Chronic granulomatous diseases; a comprehensive care Presented by Athipat Athipongarporn, MD. December15, 2017

1. Athipat Athipongarporn MD

2. OVERVIEW
▪ Chronic granulomatous disease (CGD) was first identified as a distinct immunodeficiency in
the 1950s
▪ The disease was initially termed “fatal granulomatous disease of childhood”
▪ chronic suppurative lymphadenitis, hepatosplenomegaly, pneumonia and diffuse pulmonary
infiltrates, and eczema
▪ The disease was initially described in boys (and therefore considered to be exclusively X-
linked inheritance) and was characterized by hypergammaglobulinemia
Isaac P. Thomsen et. al. JACI.2016

3. OVERVIEW
▪ Before the introduction of oral antifungals, mortality rates ranged from 2% per year among
those with autosomal-recessive CGD to 5% per year among those with X-linked CGD
▪ Although long-term survival is dependent on several factors, overall survival into adulthood
with CGD is now around 90%
▪ Although significant morbidity due to frequent infectious and inflammatory complications
remains common

4. EPIDEMIOLOGY
▪ X-CGD is characterized by defective intracellular killing of bacteria and fungi. The true
incidence of this condition is unknown, but it is estimated to occur at a frequency of 1 in
500,000 births
▪ In 1968, CGD was identified in a female patient, leading to the discovery of autosomal-
recessive forms of the disease

5. ETIOLOGY
▪ The genetic basis for CGD lies in any of the 5 structural genes encoding the phagocytic oxidase
(phox) subunits of the nicotinamide adenine dinucleotide phosphate oxidase complex
▪ Approximately two-third of CGD cases in the United States are caused by mutations in CYBB, which
is present on the X chromosome and encodes the heme-containing Nox2 subunit (also known as
gp91phox).
▪ Biallelic mutations in the other 4 genes (CYBA, neutrophil cytosolic factor 1 [NCF1], NCF2, and
NCF4) are associated with autosomal-recessive CGD.
▪ Mutations in NCF1 are the second most common cause of CGD
▪ Female CYBB mutation carriers are often phenotypically normal
▪ there are reports of women with heterozygous mutations who have the X-linked CGD phenotype due to
skewed inactivation of the normal X chromosome by lyonization
▪ when the number of neutrophils capable of a normal oxidative burst falls below approximately 15%, classic
CGD symptoms may be seen

6. PHAGOCYTOSIS

8. NADPH OXIDATION
American Society for Blood and Marrow Transplantation.2011.1083-8791

9. INHERITANCE
▪ The genetic basis for CGD lies in any of the
5 structural genes encoding the
phagocytic oxidase (phox) subunits of the
nicotinamide adenine dinucleotide
phosphate oxidase complex
Song et al. Clinical and Molecular Allergy 2011, 9:10

10. INHERITANCE
▪ Female CYBB mutation carriers are often phenotypically normal.
▪ When the number of neutrophils capable of a normal oxidative burst falls below
approximately 15%, classic CGD symptoms may be seen

11. DIAGNOSIS
▪ Early clinical manifestations of CGD include
▪ Recurrent upper and lower respiratory tract infections
▪ Failure to thrive
▪ Visceral abscesses, cellulitis, lymphadenitis
▪ Granulomatous lesions in hollow viscera without apparent organisms.
▪ Sites of infection most often include the lungs, lymph nodes, skin, and liver
▪ Chronic granulomatous disease is phenotypically diagnosed by measurement of the
neutrophil oxidative burst, which in the current era is done most commonly via the
dihydrorhodamine assay

12. INFECTION IN CGD
Clinic Rev Allerg Immunol (2010) 38:3–10
The pathogenicity of organisms was once thought to be due to their production of catalase, an enzyme that degrades
the organism’s own hydrogen peroxide, thus depriving the phagocyte of additional reactive oxygen species
American Society for Blood and Marrow Transplantation.2011.1083-8791

13. CATALASE POSITIVE BACTERIA
▪ Catalase Test
▪ The catalase test is used to differentiate staphylococci (catalase-positive) from streptococci
(catalase-negative).
▪ The enzyme, catalase, is produced by bacteria that respire using oxygen, and protects them
from the toxic by-products of oxygen metabolism.
▪ Catalase-positive bacteria include strict aerobes as well as facultative anaerobes, although
they all have the ability to respire using oxygen as a terminal electron acceptor.
▪ Catalase-negative bacteria may be anaerobes, or they may be facultative anaerobes that only
ferment and do not respire using oxygen as a terminal electron acceptor (ie. Streptococci).
Catalase positive bacteria: Staphylococcus, Bacillus spp.,
Enterobactriaceae, Listeria Monocytogenes

14. CATALASE POSITIVE BACTERIA
https://i0.wp.com/www.stomponstep1.com/

15. BIG 5 FOR INFECTION
Pathogens Characteristic Site of infection Treatment
Staphylococcus aureus Gram positive cocci in cluster,
catalase positive
Pneumonia, lymphadenitis,
liver abscess, skin infection
Cloxacillin
1st gen cephalosporin
Burkholderia cepacia
complex
Gram negative rod , 20 spp ,
catalase positive
pneumonia in
immunocompromise or CF
,infrequently sepsis
naturally resistant to many
antibiotics
Ceftazidime, Bactrim
Serratia marcescens Gram negative rod, catalase
positive
Osteomyelitis 3rd – 4th gen cephalosporin
Nocardia species Gram positive rod, catalase
positive
pneumonia Bactrim
Carbapenem+aminoglycoside
Aspergillus species mold “mulch pneumonitis” Antifungal drugs
Clinic Rev Allerg Immunol (2010) 38:3–10

16. OTHER PATHOGENS
▪ Tuberculosis and Salmonella
▪ Species are important causes of infections in regions of the world where these organisms are
prevalent severe local or regional BCG disease may be the initial CGD presentation
▪ Actinomyces species (catalase-negative organisms)
▪ Patients with CGD with actinomycosis did not present with typical signs
▪ Granulibacter bethesdensis
▪ Necrotizing lymphadenitis in patients with CGD, and the patients can have a relapse after initial
symptoms resolve

17. CHROMOBACTERIUM VIOLACEUM
▪ Chromobacterium violaceum is a soil and water saprophyte and is confined to tropical and
subtropical areas.
▪ A large motile gram-negative bacillus, is a rare entity that typically starts with a localized skin
infection or localized lymphadenitis
▪ Human infection with C. violaceum is rare; high case-fatality rates have been reported.
▪ We present a child who had invasive C. violaceum infection and was successfully treated.
▪ The medical literature was reviewed to identify prognostic factors in children with invasive C.
violaceum infection and effective antimicrobial regimens.
The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005

18. The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005

19. CHROMOBACTERIUM VIOLACEUM
▪ Summary
▪ Patients with CGD are particularly vulnerable to C. violaceum infection, but the infection is rare
▪ Our review suggests that CGD patients have a lower risk for bacteremia and death from C. violaceum
infection than the non-CGD patients
▪ Cause of dead is sepsis
▪ This review suggests that the effective drugs for invasive C. violaceum infection include ciprofloxacin,
TMP-SMX, chloramphenicol and imipenem
The Pediatric Infectious Disease Journal • Volume 24, Number 6, June 2005
Int J Appl Basic Med Res. 2012 Jan-Jun; 2(1): 70–72

20. NBT TEST
▪ REQUIREMENTS
▪ Nitro-blue tetrazolium dye This is available commercially, and is made up as a 0.2 % solution in
saline. It may require gentle heating to dissolve fully.
▪ This solution is stable at room temperature for several weeks. Discard if turbidity or discoloration
appears.
▪ Phosphate-buffered saline, pH 7.2 Plastic haemagglutination tray Pipettes to deliver 0.1 ml Slides
and coverslips (cleaned) Methanol Pappenheim's stain (methyl green-pyronine) is prepared from
the powder supplied commercially
▪ Once made up, the stain is stable for months, but will tend to intensify with time.

21. NBT TEST
▪ METHOD
▪ Blood is obtained in glass tubes, using heparin as anticoagulant (the concentration of heparin should
be 75-100 units/ml of blood).
▪ The usual amounts of blood required from the patient is never more than 10 ml. Pipette 0.1 ml of the
blood into a well of the plastic tray.
▪ Make the 'working' NBT solution by mixing equal volumes of the stock 0.2 % solution and the
phosphate-buffered saline.
▪ This solution must be made freshly for each batch of tests. Pipette 0.1 ml of the 'working' NBT
solution into each well containing blood and mix the contents.
R. FREEMAN AND B. KING. Technical method.1972

22. NBT TEST
http://biologie.chu-grenoble.fr/centre-de-diagnostic-de-la-granulomatose-septique
https://www.medbullets.com/step1-immunology/5009/chronic-granulomatous-disease

23. DHR TEST
▪ Western blot analysis
▪ SDS-PAGE immunoblot detection of cytosolic and membrane NADPH oxidase components was
performed as described
▪ The lysates (1 × 106 cell equivalents/lane) were then separated on either NuPage Novex 10% gels
(p47phox and p67phox) or 4% to 12% gradient gels
▪ CYBB mutation analysis
▪ Ferricytochrome-c reduction assay
Jirapongsananuruk et al. JACI.2003

24. DHR TEST
▪ This assay can differentiate between X-CGD and p47phox-AR-CGD in the majority of patients
▪ Typical DHR histograms and SIs in normal, p47phox-AR-CGD, X-CGD, and X-CGD carriers
Jirapongsananuruk et al. JACI.2003

25. DHR TEST
Jirapongsananuruk et al. JACI.2003

26. DHR TEST
▪ This assay can differentiate between X-
CGD and p47phox-AR-CGD in the majority
of patients, on the basis of distinctive DHR
histogram SI and pattern
Jirapongsananuruk et al. JACI.2003

27. DHR TEST
▪ SI = PMA-stimulated
unstimulated granulocytes
▪ Our expanded DHR assay database at the
NIH now includes 75 patients with X-CGD,
of whom 13 (17%) have an SI of >4.5
▪ In male patients with CGD with modest
DHR activity, defined as an SI of >4.5,
additional studies are warranted
Genotype Mean SI Range SI
Normal subject 127.9 85.2 to 264.6
X CGD 1.3 0.9 to 2.2
X CGD Carrier ? ?
AR CGD 13.2 3.5 to 52.1
AR CGD Carrier ? ?
Jirapongsananuruk et al. JACI.2003

28. DHR TESTING (PATIENT)
Patient
Control
Decrease DHR shift, broad-based histogram
Stimulation index =12

29. DHR TESTING (PATIENT’S MOTHER)
MotherControl
Bimodal distribution of histogram
(M1 and M2)

30. INFECTIOUS COMPLICATION OF CGD
Song et al. Clinical and Molecular Allergy 2011, 9:10

31. ASPERGILOSIS
▪ 7 year-old boy with CGD
▪ Chest X-ray revealed ground-glass
opacities in bilateral lung fields
▪ CT chest with contrast: diffuse ground-
glass opacities, septal thickening, nodules,
interspersed cysts, and dilated main
pulmonary artery and right ventricle
J Clin Immunol (2017) 37:333–335

32. ASPERGILOSIS
▪ Immunological work up
▪ NBT dye reduction test revealed no
reduction of NBT dye by stimulated
neutrophils and
▪ DHR assay revealed markedly reduced
stimulation index
▪ Immunoglobulin profile
▪ IgG 1710 mg/dL (540–1610)
▪ IgA <17 mg/dL (50–240)
▪ IgM 141 mg/dL (50–180)
▪ CGD with selective IgA deficiency is a rare
association
▪ The exact reason for the association of these
two primary immunodeficiency diseases is not
known
▪ CGD and hypogammaglobulinemia have also
been reported and dead with disseminated
Aspergillus infection and finally
▪ CGD patients are also predisposed to develop
inflammatory complications including
inflammatory lung disease
J Clin Immunol (2017) 37:333–335

33. ASPERGILOSIS
▪ “Mulch pneumonitis”
▪ Exposure to aerosolized decayed organic matter, such as mulch, hay, or dead leaves
▪ Inhaling numerous fungal spores and hyphae; about 2 days later, a syndrome similar to
pulmonary hypersensitivity begins with fever and dyspnea
▪ Investigations
▪ CXR: diffuse interstitial infiltrates
▪ Bronchoscopy: uninformative but may yield Aspergillus
▪ Lung biopsy: acute inflammation with necrotizing granulomata and fungi
▪ Treatment
▪ Antifungals for the infection and steroids for the inflammation
Clinic Rev Allerg Immunol (2010) 38:3–10

34. ANTIBIOTIC THERAPY
▪ Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis has been used routinely for the
prevention of infections in patients with CGD since the 1970s
▪ Gallin et al (1983)
▪ Patients with CGD, on average, suffered 1 life-threatening episode every 10 months; however, with
TMP-SMX prophylaxis, this was reduced to 1 life-threatening episode every 40 months
▪ Regelman et al (1983)
▪ Only 5% of patients with CGD remained infection-free for more than 1 year without TMP-SMX
prophylaxis, but more than 40% were infection-free for more than 1 year while taking TMP-SMX
prophylaxis

35. ANTIBIOTIC THERAPY
▪ Antibacterial prophylaxis in the presence of TMP-SMX intolerance is difficult
▪ Few orally available agents with reliable activity against both S. aureus (including methicillin-resistant
strains) and gram-negative pathogens.
▪ In the case of sulfa allergy,
▪ Trimethoprim alone can be used
▪ Other options include a fluoroquinolone
▪ likely with the addition of clindamycin or another agent with activity against methicillin resistant S
aureus in areas where these strains are prevalent

36. ANTIFUNGAL THERAPY
▪ The current standard of care for preventive therapy in patients with CGD includes daily
prophylactic itraconazole therapy to prevent superficial and invasive fungal infections
▪ Therefore, the risk-benefit ratio strongly favors the use of prophylactic itraconazole in all
patients with CGD
▪ Voriconazole, another highly active azole compound
▪ Alternative agent for antifungal prophylaxis
▪ Although not considered the first-line prophylactic agent by most experts, because of a higher cost
and unnecessarily broad spectrum against many mold species

37. IFN-GAMMA
▪ RCT in 1990
▪ Subcutaneous injections of recombinant IFN-g administered 3 times per week reduced the number
of serious infections in patients with CGD by 67%
▪ Reduced the rate of serious infections to 0.30 per patient-year and reduced mortality rate to 6.6%
over 9 years
▪ Administration of IFN-g therapy was found to be effective in both X-linked and autosomal-
recessive CGD with minimal side effects
▪ This most commonly involves “flu-like symptoms”
▪ Many experts consider the risk-benefit ratio to be favorable for the use of IFN-g to prevent
invasive infectious complications of CGD

38. IFN-GAMMA
▪ 19 CGD patient ( diagnose by NBT and DHR)
▪ May 2008 to February 2009
▪ All of the patients received prophylactic
antibiotic therapy with TMP-SMX
▪ In addition to TMP-SMX, twelve of the
patients received IFN-γ (50 μg/m2 of body
surface) subcutaneously 3 times weekly
▪ Measurment
▪ Determination nitrite and nitrate (NOx) by
Griess method
▪ Nox in vivo and in vitro
▪ Group 1: patients under treating with TMP-
SMX
▪ Group 2: IFN-γ simultaneously + TMP-SMX
▪ a control group: containing healthy
nonsmoking individuals
International Immunopharmacology 12 (2012) 689–693

39. IFN-GAMMA
International Immunopharmacology 12 (2012) 689–693
Our finding showed higher levels of serum NOx in the
patients treated with IFN-γ.

40. IFN-GAMMA
▪ This shows the effect of IFN-γ on NOx release from PMNs in the patients with CGD as well as
in the normal population
▪ We found that the patients who were treated with IFN-γ in addition to TMP-SMX had higher
levels of NOx in their serum compared with the patients who received TMP-SMX alone
▪ In our study, male subjects in the patients group treated with IFN-γ had significantly higher
NOx levels compared with female subjects
▪ We found that serum NOx levels in the patients who received IFN-γ could be related to the
month number of the receiving IFN-γ
International Immunopharmacology 12 (2012) 689–693

41. IFN-GAMMA
▪ Aim of this study
▪ IFN-γ showed that it enhanced phagocytosis and superoxide production, ongoing studies did not
reveal a significant increase of this function
▪ Here we investigated the oxidative capacity of phagocytes in Different subtypes of CGD patients on
treatment with IFN-γ in vitro.
▪ Population
▪ 57 patients with CGD, who had been diagnosed by NBT and DHR were enrolled in this multicentre
▪ Retrospective cohort, October 2011 and June 2012
▪ Intervention
▪ Blood sampling pre and post treatment with IFN-γ
▪ The median duration of IFN-γ therapy was 26 months (range: 3-173 months)
Centr Eur Immunol 2015; 40 (1): 54-60

42. IFN-GAMMA
▪ There was a difference between hours 1
and 24 although it was not statistically
significant (gp91phox subtype)
▪ As regards monocytes, the differences
between hours 0 and 1 and hours 0 and
24 were not significant
▪ This outcome led us to consider that the
effect of IFN-γ on neutrophils is likely to
become more apparent over time
Centr Eur Immunol 2015; 40 (1): 54-60

43. ▪ Conclusion
▪ in CGD cases, in vivo or in vitro IFN-γ was demonstrated to increase phagocyte superoxide
production, and led to recovery in Staphylococcus aureus, Aspergillus killing test, and the nitro blue-
tetrazolium (NBT) test response and a decrease the incidence of infection
Centr Eur Immunol 2015; 40 (1): 54-60

44. PIOGLITAZONE
Curr Opin Microbiol. 2014 February ; 0: 17–23

45. PIOGLITAZONE
PPAR𝛾
- Inhibiting inflammatory signaling
through NF-𝜅B.
- Reduce expression of TNF𝛼
- Increase expression of
monocyte chemoattractant protein-
1 (MCP-1)
- Enhances Macrophage
Phagocytosis
PPAR Research. 2015

46. PIOGLITAZONE
▪ A case report 5 mo boy with CGD and
severe pulmonary infection
▪ Recently, pioglitazone
▪ A peroxisome proliferator–activated
receptor gamma agonist approved for type
2 diabetes
▪ Induce mitochondrial (mt) reactive oxygen
species (ROS) production in mice with X-
CGD.
▪ Restored phagocytes demonstrated
significantly enhanced killing of
Staphylococcus aureus in vitro and in vivo
Maddalena Migliavacca. Letter to editor. JACI. 2016

47. PIOGLITAZONE
▪ Encouraged by the innovative findings on
the effect of pioglitazone on ROS
production and consequent protection
from infection in vitro in human cells
▪ After parent informed consent for off-
label use, pioglitazone was administered
at a starting dose of 1 mg/kg to 3 mg/kg
▪ After 10 days of pioglitazone at target
dose (3 mg/kg), the DHR test showed a
percentage of granulocytes with increased
DHR fluorescence
Maddalena Migliavacca. Letter to editor. JACI. 2016

48. PIOGLITAZONE
▪ Conclusion
▪ Effect of pioglitazone might have played a role in the protection of the patient from further infections
and in the improvement of his pulmonary situation
▪ Reducing the inflammatory status and by partial restoration of host defense through induction of
mtROS production in his granulocytes.
Maddalena Migliavacca. Letter to editor. JACI. 2016

49. PIOGLITAZONE
▪ Impaired efferocytosis in human chronic granulomatous disease is reversed by pioglitazone
treatment
▪ Peroxisome proliferator–activated receptor g (PPARg), a nuclear receptor activated by
oxidized lipids, is a driver of metabolic programming of macrophages and enhances their
ability to take up and digest dying cells
▪ Treatment of mice with CGD with pioglitazone also restored the efferocytic capability of
inflammatory macrophages and suppressed excessive inflammatory mediator production

51. MANAGEMENT: ACUTE INFECTION
▪ CGD may represent indolent bacterial infection
▪ Securing a microbiologic diagnosis is of the highest priority for any new process that does not
appear to be a self-limited illness
▪ Laboratory markers (ESR, CRP) can be very useful in the evaluation of new symptoms
▪ A significant and sustained rise is often a hallmark of occult infection that may require imaging even
if localizing symptoms are not present
▪ Imaging modalities such as computed tomography (CT) and magnetic resonance imaging
(MRI) are often critical in the evaluation of new or persistent symptoms

53. TRANSPLANTATION
▪ In 2002, Seger et al. published a survey of 27 European patients transplanted for CGD from
1985 to 2000
▪ Patients without severe active infection or inflammatory reaction owing to, for example,
inflammatory bowel disease did extremely well (18/18 patients survived)
▪ Four with active fungal infections died
▪ Conclusion
▪ Infectious foci must be detected and treated before the HSCT and that
▪ HSCT was the option for a child with a history of severe infection inflammatory reaction and with a
human leukocyte antigen-identical sibling
▪ Transplantation with a nonidentical donor was discouraged
Curr Opin Hematol 2015, 22:41–45

54. TRANSPLANTATION
▪ Soncini et al. published a series on 20 patients transplanted in Great Britain from 1998 to
2007.
▪ Half of them received matched sibling grafts (MSD) and half of them matched unrelated grafts (MUD)
▪ Eighteen survived with normal granulocyte function and two died from pretransplant fungal
infections
Curr Opin Hematol 2015, 22:41–45

55. TRANSPLANTATION
▪ In 2002, Seger et al. published a survey of 27 European patients transplanted for CGD from
1985 to 2000
▪ Patients without severe active infection or inflammatory reaction owing to, for example,
inflammatory bowel disease did extremely well (18/18 patients survived)
▪ Four with active fungal infections died
▪ Conclusion
▪ Infectious foci must be detected and treated before the HSCT and that
▪ HSCT was the option for a child with a history of severe infection inflammatory reaction and with a
human leukocyte antigen-identical sibling
▪ Transplantation with a nonidentical donor was discouraged
Curr Opin Hematol 2015, 22:41–45

56. TRANSPLANTATION
▪ In 2012, two American reports were published that supported HSCT as a first-line therapy in many
cases of CGD
▪ Tewari et al. 12 CGD patients who received myeloablative conditioning with either MSD grafts (n¼6) or
cord blood (n¼6).
▪ All of them survived with normal granulocyte function
▪ Ahlin et al.In 2013, two papers compared survival for patients transplanted and those treated
conventionally.
▪ Identified 41 Swedish patients, children and adults, 23 with X-linked disease from 1990 to 2012
▪ Mean survival time was 7.7 years and there were no late deaths
▪ 7 of 13 men with X-linked CGD treated conventionally died at a mean age of 19 years, and all others
suffered from life-threatening infections
Curr Opin Hematol 2015, 22:41–45

57. TRANSPLANTATION
▪ In 2014, A large prospective multicenter study by Gu¨ngo¨r et al., which included 56 patients,
aged 0–40 years (median age 13 years)
▪ Matched related donors or HLA nine of 10 or HLA 10/10 matched unrelated donors
▪ The results are
▪ 2-year overall survival of 96% and event-free survival of 91%.
▪ The cumulative incidence of severe acute graft versus host grade III–IV was only 4%
▪ chronic graft versus host was 7%
▪ The authors concluded that all patients with X-linked CGD or severe autosomal recessive CGD
should be offered HSCT as early as possible
Curr Opin Hematol 2015, 22:41–45

58. QUALITY OF LIFE
▪ Quality of life for nontransplanted children were significantly lower compared with healthy
children.
▪ Transplanted patients had a quality of life comparable to levels reported from healthy
children
▪ However, transplantation outcomes are probably better before infectious and inflammatory
damage accumulates.
▪ Transplantation has reversed some of the inflammatory and autoimmune complications
associated with CGD and might prevent their development

59. MORTALITY AND MORBIDITY IN CGD WITH THE
DIFFERENT TREATMENT MODALITIES
Conventional treatment HSCT
- Mortality and morbidity are
higher than AR CGD
- p47phox mutations have a better survival
- In 2000, USA study
- European study
- Mortality decrease after new antifungal
treatment
- Recent data suggest a better
survival of
▪ 88–97% at the age of 10 years,
▪ 73–87% at age 20 years
▪ 46–55% at age 30 years
▪ Death rates still are high
- Children who did not undergo transplantation
had 0.71 episodes of infection/admission/
surgery per CGD life year.
- The group studies post-HSCT (30 patients) had 0.15
episodes of infection/ admission/surgery per transplant
year
- The mean Z-score for height and BMI was significantly
better in the post-HSCT children.
- Survival at the age of 15 years was similar in both
groups, that is 90%

60. INFLAMMATORY COMPLICATIONS
▪ Whether these changes represent an
overwhelming response to infection
▪ Immune response (such as T cells and B
cells) and manifested
▪ Hyperglobulinemia
▪ Elevated acute phase reactants
▪ Failure of the compensatory “anti-
inflammatory response”
Song et al. Clinical and Molecular Allergy 2011, 9:10

61. INFLAMMATORY COMPLICATIONS
▪ The seemingly paradoxical association between primary immunodeficiencies and
autoimmune disease is well described and CGD is a prototypical example
▪ Granulomatous colitis appears to be the most common inflammatory complication of CGD,
and more than 40% of patients with X-linked CGD
▪ Other inflammatory condition are discoid lupus, polyarthritis, noninfectious granulomatous disease,
and aphthous ulcers with cutaneous lesions mimicking Behçet disease
▪ CGD-associated enteritis or colitis management
▪ Combination of luminal anti-inflammatory therapy (eg, mesalamine) and low dose corticosteroids
▪ Antimetabolites such as methotrexate or azathioprine are also helpful for recurrent cases.
▪ TNF-blocking biologics have been associated with severe infections and death

62. INFLAMMATORY COMPLICATIONS
▪ When present in hollow viscera, they can lead to obstruction, such as obstruction of the
gastric outlet or ureteral obstruction, which are relatively common in patients with X-linked
CGD
▪ Surgical intervention should be avoided, and corticosteroids, when used, are usually started
at doses of 1 mg/kg/d and then tapered after 1 week
▪ Patients with recurring problems can be kept on low-dose prednisone for years, which does
not appear to increase infection rates or impair growth
▪ In the NIH series 43% of X-linked and 11% of p47phox-deficient patients had biopsy-proved
symptomatic bowel disease
Elizabeth M. Kang. JACI. 2011

63. INFLAMMATORY COMPLICATIONS
▪ Other autoimmune diseases in patients with CGD and carriers have included
▪ IgA nephropathy, antiphospholipid syndrome, SLE, ITP, and JIA
▪ 10% of the patients with CGD have some autoimmune manifestation other IBD
▪ Dysregulated inflammation might play a role in the development of autoimmune
complications
▪ Altered NADPH oxidase function can therefore lead to aberrant
▪ Macrophage programming
▪ Impaired clearance of antigen, and intracellular elements
▪ Recruitment of neutrophils and prolonged production of IL-8, IL-1b, caspases
Elizabeth M. Kang. JACI. 2011

64. TRANSITION TO ADULT CARE
▪ Patients with CGD now routinely survive well into adulthood
▪ The basic tenets of prophylaxis (antibacterial, antifungal, and immunomodulatory agents)
▪ Disease manifestations, however, may differ substantially. Inflammatory complications may
be more frequent in adults with CGD than in children
▪ Inflammatory respiratory events
▪ Typically presented radiographically as nodules, parenchymal consolidation, or diffuse interstitial
infiltrates, often with associated ground glass opacities and/or bronchiectasis
▪ 40% of cases developed inflammatory pathology associated with concomitant fungal infections

65. TRANSITION TO ADULT CARE

66. CGD IN ADULT
▪ Chronic granulomatous disease (CGD), an inherited disorder of granulocyte function caused
by failure of intracellular superoxide production, normally presents in the first years of life
with severe recurrent bacterial and fungal infections.
▪ Population
▪ 11 CGD patients who were remarkable for an unusually late diagnosis, at 13-43 years of age.
▪ Outcome
▪ The first clinical manifestation occurred at a median age of 3- 6 years but CGD was not diagnosed
until a median age of 22 years.
▪ Pneumonias and abscesses caused by Staphylococcus aureus and Aspergillus species were the most
frequent infections. Granulomas,
▪ 8 of the patients had Xlinked CGD with small but detectable quantities of cytochrome b558
(p22phox) , normally absent in X-linked CGD
▪ 9 patients had residual production of reactive oxygen metabolites, a feature that could explain the
low incidence of infections.
J G Liese. Lancet.1995

67. CGD IN ADULT
▪ In conclusion,
▪ Any adolescent or adult with unexplained infections or granuloma formation should be investigated
for a granulocyte defect;
▪ A negative NBT test is not always sufficient to rule out CGD. Early diagnosis of CGD is important
because of the benefits of timely treatment, infection prophylaxis, and genetic counselling.

68. TRANSITION TO ADULT CARE
▪ The aims of this study were to identify the strengths and barriers to transition from pediatric
to adult care
▪ A survey was administered via a structured interview to 33 young adult participants (19-27
years of age)
Journal of Adolescent Health xxx (2017) 1-6

69. TRANSITION TO ADULT CARE
▪ Results:
▪ 76% of the participants did not understand their disease process
▪ 50% understood their prophylactic medication regimen
▪ 75% of participants perceived their transition as uneventful.
▪ 94% were independent in self management skills such as making appointments and
▪ 90% in refilling prescriptions.
▪ 50% thought that the transition process needed improvement.
▪ Conclusions:
▪ Gaps in disease-related knowledge and transition planning were identified by adolescents and young
adults living with chronic granulomatous disease.
▪ The findings suggest the need for enhancing the transition process utilizing interdisciplinary
collaboration to develop a transition policy and program.
Journal of Adolescent Health xxx (2017) 1-6

70. CONCLUSION
▪ It is difficult to estimate the actual present mortality and morbidity at a given time for the two
treatment modalities
▪ It is the opinion of the authors that HSCT should be offered to
▪ All boys and men with X-linked CGD having an HLA-identical donor, regardless of whether the donor
is MSD or MUD
▪ In autosomal recessive CGD, the severity of infection and inflammation can vary quite
extensively.
▪ However, many patients with autosomal recessive CGD have a severe, life-threatening
disease, and these patients should, therefore, be offered a transplant