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What to do when nothing can be done


Case 1: 16 year-old girl. No significant family history, no ... Jones LB, McGrogan P, Flood TJ, Gennery AR, Morton L, Thrasher A, Goldblatt D, Parker L, Cant ... – PowerPoint PPT presentation

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Title: 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
  • Lung Aspergilloma (LIL).
  • 14 -16 yo recurrent hemoptysis ?2
    life-threatening episodes ? 2 arterial
  • Oral and ophthalmic HSV1 infection and cutaneous

IgE 5040 U/ml. R382Q heterozygous mutation in
STAT3 gene
3 years
Hyper IgE syndrome
Current situation
  • Multiple bilateral pneumatocoeles and
  • 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
  • Aggressive high-dose iv antibiotic treatment.
  • Empirical treatment active against S. aureus, H.
    influenzae, S. pneumoniae.
  • Cysts, bronchiectasis, pneumatocoeles
  • Frequent bacterial/fungal superinfection
  • Lung resection difficult
  • impairment of expansion of residual lung tissue
  • involvement of other lobes
  • contamination of the pleural space

Immunomodulation in HIES
  • Poorly studied
  • Not enough evidence to give recommendations
  • IVIG
  • Levamisole
  • ?-IFN
  • H2-antagonists
  • Ascorbic Acid
  • CyA
  • Omalizumab
  • Rituximab
  • BMT

  • 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-Jun91(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 Aug81(2)153-8.
  • Studies in mice inhibits IL-4-induced IgE
  • Improves the chemotaxis of human neutrophils in
  • May lower IgE levels.
  • May decrease respiratory symptomatology.
  • Can trigger autoimmune cytopenias, such as
  • 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
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 Mar118(3)383-7.
  • Cyclosporin A

Etzioni A, Shehadeh N, Brecher A, Yorman S,
Pollack S. Cyclosporin A in hyperimmunoglobulin E
syndrome. Ann Allergy Asthma Immunol. 1997
  • Monoclonal antibodies

Trendelenburg M, Schifferli JA. Rituximab in a
patient with Hyper-IgE syndrome. Arch Dermatol.
2007 Jun143(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 Dec144(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 hyperimmunoglobulinem
ia E and recurrent infections. Am J Med. 1998
Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone
marrow transplantation does not correct the
hyper IgE syndrome. Bone Marrow Transplant. 2000
BMT does not cure the immunological features of
HIES syndrome.
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.

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
  • Subcutaneous ?-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.

(No Transcript)
Current situation
  • Subcutaneous ?-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,
  • 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
  • Severe steroid-dependent/resistant inflammatory
  • Suitable stem cell donor

Seger RA. Modern management of chronic
granulomatous disease. Br J Haematol. 2008
HSCT in CGD experience so far
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.
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 15100(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 22344(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
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
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 May152(2)211-8.
Stem cell gene therapy
May become feasible to overcome
life-threatening infections. Cure of CGD by
gene therapy alone still a distant goal.
  • CGD good candidate single gene defects.
  • Metabolic genes not involved in cell
  • 10 functional correction is enough.
  • Difficulties
  • Lack of a selective growth advantage of gene
    transduced cells (Malech 2004, Barese 2004)
  • Solutions Submyeloablative conditioning (Ott,
  • Risks
  • Insertional mutagenesis
  • Transactivation of proto-oncogenes from
    retrovirus-mediated gene 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.

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,
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