|Year : 2019 | Volume
| Issue : 5 | Page : 19-26
Drug-Induced Interstitial Lung Disease
Wei-I Lee1, Pravin Hissaria2
1 Department of Clinical Immunology and Allergy, Royal Adelaide Hospita, Adelaide SA 5000, Australia
2 Department of Immunopathology, SA Pathology, Adelaide SA 5000, Australia
|Date of Web Publication||2-Dec-2019|
Dr. Pravin Hissaria
Department of Immunopathology, SA Pathology, Royal Adelaide Hospital, Adelaide, South Australia 5000
Source of Support: None, Conflict of Interest: None
Drug-induced interstitial lung disease (DIILD) represents a rare but potentially fatal adverse drug reaction. A large number of drugs have been implicated to have this potential risk, including chemotherapeutics and disease-modifying antirheumatic drugs. The clinical presentations, laboratory investigations, pulmonary function test result, and imaging and histopathological findings associated with drug-induced pulmonary fibrosis are nonspecific. The diagnosis is achieved after the exclusion of alternative diagnosis, such as infection, pulmonary edema, and connective tissue diseases. However, sometimes, the underlying diseases (e.g., rheumatoid arthritis) and the drugs used to treat the disease (e.g., methotrexate) can both cause ILD; it is often difficult to tease out causality especially if baseline pulmonary assessment (respiratory function test and imaging) is incomplete prior to the commencement of the drug therapy. Many efforts have been put into investigating the pathogenesis of the DIILD, particularly as animal model of bleomycin-induced pulmonary fibrosis has been used as a surrogate for idiopathic pulmonary fibrosis. However, more research is required to improve our understanding of pathogenesis in order to develop more sensitive and specific diagnostic tests as well as to establish evidence-based treatment approach.
Keywords: Drug-induced, interstitial lung disease, pulmonary fibrosis
|How to cite this article:|
Lee WI, Hissaria P. Drug-Induced Interstitial Lung Disease. Indian J Rheumatol 2019;14, Suppl S1:19-26
| Introduction|| |
More than 350 drugs can cause pulmonary toxicity, and the list of the offending drugs is likely to increase over time in this age of rapid drug discovery and improved postmarket surveillance. In interstitial lung disease (ILD) registries, about 3% of cases were attributed to drugs; this diagnosis is less commonly seen compared to sarcoidosis, connective tissue diseases/vasculitis, inhalation of organic/inorganic particles, and idiopathic pulmonary fibrosis (IPF)., The most commonly implicated drugs, outlined in [Table 1], include anti-neoplastic agents, disease-modifying antirheumatic drugs (DMARDs), antibiotics and cardiology drugs.,,
The incidence of drug-induced ILD (DIILD) is variable depending on the drug implicated. The readers are encouraged to refer to Skeoch et al.'s systemic review of DIILD for its comprehensive summary table regarding drug-specific incidence. The risk of pulmonary toxicity may increase with increased duration of drug use. Amiodarone-induced pulmonary toxicity incidence increases from 4.2% to 10.6% when drug use duration increases from 1 to 5 years.
The reported incidence of DIILD varies over time. From the result of the meta-analysis of randomized controlled trials, most studies reporting methotrexate-related pneumonitis (MTX-P) occurred prior to 2002. Carson et al. initially reported the incidence of probable or possible MTX-P as 3.9/100 patients/year in a retrospective case series in the late 1980s. The diagnostic criteria used by Carson et al. included (1) a clinical course consistent with a hypersensitivity reaction, (2) resolving pulmonary infiltrate on imaging after MTX drug cessation, (3) exclusion of infection or other pulmonary disease, and (4) histology consistent with drug-induced injury. Patients fulfilling any two of the above criteria were considered to have “possible” MTX-P, whereas those fulfilling three or more criteria to have “probable” MTX-P.
However, a prospective study in 2002 found that there is no difference in pulmonary function in rheumatoid arthritis (RA) patients treated with MTX compared to other DMARDs over a 2-year follow-up period. A further large prospective study in 2012 found incidence of MTX-P (using the same diagnostic criteria as that of Carson et al.) to be 1 case for every 192 patient-year. Prospective study design and more complete baseline pulmonary function and lung imaging likely improve causality attribution in the latter two case series and may account for the apparently reduced incidence of the disease despite increased clinical recognition of MTX-P and higher MTX dose use in recent time compared to 20 years ago. Another plausible outcome of improved baseline pulmonary assessment is that patients with RA-related ILD may be less likely to be put on MTX, and the biased prescription of DMARD depending on baseline assessment may also account for the apparently reduced incidence.
This phenomenon of biased prescription also affects the prevalence of DIILD of other drugs. In a Japanese study, leflunomide-induced ILD was reported in 1.2% of RA patients receiving leflunomide. However, a case–control study of a large cohort of RA patients to whom DMARDs has been dispensed in Canada over a 5-year-period showed that the risk of ILD was not increased in patients on leflunomide if they did not have previous MTX use or a history of ILD, but the risk is increased among other patients on leflunomide. In the same Canadian study, patients with a history of ILD were more likely to be prescribed with leflunomide than other DMARDs.
Another factor to be considered when discussing the incidence of DIILD is accurate disease diagnosis. This is often difficult due to lack of sensitive and specific laboratory markers as well as often incomplete case assessment. In many case series and case reports, absence of bronchoalveolar lavage (BAL) and/or tissue biopsy precludes confident exclusion of alternative diagnoses, such as atypical infection or lymphangitic carcinomatosis. For example, in a cohort of ILD related to biological agents compiled by a Spanish working group from published articles between 1990 and 2010, histopathological description was only detailed in 20 out of 122 reported cases. In many cases, broad-spectrum antibiotics were given alongside high-dose glucocorticoid therapy for treatment given pulmonary infection cannot be excluded. This means that in many cases, drug-induced pulmonary toxicity remains presumptive or probable at best.
Furthermore, many rheumatology patients had either previous therapy with DMARDs or concomitant DMARDs, making case attribution to a specific biological agent difficult. Similarly, many cancer patients also had extensively treatment history (in many cases with combination chemotherapy); drug attribution in these cases can also be difficult.
A meta-analysis of the cancer clinical trials using immune checkpoint inhibitors (ICIs) reported incidence of pneumonitis of any grade related to PD-1 inhibitors and PD-1 L inhibitors to be 3.6% and 1.3%, respectively. Report of pneumonitis has also been made in clinical trials of melanoma patients treated with ipilimumab (cytotoxic T-lymphocyte antigen-4 [CTLA-4] inhibitor). Pneumonitis occurred at higher incidence in active or ex-smokers, when combination ICIs were used, or when ICIs was used in the treatment of lung cancer (compared to other cancer types)., However, most patients had Stage IV disease when ICIs were introduced (with baseline tumor burden in their lungs). In addition, majority had received at least one previous line of treatment before immunotherapy with a short median duration between a previous treatment line and ICI. These suggest that in these patients with suspected ILD related to ICIs, significance of radiological or pulmonary function changes may be hard to interpret as their lung architectures are likely distorted by a combination of cancer, smoking, and previous chemotherapy prior to commencement of ICIs.
Knowing the limitation of case ascertainment, this does not take away the significance of these rare drug-related adverse reactions. For example, in the case of tacrolimus-ILD reported to Japanese Pharmaceuticals and Medical Devices Agency, even though tacrolimus-induced ILD only accounted for 3% of tacrolimus-related adverse events, fatal outcome resulted from 26% (25 out of 98) cases of tacrolimus-induced ILD. Similarly, the mortality rate of DIILD associated with biological agents (mostly tumor necrosis factor [TNF] inhibitors) was reported to be 29%.
| Onset of Pulmonary Toxicity from The first Dose of Drug Administration|| |
The onset of pulmonary toxicity after drug use is drug dependent [Table 2]. In an older retrospective case series of MTX-P, MTX duration prior to pulmonary symptoms was variable and ranged from 3.5 months to 4 years., Interestingly, BAL from early-onset MTX-P (within 6 months of treatment onset) showed significantly higher neutrophil count compared to late-onset MTX-P, whereas the late-onset MTX-P showed significantly higher lymphocyte count compared to early-onset MTX-P. This suggests different mechanisms may underly the early-and late-onset MTX-P.
|Table 2: Some examples of drugs and the onset of pulmonary toxicity after drug commencement|
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In the case of rituximab-ILDs, three types of tempo of onset were observed. The early-onset hyperacute form occurred within a few hours after infusion, and these patients often developed acute respiratory distress syndrome with significant oxygen desaturation requiring respiratory support. The delayed-onset acute form occurred 2–3 weeks after the last infusion (often in cycle 3–5), and the delayed-onset chronic form occurred 1–3 months from the last rituximab infusion (often in cycles 2–5). The underlying mechanisms for these lung diseases remain unclear, but it is plausible that they may differ.
| Risk Factors|| |
Older age at the onset of drug commencement is a risk factor for amiodarone-, bleomycin-, amiodarone-, and gemcitabine-induced pulmonary toxicity.,, Preexisting lung disease predisposes to lung disease associated with MTX, tyrosine kinase inhibitor (TKI), and epidermal growth factor receptor inhibitor.,, Male sex and a history of smoking predict risk to TKI-associated lung disease. The increased incidence of TKI-, bleomycin-, and leflunomide-induced lung disease in Japanese population compared to that of the Western population implicates genetic polymorphism as a risk factor. Drug dose and oxygen administration are risk factors for bleomycin-induced pulmonary toxicity; this supports the role of direct drug toxicity and oxidative stress in its pathogenesis, which will be discussed next.,
| Mechanisms for Drug-Induced Pulmonary Toxicity|| |
The lung undergoes inflammatory response and repair upon sustaining injury; fibrosis can occur subsequent to this process. Organ-specific toxicity may be related to higher drug concentration (or metabolite) reached in the organ; in the case of lung, this may be related to its large surface area and good vascular supply.
Different drugs exert different mechanisms of injury to lung tissues. Bleomycin can induce reactive oxygen species formation and cause DNA breaks; this induces cellular death both at tumor sites and in lungs. Amiodarone can induce accumulation of phospholipids in lung tissues by inhibiting lysosomal phospholipase activity and preventing degradation of phospholipids. Using the combination of taurine (with antioxidant property) and niacin (which can increase tissue NAD level) can prophylactically protect against both bleomycin-induced and amiodarone-induced pulmonary toxicity in hamster model., This provides further evidence for the role of oxidative stress in DIILD.
Hypersensitivity mechanism likely contributes to gold- and sulfasalazine-induced lung disease. In a cohort of gold-induced pneumonitis identified from retrospectively analyzing medical literature, lymphocyte stimulation testing with peripheral blood mononuclear cells and gold was positive in 45% of cases; in the rare cases when BAL mononuclear cells were extracted and subject to lymphocyte stimulation testing with gold, some positive results were seen. This suggests the formation of likely drug-specific T cell memory, which can result in delayed-type hypersensitivity reaction affecting lungs. Furthermore, in a small case series of 17 patients with RA and gold-induced pneumonitis, 14 expressed similar MHC markers (in either HLA-A3 or HLA-B40). As evidenced by other drugs such as abacavir, carbamazepine, and allopurinol, specific HLA alleles can predispose to increased risk of drug-related hypersensitivity reactions.
The chemical structure of sulfasalazine consists of 5-aminosalicylic acid (5-ASA) and sulphapyridine. The sulphapyridine component likely mediates the hypersensitivity reaction. Patients with nonpulmonary hypersensitivity reaction to sulfasalazine demonstrated reactivity to sulphapyridine on lymphocyte transformation test. In a case report of sulfasalazine-induced pulmonary toxicity, re-challenge with sulphasalazine followed by a later challenge with sulphapyridine component was positive in both challenges. In another case report, a patient with sulfasalazine-induced pulmonary toxicity also had a positive challenge with sulphapyridine; later the patient tolerated olsalazine, another 5-ASA related drug.
Multiple mechanisms for MTX-P have been proposed including direct toxicity to pulmonary tissue and hypersensitivity. MTX can accumulate in lung tissue. Pulmonary fibrosis can develop in mice been fed with nonmyelosuppressive dose of MTX for 3–5 weeks; in addition, incubating mouse alveolar epithelial cells with MTX can result in direct cytotoxicity as evidenced by increased apoptosis. In addition, MTX can induce epithelial–mesenchymal transition on alveolar epithelial cells with evidence of change in their morphology and intracellular actin arrangement; there is evidence of increased SMAD2 phosphorylation and transforming growth factor (TGF)-beta1 secretion by final mesenchymal cell type.
Hypersensitivity was also proposed as a mechanism for MTX-P on the basis of nonspecific finding of peripheral eosinophilia and BAL finding of lymphocytosis as well as more specific finding of leukocyte migration inhibition in patients with MTX-P. Leukocyte migration inhibition test was performed more so in the 1980s–1990s in Japan to elicit drugs responsible for drug-induced pneumonitis., Reduced leukocyte migration in the presence of a drug yields a positive test and suggests the production of leukocyte migration inhibitory factors. In a small case series, patients with MTX-P had positive leukocyte migration inhibition test, whereas normal controls and patients on MTX but without pneumonitis had negative test result.
MTX re-challenge sometimes produced recurrence of pulmonary pathology (in supporting of hypersensitivity mechanism), but sometimes did not. HLA-A*31:01 was found to be significantly associated with Japanese RA patients with MTX-P compared with control Japanese RA patients without MTX-P in support of the hypersensitivity mechanism. However, the same finding cannot be replicated in an UK case–control study for MTX-P using a genome-wide association study. Taken together, it is plausible that drug toxicity accounts for some cases of MTX-P, whereas hypersensitivity accounts for other cases.
Pulmonary injury is one of the manifestations of immune-related adverse events (irAE) associated with ICIs. ICIs act to release the immune inhibition placed upon T cells, such that T cells can mediate immune response toward these cancer cells more effectively. This process likely disrupts immune tolerance and results in irAEs. irAEs can affect any organs (e.g., gastrointestinal tract, skin, liver, and thyroid). They resemble autoimmune diseases and respond to immunosuppressive therapy. One of the hypotheses proposed to explain why some patients develop irAEs but not others on ICIs is the presence of autoantibodies either before treatment or induced after treatment in patients who develop irAEs. Conflicting results have been found in the search for autoantibodies that mediate irAEs; some suggested that the presence of autoantibodies distinguished those suffered from irAE from those who tolerated ICIs, but some did not find this helpful.,,, Genetic susceptibility is also proposed, but data are lacking at this stage.
As a result of pulmonary injury, various cytokines including interleukin-1 (IL-1), TGF-β, TNF, and platelet-derived growth factors (PDGFs) are released.,,, These mediators then stimulate infiltration of inflammatory cells and proliferation of fibroblasts and result in excessive extracellular matrix deposition in the lung tissues.
| Clinical Presentation and Investigations|| |
DIILD can present in an acute or subacute manner.,, Commonly reported symptoms and signs include dyspnea, cough, fever, chest pain, crepitation, and oxygen desaturation.,, Peripheral eosinophilia can be observed in 20%–40% of cases of MTX-P, and also in 38% and 52% of gold-induced and sulfasalazine-induced pulmonary toxicity, respectively.,,, Leukocytosis and leukopenia are both possible.,,
Restrictive pulmonary function test with reduced DLCO and hypoxemia on blood gas is commonly reported.,,, Computed tomography (CT) scans of DIILD tend to show interstitial and/or alveolar infiltrates.,, Parenchymal consolidation, centrilobular nodules, pleural involvement, and bronchiectasis have also been reported., Diffuse alveolar damage (DAD) predicts longer treatment duration and worse prognosis.,
BAL tends to demonstrate lymphocytosis; both elevated CD4+/CD8+ ratio, and reduced CD4/CD8 ratio, can be observed. Eosinophilia and neutropenia in BAL can also be seen.,, Presence of foamy macrophages in BAL is consistent with amiodarone exposure, but they are present even in patients on amiodarone but did not have evidence of pulmonary toxicity. As mentioned before, another role for BAL concerns accurate microbial diagnosis which is especially important in immunosuppressed individuals.
Pulmonary biopsy histology tends to demonstrate hyperplasia of Type II pneumocytes and widening of alveolar septa with inflammatory infiltrate and fibrosis, consistent with interstitial pneumonitis and fibrosis; this occurs in pulmonary toxicity associated with amiodarone, bleomycin, gold, MTX, and sulfasalazine.,,,, Granuloma,,, hyaline membranes,,, giant cells, bronchiolitis,, honeycombing, or eosinophilic pneumonitis are also sometimes seen. Deposits of immunoglobulins were seen in some cases of gold-induced pneumonitis.
RA-related lung disease can present with insidious-onset respiratory symptoms, with further investigation revealing a spectrum of abnormality on imaging, restrictive lung function test, impaired DLCO, abnormal BAL (neutrophilia or lymphocytosis both possible), and a spectrum of histopathological findings on lung biopsy.
| Biomarkers Been Studied but not Widely Utilized|| |
Krebs von den Lungen-6 (KL-6) is a mucin-like glycoprotein secreted by proliferating Type II alveolar pneumocytes. Serum KL-6 is elevated in patients with interstitial pneumonitis but does not distinguish between the causes, for example, radiation pneumonitis, IPF, collagen vascular disease, hypersensitivity pneumonitis, and sarcoidosis., A high level of KL-6 occurs in the setting of higher pulmonary disease activity, and it reduces once the disease is brought under control., Its use has also been evaluated in the setting of DIILD., In patients with DIILD, elevated KL-6 occurred in patients with CT evidence of DAD and chronic interstitial pneumonia, but not in patients with other CT chest findings. In another study, the absolute value of KL-6 does not predict the prognosis, but the ratio of KL-6 at the onset of pulmonary symptoms to KL-6 at baseline predicts the prognosis of ILD associated with EGRF-TKI. These studies demonstrated the prognostic value of KL-6 in DIILD; however, caution still needs to be exercised with respect to the specificity of KL-6 assay as elevated level of KL-6 can also be found in the setting of pneumocystis jiroveci infection; opportunistic infection is one of the most important differential diagnoses for DIILD.
Other biomarkers that have been evaluated in DIILD and have showed some promising value as prognostic factor (but have not been assessed to the same extent as KL-6) include surfactant protein-D and serum heat shock protein 47.,
| Treatment|| |
Unfortunately, no clinical trials have been performed on patients with DIILD. Based on an observation of the case series of DIILD, drug cessation and supportive therapy are often employed. High-dose corticosteroids are often used to hasten recovery, especially when cases are severe.,, Some patients may receive antibiotic in spite of negative cultures., Other immunosuppressive regimens have been tried in some cases of DIILD, including azathioprine and cyclophosphamide.,
Imatinib is a TKI that is active against BCL-ABL, but it also has antifibrotic property and inhibits tyrosine kinase of PDGF receptors (PDGFRs). In animal models, administration of imatinib prophylactically inhibits bleomycin-induced pulmonary fibrosis by reducing the proliferation of mesenchymal cells (including lung fibroblasts). In a multicentric randomized controlled study of idiopathic lung fibrosis, imatinib did not improve lung function or survival compared to placebo after 96 weeks of treatment. Imatinib has been used in case reports for the treatment of bleomycin-induced pulmonary toxicity with mixed outcomes., Clinicians need to watch out for the side effects of imatinib including thrombocytopenia and gastrointestinal bleed.
Patients with genetic CTLA-4 deficiency suffer from immune-mediated organ toxicities similar to irAE related to ICIs. Patients with genetic LRBA deficiency experience secondary loss of CTLA-4, as LRBA is important in the internal trafficking of CTLA-4, and present with similar immune-mediated organ toxicities. Abatacept, a CTLA-4 immunoglobulin fusion protein, has been used successfully for the treatment of these immune-mediated organ toxicities in patients with genetic CTLA-4 deficiency and of ILD (with T cell interstitial infiltrate) in patients with genetic LRBA deficiency., Recently, abatacept was used to treat life-threatening, glucocorticoid-refractory myocarditis associated with nivolumab (PD-1 inhibitor) with good effect. Abatacept inhibits CD28-B7-mediated T cell co-stimulation, and intact CD28/B7 co-stimulatory pathway is essential for effective PD-1 inhibitor function. Currently, abatacept has not been tried as a treatment of DIILD associated with ICIs. Certainly, clinicians need to balance the benefit of suppressing pulmonary toxicity against the risk of cancer progression.
In animal models, IL-1 receptor antagonist, dasatinib (PDGFR and Src-kinase inhibitor), sorafenib (which antagonizes TGFβ signaling), pirfenidone, and tacrolimus have the potential to reverse established bleomycin-induced pulmonary toxicity.,,,, More research is warranted to see if they can be used clinically for DIILD. The question of why some of the drugs that have been implicated as a cause of ILD (e.g., tacrolimus and imatinib) can also be used as treatment for ILD in animal models remains puzzling. While we can attribute this partly to the differences between animal model from human model, our inadequate knowledge into disease pathogenesis should also be reflected upon. It is likely through the improvement of basic science that better treatment can be designed and trialed.
Drug re-challenge has been performed in some cases; however, this practice poses ethical issues as patients may be exposed to risks. At this stage, cross-reactivity among drugs that cause DIILD has not been reported, for example, among the members of TKIs or TNF inhibitors.,
| Conclusion|| |
DIILD is a rare but potentially fatal drug-related adverse reaction. Clinical presentation and investigation results are often nonspecific. Diagnostic criteria (consist of clinical, laboratory, radiological, and pulmonary tests and histopathological findings) for MTX-P and gold-induced pulmonary toxicity had been proposed;,, however, these are by no mean specific. Upon clinical suspicion, implicated drugs should be stopped promptly, and investigations need to be instituted with the goal of establishing the extent of pulmonary injury and excluding infection. High-dose corticosteroids should be considered. Distinguishing drug effect from the underlying disease and infection is not always easy; however, in either case, a change in treatment for the underlying disease should be considered. More research is required to improve our understanding of pathogenesis in order to develop more sensitive and specific diagnostic tests as well as establish evidence-based treatment approach.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]