Transcript What to do when nothing can be done?

What to do when
nothing can be done?
Fabiola Caracseghi
Case 1: 16 year-old girl
 No significant family history, no consanguinity.
 Several severe infections:
 3 m: Pneumocystis jirovecii pneumonia  MV 1 m.
 2 yo: Acinetobacter anitratus lung abscess.
 4 yo: multiple pneumatocoeles. Recurrent hemoptysis.
Lung Aspergilloma (LIL).
 14 -16 yo: recurrent hemoptysis 2 life-threatening episodes 
2 arterial embolizations.
 Oral and ophthalmic HSV1 infection and cutaneous candidiasis.
3 years:
IgE: 5040 U/ml.
R382Q heterozygous mutation in STAT3 gene
Hyper IgE syndrome
Current situation
 Multiple bilateral
pneumatocoeles and
bronchiectasis.
 Prophylaxis: TMP-SMX and
itraconazole.
 Monthly IVIG treatment.
 Moderate restrictive
ventilatory alteration.
 Recurrent hemoptysis 
Will the next one be fatal?
What can be done?
Management of HIES
 Difficult
 Incomplete understanding of the pathophysiology
 Mainly supportive
 Early diagnosis
 Prevention of severe systemic infections and
aggressive treatment when they occur
 Control of the pruritus and eczematoid dermatitis
Management of HIES
 Skin care
antibiotic/antimycotic treatment of infections  cold abscesses!
Surgical drainage of abscesses.
Vigilance for complications (osteomyelitis).
Prompt
 Management of pulmonary complications
ill but well-feeling  Active suspicion needed!
Aggressive high-dose iv antibiotic treatment.
Empirical treatment active against S. aureus, H. influenzae, S. pneumoniae.
Cysts, bronchiectasis, pneumatocoeles:
Severely
Frequent bacterial/fungal superinfection
Lung resection – difficult:

impairment of expansion of residual lung tissue
involvement of other lobes
contamination of the pleural space
 Immunomodulation
Immunomodulation in HIES
 Poorly studied
 Not enough evidence to give recommendations
IVIG
Levamisole
γ-IFN
H2-antagonists
Ascorbic Acid
CyA
Omalizumab
Rituximab
BMT
IVIG
 The most frequently used.
 HIES: impairment AB formation, especially against encapsulated
organisms.
 May decrease the number of infections.
 May influence IgE levels:


increased/induces Ig catabolism.
IgE neutralization via an anti-idiotype network.
Bilora F, Petrobelli F, Boccioletti V, Pomerri F. Moderate-dose intravenous immunoglobulin treatment
of Job's syndrome. Case report. Minerva Med. 2000 May-Jun;91(5-6):113-6.
Wakim M, Alazard M, Yajima A, Speights D, Saxon A, Stiehm ER. High dose intravenous Immunoglobulin
in atopic dermatitis and hyper-IgE syndrome. Ann Allergy Asthma Immunol. 1998 Aug;81(2):153-8.
IFN-gamma
 Studies in mice: inhibits IL-4-induced IgE synthesis.
 Improves the chemotaxis of human neutrophils in vitro.
 May lower IgE levels.
 May decrease respiratory symptomatology.
 Can trigger autoimmune cytopenias, such as thrombocytopenia.
 Consider in patients with very serious infections, such as aspergillosis.
King CL, Gallin JI, Malech HL, Abramson SL, Nutman TB. Regulation of immunoglobulin production in
hyperimmunoglobulin E recurrent-infection syndrome by interferon gamma.
Proc Natl Acad Sci U S A. 1989 Dec;86(24):10085-9.
Jeppson JD, Jaffe HS, Hill HR. Use of recombinant human interferon gamma to enhance neutrophil
chemotactic responses in Job syndrome of hyperimmunoglobulinemia E and recurrent infections.
J Pediatr. 1991 Mar;118(3):383-7.
Others
 Cyclosporin A
Etzioni A, Shehadeh N, Brecher A, Yorman S, Pollack S. Cyclosporin A in hyperimmunoglobulin
E syndrome. Ann Allergy Asthma Immunol. 1997 Apr;78(4):413-4.
 Monoclonal antibodies
Trendelenburg M, Schifferli JA. Rituximab in a patient with Hyper-IgE syndrome.
Arch Dermatol. 2007 Jun;143(6):807-8.
Bard S, Paravisini A, Avilés-Izquierdo JA, Fernandez-Cruz E, Sánchez-Ramón S. Eczematous
dermatitis in the setting of hyper-IgE syndrome successfully treated with omalizumab.
Arch Dermatol. 2008 Dec;144(12):1662-3.
Haematopoietic stem cell
transplantation
Nester TA, Wagnon AH, Reilly WF, Spitzer G, Kjeldsberg CR, Hill HR. Effects of allogeneic
Peripheral stem cell transplantation in a patient with Job syndrome of hyperimmunoglobulinemia E and
recurrent infections. Am J Med. 1998 Aug;105(2):162-4.
Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone marrow transplantation does not correct the
hyper IgE syndrome. Bone Marrow Transplant. 2000 Jun;25(12):1303-5.
BMT does not cure the immunological
features of HIES syndrome.
What can be done?
 Surgical resection:
High
risk of uncotrolled bleeding.
Multiple areas of affectation.
High risk of recurrence after surgery.
 Haematopoietic
progenitors transplantation:
Impairment of expansion of residual lung tissue.
Does not cure the disease.
Does not solve the hemoptysis.
High risk of oportunistic infection after immunosupression.
 Lung transplantation:
High risk of oportunistic infeccion after the required immunosupression.
Not reported.
 IFN-gamma, CyA:
To
be considered.
Will not cure the hemoptysis.
Case 2: 18 year-old male
 No significant family history, no consanguinity.
 Typical / severe infections:

Cutaneous abscess post DTP immunization

Salmonellosis

2 yo: Bilateral necrotizing Rhodococcus equi pneumonia  right
pneumectomy

14 years: pneumonia by Burkholderia cepacia MV and HFV
2 years
•Oxydation test: 0%
•Genetic study: C1028T mutation in CYBB
gene, changing the CCT codon for Pro-339 in
gp91-phox into a CAT codon for Histidine
X-linked CGD
Mother carrier of the mutation
Current situation



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
Subcutaneous γ-IFN 3 times/week.
Prophylaxis: TMP-SMX, itraconazole.
No need for domiciliary O2-therapy.
Dyspnea on moderate exertion.
His residual lung capacity only depends on his left superior lobe.
Current situation




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Subcutaneous γ-IFN 3 times/week.
Prophylaxis: TMP-SMX, itraconazole.
No need for domiciliary O2-therapy.
Dyspnea on moderate exertion.
His residual lung capacity only depends on his left superior lobe.
Will the next pneumonia be fatal?
What can be done?
Management of CGD
 Antimicrobial prophylaxis:
Antibacterial: TMP-SMX
 Antifungal: itraconazole/posaconazole
 Treatment of acute infections:
 Empirical: ciprofloxacin, teicoplanin, linezolid
 Antifungal: voriconazole, posaconazole
 Surgery
 White cell transfusions
 Immunomodulatory: IFN-gamma
 Inflammatory complications:
 Prednisolone, 5-aminosalicylate, azathioprine, infliximab.

CURE OF THE DISEASE:
•Haematopoietic stem cell transplantation
•Stem cell gene therapy
Haematopoietic stem cell transplantation




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CGD: stem cell disease  can be cured by HSCT.
The decision should be made early in life.
No predictive parameters  based on individual clinical course.
Uncomplicated CDG  NOT an indication for HSCT.
Most useful:


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Recurrent serious infections despite correct prophylaxis
Severe steroid-dependent/resistant inflammatory complications
Suitable stem cell donor
Seger RA. Modern management of chronic granulomatous disease. Br J Haematol. 2008 Feb;140(3):255-66.
HSCT in CGD: experience so far
Seger RA, Gungor T, Belohradsky BH, Blanche S, Bordigoni P, Di Bartolomeo P, Flood T, Landais
P, Müller S, Ozsahin H, Passwell JH, Porta F, Slavin S, Wulffraat N, Zintl F, Nagler A, Cant A,
Fischer A. Treatment of chronic granulomatous disease with myeloablative conditioning and an
unmodified hemopoietic allograft: a survey of the European experience, 1985-2000.
Blood. 2002 Dec 15;100(13):4344-50. Epub 2002 Aug 8.
Promising realistic option for curative treatment of CGD.
Horwitz ME, Barrett AJ, Brown MR, Carter CS, Childs R, Gallin JI, Holland SM, Linton GF, Miller JA,
Leitman SF, Read EJ, Malech HL. Treatment of chronic granulomatous disease with nonmyeloablative
conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med. 2001 Mar 22;344(12):881-8
Suzuki N, Hatakeyama N, Yamamoto M, Mizue N, Kuroiwa Y, Yoda M, Takahashi J, Tani Y,
Tsutsumi H. Treatment of McLeod phenotype chronic granulomatous disease with reduced-intensity
conditioning and unrelated-donor umbilical cord blood transplantation. Int J Hematol. 2007 Jan;85(1):70-2.
Better outcome with less ablative conditioning regimens.
Güngör T, Halter J, Klink A, Junge S, Stumpe KD, Seger R, Schanz U. Successful low toxicity
hematopoietic stem cell transplantation for high-risk adult chronic granulomatous disease patients.
Transplantation. 2005 Jun 15;79(11):1596-606.
More work is needed to improve outcome of
infected
Jones LB, McGrogan P,chronically
Flood TJ, Gennery
AR, Mortonpatients.
L, Thrasher A, Goldblatt D, Parker L, Cant
AJ. Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive
national patient-based registry. Clin Exp Immunol. 2008 May;152(2):211-8.
Stem cell gene therapy
 CGD: good candidate: single gene defects.


Metabolic genes not involved in cell proliferation.
10% functional correction is enough.
May
 Difficulties:

become feasible to overcome
Lack of a life-threatening
selective growth advantage
of gene transduced cells
infections.
(Malech 2004, Barese 2004)

Solutions: Submyeloablative conditioning (Ott, 2006)
 Risks:



Insertional
Cure ofmutagenesis
CGD by gene therapy alone:
Transactivation of proto-oncogenes from retrovirus-mediated gene
still a distant goal.
therapy
Solutions:
 Self-inactivating vectors (Modlich, 2006)
 Lentiviral vectors (Roesler, 2002)
What can be done?
 Haematopoietic progenitors transplantation:



Curative treatment.
No HLA-identical sibling donor.
Rejected for a URD transplantation because of high
risk of death if lung complications occur.
 Next pneumonia:


Could benefit from gene therapy.
Further experience needed.
Acknowledgments
P. Soler-Palacín
A. Martín
C. Figueras
UPIIP
HUVH
BCN, Spain
C. Díaz de Heredia
Pediatric Haematology and
Oncology Service
HUVH
BCN, Spain
C. Woellner and B. Grimbacher
Dept of Immunology
Medsch Hampstead
London, UK
I. Caragol, D. Detkova and
T. Español
Lab of Immunology
HUVH
BCN, Spain
M. Cruz García
Dept of Immunology
La Paz
Madrid, Spain