Pidotimod Boosts Recovery and Lowers Complications in Unvaccinated Adults with Influenza

Pidotimod Boosts Recovery and Lowers Complications in Unvaccinated Adults with Influenza | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pidotimod Boosts Recovery and Lowers Complications in Unvaccinated Adults with Influenza Claudio Ucciferri, Claudio Tana, Jacopo Vecchiet, Katia Falasca This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8263059/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Influenza A and B continue to be major global causes of morbidity and mortality. Current antiviral and vaccine strategies are limited by viral variability and the narrow window for effective treatment. Pidotimod, a synthetic immunomodulatory dipeptide, enhances both innate and adaptive immune responses; however, its efficacy in adult influenza remains underexplored. Methods We conducted a retrospective observational study in Italy involving 66 unvaccinated adults (aged 18–65) with confirmed influenza A or B who had not received antiviral therapy. Participants received either symptomatic treatment alone (control group, n = 25) or symptomatic treatment plus oral Pidotimod 800 mg twice daily for 5–10 days (treatment group, n = 41). Primary outcomes included the number and persistence of influenza symptoms at 48 hours and 5 days. Secondary outcomes were the incidence of bacterial complications and antibiotic use. Results At 48 hours, fever persisted in 39% of the Pidotimod group compared to 60% of controls (p < 0.05); at 5 days, persistence rates were 0% vs. 20%, respectively (p < 0.001). Patients receiving Pidotimod reported significantly fewer symptoms overall at bothtime points (mean symptom count at 48h: 1.53 vs. 3.70, p = 0.021; at 5 days: p = 0.001), with marked reductions in nasal congestion (p = 0.003) and sore throat (p = 0.008). Bacterial complications occurred less frequently in the treatment group (p = 0.023). No serious adverse events related to Pidotimod were observed. Conclusions In adults with influenza A or B, Pidotimod was associated with faster symptom resolution and fewer bacterial complications, supporting its potential role as an adjunct immunomodulatory therapy. These findings warrant further validation through randomized controlled trials. Orthomyxovirus outpatients Immunomodulation Symptom resolution Bacterial complications Figures Figure 1 Introduction Influenza remains a significant concern for public health, causing substantial morbidity and mortality worldwide( 1 ). Human influenza is classified into three main types: influenza A, influenza B and influenza C. Influenza A and B are the most clinical relevance in humans. While antiviral agents and vaccines are primary tools for prevention and treatment, their efficacy can be limited by viral resistance and variability in vaccine match. Influenza viruses are antigenically highly variable, which demands annual vaccine updates to maintain their effectiveness( 2 ). Annual influenza vaccination is recommended in groups with a risk of complication, such as children from 6 months to 5 years old, adults aged > 65 years old, patients with chronic diseases( 3 ). Antiviral agents, on the other hand, need to be used at the early symptoms of the illness to be effective( 4 ). However, this approach is not always possible, and this severely limits the use of these drugs in clinical practice. In symptomatic influenza infections, the innate immune response triggered is balanced but, in some individuals, the immune response to influenza virus infection can be dysregulated, with activation of proinflammatory cytokines that can cause pulmonary inflammation and acute lung injury, acute respiratory distress syndrome, sepsis, and multiorgan failure( 5 ). Consequently, adjunct therapies that modulate the immune response are of growing interest( 6 ), but studies are lacking. Pidotimod is a synthetic dipeptide molecule known to enhance both innate and adaptive immune responses. Multiple studies have highlighted its role in modulating immune function across various clinical settings by acting on both innate and adaptive immunity( 7 , 8 ). It supports the functional maturation of dendritic cells and exhibits adjuvant effects at the nasal mucosa level. Early human studies demonstrated that Pidotimod boosts bactericidal activity in alveolar macrophages and stimulates innate immune responses, particularly by enhancing natural killer (NK) cell activity( 7 , 9 , 10 ). Furthermore, Pidotimod influences dendritic cell maturation by upregulating the expression of the major histocompatibility complex class II receptor (HLA-DR), costimulatory molecules CD83 and CD86, and increasing the secretion of proinflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor (TNF)-α. These factors contribute to T cell proliferation and differentiation towards a Th1 phenotype. The primary mechanism of action for Pidotimod involves activation of Toll-like receptors (TLRs), which trigger the innate immune response. Recent research also indicates that Pidotimod can activate the G protein-coupled chemokine receptor CXCR3 by binding to guanosine triphosphate-binding proteins, orchestrating T cell responses in inflamed tissues through a complex, multifaceted mechanism ( 11 ). Recent reviews on Pidotimod have stated that it shows an optimal safety profile ( 12 , 13 ). Its efficacy in reducing the frequency of recurrent respiratory infections, especially in children, is well-documented ( 14 ). Pidotimod has been shown to modulate the effects of the cytokine cascade in COVID-19 ( 15 – 18 ). However, its potential benefits in acute viral infections like influenza in adults have not been thoroughly investigated ( 19 , 20 ). This study aims to evaluate the effectiveness of Pidotimod in reducing influenza symptoms and its complications in adults. Methods Study Design and Participants A retrospective observational study was conducted in Italy with a collaboration of general practitioner in Chieti and L’Aquila province between 31of January and 14 February 2025. Inclusion criteria adults aged between 18 years and 65 years with confirmed influenza (type A or B), no influenzas’ vaccination, data available at baseline at 48h and at 5 days. Patients were excluded if they had incomplete medical records or pregnant or use antiviral therapy for influenza virus. Intervention Intervention Patients were divided into two groups: Control Group : received any symptomatic treatment but did not receive Pidotimod Treatment Group : received any symptomatic treatment and Received Pidotimod 800 mg orally twice daily for 5–10 days. The decision to administer Pidotimod was based on physician discretion. Data Collection Data were extracted from electronic medical records, including demographics, comorbidities, symptom onset and duration, and treatment details. The primary outcome was the number of persistent symptoms (fever, cough, sore throat, headache, nasal congestion, anosmia, and dysgeusia) two- and five-days post-symptom onset. A secondary outcome are effects on compliance defined such as bacterial infection or starting antibiotic therapy or hospitalization. The study was conducted in accordance with the Declaration of Helsinki and approved by the Internal Institutional Review Board. Informed consent was obtained from all subjects involved in the study. Statistical Analysis Data are expressed as mean and standard deviation (SD) for continuous variables and were compared using Student's t-test or analysis of variance, as appropriate, based on pre- and post-intervention or based on different types of alerts. Similarly, categorical variables are expressed as number and percentage and were analyzed using χ2 and Fisher's exact tests, as appropriate. In addition, the time to implementation of effective and appropriate therapy was compared between the pre-intervention and post-intervention phases using Kaplan-Meier survival analysis with a log-rank test. A two-way ANOVA with post hoc tests was used to investigate the main effects and interaction effects of the intervention. All P values were two-sided, and P values less than 0.05 were considered statistically significant. SPSS Statistics version 28.0 was used for all statistical calculations. Results A total of 66 patients with confirmed influenza infection were included in the study, among them 41 patients (62.1%) received treatment with Pidotimod, while 25 (37.9%) did not. Influenza A was detected in 56.1% of cases, while 43.9% had Influenza B. The cohort included 53.0% females and 47.0% males, with a mean age of 44.4 +/- 13.8years (range 18–65). The prevalence of one or plus comorbidities was 56.1%. The use of medication for other chronic conditions was detected in 45.5% of patients.At the enrolment, the most common symptoms were fever (86.4%), asthenia (71.2%), arthralgia/myalgia (72.7%), cough (60.6%), and pharyngodynia (57.6%), with anosmia (13.6%) and dysgeusia (18.2%) less frequent. On day 5, a general reduction in symptom prevalence was observed, but asthenia (42.4%) and cough (42.4%) remained the most persistent complaints. Throughout the course of the illness, the frequency of fever decreased markedly in patients treated with pidotimod. At 48 hours, fever was present in only 39.0% of the pidotimod group compared to 60.0% in the untreated group (p < 0.05). By day 5 of follow-up, fever persisted in 0% of Pidotimod-treated patients compared to 20.0% in the control group (p = 0.001), indicating a significantly faster resolution of febrile episodes (Fig. 1 ). This reduction was associated with fewer febrile days and a decreased need for antipyretic medications in the treatment group. ANOVA analysis further showed that pidotimod treatment was associated with a significant reduction in the overall number of symptoms at 48 hours (mean 1.53 vs. 3.70 p = 0.021) and at 5 days (p = 0.001), as well as a significant decrease in nasal congestion (p = 0.003) and pharyngodynia (p = 0.008) at 5 days. Additionally, bacterial complications and antibiotic use occurred less frequently in the pidotimod group (p = 0.023). Hospitalization was rare, with only one case reported, occurring in a patient not receiving Pidotimod. No significant differences were found for other individual symptoms. Discussion Pidotimod demonstrated clinically meaningful effects in adult patients with influenza, may promote a faster resolution of influenza-related symptoms in adults, highlighting its potential as an adjunctive immunomodulator therapy. Treated subjects exhibited a faster resolution of upper respiratory symptoms, including fever, nasal congestion and pharyngodynia, by day 5 and reported fewer persisting symptoms overall at 2 and 5 days. Additionally, a reduced incidence of bacterial complications was noted among recipients, suggesting enhanced immune resilience against secondary infections. These clinical improvements reflect Pidotimod's well-characterized immunomodulatory profile, which includes enhancement of both innate and adaptive immune responses( 9 , 21 ). Pidotimod induces the maturation of dendritic cells by upregulating the expression of costimulatory molecules (CD80, CD83, CD86) and enhancing antigen presentation through increased HLA-DR expression( 22 ). It also promotes the expression of Toll-like receptor 2 (TLR2) and activates downstream NF-κB signaling, resulting in elevated production of pro-inflammatory cytokines such as IL-12, IFN-γ, and TNF-α. These actions collectively drive a Th1-skewed immune response, supporting rapid viral clearance and robust mucosal defense( 7 , 11 ). Influenza activates cellular immunity, and in some individuals, the dysregulated immune response to infection triggers a cascade of proinflammatory cytokines that can cause lung inflammation and acute lung injury. Influenza virus infection can also activate host type 1 interferon-related pathways early in the clinical course of severe influenza. Indeed, proinflammatory cytokines are higher in the lower respiratory tract of patients with severe influenza than in those with moderate disease( 23 , 24 ). These findings are consistent with Pidotimod’s established mechanism of action and its previously documented benefits in other respiratory infections. We observed that patients treated with Pidotimod had a significantly lower total burden of symptoms at day 2 and 5, with reductions in total number of symptoms, nasal congestion ( p = 0.003) and pharyngodynia ( p = 0.008). This mirrors earlier pediatric and adult studies, which also reported accelerated symptom resolution and reduced complication rates( 25 , 26 ). For instance, in pediatric trials of recurrent respiratory tract infections, Pidotimod shortened fever duration and reduced the need for hospitalization and antibiotic therapy, with children in the treatment arm exhibiting faster clearance of pharyngalgia and mucosal inflammation compared to controls( 13 , 14 , 27 , 28 ). Our findings also indicate a reduced significative persistent fever at day2 and 5, indicating a significantly faster resolution of febrile episodes associated with pidotimod, aligning with literature documenting a faster reduction in febrile symptoms with Pidotimod treatment in children. These converging clinical observations support the hypothesis that Pidotimod expedites acute symptom resolution in viral respiratory infections. Notably, recent clinical studies by Ucciferri et al. have extended these findings to acute viral infections such as COVID-19( 15 – 17 ). In hospitalized patients with SARS-CoV-2 infection, early treatment with Pidotimod was associated with reduced systemic inflammation (lower CRP and IL-6 levels), improved lymphocyte profiles, shorter hospital stays, and better clinical outcomes( 29 ). These results support the concept that Pidotimod enhances immune competence in the early phases of viral infections, possibly limiting disease progression( 15 , 29 ). The present study similarly observed a lower rate of bacterial complications and a reduced need for antibiotic therapy in the Pidotimod group, reinforcing the idea that it supports mucosal immunity and reduces the risk of superinfection. These findings are clinically relevant, as bacterial superinfection remains a key contributor to morbidity and mortality in seasonal influenza. The significantly reduced rate of bacterial complications ( p = 0.023) supports Pidotimod’s role in protecting against secondary infections. Historically, similar benefits have been reported, with Pidotimod reducing antibiotic use by nearly half and preventing relapses in pediatric populations( 6 ). Importantly, the benefits of Pidotimod were consistent across both influenza A and B infections, suggesting a broad, virus-independent mechanism of action centered on host immune modulation rather than direct antiviral activity. The immunological basis for these observations may involve increased neutrophil phagocytic activity and enhanced cytotoxicity of NK cells, as demonstrated in prior in vitro studies and animal models( 8 ). HIV and pediatric studies reveal increased secretory IgA levels in the nasopharyngeal mucosa, suggesting strengthened local immune defenses an important mechanism potentially operative in our adult influenza cohort( 10 , 30 , 31 ). Large pediatric randomized controlled trials have consistently demonstrated Pidotimod’s efficacy in preventing recurrent respiratory infections( 19 , 32 ). In pediatric patients, Pidotimod has been demonstrated to reduce the frequency of recurrent respiratory infections as well as decrease healthcare use, including hospitalizations and antibiotic treatments.( 12 ). This study contributes novel data supporting the translation of these effects to adults with acute viral respiratory infections, such as influenza, a population in which formal evidence has so far been limited. These data parallel our findings, reinforcing the consistency of Pidotimod’s immunomodulatory and anti-infective effects across age groups and respiratory disease spectra. A major strength is the explicit clinical correlation between Pidotimod treatment and symptom resolution, supplemented by robust statistical analysis. This study advances the field by providing evidence in adults infected with influenza, whereas most prior trials focused on pediatric populations or other respiratory pathologies. The ability of Pidotimod to hasten symptom resolution and reduce bacterial complications is especially valuable in influenza management, where secondary bacterial pneumonia remains a significant risk. By modulating innate and adaptive immunity without significant adverse effects, Pidotimod emerges as a potential adjunct to standard care, helping reduce healthcare utilization and antibiotic use. Given global concerns about antimicrobial resistance, scalable immunomodulatory strategies like Pidotimod warrant attention. Its favorable safety profile, confirmed in both pediatric and adult trials supports broad consideration. Nonetheless, limitations include the retrospective observational design, modest sample size, and absence of direct immunological markers (e.g., cytokine assays, Ig levels) in our cohort. Future randomized, controlled trials in adults, incorporating biomarker assessments, are essential to confirm causality and delineate mechanisms. Conclusion Preliminary data suggest that Pidotimod is useful in influenza infection by may reduce the duration and severity of influenza symptoms in adults. These findings warrant further investigation through randomized controlled trials to establish the efficacy and safety of Pidotimod as an adjunct therapy in influenza management. Declarations Acknowledgments : We thank general practitioner colleagues (Augusto Carducci, Gianluca Costante, Berardo D’Alò, Maria Cristina Fedele, Simone Giancristofaro, Luca Paoloni, Mariella Primante, Luigi Totani) thanks to their collaboration, made the study possible. Author Contributions Conceptualization, C.U.; Methodology, K.F.; Software, K.F.; Validation C.U. and J.V.; Formal analysis, K.F. and C.U..; Investigation,C.U..; Writing—original draft preparation, C.U., C.T.. and K.F.; Writing—review and editing, C.U., C.T. and J.V. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Institutional Review Board Statement and Consent to Participate The study was conducted in accordance with the Declaration of Helsinki. The study was approved by the internal institutional review board at the University “G. d’Annunzio” Chieti-Pescara. Informed consent was obtained from all subjects involved in the study . Consent to Publish declaration: is not applicable. Data Availability Statement The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Conflicts of Interest The authors declare no conflict of interest. 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Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression. Ital J Pediatr. 2013;39:29. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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06:21:29","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71398,"visible":true,"origin":"","legend":"","description":"","filename":"dabd2439749e4a6c929997187a0651481structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8263059/v1/1ab4cee7301c221a2a7da779.xml"},{"id":100013744,"identity":"fe9fa3e3-f1c8-4ca8-ad94-531c6a67a573","added_by":"auto","created_at":"2026-01-12 06:21:29","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80174,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8263059/v1/6247c234196537f2c1e78037.html"},{"id":100013735,"identity":"76294bea-01dc-4905-af1b-d97c4ea1c64e","added_by":"auto","created_at":"2026-01-12 06:21:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73081,"visible":true,"origin":"","legend":"\u003cp\u003eFever in the pidotimod and control group\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8263059/v1/e052f25320f9ee4a20bbd10f.png"},{"id":102529759,"identity":"8cea20c6-0552-4039-8678-568e89b9d2c1","added_by":"auto","created_at":"2026-02-12 16:11:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":528045,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8263059/v1/4c7b5a96-e403-4fa1-a3d7-7ca0190d608c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pidotimod Boosts Recovery and Lowers Complications in Unvaccinated Adults with Influenza","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInfluenza remains a significant concern for public health, causing substantial morbidity and mortality worldwide(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Human influenza is classified into three main types: influenza A, influenza B and influenza C. Influenza A and B are the most clinical relevance in humans. While antiviral agents and vaccines are primary tools for prevention and treatment, their efficacy can be limited by viral resistance and variability in vaccine match.\u003c/p\u003e \u003cp\u003eInfluenza viruses are antigenically highly variable, which demands annual vaccine updates to maintain their effectiveness(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Annual influenza vaccination is recommended in groups with a risk of complication, such as children from 6 months to 5 years old, adults aged\u0026thinsp;\u0026gt;\u0026thinsp;65 years old, patients with chronic diseases(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAntiviral agents, on the other hand, need to be used at the early symptoms of the illness to be effective(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). However, this approach is not always possible, and this severely limits the use of these drugs in clinical practice. In symptomatic influenza infections, the innate immune response triggered is balanced but, in some individuals, the immune response to influenza virus infection can be dysregulated, with activation of proinflammatory cytokines that can cause pulmonary inflammation and acute lung injury, acute respiratory distress syndrome, sepsis, and multiorgan failure(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Consequently, adjunct therapies that modulate the immune response are of growing interest(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), but studies are lacking.\u003c/p\u003e \u003cp\u003ePidotimod is a synthetic dipeptide molecule known to enhance both innate and adaptive immune responses. Multiple studies have highlighted its role in modulating immune function across various clinical settings by acting on both innate and adaptive immunity(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). It supports the functional maturation of dendritic cells and exhibits adjuvant effects at the nasal mucosa level. Early human studies demonstrated that Pidotimod boosts bactericidal activity in alveolar macrophages and stimulates innate immune responses, particularly by enhancing natural killer (NK) cell activity(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Furthermore, Pidotimod influences dendritic cell maturation by upregulating the expression of the major histocompatibility complex class II receptor (HLA-DR), costimulatory molecules CD83 and CD86, and increasing the secretion of proinflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor (TNF)-α. These factors contribute to T cell proliferation and differentiation towards a Th1 phenotype. The primary mechanism of action for Pidotimod involves activation of Toll-like receptors (TLRs), which trigger the innate immune response. Recent research also indicates that Pidotimod can activate the G protein-coupled chemokine receptor CXCR3 by binding to guanosine triphosphate-binding proteins, orchestrating T cell responses in inflamed tissues through a complex, multifaceted mechanism (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRecent reviews on Pidotimod have stated that it shows an optimal safety profile (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIts efficacy in reducing the frequency of recurrent respiratory infections, especially in children, is well-documented (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Pidotimod has been shown to modulate the effects of the cytokine cascade in COVID-19 (\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). However, its potential benefits in acute viral infections like influenza in adults have not been thoroughly investigated (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study aims to evaluate the effectiveness of Pidotimod in reducing influenza symptoms and its complications in adults.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eA retrospective observational study was conducted in Italy with a collaboration of general practitioner in Chieti and L\u0026rsquo;Aquila province between 31of January and 14 February 2025. Inclusion criteria adults aged between 18 years and 65 years with confirmed influenza (type A or B), no influenzas\u0026rsquo; vaccination, data available at baseline at 48h and at 5 days.\u003c/p\u003e \u003cp\u003ePatients were excluded if they had incomplete medical records or pregnant or use antiviral therapy for influenza virus.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eIntervention\u003c/div\u003e \u003cp\u003ePatients were divided into two groups:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eControl Group\u003c/b\u003e: received any symptomatic treatment but did not receive Pidotimod\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eTreatment Group\u003c/b\u003e: received any symptomatic treatment and Received Pidotimod 800 mg orally twice daily for 5\u0026ndash;10 days.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe decision to administer Pidotimod was based on physician discretion.\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eData were extracted from electronic medical records, including demographics, comorbidities, symptom onset and duration, and treatment details. The primary outcome was the number of persistent symptoms (fever, cough, sore throat, headache, nasal congestion, anosmia, and dysgeusia) two- and five-days post-symptom onset. A secondary outcome are effects on compliance defined such as bacterial infection or starting antibiotic therapy or hospitalization.\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki and approved by the Internal Institutional Review Board. Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData are expressed as mean and standard deviation (SD) for continuous variables and were compared using Student's t-test or analysis of variance, as appropriate, based on pre- and post-intervention or based on different types of alerts. Similarly, categorical variables are expressed as number and percentage and were analyzed using χ2 and Fisher's exact tests, as appropriate.\u003c/p\u003e \u003cp\u003eIn addition, the time to implementation of effective and appropriate therapy was compared between the pre-intervention and post-intervention phases using Kaplan-Meier survival analysis with a log-rank test.\u003c/p\u003e \u003cp\u003eA two-way ANOVA with post hoc tests was used to investigate the main effects and interaction effects of the intervention.\u003c/p\u003e \u003cp\u003eAll P values were two-sided, and P values less than 0.05 were considered statistically significant.\u003c/p\u003e \u003cp\u003eSPSS Statistics version 28.0 was used for all statistical calculations.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 66 patients with confirmed influenza infection were included in the study, among them 41 patients (62.1%) received treatment with Pidotimod, while 25 (37.9%) did not. Influenza A was detected in 56.1% of cases, while 43.9% had Influenza B. The cohort included 53.0% females and 47.0% males, with a mean age of 44.4 +/- 13.8years (range 18\u0026ndash;65). The prevalence of one or plus comorbidities was 56.1%. The use of medication for other chronic conditions was detected in 45.5% of patients.At the enrolment, the most common symptoms were fever (86.4%), asthenia (71.2%), arthralgia/myalgia (72.7%), cough (60.6%), and pharyngodynia (57.6%), with anosmia (13.6%) and dysgeusia (18.2%) less frequent. On day 5, a general reduction in symptom prevalence was observed, but asthenia (42.4%) and cough (42.4%) remained the most persistent complaints.\u003c/p\u003e \u003cp\u003eThroughout the course of the illness, the frequency of fever decreased markedly in patients treated with pidotimod. At 48 hours, fever was present in only 39.0% of the pidotimod group compared to 60.0% in the untreated group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). By day 5 of follow-up, fever persisted in 0% of Pidotimod-treated patients compared to 20.0% in the control group (p\u0026thinsp;=\u0026thinsp;0.001), indicating a significantly faster resolution of febrile episodes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This reduction was associated with fewer febrile days and a decreased need for antipyretic medications in the treatment group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eANOVA analysis further showed that pidotimod treatment was associated with a significant reduction in the overall number of symptoms at 48 hours (mean 1.53 vs. 3.70 p\u0026thinsp;=\u0026thinsp;0.021) and at 5 days (p\u0026thinsp;=\u0026thinsp;0.001), as well as a significant decrease in nasal congestion (p\u0026thinsp;=\u0026thinsp;0.003) and pharyngodynia (p\u0026thinsp;=\u0026thinsp;0.008) at 5 days. Additionally, bacterial complications and antibiotic use occurred less frequently in the pidotimod group (p\u0026thinsp;=\u0026thinsp;0.023). Hospitalization was rare, with only one case reported, occurring in a patient not receiving Pidotimod. No significant differences were found for other individual symptoms.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePidotimod demonstrated clinically meaningful effects in adult patients with influenza, may promote a faster resolution of influenza-related symptoms in adults, highlighting its potential as an adjunctive immunomodulator therapy. Treated subjects exhibited a faster resolution of upper respiratory symptoms, including fever, nasal congestion and pharyngodynia, by day 5 and reported fewer persisting symptoms overall at 2 and 5 days. Additionally, a reduced incidence of bacterial complications was noted among recipients, suggesting enhanced immune resilience against secondary infections. These clinical improvements reflect Pidotimod's well-characterized immunomodulatory profile, which includes enhancement of both innate and adaptive immune responses(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Pidotimod induces the maturation of dendritic cells by upregulating the expression of costimulatory molecules (CD80, CD83, CD86) and enhancing antigen presentation through increased HLA-DR expression(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). It also promotes the expression of Toll-like receptor 2 (TLR2) and activates downstream NF-κB signaling, resulting in elevated production of pro-inflammatory cytokines such as IL-12, IFN-γ, and TNF-α. These actions collectively drive a Th1-skewed immune response, supporting rapid viral clearance and robust mucosal defense(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Influenza activates cellular immunity, and in some individuals, the dysregulated immune response to infection triggers a cascade of proinflammatory cytokines that can cause lung inflammation and acute lung injury. Influenza virus infection can also activate host type 1 interferon-related pathways early in the clinical course of severe influenza. Indeed, proinflammatory cytokines are higher in the lower respiratory tract of patients with severe influenza than in those with moderate disease(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThese findings are consistent with Pidotimod\u0026rsquo;s established mechanism of action and its previously documented benefits in other respiratory infections. We observed that patients treated with Pidotimod had a significantly lower total burden of symptoms at day 2 and 5, with reductions in total number of symptoms, nasal congestion (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) and pharyngodynia (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008). This mirrors earlier pediatric and adult studies, which also reported accelerated symptom resolution and reduced complication rates(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). For instance, in pediatric trials of recurrent respiratory tract infections, Pidotimod shortened fever duration and reduced the need for hospitalization and antibiotic therapy, with children in the treatment arm exhibiting faster clearance of pharyngalgia and mucosal inflammation compared to controls(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur findings also indicate a reduced significative persistent fever at day2 and 5, indicating a significantly faster resolution of febrile episodes associated with pidotimod, aligning with literature documenting a faster reduction in febrile symptoms with Pidotimod treatment in children. These converging clinical observations support the hypothesis that Pidotimod expedites acute symptom resolution in viral respiratory infections. Notably, recent clinical studies by Ucciferri et al. have extended these findings to acute viral infections such as COVID-19(\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In hospitalized patients with SARS-CoV-2 infection, early treatment with Pidotimod was associated with reduced systemic inflammation (lower CRP and IL-6 levels), improved lymphocyte profiles, shorter hospital stays, and better clinical outcomes(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). These results support the concept that Pidotimod enhances immune competence in the early phases of viral infections, possibly limiting disease progression(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). The present study similarly observed a lower rate of bacterial complications and a reduced need for antibiotic therapy in the Pidotimod group, reinforcing the idea that it supports mucosal immunity and reduces the risk of superinfection. These findings are clinically relevant, as bacterial superinfection remains a key contributor to morbidity and mortality in seasonal influenza.\u003c/p\u003e \u003cp\u003eThe significantly reduced rate of bacterial complications (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) supports Pidotimod\u0026rsquo;s role in protecting against secondary infections. Historically, similar benefits have been reported, with Pidotimod reducing antibiotic use by nearly half and preventing relapses in pediatric populations(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Importantly, the benefits of Pidotimod were consistent across both influenza A and B infections, suggesting a broad, virus-independent mechanism of action centered on host immune modulation rather than direct antiviral activity. The immunological basis for these observations may involve increased neutrophil phagocytic activity and enhanced cytotoxicity of NK cells, as demonstrated in prior in vitro studies and animal models(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). HIV and pediatric studies reveal increased secretory IgA levels in the nasopharyngeal mucosa, suggesting strengthened local immune defenses an important mechanism potentially operative in our adult influenza cohort(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Large pediatric randomized controlled trials have consistently demonstrated Pidotimod\u0026rsquo;s efficacy in preventing recurrent respiratory infections(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). In pediatric patients, Pidotimod has been demonstrated to reduce the frequency of recurrent respiratory infections as well as decrease healthcare use, including hospitalizations and antibiotic treatments.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This study contributes novel data supporting the translation of these effects to adults with acute viral respiratory infections, such as influenza, a population in which formal evidence has so far been limited.\u003c/p\u003e \u003cp\u003eThese data parallel our findings, reinforcing the consistency of Pidotimod\u0026rsquo;s immunomodulatory and anti-infective effects across age groups and respiratory disease spectra.\u003c/p\u003e \u003cp\u003eA major strength is the explicit clinical correlation between Pidotimod treatment and symptom resolution, supplemented by robust statistical analysis. This study advances the field by providing evidence in adults infected with influenza, whereas most prior trials focused on pediatric populations or other respiratory pathologies. The ability of Pidotimod to hasten symptom resolution and reduce bacterial complications is especially valuable in influenza management, where secondary bacterial pneumonia remains a significant risk. By modulating innate and adaptive immunity without significant adverse effects, Pidotimod emerges as a potential adjunct to standard care, helping reduce healthcare utilization and antibiotic use.\u003c/p\u003e \u003cp\u003eGiven global concerns about antimicrobial resistance, scalable immunomodulatory strategies like Pidotimod warrant attention. Its favorable safety profile, confirmed in both pediatric and adult trials supports broad consideration.\u003c/p\u003e \u003cp\u003eNonetheless, limitations include the retrospective observational design, modest sample size, and absence of direct immunological markers (e.g., cytokine assays, Ig levels) in our cohort. Future randomized, controlled trials in adults, incorporating biomarker assessments, are essential to confirm causality and delineate mechanisms.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePreliminary data suggest that Pidotimod is useful in influenza infection by may reduce the duration and severity of influenza symptoms in adults. These findings warrant further investigation through randomized controlled trials to establish the efficacy and safety of Pidotimod as an adjunct therapy in influenza management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e: We thank general practitioner colleagues (Augusto Carducci, Gianluca Costante, Berardo D’Alò, Maria Cristina Fedele, Simone Giancristofaro, Luca Paoloni, Mariella Primante, Luigi Totani) thanks to their collaboration, made the study possible.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, C.U.; Methodology, K.F.; Software, K.F.; Validation C.U. and J.V.; Formal analysis, K.F. and C.U..; Investigation,C.U..; Writing—original draft preparation, C.U., C.T.. and K.F.; Writing—review and editing, C.U., C.T. and J.V.\u003c/p\u003e\n\u003cp\u003eAll authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki. The study was approved by the internal institutional review board at the University “G. d’Annunzio” Chieti-Pescara.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all subjects involved in the study\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish declaration:\u0026nbsp;\u003c/strong\u003eis not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEbell MH, Rahmatullah I, Hulme C, Buhr M, Kotnik JH, Geyer R, et al. 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Molnupiravir as an Early Treatment for COVID-19: A Real Life Study. Pathogens. 2022;11(10).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUcciferri C, Barone M, Vecchiet J, Falasca K. Pidotimod in Paucisymptomatic SARS-CoV2 Infected Patients. Mediterr J Hematol Infect Dis. 2020;12(1):e2020048.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePradyut Waghray GJ, Purva Thatai. Vamsi Krishna Kolukula. Efficacy and Safety of Pidotimod in SARS-CoV-2 Management: A Real-world Evidence Study. Int J Clin Skills. 2021;15(9):510\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X, Li Q, Wang X, Lu M, Shen J, Meng Q. Pidotimod in the treatment of pediatric recurrent respiratory tract infection. Pak J Med Sci. 2019;35(4):981\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD'Amato M, Simioli F, Martino M, Sorrentino N, Porzio M, Stanziola AA et al. Open label case-control study to assess Pidotimod efficacy in Non CF Bronchiectasis Disease: a pilot study. Eur Respir J.50(suppl 61):PA4063.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu R, Jin C, Lin X, Chen Y, Wang Y, Guo Y. Analysis of Factors and T-Lymphocyte Subset Changes in Pediatric Recurrent Respiratory Infections Post-Pidotimod Treatment. Altern Ther Health Med. 2025;31(1):470\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerrario BE, Garuti S, Braido F, Canonica GW. Pidotimod: the state of art. Clin Mol Allergy. 2015;13(1):8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, et al. Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza. Nat Immunol. 2018;19(6):625\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReynolds D, Vazquez Guillamet C, Day A, Borcherding N, Vazquez Guillamet R, Choreno-Parra JA, et al. Comprehensive Immunologic Evaluation of Bronchoalveolar Lavage Samples from Human Patients with Moderate and Severe Seasonal Influenza and Severe COVID-19. J Immunol. 2021;207(5):1229\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWaghray PJG, Thatai P, Kolukula VK. Efficacy and Safety of Pidotimod in SARS-CoV-2 Management: A Real-world Evidence Study. Int J Clin Skills. 2021;15:510\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNamazova-Baranova LS, Alekseeva AA, Kharit SM, Kozhevnikova TN, Taranushenko TE, Tuzankina IA, et al. Efficacy and safety of pidotimod in the prevention of recurrent respiratory infections in children: a multicentre study. 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Curr HIV Res. 2021;19(3):260\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiu H, Wang R, Jia YT, Cai Y. Pidotimod, an immunostimulant in pediatric recurrent respiratory tract infections: A meta-analysis of randomized controlled trials. Int Immunopharmacol. 2019;67:35\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarta S, Silvestri M, Rossi GA. Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression. Ital J Pediatr. 2013;39:29.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Orthomyxovirus, outpatients, Immunomodulation, Symptom resolution, Bacterial complications","lastPublishedDoi":"10.21203/rs.3.rs-8263059/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8263059/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eInfluenza A and B continue to be major global causes of morbidity and mortality. Current antiviral and vaccine strategies are limited by viral variability and the narrow window for effective treatment. Pidotimod, a synthetic immunomodulatory dipeptide, enhances both innate and adaptive immune responses; however, its efficacy in adult influenza remains underexplored.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective observational study in Italy involving 66 unvaccinated adults (aged 18\u0026ndash;65) with confirmed influenza A or B who had not received antiviral therapy. Participants received either symptomatic treatment alone (control group, n\u0026thinsp;=\u0026thinsp;25) or symptomatic treatment plus oral Pidotimod 800 mg twice daily for 5\u0026ndash;10 days (treatment group, n\u0026thinsp;=\u0026thinsp;41). Primary outcomes included the number and persistence of influenza symptoms at 48 hours and 5 days. Secondary outcomes were the incidence of bacterial complications and antibiotic use.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAt 48 hours, fever persisted in 39% of the Pidotimod group compared to 60% of controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); at 5 days, persistence rates were 0% vs. 20%, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients receiving Pidotimod reported significantly fewer symptoms overall at bothtime points (mean symptom count at 48h: 1.53 vs. 3.70, p\u0026thinsp;=\u0026thinsp;0.021; at 5 days: p\u0026thinsp;=\u0026thinsp;0.001), with marked reductions in nasal congestion (p\u0026thinsp;=\u0026thinsp;0.003) and sore throat (p\u0026thinsp;=\u0026thinsp;0.008). Bacterial complications occurred less frequently in the treatment group (p\u0026thinsp;=\u0026thinsp;0.023). No serious adverse events related to Pidotimod were observed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn adults with influenza A or B, Pidotimod was associated with faster symptom resolution and fewer bacterial complications, supporting its potential role as an adjunct immunomodulatory therapy. These findings warrant further validation through randomized controlled trials.\u003c/p\u003e","manuscriptTitle":"Pidotimod Boosts Recovery and Lowers Complications in Unvaccinated Adults with Influenza","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 06:21:25","doi":"10.21203/rs.3.rs-8263059/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c908f5f0-8a68-4791-8be6-8f7ac8f537e9","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T12:09:18+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 06:21:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8263059","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8263059","identity":"rs-8263059","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}