Autoimmunity and Delayed Diagnosis in Pediatric Idiopathic Pulmonary Hemosiderosis.

Idiopathic pulmonary hemosiderosis is characterized by a triad of iron-deficiency anemia, hemoptysis, and radiographic diffuse lung infiltrates. However, the inconsistent initial presentation in children may cause a significant delay in diagnosis. Autoimmune reactivity seems to be the most acceptable theory of pathogenesis. We reported an 8-year-old boy presenting with a cough, fever, and difficulty breathing with a history of iron-deficiency anemia and an abnormal autoimmune response in the last 3 years. Perinuclear antineutrophil cytoplasmic antibodies were positive and chest computed tomography revealed patchy ground glass haziness. Bronchoalveolar lavage fluid showed hemosiderin-laden macrophages. The respiratory symptoms improved with oral corticosteroids.

Pulmonary hemosiderosis in children with Down syndrome: a national experience.

BACKGROUND: Pulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare® network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS. METHODS: Patients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare® database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients' data were compared. RESULTS: A total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 ± 3.27 years old for non-DS and 2.9 ± 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution. CONCLUSIONS: DS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease.

Myxoinflammatory Fibroblastic Sarcoma: Review and Update.

Myxoinflammatory fibroblastic sarcoma is a rare soft tissue tumor with most occurring in the distal extremities of adult patients. It has a high rate of local recurrence and a low rate of metastasis. Because it may appear benign on clinical examination, and because the microscopic features are generally underrecognized, it is often inadequately treated and misdiagnosed. In this review, based upon experience and that of the literature, the intent is to highlight salient clinicopathologic features, detail the broad microscopic spectrum including high-grade aggressive variants, review the molecular features, and discuss its relation to hemosiderotic fibrolipomatous tumor.

Transferrin-immune complex disease: a potentially overlooked gammopathy mediated by IgM and IgG.

The combination of marked hypersideremia, hypertransferrinemia, and monoclonal gammopathy of underdetermined significance (MGUS) should alert clinicians to the possible presence of an anti-transferrin immunoglobulin, an uncommon acquired disorder also defined as transferrin-immune complex disease (TICD). The authors have previously described a case of TICD with 100% transferrin saturation and liver iron overload. However, the findings in the few cases so far reported are heterogeneous, and the presence of high transferrin saturation and liver iron overload is not universal. In this article, the authors have described the identification of two additional patients with anti-transferrin monoclonal gammopathy, hypersideremia, and hypertransferrinemia, but with incomplete transferrin saturation and no hepatic iron overload. The autoantibodies were purified by using transferrin as affinity bait and characterized. One subject showed a high-titer monoclonal anti-transferrin IgM with a κ-type light chain. This finding is the first observation of IgM autoantibodies against transferrin. The other patient developed the disease after pregnancy. In this study, monoclonal antibody was an IgG mounting a κ-type light chain with altered molecular weight. These results highlight that transferrin might induce the development of a monoclonal immune response of different classes and specificity. The identification, in a single hematologic center, of three different subjects with anti-transferrin monoclonal gammopathy suggests that the disease probably represents a still underdiagnosed condition. From a clinical standpoint, these patients must be followed up both as MGUS and as hemochromatosis.

Acquired iron overload associated with antitransferrin monoclonal immunoglobulin: a case report.

We describe a patient with an unusual combination of hypersideremia (700 microg/dL), hypertransferrinemia (570 mg/dL), hyperferritinemia (800 microg/L), and monoclonal gammopathy of undetermined significance (MGUS), in which the monoclonal immunoglobulin showed specific transferrin-binding activity. Liver histology revealed hepatic iron overload, prominent in periportal hepatocytes, suggesting intestinal iron hyperabsorption. We demonstrate that low urinary hepcidin, likely due to impaired iron delivery to erythroid cells via the transferrin cycle pathway over time, may be the mechanism for iron loading. We suggest that MGUS associated with monoclonal antibodies with antitransferrin activity should be added to the list of acquired causes of hemochromatosis.

[Antineutrophil cytoplasmic antibodies positivity in a case of idiopathic pulmonary haemosiderosis]. / Positivité des anticorps anti-cytoplasme des polynucléaires neutrophiles au cours d'une hémosidérose pulmonaire idiopathique.

Idiopathic pulmonary haemosiderosis is a rare disease of unknown etiopathogeny which is characterized by hemoptysis due to alveolar haemorrhage. We report the case of a 16 years-old girl with idiopathic pulmonary haemosiderosis, diagnosed through clinical, radiological, cytological and histopathological data. The finding of myeloperoxydase-anti-neutrophil cytoplasmic antibodies (ANCA) positivity led us to suspect an associated vasculitis which was not further demonstrated.

Idiopathic pulmonary haemosiderosis: an Oriental experience.

OBJECTIVES: Idiopathic pulmonary haemosiderosis (IPH) is a rare but potentially lethal disorder. A retrospective analysis of documented cases of IPH in our hospital was conducted in order to study the clinical spectrum and radiographic features, and to explore therapeutic strategies. METHODS: A retrospective chart review was carried out, collecting medical records of patients with pulmonary haemo-siderosis at Chang Gung Children's Hospital (CGCH), a tertiary children's hospital in northern Taiwan. Secondary causes of pulmonary haemosiderosis were excluded. RESULTS: Five patients were diagnosed as having IPH over a 25-year period. The classical triad of IPH was found at initial presentation in only 2/5 patients. One patient had well-established pulmonary fibrosis, but no pulmonary symptoms. The clinical course of IPH was exceedingly variable, with a mean delay of 9 months before diagnosis was made. Bronchoalveolar lavage (BAL) confirmed IPH in 3/5 patients. Immunological abnormalities were noted in two patients, without progression to immune disorders during follow up. While using corticosteroids alone, 4/5 patients continued to have recurrent bleeding episodes. All five patients required immunosuppressive therapy for maintenance of a symptom-free period, but survived to a mean follow up of 2 years. CONCLUSIONS: Early definitive diagnosis and aggressive immunosuppressive therapy of IPH are imperative in order to avoid pulmonary fibrosis and mortality in IPH. A chest radiograph should be included in a serial work-up of unexplained anaemia in children. An examination using BAL can confirm IPH and high-resolution thoracic computed tomography scans are useful for early detection of pulmonary fibrosis.

Cerebrospinal fluid oligoclonal IgG bands in patients with spinal arteriovenous malformation and structural central nervous system lesions.

OBJECTIVE: To investigate the incidence and characteristics of patients with structural central nervous system (CNS) lesions and cerebrospinal fluid oligoclonal IgG bands. DESIGN: A retrospective study. METHOD: The medical records of patients with cerebrospinal fluid oligoclonal IgG bands were evaluated for the presence of structural CNS lesions, their location and cause, and for clinical characteristics. SETTING: Cerebrospinal fluid oligoclonal IgG bands were examined in the Neuroimmunology Laboratory, Hadassah University Hospital, Jerusalem, Israel. PATIENTS: Two hundred seventy of 570 patients with positive cerebrospinal fluid oligoclonal IgG bands were available for analysis. Twenty patients had structural CNS lesions. RESULTS: Twenty (7.5%) of the 270 patients had structural CNS lesions: 3 patients had spinal arteriovenous malformation; 5 patients had tumors; 9 patients had compressive cervical myelopathy. Traumatic leukomalacia, Arnold-Chiari malformation type 1, and CNS hemosiderosis were present in 1 patient each. In 2 patients (1 patient with recurrent meningioma and 1 patient with posttraumatic encephalomalacia) the presence of a structural CNS lesion was followed by the development of multiple sclerosis. In all 3 patients with spinal arteriovenous malformation, oligoclonal IgG identification prolonged the time to diagnosis and therapy, which varied from a few weeks to 3 years. CONCLUSIONS: Structural CNS lesions, responsible for the neurological disorder, were present in 20 patients (7.5%) with cerebrospinal fluid oligoclonal IgG bands. The mechanism underlying oligoclonal IgG presence in spinal arteriovenous malformation and the coexistence of multiple sclerosis and structural CNS lesions is unknown, but may be related to recurrent tissue damage with repeated presentation of CNS antigens to the immune system.

[Immunological aspects of a child with idiopathic pulmonary hemosiderosis and celiac disease]. / Immunologische Aspekte bei idiopathischer Lungenhämosiderose und Zöliakie.

A case report of a girl aged 3.5 years affected by the extremely rare combination of idiopathic pulmonary haemosiderosis (IPH) and coeliac disease (CD) is presented. It is the 13th such case that has been published over the last 25 years and only the 7th to be reported in a child. We believe that the concurrence of these two diseases is not coincidental, because a gluten-free diet had beneficial effects on the pulmonary symptoms not only in our case but also in other such patients. However, the pathogenetic relation between IPH and CD remains unclear. Although circulating immune complexes were detected in our patient's serum, there was no evidence of their putative damaging effect on the basement membrane of the alveolar capillaries. Furthermore, no IgA deposits could be demonstrated in alveolar basement membranes. Therefore the hypothesis that there is a reaction between IgA reticulin or endomysial antibodies and an alveolar basement membrane antigen with consecutive structural damage is unlikely.

Tuberculosis and iron overload in Africa: a review.

Both pulmonary tuberculosis and dietary iron overload are common conditions in sub-Saharan Africa. The incidence of tuberculosis has increased markedly over the last decade, primarily as a result of the rapid spread of infection with the human immunodeficiency virus (HIV). Dietary iron overload affects up to 10% of adults in rural populations and is characterized by heavy iron deposition both in parenchymal cells and in macrophages. Mycobacterium tuberculosis grows within macrophages and, at the same time, the antimicrobial function of macrophages is important in the body's defence against tuberculosis. In vitro, the loading of macrophages with iron reduces the response of these cells to activation by interferon-gamma and diminishes their toxicity against micro-organisms. In the clinical setting, dietary iron overload appears to increase the risk for death from tuberculosis even in the absence of the acquired immunodeficiency syndrome. The combination of dietary iron overload and infection with the HIV, with impaired function of both macrophages and T-cells, may make patients especially vulnerable to tuberculosis. It is possible that the prevention and treatment of dietary iron overload could contribute to the control of tuberculosis in African populations.

Dysfunction of polymorphonuclear leukocytes in uremia.

There is increased incidence of infectious complications in uremic patients, indicating impairment of cellular host defense in these patients. Several reports confirm metabolic and functional abnormalities of polymorphonuclear leukocytes (PMNL) including altered adherence to endothelial cells, altered generation of reactive oxygen species, altered release of microbial enzymes, impaired chemotaxis, phagocytosis, intracellular killing of bacteria, altered carbohydrate metabolism, and/or impaired ATP formation. Several studies report on correlations between PMNL dysfunction, especially phagocytosis and oxidative burst, and ferritin content. Deferoxamine therapy improved PMNL function. Chronic renal failure is a state of increased cytosolic calcium. Increased cytosolic calcium is associated with several alterations of PMNL function and metabolism, which improve by normalization of cytosolic calcium either by calcium channel blockers or by lowering of elevated parathyroid hormone. Each hemodialysis session using bioincompatible membranes triggers neutrophil activation, evidenced by overexpression of adhesion molecules, elevation of cytosolic calcium, release of PMNL granular enzymes, and generation of reactive oxygen species. Several studies claim that this results in chronic downregulation of phagocyte function. Several granulocyte inhibitory compounds have been isolated and characterized from uremic serum. The uremic retention product p-cresol depresses respiratory burst activity. The following granulocyte inhibitory peptides could be isolated from dialysis patients: granulocyte inhibitory protein I and II with homology to light chain proteins and beta 2-microglobulin, degranulation inhibitory protein I and II being identical to angiogenin and complement factor D, and immunoglobulin light chains. These proteins inhibit PMNL function in nanomolar concentrations.

[Intrapulmonary hemorrhages associated with Basedow disease]. / Hémorragies intrapulmonaires associées a une maladie de Basedow.

We report the second case of intraalveolar haemorrhage associated with an autoimmune thyrotoxicosis. While intraalveolar haemorrhage was not recurrent since 7 years with corticosteroid therapy, a relapse occurred when we began the treatment for an autoimmune thyrotoxicosis. We discuss the link between intraalveolar haemorrhage and autoimmune thyrotoxicosis or its treatment.

Iron overload in African Americans.

PURPOSE: Iron overload unexplained by dietary or medicinal iron excess, transfusion, or sideroblastic anemia has been described infrequently in Americans of African descent. The purpose of this study was to characterize iron overload attributable to excessive iron absorption in African Americans. PATIENTS AND METHODS: In a community hematology and medical oncology practice during the interval 1990 to 1993, we identified and evaluated a series of cases comprised of 6 men and 1 woman, with a mean age of 55 +/- 14 (SD) years (range 33 to 69). Data on clinical features, serum iron parameters, liver and body iron stores, evaluations of anemia, human leukocyte antigen (HLA) typing, and family studies were analyzed. RESULTS: Among our patients, the serum iron parameters were: iron concentration 26 +/- 13 mumol/L, transferrin saturation 59 +/- 21%, and ferritin concentration 1,588 +/- 1,053 micrograms/L. Clinical abnormalities observed included weakness and fatigue, decreased libido and impotence, hepatopathy, arthropathy, diabetes mellitus, hypogonadotrophic hypogonadism, and hyperpigmentation. Hepatic parenchymal cell iron deposits were increased in each of the 6 patients studied, and Kupffer cell iron deposits were prominent in 4. The occurrence of iron overload was verified by liver iron quantification and therapeutic phlebotomy. Four subjects had alpha-thalassemia minor; 2 others had hemoglobin S and C traits. No proband had HLA-A3 positivity. Four probands had other family members with iron overload. CONCLUSIONS: In comparison with Caucasians with hemochromatosis, our patients have slightly lower mean values of serum iron concentration and transferrin saturation, more Kupffer cell iron deposits, a higher incidence of thalassemia and hemoglobinopathy, and infrequent positivity for HLA-A3. Iron overload in African Americans appears to be more similar to that in certain sub-Saharan African natives than to hemochromatosis.

Lipid peroxidation and changes in T lymphocyte subsets and lymphocyte proliferative response in experimental iron overload.

This study was undertaken to investigate the hypothesis that lipid peroxidation might be associated with immunological abnormalities in experimental hemosiderosis. The correlation between the degree of plasma and spleen lipid peroxidation with lymphocyte proliferative response and with the proportion of T lymphocyte subsets was studied in normal and iron overloaded male Sprague Dawley rats. The iron-loading protocol consisted of a total dose of iron-dextran (1.5 mg/Kg body weight) divided in daily i.m. injections over twenty consecutive days. Lipid peroxidation was measured by the thiobarbituric acid assay in plasma and in homogenates of spleen. Plasma lipid peroxide level increased rapidly after i.m. administration of iron-dextran and decreased sharply at 48 h after the last injection. Conversely, a progressive increase of lipid peroxidation in homogenates of spleen was observed in the course of the iron overload protocol, remaining high even at 50 days after initiation of iron-dextran injections. The increase of spleen lipid peroxide levels was associated with decreased lymphocyte proliferative response to Con A in iron overloaded rats. The addition of superoxide dismutase and catalase to lymphocyte cultures reversed the inhibition of the proliferative response, implicating reactive species of oxygen as the causative agents of these alterations. These effects may be related with the enhanced membrane and DNA damage occurring during intracellular and extracellular peroxidation. Negative correlations between helper/cytotoxic ratio and malondialdehyde levels were obtained in blood and spleen during iron administration. These results supports the hypothesis that lipid peroxidation plays a role in the immunological abnormalities observed in experimental hemosiderosis.

Effect of hepatic isoferritins from iron overloaded rats on lymphocyte proliferative response: role of ferritin iron content.

Iron and ferritin impair a variety of immunological functions. To evaluate the effect of ferritin iron content on rat lymphocyte proliferative response, isoferritins that differ in their iron content and isoelectric point (pI) were isolated from iron overload rat livers by ultracentrifugation (isoferritins with high iron content and low pI) or crystallization (isoferritins with low iron content and high pI) methods. Additionally, commercial horse splenic ferritin (with a lower pI and higher iron content than rat isoferritins) was also tested. Proliferative response to Con A was decreased in a dose-dependent manner in all assays in which spleen cells were incubated with rat and horse isoferritins. However, isoferritins with higher iron contents (rat isoferritin obtained by ultracentrifugation and horse ferritin) caused a greater decrease of proliferative response at 5 and 25 micrograms/ml than the others. Rat and horse apoferritins showed no inhibitory effect on lymphocyte proliferative response, suggesting that the effect is due to iron probably through the damaging effect of reactive oxygen species generated by iron released by the isoferritins on lymphocyte functions. Additionally, the role of serum ferritin level on proliferative response was studied in an experimental model of iron overload in rats. An inverse relationship between the proliferative response and serum ferritin levels was observed. Our results suggest that the inhibitory effect of the isoferritins on lymphocyte proliferative response is due, at least partially, to the iron content of this protein and not exclusively to variation in pI as suggested by other authors. These results are in agreement with the possible immunosuppressor role of ferritin in vivo.

Pulmonary hemosiderosis and immune complex glomerulonephritis.

Two children with a syndrome of pulmonary hemorrhage and immune complex nephritis are reported. Clinical history suggests that pulmonary lesions precede renal abnormalities. Necrotizing glomerulonephritis with granular immune deposits along the glomerular basement membrane was found. Although the etiology of this disease complex is still unknown, the clinical and pathological findings in these patients suggest that immune complex glomerulonephritis is an unusual complication of idiopathic pulmonary hemosiderosis.

Antineutrophil cytoplasmic antibodies (ANCA) in idiopathic pulmonary hemosiderosis.

Four children were diagnosed with idiopathic pulmonary hemosiderosis (IPH), over a period of 4 years. Retrospectively, antineurtrophil cytoplasmic antibodies (ANCA) were studied by indirect immunofluorescence (IIF) and ELISA in 18 sera from these patients, stored at -20 degrees C. ANCA-positive sera, from 1/20 to 1/1, 200 dilution, were found in 3/4 of the patients, by IIF. The patient with the highest titre of ANCA died 3 months later during an acute crisis, the other two patients need a minimal dose of steroids. In one case only, a patient who is still without treatment, had no ANCA. The antibodies anti-myeloperoxidase and anti-proteinase-3 were negative or at border line levels. Rheumatoid factor, antinuclear (Hep-2), anti-endomysial, anti-reticulin and antibasement membrane antibodies were negative in all sera. The surviving patients were followed-up for more than 10 years with no systemic or renal disease appearances. The presence of serum ANCA may help to classify children with pulmonary haemorrhage and may have a prognostic value.