To the Editors:
The immunostimulatory cytokine, interleukin (IL)-2, is used for the treatment of patients with cancers, such as metastatic renal cell carcinoma and melanoma 1, 2. The toxicity of IL-2 has been well described, including hypotension, a capillary leak syndrome including pulmonary oedema, thrombocytopenia and renal dysfunction 1, 3–5. Interestingly in a rare case, IL-2 administration, especially its inhalation, was reported to cause bronchoconstriction 3, 4, 6. However, little is known about the risk factors and management of IL-2-induced bronchoconstriction. We conducted a study to elucidate the clinical characteristics of patients developing IL-2-induced bronchoconstriction and to examine how to manage this condition.
The study subjects included 18 patients with malignant cutaneous haemangioendothelioma (10 males and 8 females). Most of them were elderly with a mean (range) age of 72.3 (52–95) yrs, and all had lesions on the face and head. All patients received IL-2 immunotherapy plus radiotherapy. IL-2 was administered intralesionally in four patients and intravenously in one. The remaining 13 patients received IL-2 both intralesionally and intravenously. IL-2 was usually given 2–3 times a week. Total doses of intralesional IL-2 were 1.2–56×106 U (average, 13.8×106 U) and intravenous IL-2 were 8–60×106 U (average, 32.8×106 U).
During therapy, three patients developed severe cough, dyspnoea and chest tightness. The clinical characteristics of these three patients are shown in table 1⇓. Intralesional administration of IL-2 was performed in two of these patients, while the third patient was given IL-2 intravenously. Chest auscultation showed a diffuse wheeze. Pulmonary function tests revealed obstructive impairment with no abnormal opacities on chest radiograph. Inhalation of the bronchodilator salbutamol, a short-acting β2-agonist (SABA), showed a small increase in forced expiratory volume in one second (FEV1 <10%) with little symptomatic improvement (table 1⇓). All patients developing bronchoconstriction had a history of asthma, but they were mild-intermittent asthmatics not needing regular medication, such as inhaled corticosteroids (ICS). Bronchoconstriction typically occurred 6–8 h after IL-2 administration, and continued overnight, regardless of the administration route (fig. 1⇓). Inhalation of a SABA before IL-2 administration did not prevent the bronchoconstriction. Pre-treatment with ICS (fluticasone propionate 200–400 μg b.i.d) alone or a long-acting β2-agonist (LABA; salmeterol 50 μg b.i.d) alone, which were given 1 day before IL-2 administration, decreased an IL-2-induced fall in FEV1 by <30%. However, pre-treatment with ICS plus a LABA (fluticasone propionate 200–400 μg, salmeterol 50 μg b.i.d) markedly reduced the decline in FEV1 by 70–80% with symptomatic improvement (fig. 1⇓). The serum levels of IL-4, IL-5, eosinophilic cationic protein or the plasma levels of thromboxane-B2 did not increase after IL-2 administration.
Changes in forced expiratory volume in one second (FEV1) during interleukin (IL)-2 therapy. Vehicle (•) or IL-2 (○) were injected intravenously into patient 1. Changes in FEV1 after pre-treatment with inhaled corticosteroid (▵) or a long-acting β2-agonist (□) alone, or in combination (⋄) are shown.
Characteristics of patients developing bronchoconstriction by interleukin(IL)-2 therapy
Bronchoconstriction has been reported as an adverse effect of IL-2 in several studies, but in the majority, IL-2 was administered by inhalation 6. Our study demonstrated that the intravenous and even intralesional administration of IL-2 caused bronchoconstriction. Notably, IL-2-induced bronchoconstriction occurred exclusively in patients with a history of bronchial asthma, suggesting that asthmatics are more susceptible to bronchoconstriction induced by IL-2 therapy. IL-2-induced bronchoconstriction usually appeared 6–8 h after IL-2 administration with a 40–55% decrease of baseline FEV1 that lasted overnight. To date, there has been only one case report studying the treatment of IL-2-induced bronchoconstriction 6, in which pre-treatment with a SABA successfully prevented bronchoconstriction induced by inhaled IL-2 therapy in a case of metastatic lung tumours of renal cell carcinoma. However, the present study showed that SABA pre-medication failed to prevent the bronchoconstriction. The different route of IL-2 administration may partly explain this discrepancy. Inhalation of IL-2 was reported to develop bronchoconstriction very shortly after administration 6, while bronchoconstriction induced by intralesional and intravenous injection started 6–8 h after therapy and continued overnight. Thus, a SABA is unlikely to prevent the latter bronchoconstriction because of its short-acting effect. Interestingly, pre-treatment with LABA or ICS alone induced only a small increase in an IL-2-reduced FEV1, but ICS in combination with a LABA markedly decreased a fall in FEV1 with symptomatic improvement. These results suggest that, in addition to a long-acting bronchodilator, anti-inflammatory drugs were required for preventing IL-2-induced bronchoconstriction.
In summary, our study showed that interleukin-2 administration, even intralesionally, induced severe bronchoconstriction in patients with malignant cutaneous haemangioendothelioma. Bronchoconstriction occurred exclusively in patients with a history of bronchial asthma; therefore, attention must be directed to interleukin-2-induced bronchoconstriction, especially in patients with a history of asthma. Once it occurred, interleukin-2-induced bronchoconstriction did not respond well to bronchodilators, and pre-treatment with inhaled corticosteroids in combination with a long-acting β2-agonist successfully prevented this condition.
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