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Management of interleukin-2-induced severe bronchoconstriction

T. Suda, H. Hashizume, Y. Aoshima, K. Yokomura, J. Sato, N. Inui, Y. Nakamura, T. Fujisawa, N. Enomoto, K. Chida
European Respiratory Journal 2007 29: 612-613; DOI: 10.1183/09031936.00152706
T. Suda
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H. Hashizume
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Y. Aoshima
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K. Yokomura
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J. Sato
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N. Inui
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Y. Nakamura
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T. Fujisawa
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N. Enomoto
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K. Chida
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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.

Fig. 1—
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Fig. 1—

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.

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Table 1—

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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    References

    1. ↵
      Tarhini AA, Agarwala SS. Interleukin-2 for the treatment of melanoma. Curr Opin Investig Drugs 2005;6:1234–1239.
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    2. ↵
      McDermott DF, Atkins MB. Interleukin-2 therapy of metastatic renal cell carcinoma: predictors of response. Semin Oncol 2006;33:583–587.
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    3. ↵
      Huland E, Heinzer H, Huland H. Inhaled interleukin-2 in combination with low-dose systemic interleukin-2 and interferon alpha in patients with pulmonary metastatic renal-cell carcinoma: effectiveness and toxicity of mainly local treatment. J Cancer Res Clin Oncol 1994;120:221–228.
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    4. ↵
      Gordon MS, Battiato LA, Gonin R, Harrison-Mann BC, Loehrer PJ Sr. A phase II trial of subcutaneously administered recombinant human interleukin-2 in patients with relapsed/refractory thymoma. J Immunother Emphasis Tumor Immunol 1995;18:179–184.
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      Guirguis LM, Yang JC, White DE, et al. Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases. J Immunother 2002;25:82–87.
    6. ↵
      Barutca S, Meydan N, Barlak A. Prevention of interleukin-2-induced severe bronchospasm with salbutamol. J Aerosol Med 2003;16:183–184.
      OpenUrlCrossRefPubMedWeb of Science
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    Management of interleukin-2-induced severe bronchoconstriction
    T. Suda, H. Hashizume, Y. Aoshima, K. Yokomura, J. Sato, N. Inui, Y. Nakamura, T. Fujisawa, N. Enomoto, K. Chida
    European Respiratory Journal Mar 2007, 29 (3) 612-613; DOI: 10.1183/09031936.00152706

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    Management of interleukin-2-induced severe bronchoconstriction
    T. Suda, H. Hashizume, Y. Aoshima, K. Yokomura, J. Sato, N. Inui, Y. Nakamura, T. Fujisawa, N. Enomoto, K. Chida
    European Respiratory Journal Mar 2007, 29 (3) 612-613; DOI: 10.1183/09031936.00152706
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