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The association between vitamin D levels and recurrent group A streptococcal tonsillopharyngitis in adults

Open ArchivePublished:July 30, 2012DOI:https://doi.org/10.1016/j.ijid.2012.05.1036

      Summary

      Objectives

      To determine the association between recurrent group A streptococcal (GAS) tonsillopharyngitis and serum 25-hydroxy (25(OH)) vitamin D among adult subjects.

      Methods

      Adult patients with tonsillopharyngitis between January 2007 and December 2009 were reviewed and identified retrospectively. Cases with a medical history of recurrent GAS tonsillopharyngitis were compared to age- and gender-matched individuals without a medical history of GAS tonsillopharyngitis. Recurrent tonsillopharyngitis was defined as three or more episodes of GAS tonsillopharyngitis per year for a period of two consecutive years.

      Results

      Fifty-four cases with recurrent GAS tonsillopharyngitis and 50 controls were enrolled. There were no significant differences between cases and controls with regard to mean age (41 ± 13 vs. 42 ± 12 years; p = 0.7) and male gender (55% vs. 54%; p = 0.6). Mean serum levels of 25(OH) vitamin D among subjects with recurrent GAS tonsillopharyngitis were significantly lower from the controls (11.5 ng/ml ± 4.7 vs. 26 ng/ml ± 7; p = 0.001). Multiple regression analysis showed that a serum 25(OH) vitamin D level <20 ng/ml was associated with recurrent GAS tonsillopharyngitis (odds ratio 1.62, 95% confidence interval 1.51–1.76; p < 0.001).

      Conclusions

      Our findings indicate a link between vitamin D deficiency and the recurrence of GAS tonsillopharyngitis.

      Keywords

      1. Introduction

      In the adult population, acute tonsillopharyngitis accounts for 1–2% of all visits to outpatient clinics, physician offices, and emergency departments.
      • Schappert S.M.
      Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 1996.
      Approximately 5–17% of acute tonsillopharyngitis cases are due to a bacterial infection, often to group A β-hemolytic streptococci (GAS).
      • Houvinen P.
      • Lahtonen R.
      • Ziegler T.
      • Meurman O.
      • Hakkarainen K.
      • Miettinen A.
      • et al.
      Pharyngitis in adults: the presence and coexistence of viruses and bacterial organisms.
      • Komaroff A.L.
      • Pass T.M.
      • Aronson M.D.
      • Ervin C.T.
      • Cretin S.
      • Winickoff R.N.
      • et al.
      The prediction of streptococcal pharyngitis in adults.
      The recurrence of clinical tonsillopharyngitis in adults represents a medical problem as well as an economic burden. Several factors have been considered to explain the recurrence of tonsillopharyngitis. These include low patient compliance, short duration of antibiotic treatment, low absorption of antibiotic, frequent exposure (family/peers), bacterial tolerance, and other unknown reasons.
      • Eisen S.A.
      • Miller D.K.
      • Woodward R.S.
      • Spitznagel E.
      • Przybeck T.R.
      The effect of prescribed daily dose frequency on patient medication compliance.
      • Breese B.B.
      • Disney F.A.
      • Talpey W.B.
      Penicillin in streptococcal infections: total dose and frequency of administration.
      • Khajavi A.
      • Amirhakimi G.H.
      The rachitic lung. Pulmonary findings in 30 infants and children with malnutritional rickets.
      • el-Daher N.T.
      • Hijazi S.S.
      • Rawashdeh N.M.
      • al-Khalil I.A.
      • Abu-Ektaish F.M.
      • Abdel-Latif D.I.
      Immediate vs. delayed treatment of group A beta-hemolytic streptococcal pharyngitis with penicillin V.
      • Pichichero M.E.
      • Disney F.A.
      • Talpey W.B.
      • Green J.L.
      • Francis A.B.
      • Roghmann K.J.
      • et al.
      Adverse and beneficial effects of immediate treatment of group A beta-hemolytic streptococcal pharyngitis with penicillin.
      • Gerber M.A.
      • Randolph M.F.
      • Demeo K.K.
      • Kaplan E.L.
      Lack of impact of early antibiotic therapy for streptococcal pharyngitis on recurrence rates.
      • Pichichero M.E.
      • Casey J.R.
      Systemic review of factors contributing to penicillin treatment failure in Streptococcus pyogenes pharyngitis.
      • Kim K.S.
      • Kaplan E.L.
      Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis.
      • Grahn E.
      • Holm S.E.
      • Roos K.
      Penicillin tolerance in beta-streptococci isolated from patients with tonsillitis.
      • Dagan R.
      • Ferne M.
      • Sheinis M.
      • Alkan M.
      • Katzenelson E.
      An epidemic of penicillin-tolerant group A streptococcal pharyngitis in children living in closed community: mass treatment with erythromycin.
      The association between vitamin D deficiency and the susceptibility to infections of the respiratory tract has been suggested for many years. Children with nutritional rickets have developed rachitic lung due to infections of the respiratory tract.
      • Najada A.S.
      • Habashneh M.S.
      • Khader M.
      The frequency of nutritional rickets among hospitalized infants and its relation to respiratory diseases.
      Recently, epidemiological studies have demonstrated a correlation between vitamin D concentration and the incidence of respiratory infections.
      • Sabetta J.R.
      • DePetrillo P.
      • Cipriani R.J.
      • Smardin J.
      • Burns L.A.
      • Landry M.L.
      Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults.
      • Berry D.J.
      • Hesketh K.
      • Power C.
      • Hypponen E.
      Vitamin D status has a linear association with seasonal infections and lung function in British adults.
      • Grant W.B.
      Variation in vitamin D production could possibly explain the seasonality of childhood respiratory infections in Hawaii.
      • Ginde A.A.
      • Mansbach J.M.
      • Camargo Jr., C.A.
      Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey.
      Moreover, scientific evidence shows the important role of vitamin D in the immune system.
      • Diamond G.
      • Legarda D.
      • Ryan L.K.
      The innate immune response of the respiratory epithelium.
      • Medzhitov R.
      • Janeway Jr., C.
      Innate immune recognition: mechanisms and pathways.
      The antimicrobial peptides (AMPs) defensin and cathelicidin, which are the principal defense factors of the upper respiratory tract (URT), are upregulated by vitamin D.
      • Brogden K.A.
      Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?.
      • Liu P.T.
      • Stenger S.
      • Li H.
      • Wenzel L.
      • Tan B.H.
      • Krutzik S.R.
      • et al.
      Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
      Aydin et al. showed that vitamin D insufficiency was more prevalent in children with recurrent tonsillitis than in healthy children.
      • Aydin S.
      • Aslan I.
      • Yildiz I.
      • Agachan B.
      • Toptas B.
      • Toprak S.
      • et al.
      Vitamin D levels in children with recurrent tonsillitis.
      Despite the fact that such an association between vitamin D deficiency and the susceptibility to infections of the respiratory tract has been suggested for many years, to the best of our knowledge no such evidence-based study had been undertaken in adults.
      In this study we aimed to look for a possible association between serum 25-hydroxy (25(OH)) vitamin D levels and recurrent GAS tonsillopharyngitis in adults.

      2. Materials and methods

      2.1 Subjects

      This study included adult patients with recurrent tonsillopharyngitis who were followed-up at the Infectious Diseases Unit of the Holy Family Hospital (HFH), a 150-bed primary care hospital in Nazareth, Israel. We included all individuals with recurrent tonsillopharyngitis who were followed-up between 2007 and 2009 and who were aged 18–60 years. The exclusion criteria were: (1) non-GAS tonsillopharyngitis, (2) pregnancy, and (3) individuals with: renal failure (creatinine clearance rate <35 ml/min), a malignancy with life expectancy less than 1 year, an HIV infection, splenectomy, low compliance or low adherence with antibiotic use, connective tissue diseases, organ transplant, chronic use of corticosteroid therapy, vitamin D supplementation, and substance abusers.
      The control group included 50 healthy individuals without a medical history of GAS tonsillopharyngitis who were enrolled randomly from the Medicine Clinic, HFH. The members of this group were matched with the study patients for age ± 4 years and gender, and were subject to the same exclusion criteria as the study patient group. For each case of recurrent GAS tonsillopharyngitis we selected one comparator case (1:1). The study was reviewed and approved by the local ethics committee of the FHF, Nazareth.

      2.2 Study design

      A retrospective study was carried out to examine the association between serum 25(OH) vitamin D levels and recurrent GAS tonsillopharyngitis in adults. The following were compared between the groups of subjects with and without GAS tonsillopharyngitis: age, gender, body mass index (BMI), serum iron, C-reactive protein (CRP), diabetes mellitus, and serum levels of 25(OH) vitamin D.
      Information concerning medical conditions, drug therapy, and the results of laboratory tests were extracted from the medical charts of each subject in both groups. (In general, every patient who visits the Infectious Diseases Unit or Medicine Clinic completes a standard questionnaire at every visit concerning his/her medical condition, anthropometric information, dietary habits, smoking, drug therapy, family history of different diseases, and systemic bacterial infections.)

      2.3 Sampling and measures

      Laboratory tests were performed within 4 days from the beginning of the tonsillopharyngitis symptoms and included serum CRP levels, creatinine, serum calcium, and serum iron, and a complete blood count. Serum 25(OH) vitamin D levels were measured in the winter and summer seasons (twice a year) for all patients visiting our units. Serum 25(OH) vitamin D levels were measured using a commercial enzyme immunoassay (EIA) kit (IMM, Bensheim, Germany).

      2.4 Definitions

      Tonsillopharyngitis was diagnosed by clinical signs of fever, tonsillar swelling and/or exudates, enlarged and/or tender anterior cervical lymph nodes, without rhinorrhea and cough, and a positive throat culture for GAS or positive rapid GAS antigen test.
      • Bisno A.L.
      • Gerber M.A.
      • Gwaltney Jr., J.M.
      • Kaplan E.L.
      • Schwartz R.H.
      Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis.
      Recurrent GAS tonsillopharyngitis was defined as three or more episodes of GAS tonsillopharyngitis per year for a period of two consecutive years. Obesity was defined as a BMI >30 kg/m2. For laboratory tests, levels considered normal were: CRP 0–0.5 mg/l, serum iron 60–180 μg/dl, serum creatinine 0.67–1.17 mg/dl, and serum calcium 8.1–10.4 mg/dl. The normal range for serum 25(OH) vitamin D levels was considered to be 30–50 ng/ml; we defined vitamin D insufficiency as levels of 25(OH) vitamin D <30 ng/ml and vitamin D deficiency as levels of 25(OH) vitamin D <20 ng/ml.

      2.5 Statistical analysis

      Data were analyzed using SPSS version 19 (IBM SPSS, Chicago, IL, USA). Continuous variables are expressed as the mean ± standard deviation. The Chi-square test was used to test differences in categorical variables between the cases and controls, and analysis of variance (ANOVA) or the Student's t-test was used for comparisons of continuous variables. Spearman rank correlation and univariate regression analysis were used to determine the strength of the relationship between the risk factors for recurrent GAS tonsillopharyngitis, namely age, gender, BMI, diabetes mellitus, creatinine, serum CRP, serum 25(OH) vitamin D, serum iron, and serum calcium. A multiple logistic regression analysis was done to determine the association between the different risk factors for recurrent GAS tonsillopharyngitis. A significance level of <0.05 was used in this test.

      3. Results

      The medical charts of 173 adult patients with acute tonsillopharyngitis were reviewed for the years 2007–2009. Forty-two patients were excluded because of: malignancy (n = 11), taking immunosuppressant drugs (n = 7), renal failure with creatinine clearance <35 ml/min (n = 9), pregnancy (n = 6), connective tissue disease (n = 4), low compliance (n = 3), and vitamin D supplementation (n = 2). One hundred and thirty-one patients with acute tonsillopharyngitis were assessed and a further 77 were excluded because of non-GAS tonsillopharyngitis or no recurrent GAS tonsillopharyngitis. Finally 54 patients with recurrent GAS tonsillopharyngitis were included in the study. Table 1 summarizes the differences between the cases and controls.
      Table 1Demographic clinical, and some clinical laboratory data, cases vs. controls
      CharacteristicCases (n = 54)Controls (n = 50)p-Value
      Age
      Results are mean±SD, or n (%).
      (years)
      41 ± 1342 ± 12NS
      Male sex30 (55%)27 (54%)NS
      BMI
      Results are mean±SD, or n (%).
      (kg/m2)
      27 ± 4.428 ± 5NS
      Diabetes mellitus7 (13%)6 (12%)NS
      Creatinine
      Results are mean±SD, or n (%).
      (mg/dl)
      0.7 ± 0.150.8 ± 0.14NS
      Serum CRP
      Results are mean±SD, or n (%).
      (mg/l)
      4.9 ± 3.32.8 ± 2.20.001
      Serum 25(OH) vitamin D
      Results are mean±SD, or n (%).
      (ng/ml)
      11.5 ± 4.726 ± 70.001
      Serum 25(OH) vitamin D <20 ng/ml
      Results are mean±SD, or n (%).
      50 (92%)4 (8%)0.001
      Serum iron
      Results are mean±SD, or n (%).
      (μg/dl)
      68 ± 3167 ± 40NS
      Serum calcium
      Results are mean±SD, or n (%).
      (mg/dl)
      9.2 ± 0.269.0 ± 1.16NS
      Smoking8 (15%)11 (22%)NS
      SD, standard deviation; BMI, body mass index; CRP, C-reactive protein; NS, not significant.
      a Results are mean ± SD, or n (%).
      The most clear differences were seen in the mean levels of serum CRP and 25(OH) vitamin D. Univariate analysis showed a significant association between male gender, CRP, and serum 25(OH) vitamin D. Table 2 shows the results of the multiple logistic regression analysis for identifying risk factors for recurrent GAS tonsillopharyngitis after adjusting for the confounders of BMI, diabetes mellitus, serum iron levels, serum creatinine, and serum calcium. The analysis showed that serum CRP >3 mg/l and serum 25(OH) vitamin D <20 ng/ml were associated with recurrent GAS tonsillopharyngitis.
      Table 2Results of multiple logistic regression analysis of recurrent GAS tonsillopharyngitis
      VariableOR (95% CI)p-Value
      Male gender1.15 (0. 21–6.38)0.86
      Age0.97 (0. 91–1.03)0.35
      CRP >3 mg/l1.57 (1.13–2.19)0.007
      Serum 25(OH) vitamin D <20 ng/ml1.62 (1.51–1.76)0.001
      GAS, group A Streptococcus; OR, odds ratio; CI, confidence interval; CRP, C-reactive protein.

      4. Discussion

      To the best of our knowledge, this is the first study that has investigated the association between vitamin D and recurrent GAS tonsillopharyngitis in adults. Our findings indicate a link between vitamin D deficiency and the recurrence of GAS tonsillopharyngitis.
      Vitamin D deficiency has been associated with several adverse health consequences that include autoimmune diseases, cardiovascular diseases, and infections.
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      The results of epidemiological studies have demonstrated the existence of a link between vitamin D deficiency and the increased occurrence of pulmonary tuberculosis and respiratory infections.
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      Recently we showed an association between vitamin D insufficiency and the risk of recurrent bacterial infections among adult patients with fatty liver.
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      Aydin et al. showed that vitamin D insufficiency was more prevalent in children with recurrent tonsillitis than in healthy children.
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      Two double-blind randomized controlled trials of vitamin D supplementation have shown that vitamin D reduces the incidence of URT infection.
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      • Haataja R.
      • Pihlajamaki H.
      • et al.
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      • Taha H.
      • Khateeb J.
      • Grosovski M.
      • Assy N.
      Fatty liver is associated with recurrent bacterial infections independent of metabolic syndrome.
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      The “sunshine deficit” and cardiovascular disease.
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      25-Hydroxyvitamin D and risk of myocardial infarction in men.
      The role of vitamin D as an antimicrobial agent acting through multiple mechanisms is becoming increasingly recognized. Bikle reviewed the potential boost to innate immunity by vitamin D.
      • Bikle D.D.
      Vitamin D and the immune system: role in protection against bacterial infection.
      Gombart et al. proposed that 1,25-dihydroxyvitamin D3 induces the expression of the human cathelicidin antimicrobial peptide gene.
      • Gombart A.F.
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      • Koeffler H.P.
      Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3.
      Thus vitamin D has an important role in the production of both cathelicidin and defensins, AMPs that provide a natural defense against potential pathogens, especially in URT infections.
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      • Zacharek M.A.
      Vitamin D: immunomodulation of asthma, allergic rhinitis, and chronic rhinosinusitis.
      • Bartley J.
      Vitamin D, innate immunity and upper respiratory tract infections.
      In our study, we found that CRP levels were higher in patients with recurrent GAS tonsillopharyngitis than in the comparator group, and levels >3 mg/l were found to be associated with recurrent tonsillopharyngitis. The CRP value is usually elevated in patients with GAS tonsillopharyngitis and the CRP test has also been shown to be useful in differentiating GAS tonsillopharyngitis from other kinds of throat infection.
      • Kaplan E.L.
      • Wannamaker L.W.
      C-reactive protein in streptococcal pharyngitis.
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      • Melbye H.
      Does near-to-patient testing contribute to the diagnosis of streptococcal pharyngitis in adults?.
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      • Zeitler H.P.
      Improving diagnostic accuracy of bacterial pharyngitis by near patient measurement of C-reactive protein (CRP).
      Melbye et al. showed that a periodic CRP measurement is an effective tool for monitoring patients with GAS tonsillopharyngitis during antibiotic therapy.
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      • Leinan T.
      Daily reduction in C-reactive protein values, symptoms, signs and temperature in group-A streptococcal pharyngitis treated with antibiotics.
      Previous studies have demonstrated that iron deficiency is prevalent in children with recurrent tonsillitis and in children undergoing adenotonsillectomy.
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      • Logan R.W.
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      • Mira E.
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      Low serum iron levels have been associated with abnormalities in the cell-mediated response as well as a decreased ability of phagocytic cells to kill certain types of bacteria.
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      Iron deficiency and the immune response.
      Elverland et al. showed a beneficial effect of tonsillectomy and adenoidectomy on hemoglobin and iron metabolism and found that iron deficiency was common among children with recurrent tonsillitis and upper airway obstruction.
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      • Ulvik R.J.
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      In our study, we did not find any correlation between serum iron levels and recurrent tonsillopharyngitis in adults.
      We conclude that recurrent GAS tonsillopharyngitis in adults could be related to vitamin D levels. Data from epidemiological studies indicate that vitamin D deficiency has become a common finding in recent years and appropriate replacement may offer immune and antimicrobial benefits. Because measurement of vitamin D levels is easily done and vitamin D supplements are readily obtainable and inexpensive, further studies are needed to assess whether this represents a causal association and whether vitamin D replacement therapy can prevent the recurrence of GAS tonsillopharyngitis.
      Conflict of interest: No conflict of interest to declare.

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