Severe Pertussis is 1.5 times more likely if poor vitamin D receptor

Association of Vitamin D Receptor Polymorphism with Susceptibility to Symptomatic Pertussis.

PLoS One. 2016 Feb 19;11(2):e0149576. doi: 10.1371/journal.pone.0149576. eCollection 2016.

Han WG1, Hodemaekers HM2, Nagarajah B2, Poelen MM1, Helm K1, Janssen R2, van Els CA1.

Pertussis, caused by infection with the gram negative B. pertussis bacterium, is a serious respiratory illness that can last for months. While B. pertussis infection rates are estimated between 1-10% in the general population, notifications of symptomatic pertussis only comprise 0.01-0.1% indicating that most individuals clear B. pertussis infections without developing (severe) clinical symptoms. In this study we investigated whether genetic risk factors are involved in the development of symptomatic pertussis upon B. pertussis infection. Single-nucleotide polymorphisms (SNPs) in candidate genes, MBL2, IL17A, TNFα, VDR, and IL10 were genotyped in a unique Dutch cohort of symptomatic clinically confirmed (ex-)pertussis patients and in a Dutch population cohort. Of the seven investigated SNPs in five genes, a polymorphism in the Vitamin D receptor (VDR) gene (rs10735810) was associated with pertussis. The VDR major allele and its homozygous genotype were more present in the symptomatic pertussis patient cohort compared to the control population cohort. Interestingly, the VDR major allele correlated also with the duration of reported pertussis symptoms. Vitamin D3 (VD3) and VDR are important regulators of immune activation. Altogether, these findings suggest that polymorphisms in the VDR gene may affect immune activation and the clinical outcome of B. pertussis infection.

📄 PDF

pertussis = whooping cough
A poor Vitamin D Receptor restricts the amount of vitamin D which actually gets to cells (where the benefit happens)
There is a greatly increased risk for over 30 diseases associated with poor Vitamin D Receptors

Vitamin D Receptor

Perplexity AI review of Pertutis and Vitamin D - Dec 2025

Now I have comprehensive information to generate the final report. Let me compile this into a well-structured, expert-level analysis.

Association Between Pertussis and Vitamin D

Vitamin D deficiency represents a significant global public health challenge affecting approximately one billion people worldwide. While its classical role in calcium homeostasis and bone health is well established, emerging evidence demonstrates that vitamin D functions as a critical immunomodulator with potential implications for infectious diseases, including pertussis (whooping cough) caused by the gram-negative bacterium Bordetella pertussis. This analysis synthesizes current evidence on the multifaceted relationship between vitamin D status and pertussis susceptibility, severity, and outcomes.[1]

Vitamin D Receptor Polymorphisms and Pertussis Susceptibility

The most compelling evidence linking vitamin D biology to pertussis comes from genetic association studies examining vitamin D receptor (VDR) polymorphisms. A landmark Dutch case-control study published in 2016 investigated single-nucleotide polymorphisms (SNPs) in candidate immune genes among 195 symptomatic pertussis patients and 462 population controls. Of seven investigated SNPs across five genes (MBL2, IL17A, TNFα, VDR, and IL10), only the VDR polymorphism rs10735810 (also known as FokI) demonstrated a significant association with symptomatic pertussis.[2][3]

The rs10735810 polymorphism affects VDR protein structure, producing either a longer variant (minor A allele) or a shorter version lacking three amino acids (major G allele). The study revealed that the major G allele occurred at significantly higher frequency in pertussis patients (69.8%) compared to controls (63.1%), with an odds ratio of 1.35 (95% CI: 1.05-1.75, p=0.020). At the genotype level, 50.0% of symptomatic pertussis patients possessed the homozygous G:G genotype compared to only 39.2% of controls, yielding an odds ratio of 1.55 (95% CI: 1.10-2.18).[3][2]

More strikingly, this genetic variant correlated with symptom duration. Among patients stratified by symptom persistence, the G:G genotype frequency increased progressively: 40.0% in those with symptoms <4 weeks, 47.9% with 4-8 weeks, and 53.4% with >8 weeks of symptoms (p=0.002). When analyzing only patients with symptoms persisting >4 weeks, the association strengthened considerably—the G allele frequency reached 71.9% versus 63.1% in controls (p=0.003, OR=1.50), remaining statistically significant even after Bonferroni correction for multiple testing (p=0.015).[3]

The mechanistic explanation for this association lies in the differential immunological properties of the VDR variants. Functional studies by van Etten et al. demonstrated that while both VDR variants respond to 1,25-dihydroxyvitamin D (1,25D), the major G allele produces a VDR protein associated with higher overall pro-inflammatory immune status. Specifically, monocytes and dendritic cells from individuals with the major allele show higher net expression of IL-12 despite 1,25D-mediated suppression. This enhanced pro-inflammatory phenotype may explain the paradoxical association: while Th1 and Th17 pro-inflammatory responses are essential for B. pertussis clearance, excessive inflammation drives the characteristic severe paroxysmal coughing, vomiting, and respiratory pathology that define symptomatic pertussis.[4][5][3]

Notably, the rs10735810 polymorphism has also been associated with susceptibility to other respiratory infections, including respiratory syncytial virus (RSV) bronchiolitis in children and tuberculosis, though the direction of association varies by pathogen, likely reflecting different pathogenic mechanisms. In RSV bronchiolitis, where Th2-mediated immunopathology predominates, the less pro-inflammatory minor allele (A) showed increased susceptibility—the opposite pattern from pertussis.[6][7][3]

Vitamin D Deficiency and Pertussis Disease Severity

A Chinese observational study published in 2020 provided direct evidence linking vitamin D deficiency to pertussis severity in infants. This cross-sectional investigation enrolled 116 children aged 1-12 months with culture-confirmed pertussis and 50 age-matched healthy controls. The findings revealed striking differences in vitamin D status:[8]

Serum 25-hydroxyvitamin D [25(OH)D] levels:- Mild pertussis: 27.30 ± 5.98 ng/mL- Severe pertussis: 24.40 ± 6.27 ng/mL
- Healthy controls: 30.16 ± 5.13 ng/mL (p<0.01)

Vitamin D deficiency prevalence (<30 ng/mL):- Mild pertussis: 55.9%- Severe pertussis: 78.12%- Healthy controls: 34% (p<0.01)[8]

These data demonstrate that children with severe pertussis had significantly lower vitamin D levels compared to those with mild disease, and both groups showed substantially higher deficiency rates than healthy children. The severity gradient—with the lowest vitamin D levels observed in the most severely affected patients—suggests a dose-response relationship between vitamin D insufficiency and pertussis disease severity.[8]

However, the study also revealed a complex finding regarding antimicrobial peptides. Serum levels of cathelicidin (LL-37) and human β-defensin 2 (HBD-2), both antimicrobial peptides known to be induced by vitamin D, were significantly elevated in pertussis patients compared to controls. Paradoxically, Spearman correlation analysis found no significant relationship between 25(OH)D levels and LL-37 or HBD-2 concentrations. The authors concluded that the average vitamin D level of 26.50 ng/mL in infected infants, while technically deficient, may not have fallen below the threshold necessary to impair antimicrobial peptide production. This suggests that the immune system maintains compensatory antimicrobial peptide responses even in the setting of moderate vitamin D deficiency, though this may not be sufficient to prevent severe disease.[8]

Molecular Mechanisms: Vitamin D in Innate Immunity

Vitamin D exerts its immunomodulatory effects primarily through the nuclear vitamin D receptor (VDR), which acts as a ligand-activated transcription factor. The bioactive form, 1,25-dihydroxyvitamin D [1,25(OH)₂D], is produced from circulating 25-hydroxyvitamin D [25(OH)D] by the enzyme CYP27B1 (1α-hydroxylase). A critical discovery revealed that immune cells, including monocytes, macrophages, dendritic cells, and T cells, express both VDR and CYP27B1, enabling local production of 1,25(OH)₂D in response to pathogen recognition. This autocrine/paracrine vitamin D system represents a sophisticated mechanism whereby immune cells can autonomously generate bioactive vitamin D at sites of infection.[9][10][1]

Antimicrobial Peptide Induction

One of the most well-characterized vitamin D immune functions is the induction of antimicrobial peptides (AMPs). Following activation of pattern recognition receptors like Toll-like receptor 2/1 (TLR2/1) by bacterial lipoproteins, immune cells upregulate both VDR and CYP27B1. The locally produced 1,25(OH)₂D then binds VDR and activates transcription of genes encoding cathelicidin (LL-37) and human β-defensin 2 (DEFB4). These AMPs possess broad-spectrum antimicrobial activity against bacteria, fungi, and viruses.[11][12][1][9]

In the context of respiratory pathogens related to B. pertussis, research has demonstrated that vitamin D treatment enhances cathelicidin-mediated killing of Bordetella bronchiseptica (a close relative of B. pertussis) in bronchial epithelial cells. This suggests that adequate vitamin D status could potentially enhance innate immune responses in the respiratory tract against pertussis infection.[13][1]

The human cathelicidin gene (CAMP) promoter contains three vitamin D response elements (VDREs), making it a direct transcriptional target of the VDR. Similarly, DEFB4 contains one VDRE in its promoter region. Importantly, these VDREs are unique to humans—the mouse cathelicidin homolog (CRAMP) lacks VDREs and is not directly regulated by vitamin D, which has complicated translation of findings from rodent models to human disease.[14][1]

Autophagy Enhancement

Beyond antimicrobial peptides, vitamin D promotes autophagy, a cellular process that delivers intracellular pathogens to lysosomes for degradation. Vitamin D-induced cathelicidin not only has direct bactericidal effects but also promotes colocalization of bacterial phagosomes with autophagosomes, enhancing intracellular pathogen clearance. Studies with Mycobacterium tuberculosis demonstrated that vitamin D treatment significantly augmented antimicrobial responses through this cathelicidin-autophagy axis.[15][16][17][1][9]

Vitamin D activates autophagy through multiple pathways. It upregulates expression of autophagy-related genes including ATG5, Beclin-1, and ATG16L1. The transcription factor VDR directly binds to regulatory regions of ATG16L1, making it a VDR target gene. For intracellular bacteria like Salmonella typhimurium, vitamin D-enhanced autophagy substantially improves bacterial clearance while simultaneously suppressing excessive inflammatory IL-1β production. This dual action—enhanced pathogen elimination with controlled inflammation—exemplifies the immunoregulatory sophistication of vitamin D signaling.[16][17]

Iron Homeostasis Regulation

Another mechanism by which vitamin D may influence bacterial infections involves regulation of iron metabolism through suppression of hepcidin. Hepcidin is an acute-phase protein that regulates systemic iron homeostasis by binding to ferroportin (the only cellular iron exporter), causing its internalization and degradation. This results in iron retention within cells, particularly macrophages.[18][1]

Both 25(OH)D and 1,25(OH)₂D directly suppress hepcidin (HAMP) gene transcription through VDR binding to the HAMP promoter. This suppression increases ferroportin expression and promotes cellular iron export, lowering intracellular iron concentrations. Since most intracellular bacterial pathogens, including Mycobacterium tuberculosis, Salmonella typhimurium, Chlamydia psittaci, and Legionella pneumophila, require iron for survival and replication, vitamin D-mediated iron depletion from the intracellular environment may restrict pathogen growth. Whether B. pertussis, which can exist both extracellularly and intracellularly, is similarly affected by this iron-deprivation mechanism remains to be determined.[19][18]

Immunomodulation: T Cell Responses and the Th1/Th17 Paradox

While vitamin D enhances innate antimicrobial mechanisms, it simultaneously modulates adaptive immune responses in ways that appear paradoxical for bacterial infection control. Vitamin D potently suppresses Th1 and Th17 cell differentiation and function while promoting Th2 and regulatory T cell (Treg) phenotypes.[20][21][22][23][1]

The immunological control of B. pertussis infection critically depends on Th1 and Th17 responses. Animal models demonstrate that both cell-mediated immunity (primarily Th1-associated IFN-γ production) and IL-17-producing Th17 cells are essential for effective bacterial clearance. Whole-cell pertussis vaccines, which provide superior protection compared to acellular vaccines, induce robust Th1/Th17 memory responses. In contrast, acellular pertussis vaccines predominantly elicit Th2 responses, which correlate with reduced efficacy in preventing colonization, infection, and transmission.[24][25][4]

Given that vitamin D suppresses Th1/Th17 responses while B. pertussis clearance requires these responses, one might predict that vitamin D would impair host defense against pertussis. Indeed, mouse studies showed this suppressive effect. Vitamin D treatment of CD4+ T cells reduced Th17 cytokine production (IL-17, IL-17F, IL-22) in a VDR-dependent manner through post-transcriptional mechanisms involving induction of C/EBP homologous protein (CHOP). The inhibition occurred at physiological vitamin D concentrations (10-100 nM 1,25D).[22]

However, a critical mouse experiment directly tested whether VDR deficiency affected pertussis clearance. VDR knockout (KO) mice infected with B. pertussis showed no difference in bacterial clearance compared to wild-type mice. This finding, though from unpublished data cited in a 2009 review, suggests that despite vitamin D's immunosuppressive effects on Th1/Th17 pathways, VDR signaling is not required for mounting an effective immune response to clear B. pertussis infection—at least in the mouse model.[5]

Pertussis Virulence Mechanisms: Bacterial Resistance to Antimicrobial Peptides

A crucial factor limiting the potential efficacy of vitamin D-induced antimicrobial peptides against pertussis emerged from studies of B. pertussis virulence factors. Research published in 2022 identified that B. pertussis produces a polysaccharide called Bps (Bordetella polysaccharide), a member of the poly-β-1,6-N-acetyl-D-glucosamine (PNAG/PGA) polysaccharide family, which confers potent resistance to antimicrobial peptides.[26][27][28]

The Bps polysaccharide functions through a dual mechanism:

1. Surface Shield: Bps coats the bacterial cell surface, physically blocking antimicrobial peptide binding. Deletion of the bpsA-D locus (required for Bps synthesis) or treatment with Dispersin B (a specific glycoside hydrolase that degrades Bps) increased susceptibility to LL-37-mediated killing by 3.0-log fold and polymyxin B killing by 3.5-log fold.[28][26]

2. Decoy Sink: B. pertussis secretes Bps both during laboratory growth and during mouse lung infection. This secreted Bps binds to antimicrobial peptides in the extracellular milieu, sequestering them and preventing their interaction with bacteria. Addition of purified Bps to cultures increased bacterial survival in the presence of LL-37. This "decoy receptor" mechanism represents a sophisticated evasion strategy unique among bacterial polysaccharides.[26][28]

These findings have profound implications for understanding vitamin D's potential role in pertussis. Despite vitamin D's capacity to induce robust production of cathelicidin (LL-37) and defensins, B. pertussis has evolved specific countermeasures to neutralize these antimicrobial peptides. This may explain why the Chinese pediatric study found elevated LL-37 and HBD-2 levels in pertussis patients yet still observed severe disease—the bacteria's Bps polysaccharide may render these peptides ineffective regardless of their abundance.[28][26][8]

Importantly, Bps is not a component of current acellular pertussis vaccines. The researchers demonstrated that Bps confers virulence not only to B. pertussis but also to heterologous bacteria expressing it, suggesting that next-generation pertussis vaccines incorporating Bps as an antigen might overcome current vaccine limitations.[26][28]

Clinical and Epidemiological Context: Vitamin D and Respiratory Infections

While pertussis-specific vitamin D supplementation trials are lacking, substantial evidence from respiratory infection studies provides relevant context. A 2017 meta-analysis of individual participant data from 25 randomized controlled trials (10,933 participants) found that vitamin D supplementation reduced the odds of experiencing at least one acute respiratory infection episode by 12% (OR 0.88, 95% CI: 0.81-0.96). A subsequent 2021 update including 46 trials (48,000 participants) confirmed an 8% reduction (OR 0.92, 95% CI: 0.86-0.99).[29]

Subgroup analyses revealed critical modifiers of vitamin D efficacy:[30][31]

Dosing regimen: Daily supplementation proved more effective (OR 0.81, 95% CI: 0.72-0.91) than bolus monthly or greater intervals, which showed no benefit. Daily doses ≥400 IU were most protective.[29][30]

Baseline vitamin D status: Greatest benefits occurred in vitamin D-deficient individuals, though effects were observed even in vitamin D-sufficient populations.[30]

Infection type: A 2023 meta-analysis of seven trials (5,748 children) found high-dose vitamin D supplementation (>1000 IU daily) reduced influenza/cold incidence by 57% (95% CI: 0.30-0.61), cough by 56%, and fever by 59%. However, no effect was observed on bronchitis, otitis media, or upper respiratory tract infections overall.[31]

Regarding vitamin D deficiency prevalence in children with respiratory infections, studies consistently demonstrate associations. A 2025 study from Central India found vitamin D deficiency in 72% of children with recurrent respiratory infections, with a significant inverse correlation between serum vitamin D levels and infection frequency per year (r = -0.45, p<0.001). Vitamin D-deficient children presented with more frequent upper respiratory tract infection episodes, prolonged symptom duration, and increased antibiotic requirements.[32]

For infants specifically, cord blood vitamin D levels show inverse associations with early respiratory infections. A prospective cohort study of 922 newborns found that cord blood 25(OH)D levels <25 nmol/L conferred an odds ratio of 2.16 (95% CI: 1.35-3.46) for respiratory infection by 3 months of age compared to levels ≥75 nmol/L. This suggests that maternal vitamin D status during pregnancy influences offspring susceptibility to early respiratory infections.[33]

Maternal Vitamin D Supplementation and Infant Immunity

Given that pertussis poses the greatest mortality risk in young infants—particularly those too young to have completed their primary vaccination series—maternal vitamin D supplementation during pregnancy represents a potential preventive strategy. Research demonstrates that maternal vitamin D levels strongly correlate with cord blood levels, as 25(OH)D crosses the placenta.[34][35]

Several mechanisms support potential benefits of maternal supplementation:

1. Fetal immune system development: Maternal vitamin D status modulates fetal immune system maturation. The decidua and placenta express both VDR and CYP27B1 early in pregnancy, enabling local vitamin D production that regulates immune cells at the fetomaternal interface. Vitamin D promotes tolerance-inducing regulatory T cells and modulates natural killer cells, dendritic cells, and macrophages in the decidua.[35][36][34]

2. Persistent immune programming: Prenatal vitamin D deficiency causes long-term alterations in hematopoietic stem and progenitor cells, affecting immune cell proportions in offspring throughout life. In humans, higher maternal vitamin D levels during the second trimester were associated with increased CD8+ T cell proportions and decreased granulocytes in cord blood. These findings suggest that prenatal vitamin D exposure programs the immune system with effects persisting beyond birth.[37]

3. Clinical outcomes: A 2018 meta-analysis of 24 randomized trials (5,405 participants) found maternal vitamin D supplementation during pregnancy reduced the risk of infants being small for gestational age (RR 0.72, 95% CI: 0.52-0.99) and improved infant growth at 3, 6, 9, and 12 months without increasing fetal or neonatal mortality or congenital abnormalities. Doses ≤2,000 IU/day during pregnancy were associated with reduced fetal and neonatal mortality.[35]

4. Respiratory infection prevention: A 2022 meta-analysis specifically examining maternal vitamin D supplementation for preventing respiratory infections in children found the relationship was not consistently observed across studies. However, maternal supplementation improved maternal and neonatal vitamin D status and potentially strengthened infant immune systems.[34]

The Northern Territory (Australia) "D-Kids" randomized controlled trial, though focused on First Nations populations with high vitamin D deficiency rates and acute respiratory infection (ARI) hospitalizations, exemplifies the rationale for perinatal vitamin D supplementation. This trial administered 14,000 IU/week to pregnant women from 28-34 weeks gestation until birth, then 4,200 IU/week to infants from birth to 4 months, hypothesizing a 27.5% relative reduction in ARI episodes during the infant's first year. Results, scheduled for publication by 2024, will provide crucial evidence for vitamin D's role in preventing early childhood respiratory infections.[29]

Synthesis: Reconciling Conflicting Evidence

The relationship between vitamin D and pertussis embodies several apparent paradoxes that require careful synthesis:

Paradox 1: VDR Polymorphism EffectsThe major G allele (rs10735810) associates with increased symptomatic pertussis risk and prolonged symptoms despite producing a more pro-inflammatory phenotype. This seems counterintuitive since pro-inflammatory Th1/Th17 responses are required for B. pertussis clearance. The resolution lies in understanding that excessive inflammation drives pertussis pathology—the paroxysmal coughing, respiratory distress, and prolonged symptoms result from inflammatory lung damage rather than ongoing infection. Most individuals clear B. pertussis asymptomatically (infection rates 1-10% but symptomatic disease only 0.01-0.1%). The VDR major allele may tip the balance toward pathological inflammation despite effective bacterial clearance, manifesting as more severe, prolonged symptomatic disease.[25][2][4][3]

Paradox 2: Antimicrobial Peptide Induction vs. Bacterial ResistanceVitamin D robustly induces LL-37 and HBD-2 production, yet B. pertussis has evolved sophisticated resistance mechanisms through Bps polysaccharide. The Chinese pediatric study found elevated antimicrobial peptide levels in pertussis patients but still severe disease. This suggests that while vitamin D successfully activates innate immune programs, B. pertussis has evolved specific countermeasures rendering these peptides less effective. The bacterial adaptation may explain why antimicrobial peptide levels don't correlate with disease severity—abundance is irrelevant if the bacteria can resist or sequester them.[1][11][9][28][26][8]

Paradox 3: Th1/Th17 Suppression vs. Mouse Model DataVitamin D suppresses Th1/Th17 responses critical for pertussis clearance, yet VDR knockout mice clear B. pertussis normally. This apparent contradiction may reflect compensatory mechanisms, species differences in vitamin D biology (particularly the lack of vitamin D-regulated antimicrobial peptides in mice), or that the threshold vitamin D signaling required for immune competence is quite low, with deficiency or VDR absence not reaching critical impairment in the mouse model.[23][14][5][22][1]

Paradox 4: Vitamin D Deficiency Associated with SeverityLower vitamin D levels correlate with more severe pertussis, suggesting vitamin D is protective. Yet if vitamin D suppresses the very Th1/Th17 responses needed for clearance, deficiency should theoretically improve outcomes. The reconciliation recognizes that vitamin D's innate immune benefits (antimicrobial peptides, autophagy, iron regulation) and its anti-inflammatory effects (preventing excessive tissue damage) likely outweigh any impairment of adaptive responses. The dose-response relationship between vitamin D deficiency and disease severity supports a net protective role, particularly in preventing the inflammatory complications that define severe pertussis.[8]

Mechanisms Summary

Based on the evidence reviewed, vitamin D influences pertussis through multiple interconnected mechanisms:

Potential Beneficial Effects:1. Innate immunity enhancement: Induction of cathelicidin (LL-37) and β-defensins with direct antimicrobial activity against respiratory pathogens[9][13][1]2. Autophagy activation: Enhanced intracellular pathogen clearance through autophagosome-phagosome fusion[17][16][9]3. Iron deprivation: Suppression of hepcidin promotes cellular iron export, potentially restricting intracellular bacterial growth[18][19]4. Inflammatory regulation: Limitation of excessive pro-inflammatory responses that drive pertussis pathology[22][23][3]5. Respiratory barrier function: Support of epithelial integrity and mucosal immunity[12][1]

Potential Limiting Factors:1. Bacterial evasion: B. pertussis Bps polysaccharide confers resistance to antimicrobial peptides through surface shielding and decoy mechanisms[28][26]2. Th1/Th17 suppression: Vitamin D inhibits cell-mediated immunity pathways required for optimal bacterial clearance[25][23][22]3. Treg induction: Promotion of regulatory T cells may dampen immune responses to pathogens[20][23][30]4. Individual variability: VDR polymorphisms create substantial inter-individual differences in vitamin D responsiveness[2][6][3]

The net effect likely depends on the balance of these mechanisms, the severity of vitamin D deficiency, host genetic factors, bacterial load, and timing of infection relative to vaccine-induced immunity.

Research Gaps and Future Directions

Despite accumulating evidence, significant knowledge gaps remain:

1. Intervention TrialsNo randomized controlled trials have specifically examined vitamin D supplementation for pertussis prevention or treatment. Given the resurgence of pertussis despite high vaccination coverage, such trials are warranted, particularly in high-risk populations (young infants, vitamin D-deficient populations, immunocompromised individuals).[38][4]

2. Mechanistic Studies- How do VDR polymorphisms interact with vitamin D supplementation to influence pertussis outcomes?- Can vitamin D overcome B. pertussis antimicrobial peptide resistance mechanisms?- Does vitamin D influence pertussis vaccine immunogenicity or effectiveness?- What is the role of vitamin D in preventing pertussis transmission, particularly relevant given acellular vaccine limitations?

3. Optimal Dosing and Timing- What vitamin D dosing regimen (daily vs. bolus, dose magnitude) optimizes immune function against B. pertussis?- For maternal supplementation, what are the critical windows during pregnancy and lactation?- Should vitamin D status be optimized before pertussis vaccination to enhance responses?

4. Biomarkers and Personalized Approaches- Can VDR genotyping identify individuals at higher risk for severe pertussis who might benefit from targeted vitamin D supplementation?- Do antimicrobial peptide levels or other biomarkers predict vitamin D responsiveness?- How do comorbidities (malnutrition, HIV, chronic diseases) modify vitamin D effects on pertussis susceptibility?

5. Population Studies- What is the population-attributable risk of pertussis due to vitamin D deficiency?- Do seasonal variations in vitamin D status correlate with pertussis incidence patterns?- In populations with endemic vitamin D deficiency, does supplementation reduce pertussis burden?

Clinical Implications and Recommendations

Based on current evidence, several clinical considerations emerge:

1. Vitamin D Screening in High-Risk GroupsChildren with severe or persistent pertussis symptoms may benefit from vitamin D status assessment. The finding that 78.12% of children with severe pertussis had vitamin D deficiency suggests this is a common comorbidity that could be addressed. Universal screening of all pertussis cases is not supported by current evidence, but targeted screening in severe cases, infants, and those with risk factors for deficiency (dark-skinned, limited sun exposure, malnutrition, northern latitudes) appears reasonable.[8]

2. Vitamin D Supplementation for DeficiencyFor children found to be vitamin D deficient, correction according to standard guidelines is appropriate. The Endocrine Society recommends:[29]- Infants 0-1 year: 400-1,000 IU/day depending on deficiency severity[29]- Children ≥1 year: 600-1,000 IU/day for prevention, higher doses (2,000-6,000 IU/day for 6 weeks to 3 months) for treatment of deficiency[29]

Daily dosing appears more effective than bolus administration for immune benefits.[30][29]

3. Maternal SupplementationPregnant women should maintain adequate vitamin D status (≥30 ng/mL or 75 nmol/L) through supplementation of 2,000-4,000 IU/day if deficient. This supports fetal immune system development and may reduce infant susceptibility to early respiratory infections. The safety profile of such doses during pregnancy is well established.[33][34][35][29]

4. Not a Substitute for VaccinationCritically, vitamin D supplementation should not be viewed as an alternative to pertussis vaccination. The DTaP/Tdap vaccines remain the most effective primary prevention strategy. Vitamin D optimization should be considered a complementary approach to support general immune competence, not a replacement for evidence-based vaccination schedules.[39]

5. Realistic ExpectationsGiven B. pertussis resistance mechanisms to antimicrobial peptides and vitamin D's complex immunomodulatory effects, vitamin D supplementation should not be expected to dramatically alter pertussis disease course in established infection. Benefits, if present, are more likely to be modest reductions in severity, complication rates, or symptom duration rather than cure.[23][22][26][28]

Public Health Perspective

From a population health standpoint, addressing vitamin D deficiency represents a low-cost, low-risk intervention with plausible benefits extending beyond pertussis. Given that:

Vitamin D deficiency affects approximately one billion people globally[1]
Deficiency rates in children with respiratory infections commonly exceed 50-70%[40][32][8]
Supplementation reduces overall acute respiratory infection risk by 8-12%[30][29]
Safety profiles for recommended doses are excellent[35]
Costs are minimal compared to hospitalization expenses[40]

Population-level vitamin D adequacy strategies (through fortification, supplementation programs, or public health campaigns) could yield substantial returns in reduced respiratory infection burden, of which pertussis represents one component. However, such programs must be carefully designed to avoid excessive dosing, ensure appropriate target populations are reached, and integrate with rather than detract from vaccination efforts.

The resurgence of pertussis in highly vaccinated populations highlights the need for novel complementary strategies. While vitamin D is unlikely to be a panacea, optimizing population vitamin D status may contribute to a multi-pronged approach including improved vaccines (potentially incorporating Bps antigen), maternal vaccination strategies, and nutritional optimization to reduce pertussis-associated morbidity and mortality.[4][38][26]

Conclusion

The association between vitamin D and pertussis is complex, multifaceted, and incompletely understood. Genetic evidence demonstrates that VDR polymorphisms influence susceptibility to symptomatic pertussis and disease duration, with the major pro-inflammatory allele paradoxically associated with worse outcomes—likely reflecting that excessive inflammation drives pathology. Observational evidence shows vitamin D deficiency is highly prevalent in children with pertussis (55-78%) and correlates with disease severity.[2][3][8]

Mechanistically, vitamin D enhances multiple aspects of innate immunity potentially beneficial against pertussis, including antimicrobial peptide production, autophagy, and inflammatory regulation. However, B. pertussis has evolved sophisticated resistance to these antimicrobial peptides through its Bps polysaccharide, which may limit vitamin D's protective efficacy. Additionally, vitamin D's suppression of Th1/Th17 responses required for bacterial clearance creates theoretical concerns, though mouse model data suggest VDR deficiency does not impair pertussis clearance.[5][16][9][1][26][28]

The weight of evidence supports a modest beneficial role for vitamin D adequacy in reducing pertussis severity and potentially susceptibility, though intervention trials are needed to definitively establish causality and quantify effect sizes. Vitamin D optimization should be viewed as one component of comprehensive pertussis prevention strategies centered on vaccination, with particular attention to maternal supplementation during pregnancy and correction of deficiency in high-risk children.

As pertussis continues to resurge globally despite high vaccination coverage, understanding the role of nutritional and immunological factors like vitamin D becomes increasingly important for developing next-generation prevention and treatment strategies. The evidence reviewed here suggests that while vitamin D is not a silver bullet, its immunomodulatory properties may contribute meaningfully to reducing the substantial burden of disease that pertussis continues to impose, particularly on vulnerable infants and young children.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118