-====..
~
• reviews
------4~III.~-------------
Drug-induced Pulmonary Disease*
An Update Edward C. Rosenow Ill, M.D., f:C.C.P.; Jeffrey L. ~\Iyers, AI.D., f:C.C.~: Stephen J Swensen, M. D., F.C. C. P.; and Richard J Pisani, ill. D., f:(:.C .1~
(Chest 1992; 102:239-50)
=
= =
ACE angiotension-converting enzyme; BAL bronchoalveolar lavage; BCNU carmustine; BOOP bronchiolitis obliterans with organizing pneumonia; IL-2 interleukin-2; PVOD = pulmonary veno-occlusive disease
=
=
Diagnosing drug-induced pulmonary disease remains a challenge for all pulmonologists. Keeping up with what is new in this field is also a challenge. This review is intended for the pulmonologist who has a good working knowledge of the effects of drugs on the lungs but who needs to be brought up-to-date. One of us (E. C. R.) collects monthly Med-Line searches of articles pertaining to drug-induced pulmonary disease. Interestingly, the majority of the articles referred to in this review are from journals other than the ones that pulmonologists would be expected to read. There are a number of reviews of this subject for those interested in more in-depth information.!" Drugs known to cause pulmonary disease are shown in Table 1. Not all the drugs known to induce pulmonary disease will be discussed in this review unless new information has become available in the past several years. CARDIOVASCULAR AGENTS
Angiotensin-Converting Enzume (ACE) Inhibitors
Pulmonologists frequently encounter patients with cough due to ACE inhibitors. Approximately 15 percent of patients receiving these drugs develop a cough; the mechanism is nnknown."!' Cough occurs more commonly in women than men by a ratio of 2:1 for reasons unknown. Several reports have suggested that cough results from drug-induced bronchial hyperreactivity, while others have suggested an inflammatory mechanism. There have been no reports of severe asthma or respiratory failure similar to that reported with the beta blockers, casting doubt on the role of bronchial hyperreactivity in ACE inhibitor-related lung disease. Cough occurs with all ACE inhibitors, *From the Division ofThoracic Diseases (Drs. Rosenow and Pisani), Department of Pathology (Dr. Myers), Department of Radiology (Dr. Swensen), Mayo Clinic, Rochester, Minn.
so that switching from one to the other is of no value. Nebulized cromolyn sodium may he an effective form of therapy when it is necessary to keep these patients Table I-Agents Knoum to Cause Pulmonarq Disease Chemotherapeutic Cytotoxic Azathioprine Bleomycin" Busulfan Chlorambucil Cyclophosphamide Etoposide Melphalan Mitomycin" Nitrosoureas Procarbazine Vinblastine Ifosfamide Noncytotoxic
Methotrexate" Cytosine arabinoside" Bleomycin" Procarbazine"
Antibiotic Amphoteric-in B* Nitrofurantoin Acute" Chronic SullasalazimSu lfonam ides Pentamidine An ti-i nflaIII 111at< )ry Acetylsalicyllc acid" Gold Methotrexate Nonsteroidal antiinllammatory agents Penicillamim-" 1m mu nosuppressive Cyclosporin Interleukin-Z"
Analgesics Heroin" Methudune-" Naloxone* E t hr-hI(irvynol * Propoxvphene" Salicylates" Cardiovascular Amiodaronc" Angi()tt-nsin-e()J)vt"rting e-uzvme inhibitors Anticoagulants
Beta-hlockers" Dipyridamole Fibrinolytic agents* Protamine" Tocainide Inhalants Aspirated oil (hygen* Intravenous Blood* Ethanolamine oleate- (sodium morrhuate)" Ethiodized oil (lvmphanuiogram )
mile
Fat emulsion ~I iscellaneous
Bromocriptine Dantrole-ne I lvdrochlorothiazkle" ~I et hYS('rgide Oral contraceptives lCK.·olytic agents* Tricyclics" 1.- Tryptophan Radiation Systemic- lupus ervthematosus (clrug-
induce-d)"
Complement-mediated leukostasis"
*Typically cause acute or subacute- re-spiratorv insuflicieuc«. CHEST / 102 / 1 / JULY, 1992
239
on an ACE inhibitor." There is one case report of a captopril-induced lymphocytic alveoli tis with 59 percent lymphocytes seen on bronchoalveolar lavage (BAL).I:\ Amiodarone
About 6 percent of patients who take an average of 400 mg or more of amiodarone a day for two or more months will develop pulmonary toxicity.14.15 In 10 percent to 20 percent of patients the pneumonitis will be fatal. Diagnosing amiodarone-induced pneumonitis is difficult because affected patients have complex illne sses which may affect the lung in a variety of ways; the main considerations usually include congestive heart failure , pulmonary emboli, infection, and even the adult respiratory distress syndrome (ARDS) due to other causes. The BAL specimen shows either an increase in lymphocytes or neutrophils in about two thirds of patients and is helpful in the absence of any other explanation for these changes. A gallium-67 scan is positive in almost all patients with amiodaroneinduced pneumonitis, and the erythrocyte sedimentation rate is over 50 mmlh in most ; these two tests are unlikely to be abnormal in congestive heart failure or pulmonary emholism . Computed tomography (CT) of the lung has recently heen shown to he useful in the diagnosis in that amiodarone, an iodinated compound, increases lung density in areas where it accumulates.!"!" The density of pulmonary opacities is significantly greater than that of surrounding muscle in patients with amiodarone toxicity (Fig 1). Amiodarone also can cause a masslike lesion, which can occasionally cavitate .P-" The CT study is of value in thi s setting because it highlights the increased density of the process. Recent reports describe postoperative ARDS within
18 to 72 h in patients who have been receivmg amiodarone.t':" In some cases the patients may have received oxygen at a high FIo 2 perioperatively, raising the question ofa synergistic effect analogous to oxygeninduced bleomycin toxicity. Greenspon et al24 found that nine of 18 (50 percent) patients receiving amiodarone developed ARDS within hours of cardiac surgery for malignant ventricular tachyarrhythmias, while none of 44 patients not receiving amiodarone developed ARDS . Interestingly, some of these patients received amiodarone in a loading dose for 7 to 14 days before the procedure. While it has been theorized that subclinical amiodarone-Induced pulmonary toxicity may explain the increased incidence of postoperative respiratory failure, this would not be a likely mechanism for those who received it for only one to two weeks preoperatively. Tissue manifestations of amiodarone toxicity are variable and include chronic interstitial pneumonia with fibrosis, diffuse alveolar damage, and bronchiolitis obliterans with organizing pneumonia (BOOP).5.14.25 Characteristic foamy alveolar macrophages are seen in all of these reactions, and they can also be detected in BAL specimens. The presence of foamy macrophages is not specific, however, because they can also be demonstrated in the majority of patients taking amiodarone who lack evidence of pulmonary toxicity. Beta-blockers
Pulmonary complications of beta-blocker administration are well known and will not be reviewed here. However, timolol , an ophthalmic beta-blocker used in glaucoma, has produced a number of deaths due to aggravation of chronic obstructive pulmonary disease, including asthma and emphysema. It has been suggested that betaxolol might be a safer alternative, since initial reports of its use in asthmatics showed no adverse effects.26 Despite anecdotal reports describing patients with asthma or emphysema who developed symptoms attributed to worsening of their underlying disease, pulmonary function studies did not change significantly, indicating that betaxolol does indeed appear to be a safe alternative to timolol. 21.211 Tocainide
FI
~
• reviews
------4~III.~-------------
Drug-induced Pulmonary Disease*
An Update Edward C. Rosenow Ill, M.D., f:C.C.P.; Jeffrey L. ~\Iyers, AI.D., f:C.C.~: Stephen J Swensen, M. D., F.C. C. P.; and Richard J Pisani, ill. D., f:(:.C .1~
(Chest 1992; 102:239-50)
=
= =
ACE angiotension-converting enzyme; BAL bronchoalveolar lavage; BCNU carmustine; BOOP bronchiolitis obliterans with organizing pneumonia; IL-2 interleukin-2; PVOD = pulmonary veno-occlusive disease
=
=
Diagnosing drug-induced pulmonary disease remains a challenge for all pulmonologists. Keeping up with what is new in this field is also a challenge. This review is intended for the pulmonologist who has a good working knowledge of the effects of drugs on the lungs but who needs to be brought up-to-date. One of us (E. C. R.) collects monthly Med-Line searches of articles pertaining to drug-induced pulmonary disease. Interestingly, the majority of the articles referred to in this review are from journals other than the ones that pulmonologists would be expected to read. There are a number of reviews of this subject for those interested in more in-depth information.!" Drugs known to cause pulmonary disease are shown in Table 1. Not all the drugs known to induce pulmonary disease will be discussed in this review unless new information has become available in the past several years. CARDIOVASCULAR AGENTS
Angiotensin-Converting Enzume (ACE) Inhibitors
Pulmonologists frequently encounter patients with cough due to ACE inhibitors. Approximately 15 percent of patients receiving these drugs develop a cough; the mechanism is nnknown."!' Cough occurs more commonly in women than men by a ratio of 2:1 for reasons unknown. Several reports have suggested that cough results from drug-induced bronchial hyperreactivity, while others have suggested an inflammatory mechanism. There have been no reports of severe asthma or respiratory failure similar to that reported with the beta blockers, casting doubt on the role of bronchial hyperreactivity in ACE inhibitor-related lung disease. Cough occurs with all ACE inhibitors, *From the Division ofThoracic Diseases (Drs. Rosenow and Pisani), Department of Pathology (Dr. Myers), Department of Radiology (Dr. Swensen), Mayo Clinic, Rochester, Minn.
so that switching from one to the other is of no value. Nebulized cromolyn sodium may he an effective form of therapy when it is necessary to keep these patients Table I-Agents Knoum to Cause Pulmonarq Disease Chemotherapeutic Cytotoxic Azathioprine Bleomycin" Busulfan Chlorambucil Cyclophosphamide Etoposide Melphalan Mitomycin" Nitrosoureas Procarbazine Vinblastine Ifosfamide Noncytotoxic
Methotrexate" Cytosine arabinoside" Bleomycin" Procarbazine"
Antibiotic Amphoteric-in B* Nitrofurantoin Acute" Chronic SullasalazimSu lfonam ides Pentamidine An ti-i nflaIII 111at< )ry Acetylsalicyllc acid" Gold Methotrexate Nonsteroidal antiinllammatory agents Penicillamim-" 1m mu nosuppressive Cyclosporin Interleukin-Z"
Analgesics Heroin" Methudune-" Naloxone* E t hr-hI(irvynol * Propoxvphene" Salicylates" Cardiovascular Amiodaronc" Angi()tt-nsin-e()J)vt"rting e-uzvme inhibitors Anticoagulants
Beta-hlockers" Dipyridamole Fibrinolytic agents* Protamine" Tocainide Inhalants Aspirated oil (hygen* Intravenous Blood* Ethanolamine oleate- (sodium morrhuate)" Ethiodized oil (lvmphanuiogram )
mile
Fat emulsion ~I iscellaneous
Bromocriptine Dantrole-ne I lvdrochlorothiazkle" ~I et hYS('rgide Oral contraceptives lCK.·olytic agents* Tricyclics" 1.- Tryptophan Radiation Systemic- lupus ervthematosus (clrug-
induce-d)"
Complement-mediated leukostasis"
*Typically cause acute or subacute- re-spiratorv insuflicieuc«. CHEST / 102 / 1 / JULY, 1992
239
on an ACE inhibitor." There is one case report of a captopril-induced lymphocytic alveoli tis with 59 percent lymphocytes seen on bronchoalveolar lavage (BAL).I:\ Amiodarone
About 6 percent of patients who take an average of 400 mg or more of amiodarone a day for two or more months will develop pulmonary toxicity.14.15 In 10 percent to 20 percent of patients the pneumonitis will be fatal. Diagnosing amiodarone-induced pneumonitis is difficult because affected patients have complex illne sses which may affect the lung in a variety of ways; the main considerations usually include congestive heart failure , pulmonary emboli, infection, and even the adult respiratory distress syndrome (ARDS) due to other causes. The BAL specimen shows either an increase in lymphocytes or neutrophils in about two thirds of patients and is helpful in the absence of any other explanation for these changes. A gallium-67 scan is positive in almost all patients with amiodaroneinduced pneumonitis, and the erythrocyte sedimentation rate is over 50 mmlh in most ; these two tests are unlikely to be abnormal in congestive heart failure or pulmonary emholism . Computed tomography (CT) of the lung has recently heen shown to he useful in the diagnosis in that amiodarone, an iodinated compound, increases lung density in areas where it accumulates.!"!" The density of pulmonary opacities is significantly greater than that of surrounding muscle in patients with amiodarone toxicity (Fig 1). Amiodarone also can cause a masslike lesion, which can occasionally cavitate .P-" The CT study is of value in thi s setting because it highlights the increased density of the process. Recent reports describe postoperative ARDS within
18 to 72 h in patients who have been receivmg amiodarone.t':" In some cases the patients may have received oxygen at a high FIo 2 perioperatively, raising the question ofa synergistic effect analogous to oxygeninduced bleomycin toxicity. Greenspon et al24 found that nine of 18 (50 percent) patients receiving amiodarone developed ARDS within hours of cardiac surgery for malignant ventricular tachyarrhythmias, while none of 44 patients not receiving amiodarone developed ARDS . Interestingly, some of these patients received amiodarone in a loading dose for 7 to 14 days before the procedure. While it has been theorized that subclinical amiodarone-Induced pulmonary toxicity may explain the increased incidence of postoperative respiratory failure, this would not be a likely mechanism for those who received it for only one to two weeks preoperatively. Tissue manifestations of amiodarone toxicity are variable and include chronic interstitial pneumonia with fibrosis, diffuse alveolar damage, and bronchiolitis obliterans with organizing pneumonia (BOOP).5.14.25 Characteristic foamy alveolar macrophages are seen in all of these reactions, and they can also be detected in BAL specimens. The presence of foamy macrophages is not specific, however, because they can also be demonstrated in the majority of patients taking amiodarone who lack evidence of pulmonary toxicity. Beta-blockers
Pulmonary complications of beta-blocker administration are well known and will not be reviewed here. However, timolol , an ophthalmic beta-blocker used in glaucoma, has produced a number of deaths due to aggravation of chronic obstructive pulmonary disease, including asthma and emphysema. It has been suggested that betaxolol might be a safer alternative, since initial reports of its use in asthmatics showed no adverse effects.26 Despite anecdotal reports describing patients with asthma or emphysema who developed symptoms attributed to worsening of their underlying disease, pulmonary function studies did not change significantly, indicating that betaxolol does indeed appear to be a safe alternative to timolol. 21.211 Tocainide
FI
