The alveolar haemorrhage syndrome is an acute condition, which requires rapid diagnosis and efficient treatment for the multiple clinical manifestations (dyspnoea, haemoptysis, and respiratory failure). The conditions may occur both through endogenous and exogenous iron loading. Multiple causes which underlie the triggering of the alveolar haemorrhage syndrome make the symptoms unspecific. The imaging aspect, the bronchial endoscopy with bronchoalveolar lavage and the histopathologic examination of the lung fragment obtained through lung biopsy or necropsy underlie the definitive diagnosis of this condition, at the same time excluding the neoplastic or infectious pathology.
The alveolar haemorrhage syndrome is an acute condition, which requires diagnosis and rapid and efficient treatment for the multiple clinical manifestations (dysp-noea, coughing up blood, auscultation of bilateral basal crepitant and subcrepitant rales) and the paraclinical changes such as anaemia, hypoxemia with suggestive nor-mocapnia for hypoxemic respiratory failure and diffuse lung infiltrates(1). The diagnosis is underlain by the histo-pathologic examinations obtained through lung biopsy or even necropsy, bronchoalveolar lavage obtained through bronchoscopy performed with a flexible bronchoscope and local anaesthesia, and serological tests: direct and indirect ELISA (enzyme-linked immunosorbent assay), immuno-fluorescence, as well as imaging examinations (thoracic and lung X-ray and CT scan)(1,2).
The alveolar haemorrhage syndrome is not an autonomous entity; it may have an idiopathic, autoimmune, infectious, drug-related etiology, as well as within the context of the hema-tologic diseases(1,2,3). It occurs not only through endogenous loading with iron but also through exogenous loading, in work-ers with occupational exposure to iron particles(36).
The triggering causes of the alveolar haemorrhage syn-drome are presented in Table 1(1,2,3).
The aforementioned diseases are rare diseases, some of them have unknown or incompletely determined etiology. In medical practice, the most common diseases which may mani-fest with alveolar haemorrhage are the anti-glomerular base-ment membrane disease or the Goodpasture syndrome(2), the Wegener granulomatosis, the systemic lupus erythematosus and the Henoch Schonlein purpura. Among the most uncom-mon diseases we can mention the idiopathic pulmonary hemo-siderosis (exclusion diagnosis)(6), the diffuse alveolar haemorrhage of infectious cause and a cause associated with the post-administration of a medicinal product.
The Goodpasture syndrome is a rare condition, with a prevalence of 1 to one million(2). The pathogenic mechanism is not fully known, being considered an autoimmune disease. Recent studies show the role of the environmental factors (aromatic hydrocarbons, iron ores, silicon oxide) and behav-ioural factors (smoking) in determining the evolution of the disease(2,3,4). The microscopic examination describes diffuse alveolar haemorrhage, macrophages loaded with hemosiderin, without vasculitis or septum necrosis(1). The definitive nature of the diagnosis is given by the presence of the anti-glomerular basement membrane antibodies in the plasma. The anti-glo-merular basement membrane antibodies may be identified using ELISA method and immunofluorescence(1,3,4).
The Henock-Schonlein purpura is clinically charac-terised by palpable purpura, arthritis with arthralgias, gas-trointestinal bleeding and renal and pulmonary diseases(1,13,16). Although the number of reported cases is very small, being more frequently encountered in children than in adults, we recall the occurrence of the siderophages within the first 24-48 hours from the onset of the lung alveolar haemorrhage(1).
The diffuse alveolar haemorrhage in systemic lupus erythematosus represents a severe complication of this disease, being associated with increased morbidity and mor-tality(9-12). Diffuse alveolar haemorrhage occurs more com-monly in women, the ratio women/men being 6:1, compared to the lupus disease – 9:1(10). The mechanism for the occur-rence of the alveolar haemorrhage seems to be the immune-mediated destruction of small blood vessels and of the alveolar septums(10,11). From a histopathological point of view, the lung capillarity is described with the impairment of the alveolar microcirculation. Macrophages appear being loaded with hemosiderin in the alveoli and the occlusion of the septal alveolar capillaries(12).
Granulomatosis with polyangiitis, formerly Wegener granulomatosis, is characterised by necrotizing granulomatous inflammation of the upper and lower airways and vasculitis of small vessels(1,13-15). At microscopic examina-tion, the presence of necrotizing granulomatous inflamma-tion and of necrotizing vasculitis at the level of the lung parenchyma is an important argument for the diagnosis of granulomatosis with polyangiitis(1,13). The presence of the erythrocytes in the alveolar interstitial, of hemosiderin and fibrinoid necrosis is owed to the extravasation of blood in the alveoli(13). The bronchoalveolar lavage liquid includes macrophages loaded with hemosiderin(15).
Idiopathic pulmonary hemosiderosis is a rare cause of pulmonary alveolar haemorrhage, occurring in over 80% of cases in children(6). The diagnosis of idiopathic pulmo-nary hemosiderosis can be established when the other eti-ologies have been excluded(6). It is characterised biologically by iron-deficiency anaemia; radiologically by diffuse pul-monary infiltrates, and clinically by cough, moderate degree dyspnoea and haemoptysis(5-8). Allergies, autoimmunity, genetic factors and environmental factors underlie the pathophysiology of idiopathic pulmonary hemosiderosis without being able to provide data in this regard(1,8). Under microscopic examination, intraalveolar haemorrhage, mac-rophages loaded with hemosiderin and different degrees of interstitial fibrosis are described(1).
The association between the pulmonary infections and the diffuse alveolar haemorrhage is rarely reported. Pathogenic germs act both upon immunocompromised patients and upon immunocompetent patients(17). In the immunocompetent patients, the most common agents incrim-inated for the production of diffuse alveolar haemorrhage are the flu virus (H1N1), the Malaria and Leptospirosis parasites, as well as Staphylococcus aureus, and in the immunocompro-mised hosts, the diffuse alveolar haemorrhages are caused by bacteria of types Mycoplasma and Legionella, and viruses such as the adenovirus and Cytomegalovirus(18,19). The microscopic examination shows the congestion of the alveolar capillaries, the focal alveolar destruction with formation of hyaline mem-branes and macrophages loaded with hemosiderin(17-19).
During recent years, diffuse alveolar haemorrhage has been reported following the administration of medicinal prod-ucts such as vincristine(20), rituximab(21), itraconazole(21) and heparin with small molecular mass(22). The difficult diagnosis of the alveolar haemorrhage syndrome, the late identification of the cause and the lack of therapy lead to increased risk of evolution towards exitus of these patients.
From a clinical perspective, the alveolar haemorrhage syndrome does not have specific symptoms, and may mani-fest through cough, small and repeated haemoptysis, which can be associated or not with respiratory failure(23). Haemoptysis is absent in 30% of the patients, blood cannot reach the upper airways in order to be exteriorised as haem-optysis, due to the high alveolar volume which absorbs important blood quantities(33).
The alveolar haemorrhage syndrome is biologically characterised through variable anaemia with a much decreased value of serum iron. The sudden decrease in haemoglobin within 24-48 hours and the X-ray of the interstitial and alveo-lar infiltrates increase the probability of diffuse alveolar haem-orrhage(9). The unspecific inflammatory syndrome (much increased ESR) is present, and the serologic tests specific to each disease may be useful for supporting the diagnosis. Thus, in Goodpasture syndrome can be used the plasma identifica-tion of the anti-glomerular basement membrane antibod-ies(1,3,4) and of the linear deposits of IgG and the C3 fraction of the complement(1-4), in systemic lupus erythematosus the pres-ence of increased titres of autoantibodies of the double-strand-ed DNA type, lupus anticoagulant, anti beta2-GP1, anti SM, anti Ro, anti RNP, hypocomplementemia are useful (11), and in the Henock Schonlein purpura granular deposits of IgA and the C3 fraction of the complement(14,18).
From a functionally respiratory point of view, the restrictive syndrome with the reduction in the vital capac-ity, the total lung capacity and the residual volume, and the lack of bronchial obstruction prevails. The gaseous transfer
factor through the alveolar capillar membrane (TLCO) is also decreased. In the blood gases analysis, the decrease of PaO2 and PaoCO2 is initially noticed during exercise and subsequently at rest, the alveolo-capillar gradient increas-ing during exercise.
The imaging aspects, both the simple lung X-ray (Figure 1 and the high resolution computed tomography (Figure 2) are not specific to this condition. The high resolution com-puted tomography (HRCT) with a thickness of the tomo-graphic cups of under 1 mm is highly superior to the standard chest X-ray and the standard chest computed tomography with 3-5 mm sections(25,28). On the standard chest X-ray, interstitial syndromes (fine reticular, reticulonodular and infiltrative “wooly” opacifications), condensation processes and micronodules can be noticed. In the computed tomogra-phy with a thickness of the tomographic cups of under 1 mm, lesions of “mat glass”, reticular opacifications, nodules and micronodules are present. The X-ray differential diagnosis is performed first of all with carcinomatous lymphangitis, secondary lung tuberculosis, Pneumocystis pneumonia, viral pneumonias, brochopneumonia and the respiratory distress syndrome of the adult.
Bronchoscopy with bronchoalveolar lavage under-lies the diagnosis of the alveolar haemorrhage syndrome, not by showing remarkable and characteristic endobron-chial changes, but rather through the possibility of per-forming the bronchoalveolar lavage, with a flexible bronchoscope and local anaesthesia(30).
Bronchoalveolar lavage is performed through instil-lation in the bronchial tree, in any territory or preferably at the level of the lingula or the middle lobe, due to a good recovery, of a quantity of saline solution between 100 and 300 ml. The sterile saline solution is used at a temperature of 37°C or at an environmental temperature in order to avoid the occurrence of bronchospasm. The proper cooperation of the patient and the gentleness of the examining physician lead to a satisfactory recovery of the instilled liquid, approxi-mately 70% of the total liquid used in lavage. The recovery of the instilled liquid also depends on the sealing and stabil-ity of the fibrobronchoscope at the level of the bronchia where lavage is performed. The liquid used in the lavage changes its aspect gradually, during the aspiration, depend-ing on the moment of the bleeding(34,35). It may be transpar-ent, rose-coloured, dark red, orange red or brown(24) (Figure 3). As bleeding is older, the aspect of the aspirated liquid is darker. The colour is given by the erythrocytes mixed with macrophages which contain hemosiderin(34). If bleeding is recent, the only indicator is represented by the erythrocytes in a high number in the liquid used for lavage. If at least 72 hours have passed from the alveolar bleeding, macrophages with hemosiderin are identified in the liquid(32) (Figure 4).
In optic microscopy the Prussian blue colour is used for identifying the hemosiderin (Figure 4).
Based on the number of positive macrophages and the colour intensity, the GOLDE score is determined, indicating the severity of the syndrome (Table 2).
The largest values of the GOLDE score have been identi-fied in the idiopathic pulmonary hemosiderosis, due to the disease becoming chronic. In the alveolar haemorrhage syn-drome, in addition to the macrophages loaded with hemosi-derin, the total cell count is increased even in patients who have leukopenia in the peripheral blood. After the occupa-tional exposure to iron, the erythrocyte fragments are miss-ing and the phagocytes are coloured anthracotically. Normal cells in the BAL liquid are shown in Table 3.
The surgical lung biopsy remains the gold standard in the diffuse alveolar haemorrhage syndromes, whose cause could not be established through less invasive diagnosis meth-ods. The transbronchial biopsy does not provide sufficient data for supporting the diagnosis(9). The surgical intervention is performed after the preanesthetic and presurgical examina-tion in all the patients who have an indication of pulmonary biopsy, but who have a contraindication regarding the perfor-mance of this intervention. Through minimum thoracotomy under general anaesthesia, several lung fragments are col-lected from the most relevant areas in the HRCT examination, even though from the point of view of the approach, the mid-dle and lingula lobes are the most accessible ones to the sur-geon(26) (Figure 5). The need for pulmonary biopsy also results from the fact that the medicinal treatment is changed in 50-60% of the cases after obtaining the histopathologic examination(27).
In the microscopic examination of the biopsy or necropsy fragments of lung parenchyma, numerous red blood cells and siderophages with obstructive character are noticed. The alveolar septums are thickened, in certain parts, through
processes of fibrosis and chronic inflammatory infiltrate. In certain areas there can also be noticed the hyperplasia of the pneumocyte of type I and unspecific chronic brochiolitic lesions(20) (Figure 6).
The multiple causes of the alveolar haemorrhage syn-drome, the severe clinical manifestations (haemoptysis, dysp-noea, important physical asthenia, and fatigue and weight loss) require diagnosis and emergency treatment. The correct and complete clinical examination performed, the overall biologi-cal exams (complete blood count, ESR, fibrinogen, C reactive protein etc.) or specific exams (c-ANCA, p-ANCA, anti-MBG, lupic cells etc.), functional respiratory tests, pulmonary X-ray and high resolution computed tomography, bronchoscopy with bronchoalveolar lavage and the surgical pulmonary biopsy underlie the confirmation of this pathology, excluding at the same time the neoplastic or infectious pathology.
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