- Email: [email protected]
Toxic epidermal necrolysis in a patient with cystic fibrosis
Clinical Communications Toxic epidermal necrolysis in a patient with cystic fibrosis François Tremblay, MD, FRCPCa, Hugo Chapdelaine, MD, BPharm, FRCPCb, Annick Lavoie, MD, FRCPCa, Yves Berthiaume, MD, MSc, FRCPCa,c, Laura Sabbah, MDd, Steven C. Bernstein, MD, FRCPC, FAADd, and Maïté Silviet-Carricart, MD, FRCPCa Clinical Implications
Although patients with cystic fibrosis (CF) are treated with numerous drugs that have been associated with toxic epidermal necrolysis (TEN), we reported the first case of TEN in a patient with CF. This case emphasizes the importance of monitoring for serious hypersensitivity skin reaction in patients with CF receiving antibiotics for pulmonary exacerbations.
TO THE EDITOR: It has been observed that patients with cystic fibrosis (CF) have an increased incidence of drug hypersensitivity reaction (DHR). The prevalence of antibiotics allergy in CF is estimated to be 6%-25%, with b-lactam antibiotics being the most frequent responsible drugs.1,2 The higher incidence of DHR may be explained in part by the increased antibiotic exposure and increased use of intravenous route. Even though the overall incidence of reported DHR is high, the real incidence of hypersensitivity allergic reactions does not seem to differ from the general population. Clinicians should perform complete allergy workups to properly diagnose allergy and to avoid excluding an antibiotic from the possible treatments for a patient.3 Most frequent DHR observed in CF are urticaria, rashes, fixed drug eruption, arthralgia, and drug fever. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are variants of a spectrum of DHR. SJS and TEN are type IVc hypersensitivity reaction that is mediated by cytotoxic T cells.4 TEN, also known as Lyell’s syndrome, is a rare lifethreatening DHR characterized by epidermal necrosis and detachment of greater than 30% of total body surface area (TBSA). The annual incidence of TEN is 0.4 to 1.9 cases per million individuals.5 Allopurinol, fluoroquinolones, minocycline, nonsteroidal anti-inflammatory drugs and trimethoprimsulfamethoxazole are commonly associated with TEN. The mortality associated with TEN ranges from 25% to 30%.6 Sepsis associated with multiorgan failure is the most common cause of death. However, there is a growing body of evidence supporting a survival benefit for the management of these patients in a burn unit. To our knowledge, there is no case of TEN reported in a patient with CF. This report describes a case of antibiotic therapy for pulmonary exacerbation complicated by TEN in a patient with CF.
CASE REPORT The patient is a 42-year-old man with cystic fibrosis (DF508 homozygote) diagnosed in childhood because of failure to thrive. He had stable lung functions with a forced expiratory volume in 1 second (FEV1) of 60% predicted and was chronically infected to Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). The patient was also known to have allergic bronchopulmonary aspergillosis, adrenal insufficiency, pancreatic insufficiency, and CF-related diabetes. He had a history of allergy to trimethoprim-sulfamethoxazole characterized by a morbilliform rash. His maintenance therapy consisted of azithromycin, nebulized aztreonam altering every other month with tobramycin, nebulized dornase alpha, montelukast, omalizumab, ciclesonide, budesonide/formoterol, saline nasal rinses, hydrocortisone, pancreatic enzymes, insulin, and vitamins. Also, he was taking oral ciprofloxacin regularly for pulmonary exacerbations. Two weeks before presentation, the patient had flu-like symptoms and started oral ciprofloxacin and a 5-day treatment with oseltamivir. However, his condition continued to worsen, and he was admitted for pulmonary exacerbation. Treatment with intravenous meropenem, tobramycin, and vancomycin was started. He responded well to intravenous antibiotics and after 7 days of treatment, the patient was discharged home with the same intravenous antibiotics for 9 additional days. However, the patient stopped his treatment 2 days before the end of the treatment because of an erythematous itchy rash. On physical examination, the patient was nontoxic and had no fever. He had bilateral conjonctival erythema. He had an erythematous maculopapular rash on his face, trunk, and limbs, with targetoid lesions on the palm of his hands. Also, hemorrhagic blistering of the oral mucosa was observed. The genital mucosa was spared. Because less than 15% of TBSA was affected, a clinical diagnosis of SJS was made. The patient was hospitalized. On admission, the hemoglobin, platelets, and white blood cells count were normal. Creatinine and liver enzymes were in the normal range. The erythrocyte sedimentation rate and C-reactive protein level were elevated at 52 mm/h and 15 mg/L, respectively. Immunoglobulin (Ig) M for Mycoplasma pneumonia was negative. Supportive treatment, oral prednisone, and antihistamine were started. Nevertheless, the blistering rash progressed rapidly within 24 hours, so that more than 90% of TBSA was affected (Figure 1, A-C), which led to the diagnosis of TEN. A skin biopsy was made at that time, and the histological examination demonstrated the presence of necrotic keratinocytes in every layer of the epidermis, subepidermal hemorrhagic blisters, and lymphocytic infiltrate, consistent with TEN. Direct immunofluorescence studies for IgG, IgA, IgM, C3, and C1q were negative. The patient was transferred to our burn unit for supportive care. He received intravenous immunoglobulin daily for 3 days, methylprednisolone 50 mg twice a day for 5 days, and enteral feeding through a nasogastric tube. He also received prednisolone and erythromycin eye drops, lidocaine mouthwash, and topical moisturizing cream. Four days after admission, necrotic tissue was surgically debrided and biosynthetic skin was applied. On
1
2
CLINICAL COMMUNICATIONS
J ALLERGY CLIN IMMUNOL PRACT MONTH 2015
FIGURE 1. Cutaneous findings consistent with toxic epidermal necrolysis in a 42-year-old patient with cystic fibrosis. A, Erythematous maculopapular rash on the trunk and arms, with B, oral mucosal detachment. C, Blistering and epidermal detachment on the palm of his left hand. D, Re-epithelialization of the original lesions on the abdomen 10 days after admission.
day 6, he developed septicemia with 2 blood cultures positives to MRSA that was rapidly treated with intravenous linezolid and daptomycin. After this episode, his clinical condition improved rapidly and daptomycin was stopped after 14 days but linezolid was continued orally until discharge. Over the following weeks, there was no new blister and there was gradual reepithelialization of the original lesions (Figure 1, D). The patient never necessitated endotracheal intubation or mechanical ventilation during his hospitalization, except for surgery. The patient was discharged 31 days after admission. On follow-up visit 1 month after discharge, his FEV1 was back to 60% and no pulmonary complications were observed. No pulmonary exacerbation occurred over the 6 months after discharge. At this time, we have not been able to identify the involved drug in his TEN reaction.
DISCUSSION To our knowledge, this is the first reported case of TEN in patients with CF under treatment for a pulmonary exacerbation.
This is particularly surprising considering that patients with CF are treated with numerous drugs that have been associated with TEN, especially antibiotics. Because of the potential fatal outcome associated with TEN, CF professionals should be aware of the early presentations of TEN. Prompt recognition of TEN as well as rapid and aggressive therapy in a burn unit might explain the favorable outcome in our patient. The main problem when a case of DHR occurs is to identify the culprit drug. It is even more complicated in patients with CF, because they are exposed to drugs associated with DHR, especially multiple combinations of intravenous antibiotics for the treatment of a pulmonary exacerbation. The problem is further amplified in TEN because it is a life-threatening condition and most clinicians consider it as a contraindication to perform investigation such has prick test, intradermal test, or patch test because it can potentially trigger a second episode of TEN. However, Barbaud et al7 recently evaluated the value and safety of patch test in 17 patients referred for TEN. Although they showed that the test could be performed safely, they were able to
J ALLERGY CLIN IMMUNOL PRACT VOLUME -, NUMBER -
identify the involved drug in only 4 patients (sensitivity of 24%). Even though very interesting, it should be mentioned that this work is not in line with the current EAACI-AAAAI guidelines. In vitro testing, such as the lymphocyte transformation test, is not sufficiently sensitive in TEN to be useful. Our patient first symptoms did appear 13 days after the initiation of intravenous antibiotics and 26 days after the beginning of his flu-like symptoms. This is within the timeline (between 1 and 4 weeks) recognized for the development of TEN after drug administration.6 In our patient, many drugs can be responsible for the reaction. Oseltamivir, ciprofloxacin, meropenem, tobramycin, and vancomycin have all been reported as drugs causing TEN,8-12 so we can speculate that ciprofloxacin and meropenem are more likely to be implicated in our case. Because there is no sensitive and reproductible test and because we have identified alternative antibiotics, such as colistimethate, tigecycline, and linezolid, for the treatment of a pulmonary exacerbation, we decided to postpone testing the suspected drugs in our patient. Of note, desensitization is not considered a safe option in TEN and was not considered for our patient.
CONCLUSION In conclusion, we presented the first reported case of TEN in a patient with CF. This case emphasizes the importance of monitoring for serious dermatologic reaction in patients with CF receiving antibiotics for pulmonary exacerbations and the importance of rapid and aggressive therapy if TEN is diagnosed. a
Department of Medicine, Pulmonary Division and Cystic Fibrosis Clinic, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada b Department of Allergy and Clinical Immunology, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada c Institut de recherches cliniques de Montréal, Montréal, Québec, Canada d Department of Dermatology, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts.
CLINICAL COMMUNICATIONS
3
Received for publication September 2, 2015; revised October 15, 2015; accepted for publication November 13, 2015. Available online - Corresponding author: François Tremblay, MD, FRCPC, Clinique de Fibrose Kystique, Centre Hospitalier de l’Université de Montréal, Pavillon Hôtel-Dieu, 3840 rue St-Urbain, Montréal, Québec H2W 1T8, Canada. E-mail: f.tremblay@ umontreal.ca. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.11.021 REFERENCES 1. Parmar JS, Nasser S. Antibiotic allergy in cystic fibrosis. Thorax 2005;60: 517-20. 2. Burrows JA, Nissen LM, Kirkpatrick CM, Bell SC. Beta-lactam allergy in adults with cystic fibrosis. J Cyst Fibros 2007;6:297-303. 3. Caimmi S, Sanfiorenzo C, Caimmi D, Bousquet PJ, Chiron R, Demoly P. Comprehensive allergy work-up is mandatory in cystic fibrosis patients who report a history suggestive of drug allergy to beta-lactam antibiotics. Clin Transl Allergy 2012;2:10. 4. Pichler WJ. Immune mechanism of drug hypersensitivity. Immunol Allergy Clin North Am 2004;24:373-97. 5. Schwartz RA, MacDonough PH, Lee BW. Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol 2013;69:173.e1-13. 6. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis 2010;5:39. 7. Barbaud A, Collet E, Milpied B, Assier H, Staumont D, Avenel-Audran M, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol 2013;168:555-62. 8. Luna P, Zuazaga M, Chede C, Entin E, Larralde M. Toxic epidermal necrolysis after treatment with oseltamivir: case report. Arch Argent Pediatr 2010;108: e76-8. 9. Livasy CA, Kaplan AM. Ciprofloxacin-induced toxic epidermal necrolysis: a case report. Dermatology 1997;195:173-5. 10. Paquet P, Jacob E, Damas P, Piérard GE. Recurrent fatal drug-induced toxic epidermal necrolysis (Lyell’s syndrome) after putative beta-lactam cross-reactivity: case report and scrutiny of antibiotic imputability. Crit Care Med 2002; 30:2580-3. 11. Vidal C, Gonzalez Quintela A, Fuente R. Toxic epidermal necrolysis due to vancomycin. Ann Allergy 1990;68:345-7. 12. Hannah BA, Kimmel PL, Dosa S, Turner ML. Vancomycin-induced toxic epidermal necrolysis. South Med J 1990;83:720-2.
Although patients with cystic fibrosis (CF) are treated with numerous drugs that have been associated with toxic epidermal necrolysis (TEN), we reported the first case of TEN in a patient with CF. This case emphasizes the importance of monitoring for serious hypersensitivity skin reaction in patients with CF receiving antibiotics for pulmonary exacerbations.
TO THE EDITOR: It has been observed that patients with cystic fibrosis (CF) have an increased incidence of drug hypersensitivity reaction (DHR). The prevalence of antibiotics allergy in CF is estimated to be 6%-25%, with b-lactam antibiotics being the most frequent responsible drugs.1,2 The higher incidence of DHR may be explained in part by the increased antibiotic exposure and increased use of intravenous route. Even though the overall incidence of reported DHR is high, the real incidence of hypersensitivity allergic reactions does not seem to differ from the general population. Clinicians should perform complete allergy workups to properly diagnose allergy and to avoid excluding an antibiotic from the possible treatments for a patient.3 Most frequent DHR observed in CF are urticaria, rashes, fixed drug eruption, arthralgia, and drug fever. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are variants of a spectrum of DHR. SJS and TEN are type IVc hypersensitivity reaction that is mediated by cytotoxic T cells.4 TEN, also known as Lyell’s syndrome, is a rare lifethreatening DHR characterized by epidermal necrosis and detachment of greater than 30% of total body surface area (TBSA). The annual incidence of TEN is 0.4 to 1.9 cases per million individuals.5 Allopurinol, fluoroquinolones, minocycline, nonsteroidal anti-inflammatory drugs and trimethoprimsulfamethoxazole are commonly associated with TEN. The mortality associated with TEN ranges from 25% to 30%.6 Sepsis associated with multiorgan failure is the most common cause of death. However, there is a growing body of evidence supporting a survival benefit for the management of these patients in a burn unit. To our knowledge, there is no case of TEN reported in a patient with CF. This report describes a case of antibiotic therapy for pulmonary exacerbation complicated by TEN in a patient with CF.
CASE REPORT The patient is a 42-year-old man with cystic fibrosis (DF508 homozygote) diagnosed in childhood because of failure to thrive. He had stable lung functions with a forced expiratory volume in 1 second (FEV1) of 60% predicted and was chronically infected to Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). The patient was also known to have allergic bronchopulmonary aspergillosis, adrenal insufficiency, pancreatic insufficiency, and CF-related diabetes. He had a history of allergy to trimethoprim-sulfamethoxazole characterized by a morbilliform rash. His maintenance therapy consisted of azithromycin, nebulized aztreonam altering every other month with tobramycin, nebulized dornase alpha, montelukast, omalizumab, ciclesonide, budesonide/formoterol, saline nasal rinses, hydrocortisone, pancreatic enzymes, insulin, and vitamins. Also, he was taking oral ciprofloxacin regularly for pulmonary exacerbations. Two weeks before presentation, the patient had flu-like symptoms and started oral ciprofloxacin and a 5-day treatment with oseltamivir. However, his condition continued to worsen, and he was admitted for pulmonary exacerbation. Treatment with intravenous meropenem, tobramycin, and vancomycin was started. He responded well to intravenous antibiotics and after 7 days of treatment, the patient was discharged home with the same intravenous antibiotics for 9 additional days. However, the patient stopped his treatment 2 days before the end of the treatment because of an erythematous itchy rash. On physical examination, the patient was nontoxic and had no fever. He had bilateral conjonctival erythema. He had an erythematous maculopapular rash on his face, trunk, and limbs, with targetoid lesions on the palm of his hands. Also, hemorrhagic blistering of the oral mucosa was observed. The genital mucosa was spared. Because less than 15% of TBSA was affected, a clinical diagnosis of SJS was made. The patient was hospitalized. On admission, the hemoglobin, platelets, and white blood cells count were normal. Creatinine and liver enzymes were in the normal range. The erythrocyte sedimentation rate and C-reactive protein level were elevated at 52 mm/h and 15 mg/L, respectively. Immunoglobulin (Ig) M for Mycoplasma pneumonia was negative. Supportive treatment, oral prednisone, and antihistamine were started. Nevertheless, the blistering rash progressed rapidly within 24 hours, so that more than 90% of TBSA was affected (Figure 1, A-C), which led to the diagnosis of TEN. A skin biopsy was made at that time, and the histological examination demonstrated the presence of necrotic keratinocytes in every layer of the epidermis, subepidermal hemorrhagic blisters, and lymphocytic infiltrate, consistent with TEN. Direct immunofluorescence studies for IgG, IgA, IgM, C3, and C1q were negative. The patient was transferred to our burn unit for supportive care. He received intravenous immunoglobulin daily for 3 days, methylprednisolone 50 mg twice a day for 5 days, and enteral feeding through a nasogastric tube. He also received prednisolone and erythromycin eye drops, lidocaine mouthwash, and topical moisturizing cream. Four days after admission, necrotic tissue was surgically debrided and biosynthetic skin was applied. On
1
2
CLINICAL COMMUNICATIONS
J ALLERGY CLIN IMMUNOL PRACT MONTH 2015
FIGURE 1. Cutaneous findings consistent with toxic epidermal necrolysis in a 42-year-old patient with cystic fibrosis. A, Erythematous maculopapular rash on the trunk and arms, with B, oral mucosal detachment. C, Blistering and epidermal detachment on the palm of his left hand. D, Re-epithelialization of the original lesions on the abdomen 10 days after admission.
day 6, he developed septicemia with 2 blood cultures positives to MRSA that was rapidly treated with intravenous linezolid and daptomycin. After this episode, his clinical condition improved rapidly and daptomycin was stopped after 14 days but linezolid was continued orally until discharge. Over the following weeks, there was no new blister and there was gradual reepithelialization of the original lesions (Figure 1, D). The patient never necessitated endotracheal intubation or mechanical ventilation during his hospitalization, except for surgery. The patient was discharged 31 days after admission. On follow-up visit 1 month after discharge, his FEV1 was back to 60% and no pulmonary complications were observed. No pulmonary exacerbation occurred over the 6 months after discharge. At this time, we have not been able to identify the involved drug in his TEN reaction.
DISCUSSION To our knowledge, this is the first reported case of TEN in patients with CF under treatment for a pulmonary exacerbation.
This is particularly surprising considering that patients with CF are treated with numerous drugs that have been associated with TEN, especially antibiotics. Because of the potential fatal outcome associated with TEN, CF professionals should be aware of the early presentations of TEN. Prompt recognition of TEN as well as rapid and aggressive therapy in a burn unit might explain the favorable outcome in our patient. The main problem when a case of DHR occurs is to identify the culprit drug. It is even more complicated in patients with CF, because they are exposed to drugs associated with DHR, especially multiple combinations of intravenous antibiotics for the treatment of a pulmonary exacerbation. The problem is further amplified in TEN because it is a life-threatening condition and most clinicians consider it as a contraindication to perform investigation such has prick test, intradermal test, or patch test because it can potentially trigger a second episode of TEN. However, Barbaud et al7 recently evaluated the value and safety of patch test in 17 patients referred for TEN. Although they showed that the test could be performed safely, they were able to
J ALLERGY CLIN IMMUNOL PRACT VOLUME -, NUMBER -
identify the involved drug in only 4 patients (sensitivity of 24%). Even though very interesting, it should be mentioned that this work is not in line with the current EAACI-AAAAI guidelines. In vitro testing, such as the lymphocyte transformation test, is not sufficiently sensitive in TEN to be useful. Our patient first symptoms did appear 13 days after the initiation of intravenous antibiotics and 26 days after the beginning of his flu-like symptoms. This is within the timeline (between 1 and 4 weeks) recognized for the development of TEN after drug administration.6 In our patient, many drugs can be responsible for the reaction. Oseltamivir, ciprofloxacin, meropenem, tobramycin, and vancomycin have all been reported as drugs causing TEN,8-12 so we can speculate that ciprofloxacin and meropenem are more likely to be implicated in our case. Because there is no sensitive and reproductible test and because we have identified alternative antibiotics, such as colistimethate, tigecycline, and linezolid, for the treatment of a pulmonary exacerbation, we decided to postpone testing the suspected drugs in our patient. Of note, desensitization is not considered a safe option in TEN and was not considered for our patient.
CONCLUSION In conclusion, we presented the first reported case of TEN in a patient with CF. This case emphasizes the importance of monitoring for serious dermatologic reaction in patients with CF receiving antibiotics for pulmonary exacerbations and the importance of rapid and aggressive therapy if TEN is diagnosed. a
Department of Medicine, Pulmonary Division and Cystic Fibrosis Clinic, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada b Department of Allergy and Clinical Immunology, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada c Institut de recherches cliniques de Montréal, Montréal, Québec, Canada d Department of Dermatology, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts.
CLINICAL COMMUNICATIONS
3
Received for publication September 2, 2015; revised October 15, 2015; accepted for publication November 13, 2015. Available online - Corresponding author: François Tremblay, MD, FRCPC, Clinique de Fibrose Kystique, Centre Hospitalier de l’Université de Montréal, Pavillon Hôtel-Dieu, 3840 rue St-Urbain, Montréal, Québec H2W 1T8, Canada. E-mail: f.tremblay@ umontreal.ca. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.11.021 REFERENCES 1. Parmar JS, Nasser S. Antibiotic allergy in cystic fibrosis. Thorax 2005;60: 517-20. 2. Burrows JA, Nissen LM, Kirkpatrick CM, Bell SC. Beta-lactam allergy in adults with cystic fibrosis. J Cyst Fibros 2007;6:297-303. 3. Caimmi S, Sanfiorenzo C, Caimmi D, Bousquet PJ, Chiron R, Demoly P. Comprehensive allergy work-up is mandatory in cystic fibrosis patients who report a history suggestive of drug allergy to beta-lactam antibiotics. Clin Transl Allergy 2012;2:10. 4. Pichler WJ. Immune mechanism of drug hypersensitivity. Immunol Allergy Clin North Am 2004;24:373-97. 5. Schwartz RA, MacDonough PH, Lee BW. Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol 2013;69:173.e1-13. 6. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis 2010;5:39. 7. Barbaud A, Collet E, Milpied B, Assier H, Staumont D, Avenel-Audran M, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol 2013;168:555-62. 8. Luna P, Zuazaga M, Chede C, Entin E, Larralde M. Toxic epidermal necrolysis after treatment with oseltamivir: case report. Arch Argent Pediatr 2010;108: e76-8. 9. Livasy CA, Kaplan AM. Ciprofloxacin-induced toxic epidermal necrolysis: a case report. Dermatology 1997;195:173-5. 10. Paquet P, Jacob E, Damas P, Piérard GE. Recurrent fatal drug-induced toxic epidermal necrolysis (Lyell’s syndrome) after putative beta-lactam cross-reactivity: case report and scrutiny of antibiotic imputability. Crit Care Med 2002; 30:2580-3. 11. Vidal C, Gonzalez Quintela A, Fuente R. Toxic epidermal necrolysis due to vancomycin. Ann Allergy 1990;68:345-7. 12. Hannah BA, Kimmel PL, Dosa S, Turner ML. Vancomycin-induced toxic epidermal necrolysis. South Med J 1990;83:720-2.