Gordon L. Yung and Cecilia M. Smith

In the 1940s, the term “idiopathic (diffuse) interstitial pneumonias” (IIP) was used to describe a general, ill-defined category of interstitial lung diseases of unknown origin. Subsequently, several different classifications were proposed. In the late 1990s, the term IIP was adopted to categorize and define various types of interstitial lung diseases of unclear etiology. The new classification was developed largely due to new understanding of distinct histological subtypes that were previously grouped together under the general umbrella of idiopathic pulmonary fibrosis (IPF).

CLASSIFICATION

Under the current classification, IIP is divided into seven subgroups (Table 94-1). The term “unclassifiable interstitial pneumonia” is applied when histological changes on surgical biopsy are nonspecific and do not fit with any of these subgroups. It is likely that further changes will occur in the future as we better understand these subgroups.

Adoption of this new classification by the general medical community has been slow, partly because of some misconceptions:

1.   The histological features, even in surgical (open) lung biopsy specimens, are not unique to each subtype. Other “nonidiopathic” lung conditions may share similar histological changes. In other words, it is important to exclude other systemic conditions by clinical and laboratory criteria before making a definitive diagnosis of IIP.

2.   Some IIP subtypes may coexist in the same pathologic specimen, implying that some of these conditions may share common pathologic mechanisms, whereas others may represent distinct entities. For example, up to one-third of specimens with features of usual interstitial pneumonia (UIP, the histological description of IPF) may have coexisting changes consistent with nonspecific interstitial pneumonia (NSIP). Patients with IPF also may experience an acute exacerbation of their lung condition with development of changes consistent with acute interstitial pneumonia in biopsy or autopsy specimens.

CLINICAL, RADIOGRAPHIC, AND HISTOLOGIC FEATURES

Idiopathic Pulmonary Fibrosis

IPF, also known as cryptogenic fibrosing alveolitis, is the most common form of IIP, accounting for roughly half of all cases. The true incidence of IPF is not known, as many cases remain undiagnosed or misdiagnosed. One reasonable estimate suggests an annual incidence of about 30,000 to 40,000 new cases in the United States and a prevalence of about 80,000 to 100,000 cases. Most cases occur sporadically, although approximately 10% of patients have a positive family history. Despite intensive research, understanding of this condition remains incomplete. Use of animal models does not translate to humans, as the unique histological and radiographic equivalent of IPF has never been duplicated in laboratory specimens. Unfortunately, IPF often is mistaken by many to be synonymous with any interstitial pulmonary fibrosis that does not have a clear etiology (hence “idiopathic”). The diagnosis of IPF sometimes causes significant stress in patients because the older medical literature widely available on the Internet frequently quoted an average survival of 2 to 2½ years after diagnosis. We now know that survival is quite variable; it is not uncommon for patients, especially those with atypical features and earlier diagnosis, to survive much longer. A lone report noted better survival in IPF patients who have atypical computed tomography (CT) scan findings as compared to those patients with “classical” changes. Other studies suggest that mortality may be linked to the extent of honeycombing. Therefore, it is important to adhere to strict diagnostic criteria to avoid confusion and unnecessary anxiety for patients. It also is clear that, although the clinical disease course of IPF is usually one of progressive worsening, the pace of change is not necessarily linear. Some patients can have relatively stable lung function for up to 7 to 10 years, although the usual clinical course is that of a relatively slow decline interspersed with acute exacerbations at irregular intervals. Typically, patients experience significant and permanent loss of lung function following each exacerbation; it is not uncommon to not survive an exacerbation. A definitive diagnosis of IPF only can be made by the presence of (a) appropriate clinical features and laboratory findings and (b) either classical radiographic changes on chest CT or distinct histological changes on surgical lung biopsy specimens.

1.   Clinical and laboratory findings: Unlike most other IIPs, patients with IPF tend to be older, often presenting in their 60s or 70s and rarely before the age of 50 years. There is a male predominance (approximately two-thirds) and which is more apparent in older patients. There also is an association with cigarette smoking (ex- or current), gastro–esophageal reflux disease, and a history of exposure to wood or metal dust. Up to 20% of patients have a family history of pulmonary fibrosis, suggesting an element of genetic predisposition, at least in some patients. Typically, patients present with one of the following: (i) insidious onset and progressive shortness of breath and dry cough; (ii) persistent cough and shortness of breath after an episode of respiratory tract infection; or (iii) incidental findings of interstitial changes on chest radiograph. Clinical examination can offer important clinical clues; the presence of “Velcro”-like crackles at lung bases and finger clubbing strongly suggests a diagnosis of IPF.

2.   Radiographic changes: Chest X-ray changes are never diagnostic of IPF or, indeed, of any of the IIPs. Because of convenience and relative low radiation dose, chest X-ray may be used as a screening tool in instances of acute change in respiratory symptoms. Chest CT scan offers the potential ability to differentiate various forms of IIP. When all the classical radiographic changes are present, a diagnosis of IPF can be made with more than over 90% confidence without the need for lung biopsy. The classical changes considered diagnostic of IPF include the following:

      a.   Peripheral honeycombing

      b.   Irregular reticular opacities

      c.   Traction bronchiectasis

      d.   Minimal ground-glass changes

      e.   Subpleural, posterior, lower lobe predominance

3.   Only a relatively small proportion of patients with IPF have all of the classic features. In clinical practice a probable diagnosis can be made with the presence of peripheral honeycombing in a subpleural distribution and the absence of any significant ground-glass changes.

4.   Histological changes: IPF demonstrates a pattern of histological changes called UIP. It is important to recognize that similar changes can occur in lung specimens of several lung conditions, such as sarcoidosis, scleroderma, and rheumatoid arthritis (RA). Diagnostic criteria include the presence of noninflammatory fibrosis with “temporal heterogeneity” (varying degree and stages of fibrosis, interspersed with relatively uninvolved lung parenchyma), fibroblastic foci, and no evidence of significant inflammatory cells or granuloma. Of note, fibroblastic foci are areas where fibrotic tissue is generated; the number of foci correlates with survival. These changes can be obscured by end-stage fibrosis so to improve diagnostic yields at least two biopsy specimens should be obtained, including one sample from a relatively uninvolved area of the lungs. There are some inherent risks associated with lung biopsy, especially when there is no Food and Drug Administration (FDA)-approved treatment for the condition. It is, therefore, reasonable to consider forgoing the biopsy procedure if the results would not affect clinical management or if a clinical diagnosis can reasonably be made without histology.

5.   Pulmonary function tests: IPF exemplifies the classical changes of a restrictive pattern on pulmonary function tests. Lung volumes, especially vital capacity (VC) and total lung capacity (TLC), are reduced. In addition, the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) are both reduced with relative preservation of the ratio of FEV₁/FVC. The diffusing capacity for carbon monoxide (DLCO) is perhaps the most sensitive indicator of disease progression, although it has a relatively poor specificity. Both FVC and FEV₁ have been linked to survival. In one study, the change in FVC and DLCO over a 6-month period provided accurate prediction of 2-year survival.

Although there is no uniform explanation of the unique clinical, radiographic, and histological changes in IPF, one can propose a possible model of pathogenesis. Recent studies have suggested that the presence of either telomerase mutation or telomere abnormalities may contribute to the pathogenesis of IPF. Telomeres are repetitive sequences of DNA elements found at the end of chromosomes; their length (and function) may shorten with aging and smoking. They appear to play a crucial role in cell division and, possibly, tissue repair processes. This, and other genetic changes, may explain why IPF tends to occur later in life and is associated with smoking (which more commonly causes airway injury and disease, rather than interstitial injury), and why the condition often accelerates after exacerbations associated with chest infections, when fibrosis develops in areas not involved in the infection. It has been hypothesized that the initial injury may be due to negative pressure exerted on the surface of the lungs during forced inspiration and cough, and not due to the infection itself. This pathogenesis model supports the findings that early IPF affects peripheral (subpleural) parts of the lungs, where stress/force is usually maximal during cough and inspiration. It also supports the clinical impression that IPF patients with significant cough tend to progress more rapidly, and would explain why those with a history of smoking, wood and dust exposure, and gastro–esophageal reflux disease are at higher risks of IPF (conditions associated with increased cough). Finally, this theory may explain why treatments targeted to various pathways of fibrosis have been relatively unsuccessful, even though these same pathways are shared by other forms of fibrosis that respond to antifibrotic therapies.

Nonspecific Interstitial Pneumonia

The term NSIP is both a clinical and histological diagnosis. It is the second most common form of IIP, comprising about one quarter of all cases. Patients with NSIP can present at any age. In many cases, extrapulmonary manifestations suggesting underlying rheumatologic conditions develop years after the onset of lung disease.

When referring to NSIP, it is important to specify whether the term refers to a clinical diagnosis (a subtype of IIP) or a pathologic diagnosis by biopsy, in which case several underlying conditions should be considered. The idiopathic form of NSIP generally occurs in middle-age females in their 40s and 50s with no significant history of smoking. Up to one-third of cases have a subacute presentation of respiratory symptoms. Some of these patients have nonspecific serological markers of connective tissue diseases (CTDs) and may eventually develop clinical features of conditions such as scleroderma, RA, or others of these conditions. Three types of NSIP are generally identified: cellular, fibrotic, and mixed (coexisting cellular and fibrotic changes), depending on the presence or absence of significant interstitial inflammatory changes. In general, cellular NSIP with significant inflammatory changes has a better chance of responding to immunosuppressive therapy and better overall survival. Fibrotic NSIP behaves clinically more like UIP/IPF, in both prognosis and a poor response to treatment. In fact, up to 75% of NSIP patients may show stabilization or improvement with treatment.

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