Drug-Induced Respiratory Disease and Hematological Diseases
Drug-Induced Respiratory Disease and Hematological Diseases
Patients with hematological malignancies or recipients of hematopoietic stem cell transplants may develop myriad pulmonary manifestations, as a complication of either the disease or the diverse agents used to treat the disease. Clinical, radiographic, and physiological features of drug-induced and radiation-induced pulmonary injury are often difficult to distinguish from other causes of pulmonary infiltrates (e.g., infections, pulmonary edema, alveolar hemorrhage, etc.). Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is essential to exclude infectious etiologies. In some cases, surgical lung biopsies are required to establish a specific etiological diagnosis. This review discusses the myriad causes of lung injury/toxicity that may afflict patients with hematological malignancies or transplant recipients, and presents diagnostic and therapeutic approaches.
Patients with hematological malignancies who are treated with chemotherapeutic drugs or recipients of bone marrow or hematopoietic stem cell transplants (HSCT) may develop a wide variety of potentially fatal infectious and noninfectious pulmonary complications, which represent a challenge to the pulmonary and critical care practitioner because the diagnosis is complex, and there is little time for diagnosis and treatment. The increased complexity of multimodality treatments and high-dose protocols designed to augment antineoplastic efficacy, and the context of HSCT have increased the incidence of pulmonary complications. As the incidence of infectious complications has decreased, as a result of effective prophylaxis and improved diagnosis, noninfectious and iatrogenic pulmonary complications have emerged as major causes of early and late morbidity and mortality. Patients with hematological diseases are exposed to a host of classic and newer drugs, which can cause lung injury with an incidence rate of a few percent, increasing to an alarmingly high 60% rate in some experimental protocols. Additional risk factors for lung injury include receipt of blood and blood products, radiation therapy to the thorax, and receipt of HSCT.
The older literature is replete with cases of distinct pulmonary toxicity induced by specific drugs when used as single agents to treat various hematological malignancies [e.g., busulfan, bis-chlororethyl nitrosourea (BCNU, or carmustine), bleomycin, chlorambucil, cyclophosphamide, melphalan]. Many of these drugs now are rarely used as single agents but, rather, are part of multiagent chemotherapy or conditioning regimens. Accordingly, in recent years, few cases of pulmonary toxicity due to these drugs have been reported. Nonetheless, these early reports are helpful because they identify the causative drug in multiagent chemotherapy regimens.
The diagnosis of drug-induced respiratory disease is by exclusion. The differential is broad, including pulmonary involvement from the underlying condition and opportunistic infections. Drug-induced lung disease must be rapidly and confidently differentiated from pulmonary infection because presenting features are similar. The diagnosis of drug-induced respiratory disease is often complex because (1) patients may be exposed to several pneumotoxic drugs concurrently or in sequence due to earlier treatment failure; (2) time to onset of pulmonary toxicity may differ among drugs, making it difficult to ascertain which drug is responsible for the pulmonary reaction; (3) the combination of drugs to treat malignant hematological conditions may lead to unexpected drug interactions, producing enhanced toxicity compared with the toxicity of each agent considered separately; and (4) radiation therapy to the chest or total body irradiation (TBI), changes in neutrophil counts, thrombocytopenia, coagulation deficits, volume overload, or left ventricular dysfunction can modulate the clinical expression of pulmonary drug toxicity.
Aside from overt pulmonary drug and radiation toxicity, subclinical drug-induced involvement often occurs in the form of reduced diffusing capacity for carbon monoxide (DLCO) or lung volumes or changes in cell populations in bronchoalveolar lavage (BAL) fluid. Upon cessation of exposure to the agent, most of these changes reverse slowly in a few weeks or months.
This article addresses the direct adverse respiratory consequences of drugs. Drug-induced opportunistic infections and respiratory complications after bone marrow and stem cell transplantation are covered separately. The important topic of iatrogenic, non-drug-induced lung or pleural involvement is covered elsewhere.
Patients with hematological malignancies or recipients of hematopoietic stem cell transplants may develop myriad pulmonary manifestations, as a complication of either the disease or the diverse agents used to treat the disease. Clinical, radiographic, and physiological features of drug-induced and radiation-induced pulmonary injury are often difficult to distinguish from other causes of pulmonary infiltrates (e.g., infections, pulmonary edema, alveolar hemorrhage, etc.). Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is essential to exclude infectious etiologies. In some cases, surgical lung biopsies are required to establish a specific etiological diagnosis. This review discusses the myriad causes of lung injury/toxicity that may afflict patients with hematological malignancies or transplant recipients, and presents diagnostic and therapeutic approaches.
Patients with hematological malignancies who are treated with chemotherapeutic drugs or recipients of bone marrow or hematopoietic stem cell transplants (HSCT) may develop a wide variety of potentially fatal infectious and noninfectious pulmonary complications, which represent a challenge to the pulmonary and critical care practitioner because the diagnosis is complex, and there is little time for diagnosis and treatment. The increased complexity of multimodality treatments and high-dose protocols designed to augment antineoplastic efficacy, and the context of HSCT have increased the incidence of pulmonary complications. As the incidence of infectious complications has decreased, as a result of effective prophylaxis and improved diagnosis, noninfectious and iatrogenic pulmonary complications have emerged as major causes of early and late morbidity and mortality. Patients with hematological diseases are exposed to a host of classic and newer drugs, which can cause lung injury with an incidence rate of a few percent, increasing to an alarmingly high 60% rate in some experimental protocols. Additional risk factors for lung injury include receipt of blood and blood products, radiation therapy to the thorax, and receipt of HSCT.
The older literature is replete with cases of distinct pulmonary toxicity induced by specific drugs when used as single agents to treat various hematological malignancies [e.g., busulfan, bis-chlororethyl nitrosourea (BCNU, or carmustine), bleomycin, chlorambucil, cyclophosphamide, melphalan]. Many of these drugs now are rarely used as single agents but, rather, are part of multiagent chemotherapy or conditioning regimens. Accordingly, in recent years, few cases of pulmonary toxicity due to these drugs have been reported. Nonetheless, these early reports are helpful because they identify the causative drug in multiagent chemotherapy regimens.
The diagnosis of drug-induced respiratory disease is by exclusion. The differential is broad, including pulmonary involvement from the underlying condition and opportunistic infections. Drug-induced lung disease must be rapidly and confidently differentiated from pulmonary infection because presenting features are similar. The diagnosis of drug-induced respiratory disease is often complex because (1) patients may be exposed to several pneumotoxic drugs concurrently or in sequence due to earlier treatment failure; (2) time to onset of pulmonary toxicity may differ among drugs, making it difficult to ascertain which drug is responsible for the pulmonary reaction; (3) the combination of drugs to treat malignant hematological conditions may lead to unexpected drug interactions, producing enhanced toxicity compared with the toxicity of each agent considered separately; and (4) radiation therapy to the chest or total body irradiation (TBI), changes in neutrophil counts, thrombocytopenia, coagulation deficits, volume overload, or left ventricular dysfunction can modulate the clinical expression of pulmonary drug toxicity.
Aside from overt pulmonary drug and radiation toxicity, subclinical drug-induced involvement often occurs in the form of reduced diffusing capacity for carbon monoxide (DLCO) or lung volumes or changes in cell populations in bronchoalveolar lavage (BAL) fluid. Upon cessation of exposure to the agent, most of these changes reverse slowly in a few weeks or months.
This article addresses the direct adverse respiratory consequences of drugs. Drug-induced opportunistic infections and respiratory complications after bone marrow and stem cell transplantation are covered separately. The important topic of iatrogenic, non-drug-induced lung or pleural involvement is covered elsewhere.