The association between vitamin D levels and recurrent group A streptococcal
tonsillopharyngitis in adults
William Nseira,b,e,*, Julnar Mograbia,b, Zuhair Abu-Rahmehc, Mahmud Mahamida,
Omar Abu-Elhejaa, Adel Shalatad
aDepartment of Internal Medicine, Infectious Disease Unit, Holy Family Hospital, POB 8, 16100, Nazareth, Israel
bInfectious Diseases Unit, Holy Family Hospital, Nazareth, Israel
cDepartment of Radiology, Holy Family Hospital, Nazareth, Israel
dDepartment of Pediatrics, Holy Family Hospital, Nazareth, Israel
eFaculty of Medicine on the Galilee, Bar-Ilan University, Safed, Israel
In the adult population, acute tonsillopharyngitis accounts for
1–2% of all visits to outpatient clinics, physician offices, and
emergency departments.1Approximately 5–17% of acute tonsillo-
pharyngitis cases are due to a bacterial infection, often to group A
b-hemolytic streptococci (GAS).2,3The 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), bacte-
rial tolerance, and other unknown reasons.4–13
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.14Recently, epidemiological studies have demonstrated a
correlation between vitamin D concentration and the incidence
of respiratory infections.15–18Moreover, scientific evidence
shows the important role of vitamin D in the immune
system.19,20The antimicrobial peptides (AMPs) defensin and
cathelicidin, which are the principal defense factors of the upper
respiratory tract (URT), are upregulated by vitamin D.21,22Aydin
et al. showed that vitamin D insufficiency was more prevalent in
children with recurrent tonsillitis than in healthy children.23
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 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.
International Journal of Infectious Diseases 16 (2012) e735–e738
A R T I C L E
I N F O
Received 23 December 2011
Accepted 11 May 2012
Corresponding Editor: William Cameron,
Group A Streptococcus
S U M M A R Y
Objectives: To determine the association between recurrent group A streptococcal (GAS) tonsillophar-
yngitis 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 tonsillophar-
yngitis 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
Conclusions: Our findings indicate a link between vitamin D deficiency and the recurrence of GAS
? 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +972 46508942; fax: +972 46508973.
E-mail address: email@example.com (W. Nseir).
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1201-9712/$36.00 – see front matter ? 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
2. Materials and methods
This study included adult patients with recurrent tonsillophar-
yngitis 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 tonsillo-
pharyngitis: 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).
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.24Recurrent
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 mg/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 ? stan-
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 tonsillophar-
yngitis, 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.
The medical charts of 173 adult patients with acute tonsillo-
pharyngitis 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 supplemen-
tation (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 sum-
marizes the differences between the cases and controls.
Demographic clinical, and some clinical laboratory data, cases vs. controls
Cases (n = 54)
Controls (n = 50)
Serum 25(OH) vitamin Da(ng/ml)
Serum 25(OH) vitamin D <20 ng/mla
41 ? 13
27 ? 4.4
0.7 ? 0.15
4.9 ? 3.3
11.5 ? 4.7
68 ? 31
9.2 ? 0.26
42 ? 12
28 ? 5
0.8 ? 0.14
2.8 ? 2.2
26 ? 7
67 ? 40
9.0 ? 1.16
SD, standard deviation; BMI, body mass index; CRP, C-reactive protein; NS, not significant.
aResults are mean ? SD, or n (%).
W. Nseir et al. / International Journal of Infectious Diseases 16 (2012) e735–e738
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
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 tonsillopharyngi-
Vitamin D deficiency has been associated with several adverse
health consequences that include autoimmune diseases, cardio-
vascular diseases, and infections.25–27The results of epidemiologi-
cal studies have demonstrated the existence of a link between
vitamin D deficiency and the increased occurrence of pulmonary
tuberculosis and respiratory infections.28,29Recently we showed
an association between vitamin D insufficiency and the risk of
recurrent bacterial infections among adult patients with fatty
liver.30Aydin et al. showed that vitamin D insufficiency was more
prevalent in children with recurrent tonsillitis than in healthy
children.23Two double-blind randomized controlled trials of
vitamin D supplementation have shown that vitamin D reduces the
incidence of URT infection.31,32In contrast one randomized
controlled trial showed that there was no benefit of vitamin D
supplementation in decreasing the incidence of symptomatic URT
There is a growing epidemic of vitamin D deficiency, and its
consequences beyond bone health are still not well known.
However, early reports have linked it to cardiovascular conditions,
immune diseases, and infections.25–30,34,35The 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.36Gombart et al. proposed
that 1,25-dihydroxyvitamin D3 induces the expression of the
human cathelicidin antimicrobial peptide gene.37Thus 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.38–41
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.42–44Melbye et al. showed that
a periodic CRP measurement is an effective tool for monitoring
patients with GAS tonsillopharyngitis during antibiotic therapy.45
Previous studies have demonstrated that iron deficiency is
prevalent in children with recurrent tonsillitis and in children
undergoing adenotonsillectomy.46,47Low 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.48Elverland 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.49
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
Conflict of interest: No conflict of interest to declare.
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Results of multiple logistic regression analysis of recurrent GAS tonsillopharyngitis
OR (95% CI)
CRP >3 mg/l
Serum 25(OH) vitamin D <20 ng/ml
1.15 (0. 21–6.38)
0.97 (0. 91–1.03)
GAS, group A Streptococcus; OR, odds ratio; CI, confidence interval; CRP, C-reactive
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