Usual Interstitial Pneumonia (UIP)

Usual interstitial pneumonia is the most common form of idiopathic interstitial fibrosis (70% of all cases), and unfortunately carries a poor prognosis.

This condition is characteristically most prominent subpleurally in the lower lobes of the lung.

The most important histological feature is the highly variegated lung architecture often including the entire spectrum from normal alveolar walls to end stage fibrotic lesions (honeycomb) in the same section.

Image Link (PILOT)

[ Each of the terms usual interstitial pneumonia, cryptogenic fibrosing alveolitis, and idiopathic pulmonary fibrosis stresses certain features - the cause is unknown, alveolar inflammation is an important part of the disease, fibrosis is the usual sequel, and there may be unusual forms of interstitial pneumonia. ]

The clinical, radiologic and functional features are those of restrictive lung disease.

The disease is usually diagnosed in the sixth decade.

Dyspnea of gradual onset, often over 5 to 10 years, is customary.

Electron microscopic examination reveals gross distortion and infolding of the alveolar basal lamina in the fibrotic areas.

Loose granulation tissue in the alveolar spaces leads to alveolar collapse and contraction of fibrous tissue.

About one quarter of all cases date their illness to an acute broncho-pulmonary infection, an observation that raises the possibility that the disease is sequel to viral infection.

The classic auscultatory finding consists of fine crackles at the lung bases in late inspiration.

The prognosis is bleak, with an average survival of 5 years.

The response to treatment, usually corticosteroids, is generally poor.

The etiology of usual interstitial pneumonia is not known, but the condition is usually thought of as an immunologically mediated disorder.

Evidence includes the association with collagen-vascular disease and serum protein abnormalities, the presence of circulating immune complexes, the presence of immunoglobulins in alveolar walls, and the release of a lymphokine, migration inhibitory factor, when lymphocytes of patients with the disease are exposed to collagen.

According to one theory, macrophages play a central role in the pathogenesis of usual interstitial pneumonia, and the initial damage is to collagen, by an unknown agent.

Macrophages engulf collagen fragments and secrete a fibroblast-stimulating factor, thereby leading to fibrosis.

They also release a chemotactic factor for polymorphonuclear leukocytes, which then do further damage.

A useful classification of usual interstitial pneumonia is as follows but it should be recognized that the morphologic features are the same in each:

- Usual interstitial pneumonia associated with collagen vascular diseases. These include rheumatoid arthritis, systemic lupus erythematosis, and progressive systemic sclerosis. About 20% of cases of usual interstitial pneumonia have overt evidence of a connective tissue disease.

- Usual interstitial pneumonia associated with serum abnormalities but not with collagen vascular disease. These include cryoglobulinemia, abnormal serum globulins, positive antinuclear antibodies, and positive rheumatoid factor (rarely, positive in the absence of rheumatoid arthritis). These abnormalities have been found in up to 40% of cases.

- Usual interstitial pneumonia without overt evidence of collagen vascular disease or serum abnormalities.

Microscopic features: Image Link

Histologically, there is subpleural accentuation of the fibrotic and inflammatory process with relative sparing of centri-acinar structures.

The key morphologic feature of usual interstitial pneumonia is heterogeneity of lesions, that is, different appearances in different parts of the lung, in different lung biopsies, and even in different fields of the same lung biopsy.

The variation is so great that in some fields the alveolar walls are entirely normal.

Inflammation varies from subtle increased cellularity (mainly lymphocytes) of otherwise apparently normal alveolar walls to diffuse alveolar damage with obvious alveolar wall inflammation and hyperplasia of type II cells.

Lymphoid aggregates are also seen. By the time a lung biopsy is performed fibrosis is always present, but its severity varies.

There may be subtle alveolar wall thickening, demonstrated only by special stains for collagen.

In other cases fibrosis may be obvious but alveolar walls may be maintained, although the acinar structure is somewhat simplified.

At the extreme is honeycomb lung, brought about by alveolar wall inflammation and collapse. Image Link(PILOT 2007)

Neutrophils are not a prominent feature, except in the infected cystic spaces.

However, the bronchoalveolar lavage fluid contains increased numbers of neutrophils.

The epithelial lining ranges from normal alveolar cells in undamaged areas to large rounded hyperplastic type 2 cells in diseased areas with focal ciliated columnar, goblet cells and occasionally squamous metaplasia in severely affected areas.

In areas of advanced disease, most of the fibrosis consists of eosinophilic collagen with scanty fibroblastic cells. Image Link (PILOT 2007)

The cystically dilated air spaces of contain inspissated mucus admixed with histiocytes, inflammatory cells and cell debris.

As a result of inflammation and scarring, there is also some bronchioloectasis which is well recognized by the radiologists as "traction bronchiectasis".

UIP is also characterized by the presence of “fibroblast foci”.

These are areas of active disease, consisting of fibroblastic and myofibroblastic proliferation set in a myxoid background, which represent organization of intra-alveolar exudates (ongoing fibrosis).

Fibroblast foci are an important component of the temporal heterogeneity characteristic of the disease process.

Inflammatory cellular infiltration is usually mild, although focal lymphoid hyperplasia with prominent lymphoid follicles may be present, particularly in cases associated with systemic disease.

Reactive smooth muscle hyperplasia is often marked and is particularly prominent around small bronchioles. The smooth muscle fibers are of normal morphology, unlike those seen in lymphangioleiomyomatosis which is characterized by immature smooth muscle proliferation.

Accumulation of tight clusters or loosely dispersed macrophages within alveolar spaces is commonly seen in UIP, particularly in cigarette smokers, and this DIP-like reaction in an otherwise typical case of UIP shows no correlation with the stage of the disease.

Pulmonary arterial vascular changes are often seen in fibrotic areas, but these are of little clinical significance as there is no correlation between these changes and the presence of pulmonary hypertension.

Typically, UIP is characterized by the absence of vasculitis , granulomata and asbestos bodies.

Pleural fibrosis is very rare in UIP.

The presence of conspicuous asbestos bodies should suggest asbestosis , which apart from the absence of asbestos bodies and pleural disease, UIP otherwise resembles.

Idiopathic Pulmonary Fibrosis ; Respiratory bronchiolitis-interstitial lung disease (RBILD); Non-specific interstitial pneumonia (NSIP) ; Desquamative interstitial pneumonia (DIP) ; Acute interstitial pneumonia (AIP)/organizing diffuse alveolar damage DAD); Lymphocytic Interstitial Pneumonia / Follicular Bronchiolitis.

Heterogeneous proliferation of type II pneumocytes in usual interstitial pneumonia.Pathology. 2006 Oct;38(5):433-6.

AIMS: Heterogeneous alveolar fibrosis, the most specific pathological finding in idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), enables differentiation of UIP from other interstitial pneumonias. Heterogeneous and mild alveolar injury may occur, and this will be a clue to clarifying the pathogenesis of UIP. METHODS: We examined nine lung biopsy specimens obtained from patients with IPF and five control specimens. We semi-quantitatively examined alveolar injury by measuring the density of type II pneumocytes. Serial 3 microm sections were stained with anti-Thomsen-Friedenreich (TF) antibody. We divided each UIP lesion into three areas: area near fibrosis (fibrous area), area with an apparently normal alveolar structure (normal area), and area between the fibrous and normal areas (intervening area). RESULTS: Immunostaining with anti-TF antibody stained the apical surface of type II pneumocytes and enabled us to recognise and count type II pneumocytes. The density of type II pneumocytes was increased in the fibrous area, and gradually decreased away from the fibrous lesion. The densities of type II pneumocytes in the above three areas were, respectively: 13.9+/-2.0, 7.2+/-1.6, and 9.5+/-1.6/mm alveolar length. The densities in the fibrous and intervening areas were significantly greater than those in the normal area and in control specimens (6.6+/-0.7/mm). CONCLUSIONS: If the density of type II pneumocytes indicates their degree of regeneration after alveolar injury, it reflects the severity of the pre-existing injury. This study confirms that heterogeneous and mild alveolar injury occurs in UIP.

Histologic features and pathologic diagnosis in usual interstitial pneumonia. Zhonghua Bing Li Xue Za Zhi. 2004 Apr;33(2):105-8.

OBJECTIVE: To study the pathologic features, differential diagnosis and role of open lung biopsies (OLB) in usual interstitial pneumonia (UIP). METHOD: The authors reviewed the pathologic, clinical and radiologic features of five cases of UIP (one autopsy case and four OLB cases), with follow-up information. RESULTS: The typical histologic features were a non-uniform distribution of alveolar inflammation, fibroblastic foci, interstitial fibrosis and honeycomb change. There also was associated metaplasia of bronchiolar epithelium, type II pneumocyte hyperplasia and accumulation of alveolar macrophages. CONCLUSIONS: Characteristically, UIP exhibits temporal heterogeneity under low-power light microscopy, which includes changes in both the early and end stages. Open lung biopsy is an important diagnostic adjunct for suitable patients with atypical radiologic features on computerized tomography. Correlation between clinical, radiologic and pathologic findings is also essential for a correct diagnosis.

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BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia.Eur Respir J. 2003 Aug;22(2):239-44.

Idiopathic pulmonary fibrosis (IPF), which has the histological pattern of usual interstitial pneumonia (UIP), is a progressive interstitial lung disease with a poor prognosis. Idiopathic interstitial pneumonias with a histological pattern of nonspecific interstitial pneumonia (NSIP) have a better prognosis than UIP, and may present with a clinical picture identical to IPF. The authors hypothesised that bronchoalveolar lavage (BAL) findings may distinguish between UIP and NSIP, and have prognostic value within disease subgroups. BAL findings were studied retrospectively in 54 patients with histologically proven (surgical biopsy) idiopathic UIP (n=35) or fibrotic NSIP (n=19), all presenting clinically as IPF. These findings were also compared with the BAL profile of patients with other categories of idiopathic interstitial pneumonias. BAL total and differential cell counts did not differ between the two groups. Survival was better in NSIP. In neither group were BAL findings predictive of survival or changes in lung function at 1 yr, even after adjustment for disease severity, smoking and treatment. BAL differential counts in fibrotic NSIP differed from respiratory bronchiolitis-associated interstitial lung disease, but not from desquamative interstitial pneumonia or cellular NSIP. The authors conclude that bronchoalveolar lavage findings do not discriminate between usual interstitial pneumonia and nonspecific interstitial pneumonia in patients presenting with clinical features of idiopathic pulmonary fibrosis, and have no prognostic value, once the distinction between the two has been made histologically.

Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am J Surg Pathol. 2002 Dec;26(12):1567-77.

The pathologic findings in biopsy and subsequent explant specimens from 20 patients with usual interstitial pneumonia (UIP) were reviewed to refine histologic criteria for diagnosis, to identify factors that may confound diagnosis, and to assess the relationship of UIP and nonspecific interstitial pneumonia (NSIP). One case of NSIP was also identified and included for comparison. Surgical biopsies from 15 of the 20 UIP cases were diagnosed as UIP, whereas 5 showed only nondiagnostic changes. An important new observation is that areas resembling nonspecific interstitial pneumonia (NSIP-like areas) are present in the majority of UIP cases in both biopsy and explant specimens, and they are extensive in some. Ten of the 15 UIP biopsies were considered straightforward, with typical patchy interstitial fibrosis, honeycomb change, and fibroblast foci. Five cases were considered difficult because of prominent NSIP-like areas in two, extensive honeycomb change in one, superimposed diffuse alveolar damage in one, and superimposed bronchiolitis obliterans-organizing pneumonia in one. The most helpful feature for diagnosing UIP in difficult cases was the presence of a distinct patchwork appearance to the characteristic uneven or variegated parenchymal involvement along with evidence of architectural derangement. No explant showing UIP was preceded by biopsy findings of NSIP, and the one NSIP case appeared similar at biopsy and explant. NSIP or NSIP-like areas and UIP may reflect different mechanisms of fibrosis related either to different severity of injury or to different injuries.

Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001 Nov 1;164(9):1722-7.

Findings of surgical lung biopsy (SLB) are important in categorizing patients with idiopathic interstitial pneumonia (IIP). We investigated whether histologic variability would be evident in SLB specimens from multiple lobes in patients with IIP. SLBs from 168 patients, 109 of whom had multiple lobes biopsied, were reviewed by three pathologists. A diagnosis was assigned to each lobe. A different diagnosis was found between lobes in 26% of the patients. Patients with usual interstitial pneumonia (UIP) in all lobes were categorized as concordant for UIP (n = 51) and those with UIP in at least one lobe were categorized as discordant for UIP (n = 28). Patients with nonspecific interstitial pneumonia (NSIP) in all lobes were categorized as having fibrotic (n = 25) or cellular NSIP (n = 5). No consistent distribution of lobar histology was noted. Patients concordant for UIP were older (63 +/- 9 [mean +/- SD] yr; p < 0.05 as compared with all other groups) than those discordant for UIP (57 +/- 12 yr) or with fibrotic NSIP (56 +/- 11 yr) or cellular NSIP (50 +/- 9 yr). Semiquantitative high-resolution computed tomography demonstrated a varied profusion of fibrosis (p < 0.05 for all group comparisons), with more fibrosis in concordant UIP (2.13 +/- 0.62) than in discordant UIP (1.42 +/- 0.73), fibrotic NSIP (0.83 +/- 0.58), or cellular NSIP (0.44 +/- 0.42). Survival was better for patients with NSIP than for those in both UIP groups (p < 0.001), although survival in the two UIP groups was comparable (p = 0.16). Lobar histologic variability is frequent in patients with IIP, patients with a histologic pattern of UIP in any lobe should be classified as having UIP.

Bronchiolitis obliterans and usual interstitial pneumonia. A comparative clinicopathologic study.Am J Surg Pathol. 1986 Jun;10(6):373-81.

The clinical, radiographic, and pathologic features were studied in 24 cases of bronchiolitis obliterans and 16 cases of usual interstitial pneumonia, to define better their distinguishing characteristics. Bronchiolitis obliterans had a more acute onset often associated with fever, while the presentation of usual interstitial pneumonia was insidious with dyspnea and cough. The radiographs in usual interstitial pneumonia uniformly showed bilateral interstitial opacities, while they were more variable in bronchiolitis obliterans, with air space densities in 15 and interstitial opacities in nine. Prognosis was considerably better for bronchiolitis obliterans patients. Resolution of disease occurred in nearly half, while no patient with usual interstitial pneumonia recovered. Three individuals with bronchiolitis obliterans (12.5%) died of progressive disease, compared to 10 with usual interstitial pneumonia (62.5%). Pathologically, the lesion in bronchiolitis obliterans affected mainly air spaces in a peribronchiolar distribution, while the changes in usual interstitial pneumonia were mainly interstitial and randomly distributed. The fibrosis in bronchiolitis obliterans was composed of proliferating fibroblasts, compared to collagen deposition in usual interstitial pneumonia. These findings emphasize that bronchiolitis obliterans and usual interstitial pneumonia represent separate and distinct clinicopathologic entities.

Morphological definition of a case of 'usual' interstitial pneumonia. Cytobios. 1979;26(102):131-5.

A 61-year-old Caucasian female complained of shortness of breath, fever, and a period of rapid weight loss. After routine studies, the patient underwent an open lung biopsy in order to define the characteristics of the interstitial lung disease, and initiate appropriate therapeutic intervention. Typical fibrotic and cellular proliferation were evident in the parenchyma, as determined by standard light microscopy. However, in a correlated study using light microscopy of plastic embedded tissue, as well as scanning and transmission electron microscopy, a major proliferating cell type was identified as a type II pneumocyte. These cells were the predominant lining cells of the alveoli and clearly protruded into and limited available respiratory air spaces. The predominance of type II pneumocytes in the pathogenesis of certain respiratory diseases requires that a better explanation be sought for this phenomenon.