Successful treatment of disseminated Aspergillosis in a leukemic child

The incidence of severe fungal infections in the immunocompromised patient with malignancies has increased in recent years. This appears to be associated to the profound periods of immunosuppression and the extended use of broad spectrum antibiotics. Aspergillosis is the second most common fungal infection reported in the immunocompromised cancer patients. In patients with advanced immunosupression, the mortality due to invasive aspergillosis approaches 100despite treatment with antifungal agents. Reports of complete or partial response to echinocandins are well demonstrated in adults, but very limited in the pediatric population. This report describes the case of a child with relapsed acute lymphoblastic leukemia (ALL) who developed cutaneous aspergillosis and subsequent multiorgan dissemination during therapeutic induction and was treated successfuly with caspofungin acetate.

Treatment of childhood acute immune thrombocytopenic purpura with high-dose methylprednisolone, intravenous immunoglobulin, or the combination of both.

OBJECTIVE: To compare the effectiveness of intravenous immunoglobulin (IVIG) alone, high dose methylprednisolone (HDMP) alone and the combination of IVIG and HDMP in the treatment of childhood immune thrombocytopenic purpura (ITP). BACKGROUND: Acute ITP in children is a self-limited disease with a benign course and low mortality rate. Patients with platelet count less than 20,000 x 10(9)/L are at increased risk of bleeding complications, making them candidates for treatment. METHOD: A 4 year retrospective study of 148 patients hospitalized with acute ITP was conducted to compare the effectiveness of HDMP vs IVIG vs the combination of IVIG/HDMP. Statistical methods used were descriptive statistics and variance analysis utilizing F distribution. RESULTS: The IVIG and the HDMP combination demonstrated to be superior to HDMP alone in raising the platelet count within the first 24 hours. The HDMP and IVIG combination was statistically a superior modality of treatment for patients with platelet count greater than 10,000 x 10(9)/L than was IVIG or HDMP alone. Intravenous immunoglobulin had the least effectiveness in patients with platelet count less then 10,000 x 10(9)/L within the first 24 hours. CONCLUSIONS: IVIG followed by the combination of HDMP and IVIG is the most effective therapeutic modality in rapidly increasing the platelet count to safe levels in children with acute ITP when compared to HDMP alone within the first 24 hours. For borderline low platelet count (> 10,000 x 10(9)/L) HDMP and IVIG was superior to IVIG alone.

Characterization of hemoglobin Hotel Dieu in a Puerto Rican adolescent.

PURPOSE: Hemoglobin Hotel Dieu (HbHD) is a high-oxygen affinity variant of HbA never before reported in a Hispanic patient. This Hb variant was first reported in 1981 by Blouquit et al. in a white person with erythrocytosis with a substitution in the beta 99 aspartic acid residue by glycine. METHODS: A 13-year-old Puerto Rican boy had pain in his chest, headaches, easy fatigability, and high Hb (as high as 19.1 g/dl). Protein analysis was performed by cellulose acetate, citrate agar, and isoelectric focusing electrophoresis and high-pressure liquid chromatography (HPLC), polymerase chain reaction (PCR) amplification, and DNA sequencing of the second exon of the beta gene in samples obtained from the mother, father, and the patient, and DNA fingerprinting to determine paternity. RESULTS: The variant found in the patient migrated on cellulose acetate electrophoresis to a cathodic position relative to HbF, and a band cathodal to HbA and close to HbF on isoelectric focusing electrophoresis. The patient showed an abnormal well-resolved peak on HPLC with a retention time slightly shorter than that for HbS. DNA analysis by direct sequencing of the PCR product demonstrated heterozygosity for codon 99 (GAT-->GGT) in the patient but not in either parent. DNA fingerprinting by multiplex PCR amplification of three simple tandem repeat loci showed that the patient shared alleles in all three loci with both parents, ruling out nonpaternity. CONCLUSIONS: The protein and DNA analysis indicate that the erythrocytosis is caused by the presence of HbHD in this Hispanic adolescent.

Successful allogeneic bone marrow transplantation for agnogenic myeloid metaplasia in a 3-year-old boy.

PURPOSE: Agnogenic myeloid metaplasia (AMM) is a myeloproliferative disorder characterized by marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and leukoerythroblastosis with abnormalities of red blood cell morphology. This is rarely encountered in children. No conventional curative therapy is known; however, allogeneic bone marrow transplantation (BMT) may eradicate the underlying stem cell abnormality with subsequent normal hematopoiesis. RESULTS: We report a 3-year-old Arab boy who had AMM and who had normal marrow hematopoiesis and markedly reduced fibrosis after high-dose chemotherapy and matched sibling BMT. CONCLUSIONS: Allogeneic BMT offers a potential cure for patients with agnogenic myeloid metaplasia. A preparatory regimen containing busulfan and cyclophosphamide appears promising for patients with the disease.

Intact splenic function in cystic fibrosis.

Patients with cystic fibrosis (CF) suffer from severe chronic pulmonary infections but rarely develop bacteremia/septicemia suggestive of an intact splenic mononuclear phagocyte function. The splenic function of 25 patients diagnosed with CF, aged 2 to 37 years, was evaluated using erythrocyte pit count by direct interference contrast microscopy. Results were compared with patients with sickle cell disease and normal individuals. All CF patients displayed normal splenic function by pit count. The mean percentage of pitted erythrocytes was 0.20 +/- 0.28 (range: 0.0% to 1.0%) versus 0.19 +/- 0.33 (range: 0.0% to 1.4%) in normal eusplenic controls. There were no episodes of bacteremia or septicemia despite recurrent acute exacerbations of chronic bacterial bronchitis and the use of central lines. We conclude that splenic function in CF is unabridged and may account for the rarity of bacteremia/septicemia in patients with CF despite the high prevalence of chronic bronchial infection in this population.

Reversible splenic hypofunction in hypertransfused children with homozygous sickle cell disease.

Functional hyposplenism, as documented by technetium 99 metastable sulfur colloid spleen scan and increased pocked erythrocyte count (also known as a pit count), is well described in children under 2 years of age with homozygous sickle cell anemia. We evaluated the clinical course and splenic function of 16 patients with sickle cell anemia (ages 3 to 20 years) on a hypertransfusion program for more than 6 months following a cerebrovascular accident. Patients were followed with simultaneous spleen scan and pitted erythrocyte count using direct interference contrast microscopy. Pit counts were taken prior to each transfusion and hemoglobin S level maintained at less than 20%. With the exception of two patients, splenic function was recovered only in those patients who were younger than 10 years of age at the time transfusion was initiated. There were no serious bacterial infections or other complications of sickle cell anemia documented in the hypertransfused group. Based on our results and the literature review, we conclude that some patients with sickle cell anemia receiving intensive hypertransfusion therapy for a cerebrovascular accident recover a normal splenic phagocytic function. Age and level at which the hemoglobin S is maintained are important factors in reestablishing splenic phagocytic function.

Childhood nasopharyngeal carcinoma.

A retrospective analysis identified 40 children and adolescents with nasopharyngeal carcinoma who were evaluated and treated at the Medical Center of Louisiana from 1948 through 1992. The male to female ratio was 1.8:1. Thirty-two patients had lymphoepithelioma and 8 had squamous cell carcinoma. Twenty-three children had primary lesions confined to the nasopharynx. In 8 patients, the tumor extended into the nasal cavity or oropharynx, and 7 patients had tumor invasion of skull or cranial nerve. Thirty-one had palpable cervical lymphadenopathy. There were no documented distant metastasis at presentation. All patients were treated with primary radiotherapy, and 9 patients also had chemotherapy containing cisplatin, fluorouracil, bleomycin, cyclophosphamide, and doxorubicin. Ten are alive 5 to 30 years from time of diagnosis (median 10 years). Distant metastasis was the initial cause of failure. Though not a controlled study, bias in the data insinuate an improved prognosis for male patients, age > 10 years, tumor limited to the nasopharynx without extension (T1-2), absence or single positive homolateral node (N0-1), and patients who received chemotherapy.

Treatment of acute idiopathic thrombocytopenic purpura with high-dose methylprednisolone and immunoglobulin.

In childhood idiopathic thrombocytopenic purpura (ITP), both intravenous high-dose steroids and immunoglobulin treatments have been demonstrated to raise platelet counts reliably and in most cases within 72 h, when used as separate therapeutic modalities. However, until now, the preferred emergency management of life-threatening complications in children with ITP has been immediate splenectomy. Since steroids and immunoglobulin create a partial splenic dysfunction, through different mechanisms, we investigated whether combined treatment with both drugs could produce a rapid platelet count increase comparable to that of splenectomy. Eleven patients, ages 4 months to 6 years, with a diagnosis of acute ITP were entered into this pilot study. Treatment consisted of intravenous high-dose methylprednisolone (20 mg/kg in 30 min) followed by intravenous gamma globulin (Gamimune-N, 1 g/kg over 5 h). The combined therapy resulted in rapid increments in the platelet counts of all patients within the 24-hour period. At 12-h, in particular, 9/11 patients had platelet counts of 30 x 10(9)l or more. We conclude that this combined therapy provides a prompt rise in platelet counts to a safe and hemostatic level and may offer a viable alternative for emergency splenectomy and its associated morbidity/mortality in many cases of childhood ITP.

Spleen function in children with sickle B+ thalassemia.

Splenic function in patients with sickle B+ (SB+) thalassemia has been poorly documented. We evaluated the clinical course and splenic function in 12 children with SB+ thalassemia with simultaneous technetium sulfur colloid spleen scans and determination of pitted erythrocytes by direct interference contrast microscopy (DICM). All patients displayed normal uptake of radiocolloid. Mean percentage of pitted erythrocytes was 2.2% compared to 0.06% in 10 normal eusplenic controls and 13.8% in 10 sickle cell patients. In this group of children, who were carefully monitored for 136 patient years, there was no episode of bacteremia/sepsis, and a low prevalence of vaso-occlusive episodes. The slight increase in percentage of pitted erythrocytes of SB+ thalassemia patients does not seem to herald any clinically relevant loss of splenic function. SB+ thalassemia children younger than 10 years of age who do not seem to present a higher risk of invasive bacterial infections than eusplenic children, should receive conservative treatment for isolated febrile episodes and should not be submitted to prophylactic penicillin.

Transient expression of trisomy 21 and monosomy 7 following cyclosporin A in a patient with aplastic anemia.

We present a patient with severe idiopathic aplastic anemia with no previous chromosomal abnormalities who developed trisomy 21 and monosomy 7 during treatment with intravenous (i.v.) cyclosporine. The abnormal karyotype disappeared when the drug was changed to the oral form. This cytogenetic aberration, previously unreported in association with cyclosporine, may reflect either a direct drug effect or the emergence of a hidden myelodysplastic cell clone subject to preferential survival during immunosuppression.

Successful treatment of disseminated Fusarium infection in an immunocompromised child.

We report the first know case of disseminated fungal infection due to Fusarium proliferatum in a bone marrow transplant recipient to our knowledge. Fusarium was cultured from the blood, a paranasal sinus, and necrotic skin lesions. The isolate was sensitive to amphotericin B and on further sensitivity testing, synergy was demonstrated using rifampin in combination with amphotericin B. The patient had this infection while she was receiving alternate-day amphotericin, rifampin, and 5-flucytosine (5-FC) therapy. The infection was documented within 48 h of discontinuing daily granulocyte transfusions, which she had received for 3 weeks. The 5-FC was discontinued when sensitivities showed the organism resistant. After 6 weeks of treatment she showed complete remission of the infection, although neutrophil counts remained below 0.25 X 10(9)/L. From this case and from a review of the literature, it appears that synergic antifungal agents combined with leukocyte transfusions may be beneficial in the successful treatment of fusariosis in the compromised host.

Formation of intracellular vesicles in neonatal and adult erythrocytes: evidence against the concept of neonatal hyposplenism.

Intraerythrocytic vesicles accumulate in the peripheral blood as a result of impaired clearance of these intracellular inclusions by the spleen. The observation that neonates demonstrate an increased percentage of erythrocytes containing these vesicles constitutes the primary evidence supporting the concept that the newborn is functionally hyposplenic. Neonatal erythrocytes also demonstrate an increased propensity to undergo a variety of endocytic processes. We therefore questioned whether the increase in red cell vesicles in the neonate might be the result of increased vesicle formation as opposed to impaired splenic clearance. Newborn and adult erythrocytes were incubated in vitro in synthetic medium at 37 degrees C. Several parameters confirmed the maintenance of physiologic conditions, including levels of erythrocyte phosphate metabolites monitored by nuclear magnetic resonance. The acquisition of intraerythrocytic vesicles during the course of these incubations was compared. Over a period of 144 h, 19.2% of neonatal erythrocytes acquired vesicles compared to 3.7% of the adult cells (p less than 0.001). The increase in vesicles was greater in younger density-separated erythrocytes in both the neonate (37.6%, p less than 0.0005) and the adult (10.3%, p less than 0.002), but persisted even in the oldest erythrocytes (12.2% and 2.4%, respectively). We conclude that the increase in erythrocytic vesicles in the neonate may not simply be an indication of hyposplenism, but a reflection of increased vesicle formation which overwhelms the clearance capability of the spleen.

Physiologic formation of intracellular vesicles in mature erythrocytes.

The ability of mature erythrocytes to spontaneously form intracellular vesicles has been implied from clinical studies but has not been examined experimentally. An in vitro model was developed to demonstrate whether mature erythrocytes are capable of spontaneously forming intracellular vesicles. Normal human erythrocytes were incubated in vitro at 37 degrees C for 144 hr in a synthetic medium. During the course of these incubations, approximately 4% of erythrocytes developed intracellular vesicles which were quantitated by using interference contrast microscopy. Electron microscopic studies confirmed the intracellular nature of these vesicles. Incubation of erythrocytes in autologous plasma produced similar results. The rate of vesicle acquisition in vivo was measured by quantitating erythrocyte vesicles immediately prior to and following splenectomy. The rates of vesicle acquisition in vivo and in vitro were comparable. This in vitro model confirms the ability of mature erythrocytes to spontaneously form intracellular vesicles and strongly supports the concept that this is a physiologic process.

Toxicity of high dose Ara-C in children and adolescents.

The toxicity of high dose cytosine arabinoside (Ara-C) in 23 leukemic children aged 1.5 years to 16 years 11 months was evaluated. The group included 11 children with acute lymphoblastic leukemia (ALL), nine with acute nonlymphoblastic leukemia (ANLL), two with chronic myelocytic leukemia (CML) in blastic crisis, and one with Burkitt's lymphoma. Toxicity consisted of bone marrow suppression in all patients, with a mean nadir time of 11 days for platelets and granulocytes. All patients experienced nausea and vomiting; 12 of 23 had drug induced fever; seven of 23 conjunctivitis; five of 23 mucositis; four of 23 diarrhea, and one of 23 elevated transaminase with hyperbilirubinemia. Adverse reactions were mild and reversible in all patients. No serious neurologic toxicity was seen. The toxicity observed in four patients with prior cranial irradiation was not any different from nonirradiated patients. The only life-threatening effect was neutropenia, the consequences of which were generally well controlled with antibiotic therapy. While this agent was effective in induction of remission in AML patients resistant to standard doses of Ara-C, it had no significant effect in a very small number of patients with relapsed ALL and CML in blast crisis. Side effects of high dose Ara-C though relatively substantial are manageable enough to warrant wider scale efficacy trials of this agent in childhood leukemias and solid tumors.