CLINICAL ARTICLE
Delayed Hypersensitivity Reaction to Acellular Dermal Matrix in Breast Reconstruction The Red Breast Syndrome? Ingrid Ganske, MD, MPA,* Marguerite Hoyler, BA,Þ Sharon E. Fox, MD, PhD,þ Donald J. Morris, MD,§ Samuel J. Lin, MD,§ and Sumner A. Slavin, MD§ Background: Acellular dermal matrix (ADM) has become a valuable tool in reconstructive breast surgery, in part because it has been considered to be a non-reactive and non-immunogenic entity. However, some patients who undergo breast reconstruction with ADMs develop postoperative erythema overlying their ADM grafts. The etiology of this phenomenon is poorly understood. Methods: In this article, we summarize clinical cases in which patients developed localized breast erythema following reconstruction with ADMs. We review what is known about postoperative breast erythema after ADM-based breast reconstructions and the possible antigenicity of biologic mesh implants. Results: We report 4 implant-based breast reconstruction patients who developed erythematous reactions overlying the region where ADM was placed: one demonstrated a delayed-type hypersensitivity reaction on punch biopsy of the affected skin, leading to removal of the biologic product; 2 others had a similar clinical presentation that responded to corticosteroids without removal of the biologic material, with 1 patient experiencing recrudescence of erythema that responded fully to a second course of corticosteroids; and a fourth showed erythema that was only moderately responsive to antibiotic therapy but which improved consistently after the patient initiated chemotherapy. Conclusion: We propose that the etiology of erythema overlying ADM grafts, and the so-called red breast syndrome, may in some patients be a delayed-type hypersensitivity reaction to the ADM product. Affected patients may benefit from treatment with corticosteroids or similar medications, and that such treatment may, in some cases, enable patients to retain the ADM grafts and enable salvage of the reconstructed breast. Key Words: breast reconstruction, implant-based reconstruction, ADM, acellular dermal matrices, hypersensitivity (Ann Plast Surg 2014;73: S139YS143)
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ostoperative erythema is a perplexing finding associated with acellular dermal matrix (ADM) use in breast reconstruction surgery. ‘‘Red breast syndrome’’ is diagnosed clinically as idiopathic erythema overlying the ADM or the entire neo-breast complex, in the absence of other signs and symptoms indicating infection.1,2 The syndrome may mimic cellulitis and may prompt serial laboratory tests and treatment with antibiotics. Laboratory values may be normal or nonspecific, and the condition may be responsive or refractory to antibiotics.1,2 Most significantly, anecdotal evidence indicates that
Received November 30, 2013, and accepted for publication, after revision, December 12, 2013. From the *Harvard Combined Plastic Surgery Residency, Boston; †Harvard Medical School, Boston; ‡Beth Israel Deaconess Medical Center Pathology Residency, Boston; and §Division of Plastic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA. Presented at the 2013 Northeastern Society of Plastic Surgeons Annual Meeting, Washington, D.C. Conflicts of interest and sources of funding: none declared. Reprints: Sumner A. Slavin, MD, 1101 Beacon St Suite 7E, Brookline, MA. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7302-S139 DOI: 10.1097/SAP.0000000000000130
Annals of Plastic Surgery
the red breast syndrome may prompt ADM removal or deconstruction of the reconstructed breast, which is a disappointing result for both patients and plastic surgeons. The etiology and optimal management of ADM-related breast erythema and related symptoms are poorly understood. We hypothesize that red breast syndrome represents a delayed-type hypersensitivity reaction to ADM products, and that affected patients may benefit from treatment with corticosteroids or other anti-inflammatory medications. We present representative cases and review our findings in the context of previous reports into ADM grafts, hypersensitivity reactions, and alternate possible etiologies for the red breast syndrome.
CASE DESCRIPTIONS Case 1 A.F. is a 50-year-old female patient with multicentric stage III ductal and lobular left breast cancer who underwent neoadjuvant chemotherapy, bilateral simple mastectomies, tissue expander reconstruction with human acellular dermal matrix (AlloDerm; LifeCell, Branchburg, NJ), and postoperative radiation of the left breast. Nine months after placement of the tissue expanders and ADM, following completion of tissue expander filling, the patient presented with painful erythema of her right, non-radiated breast in the distribution of the underlying AlloDerm (Fig. 1). She was treated with a course of cefadroxil antibiotic, and the erythema resolved. Over the following weeks, the patient started having fevers, soaking night sweats, pruritis, and erythema of the right breast. Over the next month, she was trialed serially on a repeat course of cefadroxil, then bactrim, and ultimately augmentin and levofloxacin, without improvement in her clinical symptoms. She continued to have intermittent fevers. The patient did not develop leukocytosis, though she intermittently demonstrated a mild eosinophilia. She was taken off all antibiotics and was treated with a Solu-medrol (methylprednisolone) dose pack. The erythema improved markedly in 2 days. The patient was concerned that the erythematous red plaque was from inf lammatory breast cancer and was seen by the dermatology service. Given her history of fevers and night sweats, the differential diagnosis included infectious and inflammatory processes. When erythema recurred after completing the Solu-medrol, a punch biopsy was performed. The results did not suggest infection or cancer (Fig. 2). The tissue cultures showed no organisms. Instead, punch biopsy pathology revealed mild epidermal spongiosis, sparse perivascular lymphocytic and eosinophilic infiltrate, and mild dermal edema, consistent with a resolving hypersensitivity-type reaction. Although the patient was successfully treated with corticosteroids, she was distraught regarding the possibility of symptom recurrence. Given a diagnosis of presumed hypersensitivity reaction, the patient elected bilateral removal of the tissue expanders, capsules, and ADM. The AlloDerm, from 2 distinct lots on the right and left breasts, was more incorporated on the right, non-radiated side than on the radiated side. Final pathology demonstrated hypersensitivity reaction extending from the subcutaneous tissue through the capsules,
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Two weeks later, the erythema had improved with the exception of a 1-cm-diameter persistent patch overlying the ADM. At that time, there was low clinical suspicion for cellulitis and high clinical suspicion that the erythema was caused by an inf lammatory response to the ADM product. The patient was prescribed a 1-month course of Singulair (montelukast) to promote resolution of the presumed inf lammatory process. She has remained asymptomatic in the intervening 4-year follow-up period.
Case 4 C.D. is a 49-year-old woman who underwent left unilateral mastectomy and implant-based breast reconstruction with Veritas ADM in April 2008 followed by adjuvant chemotherapy. Approximately 1 month after reconstruction, the patient presented with erythema over the inferolateral pole of the reconstructed breast. Symptoms did not improve with a course of Augmentin (amoxicillin/ clavulanic acid), and the patient was admitted for IV Unasyn (ampicillin/ sulbactam). Due to minimal response to this regimen, she was transitioned to a 10-day course of IV ciprofloxacin and vancomycin, oral ciprofloxacin, and Augmentin for a total antibiotic treatment course of 5 weeks.
FIGURE 1. Unilateral delayed breast erythema refractive to antibiotic therapy but responsive to steroid therapy.
bilaterally (Fig. 3). Tissue cultures grew no organisms. On postoperative follow-up, the erythema and discomfort of her right breast resolved completely.
Case 2 K.I. is a 53-year-old female patient who was diagnosed with breast cancer in her thirties and who had previously undergone bilateral mastectomies and 2-stage implant-based reconstruction. She subsequently underwent multiple breast reconstruction revisions using AlloDerm to address symmastia and recurrent implant rippling. In the most recent revision, in 2010, the patient received Strattice porcine dermal matrix (LifeCell) for the first time, placed bilaterally in the parasternal region for revision of symmastia. One month following the procedure, the patient developed bilateral erythema in the distribution of the underlying biologic mesh. The erythema was unresponsive to antibiotics but was responsive to a Solu-medrol dose pack (Fig. 4). The patient’s laboratory values were within normal limits with the exception of a transient elevation of C-reactive protein. Recurrence of erythema 1 month later was responsive to a second course of corticosteroids, and the patient had no subsequent recurrence in a 2-year follow-up period. The patient was able to keep both the ADM grafts and her breast reconstructions bilaterally.
Case 3 A.B. is a 48-year-old woman with a history of cancer of the left breast, treated with lumpectomy and radiation therapy, who subsequently underwent mastectomy of the right breast due to ductal carcinoma in situ. In November 2008, she underwent implant-based reconstruction of the right breast with a Veritas (Synovis Surgical Innovations, St. Paul, MN) bovine pericardial ADM ‘‘sling’’. The patient did well initially but presented 2 weeks after the operation with erythema overlying the lower mastectomy flap. The patient demonstrated leukocytosis, but she remained afebrile and denied other symptoms. She was prescribed Levoquin for presumed cellulitis. S140
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FIGURE 2. Punch biopsy of the skin. Punch biopsy of the involved skin demonstrates mild spongiosis (A), with sparse perivascular lymphocytic and eosinophilic (B) (*) infiltrate and mild dermal edema, consistent with a resolving hypersensitivity type reaction (H&E). * 2014 Lippincott Williams & Wilkins
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Delayed Hypersensitivity Reaction to ADM
failure of improvement on antibiotic therapy, and histologic evidence of eosinophilic infiltrate extending from the overlying dermis through the dermal matrix and breast capsule suggest that this patient had inf lammation of an allergic rather than infectious etiology. Similarly, in the case of KI, the resolution of erythema after the second course of steroids suggests that suppressed infection was not the underlying cause of the patient’s symptoms. Instead, as in the case of patient AB, improvement with steroids is consistent with an inf lammatory reaction possibly representing a hypersensitivity reaction to the dermal matrix product. In both patients, removal of the biologic mesh or implants was successfully avoided. This finding suggests that after carefully ruling out infection, and under close observation, patients with erythema and discomfort overlying acellular dermal matrix may benefit from a course of corticosteroids; in these settings implant based breast reconstruction patients may be able to maintain their breast reconstruction. Finally, in patient, CD, improvement of symptoms with chemotherapy rendered cellulitis or other infectious process unlikely; a more plausible etiology of her erythema is inf lammation responsive to immunosuppression. FIGURE 3. Breast capsule histology. The bilateral breast capsules demonstrate mild chronic inf lammatory cell and eosinophilic (*) infiltrate (H&E).
The erythema persisted with this treatment regimen, but the patient did not manifest systemic signs or symptoms of infection. The erythema was not associated with localized warmth or edema. Due to a low clinical suspicion that the ongoing erythema was of an infectious etiology, all antibiotics were discontinued, and the patient was permitted to start adjuvant chemotherapy. Upon initiating the chemotherapy protocol and for several months after, the erythema resolved fully. Approximately 1 year after reconstruction and 6 months after completion of chemotherapy, the patient was noted to have a recurrence of trace erythema over the inferior pole of the reconstructed breast. Given the lack of fevers, leukocytosis, or systemic signs of infection, the patient’s stable, mild erythema was presumed to be of an inf lammatory nature, and she was not treated. C.D. has been monitored clinically for nearly 3 years without significant change.
DISCUSSION
‘‘Red Breast Syndrome’’: Incidence and Impact Anecdotal evidence suggests that numerous plastic surgeons have encountered breast reconstruction patients suffering from postoperative breast erythema, pruritis and/or pain in the absence of a clear diagnosis of breast cellulitis. Because red breast syndrome may masquerade as infection, not infrequently, affected patients undergo removal of the ADM graft, or takedown of the entire reconstructed breast before the natural course or true etiology of the reaction is established. Additionally, in other clinical situations red breast syndrome has been observed to resolve spontaneously. As a result, the full incidence and impact of the condition may be under-diagnosed by the plastic surgery community. Indeed, although the true incidence of ‘‘red breast syndrome’’ is unknown, available data suggest that it may be more frequent than commonly thought. A prior report indicates that the incidence of red breast syndrome in implant and ADM-based reconstruction patients may be as high as 7.6%.6 AlloDerm, one of the first ADMs adopted by plastic surgeons worldwide, has already been used in over 130,000 breast reconstruction procedures (A. Sarvey, BA, MBA and M. Hoyler, BA, written communication, March 6, 2013), and an ever-growing number of ADMs are on the market. The statistics
Among other cases, these 4 cases suggest that breast erythema following ADM-based breast reconstruction may be a delayed-type hypersensitivity reaction to a component of the ADM graft. The clinical picture may resolve with anti-inflammatory medications such as corticosteroids or even chemotherapeutics. Most importantly, treatment with corticosteroids or similar agents may enable salvage of an ADM graft or an entire reconstructed breast.
Delayed-Type Hypersensitivity Type IV hypersensitivity, also known as delayed-type hypersensitivity, is a T-cell-mediated response occurring after sensitization and re-exposure to an offending agent. Common examples include chronic transplant rejection and contact dermatitis. Dermatologic manifestations may include erythema, pruritus, vesicle formation, eczema, and skin necrosis.3,4 Patients may symptomatically experience burning, stinging or pain, and, in severe cases, fever.5 Treatment typically involves removal of the offending agent and may include topical or oral corticosteroids. The case of patient A.F. demonstrated clinical and histologic findings consistent with a type IV hypersensitivity reaction to acellular dermal matrix. Breast erythema after reconstruction is concerning for infection; however, in this case, the lack of leukocytosis, * 2014 Lippincott Williams & Wilkins
FIGURE 4. Bilateral breast erythema overlying ADM, responsive to corticosteroids without necessitating removal of implants or acellular dermal matrix. www.annalsplasticsurgery.com
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alone suggest that thousands of patients may already have experienced red breast syndrome.
Red Breast Syndrome: Alternate Etiologies Acellular dermal matrices are generally assumed to be biocompatible entities, which do not elicit an immunogeneic response in patients. Several studies have found no evidence that biologic mesh stimulates cell-mediated or humoral rejection in primate7 or pediatric8 models of abdominal wall repair. The literature contains a paucity of clinical or histologic reports of either immediate or delayed rejection of biologic meshes. Accordingly, red breast syndrome has previously been attributed to causes other than hypersensitivity. These causes include foreign body reaction, dependent erythema, hyperemia secondary to neovascularization and graft incorporation, and lymphatic obstruction.2,9,10 Indeed, a red breast type syndrome has been reported in breast reconstructions which do not utilize ADM, described as an ‘‘erysipelas-like reaction’’ and attributed to lymphatic obstruction.11 These etiologies may underlie post-reconstruction breast erythema in some cases. However, these theories do not explain the pathology and inf lammatory infiltrate seen in the case of AF, nor the timing of all four patients’ symptoms and their responsiveness to corticosteroids or chemotherapy.
Potential Allergens in ADMs Although ADMs are generally assumed to be biocompatible, the medical literature does not preclude the possibility of a hypersensitivity response to ADM grafts. Allergy to ADM preservatives has been proposed as an etiology of the red breast syndrome,1 as has cutaneous histamine release, implying a type I hypersensitivity response.2 Several hypersensitivity-inducing entities have already been identified. During processing and preparation, cellular components are removed from the ADM to minimize or eliminate antigens that might trigger immunogenic or inf lammatory responses. One such epitope, 1,3-alpha-galactose, has been shown to trigger a xenogeneic rejection reactionVitself a type IV hypersensitivity responseVand is removed from Strattice mesh during processing.12 However, other epitopes may not have yet been identified and thus are not removed from xenogeneic and allogeneic meshes. In addition, ADM manufacturers acknowledge the possibility of hypersensitivity reactions to their products. AlloDerm clinical instructions list ‘‘hypersensitive, allergic or immune response’’ among the product’s potential adverse effects, Veritas clinical instructions note the risk of rejection and allergic reaction, and Strattice ‘‘should not be used in patients with known sensitivity to porcine materials.’’13Y15 Although A.F. presented with recurrent erythema of only one of the reconstructed breasts, a similar but less severe eosinophilic inf lammatory response was seen in the contralateral breast capsule as well, suggesting that potential haptens may vary between product lots or intraoperative management, such as duration of the preparatory rinses, and degree of clinical immunologic response may vary depending on the degree of incorporation and neovascularization of the product.
Breast Erythema After Reconstruction: Infection, Hypersensitivity, or Other? It is possible that a hypersensitivity reaction as seen in patient A.F. is not uncommon but is routinely misdiagnosed as either cellulitis or other manifestations of postoperative inf lammation, such as foreign body reactions. As a result, this case may provide insight into episodes of presumed cellulitis which do not respond to antibiotic therapy, or which might respond by virtue of the anti-inf lammatory capacities of many anti-microbials. These anti-inf lammatory properties may explain why some patients’ erythema abates with antibiotic therapy, even in the absence of true infection. S142
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At the same time, type IV hypersensitivity reaction is distinct from other known causes of postoperative inf lammation,16,17 including seroma16,18Y20 and foreign body reactions.9,21 The type IV hypersensitivity reaction diagnosed in A.F. did not coincide with evidence of seroma or poor integration of the mesh at time of reoperation, although the radiated side was less incorporated. This relative non-incorporation of the left breast may also help to explain the lack of erythema on that side, as the hypersensitivity reaction was presumably strongest on the side with greatest integration and allergen exposure.
Resolution of the Red Breast Syndrome: Spontaneous or Immunosuppressant-Induced? Red breast syndrome in breast reconstruction patients is often observed to resolve spontaneously or may respond to antibiotic therapy for presumed cellulitis.2 While it is possible that the red breasts documented in this series may have ultimately proven to be self-limited phenomena, of the 4 cases presented here, 3 patients’ symptoms resolved in response to corticosteroids, and 1 patient’s symptoms resolved with chemotherapy. Three of the patients demonstrated long-term remission of symptoms, despite preservation of the breast reconstructions and ongoing exposure to the ADM allergen. Treatment with corticosteroids may have induced immunologic tolerance to the allergen(s) in the ADM graft. Indeed, high-dose corticosteroids are routinely used to induce tolerance in solid-organ transplant recipients with the steroid dose subsequently tapered.22 It is also possible that the immunosuppression induced by patient C.D.’s chemotherapy regimen had a similar effect in reducing the patient’s immune response to the ADM. In the absence of steroid or other immunosuppressive treatment, spontaneous resolution may be explained by a nonYsteroidinduced tolerance to the ADM. Alternatively, the process of graft incorporation may ultimately result in a ‘‘clearing’’ of the allergen from the graft, which could also account for spontaneous resolution of erythema and related symptoms.
CONCLUSIONS In conclusion, we report 4 cases of ADM-assisted breast reconstruction patients who likely developed delayed hypersensitivity reactions to acellular dermal matrix. Further research into the preparation of acellular dermal matrices is warranted to identify potential haptens and allergens, and to elucidate potential antigenicity. Similarly, the natural course of red breast syndrome and the potential utility of corticosteroids and alternate anti-inf lammatories or immunosuppressants in breast erythema of non-infectious etiology must be explored further. REFERENCES 1. Nahabedian MY. Reply. Plast Reconstr Surg. 2010;126:1120Y1121. 2. Newman MI, Hanabergh E, Samson MC. AlloDerm performance in the setting of prosthetic breast surgery, infection, and irradiation. Plast Reconstr Surgery. 2010;126:1120; author reply 1120Y1121. 3. Kumar V, Robbins S, Cotran R. Diseases of the immune system. Robbins and Cotran Pathologic Basis of Disease. 8 ed. Philadelphia: Saunders/Elsevier; 2010. 4. Levinson W. Hypersensitivity (allergy). In W Levinson ed., Review of Medical Microbiology and Immunology. 12 ed. New York: McGraw-Hill; 2012. 5. Suurmond D. Eczema/dermatitis. In D Suurmond ed., Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 6 ed. New York: McGraw-Hill; 2009. 6. Hill JL, Wong L, Kemper P, et al. Infectious complications associated with the use of acellular dermal matrix in implant-based bilateral breast reconstruction. Ann Plast Surg. 2012;68:432Y434. 7. Xu H, Wan H, Sandor M, et al. Host response to human acellular dermal matrix transplantation in a primate model of abdominal wall repair. Tissue Eng Part A. 2008;14:2009Y2019.
* 2014 Lippincott Williams & Wilkins
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8. Meyer T, Meyer B, Schwarz K, Hocht B. Immune response to xenogeneic matrix grafts used in pediatric surgery. Eur J Pediatr Surg. 2007;17:420Y425. 9. Heyer K, Buck DW 2nd, Kato C, et al. Reversed acellular dermis: failure of graft incorporation in primary tissue expander breast reconstruction resulting in recurrent breast cellulitis. Plast Reconstr Surg. 2010;125:66eY68e. 10. Zippel D, Siegelmann-Danieli N, Ayalon S, et al. Delayed breast cellulitis following breast conserving operation. Eur J Surg Oncol. 2003;29:327Y330. 11. Cichowitz A, Stanley PA, Morrison WA. Erysipelas-like inflammation following breast surgery. J Plast Reconstr Aesthet Surg. 2007;60:490Y494. 12. Ibrahim AM, Ayeni OA, Hughes KB, et al. Acellular dermal matrices in breast surgery: a comprehensive review. Ann Plast Surg. 2013;70:732Y738. 13. LifeCell. Strattice Reconstructive Tissue Matrix. Available at: http://www.lifecell.com/ fileadmin/media/files/downloads/StratticeIFU_T11.pdf. Accessed March 13, 2013. 14. LifeCell. Alloderm Regenerative Tissue Matrix. Available at: http://www.lifecell.com/ fileadmin/media/files/downloads/Alloderm_IFU_D.pdf. Accessed March 13, 2013. 15. Synovis. Veritas Collagen Matrix. Available at: http://www.synovissurgical.com/ pdfs/VCM US.pdf. Accessed May 8, 2013.
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16. Kim JY, Davila AA, Persing S, et al. A meta-analysis of human acellular dermis and submuscular tissue expander breast reconstruction. Plast Reconstr Surg. 2012;129:28Y41. 17. Novitsky YW, Rosen MJ. The biology of biologics: basic science and clinical concepts. Plast Reconstr Surg. 2012;130:9SY17S. 18. Chun YS, Verma K, Rosen H, et al. Implant-based breast reconstruction using acellular dermal matrix and the risk of postoperative complications. Plast Reconstr Surg. 2010;125:429Y436. 19. Parks JW, Hammond SE, Walsh WA, et al. Human acellular dermis versus no acellular dermis in tissue expansion breast reconstruction. Plast Reconstr Surg. 2012;130:739Y746. 20. Sbitany H, Serletti JM. Acellular dermis-assisted prosthetic breast reconstruction: a systematic and critical review of efficacy and associated morbidity. Plast Reconstr Surg. 2011;128:1162Y1169. 21. Kim JY, Connor CM. Focus on technique: two-stage implant-based breast reconstruction. Plast Reconstr Surg. 2012;130:104SY115S. 22. Humar A, Dunn D. Transplantation. In: Brunicardi FC, Anderson DK, Billiar TR, et al eds. Schwartz’s Principles of Surgery, 9th ed. New York: McGraw-Hill; 2010.
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Delayed Hypersensitivity Reaction to Acellular Dermal Matrix in Breast Reconstruction The Red Breast Syndrome? Ingrid Ganske, MD, MPA,* Marguerite Hoyler, BA,Þ Sharon E. Fox, MD, PhD,þ Donald J. Morris, MD,§ Samuel J. Lin, MD,§ and Sumner A. Slavin, MD§ Background: Acellular dermal matrix (ADM) has become a valuable tool in reconstructive breast surgery, in part because it has been considered to be a non-reactive and non-immunogenic entity. However, some patients who undergo breast reconstruction with ADMs develop postoperative erythema overlying their ADM grafts. The etiology of this phenomenon is poorly understood. Methods: In this article, we summarize clinical cases in which patients developed localized breast erythema following reconstruction with ADMs. We review what is known about postoperative breast erythema after ADM-based breast reconstructions and the possible antigenicity of biologic mesh implants. Results: We report 4 implant-based breast reconstruction patients who developed erythematous reactions overlying the region where ADM was placed: one demonstrated a delayed-type hypersensitivity reaction on punch biopsy of the affected skin, leading to removal of the biologic product; 2 others had a similar clinical presentation that responded to corticosteroids without removal of the biologic material, with 1 patient experiencing recrudescence of erythema that responded fully to a second course of corticosteroids; and a fourth showed erythema that was only moderately responsive to antibiotic therapy but which improved consistently after the patient initiated chemotherapy. Conclusion: We propose that the etiology of erythema overlying ADM grafts, and the so-called red breast syndrome, may in some patients be a delayed-type hypersensitivity reaction to the ADM product. Affected patients may benefit from treatment with corticosteroids or similar medications, and that such treatment may, in some cases, enable patients to retain the ADM grafts and enable salvage of the reconstructed breast. Key Words: breast reconstruction, implant-based reconstruction, ADM, acellular dermal matrices, hypersensitivity (Ann Plast Surg 2014;73: S139YS143)
P
ostoperative erythema is a perplexing finding associated with acellular dermal matrix (ADM) use in breast reconstruction surgery. ‘‘Red breast syndrome’’ is diagnosed clinically as idiopathic erythema overlying the ADM or the entire neo-breast complex, in the absence of other signs and symptoms indicating infection.1,2 The syndrome may mimic cellulitis and may prompt serial laboratory tests and treatment with antibiotics. Laboratory values may be normal or nonspecific, and the condition may be responsive or refractory to antibiotics.1,2 Most significantly, anecdotal evidence indicates that
Received November 30, 2013, and accepted for publication, after revision, December 12, 2013. From the *Harvard Combined Plastic Surgery Residency, Boston; †Harvard Medical School, Boston; ‡Beth Israel Deaconess Medical Center Pathology Residency, Boston; and §Division of Plastic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA. Presented at the 2013 Northeastern Society of Plastic Surgeons Annual Meeting, Washington, D.C. Conflicts of interest and sources of funding: none declared. Reprints: Sumner A. Slavin, MD, 1101 Beacon St Suite 7E, Brookline, MA. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7302-S139 DOI: 10.1097/SAP.0000000000000130
Annals of Plastic Surgery
the red breast syndrome may prompt ADM removal or deconstruction of the reconstructed breast, which is a disappointing result for both patients and plastic surgeons. The etiology and optimal management of ADM-related breast erythema and related symptoms are poorly understood. We hypothesize that red breast syndrome represents a delayed-type hypersensitivity reaction to ADM products, and that affected patients may benefit from treatment with corticosteroids or other anti-inflammatory medications. We present representative cases and review our findings in the context of previous reports into ADM grafts, hypersensitivity reactions, and alternate possible etiologies for the red breast syndrome.
CASE DESCRIPTIONS Case 1 A.F. is a 50-year-old female patient with multicentric stage III ductal and lobular left breast cancer who underwent neoadjuvant chemotherapy, bilateral simple mastectomies, tissue expander reconstruction with human acellular dermal matrix (AlloDerm; LifeCell, Branchburg, NJ), and postoperative radiation of the left breast. Nine months after placement of the tissue expanders and ADM, following completion of tissue expander filling, the patient presented with painful erythema of her right, non-radiated breast in the distribution of the underlying AlloDerm (Fig. 1). She was treated with a course of cefadroxil antibiotic, and the erythema resolved. Over the following weeks, the patient started having fevers, soaking night sweats, pruritis, and erythema of the right breast. Over the next month, she was trialed serially on a repeat course of cefadroxil, then bactrim, and ultimately augmentin and levofloxacin, without improvement in her clinical symptoms. She continued to have intermittent fevers. The patient did not develop leukocytosis, though she intermittently demonstrated a mild eosinophilia. She was taken off all antibiotics and was treated with a Solu-medrol (methylprednisolone) dose pack. The erythema improved markedly in 2 days. The patient was concerned that the erythematous red plaque was from inf lammatory breast cancer and was seen by the dermatology service. Given her history of fevers and night sweats, the differential diagnosis included infectious and inflammatory processes. When erythema recurred after completing the Solu-medrol, a punch biopsy was performed. The results did not suggest infection or cancer (Fig. 2). The tissue cultures showed no organisms. Instead, punch biopsy pathology revealed mild epidermal spongiosis, sparse perivascular lymphocytic and eosinophilic infiltrate, and mild dermal edema, consistent with a resolving hypersensitivity-type reaction. Although the patient was successfully treated with corticosteroids, she was distraught regarding the possibility of symptom recurrence. Given a diagnosis of presumed hypersensitivity reaction, the patient elected bilateral removal of the tissue expanders, capsules, and ADM. The AlloDerm, from 2 distinct lots on the right and left breasts, was more incorporated on the right, non-radiated side than on the radiated side. Final pathology demonstrated hypersensitivity reaction extending from the subcutaneous tissue through the capsules,
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Two weeks later, the erythema had improved with the exception of a 1-cm-diameter persistent patch overlying the ADM. At that time, there was low clinical suspicion for cellulitis and high clinical suspicion that the erythema was caused by an inf lammatory response to the ADM product. The patient was prescribed a 1-month course of Singulair (montelukast) to promote resolution of the presumed inf lammatory process. She has remained asymptomatic in the intervening 4-year follow-up period.
Case 4 C.D. is a 49-year-old woman who underwent left unilateral mastectomy and implant-based breast reconstruction with Veritas ADM in April 2008 followed by adjuvant chemotherapy. Approximately 1 month after reconstruction, the patient presented with erythema over the inferolateral pole of the reconstructed breast. Symptoms did not improve with a course of Augmentin (amoxicillin/ clavulanic acid), and the patient was admitted for IV Unasyn (ampicillin/ sulbactam). Due to minimal response to this regimen, she was transitioned to a 10-day course of IV ciprofloxacin and vancomycin, oral ciprofloxacin, and Augmentin for a total antibiotic treatment course of 5 weeks.
FIGURE 1. Unilateral delayed breast erythema refractive to antibiotic therapy but responsive to steroid therapy.
bilaterally (Fig. 3). Tissue cultures grew no organisms. On postoperative follow-up, the erythema and discomfort of her right breast resolved completely.
Case 2 K.I. is a 53-year-old female patient who was diagnosed with breast cancer in her thirties and who had previously undergone bilateral mastectomies and 2-stage implant-based reconstruction. She subsequently underwent multiple breast reconstruction revisions using AlloDerm to address symmastia and recurrent implant rippling. In the most recent revision, in 2010, the patient received Strattice porcine dermal matrix (LifeCell) for the first time, placed bilaterally in the parasternal region for revision of symmastia. One month following the procedure, the patient developed bilateral erythema in the distribution of the underlying biologic mesh. The erythema was unresponsive to antibiotics but was responsive to a Solu-medrol dose pack (Fig. 4). The patient’s laboratory values were within normal limits with the exception of a transient elevation of C-reactive protein. Recurrence of erythema 1 month later was responsive to a second course of corticosteroids, and the patient had no subsequent recurrence in a 2-year follow-up period. The patient was able to keep both the ADM grafts and her breast reconstructions bilaterally.
Case 3 A.B. is a 48-year-old woman with a history of cancer of the left breast, treated with lumpectomy and radiation therapy, who subsequently underwent mastectomy of the right breast due to ductal carcinoma in situ. In November 2008, she underwent implant-based reconstruction of the right breast with a Veritas (Synovis Surgical Innovations, St. Paul, MN) bovine pericardial ADM ‘‘sling’’. The patient did well initially but presented 2 weeks after the operation with erythema overlying the lower mastectomy flap. The patient demonstrated leukocytosis, but she remained afebrile and denied other symptoms. She was prescribed Levoquin for presumed cellulitis. S140
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FIGURE 2. Punch biopsy of the skin. Punch biopsy of the involved skin demonstrates mild spongiosis (A), with sparse perivascular lymphocytic and eosinophilic (B) (*) infiltrate and mild dermal edema, consistent with a resolving hypersensitivity type reaction (H&E). * 2014 Lippincott Williams & Wilkins
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failure of improvement on antibiotic therapy, and histologic evidence of eosinophilic infiltrate extending from the overlying dermis through the dermal matrix and breast capsule suggest that this patient had inf lammation of an allergic rather than infectious etiology. Similarly, in the case of KI, the resolution of erythema after the second course of steroids suggests that suppressed infection was not the underlying cause of the patient’s symptoms. Instead, as in the case of patient AB, improvement with steroids is consistent with an inf lammatory reaction possibly representing a hypersensitivity reaction to the dermal matrix product. In both patients, removal of the biologic mesh or implants was successfully avoided. This finding suggests that after carefully ruling out infection, and under close observation, patients with erythema and discomfort overlying acellular dermal matrix may benefit from a course of corticosteroids; in these settings implant based breast reconstruction patients may be able to maintain their breast reconstruction. Finally, in patient, CD, improvement of symptoms with chemotherapy rendered cellulitis or other infectious process unlikely; a more plausible etiology of her erythema is inf lammation responsive to immunosuppression. FIGURE 3. Breast capsule histology. The bilateral breast capsules demonstrate mild chronic inf lammatory cell and eosinophilic (*) infiltrate (H&E).
The erythema persisted with this treatment regimen, but the patient did not manifest systemic signs or symptoms of infection. The erythema was not associated with localized warmth or edema. Due to a low clinical suspicion that the ongoing erythema was of an infectious etiology, all antibiotics were discontinued, and the patient was permitted to start adjuvant chemotherapy. Upon initiating the chemotherapy protocol and for several months after, the erythema resolved fully. Approximately 1 year after reconstruction and 6 months after completion of chemotherapy, the patient was noted to have a recurrence of trace erythema over the inferior pole of the reconstructed breast. Given the lack of fevers, leukocytosis, or systemic signs of infection, the patient’s stable, mild erythema was presumed to be of an inf lammatory nature, and she was not treated. C.D. has been monitored clinically for nearly 3 years without significant change.
DISCUSSION
‘‘Red Breast Syndrome’’: Incidence and Impact Anecdotal evidence suggests that numerous plastic surgeons have encountered breast reconstruction patients suffering from postoperative breast erythema, pruritis and/or pain in the absence of a clear diagnosis of breast cellulitis. Because red breast syndrome may masquerade as infection, not infrequently, affected patients undergo removal of the ADM graft, or takedown of the entire reconstructed breast before the natural course or true etiology of the reaction is established. Additionally, in other clinical situations red breast syndrome has been observed to resolve spontaneously. As a result, the full incidence and impact of the condition may be under-diagnosed by the plastic surgery community. Indeed, although the true incidence of ‘‘red breast syndrome’’ is unknown, available data suggest that it may be more frequent than commonly thought. A prior report indicates that the incidence of red breast syndrome in implant and ADM-based reconstruction patients may be as high as 7.6%.6 AlloDerm, one of the first ADMs adopted by plastic surgeons worldwide, has already been used in over 130,000 breast reconstruction procedures (A. Sarvey, BA, MBA and M. Hoyler, BA, written communication, March 6, 2013), and an ever-growing number of ADMs are on the market. The statistics
Among other cases, these 4 cases suggest that breast erythema following ADM-based breast reconstruction may be a delayed-type hypersensitivity reaction to a component of the ADM graft. The clinical picture may resolve with anti-inflammatory medications such as corticosteroids or even chemotherapeutics. Most importantly, treatment with corticosteroids or similar agents may enable salvage of an ADM graft or an entire reconstructed breast.
Delayed-Type Hypersensitivity Type IV hypersensitivity, also known as delayed-type hypersensitivity, is a T-cell-mediated response occurring after sensitization and re-exposure to an offending agent. Common examples include chronic transplant rejection and contact dermatitis. Dermatologic manifestations may include erythema, pruritus, vesicle formation, eczema, and skin necrosis.3,4 Patients may symptomatically experience burning, stinging or pain, and, in severe cases, fever.5 Treatment typically involves removal of the offending agent and may include topical or oral corticosteroids. The case of patient A.F. demonstrated clinical and histologic findings consistent with a type IV hypersensitivity reaction to acellular dermal matrix. Breast erythema after reconstruction is concerning for infection; however, in this case, the lack of leukocytosis, * 2014 Lippincott Williams & Wilkins
FIGURE 4. Bilateral breast erythema overlying ADM, responsive to corticosteroids without necessitating removal of implants or acellular dermal matrix. www.annalsplasticsurgery.com
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alone suggest that thousands of patients may already have experienced red breast syndrome.
Red Breast Syndrome: Alternate Etiologies Acellular dermal matrices are generally assumed to be biocompatible entities, which do not elicit an immunogeneic response in patients. Several studies have found no evidence that biologic mesh stimulates cell-mediated or humoral rejection in primate7 or pediatric8 models of abdominal wall repair. The literature contains a paucity of clinical or histologic reports of either immediate or delayed rejection of biologic meshes. Accordingly, red breast syndrome has previously been attributed to causes other than hypersensitivity. These causes include foreign body reaction, dependent erythema, hyperemia secondary to neovascularization and graft incorporation, and lymphatic obstruction.2,9,10 Indeed, a red breast type syndrome has been reported in breast reconstructions which do not utilize ADM, described as an ‘‘erysipelas-like reaction’’ and attributed to lymphatic obstruction.11 These etiologies may underlie post-reconstruction breast erythema in some cases. However, these theories do not explain the pathology and inf lammatory infiltrate seen in the case of AF, nor the timing of all four patients’ symptoms and their responsiveness to corticosteroids or chemotherapy.
Potential Allergens in ADMs Although ADMs are generally assumed to be biocompatible, the medical literature does not preclude the possibility of a hypersensitivity response to ADM grafts. Allergy to ADM preservatives has been proposed as an etiology of the red breast syndrome,1 as has cutaneous histamine release, implying a type I hypersensitivity response.2 Several hypersensitivity-inducing entities have already been identified. During processing and preparation, cellular components are removed from the ADM to minimize or eliminate antigens that might trigger immunogenic or inf lammatory responses. One such epitope, 1,3-alpha-galactose, has been shown to trigger a xenogeneic rejection reactionVitself a type IV hypersensitivity responseVand is removed from Strattice mesh during processing.12 However, other epitopes may not have yet been identified and thus are not removed from xenogeneic and allogeneic meshes. In addition, ADM manufacturers acknowledge the possibility of hypersensitivity reactions to their products. AlloDerm clinical instructions list ‘‘hypersensitive, allergic or immune response’’ among the product’s potential adverse effects, Veritas clinical instructions note the risk of rejection and allergic reaction, and Strattice ‘‘should not be used in patients with known sensitivity to porcine materials.’’13Y15 Although A.F. presented with recurrent erythema of only one of the reconstructed breasts, a similar but less severe eosinophilic inf lammatory response was seen in the contralateral breast capsule as well, suggesting that potential haptens may vary between product lots or intraoperative management, such as duration of the preparatory rinses, and degree of clinical immunologic response may vary depending on the degree of incorporation and neovascularization of the product.
Breast Erythema After Reconstruction: Infection, Hypersensitivity, or Other? It is possible that a hypersensitivity reaction as seen in patient A.F. is not uncommon but is routinely misdiagnosed as either cellulitis or other manifestations of postoperative inf lammation, such as foreign body reactions. As a result, this case may provide insight into episodes of presumed cellulitis which do not respond to antibiotic therapy, or which might respond by virtue of the anti-inf lammatory capacities of many anti-microbials. These anti-inf lammatory properties may explain why some patients’ erythema abates with antibiotic therapy, even in the absence of true infection. S142
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At the same time, type IV hypersensitivity reaction is distinct from other known causes of postoperative inf lammation,16,17 including seroma16,18Y20 and foreign body reactions.9,21 The type IV hypersensitivity reaction diagnosed in A.F. did not coincide with evidence of seroma or poor integration of the mesh at time of reoperation, although the radiated side was less incorporated. This relative non-incorporation of the left breast may also help to explain the lack of erythema on that side, as the hypersensitivity reaction was presumably strongest on the side with greatest integration and allergen exposure.
Resolution of the Red Breast Syndrome: Spontaneous or Immunosuppressant-Induced? Red breast syndrome in breast reconstruction patients is often observed to resolve spontaneously or may respond to antibiotic therapy for presumed cellulitis.2 While it is possible that the red breasts documented in this series may have ultimately proven to be self-limited phenomena, of the 4 cases presented here, 3 patients’ symptoms resolved in response to corticosteroids, and 1 patient’s symptoms resolved with chemotherapy. Three of the patients demonstrated long-term remission of symptoms, despite preservation of the breast reconstructions and ongoing exposure to the ADM allergen. Treatment with corticosteroids may have induced immunologic tolerance to the allergen(s) in the ADM graft. Indeed, high-dose corticosteroids are routinely used to induce tolerance in solid-organ transplant recipients with the steroid dose subsequently tapered.22 It is also possible that the immunosuppression induced by patient C.D.’s chemotherapy regimen had a similar effect in reducing the patient’s immune response to the ADM. In the absence of steroid or other immunosuppressive treatment, spontaneous resolution may be explained by a nonYsteroidinduced tolerance to the ADM. Alternatively, the process of graft incorporation may ultimately result in a ‘‘clearing’’ of the allergen from the graft, which could also account for spontaneous resolution of erythema and related symptoms.
CONCLUSIONS In conclusion, we report 4 cases of ADM-assisted breast reconstruction patients who likely developed delayed hypersensitivity reactions to acellular dermal matrix. Further research into the preparation of acellular dermal matrices is warranted to identify potential haptens and allergens, and to elucidate potential antigenicity. Similarly, the natural course of red breast syndrome and the potential utility of corticosteroids and alternate anti-inf lammatories or immunosuppressants in breast erythema of non-infectious etiology must be explored further. REFERENCES 1. Nahabedian MY. Reply. Plast Reconstr Surg. 2010;126:1120Y1121. 2. Newman MI, Hanabergh E, Samson MC. AlloDerm performance in the setting of prosthetic breast surgery, infection, and irradiation. Plast Reconstr Surgery. 2010;126:1120; author reply 1120Y1121. 3. Kumar V, Robbins S, Cotran R. Diseases of the immune system. Robbins and Cotran Pathologic Basis of Disease. 8 ed. Philadelphia: Saunders/Elsevier; 2010. 4. Levinson W. Hypersensitivity (allergy). In W Levinson ed., Review of Medical Microbiology and Immunology. 12 ed. New York: McGraw-Hill; 2012. 5. Suurmond D. Eczema/dermatitis. In D Suurmond ed., Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 6 ed. New York: McGraw-Hill; 2009. 6. Hill JL, Wong L, Kemper P, et al. Infectious complications associated with the use of acellular dermal matrix in implant-based bilateral breast reconstruction. Ann Plast Surg. 2012;68:432Y434. 7. Xu H, Wan H, Sandor M, et al. Host response to human acellular dermal matrix transplantation in a primate model of abdominal wall repair. Tissue Eng Part A. 2008;14:2009Y2019.
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8. Meyer T, Meyer B, Schwarz K, Hocht B. Immune response to xenogeneic matrix grafts used in pediatric surgery. Eur J Pediatr Surg. 2007;17:420Y425. 9. Heyer K, Buck DW 2nd, Kato C, et al. Reversed acellular dermis: failure of graft incorporation in primary tissue expander breast reconstruction resulting in recurrent breast cellulitis. Plast Reconstr Surg. 2010;125:66eY68e. 10. Zippel D, Siegelmann-Danieli N, Ayalon S, et al. Delayed breast cellulitis following breast conserving operation. Eur J Surg Oncol. 2003;29:327Y330. 11. Cichowitz A, Stanley PA, Morrison WA. Erysipelas-like inflammation following breast surgery. J Plast Reconstr Aesthet Surg. 2007;60:490Y494. 12. Ibrahim AM, Ayeni OA, Hughes KB, et al. Acellular dermal matrices in breast surgery: a comprehensive review. Ann Plast Surg. 2013;70:732Y738. 13. LifeCell. Strattice Reconstructive Tissue Matrix. Available at: http://www.lifecell.com/ fileadmin/media/files/downloads/StratticeIFU_T11.pdf. Accessed March 13, 2013. 14. LifeCell. Alloderm Regenerative Tissue Matrix. Available at: http://www.lifecell.com/ fileadmin/media/files/downloads/Alloderm_IFU_D.pdf. Accessed March 13, 2013. 15. Synovis. Veritas Collagen Matrix. Available at: http://www.synovissurgical.com/ pdfs/VCM US.pdf. Accessed May 8, 2013.
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16. Kim JY, Davila AA, Persing S, et al. A meta-analysis of human acellular dermis and submuscular tissue expander breast reconstruction. Plast Reconstr Surg. 2012;129:28Y41. 17. Novitsky YW, Rosen MJ. The biology of biologics: basic science and clinical concepts. Plast Reconstr Surg. 2012;130:9SY17S. 18. Chun YS, Verma K, Rosen H, et al. Implant-based breast reconstruction using acellular dermal matrix and the risk of postoperative complications. Plast Reconstr Surg. 2010;125:429Y436. 19. Parks JW, Hammond SE, Walsh WA, et al. Human acellular dermis versus no acellular dermis in tissue expansion breast reconstruction. Plast Reconstr Surg. 2012;130:739Y746. 20. Sbitany H, Serletti JM. Acellular dermis-assisted prosthetic breast reconstruction: a systematic and critical review of efficacy and associated morbidity. Plast Reconstr Surg. 2011;128:1162Y1169. 21. Kim JY, Connor CM. Focus on technique: two-stage implant-based breast reconstruction. Plast Reconstr Surg. 2012;130:104SY115S. 22. Humar A, Dunn D. Transplantation. In: Brunicardi FC, Anderson DK, Billiar TR, et al eds. Schwartz’s Principles of Surgery, 9th ed. New York: McGraw-Hill; 2010.
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