Idiopathic Pulmonary Hemosiderosis: a State of the Art Review

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Respiratory Medicine 176 (2021) 106234

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Respiratory Medicine

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Review article Idiopathic pulmonary hemosiderosis: A state of the art review

Biplab K. Saha

Division of Pulmonary and Critical Care Medicine, Ozarks Medical Center, West Plains, MO, USA

ARTICLE INFO ABSTRACT

Keywords: Idiopathic pulmonary hemosiderosis (IPH) is an uncommon cause of diffuse alveolar hemorrhage (DAH). Patients Hemoptysis with IPH usually present with hemoptysis, and the diagnosis is often delayed by years. Patients often present with Pulmonary hemorrhage intermittent episodes of hemoptysis interspersed between periods of relative normalcy. However, massive Idiopathic pulmonary hemosiderosis hemorrhage resulting in acute respiratory failure and non-remitting hemoptysis have also been described. The classic triad includes hemoptysis, radiologic lung infiltrate, and iron deficiency anemia. Several hypotheses regarding the pathogenesis of IPH have been proposed. These risk factors include an autoimmune, allergic or genetic predisposition, and possible environmental exposure. Since IPH appears to be responsive to corticoste roids, the autoimmune hypothesis is considered to play a crucial role. A diagnosis of IPH requires exclusion of other etiologies of DAH, including infection, medications, toxic inhalation, vasculitis, and anti-glomerular basement membrane disease, among others. Histologically, IPH is characterized by the presence of hemosiderin-laden macrophages in the alveolar space without any evidence of vasculitis or immunocomplex deposition. Corticosteroid therapy represents the primary modality of treatment. Other immunosuppressive medications have also been used with varying success, especially in the setting of steroid-refractory disease. The prognosis of IPH in adults is somewhat better compared to the pediatric population. The severity of the initial presentation does not predict future outcomes. Which risk factors and patient characteristics are associated with a poor outcome are also unknown. More research is necessary to elucidate the pathophysiology and appropriate treatment.

1. Introduction different immunologic processes has been reported, this is not a uni versal feature, and no definitive immunobiological mechanisms have Idiopathic Pulmonary Hemosiderosis (IPH) is a rare cause of diffuse been established. Identificationof hemosiderin-laden macrophages from alveolar hemorrhage (DAH). IPH is characterized by recurrent episodes bronchoalveolar lavage (BAL) specimen is suggestive, but not diagnostic of DAH without any identifiableetiology, such as infection, Goodpasture of IPH. Transbronchial and surgical lung biopsies remain the definitive syndrome, anti-neutrophil cytoplasmic antibody (ANCA) associated diagnostic test. In some patients, the disease can progress, resulting in vasculitis (AAV) and other rheumatologic diseases. In addition, exclu pulmonary fibrosis and end-stage lung disease. Risk factors that might sion of potential drug or toxin exposure and other etiologies of bland portend a poor long-term prognosis are also unknown. This manuscript pulmonary hemorrhage (anticoagulants, antiplatelets, thrombolytics, will critically review the literature and inform the clinician regarding disseminated intravascular coagulation, and cardiac valvular abnor the epidemiology, risk factors, proposed immunopathogenesis and new malities) are necessary. Rudolph Virchow provided the first post- insights, clinical presentation, diagnostic approach, and treatment of mortem description of this condition as early as 1864 [1]. Although IPH. The goal is to remind the audience of this rare disorder and to more common in the pediatric population, IPH can present at any age. consider IPH as a possibility in patients with hemoptysis, especially Due to the rarity of the condition, a definitivediagnosis is often delayed when associated with pulmonary infiltrates on chest radiography and and can cause significant distress for the patient and the families. The iron deficiency anemia. exact incidence, pathogenesis, and optimal treatment are unknown, and very few randomized clinical trials exist. Patients usually present with 2. Epidemiology recurrent episodes of hemoptysis that can be intermittent or persistent and varies considerably in amount. Although an association with The exact incidence and prevalence of IPH are currently unknown.

E-mail address: [email protected]. https://doi.org/10.1016/j.rmed.2020.106234 Received 31 July 2020; Received in revised form 10 November 2020; Accepted 11 November 2020 Available online 17 November 2020 0954-6111/© 2020 Elsevier Ltd. All rights reserved. B.K. Saha Respiratory Medicine 176 (2021) 106234

Based on the literature, the disease appears to be more common in Table 1 children compared to adults. Children represent about 80% of reported Risk factors and pathogenesis of IPH. cases [2]. The estimated incidence ranges from 0.24 to 1.23 cases per Hypothesis Supporting evidence Evidence incompatible million among children [3,4]. A single hospital retrospective study in with the hypothesis the US revealed a prevalence of 6.71 cases per 1,000,000 patients [5]. Genetic IPH has been reported among No known association with Although some studies suggested no gender preference, a recent review predisposition twins, family members, and a specific gene locus of the French pediatric registry demonstrated a significant female pre relatives Down Syndrome has Environmental exposure dominance [6–8]. Lung biopsy had shown that IPH was responsible for been associated with IPH could be responsible for familial clustering interstitial lung disease in 8% of children [9]. Based on a review of re Environmental Exposure to secondhand No report of environmental ported adult cases between 2000 and 2015, IPH was almost twice as exposure smoking and Stachybotrys exposure leading to IPH in common in men than women [10]. The authors identified 37 reported chartarum toxin (satratoxins) the adult population exists adult cases with a median age of 34 years at diagnosis, and more than was linked to IPH in children Exposure to satratoxins half the cases were diagnosed after the age of 30 years [10]. This was in Once inhaled, satratoxins causes nasal and tracheal inhibits protein synthesis, bleeding in animals but not contrast to previous reports where the disease was thought to manifest resulting in impaired pulmonary hemorrhage before 30 years [2]. It is vital to appreciate that IPH can present at any angiogenesis and pulmonary age, including during pregnancy, and impose additional challenges in capillary basement membrane the management of the patient [11]. There is no known data on the formation leading to pulmonary hemorrhage geographic and racial distribution of the disease. Immunologic A leading hypothesis Alveolar- Many cases of ANCA association capillary basement membrane associated vasculitis had 3. Risk factors and pathogenesis abnormalities with been inadvertently immunocomplex deposition reported as IPH in the Despite the long standing identificationof the disease entity, the risk were reported early Most cases earlier literature Alveolar- of IPH responds to capillary basement factors and pathogenesis of IPH remains an enigma to clinicians. It is corticosteroids and membrane abnormalities currently unknown whether the pathogenesis of IPH is similar in adults immunosuppressive drugs have been deemed and pediatric patients. Several risk factors have been proposed with Autoantibodies are identified nonspecificand can be seen varying degrees of supporting evidence. These include: in a quarter of patients during in non-pulmonary vascular the course of their illness Some beds with non-immune patients with IPH also had vascular insults A 1. Genetic predisposition coexistent celiac disease and significantnumber of 2. Environmental exposure showed remarkable reported cases have not 3. Immunologic association improvement following shown any immune 4. Allergic reaction institution of a gluten-free diet complex deposition in the alveolar-capillary unit Autoantibodies are not universal 3.1. Genetic predisposition Allergic reaction Cow’s milk protein allergy, This association is rare, both IgG and IgE, has been even in children reported in children with IPH The possibility of a genetic predisposition for IPH was conceptual ized as early as the 1970s. Several reported cases of IPH affected family ANCA, anti-neutrophil cytoplasmic antibody; IPH, idiopathic pulmonary members, including siblings, and in one report, the mother and her son hemosiderosis; Ig, immunoglobulin. [6,12,13]. Down Syndrome has been identified as a risk factor by a retrospective database review, and also possibly associated with the 1) Early research of IPH revealed the presence of abnormalities in the development of pulmonary hypertension and worse outcome [14,15]. alveolar-capillary basement membrane with [19,20] or without Despite our significant leap into the understanding of human genetics, [21–24] any identifiable deposition of immunoglobulin on the no specific genetic abnormalities have been recognized to date. The basement membrane likely challenges are the rarity of the disease and other confounding 2) Clinical response to immunosuppressive therapy [22,25]. factors, such as environmental exposures, which may have been 3) Autoantibodies have been reported in about 25% of patients during responsible for the clustering of the disease among family members. the course of the illness [26–29]. 4) Coexisting IgA deficiency [30]. 3.2. Environmental exposure A review of the French registry of the rare pediatric lung disease Exposure to secondhand smoking and highly potent fungal toxin has (RespiRare) had identified25 children with IPH, and they were followed been associated with pulmonary hemorrhage, especially in children. for a median of 5.5 years [8]. Seventeen patients were found to have Stachybotrys chartarum, an environmental fungus, had been linked to an autoantibodies at diagnosis, and six additional patients developed au outbreak of pulmonary hemorrhage [16,17]. S chartarum produces toantibodies during the follow-up. The most commonly identified anti satratoxins that causes impaired synthesis of Collagen IV, which pro bodies were anti-smooth muscle (ASM), anti-neutrophil cytoplasmic vides connective tissue scaffolding for the endothelial basement mem antibody (ANCA), anti-nuclear antibody (ANA), rheumatoid factor (RF) brane at the alveolar-capillary junction. When inhaled in high and anti-cyclic citrullinated peptide antibody (anti-CCP). Interestingly, concentration, it disrupts angiogenesis resulting in capillary fragility the evolution of ANCA positivity in this patient cohort was variable. Out and pulmonary hemorrhage. However, it is crucial to emphasize that as of the six patients, the positive ANCA disappeared in four, remained IPH is idiopathic by definition,exposure to a known toxic hemorrhagic stable in one, and the titer declined in the remaining patient. It is precipitant would not qualify as a risk factor. Exposure to pesticides has possible that the autoantibody generation in IPH is transitory and these also been cited as an association [18]. patients manifest with isolated pulmonary disease prior to diffuse sys temic involvement by the autoimmune process [31]. 3.3. Immunologic association However, contradicting results have also been reported. Several pathologic studies, including electron microscopy, found within earlier There is considerable evidence to support the immunologic associ reports of IPH, refuted the association with autoimmune diseases. These ation of IPH: studies reported that vascular injuries in IPH were nonspecificand was

2 B.K. Saha Respiratory Medicine 176 (2021) 106234 not associated with an immune phenomenon [24,32,33]. The re antibodies against cow milk protein (both IgE and IgG) in children searchers found similar microscopic vascular changes in non-pulmonary diagnosed with IPH [37]. Cow’s milk protein antibody-mediated pul vasculature in response to a multitude of injuries. These discrepancies monary disease is known as Heiner syndrome [38]. There has been no may be due to the likely misdiagnosis of AAV as IPH. Although described prospective study that has validated this association. IPH has been re in the early literature by many names, AAV syndromes were not well ported in patients with allergic asthma [39]. characterized until the late twentieth century [34]. As a result, many In summary, IPH appears to be an immunologic disease with a cases of AAV was reported as IPH. concomitant genetic component, but the exact pathogenesis still re The coexistence of IPH and Celiac disease has been described and is mains unclear. known as Lane Hamilton syndrome. In one study, 3 out of 10 children The proposed hypotheses for the pathogenesis of IPH are summa with IPH were found to have Celiac disease, and avoidance of gluten has rized in Table 1. been reported to be associated with significant improvement of pul monary symptoms [35,36]. Similarly, 28% of patients tested positive for 4. Lung damage in IPH Celiac disease in the previously mentioned French study [8]. IPH can progress to pulmonary fibrosis and end-stage lung disease. 3.4. Allergic reaction The mechanism for lung injury involves excessive iron deposition, possible inefficient handling of the iron load by the alveolar macro Like the autoimmune hypothesis, an allergic etiology has been phages, oxidative damage, inflammation and eventual fibrosis [2]. entertained. The allergic hypothesis stems from the isolation of plasma Following an episode of intra-alveolar hemorrhage, the RBCs are

Fig. 1. Diagnostic flow chart for IPH.

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oxidative damage by producing hydroxyl radicals [42]. The AM may nullify the toxic effect by utilizing iron to produce enzymes and intra cellular components, such as cytochrome C, and incorporating iron into apoferritin to produce ferritin, the intracellular storage form of iron. However, IPH causes recurrent episodes of hemorrhage; this results in rapid saturation of intracellular apoferritin and generation of free iron. The free iron can cause lipid peroxidation, cellular damage, inflammation, and subsequent fibrosis [43–45]. Similarly, the intracel lular ferritin storage reaches its maximum capacity, and more hemo siderin than ferritin is stored in the macrophages [46]. The ferritin is released into the blood from the macrophages by an unknown mecha nism and is responsible for elevated serum ferritin level seen in IPH [2].

5. Clinical manifestation

5.1. Symptoms and signs

The presentation of IPH in the adult population is variable and can be easily missed [47]. Patients often present with hemoptysis, which varies greatly in quality and quantity. The hemoptysis can range from inter mittent episodes of blood-streaked sputum to frank hemoptysis on a daily basis. Life-threatening hemorrhage with the development of acute respiratory failure is uncommon but has been reported [48,49]. He Fig. 2. Portable chest X-ray in a 49-year old male with IPH showing peri-hilar moptysis is the presenting symptom in approximately 80% of patients alveolar opacity predominantly involving mid and lower lung zones. [10]. Based on a review of all reported adult cases between 2000 and 2015, the second and third common presentations were dyspnea and anemia [10]. More than half of the adults with IPH suffered from iron deficiency.Although isolated iron deficiencyanemia without any other symptom has been reported in the pediatric population, such a clinical presentation is rarer in adults [50,51]. The disease can also follow a relapsing and remitting course. During an episode of alveolar hemor rhage, patients become symptomatic and in between exacerbations, remain relatively symptom-free. Chronic hemoptysis without remission has been reported as well. Physical examination during the acute phase may demonstrate mild crackles to overt signs of respiratory failure while being normal during the remission. The classical presentation of IPH includes the triad of hemoptysis, radiologic chest abnormalities and anemia; however, this constellation is absent in the majority. Other less frequent presentations include dry cough, chest pain, fever, fatigue, and clubbing [10].

5.2. Diagnosis

In addition to the supportive clinical presentation, a diagnosis of IPH requires compatible laboratory data, chest radiology, and histopatho logic findings. Since there is no specific serologic or pathologic marker for IPH, an exhaustive effort is needed to exclude competing diagnoses. Bronchoscopic evaluation is generally performed to identify DAH and rule out infection. In addition, structural airways abnormalities, including cancer, and arteriovenous malformation, which may mimic the symptoms of IPH, can be ruled out. A lung biopsy is necessary to Fig. 3. Coronal CT scan of the chest in a 49-year old male with IPH demon definitively exclude capillaritis as DAH from both AAV and isolated strating diffuse ground glass opacity involving all lung lobes with peripheral pulmonary capillaritis can manifest with a negative serologic workup sparing. Interlobular septal thickening is more prominent in the lower lobes. [52–55]. Moreover, some patients develop ANCA antibodies later in the There are also areas of centrilobular nodularity throughout the lungs. course of the disease, making reliance on only serologic workup insuf ficient. On average, the diagnosis of IPH is delayed by 2.3 years in the adult population [10]. A diagnostic flow chart is presented in Fig. 1. rapidly phagocytosed by the alveolar macrophages (AM). The hemo globin is broken down into heme and globin. The polypeptide globin 5.3. Laboratory data chains are catabolized to form amino acids. Free heme is highly toxic and associated with proinflammatory cytokine release, recruitment of No specific laboratory test exists for IPH. The complete blood count neutrophils, as well as the formation of reactive oxygen species (ROS) might show anemia with evidence of iron deficiency.The serum ferritin [40]. Heme also induces heme oxygenase-1 (HO-1), the inducible form level is usually normal or elevated (see the description above). of heme oxygenase (HO) responsible for the breakdown of heme into A long term follow up of two pediatric patients with a relapsing and iron, bilirubin, and carbon monoxide (CO) [41]. Free iron can cause remitting disease revealed that neutrophils might be associated with the pathogenesis of the disease. The authors identified peripheral blood

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Table 2 can mimic IPH and need to be ruled out [58]. The etiology of DAH is Clinical manifestation and diagnosis of IPH. broad and a detailed discussion can be found elsewhere [59]. Symptoms and signs Symptoms Disease course: Relapsing-remitting or progressive Common: Hemoptysis (variable in quality and 5.4. Chest radiography quantity, present in 80%) Dyspnea Anemia (Iron deficiency) Less common: Dry cough Chest pain Fever The radiographic appearance of IPH is rather nonspecific and de Fatigue Acute respiratory failure Signs: NonspecificCan be normal during remission Mild basilar crackles Clubbing pends on the acuity and severity of alveolar hemorrhage. During the Signs of respiratory failure with severe disease acute episode, chest X-ray usually shows diffuse alveolar opacity, Laboratory workup No specific laboratory tests Evidence of iron deficiency including consolidation involving the peri-hilar and lower lung zones anemia Normal to elevated ferritin Reticulocytosis (Fig. 2). However, in case of massive hemorrhage, all lung zones may be Neutropenia in the immediate pre-acute phase and eosinophilia following alveolar hemorrhage Autoimmune involved. The radiologic opacity usually decreases or changes into a diseases and vasculitis need to be ruled out: •ANCA, P- more interstitial pattern within 72 h [60]. [[,61] [][][] High resolution ANCA, c-ANCA, anti-MPO antibody, anti-PR3 antibody computed tomography (HRCT) of the chest is more sensitive and might •ANA, RF, anti-CCP, anti-dsDNA, anti-smith antibody, anti- show affected areas not previously identified by chest X-rays. HRCT SSA and SSB antibody, anti-smooth muscle antibody, anti- often shows ground glass opacities (GGOs), consolidation in the same cardiolipin antibody, anti-phospholipid antibody, anti- beta 2 glycoprotein antibody, C3, C4, serum cryoglobulin, distribution described above (Fig. 3). As hemosiderin deposits along the anti-jo antibody, aldolase, creatine phosphokinase, IgG and interlobular septa, a ‘crazy paving’ pattern might also be seen [62]. IgA tissue transglutaminase antibody, anti-gliadin Centrilobular opacities can be seen with chronic hemorrhage due to the antibody, anti-endomysial antibody Hematologic, intra-alveolar accumulation of macrophages [62]. With repeated epi metabolic, and cardiac etiologies need to be ruled out:• sodes of alveolar hemorrhage, fibrotic changes develop in the form of CBC, CMP, PT, INR, PTT, d-dimer, FDP, fibrinogen •Transthoracic echocardiogram Anti-basement membrane reticulation, subpleural honeycombing, traction bronchiectasis, and antibody bronchiolectasis in the postero-basilar areas [63]. Progressive massive Chest radiography Chest X-ray Diffuse alveolar opacity in the acute phase fibrosis involving the upper and midlung secondary to iron deposition involving perihilar and lower lobes With diffuse has also been described [64]. hemorrhage, all lung zones can be affected Alveolar opacity becomes more interstitial opacity with 72 h High MRI and radiolabeled RBC scans have been performed to demon resolution computed tomography More sensitive strate alveolar hemorrhage in patients with suspected IPH, but their role Ground-glass opacity in the same distribution ‘Crazy in the clinical setting is currently uncertain. Although uncommon, paving’ due to interlobular septal deposition of pleural manifestations of IPH have also been described, and includes, hemosiderin Centrilobular opacity from intraalveolar hemothorax, pleural thickening, fibrothorax, and trapped lung [61]. A macrophage accumulation Fibrotic changes including reticulation, honeycombing, and traction bronchiectasis comprehensive review of thoracic radiologic appearance of IPH can be Bronchoscopic Bronchoalveolar lavageDemonstration of diffuse found elsewhere [61]. evaluation alveolar hemorrhageHemosiderin laden macrophages Absence of bacterial, viral, or fungal infection. Negative 5.5. Bronchoscopic evaluation cytology to rule out malignancy False-negative result during remission Possible neutrophilic predominance in the pre-acute stage Although a sputum sample might show hemosiderin-laden macro Histopathology Required for definitive diagnosis, especially in adults phage on Prussian blue stain, the diagnostic utility of sputum is limited Surgical biopsies provide a comprehensive evaluation but as many patients with IPH do not produce any sputum. The sputum also more invasive compared to TBLB and BLCB Intraalveolar has low sensitivity and an inadequate measure to rule out pulmonary hemorrhage Free and intracytoplasmic hemosiderin in macrophages Type 2 pneumocyte hyperplasia Thickening infection [65]. Bronchoscopic evaluation is, therefore, crucial not only of interalveolar septa with hemosiderin deposition to diagnose DAH but also to rule out infection. A diagnosis of DAH is Absence of capillaritis and immune complex made by the observation of progressively more bloody return on serial deposition aliquots on BAL. If uncertain, a hematocrit level can be obtained on the ANA, antinuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; C3, samples. The BAL is usually performed from the segment that is radio complement factor 3; C4, complement factor 4; c-ANCA, cytoplasmic anti- logically affected. The cell count demonstrates the predominance of neutrophil cytoplasmic antibody; CBC, complete blood count; CCP, cyclic cit hemosiderin-laden macrophages. The fluidis also sent for microbiologic rullinated peptide; CMP, complete metabolic profile; dsDNA, double-stranded studies to rule out potential bacterial, viral, and fungal pathogens as well DNA; FDP, fibrinogen degradation product; INR, international normalized as cytologic evaluation to rule out malignancy. ratio; MPO, myeloperoxidase; p-ANCA, perinuclear anti-neutrophil cytoplasmic A BAL might yield a false negative result, especially if performed in antibody; PR3, proteinase 3; PT, prothrombin time; PTT, partial thromboplastin between the acute hemorrhagic episodes [66]. Cohen et al. reported time; RF, rheumatoid factor; TBLB, transbronchial lung biopsy; TBCB, trans bronchial cryo lung biopsy. neutrophil predominance on BAL with peripheral blood neutropenia in the pre-acute state [56]. neutropenia followed by eosinophilia, fiveto ten days before an episode 5.6. Lung biopsy and histopathology of alveolar hemorrhage [56]. These findings, however, have not been reported in any adult patients. Reticulocytosis might be present during A definitivediagnosis of IPH requires histopathologic analysis. In the the acute phase mimicking hemolytic anemia [57]. appropriate clinical setting, a diagnosis of IPH has been made in children Patients are often tested for IgG and IgA tissue transglutaminase with identification of DAH on bronchoscopy; however, in the adult antibody based on prior evidence of coexisting celiac disease. Two to population, lung biopsies have been performed in the majority of cases fifteenpercent of patients might be falsely negative due to IgA deficiency [10,67]. A recent international survey of 88 pediatric physicians taking or being on a gluten-free diet. Testing for antibodies directed against care of 274 pediatric IPH patients showed that lung biopsies were per cow’s milk protein is controversial and possibly not necessary in the formed in 51.9% of patients [67]. Specimens could be obtained by adult population. transbronchial lung biopsies (TBLB), transbronchial cryo biopsies Presence of abnormal coagulation, hepatic and renal function tests (TBCB), and surgical lung biopsies (SLB) [68,69]. might point towards a different diagnosis. In addition to many pulmo A TBLB is the least invasive and can be performed at the same time if nary infections and medication side effects, AAV, anti-glomerular BAL is consistent with DAH. A diagnosis of IPH can often be made from basement (Anti GBM) antibody disease and connective tissue diseases TBLB. However, inconclusive results are always a possibility due to the

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Table 3 considered and treated as an autoimmune disease. Corticosteroids alone Suggestive treatment and dosage in IPH. or in combination with other immunosuppressive regimens are often Presentation Treatment employed for the treatment of IPH [75,76]. Data regarding the optimal dosing and duration of therapy is limited and primarily derived from Acute respiratory failure Methylprednisolone, 500–2000 mg/day for 3–5 requiring mechanical days, followed by Ref. [80] prednisone 0.5–1 case reports or small case series. Based on the available literature, ventilation mg/kg/day immunosuppressive therapy appears to be efficacious and is associated Without mechanical Prednisone 0.5–0.75 mg/kg/day of prednisone with reduced morbidity and mortality [75,77]. A limited number of ventilation with a maximum of 60 mg/day [66,78] studies have been performed in pediatric patients, and the results are If good symptom control and radiologic often extrapolated on the adult population. Treatment is tailored to the improvement for 4–8 weeks, Taper by 5 mg every other week until a dose of severity of clinical presentation: 10–15 mg/day is reached [79] Duration of therapy 12–18 months if the patient remains well- controlled on therapy [79] 5.8. Acute alveolar hemorrhage without respiratory failure requiring Other therapies Liposteroid [25,81,82] mechanical ventilation Hydroxychloroquine [66,67] Azathioprine [76,90,91] In addition to the general supportive therapy, including oxygen and Cyclophosphamide [66,67,88,89] 6-mercaptopurine [66,67] maintenance of euvolemia, systemic corticosteroids represent the first Methotrexate [66,67] line of treatment during the acute phase of alveolar hemorrhage [2,10]. Inhaled corticosteroid [66,67] The initial dosing ranges between 0.5 and 0.75 mg/kg/day of predni Mesenchymal stem cell transplant [92] sone with a maximum of 60 mg/day [66,78]. The initial dose is usually Extracorporeal membrane oxygenation in case continued for 4–8 weeks. If the patient remains symptom-free and there of acute respiratory failure [48,49] Lung transplant [93–95] is radiologic improvement, a taper of 5 mg every other week is continued until a daily dose of 10–15 mg is reached. The optimal duration of therapy with corticosteroid is unknown. If the patient re small sample size. No study has prospectively evaluated the utility of mains well-controlled for 12–18 months, the drug is slowly tapered off TBLB in the diagnosis of IPH. TBCB provides larger samples than TBLB until discontinuation [79]. and is being used more often for evaluation of diffuse parenchymal lung disease, since first introduced in 2009 [70]. In addition, TBCB samples 5.9. Respiratory failure requiring mechanical ventilation do not have crush artifacts, and exclusion of a competing diagnosis might be possible with higher certainty [71]. However, to date, only one Patients in whom mechanical ventilation is necessary to sustain life, report of TBCB to diagnose IPH has been reported in the literature [72]. pulse dose methylprednisolone (500–2000 mg/day for 3–5 days) fol TBCB is associated with a higher risk of bleeding and is contraindicated lowed by prednisone 0.5–1 mg/kg/day is usually initiated [80]. This in patients with pulmonary hypertension (echocardiographically dosing regimen mimics the corticosteroid dosing in DAH from autoim measured systolic pressure greater than 50 mmHg), severely impaired mune causes. forced vital capacity (less than 50%) and diffusion capacity (less than Encouraging results have been reported in children with liposteroid 35%) [71]. When a diagnosis of IPH can not be secured by TBLB or therapy, both during acute bleeding and disease that was refractory to TBCB, SLB is necessary. This can be obtained by video-assisted thor low dose steroid therapy [25,81,82]. Liposteroid is a lipid-based prep acoscopic surgery (VATS) or open lung biopsy. VATS is preferred over an aration of dexamethasone palmitate that was developed and tested in open biopsy and associated with less patient morbidity and mortality Japan and had been successfully used in patients with rheumatologic [73]. The primary utility of SLB is the ability to definitively rule out diseases, including macrophage activation syndrome [83]. This lipo capillaritis and Anti-GBM disease that only involves the lung. somal based preparation of dexamethasone has several theoretical ad During an episode of alveolar hemorrhage, histopathologic analysis vantages over dexamethasone sodium, which might contribute to better of the lung tissue reveals intra-alveolar hemorrhage, free and intra efficacy and reduced adverse effects. Liposteroid accumulates at an in cytoplasmic hemosiderin within the macrophages. There is hyperplasia flammatory site at a significantly higher concentration and demon of type 2 pneumocytes and thickening of the interalveolar septa from the strates much enhanced anti-inflammatoryproperties [84]. The activated deposition of hemosiderin. These findings are similar to Goodpasture’s pulmonary macrophages easily uptake the medication, which prevents syndrome [2,33]. The most important finding in IPH is the histopatho the subsequent breakdown of heme and deposition of hemosiderin [81]. logic and immunohistologic absence of capillaritis that is seen with AAV, In experimental animal models, the liposteroid was not associated with connective tissue, and anti-GBM antibody disease [74]. Immunocomplex suppression of the pituitary-adrenal axis and demonstrated fewer side deposition or neutrophilic infiltrationof the alveolar septa is not seen in effects related to corticosteroid therapy in patients with rheumatoid IPH. Collagen deposition in the interstitial tissue is seen in patients with arthritis [85,86]. At the time of writing this therapy is not available in long-standing disease. Electron microscopy, although rarely performed, many countries. reveals swelling and vacuolization of the capillary endothelial cells, Unfortunately, recurrent bleeding during maintenance therapy is not focal thickening, and occasionally rupture of the basement membrane. uncommon and usually treated with an escalation of the steroid dose. Presence of dense deposits along the basement membrane goes against a Recurrence is less common among adults [87]. In order to prevent diagnosis of IPH [22,23]. recurrence and reduce the dose of systemic steroid, several other The clinical features and diagnostic workup of IPH are summarized immunosuppressive medications have been used. These medications in Table 2. include hydroxychloroquine, azathioprine, cyclophosphamide, metho trexate, 6-mercaptopurine, and inhaled corticosteroid [66,67,76, 5.7. Treatment 88–91]. Extracorporeal membrane oxygenation (ECMO) has been used as a rescue therapy with success in the acute hemorrhagic phase with Despite any definitive proof of autoimmune causation, IPH is often respiratory failure [49]. Whether one agent is superior to others is

6 B.K. Saha Respiratory Medicine 176 (2021) 106234 unknown. [3] B. Kjellman, G. Elinder, S. Garwicz, H. Svan, Idiopathic pulmonary haemosiderosis – Xu et al. reported the use of corticosteroid, leflunomide, and in Swedish children, Acta Paediatr. 73 (5) (1984) 584 588. [4] S. Ohga, K. Takahashi, S. Miyazaki, H. Kato, K. Ueda, Idiopathic pulmonary mesenchymal stem cell (MSC) transplant following induction therapy haemosiderosis in Japan: 39 possible cases from a survey questionnaire, Eur. J. with methylprednisolone in a cohort of ten pediatric patients [92]. All Pediatr. 154 (12) (1995) 994–995. patients achieved complete remission. The MSC transplant was associ [5] G. Thornton, M. Alotaibi, 979: Idiopathic pulmonary hemosiderosis IN adult + + patients: an epidemiologic analysis, Crit. Care Med. 44 (12) (2016) 321. ated with a decrease in Th17 cells, and an increase in CD4 , CD25 [6] N. Milman, F.M. Pedersen, Idiopathic pulmonary haemosiderosis. 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