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Mannan-binding lectin and healing of a radiation-induced chronic ulcer – a case report on mannan-binding lectin replacement therapy
Journal of Plastic, Reconstructive & Aesthetic Surgery (2011) 64, e146ee148
CASE REPORT
Mannan-binding lectin and healing of a radiationinduced chronic ulcer e a case report on mannanbinding lectin replacement therapy* ¨lmich a,* N. Maaløe a, C. Bonde b, I. Laursen c, M. Christiansen c, L.R. Ho a
Department of Plastic Surgery, Herlev University Hospital, Herlev, Denmark Department of Plastic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark c Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark b
Received 26 August 2010; accepted 22 January 2011
KEYWORDS Mannan-binding lectin; Immune deficiency; Chronic wound; Radiation-induced ulcer; Breast cancer
Summary Mannan-binding lectin is an important component of innate immunity, and insufficiency is associated with several clinical disorders. Recently, experimental replacement therapy with plasma-derived mannan-binding lectin has become an option. The current article presents the case of a patient with an insufficient level of mannan-binding lectin and a chronic radiation-induced ulcer following the treatment of breast cancer. After 15 months of initially conservative treatment and thereafter plastic surgery, the healing was still impaired with necrosis in the periphery of the ulcer. Immunological work-up of the patient revealed pronounced insufficiency of mannan-binding lectin. Following a 6-week experimental intravenous treatment with mannan-binding lectin purified from human plasma, that is, 0.2e0.3 mg mannan-binding lectin per kg body weight twice a week, the defect was completely healed. We suggest that deficiency of mannan-binding lectin can explain cases of otherwise unexplained impaired healing, and that replacement therapy is considered in such cases. ª 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
* Department of Plastic Surgery, Herlev University Hospital, Ndr. Ringvej, 2730 Herlev, Denmark. * Corresponding author. Department of Plastic Surgery, 54F8 Herlev University Hospital, Ndr. Ringvej, 2730 Herlev, Denmark. Tel.: þ45 4488 3947; fax: þ45 4488 3955. E-mail address: [email protected] (L.R. Ho ¨lmich).
Mannan-binding lectin (MBL) is a key component of the innate immune defence. Deficiency of MBL is defined as serum concentrations <100 mg l1, and it is caused by polymorphisms in the first exon and promoter region of the MBL gene. It affects 10e15% of all Caucasians, and it is the most commonly known immune defect.1 A low level of MBL can render some individuals susceptible to severe infectious diseases, and it is associated with several clinical disorders.2
1748-6815/$ - see front matter ª 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2011.01.013
Mannan-binding lectin and healing of a radiation-induced chronic ulcer Recently, experimental replacement therapy with plasma-derived MBL has become an option for select patients.3,4
Case report A 64-year-old obese woman (smoker) was diagnosed with breast cancer (stage III). She was treated according to national guidelines with neoadjuvant chemotherapy, followed by mastectomy and axillary dissection. Postoperatively, she received adjuvant chemotherapy (cyclophosphamide, epirubicin and 5-fluorouracil) and radiotherapy (24 treatments of 2 Gy, five per week). The healing was impaired and 5 months after the mastectomy, she developed an abscess in the chest wound, which perforated spontaneously. She had no previous medical history of infections or ulcers but the ulcer became chronic with persistent Staphylococcus aureus growth for 6 months as well as recurrent infections with Gram-negative and anaerobic bacteria, and the defect did not heal despite intensive wound care and antibiotics. One year after the mastectomy, and after intensive wound care the ulcer was without clinical infection, but it was 1 cm in diameter and 6 cm in depth forming a large cavity towards the axilla. At this time, the patient was referred to undergo plastic surgery, and she discontinued smoking during the first admittance. Several surgical interventions were performed. Initially an excision of the most severely damaged skin and the fistula with direct closure was attempted, but the surgery failed, and postoperatively, S. aureus was again detected in the ulcer. Then a latissimus dorsi flap was performed to cover the defect, however, this also failed. Also, negative pressure therapy was applied to the ulcer without success. Finally, a pedicled vertical rectus abdominis myocutaneous (VRAM) flap appeared vital in its central part. However, the healing progressed very slowly and after 10 days, there was still no adherence of the wound edges. A series of postoperative hyperbaric oxygen (HBO) therapy sessions resulted in healing in some areas, but large defects remained with undermining both laterally, cranially and medially to the
e147
VRAM flap (Figure 1, left photo). At this time, there were tissue necrosis and radiation-induced tissue damage, but no clinical infection, and no underlying immunological cause of the persisting ulcer was found; that is, immunoglobulins and Immunoglobulin G (IgG) subclasses were normal. Fifteen months after the mastectomy, the serum level of MBL was measured, and the result of 68 mg l1 indicated MBL deficiency. Replacement therapy with plasma-derived MBL was decided with approval from the Danish Medicines Agency. The treatment regime followed recommendations from the manufacturer (Statens Serum Institut, Copenhagen, Denmark); that is, the patient was given 0.2e0.3 mg intravenous MBL per kg body weight twice a week for 6 weeks. Blood samples were drawn at regular intervals after the first infusion, and the maximal MBL concentration was 3608 mg1, the trough level was 676 mg l1 and the halflife was 39 h. Evident effect on the healing process was observed already 5 days after the initial dose of MBL, and after 12 treatments, the ulcer was completely healed (Figure 1).
Discussion In breast cancer patients, problems associated with radiotherapy-associated complications on wound healing are well known.5 This article describes an extremely persistent case not responding to standard treatment including surgery. Although clinical infection was not evident, MBL deficiency appeared to be a main cause of the impaired healing. The effect of MBL is probably a combination of an improved elimination of microorganisms through an opsonic function and a modulation of the cytokine response to infections and inflammatory conditions.2,6 However, these mechanisms are hypothetical as no measurements of cytokines were performed. MBL deficiency is usually clinically silent. However, it has been shown to be associated with increased susceptibility and severity of infections, mainly in young children before maturation of the acquired immunity and in immunecompromised persons; furthermore, low MBL levels have been associated with severity of cystic fibrosis and
Figure 1 Left figure: The situation at start of MBL substitution after bed-side necrectomy and 15 treatments of HBO. Several areas with insufficient healing and radiation-induced tissue damage are seen in the periphery of the flap with wide undermining both laterally, cranially, and medially. Right figure: Same patient after 9 treatments of plasma-derived MBL. Undermining is absent and the defect is almost healed.
e148 autoimmune diseases.2 A study describing the epidemiology of patients with chronic foot and leg ulcers and examining the significance of MBL levels showed that the frequency of low MBL in patients with venous leg ulcer was significantly higher than that of other wound patients or healthy controls.7 This indicates different roles of MBL in the development of ulcers with different aetiologies. This is the first attempt to treat a persistent radiation-induced ulcer in an MBL-deficient patient with MBL replacement therapy. However, the successful treatment is in accordance with findings in a similar case report of an MBL-deficient patient with a chronic leg ulcer. In the latter case intermittent cessation of MBL therapy resulted in reappearance of healing problems strongly corroborating the clinical effect of MBL replacement therapy.8 Currently, therapy with plasma-derived MBL is expensive, approximately 40,500 Euro in this case. However, compared to prolonged hospital stay and risk of deterioration including life-threatening infections, it was considered acceptable. Presently, the recommended dosage regimen is based on the aim to achieve MBL plasma trough levels close to the normal level (about 1000 mg l1). However, this recommendation is not based on reasonably sized efficacy studies to indicate why the treatment may become less expensive if the dose can be reduced. As the half-life of MBL is highly variable, it is important to perform MBL concentration monitoring to assure that the treatment targets are reached.4,9,10 We suggest that MBL deficiency may cause otherwise unexplained impaired healing in radiation-induced ulcers and that MBL replacement therapy should be considered in such cases.
Conflict of interest statement SSI currently holds a patent for the production of plasmaderived MBL with Inga Laursen listed as an inventor.
N. Maaløe et al.
Acknowledgements None.
References 1. Madsen HO, Garred P, Thiel S, Kurtzhals JA, Lamm LU, Ryder LP, et al. Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol 1995;155:3013e20. 2. Kilpatrick DC. Mannan-binding lectin: clinical significance and applications. Biochim Biophys Acta 2002;1572:401e13. 3. Laursen I. Mannan-binding lectin (MBL) production from human plasma. Biochem Soc Trans 2003;31:758e62. 4. Valdimarsson H, Vikingsdottir T, Bang P, Saevarsdottir S, Gudjonsson JE, Oskarsson O, et al. Human plasma-derived mannose-binding lectin: a phase I safety and pharmacokinetic study. Scand J Immunol 2004;59:97e102. 5. Wallgren A. Late effects of radiotherapy in the treatment of breast cancer. Acta Oncol 1992;31:237e42. 6. Fraser DA, Bohlson SS, Jasinskiene N, Rawal N, Palmarini G, Ruiz S, et al. C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. J Leukoc Biol 2006;80:107e16. 7. Bitsch M, Laursen I, Engel AM, Christiansen M, Olsen Larsen S, Iversen L, et al. Epidemiology of chronic wound patients and relation to serum levels of mannan-binding lectin. Acta Derm Venereol 2009;89:607e11. 8. Bitsch M, Christiansen M, Laursen I, Engel AM, Holstein PE, Karlsmark T. Is there a connection between MBL and chronic ulcers. Acta Derm Venereol 2009;89:307e8. 9. Bang P, Laursen I, Thornberg K, Schierbeck J, Nielsen B, Valdimarsson H, et al. The pharmacokinetic profile of plasmaderived mannan-binding lectin in healthy adult volunteers and patients with Staphylococcus aureus septicaemia. Scand J Infect Dis 2008;40:44e8. 10. Frakking FN, Brouwer N, van de Wetering MD, Budde IK, Strengers PF, Huitema AD, et al. Safety and pharmacokinetics of plasma-derived mannose-binding lectin (MBL) substitution in children with chemotheraphy-induced neutropaenia. Eur J Cancer 2009;45:505e12.
CASE REPORT
Mannan-binding lectin and healing of a radiationinduced chronic ulcer e a case report on mannanbinding lectin replacement therapy* ¨lmich a,* N. Maaløe a, C. Bonde b, I. Laursen c, M. Christiansen c, L.R. Ho a
Department of Plastic Surgery, Herlev University Hospital, Herlev, Denmark Department of Plastic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark c Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark b
Received 26 August 2010; accepted 22 January 2011
KEYWORDS Mannan-binding lectin; Immune deficiency; Chronic wound; Radiation-induced ulcer; Breast cancer
Summary Mannan-binding lectin is an important component of innate immunity, and insufficiency is associated with several clinical disorders. Recently, experimental replacement therapy with plasma-derived mannan-binding lectin has become an option. The current article presents the case of a patient with an insufficient level of mannan-binding lectin and a chronic radiation-induced ulcer following the treatment of breast cancer. After 15 months of initially conservative treatment and thereafter plastic surgery, the healing was still impaired with necrosis in the periphery of the ulcer. Immunological work-up of the patient revealed pronounced insufficiency of mannan-binding lectin. Following a 6-week experimental intravenous treatment with mannan-binding lectin purified from human plasma, that is, 0.2e0.3 mg mannan-binding lectin per kg body weight twice a week, the defect was completely healed. We suggest that deficiency of mannan-binding lectin can explain cases of otherwise unexplained impaired healing, and that replacement therapy is considered in such cases. ª 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
* Department of Plastic Surgery, Herlev University Hospital, Ndr. Ringvej, 2730 Herlev, Denmark. * Corresponding author. Department of Plastic Surgery, 54F8 Herlev University Hospital, Ndr. Ringvej, 2730 Herlev, Denmark. Tel.: þ45 4488 3947; fax: þ45 4488 3955. E-mail address: [email protected] (L.R. Ho ¨lmich).
Mannan-binding lectin (MBL) is a key component of the innate immune defence. Deficiency of MBL is defined as serum concentrations <100 mg l1, and it is caused by polymorphisms in the first exon and promoter region of the MBL gene. It affects 10e15% of all Caucasians, and it is the most commonly known immune defect.1 A low level of MBL can render some individuals susceptible to severe infectious diseases, and it is associated with several clinical disorders.2
1748-6815/$ - see front matter ª 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2011.01.013
Mannan-binding lectin and healing of a radiation-induced chronic ulcer Recently, experimental replacement therapy with plasma-derived MBL has become an option for select patients.3,4
Case report A 64-year-old obese woman (smoker) was diagnosed with breast cancer (stage III). She was treated according to national guidelines with neoadjuvant chemotherapy, followed by mastectomy and axillary dissection. Postoperatively, she received adjuvant chemotherapy (cyclophosphamide, epirubicin and 5-fluorouracil) and radiotherapy (24 treatments of 2 Gy, five per week). The healing was impaired and 5 months after the mastectomy, she developed an abscess in the chest wound, which perforated spontaneously. She had no previous medical history of infections or ulcers but the ulcer became chronic with persistent Staphylococcus aureus growth for 6 months as well as recurrent infections with Gram-negative and anaerobic bacteria, and the defect did not heal despite intensive wound care and antibiotics. One year after the mastectomy, and after intensive wound care the ulcer was without clinical infection, but it was 1 cm in diameter and 6 cm in depth forming a large cavity towards the axilla. At this time, the patient was referred to undergo plastic surgery, and she discontinued smoking during the first admittance. Several surgical interventions were performed. Initially an excision of the most severely damaged skin and the fistula with direct closure was attempted, but the surgery failed, and postoperatively, S. aureus was again detected in the ulcer. Then a latissimus dorsi flap was performed to cover the defect, however, this also failed. Also, negative pressure therapy was applied to the ulcer without success. Finally, a pedicled vertical rectus abdominis myocutaneous (VRAM) flap appeared vital in its central part. However, the healing progressed very slowly and after 10 days, there was still no adherence of the wound edges. A series of postoperative hyperbaric oxygen (HBO) therapy sessions resulted in healing in some areas, but large defects remained with undermining both laterally, cranially and medially to the
e147
VRAM flap (Figure 1, left photo). At this time, there were tissue necrosis and radiation-induced tissue damage, but no clinical infection, and no underlying immunological cause of the persisting ulcer was found; that is, immunoglobulins and Immunoglobulin G (IgG) subclasses were normal. Fifteen months after the mastectomy, the serum level of MBL was measured, and the result of 68 mg l1 indicated MBL deficiency. Replacement therapy with plasma-derived MBL was decided with approval from the Danish Medicines Agency. The treatment regime followed recommendations from the manufacturer (Statens Serum Institut, Copenhagen, Denmark); that is, the patient was given 0.2e0.3 mg intravenous MBL per kg body weight twice a week for 6 weeks. Blood samples were drawn at regular intervals after the first infusion, and the maximal MBL concentration was 3608 mg1, the trough level was 676 mg l1 and the halflife was 39 h. Evident effect on the healing process was observed already 5 days after the initial dose of MBL, and after 12 treatments, the ulcer was completely healed (Figure 1).
Discussion In breast cancer patients, problems associated with radiotherapy-associated complications on wound healing are well known.5 This article describes an extremely persistent case not responding to standard treatment including surgery. Although clinical infection was not evident, MBL deficiency appeared to be a main cause of the impaired healing. The effect of MBL is probably a combination of an improved elimination of microorganisms through an opsonic function and a modulation of the cytokine response to infections and inflammatory conditions.2,6 However, these mechanisms are hypothetical as no measurements of cytokines were performed. MBL deficiency is usually clinically silent. However, it has been shown to be associated with increased susceptibility and severity of infections, mainly in young children before maturation of the acquired immunity and in immunecompromised persons; furthermore, low MBL levels have been associated with severity of cystic fibrosis and
Figure 1 Left figure: The situation at start of MBL substitution after bed-side necrectomy and 15 treatments of HBO. Several areas with insufficient healing and radiation-induced tissue damage are seen in the periphery of the flap with wide undermining both laterally, cranially, and medially. Right figure: Same patient after 9 treatments of plasma-derived MBL. Undermining is absent and the defect is almost healed.
e148 autoimmune diseases.2 A study describing the epidemiology of patients with chronic foot and leg ulcers and examining the significance of MBL levels showed that the frequency of low MBL in patients with venous leg ulcer was significantly higher than that of other wound patients or healthy controls.7 This indicates different roles of MBL in the development of ulcers with different aetiologies. This is the first attempt to treat a persistent radiation-induced ulcer in an MBL-deficient patient with MBL replacement therapy. However, the successful treatment is in accordance with findings in a similar case report of an MBL-deficient patient with a chronic leg ulcer. In the latter case intermittent cessation of MBL therapy resulted in reappearance of healing problems strongly corroborating the clinical effect of MBL replacement therapy.8 Currently, therapy with plasma-derived MBL is expensive, approximately 40,500 Euro in this case. However, compared to prolonged hospital stay and risk of deterioration including life-threatening infections, it was considered acceptable. Presently, the recommended dosage regimen is based on the aim to achieve MBL plasma trough levels close to the normal level (about 1000 mg l1). However, this recommendation is not based on reasonably sized efficacy studies to indicate why the treatment may become less expensive if the dose can be reduced. As the half-life of MBL is highly variable, it is important to perform MBL concentration monitoring to assure that the treatment targets are reached.4,9,10 We suggest that MBL deficiency may cause otherwise unexplained impaired healing in radiation-induced ulcers and that MBL replacement therapy should be considered in such cases.
Conflict of interest statement SSI currently holds a patent for the production of plasmaderived MBL with Inga Laursen listed as an inventor.
N. Maaløe et al.
Acknowledgements None.
References 1. Madsen HO, Garred P, Thiel S, Kurtzhals JA, Lamm LU, Ryder LP, et al. Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol 1995;155:3013e20. 2. Kilpatrick DC. Mannan-binding lectin: clinical significance and applications. Biochim Biophys Acta 2002;1572:401e13. 3. Laursen I. Mannan-binding lectin (MBL) production from human plasma. Biochem Soc Trans 2003;31:758e62. 4. Valdimarsson H, Vikingsdottir T, Bang P, Saevarsdottir S, Gudjonsson JE, Oskarsson O, et al. Human plasma-derived mannose-binding lectin: a phase I safety and pharmacokinetic study. Scand J Immunol 2004;59:97e102. 5. Wallgren A. Late effects of radiotherapy in the treatment of breast cancer. Acta Oncol 1992;31:237e42. 6. Fraser DA, Bohlson SS, Jasinskiene N, Rawal N, Palmarini G, Ruiz S, et al. C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. J Leukoc Biol 2006;80:107e16. 7. Bitsch M, Laursen I, Engel AM, Christiansen M, Olsen Larsen S, Iversen L, et al. Epidemiology of chronic wound patients and relation to serum levels of mannan-binding lectin. Acta Derm Venereol 2009;89:607e11. 8. Bitsch M, Christiansen M, Laursen I, Engel AM, Holstein PE, Karlsmark T. Is there a connection between MBL and chronic ulcers. Acta Derm Venereol 2009;89:307e8. 9. Bang P, Laursen I, Thornberg K, Schierbeck J, Nielsen B, Valdimarsson H, et al. The pharmacokinetic profile of plasmaderived mannan-binding lectin in healthy adult volunteers and patients with Staphylococcus aureus septicaemia. Scand J Infect Dis 2008;40:44e8. 10. Frakking FN, Brouwer N, van de Wetering MD, Budde IK, Strengers PF, Huitema AD, et al. Safety and pharmacokinetics of plasma-derived mannose-binding lectin (MBL) substitution in children with chemotheraphy-induced neutropaenia. Eur J Cancer 2009;45:505e12.