Idiopathic interstitial pneumonia (IIP) is a disease entity that can be histologically classified into different categories. Idiopathic pulmonary fibrosis has the same features as that of usual interstitial pneumonia (UIP) whereas no specific pattern or common feature is noted among the other types of IIP. The pathophysiology of IIP can be summarized in the following three stages: recruitment of inflammatory cells, abnormal collagen deposition and fibroblastic proliferation and lastly progression to fibrosis.

Idiopathic pulmonary fibrosis (IPF) has often been considered an autoimmune disease. However, it is perhaps better characterized as an abnormal and excessive deposition of fibrotic tissue in the pulmonary interstitium with minimal associated inflammation.^[1] Autoantibodies, a hallmark of autoimmune diseases, are found in a minority of patients with true idiopathic pulmonary fibrosis. Moreover, many autoimmune diseases that are associated with pulmonary fibrosis such as scleroderma, are more frequently associated with a related but more inflammatory disease, nonspecific interstitial pneumonitis.^[2] IPF is associated with smoking^[3] and exhibits some dependency on the amount of smoking.^[4]

Shown below is an image depicting IPF:

As the name implies, idiopathic non-specific interstitial pneumonia (NSIP) has very inconsistent and non-specific findings.^[5][6][7] Changes similar to other cases of interstitial pneumonia are seen which are migration of inflammatory cells in the alveolar septa and its widening with or without fibrosis. NSIP can be divided into three groups based on histopathological changes.^[8] Shown below is a table summarizing the pathological findings in the three groups of NSIP:

Bronchoalveloar lavage (BAL) reveals the presence of lymphocytes in the alveolar septum which is an evidence of the involvement of the immune system.^{[6][9][10][11]} A greater number of dendritic cells (DC), which help in antigen presentation, are visualized in close association with CD4 and CD8 lymphocytes in the biopsy of NSIS patients than in UIP.^[12] Fibroblasts are the key cells involved in fibrotic lung diseases.^[13]

The pathological mechanism of NSIP involves:

• Epithelial injury and dysregulated repair (major role)^[14]
• Cytokines
• Proteins like epimorphin (a cell surface associated protein)^[15] matrix metalloproteinases,^[16] heat shock protein,^[17] surfactant protein C^{[18][19][20][21][22]}
• The coagulation system^[23][24]
• Intercellular adhesion molecules-1,^[25] IL-4, IL-13, IL-18^[26]
• Interferon-gamma
• Pro fibrotic chemokines^[27]

• CCL7, and CCL5
• Lymphocytes^[28]
• Dendritic cells
• Fibroblasts

Some common associations between Idiopathic Non-specific Interstitial Pneumonia (NSIP) and Usual Interstitial Pneumonia (UIP) have been noted. Histologically patients can manifest lesions of both UIP and NSIP simultaneously. The reason for this presentation is still unknown but environmental exposures and genetic mutations could be some of the causes.^[29][5]

Features differentiating NSIP and UIP include:

• Irregular fibrosis
• Honeycombing
• Fibroblast predominant foci
• Fibroblasts secreting transforming growth factor–Beta (TGF-β) and fibronectin^[30]

• Cigarette smoking could be one of the major causative agent of Respiratory Bronchiolitis-Interstitial Lung Disease (RB-ILD). A relation between the duration and the intensity of cigarette smoking and visualization of opacities on chest radiographs was reported in a few studies.^{[31][32][33][34]}
• The pathology is seen in the lumen of the bronchiole. Sometimes the bronchioles, alveolar ducts and the peribronchiolar alveolar spaces may show clusters of dusty brown macrophages.^{[35][36][37][38][39][40]}
• Granular golden brown particles having plenty of cytoplasm may be seen. These particles are PAS-positive and Prussian blue–positive which implies increased iron content in the alveolar macrophages. This increased iron content could be associated with smoking.^[37][39][38]
• A common feature of histology of DIP and respiratory bronchiolitis is a mixture of alveolar septal thickening, epithelial hyperplasia and pigmented macrophages in the lumen. There are lymphocytes and histiocytes deposited in an irregular way in the submucosa. Similar to the black pigment in the macrophages, a dark black anthracotic pigment can be seen in the histiocytes.^[36][40] Type 2 hyperplastic cells and cuboidal bronchiolar type epithelium line the fibrosis around the bronchioles.

• Desquamative interstitial pneumonia (DIP) lacks the typical patchy appearance of UIP.
• In DIP alveolar walls are lined with chronic inflammatory cells and dense connective tissue and the alveolar spaces are filled with macrophages.
• In DIP mild fibrosis without honeycomb changes are present occasionally.
• Eosinophilic and plasma cell infiltration are also seen.
• Mononuclear changes within the most distal spaces is a key finding in DIP. These mononuclear cells appear as finely granular brown pigment with mottled tiny black particles. These cells are known as smoker’s macrophages, which are different from the desquamated pneumocytes.
• Some of these changes overlap in both DIP and respiratory bronchiolitis.^[41][36]

Cryptogenic organizing pneumonia (COP) is caused by disorganization of the alveolar epithelium. COP is characterized by:

• Plasma protein leakage, fibroblast migration and fibrin deposition inside the lumen
• Involvement of the vascular endothelial growth factor and matrix metalloproteinases.^[42]
• Accumulation of fibroblasts and myofibroblasts in the alveolar ducts and alveoli
• Involvement of polyps in the bronchial lumen in some patients
• Excess of granulation tissue deposition; the pattern of extension sometimes appearing like a butterfly

Some recent studies show that COP can be a rare extra-intestinal manifestation of Crohn’s Disease.^[43]

Acute Interstitial Pneumonia (AIP) has a similar appearance to Diffuse Alveolar Damage (DAD). Shown below is a table summarizing the pathological features of the three different stages of AIP. It should be noted that similar lesions belonging to the same stage are seen in AIP whereas lesions of different ages are noted in UIP in the absence of a specific unified pattern at a given point of time. ^[44][45]

• Release of tumor necrosis factor alpha, interleukin 1β, monocyte chemoattractant factor and neutrophils cause further damage. This damage in turn causes release of toxic oxygen radicals and proteases. Overall it leads to an exudate formation and cellular damage.
• A fibroblast proliferation and differentiation into myofibroblasts leads to collagen formation which widens the septa. Later hyaline membrane decreases and there is a rise in the number of type II epithelial cells.
• A few patients resolve after this stage whereas a majority progress to the next stage i.e fibrosis.

AIP shows prominent myofibroblastic proliferation whereas this finding is only seen in a few cases of ARDS secondary to infection or drug toxicity.^[46][47]

Shown below is an image depicting AIP:

• Characteristic findings of Lymphoid Interstitial Pneumonia (LIP) are lymphoid and chronic cell infiltration predominantly seen in the alveolar septa but sometimes also seen around bronchi and vessels.
• Granulomas specially non–caseating, fibrotic changes, honeycombing and loss of normal lung tissue is also seen as the disease progresses.^[48][49]
• In LIP, B cell polyclonality differentiates it from pulmonary lymphoma whereas in HIV, T cells are more predominant. However, sometimes no specific cell types are seen.^[49][50][51]
• A Bcl-6 gene mutation has been associated with mucosa-associated lymphoid tissue (MALT), HIV and EBV and other virus negative LIP.^[52]
• Features like monoclonality, hilar involvement, pleural involvement, bronchial wall involvement all point towards a malignant transformation.^[53]