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Oral manifestations in patients with hypogammaglobulinemia

Article · June 2012

DOI: 10.1016/j.oooo.2012.02.006 · Source: PubMed

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 Vol. 114 No. 3 September 2012

Oral manifestations in patients with hypogammaglobulinemia

Karin Sá Fernandes, DDS,a Cristina Maria Kokron, MD, PhD,b Myrthes Toledo Barros, MD, PhD,b
Jorge Kalil, MD, PhD,b and Marina Gallottini, DMD, PhD,c São Paulo, Brazil
UNIVERSITY OF SãO PAULO

Objective. The overall objective of this study was to assess the oral manifestations and their association with immunologic
status and health history, of individuals with hypogammaglobulinemia.
Study Design. A case-controlled study of 100 subjects with hypogammaglobulinemia and 93 control individuals was
performed. All participants were examined for dental caries, periodontal disease, mucosal lesions/infections, and general oral
health problems. Decayed, missing, filled teeth and community periodontal index were recorded. Complete blood count,
serum immunoglobulins, and lymphocyte immunophenotyping were measured on the same day of the oral health
assessment.
Results. Individuals with hypogammaglobulinemia showed higher prevalence of enamel hypoplasia and complaints of dry
mouth, and lower prevalence of dental caries and periodontal disease.
Conclusions. The systemic conditions associated with hypogammaglobulinemia were not associated with enhanced
susceptibility to caries, gingivitis, or periodontitis; however, individuals with hypogammaglobulinemia were more likely to
report more episodes of recurrent aphthous ulcers compared with control individuals. (Oral Surg Oral Med Oral Pathol Oral
Radiol 2012;114:e19-e24)

Hypogammaglobulinemia is a set of disorders charac- severe primary hypogammaglobulinemias and remains

terized by low levels of serum immunoglobulins. It is
associated with numerous etiologies and can be classi-
fied as primary or secondary.1 Primary hypogam-
maglobulinemia is a rare group of genetic disorders that
includes common variable immunodeficiency (CVID)
(prevalence of 1:50,000), X-linked agammaglobuline-
mia (XLA) (prevalence of 1:100,000), and hyper-IgM
syndrome (HIgM) (prevalence of 1:1 million).2 Sec-
ondary hypogammaglobulinemia can be caused by in-
fectious diseases, metabolic disorders, malignancies,
medications, such as glucocorticosteroids and immuno-
modulatory drugs, environmental exposures, and mal-
nutrition.3 In general, individuals with primary hypog-
ammaglobulinemia are highly susceptible to bacterial
infections, especially of the respiratory tract, infectious
and inflammatory gastrointestinal diseases, autoim-
mune conditions, and lymphoproliferative and granulo-
matous diseases.4
The type of primary hypogammaglobulinemia is de-
termined by evaluation of clinical features and labora-
tory phenotypes. CVID is one of the more common
a
Post-graduate student, Department of Oral Pathology, School of
Dentistry, University of São Paulo, Brazil.
b
Professor, Division of Clinical Immunology and Allergy, School of
Medicine, University of São Paulo, Brazil.
c
Professor and Chair, Department of Oral Pathology, School of
Dentistry, University of São Paulo, Brazil.
Received for publication Jul 10, 2011; returned for revision Jan 13,
2012; accepted for publication Feb 11, 2012.
© 2012 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
doi:10.1016/j.oooo.2012.02.006
predominantly a diagnosis of exclusion. Individuals
with CVID present with a history of recurrent infec-
tions, low immunoglobulin, and poor response to im-
munization protocols. In general, these individuals suf-
fer from the disease for many years before their
immunodeficiency is recognized.2,5,6
Oral manifestations in individuals with hypogam-
maglobulinemia have rarely been studied. The main
oral features reported include lichenoid lesions, peri-
odontal disease, pseudomembranous candidiasis, re-
current aphthous ulcer (RAU), and enamel hypopla-
sia.7,8
Despite all the knowledge about oral microbial ecol-
ogy and the role of immunoglobulins, little is known
about the oral consequences of antibody deficiencies or
how oral problems can interfere with the general well-
being of people with hypogammaglobulinemia. Immu-
noglobulin (Ig)G, IgM, and IgA antibodies may influ-
ence the oral microbiota by interfering with adherence
or by inhibiting bacterial metabolism.9 IgG antibodies
are capable of carrying out all of the functions of
immunoglobulin molecules, being a good opsonin, en-
hancing phagocytosis, and killing of oral microorgan-
isms through activation of complement. IgA plays an
important role in mucosal immunity, and enhances the
antimicrobial activity of lactoferrin, salivary peroxi-
dase, agglutinins, and mucins.10
Presently, individuals with hypogammaglobulinemia
tend to live longer because of better treatment with
immunoglobulin replacement therapy and antibiotics.
In earlier reports on CVID, 23% to 30% of individuals
died during a follow-up period of 1 to 25 years (mean

e19
ORAL MEDICINE
e20 Sá Fernandes et al.
of 7.5 years).11 In more recent years, of the 334 subjects
with CVID studied from the European Society for
Immune Deficiency Registry, only 15% (51 subjects)
died during a follow-up period of 22.5 years.11
Because of increased longevity, it is expected that
the demand for oral health services by these patients
will increase. It is important for oral health care pro-
viders to be aware of possible complications associated
with these diseases and to offer appropriate and safe
dental treatment. In this context, the aim of this study
was to assess the oral manifestations in individuals with
hypogammaglobulinemia and correlate these manifes-
tations with the participants’ immune status and health
history.
MATERIAL AND METHODS
This case-controlled study was designed to document
oral health conditions in individuals with primary hy-
pogammaglobulinemia compared with a suitable con-
trol group of persons without the disease. This project
was approved by the Ethics Committee of the Hospital
das Clinicas, Medical School of the University of Sao
Paulo (USP), and written informed consent was ob-
tained from all participants.
We enrolled 100 individuals with hypogammaglobu-
linemia (study group [SG]) who received medical care
at the Immunology and Allergy Clinic at the Medical
School Hospital and 93 individuals (control group
[CG]) with no immunologic disorders who were receiv-
ing routine dental care at the Dental School of USP.
Clinical examination was conducted by single exam-
iner, a trained oral medicine dentist, experienced in the
use of the caries and periodontal indexes, under artifi-
cial light using a mouth mirror, explorer, and a peri-
odontal probe. Demographic data; medical histories;
alcohol, tobacco and illicit drug use; self-reported co-
morbidities; medications; oral complaint question-
naires; and dental histories were elicited. Examinations
were performed to assess lymphadenopathies, salivary
gland enlargements, oral lesions, caries, and periodon-
tal statuses. A diagnosis of Sjögren’s syndrome was
established by rheumatologists from the Medical
School Hospital, following the American-European
Consensus Group classification criteria for Sjögren’s
syndrome.12
Blood samples were collected on the same day as the
oral assessments were performed. Laboratory analyses
included a complete blood cell count, serum immuno-
globulins (IgA, IgG, IgM), lymphocyte immunopheno-
typing (CD3⫹ T cells, CD4⫹ T cells, CD8⫹ T cells, B
cells, natural killer cells), and serologies for viral hep-
atitis and human immunodeficiency virus (HIV).
Oral mucosa lesions were assessed clinically, and
biopsies or brush cytologies were performed when nec-
OOOO
September 2012
essary. Gingivitis was assessed by a visual inspection
of the gingiva that took into consideration the color and
firmness of gingival tissue and the presence of bleeding
on probing. The periodontal condition of the partici-
pants was assessed through bleeding on probing, the
community periodontal index, and the simplified peri-
odontal record.13 Caries status was assessed by the
DMFT index (number of decayed, missing, and filled
teeth). Enamel hypoplasia was diagnosed by visual
examination of the teeth for white, yellow, or brownish
coloration with a rough or pitted surface. Candidiasis
was confirmed through brush cytology.
All participants were questioned about past oral
health history, such as episodes of RAU, opportunistic
infections (herpes simplex and candidiasis), oral com-
plaints, and tooth sensitivity. A dry mouth complaint
was confirmed by clinical visualization of the mucosa
and an inquiry of a subjective feeling of having too
little saliva and having difficulties in swallowing. Pres-
ence of actual or perceived oral dryness was correlated
to diseases and disorders associated with xerostomia,
such as diabetes and Sjögren’s syndrome, and the use
of medication that could cause dry mouth.
Statistical analysis was conducted using GraphPad
Prisma 5.0 (GraphPad Prism version 5.0 for Windows,
GraphPad Software, San Diego CA), assuming statis-
tical significance if P was less than .05. Fisher’s exact
test was used to compare variables, and the ␹2 test was
used to compare the CG and the SG for the occurrence
of oral manifestations, to associate oral alterations with
immune status, and to analyze the use of antibiotics
with the presence or absence of periodontal disease.
RESULTS
One hundred participants with hypogammaglobuline-
mia were matched with 93 individuals with no immu-
nologic disease, which represents almost (90%) the
totality of patients seen at the Immunology and Allergy
Clinic at the Medical School Hospital and during 2010
and 2011. Table I details matching and baseline infor-
mation. The matching procedure created 2 groups that
were very similar, except participants in the SG were
more frequently self-identified as white and less fre-
quently as smokers.
Among the 100 individuals with hypogammaglobu-
linemia, most presented with CVID (78%), followed by
XLA (8%), hypogammaglobulinemia without a defined
cause (6%), HIgM (3%), secondary hypogammaglobu-
linemia (3%), combined immunodeficiency (1%), and
specific antibody deficiency (1%). The average age of
symptomatic disease onset was 14 years, and median
time elapsed from the first signs and the establishment
of the diagnosis was 6 years. All individuals from the
SG received parenteral immunoglobulin replacement
OOOO
Volume 114, Number 3
Table I. Demographic data (n ⫽ 193)
Individuals enrolled
in the study Self-identified race Gender
100 from study group 97 White 51 female
2 Blacks 49 male
1 Asiatic origin
93 from control group 63 White 58 female
28 Mulatto 35 male
2 Asiatic origin
monthly. In spite of this, most of the participants (74/
100) reported at least 1 bacterial infection in the pre-
vious 5 years, such as gastrointestinal infection, urinary
tract infection, or pneumonia. At the time of examina-
tion, 57 subjects were using antibiotics (20 penicillin,
20 azithromycin, 15 bactrim, and 2 ciprofloxacin).
Most of the participants from the SG (86/100 indi-
viduals) reported at least 1 comorbidity, the most fre-
quent being bronchiectasis (50/100 individuals), fol-
lowed by gastritis (36/100 individuals) and anemia
(30/100 individuals). Hypertension and hypothyroidism
were reported by 11 individuals; depression by 8; dia-
betes and viral hepatitis by 6; Sjögren’s syndrome by 2;
and renal failure, HIV infection, recent myocardial
infarction, valve prolapse and heart murmur by 1 indi-
vidual. Among the 93 participants from the CG, 32
(34.4%) reported at least 1 comorbidity: hypertension
(15/93; 16.1%), diabetes (8/93; 8.6%), or anemia (6/93;
6.4%). The results of the blood sample analyses for the
SG are shown in Table II.
When questioned about their predominant oral dis-
comfort, 37 of the 100 individuals from the SG had
some complaint, such as episodes of RAU (27/37), oral
herpes (23/37), gingival bleeding (5/37; 13.5%), or
dental hypersensitivity (4/37; 10.8%).
Most oral abnormalities were diagnosed clinically
and no biopsies were required. Brush cytology was
carried out on 3 participants to confirm the diagnosis of
candidiasis. The individuals from the CG exhibited a
greater incidence of caries, gingivitis, and periodontitis
compared with the SG (P ⬍ .05).
Among the participants from the SG, 18 presented
with gingivitis and 8 with periodontitis. Nine had
bleeding on probing, 9 had calculus and bleeding on
probing, 7 had moderate pocket depths (probing depth
of 4 and 5 mm), and 1 had deep pockets (probing depth
⬎6 mm). Ten participants who presented with gingivi-
tis and 4 with periodontitis were taking broad-spectrum
antibiotics at the time of the dental examination. Sta-
tistical analysis revealed that there was no statistically
significant relationship between the use of antibiotics
and the absence of periodontal disease (P ⫽ .63).
Enamel hypoplasia and dry mouth were more prev-
alent in the SG (P ⬍ .05). Overall, the prevalence of
ORIGINAL ARTICLE
Sá Fernandes et al. e21
Alcohol Tobacco Illicit drug
Age users users users
From 15 to 77 0 5 0
Median age ⫽ 35
From 18 to 70 15 24 3
Median age ⫽ 39
dental caries in the SG was low, with 79% of the
individuals being caries free. Caries rate was lower in
the SG compared with the CG (11.93 DMFT compared
to 14.5 DMFT). Percentage of decayed teeth and miss-
ing teeth of the SG patients was lower than the CG, and
the percentage of filled teeth was higher. Table III
summarizes the oral conditions found in all the indi-
viduals enrolled in this study.
Our present study did not find a statistically signifi-
cant relationship between frequency of caries and IgA
levels (P ⫽ .7188), gingivitis and CD4⫹ T-cell count
(P ⫽ .0731), periodontitis and CD4⫹ T-cell count (P ⫽
.2862), gingivitis and IgA levels (P ⫽ 1), periodontitis
and IgA levels (P ⫽ 1) or between the use of antibiotics
and the presence of periodontal disease (P ⫽ .6376).
DISCUSSION
To the best of our knowledge, this is the largest study
focusing on oral manifestations in people with primary
hypogammaglobulinemia. Our results showed a low
frequency of oral diseases in general, and low rates of
caries and periodontal infection. This contrasts with
other studies that found a higher rate of periodontal
disease and caries in individuals with primary hypog-
ammaglobulinemia, which was attributed to the low
levels of salivary IgA.14,15 In our study, we found only
21% of the SG subjects with caries compared with the
83% (10 among 12) found by Cole et al.14 On the other
hand, our results are in agreement with Dahlén et al.,16
whose findings did not support the hypothesis that
antibody-deficient individuals show an increased risk
of developing periodontal disease or caries. One possi-
ble explanation for the different results from Cole et
al.14 can be the age of the studied patients and smaller
sample size. Cole et al.14 included children, whereas
Dahlén et al.16 studied only adults. Both groups re-
ceived treatment based on immunoglobulin replace-
ment, and the samples were composed of only 12 and 6
individuals, respectively.
Because our CG was individuals who sought dental
treatment, we compared the DMFT of the population of
the state of Sao Paulo (SP) with the CG. The results
showed that that the caries rate in the CG and of the
ORAL MEDICINE OOOO
e22 Sá Fernandes et al. September 2012

Table II. Serum immunoglobulin levels and peripheral uals from the CG, and with the population index for the
blood cells counts of subjects from SG same age range.13 The frequency of filled teeth was
Variable below reference range greater in the SG than in the CG. The larger proportion
within the reference range No. of subjects from of filled teeth in the SG could be explained by the fact
above the reference range SG 100 (100%) that individuals with hypogammaglobulinemia re-
IgA (mg/dL) n ⫽ 97 ceived more attention to their dental needs compared
⬍40 80 (82.4%)
with the CG because they were under continuous health
40-382 17 (17.5%)
⬎382 0 supervision.
IgG (mg/dL) n ⫽ 98 We did not find any relationship between low serum
⬍650 47 (47.9%) IgA levels and the periodontal diseases and caries.
650-1538 51 (52.0%) Although Kirstilä et al.19 demonstrated that plasma
⬎1538 0
levels of IgA are similar to salivary levels of IgA, we
IgM (mg/dL) n ⫽ 97
⬍40 76 (78.3%) did not measure salivary levels, which can be consid-
40-171 16 (16.5%) ered a limitation of this study.
⬎171 5 (5.2%) We have to consider that many individuals from the
CD3⫹ T cells (cells/mm3) n ⫽ 45 SG (57%) were taking broad-spectrum antibiotics at the
⬍605 4 (8.9%)
605-2460 38 (84.4%)
time of the dental clinic examination. Nevertheless, 10
⬎2460 3 (6.7%) patients who presented with gingivitis and 4 with peri-
CD4⫹ T cells (cells/mm3) n ⫽ 45 odontitis were among the antibiotic users. Of those
⬍493 16 (35.6%) patients who were not using antibiotics (n ⫽ 43), 8
493-1666 27 (60%) presented with gingivitis and 4 with periodontitis. Sta-
⬎1666 2 (4.4%)
CD8⫹ T cells (cells/mm3) n ⫽ 45
tistical analysis revealed that there was no association
⬍224 4 (8.9%) between the use of antibiotics and the absence of peri-
224-1112 32 (71.1%) odontal disease in these patients.
⬎1112 9 (20%) Enamel hypoplasia was more prevalent in individu-
CD19 (cells/mm3) n ⫽ 45 als from the SG. A history of respiratory infection,
⬍72 20/44.4%
72-520 24 (53.3%) urinary tract infection, and otitis during odontogenesis
⬎520 1 (2.2%) predisposes patients to enamel hypoplasia. Enamel hy-
NK (cells/mm3) n ⫽ 45 poplasia can also occur as a side effect of fever epi-
⬍73 11 (24.4%) sodes and certain medications, especially antibiotics,
73-654 33 (73.3%)
such as penicillin. All of these events may occur in
⬎654 1 (2.2%)
Hemoglobin (g/dl) n ⫽ 98 children with hypogammaglobulinemia.20-22
ⱕ9 1 (1%) At the time of the oral clinical examination, we
ⱕ9 - ⱖ13 29 (29.6%) observed only 2 participants from the SG with RAU
⬎13 68 (69.4%) and none with oral herpes; however, 27 individuals
Neutrophil (mil/mm3) n ⫽ 98
from this group reported repeated episodes of RAU.
⬍1 1 (1%)
1-7 97 (99%) The immunopathogenesis of RAU probably involves
Leukocytes (mil/mm3) n ⫽ 98 cell-mediated responses, involving T cells and tumor
⬍4 13 (13.3%) necrosis factor-␣,23-25 and this may explain the higher
4-11 85 (86.7%) frequency among patients with hypogammaglobuline-
NK, natural killer; SG, study group. mia. It is estimated that approximately 20% of the
general population has episodes of RAU.26
population of SP were higher than the rate among the In our study, 6 individuals from the SG complained
SG. of xerostomia and presented with oral dryness, and 2 of
The role of decreased IgA in the incidence of caries them had been previously diagnosed with Sjögren’s
is still not completely understood. Some authors have syndrome. Patients with hypogammaglobulinemia, es-
stated that salivary immunoglobulin is responsible for pecially patients with CVID, are susceptible to autoim-
covering bacteria, which may facilitate phagocytosis by mune disorders.4,27,28 The production of autoantibodies
oral neutrophils, thus reducing the risk for caries.17 may be one of the consequences of the defects in
Furthermore, IgA deactivates glycosyltransferases, antibody affinity maturation.29
which reduces extracellular glucan synthesis and bac- Most individuals with hypogammaglobulinemia
terial plaque formation.18 Our results revealed a lower present with several different comorbidities, such as
rate of caries and a lower DMFT score in individuals bronchiectasis, autoimmunity, chronic diarrhea, granu-
with hypogammaglobulinemia compared with individ- lomatous diseases, and malignancies. Bronchiectasis
OOOO ORIGINAL ARTICLE
Volume 114, Number 3 Sá Fernandes et al. e23

Table III. Oral manifestations of SG and CG individuals

Number of individuals Number of individuals
from SG presenting from CG presenting
Oral manifestations the manifestation 100 (100%) the manifestation 93 (100%) P value
Subjective information collected on
Reported herpes simplex 23 (23%) 0 ⬍.05
Reported RAU 27 (27%) 18 (19%) .2357
Disorders discovered through examination
Enamel hypoplasia* 21 (21%) 0 ⬍.05
Caries* 21 (21%) 66 (70.97%) ⬍.05
Gingivitis* 18 (18%) 31 (33.33%) ⬍.05
Periodontitis* 8 (8%) 44 (47.31%) ⬍.05
Moderate pocket (PD 4-5 mm) 7 18
Deep pocket (PD ⬎6 mm) 1 26
Dry mouth* 6 (6%) 0 ⬍.05
Geographic tongue 5 (5%) 0 .0601
RAU 2 (2%) 0 .4981
Traumatic ulcer 2 (2%) 0 .4981
Amalgam tattoo 1 (1%) 0 1
Actinic cheilitis 1 (1%) 0 1
Fissured tongue 1 (1%) 0 1
Conoid teeth 1 (1%) 0 1
Agenesis 1 (1%) 0 1
Candidiasis 0 3 (3.22%) .110
CG, control group; PD, probing depth; RAU, recurrent aphthous ulcer; SG, study group.
*Statistically significant difference between the SG and CG.

was the most frequent comorbidity that occurred in this
group. It is defined as an irreversible dilation of part of
the bronchial tree, most often secondary to an infec-
tious process. Common symptoms of bronchiectasis
include recurrent cough, sputum production, shortness
of breath, and fatigue as lung function decreases. For
these individuals, shorter visits and upright dental chair
positions are recommended.
Individuals enrolled in this study needed immuno-
globulin replacement therapy, as they were unable to
produce adequate levels of IgG, IgA, and IgM and
failed to produce antibodies against antigens. A pooled
IgG extracted from the plasma of blood donors is
administered intravenously, every 3 to 4 weeks, in a
dose ranging from 100 to 400 mg/kg of body weight.
Although parenteral Ig replacement monthly has been
shown to be safe and effective in CVID, infections are
not uncommon, and the choice of an appropriate anti-
biotic therapy is indicated in the setting of acute infec-
tion.
In general, for individuals with hypogammaglobu-
linemia under general treatment, the complete blood
cell count presents normal range values; however, even
when individuals receive parenteral immunoglobulin
replacement monthly, the serum immunoglobulin con-
centration is under the normal limits. Our results show
that 36% of the 100 SG individuals showed a CD4⫹
T-cell count below 493 cells/mm3, 30% showed hemo-
globin levels below 13 g/dL, and only 1% exhibited
neutrophil counts below 1000 cells/mm3. For the pur-
poses of routine dental treatment, including simple
tooth extractions, we considered the following values to
be critical values: platelet count below 50,000 per dL,
and neutrophil count below 500 cells/mm3.30 Although
the presence of critical values in blood counts is rare
among people with hypogammaglobulinemia, it is
mandatory to request a complete blood count examina-
tion before invasive dental procedures in these patients.
There is no scientific or clinical evidence to support the
use of prophylactic antibiotics before invasive dental
treatments in individuals with hypogammaglobuline-
mia with a normal neutrophil count.
Based on our observations in this cohort, hypogam-
maglobulinemia was not associated with enhanced sus-
ceptibility to caries, gingivitis, or periodontitis; how-
ever, enamel hypoplasia and dry mouth may be more
common in affected individuals compared with healthy
participants. Oral health care for patients with hypog-
ammaglobulinemia should be coordinated with the pa-
tient’s immunologist so that oral complaints can be
addressed in a timely manner.
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Reprint requests:
Marina Gallottini, DMD, PhD
Department of Oral Pathology, Dental School
University of São Paulo
Lineu Prestes, 2227, São Paulo
SP, Brazil 05508-000
mhcgmaga@usp.com.br