Journal of Clinical Immunology, Vol. 27, No. 3, May 2007 ( C
©
2007)
DOI: 10.1007/s10875-007-9075-1
Long-Term Follow-Up and Outcome of a Large Cohort of Patients
with Common Variable Immunodeficiency
ISABELLA QUINTI,
1,10
ANNAROSA SORESINA,
2
GIUSEPPE SPADARO,
3
SILVANA MARTINO,
4
SIMONA DONNANNO,
1
CARLO AGOSTINI,
5
PIGNATA CLAUDIO,
6
DAMMACCO FRANCO,
7
ANNA MARIA PESCE,
1
FEDERICA BORGHESE,
1
ANDREA GUERRA,
1
ROBERTO RONDELLI,
8
ALESSANDRO PLEBANI,
2
and WITHIN THE IPINET (Italian Primary Immunodeficiency Network)
9
Received November 17, 2006; accepted January 19, 2007
Published online: 14 February 2007
Common Variable Immunodeficiency belongs to the group of
rare diseases encompassing antibody deficiency syndromes of
highly variable clinical presentation and outcome. The multicen-
ter prospective study on a cohort of 224 patients with Common
Variable Immunodeficiency provides an updated view of the
spectrum of illnesses which occurred at the clinical onset and
over a long period of follow-up (mean time: 11 years) and infor-
mation on the effects of long-term immunoglobulin treatment.
The mean age at the time of diagnosis was 26.6 years. Seventy-
five patients were younger than 14 years of age. The mean age
at the onset of symptoms was 16.9 years. This implicates with a
mean diagnostic delay of 8.9 years. Respiratory tract infections
were the most prominent clinical problem observed at diagnosis
and during the follow-up. Intravenous immunoglobulin admin-
istration induced a significant reduction in the incidence of acute
1
Department of Clinical Immunology, University of Rome “La
Sapienza” Rome, Rome, Italy.
2
Department of Paediatrics, University of Brescia, Owensboro,
Kentucky.
3
Department of Allergy and Clinical Immunology, University of Naples
“Federico II,” Naples, Italy.
4
Department of Paediatrics, University of Turin, Torino, Italy.
5
Department of Internal Medicine, University of Padua, Padua, Italy.
6
Department of Pediatrics, University of Naples “Federico II,” Naples,
Italy.
7
Department of Biomedical Sciences, University of Bari, Bari, Italy.
8
Department of Onco-Haematology, University of Bologna, Bologna,
Italy.
9
IPINET: De Mattia D, Martire B, Bari, Cossu F, Cagliari, Schirillo´G,
Catania, Castagnola E, Genova, Pietrogrande MC, Delle Piane RM,
Milano, Putti C, Padova, Trizzino A, Amato GM, Palermo, Bertolini
P, Parma, Zecca M, Pavia, Consolini R, Pisa, Moschese V, Rossi P,
Cancrini C, Roma, Cazzola GA, Verona.
10
To whom correspondence should be addressed to Department of
Clinical Immunology, University of Rome “La Sapienza” Rome,
Viale dell’Universita` 37 00186, Rome, Italy; e-mail: isabella.quinti@
uniroma1.it.
infections, mainly acute pneumonia and acute otitis. However,
a progressive increase in the prevalence of patients with chronic
diseases, mainly sinusitis and lung disease, was observed in all
age groups, including the pediatric population. The morbidity
of Common Variable Immunodeficiency due to all associated
clinical conditions increased over time despite an adequate re-
placement with intravenous immunoglobulins. Our data stressed
the need to develop international guidelines for the prevention
and therapy of chronic lung disease, chronic sinusitis, chronic
diarrhoea, and chronic granulomatosis in patients with humoral
immunodeficiencies.
KEYWORDS: common Variable Immunodeficiency; intravenous im-
munoglobulins; chronic lung disease; pneumonia; mortality.
INTRODUCTION
Common Variable Immunodeficiency (CVID) is the most
frequent symptomatic antibody deficiency, characterized
by low levels of serum immunoglobulins and impaired
antibody response. Most cases are sporadic, approxi-
mately 20% are familiar, displaying autosomal dominant
and autosomal recessive traits (1–4). CVID is a late-onset
hypogammaglobulinemia, but it may also occur in
infancy (5, 6). The clinical spectrum includes respiratory
infections, gastrointestinal diseases, autoimmune
diseases, granulomatous manifestations, and cancers
(7–11). Long-term administration of immunoglobulins
reduces the incidence of infections (12–18). However,
despite IgG replacement, CVID patients may still suffer
from respiratory infections, caused by encapsulated
bacteria, leading to permanent lung damage (8–10).
Abbreviation used CVID: Common Variable Immunodeficiency; IVIG:
intravenous immunoglobulins; CLD: chronic lung disease; XLA: X-
linked Agammaglobulinemia; NHL: non-Hodgkin lymphoma.
308
0271-9142/07/0500-0308/0 C© 2007 Springer Science+Business Media, LLC

CVID AND IVIG TREATMENT 309
We have collected information on 224 CVID patients
enrolled in a multicenter prospective study in order to pro-
vide an updated view of the spectrum of illnesses which
occurred at the time of onset and over a mean of 11.5 years
of follow-up. Moreover, we gathered information on the
effect of long-term immunoglobulin replacement therapy.
METHODS
In 1999, 26 Italian Centers belonging to the Italian Pri-
mary Immunodeficiency Network started to submit data
for patients with a CVID diagnosis. Diagnosis was made
in patients over 2 years of age by approved criteria (2)
including low levels of serum IgG, IgA, and/or IgM, an-
tibody deficiency with impaired response to tetanus and
pneumococcal antigen immunization, peripheral B cell
numbers of >2%, and exclusion of hypogammaglobu-
linemia due to other primary or secondary immunodefi-
ciencies. Detailed information with personal data, pedi-
gree, date of diagnosis, immunological data and clinical
manifestations, and route and dosage of immunoglobu-
lin replacement from diagnosis to the time of enrolment
were collected in a semistructured questionnaire filed by
one physician per center at the time of enrolment and on
a yearly basis up to 2005. All data were processed in a
database and sent to the Interuniversity Computing Center
(CINECA) responsible for processing and analyzing the
data. For each patient, complete blood counts, lymphocyte
subsets, chemistries, serum immunoglobulin levels, and
cultures tests were performed four times per year. Chest
and sinus-computerized tomography (CT) scans were per-
formed every 4 years, and gastrointestinal endoscopy with
biopsy every 2 years or when indicated.
Our multicenter study has been designed according to
the World Medical Association Declaration of Helsinki
ethical principles for medical research involving human
subjects.
Statistical Methods
All information was stored, controlled, and analyzed
by an integrated system of software facilities. Differences
between males and females and of ages classes were tested
with Wilcoxon rank-sum tests. Fisher’s exact test was used
to compare differences in percentages for categorical vari-
ables. Student’s t test was adopted to compare means for
continuous variables. All p values are two-sided and val-
ues <0.05 were considered significant. The SAS package
(SAS Institute, Cary, NC) was used for the analysis of
the data. Follow-up time was calculated as the time be-
tween diagnosis and the date of last annual questionnaire
send to CINECA. The observed numbers of cancer cases
were compared with the expected numbers calculated to
yield the Standardized Prevalence Ratio (SPR). Associ-
ated 95% confidence intervals (CI) were calculated under
the assumption that the observed number of cancer cases
followed a Poisson distribution, by use of Byar’s approx-
imation. Significantly increased SPRs have lower confi-
dence limits that are above or equal to 1.01. This means
that the p value for obtaining the SPR estimate is less than
0.05 under the null hypothesis that the observed number
of cancers in the study population is not different from the
expected number in the general population. Probabilities
of survival after diagnosis of CVID were estimated from
Kaplan–Meier life tables.
RESULTS
We enrolled 224 CVID patients, 111 males and 113
females. The mean age at the time of diagnosis was
26.6 years (range 2–73). Seventy-five patients were
younger than 14 years of age. The mean age at the onset of
symptoms was 16.9 years (range 2–66). This implicates
with a mean diagnostic delay of 8.9 years (in 55% of
patients, the diagnosis was made within 5 years from the
clinical onset) (Fig. 1). Patients were followed-up for a
mean time of 11.5 years (range 3–34).
A
B
0
10
20
30
40
50
60
2_5 6_10 11_20 21_30 31_40 41_50 > 50
age groups
n
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m
b
e
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o
f
p
a
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t
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0
20
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2_5 6_10 11_15 16_20 > 20
years
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p
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t
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Fig. 1. Age at diagnosis (panel A) and years of diagnostic delay
(panel B).
Journal of Clinical Immunology, Vol. 27, No. 3, 2007