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Idiopathic Pulmonary Hemosiderosis

Winded : Part 2
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Diagnosis and reasoning

This 6 year old boy presented with respiratory failure, and has been treated and stabilized; the onus is now to determine and treat the underlying etiology. His chest x-ray provides a potent clue: the presence of reticular-nodular opacifications in the perihilar and basal region; when considered along with the prolonged history of respiratory symptoms, this is most suggestive of a childhood interstitial lung disease (chILD). The spectrum of chILD is vast, encompassing both primary lung diseases, as well as systemic conditions with pulmonary involvement; these etiologies can be broadly categorized into idiopathic interstitial pneumonias, connective tissue diseases, alveolar hemorrhage and hypersensitivity pneumonitis. Note the history of active bleeding into the endotracheal tube, despite the absence of traumatic injury during intubation; this unusual finding favors pulmonary hemorrhage; furthermore, the history of recurrent epistaxis, and the microcytic anemia in the full blood count suggests at recurrent hemorrhages in the past. It should also be appreciated that pulmonary hemorrhage can be caused by both systemic bleeding disorders and alveolar hemorrhage; the former is however made unlikely by the normal platelet count and unremarkable coagulation profile. The etiologies of alveolar hemorrhage themselves can be further classified into 2 groups: those associated with pulmonary capillaritis, and those which are not associated with capillaritis, i.e. pulmonary hemosiderosis. Pulmonary capillaritis can be primary in origin, or secondary to collagen vascular diseases such as SLE, or vasculitides such as Wegener's granulomatosis, microscopic polyangiitis and Goodpasture's syndrome. However, these secondary causes are made unlikely by the negative ANA assay, and the absence of antineutrophil cytoplasmic antibodies (C-ANCA), anti-myeloperoxidase antibodies (p-ANCA) and anti-GBM antibodies respectively. Pulmonary hemosiderosis is an umbrella term, covering primary as well as secondary forms of the pathology; the latter includes coagulopathies and cardiovascular diseases such as mitral stenosis or pulmonary venous hypertension; note that these have already been excluded by the normal coagulation profile and ECG and echocardiogram respectively. Note also that there are three variants of primary pulmonary hemosiderosis: Goodpasture's syndrome, Heiner's syndrome and idiopathic pulmonary hemosiderosis (IPH). Goodpasture's syndrome has already been excluded, while Heiner's syndrome (hemosiderosis associated with hypersensitivity to proteins in cow's milk) is also made unlikely by the absence of serum precipitins to casein and lactalbumin. Thus, we are left with either primary capillaritis or IPH as the likely etiologies; differentiation requires either bronchoscopy, bronchoalveolar lavage (BAL), or lung biopsy. Unfortunately, both bronchoscopy and BAL are contraindicated because of the respiratory instability; thus, lung biopsy is the only resort; this in turn reveals alveolar spaces filled with hemosiderin macrophages, establishing IPH to be the diagnosis. One might question as to whether it might be advisable to wait until the patient is more stable and then perform bronchoscopy or BAL; in this respect, it should be appreciated that the management of each of the above conditions is quite different - but both benefit from early initiation of treatment. Furthermore, more than a few such patients deteriorate in the acute stage, and do not recover without specific treatment - thus it is advisable to obtain a definitive diagnosis as soon as possible. Following acute management of the pulmonary hemorrhage with respiratory support, the recommended initial treatment of IPH is immunosuppression with early initiation of methylprednisolone. Treatment with second-line immunosuppressives such as azathioprine, chloroquine and cyclophosphamide is generally reserved for patients unresponsive to corticosteroids. Avoidance of dairy products is required only in Heiner's syndrome (milk-associated pulmonary hemosiderosis). Plasmapheresis is mainly used in autoimmune diseases such as Goodpasture's syndrome, and is not indicated here.


Discussion

Idiopathic pulmonary hemosiderosis (IPH) is a rare lung disease of unknown etiology which most often presents in the pediatric age group, and is characterized by alveolar capillary hemorrhage and accumulation of hemosiderin in the lungs. The incidence of IPH is estimated at 0.24 to 1.23 cases per million people in selected populations, with approximately 500 cases reported in the literature; 80% of reported cases have been children. The gender distribution is equal in children, but shifts towards males (2:1) in cases with adult onset. Diffuse alveolar hemorrhage with iron accumulation is the basic pathology underlying IPH. Iron deposition provokes fibrosis and restrictive lung disease. Secondary iron-deficiency anemia resulting from chronic hemorrhage worsens oxygen transport, interfering with cellular respiration; in longstanding disease, this results in dyspnea, failure to thrive, fatigue and severe limitation of exercise tolerance. The pathogenesis of IPH is still not well-defined, although numerous theories exist; most relate to autoimmune pathophysiologies. These hypotheses are supported by the frequent development of autoimmune disorders in association with IPH. Collagen vascular diseases, Wegener's granulomatosis or Henoch-Schonlein purpura develop in more than a quarter of IPH patients, while conditions such as Goodpasture syndrome and celiac disease are also known to occur. Primary pulmonary hemosiderosis involves pulmonary capillaritis due to autoimmune conditions such as Goodpasture's syndrome, Heiner's syndrome and idiopathic PH. Secondary pulmonary hemosiderosis is a separate entity resulting from pulmonary capillary damage consequent to overdistension in some forms of cardiac disease, or due to bleeding diatheses, collagen vascular disease and celiac disease. The classical triad of signs in IPH includes iron-deficiency anemia, hemoptysis, and diffuse parenchymal infiltrates on a chest X-ray. These are usually accompanied by respiratory symptoms such as recurrent cough, wheezing, and tachypnea. Anemia is an invariable early sign of the disease, especially when of rapid onset; it may be refractory to iron therapy. Note that the incidence of hemoptysis may be as low as 50% in pediatric patients; thus its absence does not rule out the disease. Hyperthermia and hepatomegaly have been reported in 20% of cases. The clinical course of the disease is highly variable, and a high proportion of patients fail to respond to therapy, experiencing repeated hemorrhages. Note also that IPH coexisting with celiac disease may result in severe anemia and gastrointestinal bleeding, in a background of recurrent pulmonary hemorrhage. Investigations essential in IPH include a complete blood count, which typically shows microcytic hypochromic anemia due to iron deficiency; coagulation studies to exclude bleeding disorders; and serological studies to detect or rule out coexisting autoimmune disease. Chest radiography often shows a reticulonodular pattern of pulmonary infiltrates, which is further resolved by high resolution CT; advanced imaging via nuclear scanning will show a high uptake of chromium/technetium-99 labeled erythrocytes in the presence of pulmonary hemorrhage. Demonstration of intrapulmonary hemorrhage is essential to confirm the diagnosis of IPH. This can be done by means of bronchoalveolar lavage (BAL) or lung biopsy; the latter is the current gold standard diagnostic test, having both a high sensitivity (92%) and a comparatively low degree of invasiveness. Open biopsy, bronchoscopy, BAL or sputum/gastric aspiration typically reveals hemosiderin-laden macrophages (siderophages). When coupled with chronic pulmonary symptoms, these allow an unequivocal diagnosis of IPH. The management of acute pulmonary events in the course of the disease includes oxygen supplementation, blood transfusion for correction of severe anemia, supportive respiratory therapy, mechanical ventilation in respiratory failure, and acute immunosuppression. Corticosteroids at immunosuppressive dosage are the first-line therapy in acute alveolar hemorrhage during IPH, and are effective in the majority of patients. High doses of prednisolone or equivalent doses of an intravenous preparation (eg, methylprednisolone) are recommended for the initial management of acute pulmonary hemorrhage in IPH. This is typically continued for 7 days after the cessation of bleeding, and thereafter tapered off over several weeks. Unresponsiveness to corticosteroids alone or the need to minimize Cushingoid effects of the drug are indications for introducing other immunosuppressive agents; azathioprine, hydroxychloroquine and cyclophosphamide are the drugs of most benefit in these instances. Several researchers have commented on the beneficial effects on survival and disease activity when long-term maintenance was carried out with low-dose steroids and/or adjunctive immunosuppressive agents. IPH is traditionally considered to have a poor prognosis, with mean survival no more than 2.5 to 3 years post-diagnosis. The high mortality rate is most often the consequence of acute pulmonary hemorrhage or progressive pulmonary insufficiency leading to chronic respiratory failure. Note that some studies have found that the outcome of the disease is not significantly affected by the short-term response to therapy, particularly in individuals with very low hemoglobin levels at diagnosis.


Take home messages

  1. Idiopathic pulmonary hemosiderosis (IPH) is a rare lung disease characterized by diffuse alveolar hemorrhage and accumulation of hemosiderin-laden macrophages (siderophages) in the alveoli.
  2. The classical triad of IPH includes hemoptysis, iron deficiency anemia and parenchymal infiltrates on the chest X-ray.
  3. Lung biopsy is the current gold standard for diagnosis; the presence of siderophages confirms the disease.
  4. Corticosteroids at immunosuppressive dosages are the first-line treatment in patients with acute pulmonary hemorrhage.

Insightful, fun cases to improve your diagnostic skills

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