Liposteroid Therapy for Idiopathic Pulmonary Hemosiderosis: A Scoping Review of the Literature.

Idiopathic pulmonary hemosiderosis (IPH) is a rare cause of diffuse alveolar hemorrhage (DAH). Glucocorticosteroids (CS) represent the first line therapy for IPH. Although most patients respond to CS, steroid refractoriness is seen in an appreciable minority of patients. This paper reviews and evaluates the efficacy and safety profile of liposomal dexamethasone 21-palmitate (liposteroid) for the treatment of IPH. Medline, Embase and Web of Science biomedical databases were searched between 1980 and 2020 to identify papers describing patients with IPH, who were treated with liposteroid. A total of five articles were identified. Four in the form of case reports and one as a case series. A total of 12 pediatric patients (5 boys, 7 girls) were identified, with a median age of 2.3 years (range 0.5-8.6). Liposteroid therapy in intravenous doses ranging 0.06-0.1 mg/kg body weight appeared to be effective for both remission induction therapy, and maintenance therapy. There was no mortality among patients treated with liposteroid, either in the acute phase or during follow-up. The majority of patients for whom long-term follow-up data were available, were cured or in disease remission. No acute adverse events were reported, and long-term side effects were minimal and tolerable. Liposteroid represents a potential alternative or supplement to conventional CS therapy, as it appears to be more efficacious and associated with fewer side effects. Larger prospective, controlled trials are necessary to be able to define more precisely the therapeutic role of liposteroid in IPH.

Pulmonary Nocardia infection in a child with idiopathic pulmonary hemosiderosis.

BACKGROUND: Idiopathic pulmonary hemosiderosis (IPH) encompasses a rare and agnogenic group of diffuse alveolar capillary hemorrhagic diseases. Corticosteroid treatment is the globally preferred therapeutic strategy for IPH; however, it can cause immunodeficiency. Nocardia infection often occurs in immunocompromised patients and primarily involves the pleura and lungs. Herein, we describe a case of pediatric pulmonary Nocardia infection after the corticosteroid treatment of IPH. CASE PRESENTATION: A 7-year-old girl presented with chief complaints of pale complexion persisting for 1 year and a cough for 20 days. Abundant hemosiderin-laden macrophages were detected in the gastric juice, which supported the diagnosis of IPH. Uninterrupted doses of corticosteroids were administered during the last hospitalization. After nearly 2 months of corticosteroids therapy, the patient began to cough and produce a purulent sputum. Next-generation sequencing of the bronchoalveolar lavage fluid revealed Nocardia abscessus (N. abscessus) DNA. Linezolid was administered with good response, and the patient was discharged after 18 days of hospitalization. Her symptoms and pulmonary lesions had recovered, and the IPH appeared to be well-controlled with low dose of corticosteroids in follow-up. CONCLUSIONS: Nocardia infection should be considered in the differential diagnoses for IPH patients receiving corticosteroid therapy, especially in patients with poor response to conventional empirical antibiotic therapy. Next-generation sequencing of bronchoalveolar lavage fluid may be used to quickly identify the Nocardia. Sulfonamides or linezolid are effective for pediatric pulmonary Nocardia infection.

Aggressive corticosteroid treatment in childhood idiopathic pulmonary hemosiderosis with better outcome.

BACKGROUND/PURPOSE: Idiopathic pulmonary hemosiderosis (IPH) is a rare but fatal disease characterized by a triad of anemia, hemoptysis, and increased pulmonary infiltration. This study is aimed to review the clinical manifestations, diagnostic tools, medication and outcome of childhood IPH in Taiwan. METHODS: We retrospectively enrolled the patients less than 18 years old in National Taiwan University Hospital in the past 30 years. The clinical data were collected and analyzed. RESULTS: All of the twelve children diagnosed with IPH had anemia and increased pulmonary infiltration, eight had hemoptysis, and ten were confirmed with detection of hemosiderin-laden macrophages. The mean age at diagnosis were 4.9 (interquartile range 2.5-6.3) years old. Patients with high dose corticosteroid (CS, ≥ 1 mg/kg/day prednisolone equivalent) treatment had lower odds ratio for ICU admission and significant higher Hb recovery rate than those with mild disease activity not receiving high dose CS treatment (p = 0.011). The only factor that is significantly associated with persistent anemia is the usage of high dose CS (p < 0.001) after adjusting for hemoptysis, fulfilling triad, serum ferritin level, and ICU admission by multiple regression. The only factor that is significantly associated with ICU admission is the presence of microorganism yielded in sputum (p < 0.001) after adjusting for fever, serum ferritin level, usage of invasive MV, and high dose CS treatment days. CONCLUSION: The aggressive high dose CS therapy might prevent ICU admission and improve anemia. Aggressive high dose CS treatment is suggested in IPH patients regardless of the disease activity.

Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage.

COPA (coatomer subunit α) syndrome is a newly recognised cause of interstitial lung disease in children and adults, frequently associated with arthritis and renal dysfunction. We report a 11-year-old girl with disease limited to major pulmonary haemosiderosis manifesting at the age of 2 years, due to a heterozygous p.(Arg233His) mutation in COPA Her interferon (IFN) signature was elevated (10.312 and 12.429, healthy <2.466), as was the level of serum IFNα (211 fg/mL, healthy <10 fg/mL). STAT1 phosphorylation in T lymphocytes and monocytes was increased as compared with healthy controls. Based on these results she was treated with the JAK1/2 inhibitor ruxolitinib, which resulted in reduction in IFN signalling and appeared to be associated with partial though incomplete decrease in the severity of her pulmonary disease. Patients with alveolar haemorrhage of unknown origin should be considered for COPA screening. Functional tests can help to personalise patient therapy.

Idiopathic Pulmonary Hemosiderosis as a Mimic of Pulmonary Vasculitis: A Case Report and Review of the Literature.

PURPOSE OF REVIEW: Idiopathic pulmonary hemosiderosis (IPH) is one of the rarest and least understood causes of pulmonary hemorrhage in children. Illustrated by a complex case presentation, we discuss the clinical manifestations, diagnosis, pathology, proposed etiologies, and treatment of this rare disease. We also compare IPH with anti-glomerular basement membrane antibody syndrome (anti-GBM disease), another rare causes of pediatric pulmonary hemorrhage. RECENT FINDINGS: Recent retrospective studies regarding IPH along with advanced immunotherapy have led to an improved understanding of how to best treat this condition, potential associations, and improved prognosis. Pathogenesis remains unknown, but several reports have suggested involvement of the alveolar capillary basement membrane. IPH is a poorly understood disease of unknown etiology that is a diagnosis of exclusion. Our patient was diagnosed with IPH after an exhaustive workup, including lung biopsy, into other immune-mediated causes of disease. While the pathogenesis of this rare disease remains elusive, our patient's immunofluorescent staining along the alveolar basement membrane without evidence of circulating antibody to type IV collagen raises the question of an immune-mediated pathogenesis of the disease with involvement of the alveolar basement membrane.

Respiratory Distress and Severe Anemia in a Child With Idiopathic Pulmonary Hemosiderosis.

Idiopathic pulmonary hemosiderosis is an infrequent cause of pulmonary hemorrhage in children. It is classically defined by the triad of recurrent hemoptysis, iron-deficiency anemia, and diffuse parenchymal infiltration without an obvious cause. The pathogenesis remains unexplained, diagnosis may be difficult, and the clinical course exceedingly variable. A 4-year-old girl was admitted to the hospital with complaints of dyspnea, and skin and mucous membrane pallor. The suspicion of idiopathic pulmonary hemosiderosis led to the use of corticosteroid therapy with rapid improvement in clinical condition and discharge from hospital.

Imaging findings of Copa syndrome in a 12-year-old boy.

Copa syndrome is a newly described autosomal dominant autoinflammatory disease that presents as pulmonary hemosiderosis and polyarticular arthritis. Twenty-one cases from five families have been reported to date. We present chest computed tomography (CT) and temporomandibular joint magnetic resonance (MR) findings of a 12-year-old boy presenting with dyspnea on exertion, fatigue and clubbing. Additional findings included a restrictive pattern of pulmonary involvement and positive inflammatory markers and autoantibodies. Genetic testing revealed a p.W240R variant of the COPA gene confirming the diagnosis of Copa syndrome. CT of the chest showed a nonspecific interstitial pneumonia pattern distributed mainly in the lower lobes. MR of the temporomandibular joints and follow-up CT three years later are also described.

Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST).

BACKGROUND: Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. PROCEDURE: Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter. RESULTS: In total, 267 patients (mean age 3.2 years) predominantly with ß-thalassemia (n = 176, 65.9%) were enrolled. Mean ± standard deviation deferasirox dose was 25.8 ± 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years' treatment. The proportion of patients with two or more consecutive postbaseline measurements (≥7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval [CI]: 2.1-7.9) and 4.0% (95% CI: 1.8-7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. There were no new safety signals. CONCLUSIONS: Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.

A Case of Idiopathic Pulmonary Hemosiderosis Presenting With Signs and Symptoms Mimicking Hemolytic Anemia.

Idiopathic pulmonary hemosiderosis is primarily a disorder of childhood, which is characterized by hemoptysis, iron deficiency anemia, and diffuse parenchymal infiltrates on chest x-ray secondary to recurrent attacks of alveolar hemorrhage. It can be diagnosed by showing hemosiderin laden macrophages in bronchoalveolar lavage fluid after other specific causes of diffuse alveolar hemorrhage are definitely excluded. A 5-year-old male patient was admitted to our clinic with sudden-onset pallor during iron therapy given for anemia. While he was being investigated for clinical and laboratory signs mimicking hemolytic anemia, he developed cough and dyspnea. He had infiltrates on chest x-ray and scattered patchy infiltrates in both lungs on high-resolution computed tomography. Hemosiderin laden macrophages were identified in fasting gastric juice and bronchoalveolar lavage fluid. The patient was diagnosed with idiopathic pulmonary hemosiderosis and started corticosteroid therapy.

Idiopathic Pulmonary Hemosiderosis Presenting as Anemia, Failure to Thrive, and Jaundice in a Toddler.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by the triad of hemoptysis, pulmonary infiltrates on chest radiograph, and anemia. Its diagnosis should be considered in any child presenting with moderate to severe anemia and failure to thrive of unclear etiology. Consideration of the differential diagnosis in such a child should include the review of both extravascular and intravascular causes of hemolysis. Systemic treatment of IPH with glucocorticoids has been shown to decrease morbidity, mortality, and disease progression to pulmonary fibrosis. Thus, diagnostic delays can impact prognosis. Here, we present a case of a 15-month-old boy with IPH who presented with anemia, jaundice, and failure to thrive, as well as a history of hemoptysis that was not initially elicited.

Thalassemia major between liver and heart: Where we are now.

The aim of the study was to assess the current state in terms of liver and heart iron overload as well as of liver and heart related morbidity and mortality in a large cohort of thalassemia patients. Myocardial iron loading was present in 28.9% patients, which was severe in 3.2%. Liver iron was normal in 9.3% and severe in 15%. The rate of cardiac deaths started to decrease between 2000 and 2003 and dropped significantly afterwards. The prescription of combination therapy soon after the hospital admission for decompensated heart failure was associated with a decrease in the short-term mortality. In 111 adult patients who underwent liver elastometry, 14 HCVRNA positive subjects and 2 HCVRNA negative, had stiffness values suggestive of cirrhosis. No cases of hepatocarcinoma were reported. Liver "iron free foci" occurred in a HCV negative patient and the occurrence of a malignant epithelioid hemangioendothelioma led to liver transplantation in another. The study suggests that a subset of patients continues to develop progressive hemosiderosis that may lead to cardiac disease and death. Beyond its key role in preventing myocardial iron overload, liver iron chelation is essential for hampering the onset of hepatic tumors, which may not be limited to hepatocarcinoma.

Idiopathic pulmonary hemosiderosis complicated by Down syndrome.

We report the case of a 9-year-old girl with Down syndrome (DS) diagnosed with idiopathic pulmonary hemosiderosis (IPH). Although acute pneumonia complicated by hemolytic anemia was suspected, IPH was finally diagnosed on bronchoscopy. Treatment with prednisolone achieved good clinical response. An association between IPH and DS was not able to be identified, but immunological issues in DS may contribute to the onset of IPH. Recurrent and intractable respiratory symptoms with marked infiltrative shadows in the bilateral lungs and complicated by severe anemia in patients with DS should suggest IPH.

Unexplained childhood anaemia: idiopathic pulmonary hemosiderosis.

This report demonstrates pulmonary haemorrhage as a differential cause of anaemia. Idiopathic pulmonary hemosiderosis is a rare disease in children; it is classically described as a triad of haemoptysis, pulmonary infiltrates on chest radiograph, and iron-deficiency anaemia. However, anaemia may be the only presenting feature of idiopathic pulmonary hemosiderosis in children due to occult pulmonary haemorrhage. In addition, the serum ferritin is falsely high in idiopathic pulmonary hemosiderosis which increases the diagnostic difficulty. We recommend that pulmonary haemorrhage be suspected in any child presenting with iron-deficiency anaemia and persistent bilateral pulmonary infiltrates.

Biopsy-based calibration of T2* magnetic resonance for estimation of liver iron concentration and comparison with R2 Ferriscan.

BACKGROUND: There is a need to standardise non-invasive measurements of liver iron concentrations (LIC) so clear inferences can be drawn about body iron levels that are associated with hepatic and extra-hepatic complications of iron overload. Since the first demonstration of an inverse relationship between biopsy LIC and liver magnetic resonance (MR) using a proof-of-concept T2* sequence, MR technology has advanced dramatically with a shorter minimum echo-time, closer inter-echo spacing and constant repetition time. These important advances allow more accurate calculation of liver T2* especially in patients with high LIC. METHODS: Here, we used an optimised liver T2* sequence calibrated against 50 liver biopsy samples on 25 patients with transfusional haemosiderosis using ordinary least squares linear regression, and assessed the method reproducibility in 96 scans over an LIC range up to 42 mg/g dry weight (dw) using Bland-Altman plots. Using mixed model linear regression we compared the new T2*-LIC with R2-LIC (Ferriscan) on 92 scans in 54 patients with transfusional haemosiderosis and examined method agreement using Bland-Altman approach. RESULTS: Strong linear correlation between ln(T2*) and ln(LIC) led to the calibration equation LIC = 31.94(T2*)-1.014. This yielded LIC values approximately 2.2 times higher than the proof-of-concept T2* method. Comparing this new T2*-LIC with the R2-LIC (Ferriscan) technique in 92 scans, we observed a close relationship between the two methods for values up to 10 mg/g dw, however the method agreement was poor. CONCLUSIONS: New calibration of T2* against liver biopsy estimates LIC in a reproducible way, correcting the proof-of-concept calibration by 2.2 times. Due to poor agreement, both methods should be used separately to diagnose or rule out liver iron overload in patients with increased ferritin.

Idiopathic pulmonary haemosiderosis.

In this paper, we report the case of a boy in early childhood who presented with iron-deficiency anaemia, initially thought to be nutritional, who had a subsequent diagnosis of idiopathic pulmonary haemosiderosis (IPH). This is a slowly progressive and life-threatening disorder and is of paramount importance that this is identified early and treated appropriately. His first chest CT was not typical for IPH, and this appearance should be highlighted (small cystic changes alone initially). He also had focal disease, which allowed us to make the diagnosis using CT-guided biopsy. During his treatment, he experienced an uncommon side effect to a commonly prescribed medication (bradycardia with methylprednisolone). Since starting azathioprine as a steroid-sparing agent, he has been doing well.

The palatability and tolerability of deferasirox taken with different beverages or foods.

BACKGROUND: Deferasirox is a once-daily, oral iron chelator that was developed out of a need for a long-acting, conveniently-administered chelator for patients with transfusional hemosiderosis. The approved mode of administration requires taking deferasirox on an empty stomach with water, apple juice, or orange juice to limit variation in bioavailability. This required administration schedule might not be palatable for patients. Additionally, approximately one-quarter of patients experience mild to moderate gastrointestinal (GI) symptoms, which may pose additional challenges, particularly in the younger and older age ranges. We present a trial to assess the palatability and safety of various administration modes of deferasirox in pediatric and adult patients. PROCEDURES: Participants rated palatability in a 4-week run-in phase, where deferasirox was administered per label. Subsequently, patients rated several administration modes during a 3-month assessment phase. RESULTS: Palatability was more favorable during the assessment phase, with 47% of patient ratings for palatability being favorable while only 38% were favorable during the run-in phase. The most highly rated choice was deferasirox taken with a soft food at breakfast. In addition, there was an indication of improved GI tolerability during the assessment phase (symptoms were reported in 37% of patients during run-in and 32% during the assessment phase; rates of diarrhea decreased significantly). Although trough PK values increased, no major new toxicities were observed. CONCLUSIONS: These data indicate that different administration options may improve palatability and GI tolerability, which could have a positive impact on treatment adherence. (ClinicalTrials.gov number, NCT00845871)

Iron chelation with deferasirox for the treatment of secondary hemosiderosis in pediatric oncology patients: a single-center experience.

Pediatric oncology patients are often iron overloaded, due to the multiple blood transfusions necessary during the course of chemotherapy. Our aim is to report the efficacy and safety of deferasirox, an oral iron chelator, in this patient group. Deferasirox was administered to 13 children with malignancies in remission and iron overload. Ferritin, blood urea nitrogen, creatinine, transaminases, and bilirubin were recorded at 4- to 8-week intervals, and hepatic and cardiac iron overload were assessed with magnetic resonance imaging before initiation of treatment. Deferasirox was administered for an average of 6 months (SD=4.5; range, 0.3 to 18.2). Two children presented with skin rash, 1 with gastrointestinal disturbances, and 1 with fully reversible acute renal failure. The mean monthly rate of change in ferritin levels was -10.8 µg/L before initiation of treatment (95% confidence interval [CI], -19.8 to -1.8; P=0.02) and -93.6 µg/L during deferasirox treatment (95% CI, -118.1 to -69.1; P<0.001). The difference in the monthly rate of change in ferritin levels before and after treatment initiation was -82.8 µg/L (95% CI, -111.6 to -53.9; P<0.001). Deferasirox was effective in reducing the iron burden. The adverse effects were easily monitored and managed. Further studies are warranted to investigate the effect of deferasirox on mortality and morbidity in this population.