IFN-α). This process results in the enhanced expression of chemokines MCP-1, MCP-3, and IP-10. Consequently, this amplification of inflammatory/chemotactic signals leads to the recruitment of more monocytes/macrophages and T lymphocytes to the site of infection [45]. Virus-infected macrophages not only trigger a potent pro-inflammatory response but also cause significant tissue damage by releasing excessive amounts of reactive nitrogen intermediates and reactive oxygen species (ROS). These harmful substances cannot differentiate between foreign pathogens and the body’s own cells, leading to collateral damage. The overproduction of reactive nitrogen intermediates and ROS can lead to widespread tissue damage [46].

Two immune responses of dendritic cells (DCs) to IAV are the research focus and hot topic in this field. In addition, the relationship between airway stem cells and lung injury treatment is increasingly becoming a research focus. The progenitor cell characteristics of airway basal stem cells suggest their potential in lung tissue regeneration medicine, attracting much interest in this field. Furthermore, the COVID-19 pandemic significantly impacted humans, necessitating response measures to mitigate losses. Given the high variability of influenza strains, continuous monitoring of the effectiveness of existing antiviral medications is crucial. Furthermore, the urgent discovery of new anti-inflammatory drugs to mitigate influenza-related inflammatory diseases is required.

DCs are a unique subset of hematopoietic mononuclear cells and professional antigen-presenting cells (APCs), serving as key mediators for congenital immunity and specific immunity to IAV infection [47]. DCs are located in secondary lymphoid organs and peripheral sites/surfaces. DCs are typically subdivided into two main subsets, including plasmacytoid DCs (pDCs) and conventional DCs (cDCs). pDCs are the major producers of the antiviral cytokine IFN-α. cDC1 and cDC2 are two critical mediators of cytotoxic T lymphocyte (CTL) responses to IAV infection [48]. Respiratory dendritic cells (RDCs) are targets during influenza virus infection. RDCs migrate from the lungs to draining lymph nodes, as the primary APCs, to induce adaptive immune CD8 T cell responses to viral infection [49, 50]. Studies have shown that cDC1 depletion results in insufficient specific primary CD8+ T cell activation and significant inflammation in lung, which can impair CD8+ T cell immunological memory activation and cross-reactivity. This reactive pattern reveals that cDC1 participates in the activation of primary T cells and the proliferation of effective memory CD8+ T cell precursors [51]. DCs provide the first line of defense after IAV infection, thus linking innate and adaptive immunity. Many DC populations can elicit immune responses to IAV in infected lung tissues and associated lymph nodes [52]. Besides, H1N1 influenza virus can induce abnormal arginine metabolism in nasal mucosal epithelial progenitor cells, leading to inflammation, promoting the maturation and recruitment of DCs in the nasal mucosa, thereby triggering mucosal immunity in the respiratory tract [53]. Models for DC immunotherapy, both in vivo and in vitro, have shown the significance of DCs in detecting IAV [54].

Various lung stem cells/progenitor cells are found in different ecological niches throughout the lung. These cells mediate site-specific responses to injury. Basal stem cells in the proximal airways, as resident stem cells, can self-renew in a steady state and after acute injury, repopulating nearly all cell types of the pseudostratified epithelium [55]. The remaining basal stem cells rapidly increase their proliferation rate and differentiate within the first 24 h to restore lung homeostasis when exposed to acute injury from physical injury, chemical injury, or pathogen infection [56]. Additionally, researchers have found that mice and human airway basal stem cells can sense hypoxia, triggering these stem cells to differentiate directly into solitary neuroendocrine cells. NE cell hyperplasia occurs in various lung diseases, such as asthma, congenital pneumonia, pulmonary arterial hypertension, and chronic obstructive pulmonary disease (COPD), representing a compensatory physiological response [57]. The protective peptide calcitonin gene-related peptide (CGRP) secreted by neuroendocrine cells can improve excessive damage during hypoxia, while the removal of these cells can exacerbate injury, suggesting that different forms of lung injury may elicit distinct protective NE cell responses [58]. Transplantation of basal-like cells derived from mice primary or human primary pluripotent stem cells (PSC) into genetically matched or NOD scid gama (NSG) recipient mice with polidocanol injury can achieve long-term self-renewal and sustained multipotent differentiation in vivo for at least 2 years [59]. These findings provide insights for future therapies for patients with diseases caused by airway epithelial cell injury or dysfunction.

The novel coronavirus infection is an acute infectious disease caused by a novel coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2). In March 2020, The World Health Organization declared that SARS-CoV-2 has pandemic characteristics [60]. The main clinical symptoms of patients with SARS-CoV-2 are fever, dry cough, and fatigue. Critically ill patients may experience breathing difficulties, acute respiratory distress syndrome, septic shock, multiple organ failure, and other manifestations [61]. The rapid, continuous, and unpredictable evolution of influenza viruses promotes the variability of its pathogenesis, posing challenges for influenza vaccine development and pandemic preparedness. Many basic control measures for pandemics are based on seasonal influenza measures. Therefore, establishing a sustainable global influenza vaccine production network and supply chain is crucial. Furthermore, encouraging and investing in research and development of influenza and respiratory pathogens, sustainable funding for research and innovation are necessary. Lastly, building trust, improving communication, and implementing intervention measures for patients and the public are essential [62, 63].

Mehdi Rabie-Rudsari et al. identified NA mutations in the A/H1N1 and A/H3N2 subtypes of influenza A in samples collected from Mazandaran, Iran, between 2016 and 2020. Although no mutations related to oseltamivir resistance were detected, notable differences were observed in the NA gene compared to vaccine strains. A total of 43 mutations were identified in the A/H1N1 subtype, while 66 mutations were found in the A/H3N2 subtype [64]. These findings underscore the importance of continuous monitoring for drug-resistant mutations. Recent research has demonstrated that oclacitinib, a representative compound of Janus kinase (JAK) inhibitors, effectively inhibits neutrophil and macrophage infiltration, reduces the production of pro-inflammatory cytokines, and ultimately alleviates lung damage in mice infected with a lethal strain of the influenza virus, without affecting viral titers. The efficacy of 10 JAK inhibitors was assessed using an influenza mouse model, revealing that 7 of these compounds exhibited a protective efficacy ranging from 40 to 70% against lethal influenza virus infection [65]. These results suggest that JAK inhibitors can modulate the immune response to influenza virus infection and may represent a potential treatment option for influenza.

In summary, influenza induces a systemic inflammatory response through the activation of the immune system. While this response is essential for combating the virus, excessive inflammation can lead to significant health complications. During the recovery phase from influenza, although the virus is cleared, the inflammatory response may persist, resulting in continued fatigue and weakness. C-reactive protein (CRP), recognized as a biomarker for various diseases, has the potential to contribute to our understanding of systemic inflammation. Recent advancements in diagnostic algorithms have demonstrated the ability to accurately diagnose diseases by assessing CRP levels, which holds considerable significance for understanding influenza and its associated inflammatory reactions [66].

This study has the following two levels of limitations. First, this study only contains articles from core data set of the Web of Science data base, including only English publications. Additionally, the selection process may not be perfectly refined.