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Clinical Immunology (2007) xx, xxx–xxx

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / y c l i m

Clinical features, long-term follow-up and outcome of

a large cohort of patients with Chronic Granulomatous
Disease: An Italian multicenter study
Baldassarre Martire a,⁎, Roberto Rondelli b , Annarosa Soresina c ,
Claudio Pignata d , Teresa Broccoletti d , Andrea Finocchi e , Paolo Rossi e ,
Marco Gattorno f , Marco Rabusin g , Chiara Azzari h , Rosa M. Dellepiane i ,
Maria C. Pietrogrande i , Antonino Trizzino j , Paolo Di Bartolomeo k ,
Silvana Martino l , Luigi Carpino m , Fausto Cossu n , Franco Locatelli o ,
Rita Maccario o , Paolo Pierani p , Maria C. Putti q , Achille Stabile r,
Luigi D. Notarangelo c , Alberto G. Ugazio s , Alessandro Plebani c ,
Domenico De Mattia a , IPINET (Italian Network for Primary Immunodeficiencies)

Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Italy
Dipartimento di Pediatria, Università di Bologna, Italy
Dipartimento di Pediatria, Università di Brescia, Italy
Dipartimento di Pediatria, Università di Napoli, Italy
Dipartimento di Pediatria Università di Tor Vergata, Roma, Italy
Dipartimento di Pediatria Ospedale “G. Gaslini”, Università di Genova, Italy
Dipartimento di Pediatria, Università di Trieste, Italy
Dipartimento di Pediatria, Università di Firenze, Italy
Dipartimento di Pediatria, IRCSS-Fondazione Policlinico, Università di Milano, Italy
Oncoematologia Pediatrica Ospedale “G. Di Cristina”, Palermo, Italy
Dipartimento di Ematologia Ospedale Civile di Pescara, Italy
Dipartimento di Pediatria, Università di Torino, Italy
U.O.Pediatria Ospedale “Annunziata”, Cosenza, Italy
2° Clinica Pediatrica, Università di Cagliari, Italy
Dipartimento di Oncoematologia Pediatrica, Università di Pavia, Italy
Dvisione di Pediatria Ospedale “G: Salesi” Ancona, Italy
Dipartimento di Pediatria, Università di Padova, Italy
Clinica Pediatrica Università Cattolica del “S. Cuore”, Roma, Italy
Dipartimento di Pediatria, Ospedale “Bambin Gesù”, Roma, Italy

Received 2 August 2007; accepted with revision 27 September 2007

⁎ Corresponding author. Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy. Fax: 0039 080
E-mail address: (B. Martire).

1521-6616/$ - see front matter © 2007 Elsevier Inc. All rights reserved.

Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008
2 B. Martire et al.

KEYWORDS Abstract A retrospective clinical and immunological survey was conducted in 60 patients with
Chronic Granulomatous Chronic Granulomatous Disease. A prospective controlled non-randomized study of the efficacy
Disease (CGD); of long-term IFNγ treatment was carried out.
Interferon gamma (IFNγ); The mean age at the time of diagnosis was 4.4 years; mean duration of follow-up was 10.4 years.
Cotrimoxazole (CTX); Lung and skin infections were the most frequent manifestations both prior to diagnosis and during
Itraconazole (ITRA); follow-up. Aspergillus species was the first cause of infection and of death in our cohort. The
Infections; mortality rate was 13%.
Follow up Long term prophylaxis with IFNγ did not significantly change the rate of total infection per
patient-year compared to controls (p = 0.07). Our data provide clear evidence that protocols of
continuing intensive surveillance and monitoring of compliance with anti-infective regimens may
significantly improve the quality of life and long-term survival in patients with CGD. No evidence
justifying long-term prophylaxis with IFNγ was obtained.
© 2007 Elsevier Inc. All rights reserved.

Introduction Hematology and Oncology (AIEOP), which is now part of the

Italian network of Primary Immunodeficiencies (IPINET),
Chronic Granulomatous Disease is an inherited disorder char- were invited to register the clinical data of patients with a
acterized by defects in superoxide-generating nicotinamide diagnosis of CGD, based on abnormal granulocyte function
adenine dinucleotide phosphate (NADPH) oxidase of phago- tests, in a database. A detailed individual questionnaire to be
cytes, leading to an impaired ability to kill intracellular compiled on enrolment included patients' personal data,
microorganisms [1,2]. NADPH oxidase consists of 3 membrane- family pedigree, state at diagnosis, immunologic data and
associated components: gp91phox–p22phox and rap1a, which clinical manifestations up to enrolment. An annual ques-
together form cytochrome b558 and various cytosolic factors tionnaire which included all relevant clinical features,
(p47phox–p40 phox, p67phox, Rac2) [3] The disease is due to a immunological and therapeutic data, was compiled for
mutation in one of the four genes encoding the four subunits of each year from enrolment to 2005. Sixty patients entered
the oxidase enzyme of phagocytes (gp91phox, p47phox, the study. A senior clinician was responsible for the
p67phox and p22phox, that may lead to total absence, a de- compilation of all questionnaires at each center.
creased amount, or a defective functional protein product) [4]. Diagnosis of CGD was based on abnormal granulocyte
The mutations in CYBB (gp91phox, Xp21.1) account for function tests evaluated by: nitroblue tetrazolium test (NBT)
two thirds of cases. The remainder are autosomal recessive in 50 patients (83%), dihydrorhodamine 123 flow cytometric
cases and lack either p47phox (chromosome 7q11.23) analysis in 21 cases (35%), impaired chemiluminescence
(approximately 30% of patients), p67phox (1q25) or production in 15 patients (25%), impaired or absent super-
p22phox (16q24) (5% of patients, respectively) [5–7]. oxide production by Fe3+ cytochrome C reduction in 6 cases
Patients with CGD suffer from recurrent life-threatening (10%). All tests were performed on isolated granulocytes
bacterial and fungal infections and from abnormally exuber- after stimulation with phorbol myristate acetate and/or
ant inflammatory responses leading to granuloma formation zymosan particles.
in multiple organs [1,2]. Long-term oral prophylaxis with Western Blot analysis was conducted on membrane and
cotrimoxazole and itraconazole has been shown to reduce cytosolic fractions of granulocytes in 6 patients (10%). CYBB
the rate of infection among patients with CGD [8–11]. A gene sequence analysis was carried out in 25 (42%) affected
further reduction of the infection rate has been described males and their relatives when possible. The mutation
with IFNγ [12–15]. analysis was performed by DHPLC (Denaturing High-Perfor-
There is a wide range of clinical variability in patients with mance Liquid Chromatography) followed by sequence ana-
CGD. Up to now, despite several decades of work on CGD, only lysis (data not shown).
a few large multicenter studies have been carried out with the The diagnosis of CGD was confirmed in all patients by at
aim of defining the natural history of the disease. In order to least two different diagnostic tests.
evaluate the long-term clinical course in patients with CGD, The mode of inheritance was determined according to
also with respect to currently used antimicrobial prophylactic family history and granulocyte function tests in parents and
measures, we conducted a multicenter retrospective survey of siblings when available.
60 patients with a definitive diagnosis of CGD. Patients were considered to have the X-recessive form of
the disease if they had mutation in the gene for gp91phox, or
both a positive family history of a lateral male relative with
Materials and methods the disease and their mother showing 2 distinct populations
of phagocytic cells with respect to the production of reactive
Patients oxygen metabolites. Patients were considered to have the
autosomal recessive form of the disease if a deficiency of
In 2001, 38 Italian centers belonging to the Immunodefi- p22 phox, p47 phox or p67 phox was documented by
ciency Working Group of the Italian Association of Pediatric immunoblotting.

Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008
Clinical features, long-term follow-up and outcome of a large cohort of patients with CGD 3

Statistical analysis Table 1 Infections by site before diagnosis in 60 CGD

Participating centers were required to register all consecu-
Infection °N patients (%) #N infections
tive CGD cases, adopting a web-based data-base created by
Oracle and protected by IANUS® technology, implemented at Pneumonia 28 (47%) 62
the Interuniversity Computing Center (CINECA), in Bologna. Lung abscess 2 (3%) 2
Data are stored in a central database, organized at the AIEOP Subcutaneous abscess 12 (20%) 25
Operation Office. Dermatitis 16 (26%) 23
Standard statistical descriptions of parameters were used Lymphadenitis 27 (45%) 35
to characterize the data (mean, median, and range). Fisher's Liver abscess 10 (16%) 16
exact test was used to compare differences in percentages Osteomyelitis 10 (16%) 12
for categorical variables, whereas Student's t test was Enteritis 6 (10%) 6
adopted to compare means for continuous variables. Perirectal abscess 5 (8%) 9
The infections incidence rate per patient-year of follow- Septicemia 3 (5%) 3
up for the main infection categories was calculated overall Otitis 3 (5%) 3
and for two different anti-infective prophylaxis regimens. Other ⁎ 9 (15%) 9
The measure of association used was the relative risk as °Number and percentage (%) of patients who had at least one
estimated by the odds ratio. Summary relative risks were episode of infection.
computed by the maximum likelihood method; a 95% confi- #Total number of infections.
dence interval was calculated by use of a test-based esti- ⁎Includes: 1 urinary tract infection, 1 appendicitis, 1 conjuncti-
mation procedure. A two-tailed significance test for trend vitis, 1 orchitis, 1 meningitis, 1 brain abscess, 1 hydrosadenitis,
was computed by the Mantel extension of the Mantel– 1 mammary abscess and 1 fungal esophagitis.
Haenszel procedure.
Survival (SUR) probability was calculated, overall and for families with multiple affected siblings in the same sibship
two different anti-infective prophylaxis regimens, by the only. There were 10 sets of siblings: 9 male sets, including
Kaplan–Meier method. Comparisons between probabilities in three siblings in one single family and one pair of male-and-
different patient groups were performed using the log-rank female siblings.
test. In the SUR analysis, all deaths were considered failures. X-linked inheritance was demonstrated in 39 (65%)
SUR was calculated for all cases from diagnosis to date of patients, autosomal recessive inheritance in 6 patients
death or date of last follow-up, if alive. Results were ex- (10%) (5 with gp47phox and 1 with gp22phox deficiency). In
pressed as probability and 95% confidence interval (95% CI). 15 patients (25%) the mode of inheritance remained
All P values are 2-sided and values less than 0.05 were undetermined because of inconclusive data or parents
considered statistically significant. unavailability. The diagnosis of CGD was made at a mean
Analyses used December 31, 2005 as the reference date, age of 4.4 years (median 2.5 years, range 0–38 years); the
i.e. the day at which all centers locked data on patient mean age at the onset of symptoms was 1 year (median
outcomes. 7.5 months, range 0–10 years). The age at diagnosis was
Computations were performed using the STATA package significantly lower in the X-recessive group compared with
(StataCorp LP, College Station, Texas, USA). the autosomal recessive group: mean 3.1 years (median
2 years, range 0–13 years) versus 5.8 years (median 5.5 years;
range 2–9 years), respectively. Likewise the age at onset of
Results symptoms was different between the two groups: mean
14 months (median 7 months, range 0–5 years) versus mean
Sixty patients (58 males and 2 females) with a definitive 30 months (median 1 year, range 0–9 years). The number of
diagnosis of CGD were included in the present study. Fifty-six diagnoses markedly increased during the last three decades:
patients were of Italian origin; of the remaining 4 patients, 1 half of the cohort was diagnosed in the last 10 years (Fig. 1).
was from the United States, and one each were from Albania, Although the majority of patients with CGD, i.e. 36 (60%)
Libya and Romania. were diagnosed before the age of 5 years and 12 (20%) in the
Family history was negative for CGD in 39 patients (65%) first year of life, a significant number of patients, i.e. 11
and positive in the remaining 21 (35%), who belonged to 10 (18%) were not diagnosed until the second decade and in 1
case the diagnosis was made at 38 years of age.

Clinical manifestations up to diagnosis

The clinical presentation of CGD related infections was

reviewed retrospectively from the medical records of all 60
patients. All infections were described according to the site
of infection and the infective agent when available. In
agreement with previous studies [12,15] an infection was
considered severe when hospitalization or treatment with
parenteral antibiotics or antifungals were required.
Figure 1 Number of patients with CGD diagnosed in the last 3 The frequency and type of infections reported before
decades. diagnosis are shown in Table 1.

Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008
4 B. Martire et al.

Lung infections (pneumonia/pulmonary abscess) were follow-up was 10.4 years while the total period of observation
the most prominent clinical problem, observed in 50% (30/ was 491 years. Infections remained the most relevant clinical
60) of the patients. Dermatitis/subcutaneous abscess were problem even after anti-infective prophylaxis was started.
the second most frequent clinical finding, occurring in 46% The total number of infections recorded was 316, of which
(28/60) of the patients. Lymphadenitis was diagnosed in 45% 132 (41%) were severe. The annual incidence of overall and
(27/60), while liver abscess and osteomyelitis each occurred serious infections was 0.64 and 0.26, respectively, and of mild
in 16% of the patients (10/60). Among gastrointestinal infec- infections was 0.37 (total number 184). Notably, a higher rate
tions, enteritis and perirectal abscess were recorded in 10% of total infections was documented within the autosomal
(6/60) and in 8% (5/60) of the patients, respectively. Septi- recessive patients group compared with the X-recessive
cemia and otitis were each experienced by 3 patients (5%). group (0.94 vs 0.44), although most were mild infections
Other infections were reported in 9 patients (15%), including (0.78). Conversely, the rate of serious infections resulted
2 with CNS infections (1 patient with meningitis, 1 with brain higher in the X-recessive group of patients (0.26 vs 0.15).
aspergillosis), 1 with appendicitis, 1 with hydrosadenitis, 1 Detailed data on site, type and annual incidence of
with conjunctivitis, 1 with a urinary tract infection, 1 with or- infections are reported in Table 2.
chitis, 1 with a mammary abscess and 1 with fungal esophagitis. In the overall cohort, lung (pneumonia and pulmonary
At diagnosis the majority of patients 35% (18/60) abscess) and skin infections (dermatitis and subcutaneous
presented with lymphadenitis. Notably, gastrointestinal abscess) were the commonest findings, occurring in 48.5% (23/
infections were observed in a substantial number: 26% (16/ 47) and 38% (18/47) of the patients, respectively. Interestingly,
60) of the patients, while lung infections were reported in the frequency of stomatogingivitis and gastrointestinal tract
25% (15/60) of the patients. Skin infections, osteoarthritis/ infections significantly increased during follow-up, affecting
osteomyelitis and urinary tract infections were each 35% (16/47) and 25% (12/47) of the patients, respectively.
recorded in 8% of the patients (5/60). Finally, 3 patients Lymphadenitis and liver abscess were also reported in a sig-
(5%) presented with CNS infections. nificant number of patients 28% (13/47) and 21% (10/47).
Perirectal abscess, septicemia and low urinary tract infections
Clinical manifestations during follow-up each affected 15% (7/47) of the patients. Other recorded in-
fections were: otitis in 13% (6/47) of the patients; conjunctivitis
After enrolment, the attending physicians were required and osteomyelitis in 4 patients (8.5%), respectively, brain
to compile an annual questionnaire reporting the patients' abscess and sinusitis each in 3 patients (4%). Finally, an episode
clinical data. of mastoid abscess occurred in 1 patient (2%).
During follow-up clinical data were available for 47 Stomatogingivitis and pneumonia were the infections with
patients (45 males, 2 females): 30 patients with X-recessive the highest annual infection rates encountered during the
CGD, 6 with the autosomal form and 11 with an unknown follow-up: 0.12 and 0.1, respectively.
inheritance pattern of the disease. At last follow-up Furthermore, a significant recurrence of mild infections
(December 2005) the patients' mean age was 15.6 years was observed in a small number of patients, mainly
(median 15 years, range 2–38 years), mean duration of consisting of dermatitis and low urinary tract infections (38

Table 2 Localization, frequency and annual infection incidence of 316 infections in 47 patients with CGD during follow-up
Localization All documented infections Severe infections
N infections N patients(%) ⁎Annual infection N infections N patients (%) Annual infection
incidence incidence
Stomatogingivitis 61 16 (35%) 0.12
Pneumonia 45 20 (42.5%) 0.09 45 20 (42.5%) 0.09
Lung abscess 3 3 (6%) 0.006 3 3 (6%) 0.006
Dermatitis 46 16 (34%) 0.09 8 7 (15%) 0.016
Subcutaneous abscess 2 2 (4%) 0.004 2 2 (4%) 0.004
GI tract infections 30 12 (25%) 0.06 5 5 (10%) 0.01
Luti 29 7 (15%) 0.06 3 1(2%) 0.006
Conjunctivitis 23 4 (8.5%) 0.046
Lymphadenitis 21 13 (28%) 0.04 21 13 (28%) 0.04
Septicemia 13 7 (15%) 0.026 13 7 (15%) 0.026
Liver abscess 12 10 (21%) 0.02 12 10 (21%) 0.02
Otitis 11 6 (13%) 0.02 3 1 (2%) 0.006
Perirectal abscess 7 7 (15%) 0.01 7 7 (15%) 0.01
Osteomyelitis 5 4 (8.5%) 0.01 5 4 (8.5%) 0.01
Brain abscess 4 3 (6%) 0.008 4 3 (6%) 0.008
Sinusitis 3 3 (6%) 0.006
Mastoid abscess 1 1 (2%) 0.002 1 1(2%) 0.002
Total infections 316 132
⁎The annual infection incidence was calculated as number of infections/number of years of observation.

Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008
Clinical features, long-term follow-up and outcome of a large cohort of patients with CGD 5

and 26 episodes occurred in 6 and 4 patients, respectively), Table 3 Isolation of microorganisms from 50 infections in
but also of enterocolitis and conjunctivitis (25 and 23 CGDpatients
infections reported in 7 and 4 patients).
Infection Pathogen ⁎N of
Etiology of infections
Pneumonia Aspergillus spp. 9
Candida spp. 4
Infectious agents were isolated in 50 out of the overall 521
S. pneumoniae 2
infections reported (Table 3). The search for microoganisms
Actinomyces israelii 1
was not performed in most cases, in many others negative
S. aureus 1
cultures were obtained despite a proper procedure such as
M. tuberculosis 1
bronchoalveolar lavage, blood culture, needle aspiration or
Pseudomonas 1
biopsy. Fungal infections were the first cause of illness in our
Klebsiella pneumoniae 1
patients. Aspergillus species, cultured or diagnosed by
Suppurative S. aureus 3
biopsy, was the most frequently isolated organism, found in
adenitis Atypical Mycobacteria 1
over 34% of the isolates, thus resulting the first cause of
Osteomyelitis Aspergillus spp. 4
pneumonia, brain abscess and osteomyelitis. Candida spe-
Serratia spp. 1
cies was responsible for a substantial number of pneumonia
Liver abscess S. aureus 1
and sepsis episodes (4 and 2, respectively). Staphylococcus
Serratia marcescens 1
aureus was the most prominent among the bacterial
Subcutaneous S. aureus 2
infections, resulting the first agent of suppurative adenitis
abscess Serratia spp. 2
and skin infections. Other microorganisms involved were
Suppurative S. aureus 3
Gram negative – such as Serratia marcescens and Burkol-
deria cepacia – identified in 5 and 2 infections, respectively.
Meningitis H. influentiae 1
Notably, unusual pathogens such as Mycobacteria were
Burkolderia cepacia 1
isolated in one episode each of pneumonia and lymphade-
Brain abscess Aspergillus spp. 3
nitis. Other rare findings were Actinomyces israelii and
Sepsis Candida spp. (Famata, 2
Peptostreptococcus, detected in one patient and causing
pneumonia and mastoid abscess, respectively.
Serratia marcescens 1
Salmonella spp. 1
Non-infectious findings E. coli 1
Enterocolitis Candida albicans 1
A wide spectrum of disorders was observed in patients with Mastoid abscess Peptostreptococcus 1
CGD for which no infectious etiology was identified. ⁎Number of infectious episodes in which the specific organism
Inflammatory and/or rheumatic complications were reported was isolated.
in 11 out of 47 patients (23%). Gastrointestinal manifestations
of no infectious origin were seen in most cases: in 3 patients
who had developed persistent abdominal pain and diarrhea patients with a body surface area of N 0.5 m2 or a dosage of
without an infectious cause, ulcerative rectocolitis (2 cases) 1.5 mcg/kg for those with a body surface area of b 0.5 m2;
and chronic inflammatory bowel disease (1 case) were the drug was administered subcutaneously 3 times a week.
diagnosed, confirmed by endoscopy and histopathology Sixteen patients (27%) received cotrimoxazole plus itraco-
(data not shown). One patient had esophagitis and 1 nazole and 6 (10%) commenced only cotrimoxazole. Other
esophageal diverticulitis. A diagnosis of celiac disease was prophylactic schedules were adopted in the remaining
made in 1 case. Ureteral granulomatous obstruction was patients including: cotrimoxazole with amphotericin B or
reported in 1 patient with hydronephrosis. Two patients voriconazole (2 patients each, 7% overall) or cotrimoxazole
developed systemic lupus erythematosus and discoid lupus in association with IFNγ and fluconazole (2 patients). Fur-
erythematosus, respectively. Lupus-like erythematous thermore, one patient was treated with itraconazole and
lesions were also described in one X-recessive carrier mother. IFNγ and 2 patients received no prophylaxis. At last follow-
Finally, 1 patient developed erythema nodosus on the lower up a different distribution of the patients among the
limbs and 1 chorioretinitis. Notably, all these findings were prophylactic regimens was recorded. The percentage of
observed in patients with the X-recessive form of CGD. patients treated with CTX, itraconazole and IFNγ had
reduced to 30% whereas patients who received CTX alone
Infection prophylaxis or in association with itraconazole had increased up to 11%
and 43%, respectively. Cotrimoxazole was administered in
There is a general consensus on the use of continuous anti- combination with voriconazole in 3 (6%) patients or with
bacterial (TMP_SX) and antifungal drugs, starting at diag- IFNγ in 2 (4%) patients. Finally, 3 out of 47 patients (6%)
nosis, as a prophylactic regimen for infectious episodes. refused any further prophylaxis. If we analyze the course of
Analysis of the recorded data showed a great variability in the anti-infective prophylaxis during the study period from
terms of the efficacy of the prophylactic regimen applied. At diagnosis to the last follow-up, we observe that the
diagnosis, 29 out of the 60 patients (48%) received TMP-SMX at percentage of patients receiving cotrimoxazole and itraco-
a dose of 6–8 mg/kg body weight b.i.d., itraconazole in a single nazole increased from 82% to 85% and from 63% to 72%,
dose of 10 mg/kg up to 200 mg and IFNγ at a dose of 50 mcg for respectively, whereas the percentage of patients treated

Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008
6 B. Martire et al.

Table 4 Patients characteristics and incidence of infections lasting 5 years, from enrolment in the registry to December
with different prophylaxis regimens 2005, was carried out.
Ten patients who had received prophylaxis with cotrimox-
azole, itraconazole and IFNγ since diagnosis, were compared
with 25 patients who were being treated only with
(N patients: 25) (N patients: 10) cotrimoxazole and itraconazole or had interrupted adminis-
X recessive patients 16 6
tration of IFNγ because of adverse events. The mean ages at
Autosomal recessive 3 0
first infection and at diagnosis were not statistically
different in the two groups. Patients characteristics and
the incidence of recorded infections are shown in Table 4.
Undetermined 6 4
The overall observation period was 28 and 53 years for
genotype patients
patients treated with and without IFNγ, respectively. There
N of patient-years of 53 28
were 83 infections overall during the study in the group
treated with cotrimoxazole and itraconazole, compared with
Mean age at 1st 20 8 0.09
10 infections reported in IFNγ arm, with no statistical
infection (months)
difference in the infection rate per patient-year between the
Mean age at diagnosis 70 53 0.49
two groups: 0.06 vs 0.03 (p = 0.07).
The number of severe infections was 19 and 3 in each
N of total infections 83 10
group, with a rate of infection per patient-year of 0.014 and
N of severe infections 19 3
0.01 respectively, (p = 0.68).
N of mild infections 64 7
To investigate the potential effect of IFNγ in reducing
⁎Rate of total 0.06 0.03 0.07
certain types of infection, we analyzed the incidence of each
infections per
severe infection reported in both groups of patients. In no
case did the infection rate per patient-year result signifi-
⁎Rate of severe 0.01 0.01 0.68
cantly reduced in IFNγ recipients (Table 5). Likewise no
infections per
significant difference was found in the incidence of mild
infections between the two arms of the study 0.04 vs 0.02
⁎Rate of mild 0.04 0.025 0.08
(p = 0.08), despite a lower number of infections in the IFNγ
infections per
arm (7 vs 64).
P value b 0.0 5 was considered statistically significant. Causes of death and survival rate
⁎The infection rate per patient-year of follow-up was calculated
as: number of infections/number of years of observation/number
Six (13%) out of 47 patients died during the observation
of patients.
period at a median age of 14 years (range 20 to 28 years): 3
patients with X-recessive CGD (median age 18 years, range
with IFNγ reduced from 53% to 34%. The main reason leading 22 to 28 years), 1 patient with the autosomal recessive form
to the interruption of IFNγ prophylaxis was the onset of of the disorder (age 14 years) and 2 with an unidentified
adverse events, most of all fever, then myalgia, headache, genetic form of the disease (aged 15 and 28 years).
fatigue and rash, that in some cases failed to reverse even Two out of six bone marrow transplanted patients died of
after the administration of acetaminophen. No adverse effects complications related to the transplant: 1 patient who
caused by cotrimoxazole or itraconazole were recorded. underwent transplantation from an unrelated HLA-identical
To monitor the efficacy of long-term IFNγ treatment, a donor died of cardiopulmonary failure, the other, who had
prospective controlled non-randomized open follow-up study received an HLA-identical stem cell graft, developed chronic

Table 5 Type and rate of severe infections with different prophylaxis regimens
Infection CTX + ITRA CTX + ITRA + IFNγ P
(N patients: 25) (N patients: 10)
N infections ⁎Infection rate patient/year N infections ⁎Infection rate patient/year
Pneumonia 8 0.006 0 0 0.21
Lymphadenitis 1 0.0007 2 0.007 0.08
Liver abscess 2 0.001 0 0 0.68
Osteomyelitis 0 0 1 0.003 0.17
Enteritis 2 0.001 0 0 0.68
Septicemia 4 0.003 0 0 0.46
Brain abscess 1 0.0007 0 0 0.82
Mastoid abscess 1 0.0007 0 0 0.82
P value b 0.0 5 was considered statistically significant.
⁎The infection rate per patient-year of follow-up was calculated as: number of infections/number of years of observation/number of

Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008
Clinical features, long-term follow-up and outcome of a large cohort of patients with CGD 7

reported in other studies [16,18]. One can speculate that since

the majority of cases of CGD are inherited in an X-linked
recessive fashion, there might have been a bias in favor of
testing for the disease in males and therefore in the selection
of patients.
Among our cohort, the relative preponderance of cases
with an X-recessive inheritance compared with autosomal
recessive CGD corresponds to that of other groups [18,19].
Eleven patients were diagnosed as having CGD before the
onset of symptoms, on the basis of a positive family history.
The majority of patients developed symptoms before the age
of 1 year, while median delay was 2 years between the onset
of symptoms and the diagnosis, that is significantly shorter
than the delay reported for other registries [18,19]. As in the
previous studies [16,17,19], also in our cohort patients with
the X-recessive form of CGD were diagnosed significantly
earlier than those with the autosomal recessive form of the
Figure 2 Kaplan–Meier overall survival curve after diagnosis disease. Although the numbers are not high enough to
of CGD for the entire cohort of patients. SURp: survival prob- compare the clinical courses of the different genetic types of
ability; SE: standard error. CGD, our data seem to show a higher prevalence of mild
infections among autosomal recessive patients, suggesting
that the clinical phenotypes of the X-recessive and the
autosomal recessive forms of CGD differ mainly in terms of
GVHD and died of interstitial pneumonia. (The analysis of severity rather than of the frequency of infection.
data on bone marrow transplantation is in progress.) The initial clinical manifestations of the disease vary
The remaining patients died owing to infectious causes: among series; according to literature data the most common
1 patient died of pneumonia caused by Candida famata clinical feature is lymphadenitis [19,20]. In the present study
accompanied by concurrent sepsis and multiple liver the majority of patients had experienced at least one
abscesses sustained by S. marcescens. Three patients died episode of pneumonia before diagnosis, whereas lymphade-
from Aspergillus species infection (pulmonary in 2 cases and nitis resulted the most frequent finding encountered at
cerebral in 1); in one case Aspergillus nidulans started in the diagnosis, being therefore the infection that most frequently
lung and then spread to the thoracic spine and to the right allowed physicians to diagnose CGD.
gastrocnemius muscle. Pneumonia was also the most prominent clinical problem
Infections caused by Aspergillus species resulted the most observed during follow-up, together with a significant
common cause of death, accounting for half of all deaths increase in the frequency of oral and gastrointestinal infec-
(3 patients overall). tions. Actually, stomatogingivitis resulted the third cause of
The survival rate for all 47 patients was 97%, 83% and morbidity after lung and skin infections in our cohort, and
46% at 10, 20 and 25 years since diagnosis, respectively, the first among the mild infections. Recently, it has been
displaying a prolonged survival plateau beyond this time pointed out that multiple infections in patients with CGD are
(Fig. 2). sustained by different strains of the same few species of
bacteria [21]. In agreement with these observations, we also
detected a peculiar recurrence of infections such as
Discussion dermatitis, low urinary tract infection, stomatogingivitis
and conjunctivitis in a limited number of patients.
This is the first extensive survey of CGD carried out in Italy with The incidence of infection per patients-year of exposure
the aim of gathering quantitative data on the clinical has been taken as an outcome measure to evaluate the
presentation and long-term complications associated with natural clinical course of the disease and the efficacy of
this disease. To this purpose, a detailed individual question- various prophylactic treatments. It has also been used as a
naire to be compiled on enrolment in 2001, and each year up to parameter to compare data reported in different cohorts of
2005, was obtained from 16 of the 38 Italian centers belonging patients followed in various countries.
to the Immunodeficiency Working Group of the Italian In our survey the annual incidence of overall infections
Association of Pediatric Hematology and Oncology (AIEOP). was 0.64 and 0.26 for serious infections, regardless of the
Sixty patients with a definitive diagnosis of CGD were included genetic subtype of CGD and the prophylactic regimens
in the study. From the registry, the prevalence of CGD in our adopted.
country was estimated to be approximately 1/1,000,000 We reviewed the literature for studies reporting inci-
individuals, different from the rates reported in other coun- dences of infection in patients with CGD (Table 6). Cale et al.
tries: 1/1,300,000 individuals in Japan [16] and 1/450,000 [22] found an overall rate of 0.7 infections patients-year in
individuals in Sweden [17]. Half of the cohort was diagnosed in an English cohort with CGD followed in a single center and
the last decade, so this could be due to a better knowledge and treated with prophylactic antibiotics and itraconazole with-
awareness of this disease among physicians as well as to the out IFNγ. Liese et al. [19] reported an annual infection
longer survival of patients over time. In our registry, the incidence of 0.79 in a series with only a small proportion of
incidence of CGD in female is much lower (3%) than those patients treated with IFNγ. In our study the overall rate of

Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008
8 B. Martire et al.

Table 6 Summary of the published and present studies in patients with CGD
Characteristic International International Weening Bemiller Cale Liese Marciano Martire
CGD Study CGD Study (14)
Group Group
1990 1991 1995 1995 2000 2000 2004 2007
Method Double-blind, Double-blind, Phase IV, Phase IV, Retrospective Retrospective Phase IV, Questionnaire
randomized, randomized, prospective prospective prospective survey
phase III, phase III, retrospective
prospective prospective
N of patients 65 63 28 30 21 39 76 47
Duration of 0.9 ND 3 1 10 22 9 5
Total 95 ND 68.4 31 70 610 328.4 491
Rate of ND ND ND ND 0.7 0.79 ND 0.64
per year
Rate of 1.1 0.38 0.4 0.13 ND 0.27 0.3 0.26
per year
Mortality 0 ND 0 0 0 20 6.6 13
rate (%)
Subjects 0 100 100 100 0 ND 100 34
with IFNγ
ND: not detected.

0.64 infections patients-year is lower than that of other CGD patient groups, followed in various countries, which
European cohorts. Moreover, the incidence of severe infec- may have different standard medical practice in terms of
tions (0.26) was similar to that reported by Liese (0.27), but hospitalization and/or parenteral anti-infectious therapy
lower than those seen by Weening et al. (0.4) [13] and more were compared.
recently by Marciano et al. (0.38), respectively in two In our controlled prospective follow-up study lasting
cohorts of patients all treated with IFNγ [15]. The difference 5 years, IFNγ did not significantly change the rate of total
in the relative incidence of infections between the present and severe infections per patient-year between the two
and the previous studies may be related to a variety of prophylactic regimen arms. Furthermore, the rate of infec-
factors, including the number of patients reported, the tion in both arms was the lowest ever described in multi-
changing clinical expression of the disorder over time, center studies, thus strongly suggesting that anti-infective
durations and intensities of observation and the way in prophylaxis together with intensive surveillance and expert
which information on specific infections was requested and/ management play a key role in the outcome and in the
or reported. quality of life of CGD patients.
The long-term use of IFNγ as prophylaxis for patients with Since the previous studies on CGD, the relative prevalence
CGD has been widespread since the 1990s. Despite many of different bacteria and fungi has changed [25,26]. In our
years of studies, the utility of IFNγ therapy remains study the search for microoganisms was not performed in most
controversial. While the International CGD Study Group cases, in many others it failed to detect any infectious agents
[12] reported a significant efficacy in the IFNγ arm, other despite a proper procedure; therefore our data might reflect a
European centers later demonstrated that the incidence bias in sampling, leading to an underestimation of their real
rates of infection using only antibiotic prophylaxis were prevalence. Nevertheless, the spectrum of pathogens isolated
lower than those seen in the IFNγ arm in the USA sites in this study is comparable to those already published
[19,23], thus suggesting a powerful center effect of these [16,19,20]. Aspergillus species was the most frequently
studies [24]. Recently, in an uncontrolled, open-label follow- isolated organism, accounting for one-third of the overall
up study, Marciano et al. [15] demonstrated the safety and isolates, and resulting the first cause of pneumonia, brain
efficacy of long-term IFNγ prophylaxis for CGD patients as abscess and osteomyelitis. S. aureus resulted the most common
compared to the findings of previously published studies. bacterial pathogen, isolated in the majority of cases of
Again, the crucial point is that data obtained from different suppurative adenitis and subcutaneous abscesses. Finally,

Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008
Clinical features, long-term follow-up and outcome of a large cohort of patients with CGD 9

S. marcescens was found in many patients with osteomyelitis, may be attributable to a greater awareness of the disease, to
liver and subcutaneous abscesses. Further series of patients the ability to establish a correct diagnosis early in life and to
reported in literature show unequivocally that Aspergillus the earlier start of anti-infective prophylaxis. However all
species has emerged as a significant pathogen over time and is these conditions seem only to have delayed the fatal
now the major cause of infectious complications and death in outcome to adulthood, while the survival rate in the third
patients with CGD [16,19,20]. On the other hand unusual decade of life has not significantly changed over the last
organisms, uncommon in normal hosts, are also being more 10 years. Another feature in our cohort is that half of the
frequently found in these patients [27–29]. Our data are deaths have been ascribed to Aspergillus species infection,
consistent with these observations and emphasize the crucial displaying a higher rate than the one reported by Winkelstein
importance of making a microbiologic diagnosis in every case and Liese (35% and 37%, respectively). Despite advances in
before starting anti-infective therapy. antifungal therapy, Aspergillus spp. remains the first cause
Non-infectious complications, above all inflammatory and of death for patients with CGD.
rheumatic conditions, have been widely reported in patients
with CGD [30–33]. The etiology and pathogenesis of these
disorders are still unclear. Histologically they reflect
granuloma formation, thought to occur secondarily to a
failure of phagocytes to clear both esogenous and endogen- The data presented herein provide clear evidence that the
ous antigens [34]. Polymorphisms in several components of prognosis for patients with CGD has significantly improved
the innate immune system, such as mannose binding lectin since its original description. Early diagnosis, aggressive
and Fc gamma receptors, may contribute to the develop- management of infections, continuing intensive surveillance
ment of these complications [35]. In our cohort these and monitoring of compliance to anti-infective regimens
disorders mainly involved the gastrointestinal tract. Involve- have had a positive effect on the morbidity and mortality
ment of the gut has been recently described to occur in a rates of the disease. However, the problem of invasive fungal
significant number of patients with CGD, especially among infections remains critical for these patients and only a
those with the X-linked form of the disease [36,37]. The GI longer follow-up will show whether the new advances in
pathology is characterized by a patchy distribution and well- antimicrobial therapy will allow a long-term survival or will
formed granulomata in which a dysregulated or exuberant only delay the fatal outcome for a few years. Our study does
inflammatory response appears to play a critical role [38]. not provide evidence justifying long-term prophylaxis with
The current series is not large enough to determine the IFNγ in CGD patients.
prevalence of these disorders and whether they are
correlated with different genetic types of CGD, but we Acknowledgments
noted that all complications occurred in patients with X-
recessive CGD. The occurrence of these disorders clearly has
We thank all the patients and families for their generous
a severe impact on the quality of life of patients and may
cooperation in the study. We are grateful to the Centers
have a cumulative effect as they grow into adulthood.
participating in the Italian Primary Immunodeficiencies Net-
Therefore, monitoring and assessment of these effects are
work (IPINET).
crucial steps in the management of these patients.
The outcome of patients with CGD has significantly changed
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Please cite this article as: B. Martire, et al., Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic
Granulomatous Disease: An Italian multicenter study, Clin. Immunol. (2007), doi:10.1016/j.clim.2007.09.008