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.

IgE: 5040 U/ml.

R382Q heterozygous mutation in STAT3 geneHyper IgE syndrome

3 years:

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

Management of pulmonary complications

Immunomodulation

Prompt antibiotic/antimycotic treatment of infections cold abscesses!Surgical drainage of abscesses.Vigilance for complications (osteomyelitis).

Severely 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:

Frequent bacterial/fungal superinfectionLung resection – difficult:

impairment of expansion of residual lung tissueinvolvement of other lobescontamination of the pleural space

Poorly studied Not enough evidence to give recommendations

IVIGLevamisole

γ-IFNH2-antagonistsAscorbic Acid

CyAOmalizumab

RituximabBMT

Immunomodulation in HIES

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

Monoclonal antibodies

Etzioni A, Shehadeh N, Brecher A, Yorman S, Pollack S. Cyclosporin A in hyperimmunoglobulinE syndrome. Ann Allergy Asthma Immunol. 1997 Apr;78(4):413-4.

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

BMT does not cure the immunological features of HIES syndrome.

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.

What can be done? Surgical resection:

Haematopoietic progenitors transplantation:

Lung transplantation:

IFN-gamma, CyA:

?High risk of uncotrolled bleeding.Multiple areas of affectation.High risk of recurrence after surgery.Impairment of expansion of residual lung tissue.Does not cure the disease.

Does not solve the hemoptysis.

High risk of oportunistic infection after immunosupression.

High risk of oportunistic infeccion after the required immunosupression.Not reported.

To be considered.Will not cure the hemoptysis.

•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

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

X-linked CGD

Mother carrier of the mutation

2 years

Current situation

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

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

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:

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.

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.

Güngör T, Halter J, Klink A, Junge S, Stumpe KD, Seger R, Schanz U. Successful low toxicityhematopoietic stem cell transplantation for high-risk adult chronic granulomatous disease patients. Transplantation. 2005 Jun 15;79(11):1596-606.

Jones LB, McGrogan P, Flood TJ, Gennery AR, Morton 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.

Promising realistic option for curative treatment of CGD.

Better outcome with less ablative conditioning regimens.

More work is needed to improve outcome of chronically infected patients.

Stem cell gene therapy CGD: good candidate: single gene defects.

Metabolic genes not involved in cell proliferation. 10% functional correction is enough.

Difficulties: Lack of a selective growth advantage of gene transduced cells

(Malech 2004, Barese 2004) Solutions: Submyeloablative conditioning (Ott, 2006)

Risks: Insertional mutagenesis Transactivation of proto-oncogenes from retrovirus-mediated gene

therapy

Solutions: Self-inactivating vectors (Modlich, 2006) Lentiviral vectors (Roesler, 2002)

May become feasible to overcome life-threatening infections.

Cure of CGD by gene therapy alone: still a distant goal.

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-PalacínA. Martín

C. FiguerasUPIIPHUVH

BCN, Spain

C. Díaz de HerediaPediatric Haematology and

Oncology ServiceHUVH

BCN, Spain

C. Woellner and B. Grimbacher Dept of ImmunologyMedsch Hampstead

London, UKI. Caragol, D. Detkova and

T. EspañolLab of Immunology

HUVHBCN, Spain

M. Cruz GarcíaDept of Immunology

La PazMadrid, Spain