Updates in idiopathic pulmonary hemosiderosis in 2022: A state of the art review.

This manuscript reports the recent advances in idiopathic pulmonary hemosiderosis (IPH), a rare cause of diffuse alveolar hemorrhage in children and adults. This narrative review of the literature summarizes different aspects of IPH, including proposed pathogenesis, patient demographics, clinical and radiological characteristics, treatment, and prognosis. Additionally, the association between Celiac Disease (CD) and IPH is carefully evaluated. IPH is a frequently misdiagnosed disease. The delay in the diagnosis of IPH is often significant but fortunately, appears to have decreased in recent years. IPH in adults and children have distinct demographic preferences. The autoantibodies are common in IPH but with a definite difference between the adult and pediatric populations. The definitive diagnosis of IPH requires lung biopsy and careful exclusion of all competing diagnoses, even with lung biopsy showing bland pulmonary hemorrhage. The presence of nonspecific inflammatory cells or lymphoid aggregates may suggest a secondary immunologic phenomenon and needs careful evaluation and follow-up. A substantial number of patients suffer from coexisting CD, also known as Lane-Hamilton syndrome (LHS), and all patients with IPH need to be evaluated for LHS by serology. Although strict gluten free diet can manage the majority of patients with LHS, other patients generally require immunosuppressive therapy. The corticosteroids are the backbone of IPH therapy. Recently utilized experimental treatment options include mesenchymal stem cell transplant, liposteroid and bronchial artery embolization. The immunosuppression should be adjusted to achieve optimal disease control. Patients may progress to end-stage lung disease despite all measures, and lung transplantation may be the only viable option.

Pathological and Radiological Correlation in Prolonged Myeloperoxidase Anti-neutrophil Cytoplasmic Antibody-related Diffuse Alveolar Hemosiderosis.

A 60-year-old woman with a 20-year history of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis visited our hospital due to productive cough and a low-grade fever for several weeks. Thoracic computed tomography demonstrated scattered tiny nodules, patchy consolidation, ground glass opacities, and thickening interlobular septa. On video-assisted thoracic surgery, those abnormalities were found to correspond to the accumulation of hemosiderin-laden alveolar macrophages (AMs) in the alveolar spaces and alveolar septa due to MPO-ANCA vasculitis. The radiological findings persisted for a further two years, indicating the possibility of persistent vasculitis in the lung or evidence of incomplete clearance of hemosiderin-laden AMs.

Rare neonatal interstitial lung disease masquerading as pulmonary hemosiderosis.

A preterm 32-week neonate presented on the 14th day of life with respiratory distress and cyanosis. The respiratory distress worsened progressively, which was managed with continuous positive airway pressure support. The neonate had blood-tinged oral secretions on the 39th day of life, for which bronchoscopy was performed, whose findings were suggestive of pulmonary hemosiderosis. Lung biopsy confirmed the diagnosis of pulmonary interstitial glycogenosis with pulmonary arterial hypertension. The neonate was treated successfully with systemic corticosteroids and discharged home at 3 months of age.

Pulmonary Hemorrhage in Children: Etiology, Clinical Profile and Outcome.

OBJECTIVE: To describe etiology, clinical profile, treatment and outcome of children with pulmonary hemorrhage. METHODS: A chart review of children with pulmonary hemorrhage attending Pediatric Pulmonology services of a tertiary care hospital in North-India was done. RESULTS: Data of 44 children (mean age 59.2 ± 32.1 mo; 28 boys) were included for the study. Possible idiopathic pulmonary hemosiderosis 16 (36.4%), post infectious complications 11 (25%), immune mediated disorders 8 (18.2%), cardiac and vascular disorders 7 (15.9%), and airway pathologies 2 (4.5%) were the etiologies of pulmonary hemorrhage. Treatment options like medications, bronchial artery embolization and surgical resections were offered according to the etiology. Children with idiopathic pulmonary hemosiderosis and those with immune mediated diseases were treated with systemic steroids and steroid sparing agents; the latter group took longer time to respond and had more relapses. CONCLUSIONS: Identification of main etiological categories of pulmonary hemorrhage in children could be useful to plan investigations and management of wide range of causes in more practical way.

Aceruloplasminemia with Abnormal Compound Heterozygous Mutations Developed Neurological Dysfunction during Phlebotomy Therapy.

Aceruloplasminemia is an autosomal recessive inherited disorder caused by ceruloplasmin gene mutations. The loss of ferroxidase activity of ceruloplasmin due to gene mutations causes a disturbance in cellular iron transport. We herein describe a patient with aceruloplasminemia, who presented with diabetes mellitus that was treated by insulin injections, liver hemosiderosis treated by phlebotomy therapy, and neurological impairment. A genetic analysis of the ceruloplasmin gene revealed novel compound heterozygous mutations of c.1286_1290insTATAC in exon 7 and c.2185delC in exon 12. This abnormal compound heterozygote had typical clinical features similar to those observed in aceruloplasminemia patients with other gene mutations.

Corticosteroid in Combination with Leflunomide and Mesenchymal Stem Cells for Treatment of Pediatric Idiopathic Pulmonary Hemosiderosis.

Background: This study evaluated the efficiency of corticosteroid, leflunomide and mesenchymal stem cells (MSCs) in the treatment of pediatric idiopathic pulmonary hemosiderosis (IPH). Methods: Ten patients were included in the study. The diagnosis of IPH was based on clinical symptoms, laboratory examinations and pulmonary hemosiderosis. Induction therapy consisted of methylprednisolone pulse therapy, followed by prednisone plus leflunomide. Maintenance therapy consisted of low-dose prednisone, leflunomide and administration of MSCs. Results: All the patients achieved complete response after treatment with corticosteroid, leflunomide and MSCs. The median follow-up was 23 months (range: 4-34 months). Moreover, administration of MSCs induced an increase in the percentage of CD4+ CD25+ regulatory T cells but a decrease in the percentage of Th17 cells. Conclusion: Treatment with corticosteroid, leflunomide and MSCs for pediatric IPH was safe and effective.

[Approach to the Patient with Elevated Serum Ferritin]. / CME: Zufallsbefund Hyperferritinämie.

An increase of the serum ferritin may appear as an incidental finding in asymptomatic patients in the routine laboratory examination. On the one hand, ferritin reflects the iron stores of the body and can therefore indicate an iron overload of various causes. On the other hand, it is an acute phase protein and thus increases in inflammatory and malignant diseases. We aim to describe an approach to the incidental finding hyperferritinemia with possible evaluation strategy and to explain the most important differential diagnoses.

A physician survey reveals differences in management of idiopathic pulmonary hemosiderosis.

BACKGROUND: Idiopathic pulmonary hemosiderosis (IPH) is a rare disorder of unknown etiology characterized by chronic pulmonary hemorrhage and presents with a triad of anemia, hemoptysis and pulmonary infiltrates. IPH is a diagnosis of exclusion with a variable and disparate clinical course. Despite existing therapies, few children achieve full remission while others have recurrent hemorrhage, progressive lung damage, and premature death. METHODS: We surveyed physicians who care for patients with IPH via a web-based survey to assess the most common practices. 88 providers responded, caring for 274 IPH patients from five continents. RESULTS: 63.3 % of respondents had patients that were initially misdiagnosed with anemia (60.0 %) or gastrointestinal bleed (18.2 %). Respondents varied in diagnostic tools used for evaluation. The key difference was in the use of lung biopsy (51.9 %) for diagnosis. Common medications respondents used for treatment at initial presentation and chronic maintenance therapy were corticosteroids (98.7 and 84.0 %, initial and chronic therapy respectively), hydroxychloroquine (33.3 and 64.0 %), azathioprine (8.0 and 37.3 %), and cyclophosphamide (4.0 and 16.0 %). There was agreement on the use of corticosteroids for exacerbation amongst all respondents. Reported deaths before adulthood occurred in 7.3 % of patients. We conclude that there were common features and specific variations in physician management of IPH. Respondents were divided on whether to perform lung biopsy for diagnosis. CONCLUSION: Despite the availability of various immunomodulators, corticosteroids remained the primary therapy. We speculate that the standardization of care for diffuse alveolar hemorrhage will improve patient outcomes.

Diagnostic and therapeutic challenges in superficial CNS siderosis.

INTRODUCTION: Superficial CNS siderosis was previously almost unknown but is now diagnosed with increasing frequency owing to magnetic resonance imaging. Patients may present with sensory deafness, gait ataxia, various sensorimotor signs and, eventually, cognitive decline. They typically have a history of traumatic brain or spinal cord injury or previous neurosurgery, or may harbour congenital malformations. However, knowledge about treatment outcomes remains scarce. METHODS: We present a series of nine consecutive patients from a large tertiary neuroscience centre in order to highlight the challenges related to the diagnosis and treatment of superficial siderosis. RESULTS: A potential bleeding aetiology was identified in all patients, but removal of the offending bleeding source was achieved only in three (33%). Symptom progression was halted in just one patient (11%), which suggests that neurodegeneration due to haemosiderin-associated iron toxicity becomes irreversible with time. CONCLUSION: Surgical therapy in superficial CNS siderosis is rarely achieved. We suggest that prospective, large-scale multicentre studies are needed to search for non-surgical therapies that reverse (or prevent) ongoing neurotoxicity due to accumulating iron toxicity. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Idiopathic pulmonary haemosiderosis: spectrum of thoracic imaging findings in the adult patient.

Idiopathic pulmonary haemosiderosis (IPH) is a rare disease characterized by alveolar capillary haemorrhage resulting in deposition and accumulation of haemosiderin in the lungs. Although its precise pathophysiology remains unclear, several hypotheses have been proposed to explain the aetiology of the disorder, including autoimmune, environmental, allergic, and genetic theories. IPH is typically diagnosed in childhood, usually before the age of 10 years; however, this entity may be encountered in older patients given the greater awareness of the diagnosis, availability and utilization of advanced imaging techniques, and improved treatment and survival. The classic presentation of IPH consists of the triad of haemoptysis, iron-deficiency anaemia, and pulmonary opacities on chest radiography. The diagnosis is usually confirmed via bronchoscopy with bronchoalveolar lavage (BAL), at which time haemosiderin-laden macrophages referred to as siderophages, considered pathognomonic for IPH, may be identified. However, lung biopsy may ultimately be necessary to exclude other disease processes. For children with IPH, the disease course is severe and the prognosis is poor. However, adults generally have a longer disease course with milder symptoms and the prognosis is more favourable. Specific imaging features, although non-specific in isolation, may be identified on thoracic imaging studies, principally chest radiography and CT, depending on the phase of disease (acute or chronic). Recognition of these findings is important to guide appropriate clinical management.

[Evaluation of transfusion hemochromatosis prevalence, SFVTT-01 study: preliminary results of the SFVTT working group]. / Évaluation de la prévalence de l'hémosidérose post-transfusionnelle, étude SFVTT-01: résultats préliminaires du groupe de travail de la SFVTT.

RATIONAL: Although notification of post-transfusion hemosiderosis is mandatory since 1994 among the French hemovigilance network, it is so far largely under reported. PATIENTS AND METHODS: We screened 42,443 patients hospitalized for blood diseases in France in 2009 and 2010 and determined which patients had received more than 20 PRC. Among them, we selected those having at least one measure of serum ferritin, and subsequently those which ferritin was greater than or equal to 1000 ng/mL. RESULTS: Three thousand eight hundred and twelve patients (9%) received more than 20 PRC, 1935 (4.5%) had a ferritin assay, which was increased in 1216 patients (2.9%). Eight hundred and eighty-one patients underwent an hemovigilance report form. Forty-nine percent had low-risk myelodysplasia or acute leukemia, 7% hemoglobinopathies. Hemosiderosis was asymptomatic for 680 patients (77%), serious 188 (88%) and life-threatening for 11 (1%). Two patients died of terminal heart failure. The most severe hemosiderosis (≥ grade 2) were low-risk myelodysplasia and idiopathic aplastic anemia. Ninety-two percent of thalassemia patients and 46% of sickle cell anemia patients received an iron chelator. For low-risk myelodysplastic syndromes and idiopathic aplastic anemia, 228 of the 317 patients whose treatment is known and who could benefit from iron chelation (72%) have not received it. CONCLUSION: These results encourage seeking optimal transmission of information (over 20 CGR) to the clinician, and prolonging hemovigilance action towards a more comprehensive statement of post-transfusion hemochromatosis.

In vitro extraction of intra-corneal iron using reverse iontophoresis and vitamin C.

PURPOSE: The aim of this study was to optimize reverse iontophoretic (RI) extraction of ferric/ferrous ions from the cornea. METHODS: Group I consisted of the right eye corneas from 20 normal rabbits. Corneal blood staining was induced in 60 right eyes. The corneal depths from the endothelium to the epithelium layers were divided into three groups by slit-lamp examination: Group II, one-third corneal thickness; Group III, one-half corneal thickness; Group IV, full corneal thickness. RI was performed using vertical diffusion cells. The lower chamber was loaded with glutathione bicarbonate Ringer's buffer (GBR; pH 7.0) or vitamin C (12.5 mg/mL) and GBR (pH 7.0), while the upper chamber was filled with 1 mL GBR. Progress of corneal blood staining removal was evaluated. RESULTS: Application of 1.5 mA to the cornea increased flux by 1.72- and 2.19-fold in Groups III and IV, respectively, but not in Groups I or II, compared to the control. When vitamin C was included, we observed significant flux increases in the controls (1.5-, 2.06-, 2.60-, and 4.59-fold) for Groups I, II, III, and IV, and under RI conditions for Groups III and IV. Following RI, the corneal endothelia appeared similar to corneas from untreated control rabbits, while Draize scores were zero. CONCLUSIONS: These results suggested that extracellular ferric/ferrous ions could be extracted from the cornea in vitro by RI, and that vitamin C reduced Fe(3+) to Fe(2+) in the cornea and altered its permselectivity, thus increasing the RI contribution to iron extraction.

Extracorporeal life support for a 5-week-old infant with idiopathic pulmonary hemosiderosis.

UNLABELLED: Idiopathic pulmonary hemosiderosis is a rare disease defined by the triad of iron deficiency anemia, hemoptysis, and diffuse pulmonary infiltrates on chest radiograph. Idiopathic pulmonary hemosiderosis is known to cause dyspnea and, in some cases, acute onset of massive pulmonary hemorrhage which is traditionally treated with conventional mechanical ventilation or high-frequency oscillation in conjunction with immunosuppressive therapy. In this case report, we describe a 5-week-old infant presenting with hemoptysis, massive pulmonary hemorrhage, and significant hypercapnic respiratory failure. The patient failed conventional ventilation but responded well to extracorporeal life support that was initiated early in his course. Idiopathic pulmonary hemosiderosis was suspected in light of his response to high-dose steroids and was confirmed by subsequent lung biopsies. CONCLUSION: Patients with severe pulmonary hemorrhage secondary to idiopathic pulmonary hemosiderosis can be safely supported with extracorporeal life support when conventional therapies have been exhausted.

On myocardial siderosis and left ventricular dysfunction in hemochromatosis.

BACKGROUND: Chronically increased intestinal iron uptake in genetic hemochromatosis (HC) may cause organ failure. Whilst iron loading from blood transfusions may cause dilated cardiomyopathy in conditions such as thalassemia, the in-vivo prevalence of myocardial siderosis in HC is unclear, and its relation to left ventricular (LV) dysfunction is controversial. Most previous data on myocardial siderosis in HC has come from post-mortem studies. METHODS: Cardiovascular magnetic resonance (CMR) was performed at first presentation of 41 HC patients (58.9 ± 14.1 years) to measure myocardial iron and left ventricular (LV) ejection fraction (EF). RESULTS: In 31 patients (genetically confirmed HFE-HC), the HFE genotype was C282Y/C282Y (n = 30) and C282Y/H63D (n = 1). Patients with other genotypes (n = 10) were labeled genetically unconfirmed HC. Of the genetically confirmed HFE-HC patients, 6 (19%) had myocardial siderosis (T2* <20 ms). Of these, 5 (83%) had heart failure and reduced LVEF which was correlated to the severity of siderosis (R2 0.57, p = 0.049). Two patients had follow-up scans and both had marked improvements in T2* and LVEF following venesection. Myocardial siderosis was present in 6/18 (33%) of patients with presenting ferritin ≥ 1000 µg/L at diagnosis but in 0/13 (0%) patients with ferritin <1000 µg/L (p = 0.028). Overall however, the relation between myocardial siderosis and ferritin was weak (R2 0.20, p = 0.011). In the 10 genetically unconfirmed HC patients, 1 patient had mild myocardial siderosis but normal EF. Of all 31 patients, 4 had low LVEF from other identifiable causes without myocardial siderosis. CONCLUSION: Myocardial siderosis was present in 33% of newly presenting genetically confirmed HFE-HC patients with ferritin >1000 µg/L, and was the commonest cause of reduced LVEF. Heart failure due to myocardial siderosis was only found in these HFE-HC patients, and was reversible with venesection. Myocardial iron was normal in patients with other causes of LV dysfunction.

Superficial siderosis of the central nervous system: a rare cause of dementia with therapeutic consequences.

A 75-year-old patient was evaluated for dementia. His past medical history included an ischaemic cardiomyopathy treated with aspirin daily. His neurological examination showed mild ataxia syndrome and central deafness. The neuropsychological examination did not suggest Alzheimer's disease. No specific aetiology was found from biological investigations, but MRI scans revealed a superficial siderosis, which was further confirmed with CSF exams. This case highlights the interest of MRI with echo-gradient-T2 weighted sequences in patients investigated for memory disorders. Once the diagnosis is known, specific preventive measures have to be taken: searching for a treatable source of bleeding and the interruption of antiplatelet aggregation or anticoagulant treatments.

Clinical case of the month. Idiopathic pulmonary hemosiderosis presenting as a rare cause of iron deficiency anemia in a toddler--a diagnostic challenge.

Iron deficiency anemia is the most common cause of anemia in all age groups. Idiopathic pulmonary hemosiderosis is an extremely rare etiology of iron deficiency anemia seen predominantly in the pediatric population. Idiopathic pulmonary hemosiderosis is characterized by the triad of symptoms consisting of iron deficiency anemia, diffuse pulmonary infiltrates, and hemoptysis. The clinical presentation is extremely variable, and all three symptoms may not always be seen. Due to the rarity of the disease and the variability in clinical presentation, diagnosis is usually delayed. Early diagnosis and treatment with corticosteroids prevents further episodes of recurrent alveolar hemorrhage and improves the clinical outcome. Hence, a high index of suspicion is required for the diagnosis of this condition in young patients presenting with severe iron deficiency anemia and diffuse pulmonary infiltrates. We report a toddler with idiopathic pulmonary hemosiderosis whose initial clinical presentation was severe iron deficiency anemia.