Publications by authors named "Paul A Veys"

14 Publications

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Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2020 07 9;26(7):1247-1256. Epub 2020 Mar 9.

BMT & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin.

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years the field has not only seen an improvement in transplantation technology, thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells, including chimeric antigen receptor T cells and engineered T-cell receptors, has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established a multiple stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on indications for HCT and IECT. This article presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but have been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exists but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early-phase clinical studies show HCT/IECT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.002DOI Listing
July 2020

Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis.

Lancet Haematol 2017 Jul 13;4(7):e325-e333. Epub 2017 Jun 13.

Service d'Haematologie et Therapie Cellulaire, Hôpital Saint Antoine, Paris, France.

Background: The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation.

Methods: We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model.

Findings: Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08-2·21, p=0·018), three (2·04, 1·44-2·89, p=0·0001), and four or more alleles (3·15, 2·16-4·58, p<0·0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1·18, 95% CI 0·80-1·72, p=0·39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1·40, 95% CI 1·13-1·74, p=0·0020), reduced intensity compared with myeloablative conditioning regimens (HR 1·36, 1·10-1·68, p=0·0041), transplantation of units with total nucleated cell dose of more than 21 × 10 cells per kg compared with 21 × 10 cells per kg or less (HR 1·47, 1·11-1·95, p=0·0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1·64, 1·31-2·04, p<0·0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose, and transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality.

Interpretation: These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1.

Funding: National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services-Health Resources and Services Administration; and US Department of Navy.
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http://dx.doi.org/10.1016/S2352-3026(17)30104-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699478PMC
July 2017

Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2015 Nov 7;21(11):1863-1869. Epub 2015 Aug 7.

Sarah Cannon, Nashville, TN.

Approximately 20,000 hematopoietic cell transplantation (HCT) procedures are performed in the United States annually. With advances in transplantation technology and supportive care practices, HCT has become safer, and patient survival continues to improve over time. Indications for HCT continue to evolve as research refines the role for HCT in established indications and identifies emerging indications where HCT may be beneficial. The American Society for Blood and Marrow Transplantation (ASBMT) established a multiple-stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on "routine" indications for HCT. This white paper presents the recommendations from the task force. Indications for HCT were categorized as follows: (1) Standard of care, where indication for HCT is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but HCT has been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where HCT has demonstrated effectiveness but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early phase clinical studies show HCT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT. The ASBMT will periodically review these guidelines and will update them as new evidence becomes available.
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http://dx.doi.org/10.1016/j.bbmt.2015.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830270PMC
November 2015

Hematopoietic stem cell transplantation for infantile osteopetrosis.

Blood 2015 Jul 26;126(2):270-6. Epub 2015 May 26.

Center for International Blood and Marrow Transplant Research, Department of Medicine, and.

We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty-four percent of transplants used grafts from HLA-matched siblings, 13% from HLA-mismatched relatives, 12% from HLA-matched, and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLA-mismatched related, HLA-matched unrelated, or mismatched unrelated donor transplantation. The 5- and 10-year probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (P = .01 and P = .002, respectively). Graft failure was the most common cause of death, accounting for 50% of deaths after HLA-matched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA-matched sibling and 61% after alternative donor transplantation (P = .49). The median age of surviving patients is 7 years. Of evaluable surviving patients, 70% are visually impaired; 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors >5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%. Though allogeneic transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed.
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http://dx.doi.org/10.1182/blood-2015-01-625541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497967PMC
July 2015

Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning.

Br J Haematol 2015 Jun 27;169(5):711-8. Epub 2015 Mar 27.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.
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http://dx.doi.org/10.1111/bjh.13347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433436PMC
June 2015

The many faces of Artemis-deficient combined immunodeficiency - Two patients with DCLRE1C mutations and a systematic literature review of genotype-phenotype correlation.

Clin Immunol 2013 Dec 27;149(3):464-74. Epub 2013 Aug 27.

Department of Immunology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

Defective V(D)J recombination and DNA double-strand break (DSB) repair severely impair the development of T-lymphocytes and B-lymphocytes. Most patients manifest a severe combined immunodeficiency during infancy. We report 2 siblings with combined immunodeficiency (CID) and immunodysregulation caused by compound heterozygous Artemis mutations, including an exon 1-3 deletion generating a null allele, and a missense change (p.T71P). Skin fibroblasts demonstrated normal DSB repair by gamma-H2AX analysis, supporting the predicted hypomorphic nature of the p.T71P allele. In addition to these two patients, 12 patients with Artemis-deficient CID were previously reported. All had significant morbidities including recurrent infections, autoimmunity, EBV-associated lymphoma, and carcinoma despite having hypomorphic mutants with residual Artemis expression, V(D)J recombination or DSB repair capacity. Nine patients underwent stem cell transplant and six survived, while four patients who did not receive transplant died. The progressive nature of immunodeficiency and genomic instability accounts for poor survival, and early HSCT should be considered.
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http://dx.doi.org/10.1016/j.clim.2013.08.006DOI Listing
December 2013

Pleuroparenchymal fibroelastosis in patients with pulmonary disease secondary to bone marrow transplantation.

Mod Pathol 2011 Dec 5;24(12):1633-9. Epub 2011 Aug 5.

Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

This study presents four patients who underwent bone marrow transplantation and subsequently developed pleuroparenchymal fibroelastosis, hitherto reported as an idiopathic condition. All presented clinically with pneumothorax and subpleural fibrosis on high-resolution computed tomography. In addition to the expected obliterative bronchiolitis, histopathology showed coexistent subpleural changes, and the relationship of pathology in multiple anatomic compartments in post bone marrow transplantation pulmonary disease is discussed.
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http://dx.doi.org/10.1038/modpathol.2011.114DOI Listing
December 2011

Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study.

Lancet 2009 Sep 2;374(9693):912-20. Epub 2009 Sep 2.

Great Ormond Street Children's Hospital, London, UK.

Background: Stem-cell transplantation can cure primary immunodeficiencies. However, in patients with pre-existing organ toxicity, patients younger than 1 year, and those with DNA or telomere repair disorders, chemotherapy-based conditioning is poorly tolerated and results in major morbidity and mortality. We tested a novel antibody-based minimal-intensity conditioning (MIC) regimen to assess whether this approach allowed curative donor stem-cell engraftment without non-haemopoietic toxicity.

Methods: 16 high-risk patients underwent stem-cell transplantation for primary immunodeficiencies with an MIC regimen consisting of two rat anti-CD45 monoclonal antibodies YTH 24.5 and YTH 54.12 for myelosuppression, and alemtuzumab (anti-CD52) and fludarabine, and low dose cyclophosphamide for immunosuppression. Donors were matched siblings (n=5), and matched (9) and mismatched (2) unrelated donors.

Findings: Antibody-based conditioning was well tolerated, with only two cases of grade 3 and no grade 4 toxicity. Rates of clinically significant acute (n=6, 36%) and chronic graft-versus-host disease (GVHD) (n=5, 31%) were acceptable. 15 of 16 patients (94%) engrafted, of whom 11 (69%) achieved full or high-level mixed chimerism in both lymphoid and myeloid lineages, and three achieved engraftment in the T-lymphoid lineage only. One patient needed retransplantation. At a median of 40 months post-transplant, 13 of 16 patients (81%) in this high-risk cohort were alive and cured from their underlying disease.

Interpretation: Monoclonal antibody-based conditioning seems well tolerated and can achieve curative engraftment even in patients with severe organ toxicity or DNA repair defects, or both. This novel approach represents a shift from the paradigm that intensive chemotherapy or radiotherapy, or both, is needed for donor stem-cell engraftment. This antibody-based conditioning regimen may reduce toxicity and late effects and enable SCT in virtually any primary immunodeficiency patient with a matched donor.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(09)60945-4DOI Listing
September 2009

Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies.

Blood 2008 Nov 21;112(9):3907-13. Epub 2008 Jul 21.

Department of Psychosocial Services, Great Ormond Street Hospital National Health Service (NHS) Trust, London, UK.

Hematopoietic stem cell transplantation (HSCT) is a highly successful treatment for severe congenital immunodeficiencies. However, some studies have suggested that children may experience cognitive difficulties after HSCT. This large-scale study assessed cognitive and behavioral function for the cohort of children treated by HSCT at one center between 1979 and 2003 to determine the frequency and severity of problems and to identify risk factors. A total of 105 patients were assessed on standardized measures of cognitive and emotional and behavioral function together with a control group of unaffected siblings. The average IQ for the cohort was 85 (95% confidence interval, 81-90), significantly lower than both the population average of 100 (P < .001) and unaffected siblings. Multivariate analysis indicated that the underlying genetic defect, diagnosis of adenosine deaminase-deficient severe combined immunodeficiency, and consanguinity were associated with worse outcome but that age at transplantation and chemotherapy conditioning were not. Children treated by HSCT for severe immunodeficiency have an increased risk of long-term cognitive difficulties and associated emotional and behavioral difficulties. The specific genetic diagnosis, consanguinity, and severe clinical course are associated with poor outcome. Long-term follow-up of these patients should include screening to identify and manage these problems more effectively.
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http://dx.doi.org/10.1182/blood-2008-04-151332DOI Listing
November 2008

Treosulfan-containing regimens achieve high rates of engraftment associated with low transplant morbidity and mortality in children with non-malignant disease and significant co-morbidities.

Br J Haematol 2008 Jun 19;142(2):257-62. Epub 2008 May 19.

Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, UK.

Treosulfan is an immuno-suppressive and myeloablative alkylating agent that has been introduced as a conditioning agent in stem cell transplantation (SCT). Most studies have been performed in adult patients with malignancy where a low incidence of regimen-related toxicity has been reported. We report the use of treosulfan in 32 consecutive children undergoing SCT for non-malignant disease. Patients received a total treosulfan dose of 36 or 42 g/m(2)/patient given in three daily, divided doses. A range of other conditioning agents and serotherapy was administered to patients who underwent family donor SCT (n = 11), or unrelated donor SCT (n = 21). One patient (3%) died early. Transplant morbidity was limited and mucositis was only mild. Dermatological toxicity was frequent but mild. Twenty-eight patients (87.5%) established donor cell engraftment. In 25 patients (78%) there was adequate, stable donor engraftment. Four patients have required additional transplant procedures to maintain adequate donor-derived haemopoiesis. Twenty-seven patients (84%) survive with a median follow up of 417 d. There were four late deaths due to progression of the underlying disease, graft-versus-host disease or infection. Treosulfan-based conditioning regimens achieve excellent engraftment with reduced regimen-related toxicity in children with non-malignant disease at high risk for both regimen-related toxicity and graft failure.
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http://dx.doi.org/10.1111/j.1365-2141.2008.07064.xDOI Listing
June 2008

CD34 stem cell top-ups without conditioning after initial haematopoietic stem cell transplantation for correction of incomplete haematopoietic and immunological recovery in severe congenital immunodeficiencies.

Br J Haematol 2006 Nov 10;135(4):533-7. Epub 2006 Oct 10.

Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, UK.

Haematopoietic stem cell transplantation can be limited by ineffective haematopoiesis and poor immune recovery. A CD34(+) cell infusion without conditioning has the potential to improve stem cell function with limited toxicity. Eighteen patients with congenital immunodeficiencies received CD34(+) boosts for various defects. When given <1 year after the original graft, six of seven cytopenic patients achieved transfusion independence. A second cohort (n = 11) received boosts >1 year after the original graft; only minimal changes in immune function or chimaerism were noted. Unconditioned stem cell boosts have limited toxicity but should be given early after the original graft to be effective.
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http://dx.doi.org/10.1111/j.1365-2141.2006.06333.xDOI Listing
November 2006

Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning.

Mol Ther 2006 Oct 14;14(4):505-13. Epub 2006 Aug 14.

Molecular Immunology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.

Gene therapy is a promising treatment option for monogenic diseases, but success has been seen in only a handful of studies thus far. We now document successful reconstitution of immune function in a child with the adenosine deaminase (ADA)-deficient form of severe combined immunodeficiency (SCID) following hematopoietic stem cell (HSC) gene therapy. An ADA-SCID child who showed a poor response to PEG-ADA enzyme replacement was enrolled into the clinical study. Following cessation of enzyme replacement therapy, autologous CD34(+) HSCs were transduced with an ADA-expressing gammaretroviral vector. Gene-modified cells were reinfused following one dose of preconditioning chemotherapy. Two years after the procedure, immunological and biochemical correction has been maintained with progressive increase in lymphocyte numbers, reinitiation of thymopoiesis, and systemic detoxification of ADA metabolites. Sustained vector marking with detection of polyclonal vector integration sites in multiple cell lineages and detection of ADA activity in red blood cells suggests transduction of early hematopoietic progenitors. No serious side effects were seen either as a result of the conditioning procedure or due to retroviral insertion. Gene therapy is an effective treatment option for the treatment of ADA-SCID.
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http://dx.doi.org/10.1016/j.ymthe.2006.06.007DOI Listing
October 2006

Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen.

Blood 2005 Jan 14;105(2):879-85. Epub 2004 Sep 14.

Department of Bone Marrow Transplant, Great Ormond Street Hospital, London, United Kingdom.

The optimal approach to stem cell transplantation in children with immunodeficiency who lack a matched family donor is controversial. Unrelated donor stem cell transplantation gives equivalent outcome to mismatched family donor stem cell transplantation in severe combined immunodeficiency, whereas unrelated donors may be preferable in non-severe combined immunodeficiency children. However, unrelated donor stem cell transplantation with conventional conditioning regimens has been associated with significant treatment-related toxicity, particularly in non-severe combined immunodeficiency patients with preexisting organ dysfunction. We report the outcome of a series of 33 consecutive unrelated donor transplantations performed at our center in children with primary immunodeficiency using a reduced-intensity conditioning regimen between 1998 and 2001. We have compared these outcomes with a retrospective control cohort of 19 patients who underwent transplantation with myeloablative conditioning between 1994 and 1998. All children in both groups had primary engraftment. There was no statistical difference in the speed of immune reconstitution or incidence of graft-versus-host disease between the 2 groups. Overall survival was significantly better in the reduced-intensity conditioning group: 31 (94%) of 33 patients survived, compared with 10 (53%) of 19 in the myeloablative conditioning group (P = .014). We conclude that the reduced-intensity conditioning regimen results in improved survival and reduced transplantation-related mortality compared with myeloablative conditioning in high-risk patients undergoing unrelated donor transplantation.
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http://dx.doi.org/10.1182/blood-2004-03-0960DOI Listing
January 2005

The radiological spectrum of invasive aspergillosis in children: a 10-year review.

Pediatr Radiol 2003 Jul 9;33(7):453-60. Epub 2003 May 9.

Department of Diagnostic Radiology, Great Ormond Street Hospital for Children, Great Ormond Street, London, UK.

Background: Invasive aspergillosis is an uncommon but life-threatening event in the immunocompromised child. Attempts at fungal isolation are often unrewarding and a high index of radiological suspicion is essential in the early diagnosis of infected children.

Objective: To document the radiological spectrum of disease in invasive aspergillosis in the paediatric population.

Materials And Methods: A retrospective review of the imaging performed in 27 consecutive patients (age 7 months to 18 years) with documented invasive Aspergillosis encountered over a 10-year period at a single institution.

Results: Radiographic findings of pulmonary disease (20 patients) included segmental and multilobar consolidation, perihilar infiltrates, multiple small nodules, peripheral nodular masses and pleural effusions. No cavitating lesions were seen on CXR. Small cavitating nodules were present on CT in two of eight children. Chest wall disease was particularly associated with underlying chronic granulomatous disease. Disseminated disease manifested as osteomyelitis (n=5), cerebral (n=3), oesophageal (n=1), hepatic (n=2), renal (n=2) and cutaneous (n=5) involvement. Imaging findings are discussed. Twelve patients (44%) subsequently died from Aspergillus-related complications.

Conclusions: Invasive aspergillosis presents with a wide variety of radiographic findings involving multiple organ systems. Respiratory findings are varied but often non-specific, and a high index of suspicion is necessary in immunocompromised patients. In contrast to adult disease, the incidence of cavitation of pulmonary lesions appears low.
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http://dx.doi.org/10.1007/s00247-003-0919-4DOI Listing
July 2003