In the nascent years of the 18th century, De Morbis Artificum Diatriba, one of the most influential documents pertaining to occupational lung diseases, appeared in Modena, Italy. The treatise was written by Bernardino Ramazzini da Capri (1633–1714) and was printed in Padua in 1713 (Figure 1-1). In the chapter titled, “The Diseases of the Sifters, Measurers, and Handlers of Grain,” the author described the occurrence of dry cough, weight loss, breathing difficulty, and dropsy in the patients. He wrote, “Hence whenever is necessary to sift wheat and barley or other kinds of grain to be ground in the mill, or to measure it when corn-merchants convey it hither or thither, the men who sift and measure are so plagued by this kind of dust that when the work is finished they heap a thousand curses on their calling. The throat, lungs, and eyes are keenly aware of serious damage; the throat is choked and dried up with the dust, the pulmonary passages become coated with a crust formed by dust and results in a dry and obstinate cough; the eyes are much inflamed and watery; and almost all who make a living by shifting or measuring grain are short of breath and cachectic and rarely reach old age; in fact they are liable to lapse into orthopnea, and finally dropsy.” This, then, was the first observation and description of interstitial lung diseases (ILDs) and related complications caused by inhalation of organic antigens.1
In 1868, Austin Flint, an American physician, described a vague, nondescript lung disorder and named it chronic pneumonitis. He observed, “The condition is solidification caused by the presence of an exudation which is not absorbed and which is not liquefied by suppuration. The exudation becomes fibroid, and the solidification which it causes is permanent. The bronchial tubes are more or less dilated, this is a mechanical effect of the contraction of exudation. The inflammatory exudates that resulted in solidification and fibrosis of the lungs had no pus.”2 Flint noticed that Carl Rokitansky of Vienna had described a similar lesion in which the exudation was seen in the interlobular and intervesicular areolar tissue and asserted that the illness be called as interstitial pneumonitis (Figure 1-2). The entity led to small lungs and was very different from the fibroid tuberculosis and chronic pleuritis causing reduced lung volumes. Flint also noticed that a few years earlier, Dominic Corrigan, an Edinburgh trained Irish cardiologist, considered the lung illness analogous, if not identical, to cirrhosis of the liver, and called it cirrhosis of the lung (Figure 1-3). Flint recognized that the newly discovered pulmonary condition was rare.
It seems that two significant clinical features of the illness were discovered during the 19th century; Corrigan described the occurrence of traction bronchiectasis in interstitial pneumonitis, and Flint noticed that the finger tips of one of the patients with interstitial pneumonitis had assumed a bulbous appearance. He was, therefore, the first one to link clubbing with interstitial lung disease.
In 1888, Wilson Fox, Professor of Pathological Anatomy at University College, London, recorded the microscopic changes of capillary edema, accumulation of pigmented epithelium in the alveoli, and thickening of the walls of the alveoli, arteries, and veins in lungs with interstitial pneumonitis (Figures 1-4 to 1-6). Fox was clear in pointing out that the condition he was describing was not related to tuberculosis. He noted that in 39 cases with pulmonary indurations, 37 had bronchodilatation.
He went on to say, “Sir Dominic Corrigan, as is well known, attributed dilatation to traction on the walls of the bronchi by fibroid lung.” Fox, like Flint, also credited Rokitansky for recognizing the fibrous thickening of the alveoli as the principle abnormality in this condition. He also stated that Virchow, his old teacher, had not described the condition involving the thickening of the alveolar walls.3
In 1888, William Osler, while at the Johns Hopkins Hospital, Baltimore, described a rare case of pulmonary fibrosis. “In one of Charcot's cases…death occurred about 3.5 months after the onset of acute disease, and the lung was two-third of the normal size, grayish in color, and hard as cartilage. In the only case of its kind that has come under my observation, the patient died about a month after the onset of the chill. Microscopically, these areas showed advanced fibrotic changes and great thickening of the alveolar walls. Osler stated that the term cirrhosis should be applied only to cases in which a lung was densely fibrosed, whether fibrosis had originated in the lung parenchyma or in the pleura.” In addition, he, like Flint, advised that the new entity be distinguished from fibrosis caused by tuberculosis4 (Figure 1-7).
In 1907, Sandoz described the first case of the familial occurrence of pulmonary fibrosis.5 The importance of a family history of fibrotic lung disease has been recognized recently. It is reported that familial cases account for 0.5–2.0% of all cases of idiopathic pulmonary fibrosis (IPF). It occurs as an autosomal dominant disorder with variable penetrance. To date no gene has been consistently identified to be associated with IPF. There is, however, a strong association of IPF with surfactant protein C gene mutations.6
Mutations in the genes encoding telomerase components have also been reported.7
In the second half of the 19th century, interstitial pneumonitis was recognized as an entity by clinicians and pathologists alike, but its importance and clinical course remained unclear. In 1944, Louis Hamman and Arnold Rich at Johns Hopkins Hospital described four young patients who had died of progressive dyspnea and respiratory failure within six months of the onset of the illness7 (Figure 1-8). The clinical profile of the illness was similar to that described previously by Flint, Corrigan, Fox, Charcot, Rokitansky, and Osler. The term Hamman-Rich syndrome became synonymous with acute, fatal pneumonitis of unknown cause. In the 1960s, my teacher, Eli Rubin, in association with Harold Lubliner reviewed 48 cases of this new syndrome and added 15 cases of their own. Diffuse interstitial pneumonitis could no longer be considered a rarity.8
Averill Liebow, based on his vast experience, arranged histological patterns and classified interstitial pneumonia into five distinctive groups: usual interstitial pneumonia, desquamative interstitial pneumonia, bronchiolitis obliterans with interstitial pneumonia, lymphoid interstitial pneumonia, and giant cell interstitial pneumonia9 (Figure 1-9). The classification was augmented and simplified by removing lymphoid interstitial pneumonia and giant cell interstitial pneumonia.10 Katzenstein and Fiorelli coined the term nonspecific interstitial pneumonitis (NSIP) to describe an entity that lacked the heterogeneity of usual interstitial pneumonia and differed from bronchiolitis obliterans with interstitial pneumonia in having an acute or subacute course.11 It was recognized that NSIP was not a predominantly male disease and had a better prognosis than IPF. The new classification of interstitial pneumonias includes usual interstitial pneumonia (UIP), desquamative interstitial pneumonias combined with respiratory bronchiolitis (RB-ILD), two smoking related illnesses, acute interstitial pneumonitis, Hamman-Rich syndrome and the new entity, NSIP. Bronchiolitis obliterans organizing pneumonia (BOOP), now called cryptogenic organizing pneumonitis (COP), is given its own separate place because it is primarily an intraluminal disease.12 The American Thoracic Society and the European Respiratory Society enhanced the nomenclature and typical patterns of idiopathic interstitial pneumonias based on histological criteria and high resolution computerized tomographic patterns associated with each disease.13
Clinical recognition of these disorders is now easier than it was in the time of Flint and Osler. High-resolution computerized tomography is now an essential part of the diagnostic algorithm for diagnosing diffuse parenchymal lung diseases. Many studies have supported the diagnostic accuracy of high resolution computerized tomography in this group of diseases based on the presence of distortion of lung architecture, reticular attenuation and honeycombing pattern, interlobular septal thickening, ground-glass attenuation, and traction bronchiectasis.14
It is clear that the typical features of usual interstitial pneumonitis/idiopathic pulmonary fibrosis in the appropriate clinical setting can clinch the diagnosis without resorting to lung biopsy.15 Thus, the pursuit of surgical lung biopsy has steadily declined as HRCT technology and interpretation of various disease patterns have advanced. A recent survey of the American College of Chest Physicians (ACCPs) fellows found that surgical lung biopsy is now infrequently used for the diagnosis of IPF.16 The pattern recognition of abnormal morphological changes, however, is susceptible to the interpretive-diagnostic skills of a radiologist. Thus, it is the clinician's responsibility to diligently integrate radiological information with clinical findings before arriving at the final diagnosis. The diagnostic pattern of UIP/IPF consists of bilateral, peripheral and basilar predominant reticular infiltrates, honeycombing, traction-bronchiectasis, and the absence of more than small amounts of ground-glass attenuation or other radiographic features that might suggest an alternative diagnosis, e.g., massive pleural effusion, pleural calcification, massive hilar, or mediastinal adenopathy. In patients with less characteristic or atypical patterns, surgical biopsy should be performed.
One stumbling block in establishing the diagnosis of IPF without a surgical biopsy is the unavailability of a non-invasive biomarker or a serological test of the disease, such as troponin for acute coronary heart disease. A recent study appears to be a light at the end of the diagnostic tunnel. A combination of serum matrix metalloproteinase (MMP)1 and MMP7 has good sensitivity and specificity for IPF when compared with chronic obstructive pulmonary disease, hypersensitivity pneumonitis, sarcoidosis, and normal controls.17
The bronchoscope is quite indispensable in the study of lung disease; however, the role of bronchoscopy in diagnosing and managing interstitial pneumonias is somewhat limited18 (Figure 1-10). Nagai et al. correlated seven histological subtypes of idiopathic interstitial pneumonias with distinctive cellular profiles in BAL fluid.19 BAL investigations have discovered genetic defects in surfactant protein A2 in IPF patients.20 BAL fluid show increased concentration and overexpression of MMP7 and MMP1 genes in IPF patients as compared with controls.17 Various cytokine and chemokines levels are elevated in IPF.20 The levels of several CC chemokines, CCL2, CCL17, and CCL22 suggest a poor outcome in IPF patients.21, 22
Acute, fatal Hamman-Rich syndrome is very different from the chronic, progressive, and inexorable idiopathic pulmonary fibrosis, but now we learn that acute decompensation or exacerbation can be a major contributory factor to the mortality in IPF. Martinez et al. found that 89% of patients with IPF die of IPF; of these 47% die as the result of an acute exacerbation of their disease.23 An acute exacerbation in IPF is defined as: concurrent or pre-existing IPF, unexplained new or worsening of the existing respiratory symptoms of 30 days or less duration, new or increased radiographic abnormalities and no evidence of pulmonary infection or other causes of acute lung injury (acute respiratory distress syndrome).24 Curiously, acute exacerbations are not only an important feature of IPF but also occur in connective tissue lung disease, hypersensitivity pneumonitis, drug-induced lung disease, NSIP, and asbestosis.25–28
Another complication that influences the prognosis of IPF is pulmonary hypertension. One-third of the patients of IPF at the time of initial diagnosis have pulmonary hypertension. IPF patients with pulmonary hypertension have more shortness of breath, greater impairment of exercise capacity and an increase in one year mortality when compared with their counterparts without pulmonary hypertension. Right heart catheterization remains the gold standard to diagnose and assess severity of pulmonary hypertension.29, 30
Although, the diagnosis of idiopathic interstitial lung disease has become easier to secure, but the assessment of its course and prognosis remain unsatisfactory. Recent studies have explored the prognostic of lung function assessment in both idiopathic pulmonary fibrosis and NSIP. Recent studies show that forced vital capacity (FVC) over time correlates highly with survival. It is a single variable with the greatest prognostic significance. Indeed, change in FVC has been used as a primary endpoint for many recent trials. A more than 10% decrease in forced vital capacity over six months and trough oxygen saturation of less than 86% during a room-air six-minute walk test (6MWT) are poor prognostic signs.31 DLCO measurement has been shown to have a similar albeit less robust predictive value when using a cutoff value of 15% change from predictive normal. Jegal et al. have shown that impaired diffusing capacity in interstitial lung disease patients predict reduced survival independent of the histological pattern.32 In the US, 6MWT is commonly used exercise test to assess prognosis of IPF.33 A four-minute walk test and 15-step climbing test have also been used to predict outcome. Both Lederer et al and Caminati et al have shown that a six-minute walk distance of less than 210 m predicts a significantly lower survival than a distance of 210 m.34, 35 It is evident that lung function measurement is essential for assessing severity of the disease, predicting prognosis, and monitoring patients with idiopathic pulmonary fibrosis. An integrated ‘clinical-radiographic-physiologic’ scoring system provides a reliable prognostic model.36, 37
Drugs, including corticosteroids, methotrexate, immunosuppressive agents, antioxidants, antifibrotic drugs, anticoagulants, and a wide array of other therapeutic approaches are available to subdue the inflammation, control injury, and check the fatal course of idiopathic pulmonary fibrosis. None of the drugs, however, prevents or cures the relentless fibrosis; at best it might provide a temporary respite. Pirfenidone, an antifibrotic compound, inhibits tumor necrosis factor-α, platelet derived growth factor and transforming growth factor-β, signal transduction, all of which have been implicated in the pathogenesis of idiopathic pulmonary fibrosis.38 The drug has been approved to be sold in Japan. The drug, however, has a limited benefit. A comprehensive review of all ongoing trials can be read at clinical trials. The Idiopathic Pulmonary Fibrosis Network is a consortium of the US medical centers that participate in National Heart and Lung and Blood Institute-sponsored clinical trials. The goal of the network is to find effective treatment for idiopathic pulmonary fibrosis.39
However, till we find the cause of idiopathic pulmonary fibrosis and solve many complex problems related to its clinical presentations and course, the search for its cure remains an admirable exercise for imagination, but arduous, inconclusive and of little help to the sufferer of idiopathic pulmonary fibrosis (Figure 1-11).
- Ramazzini B. De morbis artificum diatriba. University of Chicago Press, Chicago: 1940.
- Flint A. A treatise on the principles and practice of medicine. H. C. Lea; Philadelphia: 1988. p. 193.
- Fox W. An atlas of pathological anatomy of the lungs. J & A Churchill; London: 1988. p. 52.
- Osler W. The principles and practice of medicine. Appleton; New York: 1892. p. 539.
- Sandoz E. Uber zwei falle von fotaler bronchektasie. Beitr Pathol Anat. 1907; 41: 496–517.
- Alam JS, Limper AH. Idiopathic pulmonary fibrosis: is it a familial disease? Curr Opin Pulm Med. 2006; 12: 312–7.
- Hamman L, Rich AR. Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hospital. 1944; 74: 177–212.
- Rubin E, Lubliner H. The hamman-rich syndrome: review of the literature and analysis of 15 cases. Medicine (Baltimore). 1957; 36: 397–405.
- Liebow A. Definition and classification of interstitial pneumonias in human pathology. Prog Respir Dis. 1975; 8: 1–33.
- Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Cri Care Med. 1988; 157: 1301–15.
- Katzenstein A, Fiorelli R. Nonspecific interstitial pneumonitis/fibrosis. Histologic features and clinical significance. Am J Surg Pathol. 1994; 18: 136–47.
- Ryu J, Colby T. Idiopathic pulmonary fibrosis: current concepts. Mayo Clin Proc. 1998; 73: 1085–1101.
- American Thoracic Society. Idiopathic Pulmonary Fibrosis: diagnosis and treatment: international consensus statement. American Thoracic Society (ATS) and European Respiratory society (ERS). Am J Respir Crit Care Med. 2000; 161; 646–64.
- Muller NL, Colby TV. Idiopathic pneumonias: high resolution CT and histologic findings. Radiographics. 1997; 17: 1016–22.
- Aziz A, Wells AU, Hansell DM, et al. HRCT diagnosis of diffuse parenchymal lung disease: interobserver variation. Thorax. 2004; 59: 506–11.
- Peikert T, Daniels C, Beebe T, et al. Assessment of current practice in the diagnosis and therapy of idiopathic pulmonary fibrosis. Respir Med. 2008; 102: 1342–48.
- Rosas IO, Richards TJ, Konishi K, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008; 5: e93.
- Reynolds HY. Present status of bronchoalveolar lavage in interstitial lung disease. Curr Opin Pulm Med. 2009; 15: 479–85.
- Nagai S, Handa T, Ito Y, et al. Bronchoalveolar lavage in idiopathic interstitial lung diseases. Semin Respir Crit Care Med. 2007; 28: 496–503.
- Wang Y, Kuan PJ, Xing C, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009; 84: 52–9.
- Vasakova M, Sterclova M, Kolesar L, et al. Bronchoalveolar lavage fluid cellular characteristics, functional parameters and cytokine and chemokine levels in interstitial lung diseases. Scand J Immunol. 2009; 69: 268–74.
- Behr J, Thannickal V. Update in diffuse parenchymal lung disease 2008. Am J Respire Crit Care Med. 2009; 179: 439–44.
- Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005; 142: 963–7.
- Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007; 176: 636–43.
- Olson AL, Huie TJ, Groshong SD, et al. Acute exacerbations of fibrotic hypersensitivity pneumonitis: a case series. Chest. 2008; 134: 844–50.
- Akira M, Kozuka T, Yamamoto S, et al. Computed tomography findings in acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008; 178; 372–8.
- Agarwal R, Jindal SK. Acute exacerbation of idiopathic pulmonary fibrosis: a systematic review. Eur J Int Med. 2008; 19: 227–35.
- Clinical case conference. N Engl J Med. 2010; 362: 1522–31.
- Nathan SD, Schlobin OA, Ahmad S, et al. Serial development of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respiration. 2008; 76: 288–94.
- Glaser S, Noga O, Koch B, et al. Impact of pulmonary hypertension on gas exchange and exercise capacity in patients with pulmonary fibrosis. Respir Med. 2009; 103: 317–24.
- Jegal Y, Kim DS, Shim TS, et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med. 2005; 171: 639–44.
- Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003; 168: 1084–90.
- Caminati A, Bianchi A, Cassandro R, et al. Walking distance on 6-MWT is a prognostic factor in idiopathic pulmonary fibrosis. Respir Med. 2009; 103: 117–23.
- Lederer DJ, Arcasoy SM, Wilt JS, et al. Six-minute-walk distance predicts waiting list survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006; 174: 659–64.
- Collard HR, King TE, Bartelson BB, et al. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respire Crit Care Med. 2003; 168: 538–42.
- King TE Jr, Tooze JA, Schwartz MI, et al. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respire Crit Care Med. 2001; 164: 1171–81.
- Raghu G, Brown KK, Costabel U, et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory placebo-controlled trial. Am J Respir Crit Care Med. 2008; 178: 948–55.
- Frankel SK, Schwartz MI. Update in idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 2009; 15: 463–9.