Evidence Of Organ Involvement Research Articles

#2199 Kidney involvement aspects in women with Fabry disease from the Romanian cohort

Abstract Background and Aims Fabry disease (FD) is an X-linked rare lysosomal storage disease causing progressive nervous system, kidney and heart disorders. Progressive kidney impairment is common, and an important cause of morbidity and mortality. In FD females, treatment guidelines recommend therapy initiation when there is evidence of organ involvement, but determining the proper moment to start FD specific treatment could be a real challenge in the cases. The aim of our retrospective study is to investigate clinical and histological aspects of kidney involvement in female patients with genetically confirmed FD evaluated in our Expert Center for Rare Diseases of the Reno-Urinary System between 2015–2023, with focus on the clinical phenotype and initiation of FD specific treatment. Method All patients had comprehensive assessment for target organ manifestations of Fabry disease. Renal function was assessed using serum creatinine, albumin creatinine ratio and proteinuria. Also, 14 (40%) FD females underwent kidney biopsy (KB) in order to reveal the FD specific lesions and/or to establish the indication for FD pathogenic therapy. Kidney biopsy specimens were analyzed by light and electron microscopy. Results Our study included 35 heterozygous adult females with FD from 25 unrelated families. Most females (91.4%) were diagnosed through family screening, while 3 females (8.6%) were index cases. The mean age at diagnosis was 43.8 ± 15.3 years (range 17-73 years), although mean age of symptoms onset was 34.3 ± 13.5 years (range 14-61 years). Six women from our cohort were considered healthy carriers, three females presented only neurological manifestations, nine patients had combined renal and neurological involvement, one patient had cardiac and renal involvement and the others presented multiple organ involvement. Significant co-morbidities were: arterial hypertension in 13 patients, diabetes mellitus in 2 patients, and obesity in 9 patients. Overall baseline mean eGFR was 79.9 ± 28.2 (range 25-135) ml/min/1.73 m2. Eleven patients had no obvious kidney involvement, 10 patients presented chronic kidney disease (CKD) stage 2, 11 patients CKD stage 3, one CKD stage 4 and 1 was hemodialyzed. Seventeen patients presented normal UACR, thirteen patients showed microalbuminuria, and four patients presented macroalbuminuria. Overt proteinuria (> 0.3 g/24 h) was noticed in 8 patients. Thirteen females performed KB before the initiation of FD specific treatment, and one patient was already treated. At the moment of KB, five patients had normal biologic kidney assessment, three patients presented CKD stage 2 (microalbuminuria in 2 cases and proteinuria in 1 case), and five patients presented CKD stage 3 (normoalbuminuria in 1 case, microalbuminuria in 1 case and overt proteinuria in 3 cases). All KBs showed lysosomal accumulation in the podocytes, 92.8% showed inclusions in the parietal cells of the Bowman capsule, 85.7% in the tubules, while vascular inclusions were found in 78.5% of cases. Also, we observed segmental glomerular sclerosis in 5 cases, interstitial fibrosis and tubular atrophy in 3 cases, each. Only 2 patients were treated with pathogenic therapy before the first evaluation in our center. After multidisciplinary evaluation, 22 patients (62.8%) from our cohort received recommendation to initiate FD specific treatment, and 11 patients entered in our follow-up program. Evidence of specific FD lesions in KB was a strong reason to support the recommendation to initiate FD specific treatment. Conclusion Our results showed that kidney involvement in FD females can vary from asymptomatic or mildly symptomatic, to severely symptomatic, with end stage kidney disease. Thus, females should be carefully evaluated and monitored in a multidisciplinary team, in order to diagnosed FD affected organs. Also, we underline that a normal standard assessment of the kidney cannot rule out kidney involvement in female patients with FD, and strengthen the importance of KB for detection of early kidney involvement and for additional support for early initiation of FD specific therapy.

Frequency Of Multi-organ Involvement In Athletes Assessed 10-28 Days After Onset Of SARS-CoV-2 Infection

SARS-CoV-2 infection can affect multiple organ systems. The frequency of multi-organ involvement that influences clinical return-to-play (RTP) decisions in athletes with a recent COVID-19 infection is not well documented. PURPOSE: To determine the frequency (%) of multi-organ/system involvement (symptoms, clinical signs and abnormal special investigations) that influences RTP decisions in athletes with a recent SARS-CoV-2 infection. METHODS: 95 athletes (25.0 ± 7.1 years) with confirmed SARS-CoV-2 infection (polymerase chain reaction or antigen testing) attended a SARS-CoV-2 clinic for athletes to determine safe RTP. Participants were assessed 10-28 days after onset of SARS-CoV-2 infection (or + ve test if asymptomatic; n = 4). 96 athlete assessments (including 1 assessment of a participant with a repeat infection >8 weeks after initial infection) included current symptoms, physical examination and laboratory tests: resting and submaximal exercise electrocardiogram (EKG), resting and post-exercise pulmonary function tests (PFT), echocardiogram (Echo), cardiac magnetic resonance (CMR) with late gadolinium enhancement, total white cell count (WCC), neutrophil and lymphocyte counts, C-Reactive protein (CRP), high sensitivity troponin-T (hs-trop T), aspartate transaminases (AST), alanine transaminases (ALT) and creatine kinase (CK). RESULTS: 29 athletes (30%) had no abnormal findings, while 67 (70%) had evidence of organ involvement [1 organ system = 40 (42%), 2 organ systems = 19 (20%) and > 3 organ systems = 8 (8%)]. The most common systems affected were cardiovascular (n = 32; 33%) [abnormal resting EKG = 3 (3%), submaximal exercise EKG = 9 (9%), echo = 2 (2%) or CMR = 21 (22%)], nervous system (excessive tiredness = 23; 24%), digestive tract (elevated AST/ALT = 21; 22%). Less frequently affected were muscle (increased CK = 10; 10%), immune system (abnormal WCC/ CPR = 10; 10%), ocular (n = 3; 3%) and skin (n = 2; 2%). CONCLUSION: Clinical and laboratory evidence of multi-organ system involvement that influences RTP decisions in athletes 10-28 days after SARS-CoV-2 infection is common. Organ systems mostly affected are the cardiovascular and nervous system (excessive fatigue).

Localized Pulmonary Amyloidosis: A Single Institution Experience

Introduction: Amyloidosis is a disease characterized by deposition of congophilic amyloid fibrils in the extracellular matrix of tissues and organs. Although pulmonary involvement in amyloidosis is common, it is rarely symptomatic. The clinical course is considered indolent or benign, however literature available on biology and history of this disease is limited. Sub-typing of pulmonary amyloidosis has been historically difficult. Pulmonary amyloidosis can be a part of an underlying plasma cell dyscrasia or related to an underlying inflammatory systemic disease. Our aim was to identify the further workup done after a biopsy proven diagnosis of pulmonary amyloidosis and the relation to monoclonal gammopathy. We also investigated the frequency of utilization of mass spectrometry for amyloid typing at our institution. Methods: We reviewed medical records of adult patients ≥ 18 years with localized pulmonary amyloidosis from January 1st 2010 to June 30th 2019. The word "amyloidosis" was used to search for cases of localized pulmonary amyloidosis in the hospital's electronic medical records to generate a patient list. We recorded age and gender, medical history, work up for paraproteinemia, renal and hepatic function, pathology results including bone marrow biopsy, imaging studies, treatment and survival. Results: We identified 10 patients with amyloidosis on lung biopsy, out of which 4 were females (40%) and 6 were males (60%). Patient age ranged from 53 to 87 years with a median age of 80 years. (Table - 1) Four out of the 10 patients were found to have kappa light chains. Out of these 4 patients, 3 had kappa light chain restriction on the amyloid deposit of lung biopsy specimen by immunohistochemistry (IHC). One patient had expression of both kappa and lambda light chains. His B-cell polymerase chain reaction (PCR) was negative. Mass spectrometry was done in 1 patient which confirmed Immunoglobulin light chain (AL) amyloidosis. Bone marrow biopsy was performed in 3 out of 4 patients and interestingly, the patient with negative IHC in the amyloid had 19% plasma cells while the other 2 patients had 1.8% and 3%. All the 4 patients had normal renal function, hepatic function, serum albumin. They also had no bone lesions or organomegaly. Out of the 10 patients, 1 patient had a history of hairy cell leukemia and the amyloid nodule showed lambda light chain restriction, likely related to the B-cell Lymphoproliferative disorder. He had no evidence of a monoclonal gammopathy or evidence of organ involvement. The remaining 5 patients were suspected to have amyloid A (AA) amyloidosis and 4 of them had documented underlying systemic disease. None of these patients had evidence of other organ involvement. One patient with suspected AA amyloid nodule had excision of the lesion. All the patients had stable lung nodules and none of them had evidence of progressive systemic amyloidosis. None of the patients were given systemic therapy. Eight out of 10 patients were alive at the time of data cut-off. The 2 deaths were unrelated to amyloidosis were due to hairy cell leukemia in one patient and sepsis secondary to urinary tract infection in the other. Conclusion: Our institutional review of localized pulmonary amyloidosis showed no evidence of disease progression and had good clinical outcome. Interestingly, one of our patients with smoldering myeloma with pulmonary amyloid nodule had negative IHC stain which may point towards the fact that these patients may have amyloid which is unrelated to the paraprotein. Even though mass spectrometry is the gold standard for confirmation of amyloid, it is not widely available and may not be indicated in every case. In our study, we found only 10% rate of utilization of mass spectrometry. The other interesting finding was that patients with B-cell lymphoproliferative disorders can have amyloid with light chain restriction which is a part of the disorder rather than AL amyloidosis. Disclosures No relevant conflicts of interest to declare.

NONPRODUCTIVE COUGH AS PREAMBLE OF RESPIRATORY FAILURE IN A PATIENT WITH HYPEREOSINOPHILIC SYNDROME

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Hypereosinophilic syndrome (HES) is a rare disorder characterized by peripheral blood eosinophilia of 〖1.5 x 10〗ˆ3/μL or higher and evidence of end organ manifestations attributable to the eosinophilia and not otherwise explained in the clinical setting. HES has an unknown prevalence, most often affects people age 20 through 50. Few patients with prolonged eosinophilia develop organ dysfunction that characterizes HES. CASE PRESENTATION: This is the case of a healthy 52-year-old man without history of significant systemic illness who presents with non-productive cough, daily febrile episodes and left upper extremity pain for a period 2 months. On physical examination, lungs are clear upon chest auscultation and left sided axillary pain is elicited upon arm abduction. Initial blood work revealed WBC 〖40.62 x 10〗ˆ3/μL; eosinophil count 〖23.56 x 10〗ˆ3/μL, elevated sedimentation rate 112 mm/hr. Initial diagnosing testing for HES was performed. Complete blood count was remarkable for increasing trend in leukocytes and eosinophils. Routine chemistries, including liver function tests were within normal limits. Quantitative serum immunoglobulin levels, including IgE were normal. Serum troponin, echocardiogram, electrocardiogram, Pulmonary function tests revealed no abnormalities. Bone marrow biopsy including cytogenetics had no myeloproliferative abnormalities. Flexible bronchoscopy with bronchoalveolar lavage revealed eosinophils count less than 3%, no evidence of bacteria, viral or fungal infection. Serology examination for diagnosis of parasitic infection, HIV testing, antineutrophil antibodies ANCA, Serum tryptase and B12 levels, PET scan, lymph node biopsy, EBV viral load were completely negative. The patient’s eosinophilia continued to rise, peaking at 56.00 x 103/μL, despite high-dose prednisone therapy (200 mg by mouth daily), he went in to respiratory failure, cardiac arrest and developed multi organ dysfunction. Hydroxyurea (1 g daily) was added. He improved after the addition of hydroxyurea, and a decrease trending of his eosinophil count was seen. Hydroxyurea was discontinued, and prednisone was tapered. DISCUSSION: HES is a rare heterogeneous disease, any organ system is vulnerable to get affected. The symptoms are common in many other medical problems, making an initial diagnosis more difficult. Sometimes no underlying cause can be found for an observed eosinophilia, even after an extensive diagnostic evaluation. In the absence of an identifiable reactive cause for the eosinophilia, a diagnosis of idiopathic HES can be established if there is evidence of organ involvement and dysfunction. CONCLUSIONS: Our case illustrates the importance of considering diagnosis in patients with significant eosinophilia. Have a high index of suspicion in the background of persistent peripheral eosinophilia; after exclusion of secondary causes. Reference #1: https://doi.org/10.1182/asheducation-2018.1.326 ASH Education Book November 30, 2018 vol. 2018 no. 1 326-331 Reference #2: Klion AD. How I treat hypereosinophilic syndromes. Blood. 2015;126(9):1069-1077. Reference #3: Khoury P, Abiodun AO, Holland-Thomas N, Fay MP, Klion AD. Hypereosinophilic syndrome subtype predicts responsiveness to glucocorticoids. J Allergy Clin Immunol Pract. 2018;6(1):190-195. DISCLOSURES: No relevant relationships by Hector Cintron-Colon, source=Web Response No relevant relationships by Ricardo Fernandez, source=Web Response No relevant relationships by Vanessa Fonseca Ferrer, source=Web Response No relevant relationships by WIlliam Marrero, source=Web Response No relevant relationships by Luis Piñeiro, source=Web Response

Do we need to demonstrate Amyloid in tissue?

Background Famililal amyloid polyneuropathy due to mutations in the Transthyretin gene (TTR FAP) is a constantly disabling condition leading to death from cardiac or renal failure, or cachexia linked to end-stage neuropathy with autonomic involvement. It has an autosomal dominant inheritance and according to the literature, the phenotypic presentation has a bimodal age of onset with early onset cases occurring before 50 years of age and so-called late onset cases occurring thereafter. To date, therapeutic options are proposed to people who carry a TTR mutation and have evidence of organ involvement. Additional histopathologic demonstration of amyloid deposits in a tissue sample is often considered mandatory to start treatment, although this relies more on professional agreement than on medical or scientific evidence.

Multiple Targetoid Lesions in the Spleen

Chronic lymphocytic leukemia (CLL) is the most prevalent hematologic malignancy of adults in the western hemisphere. Involvement of the spleen is not uncommon, often presenting as diffuse enlargement due to infiltration of neoplastic cells. A case is presented of an 81-year-old woman with a past medical history of CLL who was incidentally found to have multiple, focal splenic infiltrates on sonography. The patient had a normal sized spleen, which is a less common occurrence with splenic invasion by CLL. As current CLL guidelines discourage imaging but rely on evidence of organ involvement, this finding was critical in staging the patient properly. The sonographic appearance of this rare condition is described, and the advantages of sonography in its evaluation are discussed.

Monoclonal B-Cell Lymphocytosis Exhibiting Immunophenotypic Features Consistent with Marginal Zone Origin: What Is This Entity?

AbstractAbstract 1587Monoclonal B-cell lymphocytosis (MBL) with an immunophenotype consistent with marginal zone origin (MBL-MZ), that can be either CD5− or CD5+ but atypical for CLL, and also lacking an IGH/CCND1 translocation, is an increasingly recognised entity with poorly understood biological background and clinical significance. In particular, it is not yet clarified whether it represents a precursor state to one of the distinct lymphoma entities recognized by WHO as deriving from MZ cells or whether it constitutes a novel entity, likely with similar ontogeny. To obtain insight into this issue we retrospectively evaluated a series of 71 patients (male/female: 35/36, median age: 73.3 years) with lymphocytosis (median lymphocyte count: 5.77 × 109/l) detected incidentally on a routine blood test. No case had lymphadenopathy, organomegaly or any clinical features to suggest a concurrent marginal zone lymphoma. Hemoglobin and platelet counts were normal in all cases; 15/57 (26%) cases had paraproteinemia. Peripheral blood immunophenotyping revealed the presence of a clonal B-cell population with Matutes score <2 in all cases. Individual markers were expressed as follows: CD5: 15/71, CD23: 7/70, CD79β: 60/64, FMC7: 50/67, CD49d: 35/35, CD38: 6/53. In 8/45 cases assessed with CT-scan and/or ultrasound, borderline splenomegaly was observed. Histopathological examination of the bone marrow biopsy (BMB) was available in 11 cases and demonstrated mostly mixed patterns of neoplastic lymphocytic inflitration from small B cells. Karyotype data were available in 66 cases; 48/66 (72.7%) had abnormal karyotype. Main cytogenetic findings are as follows: (1) translocations: n=16 cases of which 3 carried t(2;7)(p11;q21/22); (2) isochromosome 17q: n=8; (3) trisomy 12: n=8; (4) del(7q): n=7; (5) trisomy 3: n=4. Immunogenetic analysis revealed overusage of the IGHV4–34 gene (15/63, 23.8%). Notably, the IGHV1–2 gene was utilized by a single case, thus sharply contrasting (p<0.0001) splenic marginal-zone lymphoma (SMZL) with a reported frequency of IGHV1–2 in excess of 30%. Seven of 63 rearrangements (11.1%) carried IGHV genes with no somatic mutations, whereas the remainder (56/63, 88.9%) exhibited some impact of somatic hypermutation (SHM), ranging from minimal to (mostly) pronounced. Overall, cases of the present study exhibited a significantly (p<0.005) higher SHM load compared to SMZL. With a median follow-up of 4.9 years (0.8–20), 54 cases (group A) remain stable with no signs of progression. The remaining 17 cases (group B) have MBL along with clinical or histopathologic evidence of lymphoma. In particular: (i) a female with MBL as an incidental finding, also carrying t(2;7), was eventually diagnosed with gastric MALT lymphoma at +11 months from presentation; immunogenetic analysis confirmed clonal identity between the MBL and the lymphoma; (ii) 2 cases developed lymphadenopathy; (iii) a single case developed diffuse large B cell lymphoma of the skin; and, (iv) 13 cases developed splenomegaly and, thus, can be considered as either SMZL or splenic lymphoma/leukemia unclassifiable (SLLU). Groups A and B did not differ in terms of demographics, diagnostic blood counts (including clonal MBL count) and SHM status; the only difference concerned cytogenetic profiles, with i(17)(q10) and del(7q) being almost exclusive to group A. In conclusion, we demonstrate that MBL-MZ can be the presenting feature of occult MZ lymphoma, most frequently SMZL/SLLU. However, in a sizeable proportion of cases, MBL-MZ remains stable over time with no evidence of organ involvement and distinct immunogenetic features from SMZL, thereby raising the possibility that it might represent a newcomer to the spectrum of B-cell lymphoproliferations of MZ origin. Disclosures:No relevant conflicts of interest to declare.

Autologous Hematopoietic Stem Cell Transplantation Versus Intravenous Pulse Therapy Cyclophosphamide for Severe or Rapidly Progressive Systemic Sclerosis, the Astis Trial

AbstractAbstract ▪964▪This icon denotes a clinically relevant abstract Background:High dose immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) has shown efficacy in severe or rapidly progressive systemic sclerosis (SSc) in phase 1 and 2 trials with durable responses in two thirds of patients (pts), while a recent phase 2 randomised trial in 19 SSc pts showed superior benefit of HSCT over iv pulse cyclophosphamide (Cy) on skin score and lung function. Methods:The ASTIS-trial (Autologous Stem cell Transplantation International Scleroderma trial) is a multinational prospective randomized controlled phase 3 trial, comparing safety and efficacy of HSCT versus Cy in early progressive dcSSc pts with disease duration of a) 4 years or less and evidence of organ involvement or b) of 2 years or less and evidence of systemic inflammation with or without major organ involvement. Major exclusion criteria were: concomitant severe SSc disease (mean PAP > 50 mmHg, DLCO < 40% predicted, creatinine clearance (CCl) <40 ml/min, LVEF <45%, uncontrolled arythmia, infection, previous Cy (>5gr iv or >3months oral) treatment), liver failure. Pts randomized to the transplant arm underwent mobilization with Cy 2×2 g/m2 + G-CSF 10mcg/kg/d, conditioning with Cy 200 mg/kg, rbATG 7.5 mg/kg, followed by reinfusion of CD34+ autologous HSCT. Controls were treated with 12× monthly iv pulse Cy 750 mg/m2. Crossing over was allowed after 2 years. The primary endpoint was event-free survival (EFS), defined as survival until death or development of major organ failure at 2 yrs. Toxicity according to WHO criteria and progression free survival (defined as worsening of modified Rodnan skin score, functional ability, major organ function) were the main secondary endpoints. The effects of treatment were analyzed on an ITT basis and by comparing EFS using the KM survival curves (using log-rank test) and Cox models. Results:156 pts (female 59%), from 27 centers were enrolled in 10 countries from March 2001 until October 2009 and randomized to HSCT (n=79) or iv pulse Cy (n=77). Seventy-five pts in each arm started treatment, 70 pts in HSCT and 58 pts in control groups completed treatment. The median time (Interquartile Range (IR)) from randomization to completion of treatment was 93 (43.0) days in the HSCT and 338 (41.75) days in the control groups respectively. Baseline characteristics (mean (SD)) of the pts were: age 44 (11.2) yrs, SSc duration 1.4 (1.3) yrs, BMI 24 (14.4), Rodnan skin score 25 (8), HAQ 1.35 (0.8), prior Cy therapy 22%, creat cl 116 (39.5) ml/min, LVEF 65% (8.5), DLCO 59% (14), with no significant differences between the 2 arms.With data cut at 1 May 2012, median follow-up (IR) are 33 (42.0) and 27 (34.0) months in the HSCT and control groups respectively. Forty two events occurred : 18 in the HSCT group (16 deaths and 2 irreversible renal failures) and 24 in the control group (24 deaths). Event-free survival was time-dependent with a hazard ratio at 84 months of 0.22 (95% CI 0.08–0.58, P= 0.002). Eight deaths (including 1 during mobilization and 1 after conditioning) in the HSCT group were deemed treatment-related by the independent data monitoring committee with heart failure (3), ARDS (2), multiple organ failure (2) and pulmonary oedema (1) as the causes of death. In the control group, none died from treatment causes and most deaths were due to progressive disease. Eight pts in the control arm received rescue HSCT treatment, one of whom later died from secondary acute myeloid leukaemia. Two HSCT pts received rescue iv Cy therapy. Conclusions:The ASTIS-trial is the first international, investigator-initiated, phase 3 HSCT trial in early diffuse cutaneous systemic sclerosis. The data show that despite 10% treatment-related mortality, long term event-free survival and overall survival were better in the HSCT group than in the group treated with iv pulse cyclophosphamide.(Funded by the European Group for Blood and Marrow Transplantation, European League Against Rheumatism, AP-HP, NIHR, DIGR, Imtix-Sangstat, Miltenyi-Biotec, Amgen Europe; Current Controlled Trials number, ISRCTN 54371254). Disclosures:No relevant conflicts of interest to declare.

Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin

Glycogen storage diseases are a group of inborn errors of glycogen synthesis or catabolism. The outcome for untreated patients can be devastating. Given the genetic heterogeneity and the limited availability of enzyme study data, the definitive diagnosis of glycogen storage diseases is made on the basis of sequence analysis of selected potentially causative genes. A massively parallel sequencing test was developed for simultaneous sequencing of 16 genes known to cause muscle and liver forms of glycogen storage diseases: GYS2, GYS1, G6PC, SLC37A4, GAA, AGL, GBE1, PYGM, PYGL, PFKM, PHKA2, PHKB, PHKG2, PHKA1, PGAM2, and PGM1. All the nucleotides in the coding regions of these 16 genes have been enriched with sufficient coverage in an unbiased manner. Massively parallel sequencing demonstrated 100% sensitivity and specificity as compared with Sanger sequencing. Massively parallel sequencing correctly identified all types of mutations, including single-nucleotide substitutions, small deletions and duplications, and large deletions involving one or more exons. In addition, we have confirmed the molecular diagnosis in 11 of 17 patients in whom glycogen storage diseases were suspected. This report demonstrates the clinical utility of massively parallel sequencing technology in the diagnostic testing of a group of clinically and genetically heterogeneous disorders such as glycogen storage diseases, in a cost- and time-efficient manner.

Early Differential Resolution of Right and Left Ventricular Obliteration in Löffler Endocarditis After Chemotherapy and Anticoagulation

A 27-year-old woman diagnosed of T-cell non-Hodgkin lymphoma was referred to our hospital for allogenic hemopoietic stem cell transplantation. In childhood, the patient was diagnosed with hypereosinophilic syndrome. One week before admission, the patient started to develop progressive dyspnea. On chest x-ray, there were signs consistent with congestive heart failure. Her white cell count was 5990/mm3 with 59% eosinophils. A transthoracic echocardiogram disclosed a complete obliteration of the apexes of both ventricles, which were filled with a mildly echogenic material consistent with fibrosis or thrombosis. The right and left atria were enlarged, and pulsed wave Doppler examination showed a restrictive left ventricular (LV) filling pattern (Figure 1A through 1C). All of these findings were compatible with the diagnosis of Loffler endocarditis. The patient was anticoagulated and received conventional treatment for heart failure, resulting in clinical improvement. One week after admission, chemotherapy with fludarabine and melphalan was started, and a nonmyeloablative transplantation was carried out using hematopoietic progenitors from a human leukocyte antigen–compatible brother. Four weeks after chemotherapy, a repeat echocardiogram showed the total disappearance of the LV obliteration and a normal filling …

Pediatric Hypereosinophilic Syndrome (HES) Differs From Adult HES

Purpose of the Study. To highlight specific differences between pediatric and adult patients with hypereosinophilic syndrome (HES). Study Population. The case report involved a 15-year-old male who presented with abdominal pain, diarrhea, and a 10-lb weight loss. Colonoscopy revealed colitis. A nonproductive cough, night sweats, and a diffuse pruritic, papular rash developed. His initial absolute eosinophil count was 1890/mm3 (reference: &amp;lt;400/mm3), which increased to 52 000/mm3. Additional laboratory studies included: immunoglobulin E, 8561 U/mL (7–110 U/mL); alkaline phosphatase, 1149 U/mL (reference: 50–280 U/mL); γ-glutamyl transpeptidase, 193 (reference: 0–50 U/mL); and serum tryptase, 4.7 μg/L (reference: 1.9–13.5 μg/L). Ultrasound of the liver revealed an abnormal parenchymal pattern with dilated bile ducts. Molecular analysis of the patient’s peripheral blood for the Fip1-like-1 platelet-derived growth factor receptor α chain (FIP1L1-PDGFRA) fusion tyrosine kinase associated with HES in adults was negative. Open lung biopsy revealed patchy interstitial and intra-alveolar inflammation with a predominance of eosinophils. A skin biopsy showed acute neutrophilic folliculitis with perivascular dermatitis with eosinophils. Bone marrow biopsy demonstrated a hypercellular marrow with predominantly eosinophils, which is consistent with idiopathic HES. Methods. The investigators compared this case report of pediatric HES and additional published cases of pediatric and adult patients with HES. Results. Pediatric HES has only a slight male predominance (55.3% male vs 44.7% female), whereas adult HES is reported to be more common among males than females, with a ratio of 9 to 1. In adults, the frequencies of symptoms found on presentation are: fatigue (26%), cough (24%), dyspnea (16%), rash (12%), and fever (12%). Fever (58.8%), arthralgias (23%), and rash (23.5%) were more common in pediatric cases. As with adults, involvement of the cardiovascular system is the major source of morbidity and mortality. Pediatric HES is commonly associated with chromosomal abnormalities, and in ∼40% of the cases, it has been associated with acute leukemia. As opposed to the vast majority of adult HES cases, no pediatric case with the FIP1L1-PDGFRA fusion gene has been reported. Conclusion. There are several distinct features of pediatric, compared with adult, HES. Reviewer Comments. Most of the published information on the HES has focused on adult patients. This report compares a pediatric case report of HES and a review of published pediatric cases of this condition to adult patients with this syndrome. This is an insightful clinical report that should be useful in the overall workup of pediatric patients who present with dramatic eosinophilia (&amp;gt;1500/mm3) for &amp;gt;6 months’ duration without other known causes of eosinophilia and who have evidence of organ involvement that might be attributable to HES.

Chicken pox after pediatric liver transplantation

Previous case series have reported serious complications of chicken pox (CP) after pediatric liver transplantation (PLT), mainly due to visceral dissemination. The goal of our study was to determine the incidence, risk factors, and outcomes of CP after PLT. A case-control study of all CP infections in pediatric transplant recipients followed at our center from September 1993 to April 2004 was performed. Data were collected before and after infection and at the same time points in age-, gender-, and transplant year-matched controls. Potential risk factors prior to CP and adverse outcomes after infection were compared between cases and controls. Twenty (6.2%) developed CP at a median of 1.8 yr (0.6-4.8) after PLT. All CP infections were cutaneous, with no evidence of organ involvement. Twelve were hospitalized: 9 only to receive intravenous acyclovir and 3 stayed > or =2 weeks for other complications. Risk factors were not statistically different among cases and controls. Of the outcomes analyzed, cases were significantly more likely to develop non-CP infections within one year of CP than controls (Hazard Ratio = 12.6, 95% confidence interval = 3.1-51.7; P < 0.001). These infections were often bacterial and occurred long after CP infection. In conclusion, CP is uncommon after PLT and has a low likelihood of organ dissemination. No risk factors were identified. Some cases required prolonged hospitalizations. Close monitoring for the development of late bacterial infections is warranted.

Soluble HLA-I (s-HLA-I) synthesis in systemic lupus erythematosus.

Our objective was to study a possible contribution of major histocompatibility complex (MHC) genes to soluble HLA-I synthesis in patients with systemic lupus erythematosus (SLE). Solid-phase enzyme-linked immunoassay (ELISA) was used to measure sHLA-I in the sera of 20 patients with SLE and 76 normal controls with known HLA phenotypes. Serial serum samples ( n=108) from the above group of patients ( n=19) were further investigated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. Soluble HLA-I levels were abnormally higher in patients with SLE than normal controls ( P<0.0002). No complete HLA haplotype has been identified to be correlated with high or low sHLA-I secretion. Only the sera of HLA-A23- or -A24- (splits of HLA-A9) positive individuals were found to contain high sHLA-I concentrations in both populations studied. The difference between sHLA-I of HLA-A24 patients ( n=7) and HLA-A24 normal controls ( n=19) was statistically highly significant ( P<0.0079). The results suggest that HLA-A24 may confer additional risk of more severe disease expression in female patients with SLE. The data imply that SLE patients carrying 39-kDa sHLA-I have increased risk of developing renal disease. A higher prevalence of 35-37 kDa was observed in patients with mild disease. Interestingly, 44-46 kDa was the predominant molecular form of sHLA-I in SLE patients with lymphocytosis with no evidence of organ involvement. Notably, all these variations were not reflected by differences in HLA phenotypes, with the exception of HLA-A24-positive patients, in whom the 44-46-kDa form occurs consistently but not exclusively. In summary, the results show a genetic heterogeneity of SLE with MHC control of the expression of sHLA-I concentrations and possible involvement of disease-associated factors that might potentiate a specific sHLA-I molecule synthesis.

Toxoplasmosis after hematopoietic stem cell transplantation.

Forty-one cases of toxoplasmosis were diagnosed in 15 European transplantation centers in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT) from 1994 through 1998. Most patients (39 [94%]) were seropositive for Toxoplasma gondii before they underwent transplantation, and 30 (73%) had developed moderate to severe acute graft-versus-host disease before they developed toxoplasmosis. Thirty-five (85%) patients had Toxoplasma disease with evidence of organ involvement, whereas 6 (15%) patients had Toxoplasma infection, as defined by fever and a positive polymerase chain reaction (PCR) finding for T. gondii in blood. Nine patients were diagnosed at autopsy. Thirty patients (73%) had not received antimicrobial prophylaxis with anti-Toxoplasma activity after undergoing transplantation. The median day of onset of disease after HSCT was 64. Twenty-two (63%) patients died from toxoplasmosis, and 23 (66%) received adequate anti-Toxoplasma therapy for > or =3 days. Among these 23 patients, 11 (48%) showed a complete response and 3 (13%) showed improvement. In univariate and multivariate analyses, having received adequate therapy and experiencing late infection (>63 days after HSCT) were associated with a lower risk of dying from toxoplasmosis. Toxoplasmosis after HSCT is a severe infection with a high mortality rate even when diagnosed soon after HSCT, and PCR may help establish the diagnosis earlier.

Eosinophilia Associated with Clonal T-Cell Proliferation

Eosinophilia associated with the expansion of cloned T-cells is reviewed in relation to cytokine production. It has been proved that eosinophilopoiesis is caused by eosinophil-stimulating cytokines, including interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor and interleukin-3, which are secreted from T-cells. Recently, we and other groups have reported several cases of eosinophilia including hypereosinophilic syndrome (HES) accompanied with proliferation of abnormal T-cells with an unusual phenotype CD3−CD4+ or CD3+CD4−CD8− in the peripheral blood. The T-cells clonally proliferate, as confirmed by clonal rearrangements of the T-cell receptor (TCR) gene, and produce eosinophil-stimulating cytokines, especially IL-5, with or without stimulation in vitro. Although HES is defined by the combination of unexplained prolonged eosinophilia and evidence of organ involvement, these observations suggest that increased production of eosinophil-stimulating cytokines from the abnormal T-cells with phenotype CD3−CD4+ or CD3+CD4−CD8− may cause eosinophilia, some of which have been diagnosed as HES.

The Idiopathic Hypereosinophilic Syndrome

THE IDIOPATHIC hypereosinophilic syndrome represents a leukoproliferative process likely caused by a number of disorders, all of which are marked by sustained overproduction of eosinophils. 1 In addition to the hallmark eosinophilia, this syndrome is distinctive because of its predilection for damaging specific organs, including the heart. The consequent endomyocardial fibrosis is not restricted to the idiopathic hypereosinophilic syndrome; identical cardiac damage may develop with eosinophilias secondary to other diseases with identifiable causes. Notably, not all patients with hypereosinophilia develop the organ damage characteristic of the hypereosinophilic syndrome. No specific tests are diagnostic of the hypereosinophilic syndrome; rather, the syndrome is defined by the combination of unexplained prolonged eosinophilia and evidence of organ involvement. DEFINITION OF THE SYNDROME From analyses of eosinophilic patients referred to the National Institutes of Health and other reported cases of hypereosinophilic syndrome, Chusid and colleagues 2 in 1975 identified the three defining features of the

The Idiopathic Hypereosinophilic Syndrome

AbstractTHE IDIOPATHIC hypereosinophilic syndrome (HES) is a leukoproliferative disorder, or more likely disorders, marked by a sustained overproduction of eosinophils. The distinctiveness of the syndrome, in addition to its eosino-philia, is its marked predilection to damage specific organs, including the heart. Such cardiac pathology is not unique to the idiopathic HES, because it may develop with eosinophilia associated with other diseases with identifiable etiologies. Conversely, yet enigmatically, not all patients with hypereo-sinophilia develop the organ damage characteristic of the HES. There are no specific tests diagnostic of the HES rather, the syndrome is defined by the combination of unexplained prolonged eosinophilia and evidence of organ involvement. We first review the more common and variable hematologic and clinical manifestations of this disorder because these are the features encountered clinically and that must be explained by investigation of the pathogenesis of HES. After considering the current understanding of the etiology and pathogenesis of the manifestations of HES, we review the therapies that may be used for HES.