Drug induced pulmonary toxicity

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]

The idiopathic interstitial pneumonias (IIP) are a broad range of interstitial lung diseases of unknown etiology characterized by expansion of the interstitial compartment initially by inflammatory cells ending by fibrosis due to fibroblasts proliferation and subsequent collagen deposition. It generally manifests non specifically as breathlessness and cough and characterized by bilateral abnormal opacities of various types on conventional chest radiographs or computed tomographic (CT) scans. The prognosis of IIP differs according to the clinical course and pattern of the disease. The most common is chronic Idiopathic pulmonary fibrosis (IPF), however the worst prognosis is the acute interstitial pneumonia (AIP). The diagnosis can only be reached correctly with multidisciplinary approach among different specialists after excluding a lot of known factors that could cause the same presentations. Unfortunately most of the available treatments till today did not show any survival benefit or reducing the mortality.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]; Chetan Lokhande, M.B.B.S [3]

Averill Liebow published a paper in 1975 about definition and classification of interstitial pneumonias in human pathology. His classification was based on histological morphology in different types of idiopathic interstitial pneumonias. Usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP) have persisted as important histologic groups. However others of his classification as bronchiolitis obliterans with classical interstitial pneumonia (BIP) and giant cell interstitial pneumonia (GIP) have disappeared from subsequent classification. Liebow emphasized that it was histological patterns rather than distinctive diagnostic entities, that could occur in a variety of clinical contexts. Regardless of the clinical context, however, he maintained that precise histological classification of interstitial pneumonias provides clues to etiology, pathogenesis, natural history, and prognosis. In other words, although individual histological variations do not offer distinguished diagnostic entities, However each significantly limits the differential diagnosis and can predict treatment response and outcome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]; Chetan Lokhande, M.B.B.S [3]

An idiopathic interstitial pneumonias (IIPs) classification faced difficulties as the disease behavior is overlapping, which makes it difficult to be classified from other pulmonary diseases of heterogenous clinical course.^[1] . However the American Thoracic Society/European Respiratory Society (ATS/ERS) Classification of 2002 defined seven specific entities provided standardized terminology and diagnostic criteria.Later, many publications have led to adopt general changes in the 2007 statement update by ATS/ERS. The new changes emphasized that the histologic diagnosis as a historical gold standard is replaced by a multidisciplinary approach with close interaction of clinician, radiologist, and pathologist. With the era of molecular markers and multidisciplinary approach, surgical biopsy to diagnose the respiratory bronchiolitis-interstitial lung disease is not needed anymore, nonspecific interstitial pneumonia is now better defined and rare disease as pleuroparenchymal fibroelastosis is introduced. The heterogeneous mixed pattern with acute exacerbation is now defined as a clinical course for idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia.

• Idiopathic pulmonary fibrosis
• Idiopathic nonspecific interstitial pneumonia
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Cryptogenic organizing pneumonia
• Acute interstitial pneumonia previously Hamman-Rich Syndrome.

• Idiopathic lymphoid interstitial pneumonia
• Idiopathic pleuroparenchymal fibroelastosis

• Inadequate clinical, radiologic, or pathologic data
• Major discordance between clinical, radiologic, and pathologic findings that may occur in the following situations

• Previous therapy resulting in substantial alteration of radiologic or histologic findings (e.g., biopsy of desquamative interstitial pneumonia after steroid therapy, which shows only residual nonspecific interstitial pneumonia.
• New entity, or unusual variant of recognized entity, not adequately characterized by the current American Thoracic Society/European Respiratory Society classification (e.g., variant of organizing pneumonia with supervening fibrosis).
• Multiple high-resolution computed tomography and/or pathologic patterns that may be encountered in patients with idiopathic interstitial pneumonia.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]

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]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]; Chetan Lokhande, M.B.B.S [3]

Idiopathic interstitial pneumonias are broad subsets of pulmonary diseases due to unidentifiable causes. Therefore, the diagnosis of idiopathic pulmonary pneumonia should lead to a careful clinical workup for the known etiological factors and possible adverse drug reaction before Idiopathic interstitial pneumonia is diagnosed.

The most common collagen vascular disease in the lung that should be excluded first are

• Rheumatoid arthritis
• Systemic lupus erythematosus
• Sjögren’s syndrome
• Polymyositis
• Dermatomyositis
• Progressive systemic sclerosis
• Mixed connective tissue disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]

Careful and extensive investigations in multiple visits to ensure the idiopathic interstitial pneumonia is accurately diagnosed. :*10 to 20% of patients with IPF have positive rheumatoid factor or positive circulating anti-nuclear antibodies (ANAs), but rarely are titers high. However only the presence of high titers (> 1:160) would suggest the presence of a connective tissue disease . ^{[1] [2] [3]}*

• Sarcoidosis
• Hypersensitivity pneumonitis
• Collagen vascular disease
• Human immunodeficiency virus, NSIP is commonly occuring in patients who have AIDS.^{[4][5][6][7][8]}
• Antiphospholipid antibody syndrome
• Chronic obstructive pulmonary disease
• Coalworker’s pneumoconiosis
• Drug induced pulmonary toxicity
• Lymphocytic interstitial pneumonia
• Idiopathic pulmonary fibrosis
• Diaphragmatic paralysis
• Primary pulmonary hypertension
• Restrictive lung disease
• Silicosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]

The true incidence is unknown. UIP is the most common (50%-60%) of the idiopathic interstitial pneumonia, then NSIP 14%-36%, then DIP/RB-ILD (10%-17%) and AIP (0%-2%)^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]

The heterogeneous nature of idiopathic interstitial pneumonia with its various clinical picture makes the outcomes and prognosis is different for each subtype. Acute interstitial pneumonia is of sudden onset and extremely rapid respiratory failure with deteriorating hypoxemia with over than 60% mortality in 6 month.^[1] However chronic interstitial pneumonia may be nonspecific cellular which would have a long survival period over than 10 years, of better outcome than chronic nonspecific fibrosing.^[2] Different quantitative parameters have been suggested and still being validated to assess to severity and predict the outcomes. Patient scoring system is simply a way to involve different clinical, radiological, histopathological and biomarkers parameters to define what will be accurately correlated with the real clinical events.

• The diagnosis of acute exacerbation of IIPs requires an evidence of respiratory deterioration and exclusion of common causes, such as infection, pulmonary embolism, heart failure, and pneumothorax.^[3] Acute exacerbation of IPF has been associated with increased mortality; in fact, recent studies have suggested mortality rates ranging from 20 to 86% following an acute exacerbation of IPF.^[4][5] In addition, a retrospective study showed that 50% of the mortality of IPF patients occurred in the context of an acute deterioration in pulmonary function associated with an acute exacerbation. ^[6].Shown below is an image depicting different pattern of changes in the pulmonary functions over years after diagnosis.

Predictors for survival

• Controversial debate among the patient age and the baseline pulmonary function, as some studies found that may have predictive significance however other studies found that inconsistent with any prognostic value.

• Histological and radiological parameters were considered over the past decade as an estimate for the patient outcome.

• Conventional radiological findings as mild ground glass attenuation predicts physiologic improvement after steroid treatment.^[7] As mild ground glass opacity on CT often regresses on treatment in patients who have histological DIP, but may not decrease as readily in those with histologic UIP.^[8] However some areas of ground glass opacity not only regress with treatment, but it may progress to reticular opacity or honeycombing on follow-up evaluation^[9] Predominant reticular opacity or honeycombing usually progress despite treatment. The extent of lung fibrosis on CT is an important predictor of survival.^[10]

• High resolution Computed Tomography (RCT) has a prognostic value as consistent HRCT findings such as symmetric bilateral reticulation, architectural distortion and lower lobes subpleural lung regions honeycombing are associated with the worst survival with median survival of 2.08, however inconsistent HRCT findings are associated with less mortality with more median survival 5.79.^[11]

• Composite index increases the prognostic power as multiple parameters are more accurate than single parameter.

• Composite physiologic index (CPI) from simple spirometry and DlCO and demonstrated that CPI was linked to mortality more closely than the individual pulmonary function test values.^[11]

• The CPI score is easier to generate because no radiographic scoring or exercise data are required. But still wide validation studies for CPI are required

Idiopathic Pulmonary Fibrosis

• The most common and the worst prognosis of chronic IIPs.
• survival time depends on the definition of the diagnosis ( reticular background on conventional X-ray or onset of the symptoms which usually is 2-3 years after the radiological findings)^[5]
• 5-yr mortality 80%, median survival 2-3 year
• Mortality is most frequently due to respiratory failure (38.7%); other causes of death include heart failure (14.4%), bronchogenic carcinoma (10.4%), ischemic heart disease (9.5%), infection (6.5%), and pulmonary embolism (3.4%)^[12]

• Nonfatal disease-associated complications include pneumothorax, corticosteroid-induced metabolic side effects and myopathy, and therapy-related immunosuppression.

Idiopathic Nonspecific Interstitial Pneumonia

• Better outcome than IPF.
• Cellular type is more common than Fibrotic type.
• The cellular NSIP is better than fibrosing type of NSIP.
• Larger studies are needed to understand the clinical course of NSIP.
• Cellular NSIP median survival > 10 years, however fibrotic NSIP median survival is 6-8 years.
• Cellular NSIP 5-year mortality is <10%, however fibrotic NSIP 5-year mortality is >10%^[2]
• Other studies showed that 10-year survival of fibrotic NSIP is 35%,^[13] 5-Yr survival rate is 43%, ^[14] 25% deterioration of lung function despite treatment.^[15]

Cryptogenic Organizing Pneumonia

• 5-year mortality < 5%^[2]

Acute Interstitial Pneumonia (Hamman-Rich Syndrome)

• 60% mortality in 6 months^[2][5]

Respiratory Bronchiolitis-Interstitial Lung Disease

• No death reported, 5-year mortality < 5%^[2]

Desquamative Interstitial Pneumonia

• No death reported, 5-yr mortality < 5%^[2]

The functional lung capacity, pulmonary functions and mortality have been linked to some biomarkers. For example some studies showed that rapidly deteriorating lung function and higher mortality have been associated with high serum level of epithelial or macrophage-related proteins such as SP-A, SP-D, KL-6 (Krebs von den Lungen-6), CCL18 (chemokine ligand-18), and MMP-7 (matrix metalloproteinase-7)^[16][17][18]

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