- Email: [email protected]
Design flaws plus delivery flaws equal faux conclusions
Correspondence 221
J ALLERGY CLIN IMMUNOL VOLUME 120, NUMBER 1
Mario Geller, MD, FAAAAI, MACP From Geller Allergy and Immunology Clinic, Rio de Janeiro, Brazil. E-mail: [email protected]. Disclosure of potential conflict of interest: M. Geller has declared that he has no conflict of interest.
2. Waibel KH. Aspiration before immunotherapy injection is not required. J Allergy Clin Immunol 2006;118:525-6. 3. Package insert epinephrine injection, USP 1:1000. Available at: http://www. americanregent.com/PDF_For_Products/Epinephrine%20IN1071%20Rev% 207-03.pdf. Accessed February 28, 2007. Available online April 6, 2007. doi:10.1016/j.jaci.2007.03.003
REFERENCES 1. Waibel KH. Aspiration before immunotherapy injection is not required. J Allergy Clin Immunol 2006;118:525-6. 2. Allergen immunotherapy: a practice parameter. American Academy of Allergy, Asthma and Immunology. American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 2003;90(suppl 1):S1-S40. Available online April 6, 2007. doi:10.1016/j.jaci.2007.02.039
Reply To the Editor: I would like to thank Dr Geller1 for sharing his experience from a large outpatient allergy clinic. Although Dr Geller’s observation of no blood return during syringe aspiration in more than 40,000 allergy shots supports my observations and recommendations, I have found the application of clinic research to this class IV recommendation (ie, aspiration before injection) enlightening, with opinions polarized to both sides of my recommendations.2 Dr Geller also shares his methods of epinephrine administration.1 When administering 1:1000 epinephrine for intramuscular injection, we also aspirate before injection because inadvertent intravenous injection might cause cerebrovascular hemorrhage. There are 2 points, though, regarding this practice that I believe are worth mentioning. First, although 1:1000 epinephrine is recommended for subcutaneous or intramuscular injection, the package insert regarding dosing and administration does not mention aspiration.3 Second, some allergists and emergency department physicians use the more convenient epinephrine autoinjector for the treatment of acute anaphylaxis rather than drawing up 1:1000 epinephrine in a syringe. An autoinjector has distinct advantages but does not allow for aspiration. Should providers who both advocate aspiration before epinephrine injection and practice in a hospital-based environment ensure that epinephrine through a syringe is preferentially used over an epinephrine autoinjector? Kirk H. Waibel, MD From the Allergy/Immunology Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, Tex. E-mail: kirk.waibel@ amedd.army.mil. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Disclosure of potential conflict of interest: K. H. Waibel has received grant support from an Education and Research Trust Research Grant and is employed by the American Academy of Pediatrics Pediatric Review and Education Program Editorial Board.
REFERENCES 1. Geller M. Aspiration before immunotherapy injection is required. J Allergy Clin Immunol 2007;120:220-1.
Design flaws plus delivery flaws equal faux conclusions To the Editor: At first glance, Ebbens1 and a dozen other Europeans from 6 centers designed a credible study with one objective in mind: ‘‘To clarify the role of intranasal antifungal drugs in the treatment of CRS (chronic rhinosinusitis), we conducted a large, double-blinded, placebo-controlled, multicenter study comparing the effectiveness of amphotericin B nasal lavages with placebo.’’ Peering beyond the buzz words ‘‘large, double-blinded, placebo-controlled,’’ an analytical reading revealed serious design flaws. The most egregious was unabashedly admitted: ‘‘Because we did not study a reduction in fungal load, we cannot rule out the presence of persistent high fungal loads on amphotericin B treatment in our study.’’ It is astonishing that this unintelligent design would be permitted by serious scientists to determine efficacy of an antifungal drug and never measure the targeted fungi at baseline, during and after drug delivery. How could those investigators determine whether adequate therapeutic levels of amphotericin B were either reached or maintained at the target site (nasal mucus) if they failed to study the fungal load? How could those investigators determine whether they were able to deliver any antifungal drug to target if they failed to measure drug levels or the levels of inflammatory mediators (IL-5 and eosinophil-derived neurotoxin) at the target site? Yes, they failed to show a positive drug effect over placebo, but with a failure to measure either drug levels or inflammatory mediators in the target mucus, how can they starkly state to either the scientific community or to the community of patients that ‘‘amphotericin B lavages in the described dosing and time schedule are ineffective and therefore not advised in the treatment of patients with CRS’’? Their failed drug trial neither clarifies nor proves anything, except that they failed to prove adequate drug delivery. Their concluding statement was wanting in scientific proof: ‘‘Our results suggest that extramucosal fungi are innocent bystanders in the upper respiratory tract and play no demonstrable role in the pathophysiology of CRS in immunocompetent patients.’’ They failed to provide any solution or further the understanding regarding the underlying pathophysiology (cause) of CRS. Unintelligent design delivers faux science, and faux science delivers faux conclusions. Eugene B. Kern, MD, MS From the Mayo Foundation: Rhinology and Facial Plastic Surgery, Mayo Clinic Medical School, Rochester, Minn. E-mail: [email protected].
222 Correspondence
J ALLERGY CLIN IMMUNOL JULY 2007
Disclosure of potential conflict of interest: E. B. Kern owns stock in Accentia Biopharmaceuticals and has patent licensing arrangements with the Mayo Foundation.
REFERENCE 1. Ebbens FA, Scadding MA, Badia L, Hellings PW, Jorissen M, Mullol J, et al. Amphotericin B nasal lavages: not a solution for patients with chronic rhinosinusitis. J Allergy Clin Immunol 2006;118:1149-56. Available online April 25, 2007. doi:10.1016/j.jaci.2007.02.043
Reply To the Editor: Few will be unaware of the intriguing proposition from Dr Kern and colleagues1 that most if not all chronic inflammation in the nose and sinuses was a response to inhaled fungal material. Predicated on this, impressive claims were made for the effects of topical intranasal amphotericin, provoking much media interest and the widespread use of this treatment in the United States despite the lack of well-powered level 1 evidence. The mechanism by which amphotericin might work in these circumstances also remains unclear. It was against this background that this, the largest double-blind, placebo-controlled multicenter trial, was conceived and undertaken. It is therefore
ironic that our study should be attacked for omissions common to Dr Kern’s own work.2 To criticize the instillation of a similar quantity of amphotericin solution (using a truly soluble preparation) via a well-established delivery system is an understandable response if one does not like the result! Fenna A. Ebbens, MD Valerie Lund, MS, FRCS, FRCSEd Wytske J. Fokkens, MD, PhD From the Department of Otorhinolaryngology, Head and Neck Surgery, Academic Medical Center, Amsterdam, The Netherlands. E-mail: [email protected]. Disclosure of potential conflict of interest: V. Lund has consulting arrangements with Schering-Plough; has received grant support from GlaxoSmithKline; and is on the speakers’ bureau for Schering-Plough. W. J. Fokkens has consulting arrangements with GlaxoSmithKline and Schering-Plough and has received grant support from GlaxoSmithKline, Schering-Plough, and Optinose. F. A. Ebbens has declared that she has no conflict of interest.
REFERENCES 1. Kern EB. Design flaws plus delivery flaws equal faux conclusions. J Allergy Clin Immunol 2007;120:221-2. 2. Ponikau JU, Sherris DA, Kita H, Kern EB. Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis. J Allergy Clin Immunol 2002; 110:862-6. Available online May 11, 2007. doi:10.1016/j.jaci.2007.02.044
J ALLERGY CLIN IMMUNOL VOLUME 120, NUMBER 1
Mario Geller, MD, FAAAAI, MACP From Geller Allergy and Immunology Clinic, Rio de Janeiro, Brazil. E-mail: [email protected]. Disclosure of potential conflict of interest: M. Geller has declared that he has no conflict of interest.
2. Waibel KH. Aspiration before immunotherapy injection is not required. J Allergy Clin Immunol 2006;118:525-6. 3. Package insert epinephrine injection, USP 1:1000. Available at: http://www. americanregent.com/PDF_For_Products/Epinephrine%20IN1071%20Rev% 207-03.pdf. Accessed February 28, 2007. Available online April 6, 2007. doi:10.1016/j.jaci.2007.03.003
REFERENCES 1. Waibel KH. Aspiration before immunotherapy injection is not required. J Allergy Clin Immunol 2006;118:525-6. 2. Allergen immunotherapy: a practice parameter. American Academy of Allergy, Asthma and Immunology. American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 2003;90(suppl 1):S1-S40. Available online April 6, 2007. doi:10.1016/j.jaci.2007.02.039
Reply To the Editor: I would like to thank Dr Geller1 for sharing his experience from a large outpatient allergy clinic. Although Dr Geller’s observation of no blood return during syringe aspiration in more than 40,000 allergy shots supports my observations and recommendations, I have found the application of clinic research to this class IV recommendation (ie, aspiration before injection) enlightening, with opinions polarized to both sides of my recommendations.2 Dr Geller also shares his methods of epinephrine administration.1 When administering 1:1000 epinephrine for intramuscular injection, we also aspirate before injection because inadvertent intravenous injection might cause cerebrovascular hemorrhage. There are 2 points, though, regarding this practice that I believe are worth mentioning. First, although 1:1000 epinephrine is recommended for subcutaneous or intramuscular injection, the package insert regarding dosing and administration does not mention aspiration.3 Second, some allergists and emergency department physicians use the more convenient epinephrine autoinjector for the treatment of acute anaphylaxis rather than drawing up 1:1000 epinephrine in a syringe. An autoinjector has distinct advantages but does not allow for aspiration. Should providers who both advocate aspiration before epinephrine injection and practice in a hospital-based environment ensure that epinephrine through a syringe is preferentially used over an epinephrine autoinjector? Kirk H. Waibel, MD From the Allergy/Immunology Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, Tex. E-mail: kirk.waibel@ amedd.army.mil. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Disclosure of potential conflict of interest: K. H. Waibel has received grant support from an Education and Research Trust Research Grant and is employed by the American Academy of Pediatrics Pediatric Review and Education Program Editorial Board.
REFERENCES 1. Geller M. Aspiration before immunotherapy injection is required. J Allergy Clin Immunol 2007;120:220-1.
Design flaws plus delivery flaws equal faux conclusions To the Editor: At first glance, Ebbens1 and a dozen other Europeans from 6 centers designed a credible study with one objective in mind: ‘‘To clarify the role of intranasal antifungal drugs in the treatment of CRS (chronic rhinosinusitis), we conducted a large, double-blinded, placebo-controlled, multicenter study comparing the effectiveness of amphotericin B nasal lavages with placebo.’’ Peering beyond the buzz words ‘‘large, double-blinded, placebo-controlled,’’ an analytical reading revealed serious design flaws. The most egregious was unabashedly admitted: ‘‘Because we did not study a reduction in fungal load, we cannot rule out the presence of persistent high fungal loads on amphotericin B treatment in our study.’’ It is astonishing that this unintelligent design would be permitted by serious scientists to determine efficacy of an antifungal drug and never measure the targeted fungi at baseline, during and after drug delivery. How could those investigators determine whether adequate therapeutic levels of amphotericin B were either reached or maintained at the target site (nasal mucus) if they failed to study the fungal load? How could those investigators determine whether they were able to deliver any antifungal drug to target if they failed to measure drug levels or the levels of inflammatory mediators (IL-5 and eosinophil-derived neurotoxin) at the target site? Yes, they failed to show a positive drug effect over placebo, but with a failure to measure either drug levels or inflammatory mediators in the target mucus, how can they starkly state to either the scientific community or to the community of patients that ‘‘amphotericin B lavages in the described dosing and time schedule are ineffective and therefore not advised in the treatment of patients with CRS’’? Their failed drug trial neither clarifies nor proves anything, except that they failed to prove adequate drug delivery. Their concluding statement was wanting in scientific proof: ‘‘Our results suggest that extramucosal fungi are innocent bystanders in the upper respiratory tract and play no demonstrable role in the pathophysiology of CRS in immunocompetent patients.’’ They failed to provide any solution or further the understanding regarding the underlying pathophysiology (cause) of CRS. Unintelligent design delivers faux science, and faux science delivers faux conclusions. Eugene B. Kern, MD, MS From the Mayo Foundation: Rhinology and Facial Plastic Surgery, Mayo Clinic Medical School, Rochester, Minn. E-mail: [email protected].
222 Correspondence
J ALLERGY CLIN IMMUNOL JULY 2007
Disclosure of potential conflict of interest: E. B. Kern owns stock in Accentia Biopharmaceuticals and has patent licensing arrangements with the Mayo Foundation.
REFERENCE 1. Ebbens FA, Scadding MA, Badia L, Hellings PW, Jorissen M, Mullol J, et al. Amphotericin B nasal lavages: not a solution for patients with chronic rhinosinusitis. J Allergy Clin Immunol 2006;118:1149-56. Available online April 25, 2007. doi:10.1016/j.jaci.2007.02.043
Reply To the Editor: Few will be unaware of the intriguing proposition from Dr Kern and colleagues1 that most if not all chronic inflammation in the nose and sinuses was a response to inhaled fungal material. Predicated on this, impressive claims were made for the effects of topical intranasal amphotericin, provoking much media interest and the widespread use of this treatment in the United States despite the lack of well-powered level 1 evidence. The mechanism by which amphotericin might work in these circumstances also remains unclear. It was against this background that this, the largest double-blind, placebo-controlled multicenter trial, was conceived and undertaken. It is therefore
ironic that our study should be attacked for omissions common to Dr Kern’s own work.2 To criticize the instillation of a similar quantity of amphotericin solution (using a truly soluble preparation) via a well-established delivery system is an understandable response if one does not like the result! Fenna A. Ebbens, MD Valerie Lund, MS, FRCS, FRCSEd Wytske J. Fokkens, MD, PhD From the Department of Otorhinolaryngology, Head and Neck Surgery, Academic Medical Center, Amsterdam, The Netherlands. E-mail: [email protected]. Disclosure of potential conflict of interest: V. Lund has consulting arrangements with Schering-Plough; has received grant support from GlaxoSmithKline; and is on the speakers’ bureau for Schering-Plough. W. J. Fokkens has consulting arrangements with GlaxoSmithKline and Schering-Plough and has received grant support from GlaxoSmithKline, Schering-Plough, and Optinose. F. A. Ebbens has declared that she has no conflict of interest.
REFERENCES 1. Kern EB. Design flaws plus delivery flaws equal faux conclusions. J Allergy Clin Immunol 2007;120:221-2. 2. Ponikau JU, Sherris DA, Kita H, Kern EB. Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis. J Allergy Clin Immunol 2002; 110:862-6. Available online May 11, 2007. doi:10.1016/j.jaci.2007.02.044