(1)
Institute of Pathology, Medical University Graz, Graz, Austria
14.1 Drug-Induced Interstitial Lung Diseases
Drug-induced interstitial lung diseases present with a variety of tissue reaction, most of them already discussed in previous chapters. A common presentation is diffuse alveolar damage as an acute reaction, often followed by organizing DAD, where hyaline membranes can still be recognized, and finally ending as organizing pneumonia and lung fibrosis. Other drugs induce NSIP-like tissue reactions. The major problem in interpreting drug reaction in the lung is our limited understanding of drug metabolism. Some drugs will induce toxic injury of endothelial cells, thus the blood barrier is leaking, and proteins can enter the interstitium and finally the alveolar lumen. Here these proteins will form complexes and by the action of respiration hyaline membranes will form. In addition the exudate from the capillaries will cause a transient edema and this is followed by hypoxia affecting the pneumocytes. This damage will contribute to DAD development (Fig. 14.1). Later on organizing pneumonia can result. Other drugs act on the immune system, forming immune complexes either because they are immunogenic by themselves or by complexing with endogenous proteins like a hapten. In these cases a NSIP or LIP pattern can result. In these cases scattered eosinophils are regularly found. Rarely granulomas are formed, usually pointing to an underlying immune mechanism. Since our understanding is so limited and no systematic experimental investigation has been performed, we still need to rely on databases, summarizing all described drug reactions in a systematic way (www.pneumotox.com; [1–8]).
Fig. 14.1
Lung disease induced by a neuroleptic is a good example how to analyze such a drug reaction. (a) In this overview there is acute bleeding, intra-alveolar fibrin, thickening of alveolar septa, and some organization. (b) Shows organizing pneumonia associated with pink material corresponding to hyaline membranes in organization, but some of these granulation processes are within the alveolar septa and look almost like fibroblast foci. The arteries have thickened walls. (c) Here fibrin is organized by granulation tissue out of the wall; this granulation tissue appears myxoid; in (d) there is a fibrin cloth within the blood vessel. This points to an injury coming from the blood stream! In (e) the interstitial granulation tissue is shown, and with this magnification one can see that this fibrosis is associated with blood vessels, which are lost. Also remnants of hyaline membranes are there. In (f) the fibrosis follows the capillaries, which are shifted into the center of the septum. In (g) this association with the blood vessels is highlighted by the Movat stain, which shows immature collagen and destroyed elastic fibers from blood vessels and alveolar septa. H&E, Movat, bars 100, 50, 20 μm
14.2 Action of Drugs and Morphologic Changes Associated with Drug Metabolism
There are different mechanisms a drug can act with:
- 1.
Drugs taken up parenterally are moving through the liver, might be metabolized, and reach the lung. At this first passage, the concentration is high. This can induce early lesions of the pulmonary endothelia, followed by edema, hemorrhage, and vasculitis and DAD. Biological mechanisms behind this reaction can be formation of oxygen radicals and lipid peroxides.
- 2.
Drugs or their metabolites can be poisonous for mitotic spindle proteins and thus inhibit mitosis and regeneration.
- 3.
Drugs and their metabolites can interfere with normal metabolism, for example, the glucose metabolism.
- 4.
An interaction with lipid metabolism can result in lipoproteinosis, but also the formation of lipid peroxides, or an interference with surfactant lipids and proteins.
- 5.
A vasculopathy can be induced by drugs most likely by deposition of immune complexes, which do not activate the complement system and therefore do not elicit an infiltration of leukocytes.
Morphologic patterns drugs can cause:
14.2.1 Granulomatous Reactions
In this case the drug associates with some endogenous protein(s) and forms immunogenic complexes, which are deposited in the lung stroma. These complexes are either too large to be dissolved by leukocytes or their chemical property does prohibit the uptake and digestion by these cells. The reaction can be a simple foreign body granuloma, when the complex is just too large, or it can be a histiocytic or epithelioid cell granuloma, when the complex has immunogenic properties (Fig. 14.2).
Fig. 14.2
Drug reaction with intravascular and bronchial epithelioid cell granulomas, pointing to an allergic mechanism. The drug could not be identified. H&E, bars 200 and 50 μm
14.2.2 DAD Pattern
If a drug is toxic by itself or metabolites derived from the drug, a DAD reaction can be caused. In these cases the first action of the drug is on endothelial cells causing necrosis. This is followed by edema and extravasation of proteins from the circulation. These proteins enter the alveolar lumina, coagulate, and will be compressed by breathing and finally form hyaline membranes. Since edema and protein extravasation will result in hypoxia, also pneumocytes will die and thus contribute to the development of DAD (Figs. 14.3 and 14.4).
Fig. 14.3
Drug reaction of leflunomide, a basic medication for rheumatoid arthritis. In a small fraction of patients, this drug will cause DAD, followed by organizing pneumonia and fibrosis, and can cause death of the patient. Here organizing pneumonia is shown at an early stage of development still with many hyaline membranes (top and middle panels). In the lower panel, there is cystic remodeling of the lung architecture with prominent bronchiolar cell metaplasia in the remaining alveoli. Some of the fibrotic foci resemble fibroblast foci. Note also atypia of single cells (middle panel). H&E, bars 100 μm, and ×100 and 200
