Terence Flood

Unrelated donor and HLA-identical sibling haematopoietic stem cell transplantation cure chronic granulomatous disease with good long-term outcome and growth

Chronic granulomatous disease (CGD) causes recurrent infection and inflammatory disease. Despite antimicrobial prophylaxis, patients experience frequent hospitalisations and 50% mortality by 30 years. Haematopoietic stem cell transplantation (HSCT) can cure CGD with resolution of infection and colitis. This study reports the survival and long‐term outcome in 20 conditioned patients treated between 1998 and 2007, using 10 matched sibling (MSD) and 10 unrelated donors (URD). Age at HSCT, graft‐versus‐host disease (GvHD), growth, and outcome were analysed. Fourteen had ≥1 invasive infection, 10 had colitis and seven had growth failure before HSCT. Median age at transplantation was 75 months (range 15 months–21 years). Eighteen (90%) were alive 4–117 months (median 61) after HSCT with normal neutrophil function. Two died from disseminated fungal infection. Two experienced significant chronic GvHD, with continuing sequelae in 1. Colitis resolved within 8 weeks of HSCT. Mean weight and height for age Z scores on recovery from HSCT rose significantly (P < 0·001). HSCT with MSD or URD gave excellent engraftment and survival, remission of colitis and catch‐up growth, with low incidence of significant GvHD. Transplant‐associated complications were restricted to those with pre‐existing infection or inflammation, supporting the argument for early HSCT for more CGD patients with a well matched donor.

Unsuspected Pneumocystis carinii pneumonia at presentation of severe primary immunodeficiency.

BACKGROUND Pneumocystis carinii is an important pathogen in immunodeficiency but may be an unrecognised cause of respiratory compromise. OBJECTIVES To ascertain the incidence of P cariniipneumonia (PCP) at presentation of severe combined immunodeficiency (SCID), whether it had been diagnosed, and the effect of treatment on outcome. SETTING The supraregional paediatric bone marrow transplant unit for primary immunodeficiencies at Newcastle General Hospital. METHODS Retrospective case note review of infants referred with a diagnosis of SCID from 1992 to 1998. RESULTS Ten of 50 infants had PCP at presentation; only one was diagnosed before transfer. Eight were diagnosed by bronchoalveolar lavage and two by lung biopsy. In only one was P cariniiidentified in nasopharyngeal secretions. Five required ventilation for respiratory failure but all were successfully treated with co-trimoxazole and methylprednisolone with or without nebulised budesonide. Nine survived to bone marrow transplantation and four are long term survivors after bone marrow transplantation; no deaths were related to PCP. CONCLUSIONS PCP is a common presenting feature of SCID but is rarely recognised. Bronchoalveolar lavage or lung biopsy are needed for diagnosis. Treatment with co-trimoxazole is highly successful.

Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome.

Zohreh Nademi, PhD, Mary A. Slatter, MD, Christopher C. Dvorak, MD, Benedicte Neven, MD, Alain Fischer, MD, Felipe Suarez, MD, Claire Booth, MD, Kanchan Rao, MD, Alexandra Laberko, MD, Julia Rodina, MD, Yves Bertrand, MD, Sylwia Kołtan, MD, Robert Dębski, MD, Terence Flood, MD, Mario Abinun, MD, Andrew R. Gennery, MD, Sophie Hambleton, DPhil, Stephan Ehl, MD, Andrew J. Cant, MD, on behalf of the Inborn Errors Working Party of EBMT and ESID

Adenovirus Type F Subtype 41 Causing Disseminated Disease following Bone Marrow Transplantation for Immunodeficiency

ABSTRACT Adenovirus causes disseminated disease following bone marrow transplantation (BMT). We report a child who underwent T-cell-depleted BMT. Adenovirus subgenus F serotype 41 was detected antemortem by PCR in cerebrospinal fluid and postmortem in other tissues. Serotypes 40 and 41, associated with gastrointestinal disease, have not previously been implicated in disseminated disease.

Lesson of the week - Recurrent bacterial meningitis: the need for sensitive imaging

Sensitive imaging is needed in children with recurrent bacterial meningitis to detect cranial anatomical defects Recurrent bacterial meningitis in childhood is unusual and should prompt a search for immune deficiency. A variety of immunological defects may predispose to recurrent meningitis, including antibody or complement deficiency and hyposplenism. It is equally important to consider cranial anatomical defects such as skull fractures, particularly those affecting the base of the brain and extending to the sinuses and petrous pyramids.1 Craniospinal dermal sinuses, neurenteric or dermoid cysts, occult intranasal encephaloceles, or transethmoidmeningoceles are also potential portals of entry for pathogens into the subarachnoid space. 2 3 Encephaloceles may occur anywhere in the midline and arise from failure of closure of the embryonic neuraxis, creating a defect in the dura and cranium with or without protrusion of brain and meningeal tissue. Basal ethmoidal encephaloceles may extend into the nose and be mistaken for nasal polyps2 or into ethmoid sinuses or orbits. Sometimes there may be a delay in establishing a diagnosis owing to a failure to consider anatomical defects or the use of insufficiently sensitive imaging procedures. We describe two children with recurrent bacterial meningitis due to cranial anatomical defects in whom diagnosis was delayed. ### Case 1 A 9 year old boy presented with pneumococcal …

Outcome of hematopoietic stem cell transplantation in severe combined immune deficiency with central nervous system viral infection.

Background: Patients with severe combined immunodeficiency and preexisting viral pneumonitis formally had a poor outcome from hematopoietic stem cell transplantation. With inhaled steroid and antitumor necrosis factor α antibody treatment, results improved. The poor outcome of patients with viral central nervous system infection prompted this retrospective single center review. Results: Eight of 71 patients with severe combined immunodeficiency transplanted since 1987 were identified with viral central nervous system infection (adenovirus [1], cytomegalovirus [2], Epstein-Barr virus [2], parvovirus [1], varicella zoster virus [1], human herpesvirus 6 [1]). Nonspecific neurologic symptoms included drowsiness, irritability, head lag, fisting and floppiness. Later symptoms included unresponsiveness, apnea, posturing, hypotonia, hyperreflexia and seizures. All had neuroradiologic investigations. Only one had an initially normal computed tomography scan. Magnetic resonance image abnormalities included cerebral atrophy, basal ganglia changes, diffuse leukoencephalopathy, and multifocal mass lesions. Five patients had virus identified from cerebrospinal fluid by polymerase chain reaction and brain tissue examination from 3 patients identified human herpesvirus 6, adenovirus type 41 and varicella zoster virus. Three children remain alive, 2 received replete marrow and one remains untransplanted. Others who received T cell depleted marrow died of neurologic sequelae. Conclusion: Outcome of viral central nervous system infection after hematopoietic stem cell transplantation for severe combined immunodeficiency is poor, particularly associated with T cell depleted marrow.

Treosulfan and Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Children with Primary Immunodeficiency: UK Experience

We previously published results for 70 children who received conditioning with treosulfan and cyclophosphamide (n = 30) or fludarabine (n = 40) before undergoing hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency (PID). Toxicity was lower and T cell chimerism was better in the patients receiving fludarabine, but cohort numbers were relatively small and follow-up was short. Here we report outcomes of 160 children who received homogeneous conditioning with treosulfan, fludarabine, and, in most cases, alemtuzumab (n = 124). The median age at transplantation was 1.36 years (range, .09 to 18.25 years). Donors included 73 matched unrelated, 54 1 to 3 antigen-mismatched unrelated, 12 matched sibling, 17 other matched family, and 4 haploidentical donors. Stem cell source was peripheral blood stem cells (PBSCs) in 70, bone marrow in 49, and cord blood in 41. Median duration of follow-up was 4.3 years (range, .8 to 9.4 years). Overall survival was 83%. No patients had veno-occlusive disease. Seventy-four patients (46%) had acute GVHD, but only 14 (9%) greater than grade II. Four patients underwent successful retransplantation for graft loss or poor immune reconstitution. Another patient experienced graft rejection and died. There was no association between T cell chimerism >95% and stem cell source, but a significant association was seen between myeloid chimerism >95% and use of PBSCs without an increased risk of significant GVHD compared with other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth were alive at up to 8.7 years of follow-up. Long-term studies are needed to determine late gonadotoxic effects, and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine, and alemtuzumab is associated with excellent results in HSCT for PID.

Identification of Heterozygous Single- and Multi-exon Deletions in IL7R by Whole Exome Sequencing.

PurposeWe aimed to achieve a retrospective molecular diagnosis by applying state-of-the-art genomic sequencing methods to past patients with T-B+NK+ severe combined immunodeficiency (SCID). We included identification of copy number variations (CNVs) by whole exome sequencing (WES) using the CNV calling method ExomeDepth to detect gene alterations for which routine Sanger sequencing analysis is not suitable, such as large heterozygous deletions.MethodsOf a total of 12 undiagnosed patients with T-B+NK+ SCID, we analyzed eight probands by WES, using GATK to detect single nucleotide variants (SNVs) and small insertions and deletions (INDELs) and ExomeDepth to detect CNVs.ResultsWe found heterozygous single- or multi-exon deletions in IL7R, a known disease gene for autosomal recessive T-B+NK+ SCID, in four families (seven patients). In three families (five patients), these deletions coexisted with a heterozygous splice site or nonsense mutation elsewhere in the same gene, consistent with compound heterozygosity. In our cohort, about a quarter of T-B+NK+ SCID patients (26%) had such compound heterozygous IL7R deletions.ConclusionsWe show that heterozygous IL7R exon deletions are common in T-B+NK+ SCID and are detectable by WES. They should be considered if Sanger sequencing fails to detect homozygous or compound heterozygous IL7R SNVs or INDELs.

Infection-Related Death among Persons with Refractory Juvenile Idiopathic Arthritis.

Bacterial sepsis led to multiorgan failure in persons receiving immunosuppressive and antiinflammatory drugs.

Haematopoeitic stem cell transplantation for chronic granulomatous disease - a single-centre experience

83 Inhibitory KIR-ligand mismatching is associated with decreased incidence of relapse and improved diseasefree survival after unrelated cord blood stem cell transplantation for patients with acute leukaemia R. Willemze*, C. Arrais Rodrigues, M. Labopin, I. Ionescu, K. Boudjedir, G. Sanz, G. Michel, G. Socié, B. Rio, J. Garcia, G. Kögler, L. Lecchi, P. Loiseau, E. Gluckman, V. Rocha on behalf of Eurocord-Netcord* and Acute Leukaemia Working Party of the EBMT, Paris