- Email: [email protected]
Eosinophilic infiltrates in a pulmonary allograft: a case and review of the literature
CASE REPORTS
Eosinophilic Infiltrates in a Pulmonary Allograft: A Case and Review of the Literature Peter J. Mogayzel, Jr, MD, PhD,a Stephen C. Yang, MD,b Barbara V. Wise, RN, PhD,c and Paul M. Colombani, MDc An unusual case of peribronchial eosinophilic infiltrates associated with peripheral blood eosinophilia in a lung transplant patient is described. The role that eosinophils play in lung allograft rejection is reviewed. Tissue eosinophils have been associated with acute pulmonary allograft rejection. Although, eosinophils in bronchoalveolar lavage fluid (BAL) have been observed in allograft rejection, this relationship is less well defined. The role of eosinophils in the pathophysiology of allograft rejection is unclear. J Heart Lung Transplant 2001;20:692–695.
A
cute pulmonary allograft rejection is typically characterized by perivascular infiltrates composed of mononuclear cells.1 The presence of eosinophils has been associated with acute rejection in kidney,2–5 liver,6,7 and heart8,9 transplantation. However, the role of eosinophils in lung allograft rejection is not well defined. Although, scattered eosinophils are often observed in acute pulmonary rejection, large numbers of eosinophils are rarely seen.10 –13 This case illustrates an instance where mild perivascular lymphocytic infiltrates were associated with significant peribronchial eosinophilic infiltrates and peripheral blood eosinophilia.
HISTORY S.A. is a white female who received a bilateral cadaveric lobar lung transplant as treatment for end-stage From the aEudowood Division of Pediatric Respiratory Sciences and Divisions of bThoracic and cPediatric Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Submitted May 5, 2000; accepted August 11, 2000. Reprint requests: Dr. Peter J. Mogayzel, Jr., Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins Hospital, 600 North Wolfe Street, Park 316, Baltimore, MD 21287-2533. Telephone: 410-614-5637. Fax: 410-955-1030. E-mail: [email protected]. Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00218-7
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cystic fibrosis at 12 years of age. She is homozygous for the ⌬F508 mutation in the CFTR gene. The donor was a 44-year-old black male with no significant past medical history who died of a gunshot wound. S.A. required prolonged mechanical ventilation following her transplant; however, she had rapid improvement in her pulmonary function following tracheostomy decannulation on postoperative Day 63. Her pulmonary function was normal within 8 months of transplantation. The patient underwent bronchoscopy and transbronchial biopsy under a protocol that has previously been described.14 Twenty-five months after her transplant, S.A. developed dyspnea, a nonproductive cough, and low-grade fever. She had no exposures to ill contacts or known allergens. Her maintenance immunosuppression consisted of tacrolimus (Prograf, Fujisawa), mycophenolate mofetil (CellCept, Roche Pharmaceuticals), and prednisone 5 mg (0.15 mg/kg) q.o.d. The patient’s other medications were pancreatic enzymes (Pancrease MT16, Ortho-McNeil), ADEK vitamins (ScandiPharm), and insulin (Humulin, Lilly) and albuterol as needed. Examination revealed a patient with mild tachypnea who appeared otherwise well. Auscultation revealed bilateral crackles, breath sounds were symmetric, and no wheezing was present. A chest radiograph demonstrated patchy, bilateral infiltrates in the lower lung fields. Laboratory studies included a normal white blood cell count
The Journal of Heart and Lung Transplantation Volume 20, Number 6
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FIGURE 2 Transbronchial lung biopsy stained with
hematoxylin and eosin demonstrating a prominent peribronchial eosinophilic infiltrate located in a larger airway. (Original magnification ⫻250)
FIGURE 1 Panel A—Patient’s pulmonary function
testing for 16 to 32 months following her transplant. 䊐 Forced vital capacity (FVC) and E forced expiratory volume in 1 second (FEV1) are expressed as percentage of size matched normal children. ■ FEV1/FVC ratio. Oral and intravenous steroid treatments are indicated by the horizontal bars. The eosinophilic pneumonitis and A2 rejection episodes are indicated by the arrows. Panel B—Patient’s peripheral blood eosinophil count. The upper limit of a normal eosinophil count is indicated by the horizontal line.
(9,300 cells/mm3) and peripheral blood eosinophilia (700 cells/mm3). The patient was treated with oral amoxicillin/ clavulanic acid (Augmentin, SmithKline Beecham). The patient’s symptoms did not improve over the next 2 days and her home spirometry values fell significantly. Her physical examination had not changed significantly; however, pulmonary function testing showed significant airway obstruction and more pronounced peripheral blood eosinophilia (Figure 1). Bronchoscopy was performed revealing mild airway inflammation and minimal secretions. Cultures of BAL did not grow any bacteria, fungi, or viruses. Transbronchial biopsies revealed mild perivascular lymphocytic infiltrates with prominent mixed peribronchial infiltrates composed of eosinophils and lymphocytes (Figure 2). Immunohistochemical staining with anti-CD3 antibodies showed only scattered T-cells in the peribronchial and perivascular infiltrates. There was no evidence of cytomegalovirus (CMV) infection by immunohistochemical staining. Examination of the patient’s stool did not reveal any ova or parasites. The patient was treated with 40 mg of prednisone (1
mg/kg) orally for 5 days followed by a steroid taper over 2 weeks to 20 mg daily. Repeat transbronchial biopsies showed acute inflammation with resolution of the eosinophilic infiltrates. BAL cultures grew Pseudomonas aeruginosa and Hemophilus influenzae. When the patient’s spirometry did not improve 1 month after appropriate antibiotic therapy repeat transbronchial biopsies were obtained that demonstrated mild acute allograft rejection (ISHLT grade A2). Her white blood cell count was 12,600 cells/mm3 with 9.2% eosinophils (1,160 cells/mm3) at that time. The patient was then treated with intravenous methylprednisolone (10 mg/ kg/day for 3 days) which led to resolution of the rejection episode. Although the patient’s pulmonary function improved she has mild residual airway obstruction (Figure 1A).
DISCUSSION The role of eosinophils in the pathophysiology of acute pulmonary allograft rejection is poorly defined. Eosinophils are part of an inflammatory response that has been well characterized in asthma, hypersensitivity reactions, infections by parasites and other organisms, rheumatologic diseases and several uncommon pulmonary disorders.15–18 This case illustrates an unusual eosinophilic pneumonitis in a pulmonary allograft associated with peripheral blood eosinophilia. The scattered perivascular lymphoid infiltrates taken in isolation would be consistent with mild acute cellular rejection (ISHLT grade A2), but the admixture of B and T cells in the nodules suggests a reactive process. The prominent eosinophil infiltrates in large bronchioles, however, raise the question of allergy, hypersensitivity reaction or recent infection. No infection was
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found at the time of bronchoscopy. A drug reaction could explain both the eosinophilic pulmonary infiltrates and peripheral blood eosinophilia. Our patient had been taking her chronic medications for many years, although she began taking oral amoxicillin/ clavulanic acid 2 days prior to the transbronchial biopsies. This antibiotic, which the patient had taken many times previously, was started after peripheral blood eosinophilia was documented. However, no formal allergy testing was performed and other causes of eosinophilic lung disease cannot be excluded. Initial steroid treatment led to resolution of both the tissue and peripheral blood eosinophilia but did not improve her pulmonary function testing. Repeat biopsies demonstrated acute rejection that later responded to treatment with high-dose intravenous steroids. The presence of parenchymal eosinophils has been associated with acute allograft rejection in solid organ transplantation. Eosinophils have been observed in the perivascular infiltrates associated with acute pulmonary allograft rejection.10 –13 The number of eosinophils is often reduced after treatment of allograft rejection with steroids.10 Review of 886 lung biopsies revealed that ⬃12% of the cases of ISHLT grades II to IV rejection contained eosinophils.11,12 Tissue eosinophils were associated with the presence of cytotoxic eosinophil-derived cationic proteins in tissue samples but were not associated peripheral blood eosinophilia. Yousem13 reviewed 112 lung biopsies with acute rejection. He found scattered eosinophils were present in 22%, 78%, and 100% of biopsies with mild, moderate, or severe rejection, respectively. Nine biopsies were identified where ⬎50% of the infiltrating cells were eosinophils. Five of these patients had acute allograft rejection that occurred within 40 days of transplantation. One of these patients also had peripheral blood eosinophilia and none had significant eosinophilia in BAL. The remaining 4 patients had acute infectious processes without rejection. A follow-up study demonstrated that tissue eosinophils were twice as common in clinically silent episodes of rejection that progressed when compared to those that did not.19 El-Gamel et al20 found that tissue eosinophils were associated with lung allograft fibrosis in a review of 780 transbronchial biopsies from 91 patients. These data suggest that tissue eosinophils tend to be present in more aggressive episodes of acute rejection. However, the presence of tissue eosinophils is not necessarily associated with either BAL or peripheral blood eosinophilia. Using a rat allogenic transplantation model Kondo et al21 demonstrated that both peribronchial and perivascular eosinophilic infiltrates were present in
The Journal of Heart and Lung Transplantation June 2001
lungs with acute allograft rejection. Although the eosinophils were present, within 2 days of transplantation they became less prominent features as the rejection worsened. Analysis of BAL has yielded conflicting results regarding the role of eosinophils in acute pulmonary allograft rejection. Riise et al22 retrospectively studied 38 BAL samples from 11 lung and 4 heart-lung transplant recipients and found that eosinophil cationic protein (ECP) and eosinophils correlated with acute rejection. However, the majority of patients with rejection had minimal changes in these parameters. The levels of BAL or circulating adhesion molecules were also not altered with rejection. A prospective study of 138 BAL samples by the same investigators failed to show a relationship between inflammatory markers, including ECP, and acute rejection.23 Although ECP levels were higher in patients with rejection this difference was not significantly significant. Hohlfeld et al24 found that BAL from lung transplant patients contained more eosinophils when compared to controls, however, he also failed to find increased BAL eosinophils with acute rejection. Analysis of 50 BAL samples from 38 patients following lung or heart-lung transplantation by Dosanjh et al25 demonstrated that elevated levels of ECP was associated with acute rejection, CMV infection or the presence bacterial pathogens. This group later reported that the levels of IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) in the BAL fluid did not correlate with the presence of ECP or allograft rejection.11 Recently, Bewig et al26 described 4 patients who had recurrent BAL eosinophilia that was associated with persistent acute rejection. The eosinophils regressed when the patients’ rejection resolved after steroid treatment. Interestingly, the presence of eosinophils was also not associated with elevated levels of IL-5 or the cellular pattern of IL-5 expression in BAL. These studies did not find increased IL-5 or GM-CSF levels associated with BAL eosinophilia, suggesting that other chemoattractants may be responsible for the presence of ECP or eosinophils in BAL. Although the importance of eosinophils or ECP in BAL from patients with acute rejection is unclear, elevated ECP has been found in BAL from patients with obliterative bronchiolitis.27 The relationship between peripheral blood eosinophilia and acute pulmonary allograft rejection has received less attention. Trull et al9 compared eosinophil counts prior to 84 biopsies with acute rejection to 28 biopsies without rejection in 54 patients. These authors found that the mean maximum eosinophil count was elevated 3 days prior to an episode of
The Journal of Heart and Lung Transplantation Volume 20, Number 6
rejection. The first increase in eosinophil count began a median of 5 days before the episode of rejection was diagnosed. An eosinophil count of ⱖ 0.06 ⫻ 109 cells/l (60 cells/l) had a sensitivity of 72% and a specificity of 75% for the detection of acute pulmonary allograft rejection. The peripheral blood eosinophil count in heart transplant recipients also correlated with rejection episodes and was inversely related to maintenance steroid dose in the same study. The relationship between eosinophils and the pulmonary allograft is complex. The presence of tissue eosinophils has been associated with acute allograft rejection in several studies. Eosinophils tend to be associated with more aggressive rejection episodes. However, the presence of eosinophils and eosinophil products in BAL do not clearly define rejection episodes. Peripheral blood eosinophilia can also accompany acute pulmonary allograft rejection. To further complicate matters, eosinophils or eosinophil products have been found in viral, fungal, and bacterial infections in lung transplant patients. Additional studies are needed to elucidate the mechanism of eosinophil migration and activation in pulmonary allografts. This case illustrates that both tissue and peripheral blood eosinophils can be important indicators of significant pulmonary allograft dysfunction. Eosinophils produce several cytotoxic agents including ECP that can instigate or maintain an aggressive inflammatory response leading to tissue damage. Lung transplant recipients may be especially susceptible to eosinophilinduced cytotoxicity because of altered antioxidant defenses.27 Dr. Mogayzel is supported by a Shwachman Clinical Investigator Award from the Cystic Fibrosis Foundation and has received research funding from Fujisawa.
REFERENCES 1. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: lung rejection study group. J Heart Lung Transplant 1996;15:1–15. 2. Almirall J, Campistol JM, Sole M, et al. Blood and graft eosinophilia as a rejection index in kidney transplant. Nephron 1993;65:304 –9. 3. Hongwei W, Nanra RS, Stein A, et al. Eosinophils in acute renal allograft rejection. Transpl Immunol 1994;2:41– 6. 4. Nolan CR, Saenz KP, Thomas CA, 3rd, Murphy KD. Role of the eosinophil in chronic vascular rejection of renal allografts. Am J Kidney Dis 1995;26:634 – 42. 5. Thomson PD, Meyers KE. Eosinophilia as an early predictor of acute cellular rejection in pediatric renal transplants. Transplant Proc 1994;26:69 –71. 6. Ben-Ari Z, Dhillon AP, Garwood L, et al. Prognostic value of eosinophils for therapeutic response in severe acute hepatic allograft rejection. Transplant Proc 1996;28:3624 – 8.
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7. Nagral A, Ben-Ari Z, Dhillon AP, Burroughs AK. Eosinophils in acute cellular rejection in liver allografts. Liver Transpl Surg 1998;4:355– 62. 8. Endoh M, Kawauchi M, Oka T, et al. Significance of eosinophil infiltration in cardiac rejection. Transplant Proc 1998;30:3350. 9. Trull A, Steel L, Cornelissen J, et al. Association between blood eosinophil counts and acute cardiac and pulmonary allograft rejection. J Heart Lung Transplant 1998;17:517–24. 10. Clelland CA, Higenbottam TW, Stewart S, et al. The histological changes in transbronchial biopsy after treatment of acute lung rejection in heart-lung transplants. J Pathol 1990;161:105–12. 11. Dosanjh AK, Robinson TE, Strauss J, Berry G. Eosinophil activation in cardiac and pulmonary acute allograft rejection [letter]. J Heart Lung Transplant 1998;17:1038. 12. Robinson TE, Berry GJ, Robbins RC, et al. Tissue eosinophilic infiltration and eosinophilic activation in moderate to severe cardiac and lung transplant rejection. J. Heart Lung Transplant 1997;16:46. 13. Yousem SA. Graft eosinophilia in lung transplantation. Hum Pathol 1992;23:1172–7. 14. Mendeloff EN, Huddleston CB, Mallory GB, et al. Pediatric and adult lung transplantation for cystic fibrosis. J Thorac Cardiovasc Surg 1998;115:404 –13; discussion 413– 4. 15. Allen JN, Davis WB. Eosinophilic lung diseases. Am J Respir Crit Care Med 1994;150:1423–38. 16. Kroegel C, Virchow JC, Jr., Luttmann W, et al. Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part I). Eur Respir J 1994;7:519 – 43. 17. Kroegel C, Warner JA, Virchow JC, Jr., Matthys H. Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part II). Eur Respir J 1994;7:743– 60. 18. Shannon JJ, Joseph P. Lynch I. Eosinophilic pulmonary syndromes. Clin Pulmon Med 1995;2:19 –38. 19. Yousem SA. Significance of clinically silent untreated mild acute cellular rejection in lung allograft recipients. Hum Pathol 1996;27:269 –73. 20. El-Gamel A, Awad M, Sim E, et al. Transforming growth factor-beta1 and lung allograft fibrosis. Eur J Cardiothorac Surg 1998;13:424 –30. 21. Kondo T, Wu GD, Saito R, et al. Immunocytologic analysis of cells obtained from bronchoalveolar lavage in a model of rat lung allograft rejection. J Surg Res 1993;55:351– 6. 22. Riise GC, Schersten H, Nilsson F, et al. Activation of eosinophils and fibroblasts assessed by eosinophil cationic protein and hyaluronan in BAL. Association with acute rejection in lung transplant recipients. Chest 1996;110:89 –96. 23. Riise GC, Kjellstrom C, Ryd W, et al. Inflammatory cells and activation markers in BAL during acute rejection and infection in lung transplant recipients: a prospective, longitudinal study. Eur Respir J 1997;10:1742– 6. 24. Hohlfeld JM, Tiryaki E, Hamm H, et al. Pulmonary surfactant activity is impaired in lung transplant recipients. Am J Respir Crit Care Med 1998;158:706 –12. 25. Dosanjh AK, Elashoff D, Kawalek A, et al. Activation of eosinophils in the airways of lung transplantation patients. Chest 1997;112:1180 –3. 26. Bewig B, Stewart S, Bottcher H, et al. Eosinophilic alveolitis in BAL after lung transplantation. Transpl Int 1999;12:266 –72. 27. Riise GC, Williams A, Kjellstrom C, et al. Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased antioxidant status in the lung. Eur Respir J 1998;12:82– 8.
Eosinophilic Infiltrates in a Pulmonary Allograft: A Case and Review of the Literature Peter J. Mogayzel, Jr, MD, PhD,a Stephen C. Yang, MD,b Barbara V. Wise, RN, PhD,c and Paul M. Colombani, MDc An unusual case of peribronchial eosinophilic infiltrates associated with peripheral blood eosinophilia in a lung transplant patient is described. The role that eosinophils play in lung allograft rejection is reviewed. Tissue eosinophils have been associated with acute pulmonary allograft rejection. Although, eosinophils in bronchoalveolar lavage fluid (BAL) have been observed in allograft rejection, this relationship is less well defined. The role of eosinophils in the pathophysiology of allograft rejection is unclear. J Heart Lung Transplant 2001;20:692–695.
A
cute pulmonary allograft rejection is typically characterized by perivascular infiltrates composed of mononuclear cells.1 The presence of eosinophils has been associated with acute rejection in kidney,2–5 liver,6,7 and heart8,9 transplantation. However, the role of eosinophils in lung allograft rejection is not well defined. Although, scattered eosinophils are often observed in acute pulmonary rejection, large numbers of eosinophils are rarely seen.10 –13 This case illustrates an instance where mild perivascular lymphocytic infiltrates were associated with significant peribronchial eosinophilic infiltrates and peripheral blood eosinophilia.
HISTORY S.A. is a white female who received a bilateral cadaveric lobar lung transplant as treatment for end-stage From the aEudowood Division of Pediatric Respiratory Sciences and Divisions of bThoracic and cPediatric Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Submitted May 5, 2000; accepted August 11, 2000. Reprint requests: Dr. Peter J. Mogayzel, Jr., Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins Hospital, 600 North Wolfe Street, Park 316, Baltimore, MD 21287-2533. Telephone: 410-614-5637. Fax: 410-955-1030. E-mail: [email protected]. Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00218-7
692
cystic fibrosis at 12 years of age. She is homozygous for the ⌬F508 mutation in the CFTR gene. The donor was a 44-year-old black male with no significant past medical history who died of a gunshot wound. S.A. required prolonged mechanical ventilation following her transplant; however, she had rapid improvement in her pulmonary function following tracheostomy decannulation on postoperative Day 63. Her pulmonary function was normal within 8 months of transplantation. The patient underwent bronchoscopy and transbronchial biopsy under a protocol that has previously been described.14 Twenty-five months after her transplant, S.A. developed dyspnea, a nonproductive cough, and low-grade fever. She had no exposures to ill contacts or known allergens. Her maintenance immunosuppression consisted of tacrolimus (Prograf, Fujisawa), mycophenolate mofetil (CellCept, Roche Pharmaceuticals), and prednisone 5 mg (0.15 mg/kg) q.o.d. The patient’s other medications were pancreatic enzymes (Pancrease MT16, Ortho-McNeil), ADEK vitamins (ScandiPharm), and insulin (Humulin, Lilly) and albuterol as needed. Examination revealed a patient with mild tachypnea who appeared otherwise well. Auscultation revealed bilateral crackles, breath sounds were symmetric, and no wheezing was present. A chest radiograph demonstrated patchy, bilateral infiltrates in the lower lung fields. Laboratory studies included a normal white blood cell count
The Journal of Heart and Lung Transplantation Volume 20, Number 6
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FIGURE 2 Transbronchial lung biopsy stained with
hematoxylin and eosin demonstrating a prominent peribronchial eosinophilic infiltrate located in a larger airway. (Original magnification ⫻250)
FIGURE 1 Panel A—Patient’s pulmonary function
testing for 16 to 32 months following her transplant. 䊐 Forced vital capacity (FVC) and E forced expiratory volume in 1 second (FEV1) are expressed as percentage of size matched normal children. ■ FEV1/FVC ratio. Oral and intravenous steroid treatments are indicated by the horizontal bars. The eosinophilic pneumonitis and A2 rejection episodes are indicated by the arrows. Panel B—Patient’s peripheral blood eosinophil count. The upper limit of a normal eosinophil count is indicated by the horizontal line.
(9,300 cells/mm3) and peripheral blood eosinophilia (700 cells/mm3). The patient was treated with oral amoxicillin/ clavulanic acid (Augmentin, SmithKline Beecham). The patient’s symptoms did not improve over the next 2 days and her home spirometry values fell significantly. Her physical examination had not changed significantly; however, pulmonary function testing showed significant airway obstruction and more pronounced peripheral blood eosinophilia (Figure 1). Bronchoscopy was performed revealing mild airway inflammation and minimal secretions. Cultures of BAL did not grow any bacteria, fungi, or viruses. Transbronchial biopsies revealed mild perivascular lymphocytic infiltrates with prominent mixed peribronchial infiltrates composed of eosinophils and lymphocytes (Figure 2). Immunohistochemical staining with anti-CD3 antibodies showed only scattered T-cells in the peribronchial and perivascular infiltrates. There was no evidence of cytomegalovirus (CMV) infection by immunohistochemical staining. Examination of the patient’s stool did not reveal any ova or parasites. The patient was treated with 40 mg of prednisone (1
mg/kg) orally for 5 days followed by a steroid taper over 2 weeks to 20 mg daily. Repeat transbronchial biopsies showed acute inflammation with resolution of the eosinophilic infiltrates. BAL cultures grew Pseudomonas aeruginosa and Hemophilus influenzae. When the patient’s spirometry did not improve 1 month after appropriate antibiotic therapy repeat transbronchial biopsies were obtained that demonstrated mild acute allograft rejection (ISHLT grade A2). Her white blood cell count was 12,600 cells/mm3 with 9.2% eosinophils (1,160 cells/mm3) at that time. The patient was then treated with intravenous methylprednisolone (10 mg/ kg/day for 3 days) which led to resolution of the rejection episode. Although the patient’s pulmonary function improved she has mild residual airway obstruction (Figure 1A).
DISCUSSION The role of eosinophils in the pathophysiology of acute pulmonary allograft rejection is poorly defined. Eosinophils are part of an inflammatory response that has been well characterized in asthma, hypersensitivity reactions, infections by parasites and other organisms, rheumatologic diseases and several uncommon pulmonary disorders.15–18 This case illustrates an unusual eosinophilic pneumonitis in a pulmonary allograft associated with peripheral blood eosinophilia. The scattered perivascular lymphoid infiltrates taken in isolation would be consistent with mild acute cellular rejection (ISHLT grade A2), but the admixture of B and T cells in the nodules suggests a reactive process. The prominent eosinophil infiltrates in large bronchioles, however, raise the question of allergy, hypersensitivity reaction or recent infection. No infection was
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found at the time of bronchoscopy. A drug reaction could explain both the eosinophilic pulmonary infiltrates and peripheral blood eosinophilia. Our patient had been taking her chronic medications for many years, although she began taking oral amoxicillin/ clavulanic acid 2 days prior to the transbronchial biopsies. This antibiotic, which the patient had taken many times previously, was started after peripheral blood eosinophilia was documented. However, no formal allergy testing was performed and other causes of eosinophilic lung disease cannot be excluded. Initial steroid treatment led to resolution of both the tissue and peripheral blood eosinophilia but did not improve her pulmonary function testing. Repeat biopsies demonstrated acute rejection that later responded to treatment with high-dose intravenous steroids. The presence of parenchymal eosinophils has been associated with acute allograft rejection in solid organ transplantation. Eosinophils have been observed in the perivascular infiltrates associated with acute pulmonary allograft rejection.10 –13 The number of eosinophils is often reduced after treatment of allograft rejection with steroids.10 Review of 886 lung biopsies revealed that ⬃12% of the cases of ISHLT grades II to IV rejection contained eosinophils.11,12 Tissue eosinophils were associated with the presence of cytotoxic eosinophil-derived cationic proteins in tissue samples but were not associated peripheral blood eosinophilia. Yousem13 reviewed 112 lung biopsies with acute rejection. He found scattered eosinophils were present in 22%, 78%, and 100% of biopsies with mild, moderate, or severe rejection, respectively. Nine biopsies were identified where ⬎50% of the infiltrating cells were eosinophils. Five of these patients had acute allograft rejection that occurred within 40 days of transplantation. One of these patients also had peripheral blood eosinophilia and none had significant eosinophilia in BAL. The remaining 4 patients had acute infectious processes without rejection. A follow-up study demonstrated that tissue eosinophils were twice as common in clinically silent episodes of rejection that progressed when compared to those that did not.19 El-Gamel et al20 found that tissue eosinophils were associated with lung allograft fibrosis in a review of 780 transbronchial biopsies from 91 patients. These data suggest that tissue eosinophils tend to be present in more aggressive episodes of acute rejection. However, the presence of tissue eosinophils is not necessarily associated with either BAL or peripheral blood eosinophilia. Using a rat allogenic transplantation model Kondo et al21 demonstrated that both peribronchial and perivascular eosinophilic infiltrates were present in
The Journal of Heart and Lung Transplantation June 2001
lungs with acute allograft rejection. Although the eosinophils were present, within 2 days of transplantation they became less prominent features as the rejection worsened. Analysis of BAL has yielded conflicting results regarding the role of eosinophils in acute pulmonary allograft rejection. Riise et al22 retrospectively studied 38 BAL samples from 11 lung and 4 heart-lung transplant recipients and found that eosinophil cationic protein (ECP) and eosinophils correlated with acute rejection. However, the majority of patients with rejection had minimal changes in these parameters. The levels of BAL or circulating adhesion molecules were also not altered with rejection. A prospective study of 138 BAL samples by the same investigators failed to show a relationship between inflammatory markers, including ECP, and acute rejection.23 Although ECP levels were higher in patients with rejection this difference was not significantly significant. Hohlfeld et al24 found that BAL from lung transplant patients contained more eosinophils when compared to controls, however, he also failed to find increased BAL eosinophils with acute rejection. Analysis of 50 BAL samples from 38 patients following lung or heart-lung transplantation by Dosanjh et al25 demonstrated that elevated levels of ECP was associated with acute rejection, CMV infection or the presence bacterial pathogens. This group later reported that the levels of IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) in the BAL fluid did not correlate with the presence of ECP or allograft rejection.11 Recently, Bewig et al26 described 4 patients who had recurrent BAL eosinophilia that was associated with persistent acute rejection. The eosinophils regressed when the patients’ rejection resolved after steroid treatment. Interestingly, the presence of eosinophils was also not associated with elevated levels of IL-5 or the cellular pattern of IL-5 expression in BAL. These studies did not find increased IL-5 or GM-CSF levels associated with BAL eosinophilia, suggesting that other chemoattractants may be responsible for the presence of ECP or eosinophils in BAL. Although the importance of eosinophils or ECP in BAL from patients with acute rejection is unclear, elevated ECP has been found in BAL from patients with obliterative bronchiolitis.27 The relationship between peripheral blood eosinophilia and acute pulmonary allograft rejection has received less attention. Trull et al9 compared eosinophil counts prior to 84 biopsies with acute rejection to 28 biopsies without rejection in 54 patients. These authors found that the mean maximum eosinophil count was elevated 3 days prior to an episode of
The Journal of Heart and Lung Transplantation Volume 20, Number 6
rejection. The first increase in eosinophil count began a median of 5 days before the episode of rejection was diagnosed. An eosinophil count of ⱖ 0.06 ⫻ 109 cells/l (60 cells/l) had a sensitivity of 72% and a specificity of 75% for the detection of acute pulmonary allograft rejection. The peripheral blood eosinophil count in heart transplant recipients also correlated with rejection episodes and was inversely related to maintenance steroid dose in the same study. The relationship between eosinophils and the pulmonary allograft is complex. The presence of tissue eosinophils has been associated with acute allograft rejection in several studies. Eosinophils tend to be associated with more aggressive rejection episodes. However, the presence of eosinophils and eosinophil products in BAL do not clearly define rejection episodes. Peripheral blood eosinophilia can also accompany acute pulmonary allograft rejection. To further complicate matters, eosinophils or eosinophil products have been found in viral, fungal, and bacterial infections in lung transplant patients. Additional studies are needed to elucidate the mechanism of eosinophil migration and activation in pulmonary allografts. This case illustrates that both tissue and peripheral blood eosinophils can be important indicators of significant pulmonary allograft dysfunction. Eosinophils produce several cytotoxic agents including ECP that can instigate or maintain an aggressive inflammatory response leading to tissue damage. Lung transplant recipients may be especially susceptible to eosinophilinduced cytotoxicity because of altered antioxidant defenses.27 Dr. Mogayzel is supported by a Shwachman Clinical Investigator Award from the Cystic Fibrosis Foundation and has received research funding from Fujisawa.
REFERENCES 1. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: lung rejection study group. J Heart Lung Transplant 1996;15:1–15. 2. Almirall J, Campistol JM, Sole M, et al. Blood and graft eosinophilia as a rejection index in kidney transplant. Nephron 1993;65:304 –9. 3. Hongwei W, Nanra RS, Stein A, et al. Eosinophils in acute renal allograft rejection. Transpl Immunol 1994;2:41– 6. 4. Nolan CR, Saenz KP, Thomas CA, 3rd, Murphy KD. Role of the eosinophil in chronic vascular rejection of renal allografts. Am J Kidney Dis 1995;26:634 – 42. 5. Thomson PD, Meyers KE. Eosinophilia as an early predictor of acute cellular rejection in pediatric renal transplants. Transplant Proc 1994;26:69 –71. 6. Ben-Ari Z, Dhillon AP, Garwood L, et al. Prognostic value of eosinophils for therapeutic response in severe acute hepatic allograft rejection. Transplant Proc 1996;28:3624 – 8.
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