ALVEOLAR HEMORRHAGE IN PATIENTS WITH RHEUMATIC DISEASE

doi:10.1016/S0889-857X(05)70336-7

Rheumatic Disease Clinics of North America

Volume 23, Issue 2, 1 May 1997, Pages 395-410

https://doi.org/10.1016/S0889-857X(05)70336-7 Get rights and content

The terms pulmonary hemorrhage, intrapulmonary hemorrhage, pulmonary capillary hemorrhage, lung hemorrhage, diffuse microvascular lung hemorrhage, alveolar hemorrhage (AH), immune alveolar hemorrhage, and pulmonary alveolar hemorrhage are often used interchangeably in the literature. Usually these terms refer to bleeding that originates in small vessels of the pulmonary circulation (capillaries, venules, and arterioles), and, usually, the majority of the alveolar capillary basement membrane surface is involved. This makes such bleeding distinctly different from other far more common causes of hemoptysis caused by focal problems in the airways and lung parenchyma (Table 1).

Outlined in Figure 1 are the sources of pulmonary bleeding. These include the pulmonary circulation, a low-pressure circuit with normal pulmonary artery pressures of 15 to 20 mmHg systolic and 5 to 10 mmHg diastolic, and the bronchial circulation, consisting of bronchial arteries, which branch from the aorta and have systemic arterial pressures, and bronchial veins, which drain into the systemic veins to the right side of the heart. Normal bronchial and pulmonary circulation are interconnected thus: the bronchial arterial blood feeding the proximal airways (e.g., trachea and mainstem bronchi) drains into bronchial veins and empties into the right side of the heart, whereas bronchial arterial blood feeding the intrapulmonary airways and lung tissue drains through bronchopulmonary anastomoses into the pulmonary veins and left side of the heart.⁶⁰

In most causes of hemoptysis listed in Table 1 (except alveolar hemorrhage), the bronchial rather than the pulmonary circulation is the source of the bleeding. The alveoli are only affected secondarily when blood from larger airways is aspirated. In rheumatic diseases, however, the small vessels of the pulmonary circulation are usually the source of the bleeding, and the majority of the alveolar capillary basement membrane surface is involved, producing diffuse alveolar hemorrhage. For consistency and clarity, the term alveolar hemorrhage will be used in the rest of this chapter, avoiding modifiers like immune (because an immune etiology cannot always be substantiated) or diffuse (because the process can be focal). The less specific term hemoptysis or pulmonary hemorrhage will be reserved for situations when the source of bleeding is not clear or is not important to specify.

Section snippets

ETIOLOGY

Pulmonary hemorrhage in patients with rheumatic disease can occur as the result of uremia, congestive heart failure, infection, pulmonary embolism, or coagulopathy. These causes of pulmonary hemorrhage, however, need to be distinguished from alveolar hemorrhage that is a primary manifestation of anti-basement membrane antibody (ABMA) disease, systemic vasculitis, or systemic lupus erythematosus (SLE). Alveolar hemorrhage can also be caused by drugs and a multitude of nonrheumatic diseases

PATHOLOGIC CONDITIONS

Several studies have described the pathologic features of AH.39, 44, 45, 59, 62, 63 Regardless of the underlying disease, the pathologic conditions of the AH syndromes are similar. Acutely, red blood cells and fibrin fill the air spaces and are often associated with hemosiderin-laden macrophages. Capillaritis (necrotizing or nonnecrotizing) limited to the alveolar wall is observed in as many as 88% of these patients regardless of the specific type of immunologic disorder.39, 45, 63 Although

CLINICAL PRESENTATION

The clinical presentation of AH is fairly constant regardless of the underlying disorder. Although nonspecific, diffuse bleeding from pulmonary vasculature results in blood-filled alveoli leading to the classic triad of hemoptysis, diffuse radiographic infiltrates, and anemia.³³ Although detected at some point in the majority of cases, these features may not occur simultaneously; furthermore, hemoptysis and infiltrates are common manifestations of many pulmonary conditions, and anemia has many

LABORATORY EVALUATION

In patients with hemoptysis and pulmonary infiltrates, some diagnostic tests may be helpful in clarifying the cause of the pulmonary infiltrates and the underlying systemic illness. These include microscopic examination of the urine, serologic tests, pulmonary function testing, bronchoscopy, and open-lung biopsy.

Measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) can be helpful in diagnosing AH. A 30% increase in the DLCO over a baseline value, or a single value that is

Goodpasture's Syndrome

The term Goodpasture's syndrome refers to patients with either simultaneous or sequential glomerulonephritis and AH and evidence of IgG anti-GBM antibodies (either circulating or on examination of biopsy material). Goodpasture's syndrome is frequently associated with circulating anti-GBM antibodies (at least 90%) and antibody transfer experiments have directly implicated these antibodies in the immunopathogenesis of the disease.56, 64, 65 Immunopathologic techniques demonstrate characteristic

MICROSCOPIC POLYANGIITIS

Microscopic polyangiitis (MPA) is a form of vasculitis with characteristic features of segmental necrotizing glomerulonephritis and systemic necrotizing vasculitis (without granuloma) affecting capillaries, venules, arterioles, but rarely affects medium-sized arteries. MPA has common manifestations rarely seen in polyarteritis nodosa (PAN), including AH, rapidly progressing glomerulonephritis, and P-ANCA (less commonly C-ANCA) positivity. In addition, abdominal and renal vasculitis, common

DIAGNOSTIC APPROACH

Table 3 summarizes the differentiating clinical and serologic features of the more common causes of AH. See Figure 3 for an outline of an algorithmic approach to how these features can be utilized in the evaluation of AH. Patients with AH should be examined by experienced clinicians early in their course. The physical examination should include a careful cardiac examination, examination of the skin, eyes, nose, and mucous membranes for typical features of SLE or vasculitis, and a search for

THERAPEUTIC CONSIDERATIONS

Successful treatment of patients with AH requires a two-pronged strategy: (1) suppression of the underlying disorder, and (2) use of supportive measures to keep the patient alive long enough for immunosuppression to work. There are no prospective, randomized trials evaluating different regimens used in the treatment of AH. Most information available is based on anecdotal reports and experience.

High-dose (pulse) methylprednisolone therapy (1 g/day for 3 days) appears to control acute active AH

SUMMARY

Alveolar hemorrhage is an uncommon event that is associated with several underlying disorders, many of which are immunologically mediated. Careful evaluation of basic laboratory tests, extrapulmonary physical findings, and serology usually leads to the correct diagnosis. Significant overlap, however, exists, and pathologic (especially immunopathologic) evaluation of pulmonary or renal biopsies may be necessary. An accurate diagnosis is essential because treatment is most helpful when directed

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Chronic respiratory disfunction due to diffuse alveolar hemorrhage in patients with systemic lupus erythematosus and primary vasculitis
2013, Reumatologia Clinica
La hemorragia pulmonar (HP) se presenta en el 2 al 5% de los pacientes con lupus eritematoso sistémico (LES) y puede alcanzar una mortalidad del 70 al 90%. Los criterios para el diagnóstico de HP son: a) infiltrados alveolares en 3 cuartas partes de los campos pulmonares en la radiografía de tórax; b) insuficiencia respiratoria de inicio agudo, y c) descenso de la hemoglobina > 3 g/dl. La HP puede conducir a neumonía organizada, depósito de colágeno en vías aéreas pequeñas y, consecuentemente, fibrosis pulmonar, lo cual puede alterar la función pulmonar con cambios obstructivos o restrictivos.
Establecer, mediante pruebas de funcionamiento respiratorio (PFR), si existen alteraciones en la función respiratoria después de haber presentado una HP.
Se incluyó a pacientes con LES o con vasculitis primaria que presentaron HP. En el momento de la HP, se determinó actividad con SLEDAI para los pacientes con LES, «five factor store» (FFS) para poliangitis microscópica (PAM) y «Birmingham Vasculitis Activity Store» (BVAS) para granulomatosis con poliangitis (GP) (Wegener). Se determinaron el número de eventos de HP, el tratamiento utilizado y el requerimiento de asistencia mecánica ventilatoria (AMV) para determinar su probable asociación con las alteraciones de la función respiratoria medidas por pletismografía y/o espirometría.
Se incluyó a 10 pacientes, 7 con LES y 3 con vasculitis primaria (2 con PAM y uno con GP (Wegener). La media ± desviación estándar de SLEDAI fue de 20,4 ± 7,5, la de FFS 2 y la de BVAS 36. Un paciente presentó 2 episodios de HP y otro 5. El tratamiento fue metilprednisolona (MPD) en 3 pacientes, MPD más ciclofosfamida (CFM) en 6 pacientes y MPD, CFM, inmunoglobulina por vía intravenosa y plasmaféresis en un paciente. Cinco pacientes requirieron AMV. Se encontró disfunción pulmonar en 8 pacientes; 3 tuvieron patrón obstructivo y 5 patrón restrictivo; 2 tuvieron PFR normales. No se encontró asociación significativa entre las variables y las alteraciones de la función respiratoria.
La HP causa alteraciones de la función respiratoria en un alto porcentaje de pacientes y es probable que se requiera tratamiento inmunosupresor a largo plazo una vez resuelto el episodio agudo.
Pulmonary hemorrhage (PH) occurs in 2-5% of SLE patients, and is associated with a high mortality rate (79-90%). Diagnostic criteria for this complication include: 1) Pulmonary infiltrates, with at least ¾ of lung tissue involved in a chest x ray, 2) Acute respiratory failure, 3) A decrease of 3 g/dL or more in hemoglobin levels. PH might lead to organized pneumonia, collagen deposition, and pulmonary fibrosis which in time might cause changes in pulmonary function tests with either restrictive or obstructive patterns.
To evaluate the existence of abnormalities in pulmonary function tests after a PH episode.
We included patients with SLE and primary vasculitis that developed PH. During the acute episode, we measured SLEDAI in SLE patients, five factor score in microscopic polyangiitis (MPA) and Birmingham Vasculitis Activity Store (BVAS) in granulomatosis with polyangiitis (GPA) (Wegener). We determined the number of PH events, treatment, and ventilator assistance requirements and correlated its association with abnormal pulmonary function tests.
We included 10 patients, 7 with SLE, 2 with MPA and 1 with GPA (Wegener). The mean activity measures were: SLEDAI 20.4 ± 7.5, FFS 2, and BVAS 36. Treatment consisted in methylprednisolone (MPD) in 3 patients, MPD plus cyclophosphamide (CY) in 6 patients, and MPD, CY, IV immunoglobulin, and plasmapheresis in one patient. Five patients required ventilatory support. We found abnormalities in pulmonary function tests in 8 patients, three had an obstructive pattern and five a restrictive pattern; 2 patients did not show any change. We did not find a significant association with any of the studied variables.
PH might cause abnormalities in pulmonary function tests and prolonged immunosuppressive treatment could be required.
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Citation Excerpt :
A study by Rabiller et al. showed that bronchoalveloar lavage (BAL) samples from PVOD patients consistently demonstrated increased numbers of haemosiderin-laden macrophages and higher average Golde score compared to idiopathic PAH [61], indicating a high rate of subclinical alveolar hemorrhage in PVOD. However, subclinical alveolar hemorrhage may develop in CTD patients in the absence of this complication [62]. No study has been undertaken to specifically examine the diagnostic potential of BAL in CTD-associated PVOD.
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension that may develop in patients with connective tissue diseases (CTD). Most cases have been reported in patients with systemic sclerosis, though associations with systemic lupus erythematosis and mixed connective tissue disease have also been described. PVOD is characterised by progressive obstruction of small pulmonary veins and venules that leads to increased pulmonary vascular resistance, right heart failure and premature death. Distinguishing PVOD from pulmonary arterial hypertension (PAH) is often difficult, though use of a diagnostic algorithm may improve diagnostic accuracy and preclude recourse to lung biopsy. The finding of normal left-heart filling pressures in the context of radiological studies suggestive of pulmonary oedema is an important diagnostic clue, particularly if this clinical scenario coincides with the introduction of vasodilator therapy. There are no approved treatments for the disorder, though cautious use of PAH specific therapy may improve short-term outcomes in selected idiopathic PVOD cases. This review summarises the epidemiologic, clinico-pathologic and imaging characteristics of PVOD in the setting of CTD and discusses potential management approaches.
Chapter 3 Pathogenesis of Renal Disease: Cytokines and Other Soluble Factors
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Administration of IL-6 augments and accelerates disease (Finck et al., 1994), while immunoneutralization of IL-6 attenuates disease (Kiberd, 1993; Finck et al., 1994). IL-18 inhibition (by cDNA vaccination) attenuates (Bossu et al., 2003), while IL-18 injection increases disease (Esfandiari et al., 2001). IFN-γ is a potential therapeutic target, as evidenced by augmentation of disease by its administration and attenuation of disease observed by its neutralization (Jacob et al., 1987) or genetic deletion (Balomenos et al., 1998; Schwarting et al., 1998).
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ALVEOLAR HEMORRHAGE
2006, Encyclopedia of Respiratory Medicine: Volume 1-4
Bleeding into the alveoli characterizes the syndrome of diffuse alveolar hemorrhage (DAH) and represents a potential life-threatening condition. There are many causes of DAH, including vasculitides, such as Wegener's granulomatosis, microscopic polyangiitis, Good pasture's syndrome, connective tissue disorders, and other conditions. Pathologically, the syndrome is due to pulmonary vasculitis, to a ‘bland’ alveolar hemorrhage, or it represents the nondominant pathology, as seen in diffuse alveolar damage from acute respiratory distress syndrome (ARDS). Most patients present with dyspnea, cough, hemoptysis (the latter in only 66% of the cases), anemia, and new pulmonary infiltrates. Urgent bronchoscopy and bronchoalveolar lavage is generally required to confirm the diagnosis, with a superior yield when it is performed in the first 48 h. In patients with evidence of DAH and renal involvement (pulmonary–renal syndrome), kidney biopsy may be considered to identify the etiology and direct the therapy. This chapter will describe the mean features of the DAH syndrome and review in short the main causes of alveolar bleeding.
Alveolar Hemorrhage
2006, Encyclopedia of Respiratory Medicine, Four-Volume Set
Bleeding into the alveoli characterizes the syndrome of diffuse alveolar hemorrhage (DAH) and represents a potential life-threatening condition. There are many causes of DAH, including vasculitides, such as Wegener's granulomatosis, microscopic polyangiitis, Good pasture's syndrome, connective tissue disorders, and other conditions. Pathologically, the syndrome is due to pulmonary vasculitis, to a ‘bland’ alveolar hemorrhage, or it represents the nondominant pathology, as seen in diffuse alveolar damage from acute respiratory distress syndrome (ARDS). Most patients present with dyspnea, cough, hemoptysis (the latter in only 66% of the cases), anemia, and new pulmonary infiltrates. Urgent bronchoscopy and bronchoalveolar lavage is generally required to confirm the diagnosis, with a superior yield when it is performed in the first 48 h. In patients with evidence of DAH and renal involvement (pulmonary–renal syndrome), kidney biopsy may be considered to identify the etiology and direct the therapy. This chapter will describe the mean features of the DAH syndrome and review in short the main causes of alveolar bleeding.
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View all citing articles on Scopus

: Address reprint requests to Joseph M. Cash, MD, Department of General Internal Medicine, A–91, Cleveland Clinic Foundation, 9500 Euclid Avenue, A41, Cleveland, OH 44195

^*: From the Department of Pulmonary and Critical Care Medicine (RAD, ACA), and the Departments of General Internal Medicine and Rheumatic and Immunologic Diseases (JMC), Cleveland Clinic Foundation, Cleveland, Ohio

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ALVEOLAR HEMORRHAGE IN PATIENTS WITH RHEUMATIC DISEASE

Section snippets

ETIOLOGY

PATHOLOGIC CONDITIONS

CLINICAL PRESENTATION

LABORATORY EVALUATION

Goodpasture's Syndrome

MICROSCOPIC POLYANGIITIS

DIAGNOSTIC APPROACH

THERAPEUTIC CONSIDERATIONS

SUMMARY

Chest

Kidney Int

Clin Radiol

Lancet

Rheum Dis Clin North Am

Am J Med

Chest

Am J Med Sci

Rheum Dis Clin North Am

Lancet

Hum Pathol

Rheum Dis Clin North Am

Kidney Int

Am J Med

Semin Arthritis Rheum

Am J Med

British Journal of Tuberculosis and Diseases of the Chest

Am J Med

Kidney Int

Fatal pulmonary hemorrhage in systemic lupus erythematosus: Occurrence without hemoptysis

J Rheumatol

Immunofluorescence of transbronchial lung biopsies in Goodpasture's syndrome

Am Rev Respir Dis

Glomerulonephritis associated with hydrocarbon solvents mediated by antiglomerular basement membrane antibody

Arch Environ Health

Antineutrophil cytoplasmic antibody-associated alveolar capillaritis in patients presenting with pulmonary hemorrhage

Arch Pathol Lab Med

Pulmonary hemorrhage and immune complex deposition in the lung: Complications in a patient with systemic lupus erythematosus

Arch Pathol Lab Med

Systemic necrotizing glomerulonephritis with antineutrophil antibody: Possible arbovirus etiology? [Short report]

Br Med J

Pulmonary hemorrhage in lupus erythematosus without evidence of an immunologic cause

Arch Intern Med

Pulmonary-renal syndrome with “triad” involvement due to small vessel vasculitis

J Rheumatol

Cigarette smoking and lung hemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane

Lancet

Diagnostic lavage and occult pulmonary hemorrhage in thrombocytopenic immunocompromised patients

Am Rev Respir Dis

Pulmonary hemorrhage in systemic lupus erythematosus

Medicine

Pulmonary manifestations of Behçet's syndrome

Q J Med

Idiopathic pulmonary hemosiderosis: Ultrastructural abnormalities in the capillary walls

Am Rev Respir Dis

Use of combined plasmapheresis and immunosuppression in the treatment of Goodpasture's syndrome

Mayo Clin Proc