—  SHORT COURSE #08  —

Cardiovascular and Pulmonary Pathology in Systemic Disease

Case 2 - Diagnosis: Systemic lupus erythematosus with:
2a - Intra-alveolar hemorrhage with focal necrotizing
capillaritis and diffuse alveolar damage
2b - Nonbacterial thrombotic endocarditis

Henry D. Tazelaar and Marie-Christine Aubry


PDF File (12.9 MB)

Clinical History
A 34-year-old woman, with a 10-year history of systemic lupus erythematosus, presented with hemoptysis and bilateral pulmonary infiltrates. She underwent a pulmonary wedge biopsy. During the course of her work-up and treatment, she died suddenly in the hospital. An autopsy was performed.

Illustrative slides for Case 2a are in the accompanying PDF of the Powerpoint presentation. At low power, the interstitium is thickened by a combination of proliferating fibroblasts and hyperplastic type II pneumocytes. Hyaline membranes are identified. These features are those of organizing diffuse alveolar damage (DAD). Focally, intralveoalr fibrin with rare hemosiderin laden macrophages suggestive of alveolar hemorrhage is identified. Clusters of neutrophils centered on the alveolar septa are also seen, resulting in expansion and even disruption of the septa. Nuclear dust is present. Rare small veins contained medial necrosis associated with neutrophils and nuclear dust affecting only a small portion of the wall. These findings support a diagnosis of capillaritis.

Fibrosis and focal calcifications distort the architecture of the valve. On the surface of the valve, small fibrinous deposits are present containing rare neutrophils and no microorganisms, representing sterile vegetations. These features are those of a nonbacterial thrombotic endocarditis (NBTE).

Discussion
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with an incidence of approximately 7.3 per 100 000 in the USA and a prevalence as high as 1 in 2500. The clinical manifestations of SLE are quite variable and the American Rheumatism Association has devised a list of criteria for the diagnosis and classification of SLE, which was revised in 1997 (Table 1). The neurologic and psychiatric manifestations were redefined in a 1999 consensus document and are now comprised of 19 different syndromes under the heading neuropsychiatric manifestation of SLE.

A patient is diagnosed with SLE if any four or more of the eleven criteria established by the American Rheumatism Association are present serially or simultaneously.

Table 1: Revised Criteria for the Classification of SLE (Tan et al 1982 and Hochberg 1997)
Criteria Definition
1. Malar rash Fixed erythema over the malar eminences tending to spare the nasolabial folds
2. Discoid rash Erythematous raised patches with keratotic scaling and follicular plugging
3. Photosensitivity Skin rash due to unusual reaction to sunlight
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless
5. Arthritis Nonerosive arthritis involving 2 or more peripheral joints, with tenderness, swelling or effusion
6. Serositis Pleuritis- pleuritic chest pain, rub, pleural effusion or Pericarditis- by ECG, rub or pericardial effusion
7. Renal disorder Persistent proteinuria, or Cellular casts
8. Neurologic disorder Seizures, or Psychosis
9. Hematologic disorder Hemolytic anemia, or Leukopenia, or Lymphopenia, or Thrombocytopenia
10. Immunologic disorder Anti-DNA antibody to native DNA (double-stranded) abnormal titer, or Anti-Sm, or Positive findings for antiphospholipid antibodies
11. Antinuclear antibody Abnormal titer of antinuclear antibody by IF

SLE occurs more commonly in women of childbearing age with a reported ratio of 9:1. The disease can develop at any age, including in children and patients older than 65 years. The cause of SLE remains unknown and is likely multifactorial characterized by the presence of numerous autoantibodies, particularly antinuclear antibodies (ANA). Mortality related to SLE has decreased significantly over the last years with 10-year survival rate around 75 to 85%. Although infection is a major cause of mortality, atherosclerosis has now become the leading cause of late deaths. Thrombosis, usually secondary to antiphospholipid syndrome (APS), is a common cause of morbidity and mortality. APS is defined by the occurrence of vascular thrombosis and/or recurrent miscarriages, in association with antiphospholipid antibodies, either anticardiolipin antibody or lupus anticoagulant. APS can be primary (ie with no evidence of underlying disease), secondary to rheumatic and connective tissue diseases including SLE, or be associated with other diseases, such as infections or lymphoproliferative disorders (Table 2).

Table 2: Clinical Association with Antiphospholipid Antibodies (Modified from Greaves, Lancet 1999)

1 - Primary antiphospholipid syndrome
2 - Secondary antiphospholipid syndrome in rheumatic and connective tissue disorder:
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Systemic sclerosis
• Sjögren's syndrome
• Others
3 - Other associations
• Infections (HIV, hepatitis C, syphilis, malaria)
• Lymphoproliferative disorders
• Drug exposure (hydralazine, phenytoin)
• Others

Cardiovascular and pulmonary manifestations of SLE are numerous and related not only to the disease itself but can also result from complications related to the drugs used in the treatment of the disease (Table 3).

Table 3: Cardiovascular and Pulmonary Manifestations of Systemic Lupus Erythematosus
Cardiovascular Pulmonary
Pericardium
Pericarditis
Pericardial effusion 		Pleura:
Fibrinous pleuritis with effusion
Pleural fibrosis
Valves
Nonbacterial thrombotic endocarditis
Diffuse fibrosis
Infective endocarditis 		Parenchyma:
Nonspecific interstitial pneumonia
BOOP
DAD
Alveolar hemorrhage syndrome
Amyloidosis
Lymphoproliferative disorder
Coronary arteries
Atherosclerosis
Vasculitis
Aneurysm
Thrombosis/embolism 		Vessels:
Acute reversible hypoxemia syndrome
Pulmonary hypertension
Vasculitis
Thromboembolism (antiphospholipid syndrome)
Myocardium
Myocarditis 		Respiratory muscle:
Shrinking lung syndrome
Conduction system and arrhythmia
Inflammation
Fibrosis 		Pulmonary infections
Aorta and peripheral vessels
Aortitis
Atherosclerosis
Thrombosis/embolism (antiphospholipid syndrome) 		Upper airway:
Epiglottitis
Hypopharyngeal ulceration
Subglottic stenosis
Drug toxicity to
Cyclophosphamide with myocarditis
Chloroquine with cardiomyopathy 		Drug toxicity to:
Cyclophosphamide with DAD, CIP, UIP, BOOP, hemorrhage
Methotrexate with CIP, HP, BOOP, DAD

BOOP = bronchiolitis obliterans organizing pneumonia
DAD = diffuse alveolar damage
CIP = cellular interstitial pneumonia
UIP = Usual interstitial pneumonia
HP = hypersensitivity pneumonia

Cardiovascular Manifestations of SLE
SLE may affect all parts of the heart. The cardiovascular involvement has been increasingly recognized with the advent of advanced diagnostic methods and the prevalence estimated to be more than 50%.

Valvulopathies, including valve thickening and nonbacterial thrombotic endocarditis (NBTE) are one of the most common cardiac abnormalities. An increased risk for infective endocarditis has been reported. The pathogenesis of SLE associated valvular heart disease is unknown and can result from fibrinoid degeneration, valvulitis, vegetations, chordal rupture and scarring. Although APS likely plays an important role in its pathogenesis, valvular heart disease does occur in patients without APS.

Nonbacterial Thrombotic Endocarditis (NBTE)
The most classic and well-known valvular abnormality in patients with SLE is NBTE, also known as marantic endocarditis or Libman-Sacks endocarditis. Controversy exists regarding the relationship between Libman-Sacks and NBTE. Indeed some authors consider Libman-Sacks endocarditis to be distinct from NBTE. Others consider it a subset of NBTE, stating that they are similar except for the location of the thrombi and the presence of hematoxylin bodies within the thrombi. In the Mayo Clinic experience, that distinction is not always so clear and the pathologic features of NBTE in patients with SLE have been usually identical to NBTE occurring in other clinical settings (Table 4). Some of these discrepancies can be explained by the introduction of steroids in the treatment of SLE as well as earlier recognition of the abnormality prior to death with the advent of echocardiography. Indeed, Libman and Sacks first describe what they termed "atypical verrucous endocarditis" in four patients with SLE. All patients had involvement of the tricuspid as well as the mitral valve, and half had involvement of the aortic and pulmonic valves. Subsequent studies also showed frequent involvement of the right-sided valves. The vegetations were situated on both surfaces of the valves, particularly the ventricular surfaces of the atrioventricular valves. The involved leaflets commonly showed foci of necrosis and rarely fibrosis. No cases of valvular dysfunction were reported. Since the introduction of the steroids, the right-sided valves are only infrequently involved and the vegetations are less seen on the ventricular aspect of the valves. Additionally, acute valvulitis is rarely seen and fibrosis of the underlying valve is more common. Valvular dysfunction, often requiring surgery, is also increasingly recognized.

Table 4: Causes of NBTE

Causes Autopsy Series Surgical Series
Malignancy 28-100% 0%
APS * 31%
Disseminated intravascular coagulopathy 3-27% 0%
Autoimmune diseases 6% 31%
Valvular heart diseases 0-85% 19%

* These series were mostly form the 1980's and earlier, at a time were APS was only starting to be defined. However, thrombosis was a common reported finding and raises the possibility of APS, yet unrecognized.

Clinical presentation:
The exact prevalence of NBTE in SLE is unknown and varies widely, between 13 to 74%, depending on the type of study and patient populations (autopsy vs. non-autopsy). The incidence is estimated at 1.3%. The presence of valvular disease does not appear to correlate with the severity/activity of SLE. Clinical diagnosis is very difficult with no specific findings. Echocardiogram abnormalities are suggestive of the diagnosis, however subtle abnormalities may be missed. Reported prevalence of significant valve dysfunction, either regurgitation or stenosis, varies between 3 and 25% and valvular replacement is necessary in 1 to 9% of patients. The dysfunction can result from the NBTE itself, the underlying valvulitis or subsequent healing with fibrosis. Regurgitation, aortic or mitral, occurs more frequently than stenosis. Embolization with systemic infarct, mainly of the brain and kidneys, is another potential complication of NBTE, with reported prevalence between 14 and 91%.

Pathologic description:
Initial studies on NBTE reported the tricuspid valve to be more commonly involved. Although recent studies now suggest more common implication of the mitral valve, any valve can be affected and multivalvular involvement often occurs. Vegetations are generally small, between 1 to 4mm, and characteristically described as being situated between the mitral posterior leaflet and ventricular wall, on the ventricular side near the base. However, the vegetations often involve both sides of the valve and in a recent series, they were situated mostly on the atrial side on the mitral valve and vascular side of the aortic valve. They are also commonly found at the edge of the valve as well as the commissures, tendinous cords, papillary muscles and atrial and ventricular endocardium.

Histologically, the vegetations are composed of an eosinophilic granular material comprised of fibrin and platelets. Hematoxylin bodies can be present. No microorganisms are identified. The vegetations can show organization with granulation tissue formation or hyalinization with some calcification. It is not uncommon to see vegetations, acute or healing/healed, in the same valve specimen. The underlying valve may be involved by a valvulitis with fibrinoid necrosis. Fibrosis with architectural distortion as seen with postinflammatory valvular (for example rheumatic) heart disease may be present or subsequently develop. The vegetations are very friable and only minuscule remnants can occasionally be seen. These are better appreciated with an elastic stain since the collagen of the underlying leaflet has a different tinctorial affinity than the fibrin from the vegetation. The elastic stain also permits a good evaluation of the architecture of the underlying valve. Deposition of immunoglobulins, including anticardiolipin antibody, and complement in the base of the valves, as well as the edge of the leaflets and in the vegetations, have been described.

Differential diagnosis: Infective endocarditis is the main differential diagnosis of valvular disease with vegetations. Clinically, it may present as an acute, lethal process, or appear insidiously, depending on the virulence of the organism. Patients present with fever and systemic symptoms.Cardiac complications with acute valvular dysfunction and embolic complications are more frequent. Blood cultures are usually positive. By echocardiography, the images can be indistinguishable form NBTE, although the vegetations are usually more conspicuous and tend to prolapse in the cavities. As with NBTE, the left-sided valves are more commonly involved. Grossly, the vegetations are bulky and often destructive, perforating cusp and rupturing tendinous cords. Histologically, the vegetations contain not only fibrin but also inflammatory cells and organisms, better visualized with Gram and silver stains. The underlying valve contains marked acute and chronic inflammation, often with ulceration and necrosis. Treated/healing endocarditis shows residual inflammation in the valve. The "dead" bacterial colonies may still be visible and are often calcified.

Acute rheumatic heart disease is a most uncommon disease encountered by pathologists in North America today, even though rheumatic fever still remains an important health problem. However, it is one of the valvular heart diseases associated with vegetations. Patients with acute rheumatic heart disease have associated stigmata of rheumatic fever. Left-sided valves are the most commonly involved. The vegetations are numerous, very small and situated along the lines of closure of the valves. They are comprised of fibrin and are usually situated on an erosion characterized by fibrinoid necrosis and inflammation.

Post-inflammatory valvular disease is a chronic valvular disease most commonly (>95% cases) related to a history rheumatic disease (i.e. chronic rheumatic heart disease). Rarely, it is can be seen with connective tissue disease, such as SLE, or following radiation treatment. The characteristic gross findings include leaflet/cusp thickening by fibrosis and calcification, commissural fusion, and shortening and thickening of the tendinous cords. These findings are similar for all etiologies, including SLE. The pathogenesis in SLE can result from valvulitis itself but healing of NBTE has also been implied.

Pulmonary Manifestations of SLE
Pulmonary involvement is relatively common and may follow a variable course from incidental radiologic findings to acute dramatic or chronic disease. The most common thoracic manifestation is pleuritis present in up to 60% of patients. Some patients may have more than one form of involvement during the course of their disease.

Acute Pulmonary Disease

Acute pulmonary disease is an uncommon and life-threatening disease, which tends to develop in association with generalized lupus activity. It is comprised of acute lupus pneumonitis and diffuse alveolar hemorrhage. As in our patient, features from both diseases can overlap in a single biopsy, almost a fifth of cases.

Acute Lupus Pneumonitis

Clinical presentation:
Acute lupus pneumonitis occurs in 1-4% of patients and can be the initial manifestation of SLE. It is characterized by an abrupt onset of fever, cough, dyspnea with hypoxemia and patchy alveolar infiltrates. Other underlying etiologies particularly infection must be ruled out. The alveolar infiltrates can be unilateral or bilateral with lower lung zone predominance. Hypoxemia is normally present on blood gas. Commonly, acute lupus pneumonitis occurs in patients with a generalized flare of the disease and other systemic manifestations are present. Favorable response to steroids can be achieved in patients but the course is commonly fulminant and fatal in up to 50% of patients. If patients are recalcitrant to steroids, immunosuppressive or cytotoxic agents can be used. Patients who survive often have no residual pulmonary defects. However, patients with persistent pulmonary infiltrates and abnormal pulmonary function tests, evolving into chronic interstitial lung disease, have been described.

Pathologic description:
The histologic features of acute lupus pneumonitis are not specific and usually consist of DAD, commonly at the stage of organization. The histologic manifestations of DAD occur in two chronologic distinct phases, which may overlap. The early or exudative phase and late or organization phase. The exudative phase begins with interstitial and alveolar edema followed by the appearance of hyaline membranes. These densely eosinophilic membranes line the alveolar septa and respiratory bronchioles. They are comprised of plasmatic proteins, necrotic debris and surfactant. The hyaline membranes are pathognomonic of DAD. The organization stage is characterized by the proliferation of fibroblasts and epithelial cells. Hyperplastic type II pneumocytes, occasionally quite atypical, line the alveolar septa. Squamous metaplasia of bronchiolar epithelium is often present and can be very prominent. Proliferating fibroblasts in a myxoid background diffusely thicken the alveolar septa. Remnants of hyaline membranes can be identified within the alveolar septa, admixed with the fibroblasts. Fibrinous thrombi are often seen within small vessels. In patients with SLE, hematoxylin bodies can rarely be seen. In the final stage of organization, the parenchyma can become markedly altered and honeycomb changes develop.

DAD is a nonspecific pattern of acute lung injury and can be the result of numerous etiologies also present in patients with SLE, the most important of which is infection. Indeed, patients with SLE are potentially immunocompromised hosts as a result not only of their immunosuppressive therapy but also in relation to several immune defects related to their disease. Infectious etiologies causing DAD are numerous, including virus, bacteria, fungi, and particularly Pneumocystis carinii, which should be sought for with a silver stain. DAD can also result from drugs used in the treatment of SLE such as cyclophosphamide and methotrexate, or uremia associated with lupus nephritis.

Differential diagnosis (Table 5): The main histologic differential diagnosis is with bronchiolitis obliterans-organizing pneumonia (BOOP). In contrast to DAD, BOOP is a patchy process in which the distal bronchioles, alveolar ducts and peribronchiolar alveoli are primarily involved. The lesion is comprised of proliferating fibroblasts in a myxoid stroma admixed with some inflammatory cells. The fibroblasts proliferate predominantly within the airspaces, rather than the interstitium, forming intraluminal plugs obliterating the alveolar ducts and surrounding alveoli. Hyaline membranes are not seen.

The differential diagnosis also includes nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP), which will be discussed in detail in case 3 and is summarized in Table 5. TABLE 5: HISTOLOGIC Differential Diagnosis OF DAD (from Katzenstein, Am J Respir Crit Care Med 1998)
Histologic features DAD BOOP UIP NSIP
Temporal appearance Uniform Uniform Heterogeneous Uniform
Interstitial inflammation Scant Patchy
Scant-moderate 		Scant Usually prominent
Collagen fibrosis No No Patchy Variable, diffuse
Fibroblast proliferation Diffuse, interstitial Patchy, airspace Patchy (fibroblast foci) Occasional
BOOP areas Rare --- No Rare
Honeycomb changes Rare No Yes Rare
Hyaline membranes Yes, often focal No No No

Diffuse Alveolar Hemorrhage (DAH)

Clinical presentation:
The reported frequency of diffuse alveolar hemorrhage syndrome (DAH) in patients with SLE varies between 1 to 5.4%, and as with acute lupus pneumonitis, it usually occurs in patients with known history of SLE. However, it can be the initial manifestation of the disease in up to 20% of cases. Patients are more commonly women with a mean age varying between 23 and 39 years. They present with dyspnea, hypoxemia, hemoptysis (42-100%) (Table 6), rapid onset of anemia, and diffuse alveolar infiltrates.

Table 6: Differential Diagnosis of Hemoptysis in SLE

Alveolar hemorrhage
Congestive heart failure
Pneumonia
Uremia
Pulmonary embolism
Antiphospholipid syndrome
Pulmonary hypertension

Glomerulonephritis is often present (up to 94%) and SLE associated alveolar hemorrhage comprises one of the pulmonary-renal syndromes. Pulmonary-renal syndrome is defined by the combination of rapidly progressive renal failure and DAH, and has been reported with several conditions (Table 7). DAH can accelerate rapidly leading to respiratory failure and death, with overall mortality ranging between 23-92%. Treatment consists of steroids often associated with other immunosuppressants such as cyclophosphamide and azathioprine. In patients refractory to this treatment, plasmapheresis is another therapeutical option. Concomitant infection can be documented in a third of these patients. Organisms identified included CMV, herpes simplex, Legionella, Staphylococcus and Aspergillus.

Table 7: Diseases Associated with Pulmonary-renal Syndrome

Connective tissue disease
Systemic lupus erythematosus
Systemic sclerosis
Vasculitis
Wegener granulomatosis
Microscopic polyangiitis
Mixed cryoglobulinemia
Henoch-Schönlein purpura
Goodpasture syndrome

Pathologic description:
Histologically, airspace filling with red cell admixed with fibrin and hemosiderin-laden macrophages are typical features. Vasculitis of medium or small sized vessels and tissue necrosis are uncommon. However, capillaritis is present in up to 100% (range 14-100%). Capillaritis can be very subtle and is characterized by a patchy neutrophilic infiltration of the alveolar septa. The neutrophils focally expand and disrupt the alveolar septa and are associated with septal and alveolar karyorrhectic debris, the result of interstitial necrosis. Deposits of IgG, IgM, C3, corresponding to immune complex deposition, can be seen as granular staining of the capillary basal membrane by immunofluorescence in up to 100% of patients. The granular staining can also be present within the nuclei of type II pneumocytes, representing anti-DNA antibodies. The presence of these immune complex deposits supports their role in the mechanism of tissue damage.

Some studies have reported DAD as an underlying histologic finding in patients with DAH; however, DAD was always accompanied by capillaritis or acute pneumonia.

Differential diagnosis:
Capillaritis is a nonspecific pattern of lung injury, which is the result of numerous conditions other than SLE (Table 8). Clinical correlation and serologic studies usually allow the identification of the specific underlying etiology. Direct immunofluorescence of the lung is potentially useful, but biopsies from other sites, such as skin or kidney, with light microscopy and immunofluorescence, are more commonly performed, when necessary.

Table 8: Causes of Pulmonary Capillaritis

Vasculitis
Wegener granulomatosis
Microscopic polyangiitis
Churg-Strauss syndrome
Mixed cryoglobulinemia
Henoch-Schönlein purpura
Behçet's disease
Connective tissue disease
Systemic lupus erythematosus
Rheumatoid arthritis
Polymyositis
Mixed connective tissue disease
Drugs
Retinoic acid
Diphenylhydantoin
Propylthiouracil
Crack cocaine
Penicillamine
Idiopathic/isolated
Other
Antiphospholipid syndrome
Idiopathic pulmonary fibrosis

Pulmonary hemorrhage results not only from DAH but also from various other causes, including infection, coagulopathies, chronic venous pulmonary hypertension, diverse large airway diseases, more commonly chronic bronchitis, and neoplasms. The causes of DAH obviously overlap with those of pulmonary capillaritis and other etiologies include Goodpasture syndrome, bone marrow transplantation and idiopathic pulmonary hemosiderosis.

Clinical correlation with ancillary laboratory tests is often necessary to determine the underlying etiology. However, a pulmonary biopsy will be performed to either confirm the hemorrhage and/or to identify a specific diagnosis, if present. In the appropriate clinical setting ie SLE, bronchoscopy and transbronchial biopsy can be sufficient to make the diagnosis of pulmonary hemorrhage. However, a wedge biopsy is more likely to show features of a specific cause, such as neoplasm or Wegener granulomatosis.

Fresh blood related to the trauma of the procedure is a common artefact in transbronchial or wedge biopsy, particularly those obtained from thoracoscopy. In true pulmonary hemorrhage, the red cells are admixed with fibrin and very commonly with some hemosiderin-laden macrophages.

Similarly, hemosiderin-laden macrophages should not be confused with smoker's macrophages (respiratory bronchiolitis- RB). The pigment in macrophages of RB contains iron and therefore stains positively for Prussian blue, like hemosiderin. However, the pigment of RB is brown-black and finely granular whereas hemosiderin is a refractile, golden brown, coarsely granular pigment.

Acute necrotizing pneumonia is an important differential diagnosis since the treatment and its potential consequences are very different. It is also a difficult one. In general, with infection, the neutrophils accumulate predominantly within the airspaces whereas in capillaritis, the neutrophils tend to remain within or centered on the alveolar septa. If the capillaritis is severe, the spilling of the neutrophils into the airspace will occur and thorough sampling will help identify more typical areas of capillaritis. Clinical correlation with appropriate smears and cultures is also very useful.

The role of direct immunofluorescence (IF) in the lung biopsies

This is a very difficult question to answer since the studies on the subject are rare.

In the clinical setting of unknown yet suspected systemic disease, serologic testing (anti-dsDNA, ANCA, anti-GBM antibodies, antiphospholipid antibodies), in conjunction with a thorough clinical examination, is usually sufficient to make a specific diagnosis. However, the turn around time for these tests is much longer than IF, and therefore, in life-threatening situations, such as alveolar hemorrhage or acute respiratory failure, IF in association with the histologic features on a biopsy may be more useful. The site of biopsy depends on the clinical situation and other organs than the lung might be more appropriate. A lung biopsy is considered when diagnostic tissue can not be obtained from other sites and then should represent a wedge biopsy rather than a transbronchial biopsy.

The most useful role of IF in lung biopsy is mostly to distinguish Goodpasture syndrome from other immune and non-immune causes of pulmonary hemorrhage. Indeed, linear deposits of IgG found along alveolar basement membrane are specific for Goodpasture. While granular deposits of IgG, IgM, C1q and C3 are more commonly found in SLE, they are not specific to this disease and have been described in patients with rheumatoid arthritis, polymyositis, and mixed cryoglobulinemia. And not only are they not always present in SLE associated pulmonary hemorrhage but they have also been described in other types of pulmonary diseases associated with SLE such as DAD, pulmonary hypertension and chronic interstitial lung disease. Thus, the identification of immunoglobulins and/or complements by IF does not always correlate with the presence of capillaritis, and conversely negative IF has been reported in patients with capillaritis of undetermined etiology. The most recent and exhaustive study on IF in medical lung diseases was performed in 57 patients. Although the authors tried to make the point that IF is useful for the diagnosis and establishing pathogenesis for various diseases, their data show significant overlap in the pattern of staining amongst disease, as well as immunoreactivity in non-immunologically mediated diseases, suggesting very low specificity.

Table 9: Results of Immunofluorescence Modified from Magro Et Al, 2003
Diseases No of cases IgG IgM IgA C3 C5b-9
Collagen vascular disease
SLE
RA
Dermatomyositis
1
3
1
0
2
1
1
3
1
1
1
0
1
2
1
1
3
1
Familial PF/seronegative PF 3 0 0 0 1 1
Capillaritis
ANCA-neg
ANCA-pos
12
5
8
¼
12
4
9
3
11
3
12
3
Anti-GBM 1 1 1 1 1 1
Non-immunologically mediated lung injury 6 2 2 3 4 4

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