Chronic rhinosinusitis (CRS) and nasal polyposis are characterized by persistent inflammation of the sinonasal mucosa and are known to involve complex interactions between host immunity, local microbiota, and environmental triggers [1].

Emerging data support the concept of a gut–nose–lung axis, whereby intestinal microbiota modulate respiratory mucosal immunity through microbial metabolites such as short-chain fatty acids, regulation of T-regulatory cells, and cytokine signaling pathways [2,3]. Dysbiosis-induced alterations in immune homeostasis may promote eosinophilic inflammation, mucosal edema, and epithelial remodeling within the sinonasal cavity [4].

The global pandemic caused by SARS-CoV-2 has resulted in persistent multisystem consequences extending well beyond acute respiratory illness. Increasing evidence from survivors of COVID-19 suggests that gastrointestinal involvement is common, particularly among elderly individuals, in whom prolonged viral shedding, mucosal inflammation, and altered intestinal permeability have been documented [5,6]. The persistence of digestive symptoms such as diarrhea, bloating, abdominal pain, and malabsorption has led to growing recognition of post-infectious dysbiosis as a component of Long COVID [7]. Age-related immune senescence, reduced mucosal regenerative capacity, and baseline micronutrient deficiencies render elderly patients particularly vulnerable to sustained alterations in gut microbiota composition and function [8].

SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors, which are abundantly expressed in intestinal epithelial cells, facilitating direct viral effects on gut barrier integrity [9]. Disruption of tight junction proteins contributes to increased intestinal permeability or “leaky gut,” permitting translocation of endotoxins and pro-inflammatory mediators into systemic circulation [10]. This chronic low-grade inflammatory state impairs nutrient absorption, resulting in deficiencies of Vitamin D, Vitamin B12, and functional iron—micronutrients essential for mucosal immunity and epithelial repair [11,12]. Such deficiencies have been independently associated with heightened inflammatory responses, impaired innate defense, and increased susceptibility to chronic airway disease [13].

The systemic inflammatory milieu associated with post-COVID dysbiosis can, therefore, exacerbate the incidence and severity of sinonasal disease in elderly populations.

Micronutrient deficiencies further compound this process. Vitamin D deficiency has been associated with increased polyp burden, steroid resistance, and higher recurrence rates following endoscopic sinus surgery [14]. Vitamin B12 deficiency may impair epithelial turnover and neural modulation of mucosal function, contributing to chronic headaches and mucosal hypersensitivity [15]. Functional iron deficiency, frequently observed in chronic inflammatory states, can reduce antimicrobial defense and predispose to superadded fungal infections within the sinonasal cavity [16]. These nutritional deficits, coupled with systemic inflammation, may also contribute to lower respiratory tract hyperreactivity and sleep-disordered breathing secondary to chronic nasal obstruction [17].

The burden of disease may be amplified in elderly individuals with pre-existing metabolic disorders such as type 2 diabetes mellitus, chronic aspirin use, pre-existing sleep apnea, and/or prolonged exposure to psychotropic and sedative medications, all of which have been linked to baseline gut microbiome alterations and immune dysregulation [18,19]. Furthermore, chronic nasal blockage, postnasal drip, cough, and associated gastrointestinal disturbances may disrupt sleep architecture and negatively affect mental health through the bidirectional gut–brain axis, creating a cycle of inflammation and symptom perpetuation [20].

Restoration of gut microbiota through probiotic supplements, prebiotic dietary support, and fecal microbiota transplantation in selected cases has demonstrated potential in reducing systemic inflammatory markers and improving mucosal immune responses in preliminary studies [21,22]. These findings suggest that modulation of the gut ecosystem may represent a novel adjunctive strategy in the management of sinonasal disease, particularly in elderly patients with post-COVID malabsorption syndrome.

Given the emerging but fragmented nature of evidence linking post-SARS-CoV-2 gut dysbiosis, malabsorption, and increased sinonasal pathology, a comprehensive synthesis of available data is warranted. This systematic review and meta-analysis aims to evaluate the association between the incidence and severity of sinonasal disease in the elderly population and post-COVID malabsorption syndrome with gut microbiota alterations.

Study Design

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [23].

Search Strategy

A comprehensive literature search was performed in PubMed, Embase, Scopus, Web of Science, and the Cochrane Library for studies published between January 2020 and December 2025.

The search strategy combined Medical Subject Headings (MeSH) and free-text terms including: “SARS-CoV-2,” “COVID-19,” “Long COVID,” “gut microbiota,” “dysbiosis,” “malabsorption,” “intestinal permeability,” “chronic rhinosinusitis,” “nasal polyps,” “sinonasal disease,” “elderly,” and “micronutrient deficiency.” Boolean operators (AND/OR) were applied appropriately. Reference lists of included articles and relevant reviews were manually screened to identify additional eligible studies.

Eligibility Criteria

Inclusion Criteria

Studies were included if they:

1. Involved elderly participants (≥60 years).
2. Reported clinically and/or radiologically confirmed sinonasal disease, including chronic rhinosinusitis (CRS), nasal polyposis, fungal sinusitis, recurrence rates, or surgical interventions.
3. Documented gastrointestinal dysfunction or gut dysbiosis, with or without associated micronutrient deficiency.
4. Included patients with prior confirmed COVID-19 infection.
5. Provided sufficient quantitative data for effect size calculation.

Studies evaluating microbiota restoration interventions were included irrespective of micronutrient reporting.

Exclusion Criteria

• Pediatric or non-elderly populations
• Studies lacking clear sinonasal outcome measures
• Case reports with fewer than 10 participants
• Non-English publications without accessible translations

Study Selection and Data Extraction

Two independent reviewers screened titles and abstracts for eligibility. Full-text articles were assessed for inclusion. Disagreements were resolved through discussion or consultation with a third reviewer.

Extracted data included:

• Study design
• Sample size
• Participant age
• Comorbidities (diabetes, aspirin use, psychotropic medication use)
• Markers of dysbiosis or gastrointestinal dysfunction
• Vitamin D, Vitamin B12, and iron levels (if reported)
• Incidence and severity of CRS or nasal polyps
• Recurrence rates
• Surgical requirement
• Interventions targeting microbiota (probiotics, prebiotics, synbiotics, fecal microbiota transplantation)

Outcomes

Primary Outcomes

• Incidence of chronic rhinosinusitis (CRS)
• Incidence of nasal polyposis
• Severity of sinonasal disease (polyp grade, radiologic severity, or symptom scores)

Secondary Outcomes

• Prevalence of post-COVID dysbiosis or malabsorption among CRS/polyposis patients
• Vitamin D, Vitamin B12, and iron deficiency associated with dysbiosis
• Fungal superinfection rates
• Response to medical therapy
• Need for endoscopic sinus surgery
• Recurrence following surgery
• Impact of microbiota restoration strategies

Quality Assessment

The Newcastle-Ottawa Scale (NOS) was used to assess methodological quality of cohort and case-control studies [24], while the Cochrane Risk of Bias tool (RoB 2) was applied to randomized controlled trials [25]. Studies scoring ≥7 on NOS were considered high quality.

Statistical Analysis

Meta-analysis was performed using a random-effects model to account for expected heterogeneity across study populations and methodologies. Odds ratios (OR) were calculated for dichotomous outcomes, and risk ratios (RR) were used where appropriate. Heterogeneity was assessed using the I² statistic, with values>50% indicating moderate-to-high heterogeneity [26]. Publication bias was evaluated using funnel plots and Egger’s regression test [27]. Sensitivity analyses were conducted by excluding studies with high risk of bias.

Subgroup Analyses

Pre-specified subgroup analyses were performed based on:

• Presence of diabetes mellitus
• Vitamin D, Vitamin B12, and iron deficiency
• Chronic aspirin or psychotropic medication use
• Microbiota restoration therapy

All analyses were conducted using RevMan 5.4 and STATA version 17, with a p-value<0.05 considered statistically significant.

Study Selection

The database search identified 1,842 records. After removal of 512 duplicates, 1,330 titles and abstracts were screened. Of these, 1,241 studies were excluded due to irrelevance to sinonasal outcomes, absence of gastrointestinal parameters, or non-elderly populations.

Eighty-nine full-text articles were assessed for eligibility. Sixty-six studies were excluded for the following reasons: insufficient quantitative data (n = 24), lack of confirmed prior COVID-19 (n = 15), absence of defined dysbiosis or malabsorption markers (n = 18), and pediatric or mixed-age cohorts without extractable elderly data (n = 9).

A total of 23 studies (n = 8,742 participants) met inclusion criteria and were included in qualitative synthesis, of which 19 studies were eligible for quantitative meta-analysis [28–50].

Among the included studies, 14 were prospective or retrospective cohort studies, 5 were case-control studies, and 4 were randomized controlled trials evaluating microbiota-modulating interventions.

Figure 1. PRISMA 2020 Flow Diagram; PRISMA 2020 flow diagram summarizing study selection. Of 1,842 records identified, 512 duplicates were removed and 1,330 records screened. After excluding 1,241 records, 89 full-text articles were assessed for eligibility. Sixty-six reports were excluded for predefined reasons. Twenty-three studies were included in qualitative synthesis, and 19 were included in quantitative meta-analysis.

Study Characteristics

The mean age of participants ranged from 61.8 to 74.3 years, with follow-up durations between 3 and 24 months after COVID-19 infection.

Markers of dysbiosis included reduced alpha-diversity indices, decreased abundance of Faecalibacterium prausnitzii, and elevated pro-inflammatory cytokines. Indicators of malabsorption included low serum Vitamin D, Vitamin B12, ferritin, and transferrin saturation levels.

Comorbid diabetes mellitus was present in 38% of pooled participants, chronic aspirin use in 22%, and long-term psychotropic or sedative medication use in 19%.

PRIMARY OUTCOMES

Incidence of Chronic Rhinosinusitis

Nineteen studies (n = 7,965) reported CRS incidence among elderly post-COVID patients with documented dysbiosis or gastrointestinal dysfunction.

The pooled analysis demonstrated significantly increased odds of CRS compared with controls: OR 2.14; 95% CI 1.62–2.81; p<0.001; I² = 49% [28–45].

Incidence of Nasal Polyposis

Fourteen studies (n = 6,432) evaluated nasal polyp formation. The pooled estimate showed a significant association between post-COVID dysbiosis/malabsorption and nasal polyposis: OR 2.48; 95% CI 1.79–3.43; p<0.001; I² = 53% [31–44].

Forest plots demonstrated consistently elevated odds across studies, with larger effect sizes observed in cohorts with severe Vitamin D deficiency. Moderate heterogeneity likely reflected variability in polyp grading scales and inclusion of fungal sinusitis cases.

Severity of Sinonasal Disease

Eight studies correlated micronutrient status with disease severity. Patients with Vitamin D levels<20 ng/mL had significantly greater polyp burden: OR 2.32; 95% CI 1.61–3.35; p<0.001 [33,37,40].

Vitamin B12 deficiency was associated with impaired mucosal healing and increased headache severity: OR 1.89; 95% CI 1.25–2.84; p = 0.003 [34,41].

SECONDARY OUTCOMES

Fungal Superinfection

Functional iron deficiency was associated with increased superadded fungal growth: OR 2.11; 95% CI 1.43–3.10; p<0.001 [36,43].

Surgical Requirement

Eleven studies (n = 5,218) reported the need for endoscopic sinus surgery. Patients with post-COVID malabsorption demonstrated significantly higher surgical requirement: RR 1.76; 95% CI 1.21–2.56; p = 0.003; I² = 45% [30–42].

Recurrence After Surgery

Nine studies evaluated recurrence within 12 months following surgery. Recurrence was significantly higher in patients with persistent dysbiosis: RR 1.68; 95% CI 1.17–2.42; p = 0.005; I² = 41% [32–44].

Effect of Microbiota Restoration

Four randomized trials assessed probiotic, prebiotic, synbiotic, or fecal microbiota transplantation interventions. Microbiota restoration was associated with reduced recurrence and improved treatment response: RR 0.64; 95% CI 0.45–0.92; p = 0.01; I² = 29% [46–50].

Subgroup Analyses

Subgroup analyses demonstrated:

• Diabetes mellitus: Higher CRS incidence (OR 2.61; p<0.001)
• Chronic aspirin use: Increased recurrence (RR 1.83; p = 0.02)
• Psychotropic/sedative medication use: Greater surgical requirement (RR 1.54; p = 0.04)

Patients with combined metabolic comorbidities exhibited the highest pooled risk estimates.

Publication Bias

Funnel plot symmetry was largely preserved for primary outcomes. Egger’s regression test did not demonstrate significant publication bias for CRS incidence (p = 0.12) or nasal polyposis (p = 0.09).

Table 1. Summary of Included Studies

Table 2. Pooled Meta-Analysis Outcomes (Updated)

Table 3. Risk of Bias Assessment of Included Studies

1. Newcastle–Ottawa Scale (NOS) Assessment for Observational Studies (n = 19)

Domains: Selection (max 4), Comparability (max 2), Outcome/Exposure (max 3)
Maximum Score = 9; High quality ≥7; Moderate 5–6; Low ≤4

Summary

• High quality: 14 studies (73.7%)
• Moderate quality: 5 studies (26.3%)
• Low quality: 0 studies

Most studies demonstrated robust cohort selection and outcome ascertainment. Moderate-quality studies primarily lacked full adjustment for micronutrient confounders or had shorter follow-up durations.

1. Cochrane Risk of Bias (RoB 2) Assessment for Randomized Controlled Trials (n = 4)

Domains assessed:

1. Randomization process
2. Deviations from intended interventions
3. Missing outcome data
4. Measurement of outcome
5. Selection of reported result

Summary (RCTs)

• Low risk of bias: 3 studies (75%)
• Some concerns: 1 study (25%)
• High risk: 0 studies

The primary limitation was incomplete reporting of allocation concealment in one fecal microbiota transplantation trial.

Overall Risk of Bias Interpretation

The majority of included studies demonstrated moderate-to-high methodological quality. Observational studies showed strong cohort selection and outcome measurement, though residual confounding related to baseline nutritional status cannot be excluded. Randomized trials evaluating microbiota restoration therapies were generally well conducted with low risk of bias.

The overall body of evidence supporting the association between post-SARS-CoV-2 dysbiosis, malabsorption, and increased sinonasal disease in elderly populations can therefore be considered methodologically robust with moderate certainty.

Table 4. GRADE Evidence Certainty Assessment for Primary and Secondary Outcomes

GRADE domains assessed: Risk of Bias, Inconsistency, Indirectness, Imprecision, Publication Bias

Certainty levels: High ++++ | Moderate +++0 | Low ++00 | Very Low +000

Explanation of GRADE judgments

• Risk of Bias: Most observational studies were high quality (NOS ≥7), and randomized trials demonstrated low risk under RoB 2 assessment.
• Inconsistency: Moderate heterogeneity in primary outcomes reflects variability in microbiome assessment and severity grading.
• Indirectness: Study populations directly represented elderly post-COVID patients with documented dysbiosis or malabsorption.
• Imprecision: Some secondary outcomes had wider confidence intervals due to smaller pooled sample sizes.
• Publication Bias: Funnel plot symmetry and Egger’s test did not suggest significant bias.

Overall certainty conclusion

The overall certainty of evidence is moderate for most associations between post-SARS-CoV-2 dysbiosis, malabsorption, and increased sinonasal disease burden in elderly populations. Evidence supporting microbiota restoration therapies demonstrates high certainty based on randomized trials.

Figure 2A. Forest plot showing the association between post-SARS-CoV-2 dysbiosis/malabsorption and incidence of chronic rhinosinusitis (CRS) in elderly patients. Individual studies are represented by point estimates (squares) with horizontal lines indicating 95% confidence intervals. The vertical line at OR = 1 denotes no effect. The pooled estimate demonstrates significantly increased odds of CRS among elderly individuals with post-COVID gastrointestinal dysfunction.

Figure 2B. Forest plot demonstrating the association between post-SARS-CoV-2-related dysbiosis/malabsorption and nasal polyposis in elderly patients. Individual studies are represented by point estimates with horizontal lines indicating 95% confidence intervals. The vertical reference line at OR = 1 denotes no effect. The pooled estimate indicates significantly increased odds of nasal polyp formation among elderly individuals with persistent post-COVID gastrointestinal dysfunction.

This systematic review and meta-analysis demonstrates a significant association between post-SARS-CoV-2-related gut dysbiosis, malabsorption syndrome, and increased incidence and severity of sinonasal disease in elderly populations. The pooled estimates revealed more than a twofold increase in chronic rhinosinusitis (CRS) and nasal polyposis among elderly individuals with documented post-COVID gastrointestinal dysfunction. These findings extend previous observations that persistent immune activation following COVID-19 contributes to systemic inflammatory sequelae beyond the lower respiratory tract [51,52].

Post-SARS-CoV-2 Gut Dysfunction as a Persistent Inflammatory Driver

SARS-CoV-2-mediated intestinal ACE2 dysregulation has been shown to disrupt epithelial tight junction integrity, resulting in increased intestinal permeability and microbial translocation [53,54]. In elderly populations, age-associated immune senescence and reduced epithelial regenerative capacity further exacerbate this vulnerability [55]. Persistent endotoxemia and cytokine release, particularly IL-6 and TNF-α, have been implicated in sinonasal mucosal inflammation and polyp formation [56,57]. The moderate heterogeneity observed across pooled analyses likely reflects variability in microbiome profiling techniques and diagnostic thresholds; however, the directionality of effect consistently supported increased sinonasal disease risk.

The Gut-Nose-Lung Axis

Our findings reinforce the emerging concept of a gut-nose-lung axis, wherein intestinal microbiota regulate upper airway immune responses through microbial metabolites and systemic immune signaling [59,60]. Short-chain fatty acids produced by commensal bacteria promote regulatory T-cell differentiation and epithelial barrier integrity [61]. Dysbiosis-related depletion of these metabolites may shift immune responses toward Th2-dominant inflammation, a hallmark of eosinophilic CRS with nasal polyposis [62]. Experimental models have demonstrated that loss of SCFA-producing bacteria enhances airway hyperreactivity and mucosal remodeling, supporting the mechanistic plausibility of our pooled clinical observations [63].

Micronutrient Malabsorption and Disease Severity

Micronutrient deficiencies emerged as key contributors to disease severity. Vitamin D deficiency was significantly associated with increased polyp burden and recurrence, consistent with its immunomodulatory role in epithelial repair and Th2 cytokine suppression [64,65]. Previous studies have reported lower serum Vitamin D levels in CRS patients compared with controls [66]. Vitamin B12 deficiency may impair epithelial turnover and neurosensory regulation, potentially contributing to persistent mucosal hypersensitivity and headache syndromes [67]. Functional iron deficiency, frequently observed in chronic inflammatory states, may reduce antimicrobial defense and predispose to fungal superinfection [68]. Reports of COVID-19-associated fungal sinusitis further highlight this vulnerability [69].

Influence of Metabolic and Pharmacologic Comorbidities

Subgroup analyses demonstrated amplified risk among elderly individuals with diabetes mellitus, chronic aspirin exposure, and long-term psychotropic or sedative medication use. Diabetes is associated with baseline gut microbiome alterations and systemic inflammation [70]. Aspirin-exacerbated respiratory disease reflects dysregulated inflammatory pathways and nasal polyposis [71]. Psychotropic medications have been linked to microbiome perturbations and metabolic dysfunction [72], suggesting a cumulative “second-hit” effect in susceptible elderly populations.

Microbiota Restoration as a Therapeutic Strategy

Randomized trials included in this review demonstrated that probiotic, prebiotic, synbiotic, and fecal microbiota transplantation interventions were associated with reduced recurrence and improved response to medical therapy. Restoration of microbial diversity has been shown to decrease systemic inflammatory signaling and enhance mucosal immune resilience [73,74].

Fecal microbiota transplantation has demonstrated efficacy in restoring gut microbial equilibrium in refractory dysbiosis states [75]. Although standardized protocols and long-term safety data in elderly CRS populations remain limited, the high GRADE certainty observed for microbiota restoration supports its therapeutic potential.

Clinical Implications

The findings underscore the importance of integrating gastrointestinal evaluation into sinonasal disease management in the post-pandemic era. Screening for Vitamin D, Vitamin B12, and iron deficiency may identify reversible contributors to persistent inflammation. Multidisciplinary collaboration between otolaryngologists, gastroenterologists, and geriatricians may facilitate holistic management.

Recognition of the gut-nose-lung axis may reduce recurrence rates and surgical burden in elderly CRS patients.

Strengths and Limitations

This review adhered toPRISMA 2020 guidelines and incorporated both observational studies and randomized trials, strengthening the evidence base. Risk-of-bias assessments demonstrated predominantly high methodological quality, and GRADE evaluation indicated moderate-to-high certainty for primary outcomes. However, most included studies were observational, limiting causal inference. Variability in microbiome assessment methods and micronutrient thresholds contributed to heterogeneity. Additionally, standardized diagnostic criteria for post-COVID malabsorption syndrome remain lacking [76].

Future Directions

Future research should prioritize longitudinal microbiome sequencing in elderly post-COVID cohorts, biomarker-guided CRS phenotyping, and multicenter randomized trials evaluating microbiota restoration therapies. Exploration of postbiotic metabolites and precision-medicine approaches targeting mucosal immune modulation may further clarify mechanistic pathways within the gut-nose-lung axis [77].

Overall Interpretation

Collectively, these findings suggest that the increased burden of sinonasal disease observed in elderly populations may, in part, be attributed to persistent gut dysbiosis and malabsorption following SARS-CoV-2 infection. Addressing underlying gastrointestinal dysfunction may represent a paradigm shift in chronic rhinosinusitis management in the post-pandemic era.

This systematic review and meta-analysis demonstrates a significant association between post-SARS-CoV-2-related gut dysbiosis, malabsorption syndrome, and increased incidence and severity of sinonasal disease in elderly individuals. The pooled evidence indicates that persistent gastrointestinal dysfunction following COVID-19 may contribute to higher rates of chronic rhinosinusitis, nasal polyposis, greater disease severity, increased surgical requirement, and recurrence [78,79].

The findings support the emerging concept of a gut-nose-lung axis, wherein alterations in intestinal microbiota influence upper airway immune responses through systemic inflammatory pathways and reduced production of beneficial microbial metabolites [80]. Malabsorption of key micronutrients, particularly Vitamin D, Vitamin B12, and functional iron, appears to further exacerbate mucosal immune dysregulation and predispose to complications such as fungal superinfection and treatment resistance [81,82].

Elderly individuals with metabolic comorbidities and chronic medication exposure may be especially vulnerable, suggesting a synergistic interaction between baseline microbiome alterations and post-COVID dysbiosis [83]. These observations highlight the importance of recognizing sinonasal disease in this population as a manifestation of systemic immune and metabolic imbalance rather than a purely localized inflammatory disorder.

Importantly, microbiota restoration strategies, including probiotic and prebiotic interventions and fecal microbiota transplantation, demonstrated promising reductions in recurrence and improved therapeutic response, suggesting a potential adjunctive role in comprehensive management [84].

In conclusion, early identification of gastrointestinal dysfunction and targeted correction of dysbiosis and micronutrient deficiencies may represent an integrative approach to improving outcomes in elderly patients with chronic sinonasal disease in the post-pandemic era. Future research should focus on longitudinal microbiome profiling, biomarker-guided risk stratification, and standardized therapeutic protocols to refine precision management strategies [85].

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