Bleomycin is a cytostatic agent used in the treatment of cancer.1 – 3 The most worrisome adverse effect is lung toxicity, with a mortality rate of 1% to 5%.2– 4 This side effect is dose-dependent, develops over a period of weeks to months, and is rare when doses <300 mg are used, especially in children without risk factors.1, 2 In exceptional cases, some patients may develop acute hypersensitivity pneumonitis, which usually responds to steroids.2– 4
Since 1977, bleomycin has been used as an effective intralesional treatment of vascular and lymphatic
malformations.5 Large series have not reported any systemic side effects after low doses of bleomycin intralesional injection, and conclude that it is safe for the management of these malformations.5 – 10 Acute pulmonary complications have only been previously described in 1 infant after intralesional administration of bleomycin (1.2 mg/kg; 1.8 U/kg).1 We report a case of severe acute lung toxicity after intralesional sclerosis of a cervical low-flow venous malformation using a low dose of bleomycin in a 5-year-old girl.
Acute Lung Toxicity After Intralesional Bleomycin SclerotherapyAna Méndez-Echevarría, MD, PhD, a Andres Fernandez-Prieto, MD, b Olga de la Serna, MD, c Juan-Carlos Lopez-Gutierrez, MD, PhD, d Manuel Parron, MD, e Begoña Marin-Aguilera, MD, b Cristina Calvo, MD, PhDa
Bleomycin has progressively been used to treat low-flow vascular malformations in children. No significant systemic side effects have been reported in large series after low doses, but some authors are still concerned about its use. We report a case of a severe acute lung toxicity after a low dose of a second bleomycin intralesional injection in a 5-year-old girl. She had no risk factors and presented a cervical low-flow venous malformation. Twenty-four hours after this second administration, she presented with fever and respiratory distress. A chest radiograph showed bilateral opacities and computerized tomography revealed extensive and diffuse lung ground-glass opacities. The patient started to receive intravenous methylprednisolone, but she experienced progressively increased dyspnea, and montelukast was added. She improved and was discharged from the hospital without oxygen support, with montelukast and prednisolone for tapering doses during months. Five months after onset, the patient is developing well, is active, and walks and talks without dyspnea. A new low-dose computed tomography shows improvement in radiologic findings. This is the second case of pulmonary toxicity observed in a child after bleomycin intralesional administration, and the first reported after the lowest dose of this drug to date (7 mg: 0.28 mg/kg; 10 U: 0.4 U/kg). A delay in the diagnosis and treatment of this complication can be fatal. Any physician who treats these patients must be alert and consider this complication in children with respiratory symptoms after bleomycin sclerotherapy. Early detection of pulmonary toxicity would allow prompt therapy and could avoid pulmonary damage.
abstract
To cite: Méndez-Echevarría A, Fernandez-Prieto A, de la Serna O, et al. Acute Lung Toxicity After Intralesional Bleomycin Sclerotherapy. Pediatrics. 2018;141(1):e20161787
Departments of aGeneral Pediatrics and Infectious and Tropical Diseases, bRadiology, Interventional Neuroradiology Unit, cPediatric Pneumology, and dPediatric Surgery, and ePediatric Radiology Section, Hospital La Paz, Madrid, Spain
Drs Méndez-Echevarría and Calvo conceptualized and designed the article, corresponded with all the coauthors, and drafted the initial manuscript; Drs Fernandez-Prieto, Lopez-Gutierrez, and Marin-Aguilera collected all the data of the sclerosis procedure and the fluoroscopy/phlebography, reviewed the bleomycin doses and the fraction of inspired oxygen administrated during general anesthesia, and critically reviewed the manuscript; Dr de la Serna reviewed the capnography, the spirometry, and the 6-minute walk test results and performed the review of the literature regarding pulmonary toxicity of bleomycin and follow-up of pulmonary function in patients after the drug administration; Dr Parron reviewed the radiology results (chest radiograph and computerized tomography) and performed the review of the literature regarding the several pulmonary syndromes associated with bleomycin toxicity and their correlation with radiological imaging found; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Address correspondence to Ana Méndez-Echevarría, MD, PhD, Department of General Pediatrics and Infectious and Tropical Diseases, Hospital La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain. E-mail: [email protected]
A previously healthy 5-year-old girl with a cervical low-flow venous malformation (Fig 1) received a first intralesional percutaneous bleomycin injection (7 mg; 0.28 mg/kg) after fluoroscopy venography.9 Bleomycin was administrated as a liquid and was reconstituted with saline and nonionic contrast media (concentration: 1 U/mL) to allow its direct visualization during the injection through a 23-gauge needle, 9 without side effects.
The malformation shrank slightly, and a second injection was indicated 3 months later (7 mg: 0.28 mg/kg; 10 U: 0.4 U/kg). Ultrasound guidance during the sclerotherapy showed no global change of its size.
The second procedure was also performed under general anesthesia, without radiologic evidence of venous systemic drainage at venography (Fig 2). The lowest fraction of inspired oxygen to maintain 93% pulse oxygen saturation (Spo2) was used.
Twenty-four hours after the second administration, the patient presented with low-grade fever, asthenia, and
progressive dyspnea, arriving at the emergency department with significant respiratory distress. The respiratory rate was 60 breaths per minute, with 94% Spo2. Lung auscultation revealed diminished breath sounds on the right lung basal region without expiratory wheezes. A chest radiograph showed bilateral opacities with an incipient right basal lung consolidation. She was admitted with intravenous ampicillin and azithromycin, but after 24 hours, she presented with central cyanosis, requiring oxygen support with 1 L per minute to maintain an Spo2 ≥94%. The echocardiography and the electrocardiography were normal. A computerized tomography (CT) of the chest (Fig 3) revealed extensive and diffuse lung ground-glass opacities predominantly in the upper lobes with a peripheral distribution. A ventilation-perfusion scan ruled out the possibility of pulmonary thromboembolism. Prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer levels were all within normal limits. The eosinophil count was normal at admission and during the subsequent weeks. Capnography did not detect
abnormal Co2 concentrations. At admission, spirometry was abnormal with moderate restrictive defects, forced vital capacity (FVC) was 63% of the predicted volume, and the forced expiratory volume in 1 second/FVC ratio was 91%. Specimens of nasopharyngeal aspirate were taken for virological study by using polymerase chain reaction to detect a total of 16 respiratory viruses as well as Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae serology. No evidence of viral or bacterial infection was observed. The patient had started to receive intravenous methylprednisolone (2 mg/kg per day). On the sixth day of therapy, dyspnea increased, hypoxemia reappeared, and montelukast was added at a dose of 5 mg per day orally. The patient improved and oxygen was discontinued after 15 days. She was discharged from the hospital with oral montelukast and prednisolone, which was tapered from 2 mg/kg per day orally at intervals of 2 to 4 weeks until discontinued. However, after prednisolone was discontinued, the patient experienced oxygen desaturation during the 6-minute walk test (79% Spo2, and walking distance
MéNDEz-ECHEVARRíA et al2
FIGURe 1A, Cervical MRI, T2-weighted image, sagittal plane. The lobulated T2, hyperintense, intramuscular cervical lesion is depicted, well defined, showing hypointense phleboliths inside, consistent with a venous superficial malformation. B, Cervical MRI, T2-weighted image, axial plane. The intramuscular cervical extent of the venous malformation is shown.
FIGURe 2Nonsubtracted image of the double fluoroscopic percutaneous bleomycin injection mixed with nonionic contrast media and saline (50%). No venous systemic drainage of the substance is seen.
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of 480 m), and steroids were again prescribed in tapering doses for 4 more months. She did not use oxygen support after she was discharged from hospital.
At the most recent follow-up, 5 months after the onset of the symptoms, the patient is thriving and developing well without needing supplemental oxygen. She is active, walks and talks without dyspnea, and she does not present oxygen desaturation during the 6-minute walk test (98% Spo2, walking distance of 507 m). Her last spirometry (4 months after hospital discharge) revealed normal respiratory function (FVC 87% of the predicted volume). A new low-dose CT shows an evident improvement in radiologic findings (Fig 4).
DIsCUssIOn
The appropriate option for vascular malformation treatment should be selected according to its type, size, location, age of the patient, or associated symptoms.10 Sclerotherapy is widely accepted as the preferred treatment option for vascular malformations, 5 but surgical excision should be considered for nonresponding patients, small lesions located in critical areas, or for malformations with large draining veins. Complete excision of large malformations is difficult and recurrence is common.11
The ideal sclerosing agent in the pediatric population remains to be discovered. Multiple sclerosing materials have been employed in children, such as ethanol, 3% sodium tetradecyl sulfate, ethibloc, or polidocanol. Risk of systemic toxicity, local necrosis, or pain has been described with the use of these different agents.5
Bleomycin was first used to treat vascular malformations in 1977, and its use has progressively increased. The drug can properly reduce the size of malformations with few systemic
side effects reported compared with other sclerosants.5 – 10 Intralesional administration of the drug induces endothelial mesenchymal transition, where endothelial cells change into fibroblastlike cells.12 This produces a sclerotherapeutic effect, but it could also play a role in the development of inflammation and pulmonary fibrosis.2, 4, 12
Several distinct pulmonary syndromes have been associated with the systemic use of bleomycin in patients with cancer.3 The most frequent and worrisome pulmonary complication is pulmonary fibrosis. This is a chronic complication that usually develops when doses <400 mg are used, which is much higher than doses given during sclerotherapy (<10 mg per session; 15 U per session).2, 9, 11 Other risk factors include cumulative dose,
reduced renal function, increased age, smoking, use of granulocyte colony-stimulating factor, or mediastinal radiation.4
However, acute pulmonary complications, such as eosinophilic hypersensitivity pneumonitis, have also been described. Although interstitial pneumonitis and fibrosis are observed with high and cumulative doses, bleomycin hypersensitivity can occur within hours of administration, 1, 2 as we observed in our patient, and with doses as low as 20 mg2. Its clinical manifestation seems like a hypersensitivity reaction, presenting with fever and diffuse infiltrate at chest radiograph with eosinophilia.2
Only 1 case of pulmonary toxicity has been reported over the past 15 years.1, 8, 10 This patient
PEDIATRICS Volume 141, number 1, January 2018 3
FIGURe 3A, Coronal and B, axial CT showing bilateral and scattered consolidations and ground-glass opacities predominantly in the upper lobes with a peripheral distribution.
FIGURe 4A, Coronal and B, axial low-dose CT. Improvement in radiologic findings with a minimal ground glass-opacity in right upper lobe 5 months after bleomycin injection.
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was an 8-month-old girl who developed pneumothorax and pneumomediastinum 1 day after bleomycin administration, requiring corticosteroids, pentoxifylline, and supportive care, with complete recovery 5 months after this event.1 A higher dose of intralesional bleomycin, relative to the size of the patient, was used in this case, which may have contributed to the drug toxicity.
Currently, 3 child pulmonary-related deaths have been reported after bleomycin intralesional injection, but they did not seem related to bleomycin toxicity.10 Besides, these patients had lesions with direct connection to systemic vasculature and higher doses were used.11 To our knowledge, until our report, there have been no documented cases of pulmonary toxicity using doses as low as 0.28 mg/kg; 0.4 U/kg.9 However, our patient presented with an acute hypersensitivity reaction, which is not usually dose-dependent.
Patients with chronic lung toxicity can also be asymptomatic.4 Zorzi et al3 demonstrated that up to 59% of children with cancer treated with bleomycin could have abnormal pulmonary function tests with restrictive ventilatory defects 2 years after therapy. These authors refer to chemotherapeutic use of bleomycin, where high systemic and cumulative doses are used. However, our patient was treated for a venous malformation rather than lymphatic, and the systemic dose was therefore likely to be higher, despite the lack of visible systemic venous drainage observed during the sclerotherapy.
Baseline pulmonary function tests are not routinely performed on children before sclerotherapy, and there is a lack of adequate follow-up of pulmonary function in many series, especially among pediatric cases.6 However, authors who have performed pulmonary function tests did not identify pulmonary complications8, 9
after a mean follow-up period of 3.2 years (range: 1.5–5 years).9
The treatment for acute lung hypersensitivity is high doses of steroids.2 The response is sometimes suboptimal, and a prolonged course may be necessary.1 Anecdotal reports have suggested a beneficial effect of pentoxifylline for bleomycin-induced lung toxicity.1 This treatment was offered to our patient, and its off-label use was discussed with her family, who rejected its administration. Pharmacologic inhibition of leukotriene activity attenuates bleomycin-induced lung injury, and increased leukotriene levels have been found in animal models after intratracheal administration of bleomycin.13, 14 For these reasons, we decided to use montelukast as a complement to steroid therapy for our patient.
Prevention of hyperoxia during the injection may avoid pulmonary complications.4, 15 Young children and infants usually need general anesthesia during percutaneous bleomycin therapy, and providing safe anesthesia avoiding hyperoxia is important.15 These children must have the inspired oxygen concentration limited to the lowest level to maintain satisfactory oxygen saturation levels.8, 15 An adequate state-of-the-art Spo2 monitor serves as a guide for when to increase the fraction of inspired oxygen and by how much. Preoxygenation must be avoided and supplemental oxygen restricted, aiming for a normal oxygen concentration and a target minimum Spo2 of 94%. Some cases can be managed with a laryngeal mask airway or oropharyngeal airway, avoiding desaturation associated with extubation.15 During recovery, no supplemental oxygen is prescribed unless the oxygen saturation decreases to <94%, and, if required, the lowest effective supplementation is used.15
In our case, no bronchioalveolar lavage or lung biopsy was performed to exclude other etiologies. However,
all microbiological studies were negative, and the possibility of pulmonary thromboembolism was ruled out. The prompt clinical manifestation after bleomycin administration and the response to corticosteroids suggest that bleomycin was the etiology of this event.
An important limitation on correct follow-up of our patient was the difficulty of performing pulmonary function tests. Nevertheless, her symptoms disappeared, and the walk test improved progressively during the follow-up period, with the patient presenting with an almost normal chest CT scan 5 months after the onset of respiratory failure.
Given the rarity of this complication and the difficulty of performing pulmonary function tests in children, routine spirometry is not indicated. However, any physician who treats these patients must be alert and consider this complication in children who present with respiratory symptoms after bleomycin intralesional administration. Because the use of intralesional bleomycin for the treatment of vascular malformations is increasing, institutions should establish guidelines for specific procedures for intralesional bleomycin injections in children. We recommend performing pulmonary function tests both after and before sclerosis, with close follow-up of these patients. Due to the different challenges in terms of the performance of reliable tests in the pediatric setting, it is important that these tests are performed by well-trained staff. A delay in the diagnosis and treatment of this complication can have dire consequences, allowing progression to pulmonary fibrosis.4
MéNDEz-ECHEVARRíA et al4 by guest on March 23, 2020www.aappublications.org/newsDownloaded from
ReFeRenCes
1. Atwa K, Abuhasna S, Shihab z, Hashaykeh N, Hasan R. Acute pulmonary toxicity following intralesional administration of bleomycin for a lymphovenous malformation. Pediatr Pulmonol. 2010;45(2):192–196
2. Azambuja E, Fleck JF, Batista RG, Menna Barreto SS. Bleomycin lung toxicity: who are the patients with increased risk? Pulm Pharmacol Ther. 2005;18(5):363–366
3. zorzi AP, Yang CL, Dell S, Nathan PC. Bleomycin-associated lung toxicity in childhood cancer survivors. J Pediatr Hematol Oncol. 2015;37(8):e447–e452
4. Shippee BM, Bates JS, Richards KL. The role of screening and monitoring for bleomycin pulmonary toxicity. J Oncol Pharm Pract. 2016;22(2):308–312
5. Horbach SE, Lokhorst MM, Saeed P, de Goüyon Matignon de Pontouraude CM, Rothová A, van der Horst CM. Sclerotherapy for low-flow vascular malformations of the head and neck: a systematic review of sclerosing agents. J Plast Reconstr Aesthet Surg. 2016;69(3):295–304
6. Mohan AT, Adams S, Adams K, Hudson DA. Intralesional bleomycin injection in management of low flow vascular malformations in children. J Plast Surg Hand Surg. 2015;49(2):116–120
7. Xu DP, zhai QK, Cheng C, Gong H, Wang HW, Wang XK. Appraisal of efficacy and safety of intralesional injection of high concentration of bleomycin A5 for treatment of huge macrocystic lymphatic malformations in cervical region. J Craniofac Surg. 2014;25(5):1707–1709
8. Sainsbury DC, Kessell G, Fall AJ, Hampton FJ, Guhan A, Muir T. Intralesional bleomycin injection treatment for vascular birthmarks: a 5-year experience at a single United Kingdom unit. Plast Reconstr Surg. 2011;127(5):2031–2044
9. Chaudry G, Guevara CJ, Rialon KL, et al. Safety and efficacy of bleomycin sclerotherapy for microcystic lymphatic malformation. Cardiovasc Intervent Radiol. 2014;37(6):1476–1481
10. Horbach SE, Rigter IM, Smitt JH, Reekers JA, Spuls PI, van der Horst CM. Intralesional bleomycin injections for vascular malformations: a systematic
review and meta-analysis. Plast Reconstr Surg. 2016;137(1):244–256
11. Hoff SR, Rastatter JC, Richter GT. Head and neck vascular lesions. Otolaryngol Clin North Am. 2015;48(1):29–45
12. zhang W, Chen G, Ren JG, zhao YF. Bleomycin induces endothelial mesenchymal transition through activation of mTOR pathway: a possible mechanism contributing to the sclerotherapy of venous malformations. Br J Pharmacol. 2013;170(6):1210–1220
13. Failla M, Genovese T, Mazzon E, et al. Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury. Respir Res. 2006;7:137
14. Peters-Golden M, Bailie M, Marshall T, et al. Protection from pulmonary fibrosis in leukotriene-deficient mice. Am J Respir Crit Care Med. 2002;165(2):229–235
15. Kessell G, Panchatsharam S, Kothmann E, et al. General anaesthesia for intralesional bleomycin therapy of vascular malformations: initial 3 yr experience. Br J Anaesth. 2009;102(3):431–432
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FInanCIaL DIsCLOsURe: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUnDInG: No external funding.
pOTenTIaL COnFLICT OF InTeResT: The authors have indicated they have no potential conflicts of interest to disclose.
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DOI: 10.1542/peds.2016-1787 originally published online December 21, 2017; 2018;141;Pediatrics
Lopez-Gutierrez, Manuel Parron, Begoña Marin-Aguilera and Cristina CalvoAna Méndez-Echevarría, Andres Fernandez-Prieto, Olga de la Serna, Juan-Carlos
Acute Lung Toxicity After Intralesional Bleomycin Sclerotherapy
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