Letters to the Editor
* 2014 Lippincott Williams & Wilkins
when the donor is female (8, 9, 13). The risk of PLS is dependent on the likelihood of transfer of donor-derived lymphocytes and is more common in hemopoietic cell transplants followed by heart and lung, liver, and finally kidney transplants (2). Anti-D is characteristically an IgG antibody which causes extravascular hemolysis. Conversely, intravascular hemolysis is typically the result of an IgM antibody which can link two antigen sites on the red cell membrane and activate complement. To date, in previous cases of PLS after renal transplantation, only IgG anti-D has been identified on DAT testing, in keeping with extravascular hemolysis. In our case, in addition to IgG, C3d and IgM were detected, raising the possibility of intravascular hemolysis. Rarely, severe hemolytic reactions associated with anti-D have been reported in the setting of immune thrombocytopenia. Postulated mechanisms to explain the severe reactions include the overexpression of the D antigen on recipient red cells allowing IgG molecules to link and activate complement, the presence of trace amounts of IgM anti-D, or the overloading of the extravascular clearance mechanism allowing free hemoglobin to spill into the circulation (10). In our case, any of these mechanisms would seem possible and may have been augmented by P. aeruginosa UTI on postoperative day 9 (3). Although the presence of C3d on the red cell surface may have indicated an augmented hemolytic reaction as postulated above, conversely this may simply have reflected immune stimulation associated with his previous infection. Given the apparent rare occurrence of antiYD-mediated PLS, and equally im-
portantly the self-limiting nature of the condition, in our opinion, routine screening of donors or risk stratification (if it were possible) of recipients is unlikely to have an acceptable risk-versus-benefit profile. Renal transplants can safely be performed in this scenario as long as the clinical teams caring for the patient are aware of the possibility of PLS as a selflimiting cause of anemia 7 to 14 days after transplantation with an ABO or Rhesus-D mismatched donor. Prashanth Karanth, MRCP1 Janet Birchall, FRCPath2 Sarinder Day, Phd1 David J Unsworth, Phd1 Rommel Ravanan, MD1
4.
5.
6.
7.
1
Renal Transplant Centre Southmead Hospital Bristol, UK 2 NHS Blood & Transplant and North Bristol NHS Trust Bristol, UK The authors declare no funding or conflicts of interest. Address correspondence to: Prashanth Karanth, M.D., 26 Efford Road, Plymouth, Devon, UK. E-mail: [email protected] Received 9 December 2013. Accepted 31 January 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9709-e53 DOI: 10.1097/TP.0000000000000100
8. 9.
10.
11.
12.
REFERENCES 1.
2. 3.
Ramsey G, Israel L, Lindsay GD, et al. Anti-Rho (D) in two Rh-positive patients receiving kidney grafts from an Rh immunized donor. Transplantation 1986; 41: 67. Ramsey G. Red cell antibodies arising from solid organ transplants. Transfusion 1991; 31: 76. Nadarajah L, Ashman N, Thuraisingham R, et al. Literature review of passenger lym-
13.
14.
e55
phocyte syndrome following renal transplantation and two case reports. Am J Transplant 2013; 13: 1594. Knoop C, Andrien M, Antoine M, et al. Severe hemolysis due to a donor anti-D antibody after heart-lung transplantation. Association with lung and blood chimerism. Am Rev Respir Dis 1993; 148: 504. Cserti-Gazdewich CM, Waddell TK, Singer LG, et al. Passenger lymphocyte syndrome with or without immune hemolytic anaemia in all Rh-positive recipients of lungs from rhesus alloimmunized donors: three new cases and a review of the literature. Transfus Med Rev 2009; 23: 134. doi: 10.1016/j.tmrv. 2008.12.003. Fung MK, Sheikh H, Eghtesad B, et al. Severe hemolysis resulting from D incompatibility in a case of ABO-identical liver transplant. Transfusion 2004; 44: 1635. Swanson J, Sebring E, Sastamoinen R, et al. Gm allotyping to determine the origin of the anti-D causing hemolytic anaemia in a kidney transplant recipient. Vox Sang 1987; 52: 228. Saba NF, Sweeney JD, Penn LC, et al. AntiD in a D-positive renal transplant patient. Transfusion 1997; 37: 321. Ainsworth CD, Crowther MA, Treleaven D, et al. Severe hemolytic anaemia post-renal transplantation produced by donor anti-D passenger lymphocytes: case report and literature review. Transfus Med Rev 2009; 23: 155. Despotovic JM, Lambert MP, Herman JH, et al. RhIG for the treatment of immune thrombocytopenia: consensus and controversy. Transfusion 2012; 52: 1126. Schwartz D, Gotzinger P. Immune-haemolytic anaemia (IHA) after solid organ transplantation due to rhesus antibodies of donor origin: report of 5 cases. Beitr Infusionsther 1992; 30: 367. Frohn C, Jabs WJ, Fricke L, et al. Hemolytic anaemia after kidney transplantation: case report and differential diagnosis. Ann Hematol 2002; 81: 158. Pomper GJ, Joseph RA, Hartmann EL, et al. Massive immune hemolysis caused by antiD after dual kidney transplantation. Am J Transplant 2005; 5: 2586. Solheim BG, Albrechtsen D, Berg KJ, et al. Auto-antibodies against erythrocytes in transplant patients produced by donor lymphocytes. Transplant Proc 1987; 19:4520.
CMV Sinusitis in a HIV-Negative Renal Transplant Recipient 53-year-old Sudanese woman was admitted to our hospital with a 4-week history of headache, nasal congestion, and bilateral periorbital pain 11 months after deceased-donor renal transplant. Her past medical history included hypertension, gastroesophageal reflux, treated cerebral tuberculosis, and end-stage renal disease secondary to IgA nephropathy. Before transplantation she had been on hemodialysis for 6 years.
A
The transplant had been uncomplicated apart from 2 weeks of delayed graft function. Immunosuppression included induction therapy with basiliximab and ongoing triple maintenance therapy with tacrolimus, mycophenolate mofetil (MMF), and prednisolone. With respect to the CMV match, the donor was of equivocal status, whereas the recipient was CMV positive. The patient had received 5 months of prophylactic oral valganciclovir therapy
and had undetectable CMV virus by PCR on routine screening throughout this period and up until 3 months before her presentation. At the time of presentation, immunosuppression included tacrolimus 7 mg bd (level 4.7 Kg/L), MMF 750 mg bd, and prednisolone 5 mg daily. Steroid dose had been gradually weaned from 20 mg at the time of transplantation and MMF dose had been recently reduced from
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e56
www.transplantjournal.com
Transplantation
FIGURE 1. CT scan showing near-complete opacification of the patient’s right paranasal and maxillary sinuses with associated maxillary wall destruction and lesser involvement of the left side. 135135 mm (9696 DPI).
1000 mg bd because of anemia (hemoglobin, 77 g/L) and lymphopenia (lymphocyte count, 0.13 10^9/L) without neutropenia. Serum creatinine was 1.92 mg/dL. On examination, the patient was afebrile with extremely tender forehead and facial bones and significant nasal congestion. A CT scan of her sinuses revealed near-complete opacification of the right paranasal and maxillary sinuses with associated maxillary wall destruction and lesser involvement of the left side (Fig. 1). She subsequently underwent surgical debridement and washout of her sinuses. Smears and cultures for bacterial, fungal, and acid fast organisms were all
negative. Histologic examination of the sinus tissue revealed active chronic inflammation with numerous intracellular cytomegalic inclusions immunoreacting with CMV antibodies diagnostic for active CMV sinusitis (Fig. 2A and B). There was no other clinical or investigative evidence of disseminated CMV infection. HIV serology was negative as was HIV PCR. The patient was commenced on intravenous ganciclovir (2.5 mg/kg/day) as well as intravenous antibiotics for possible superimposed bacterial infection of her sinuses. Her prednisolone dose was increased to 50 mg daily because of her active sinusitis, MMF dose was reduced to
& Volume 97, Number 9, May 15, 2014 250 mg bd, and tacrolimus dose was decreased to 6 mg bd (level, 3.0Y4.5 Kg/L). For the first 2 weeks of therapy, CMV viral load continued to increase and peaked at 32,320 copies/mL. She had daily nasal washouts and required further surgical debridement. By week 3, CMV viral load began to fall and the patient’s symptoms subsided. She continued on intravenous ganciclovir for a total of 4 weeks and was converted to oral valganciclovir (450 mg/day) when her CMV viral load had fallen to 1,175 copies/mL. At last review, 3 months after presentation, the patient’s CMV viral load was undetectable, and her symptoms had completely resolved. She remains on valganciclovir 450 mg daily, as well as MMF 250 mg bd, tacrolimus 6 mg bd (level 5.1 Kg/L), and prednisolone 10 mg daily. Last serum creatinine was 2.24 mg/dL. In light of the uncommonness of the clinical presentation, follow-up testing was performed to assess the patient’s immune competency. The patient was not known to have any immune deficiency prior to transplantation and had responded appropriately while on dialysis to vaccination for hepatitis B. Subsequent testing confirmed normal quantitative immunoglobulin levels but B and T cell lymphopenia. CD19+ (B Cells) were 28 KL (normal, 80Y400/KL) and CD3+ (T-cells) were 390/KL (normal, 530Y2030/KL). These abnormalities improved following dose reduction in MMF. CMV sinusitis is an uncommon clinical entity and has been reported in patients with impaired cellular immunity mainly in association with HIV infection (1Y4) and more rarely, in patients undergoing bone marrow transplant
FIGURE 2. A, Chronic active sinusitis with numerous intracellular CMV inclusions (arrow) (H & E), 173129 mm (300300 DPI). B, CMV inclusions present in cells (CMV immunoperoxidase). 173129 mm (300300 DPI).
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Letters to the Editor
* 2014 Lippincott Williams & Wilkins
for hematologic malignancies (5, 6). A review of the literature revealed one case report of CMV sinusitis in an immunocompetent patient in association with bacterial infection (7). In line with published reports of CMV sinusitis in HIV-infected individuals, our case demonstrates that early surgical intervention as a diagnostic and therapeutic modality with timely initiation of ganciclovir is necessary in advanced sinus infections (8). The correlation between plasma CMV viral load and disease activity in CMV sinusitis remains unclear, although we were guided by the evolution of clinical symptoms and viral load when defining treatment response and duration. High-dose steroids were used to treat localized inflammation of the sinus mucosa in our patient. This may explain the initial rise in the patient’s CMV viral load that was observed, despite the simultaneous reduction in MMF and tacrolimus dose. Literature review confirmed that steroids have not been part of the treatment of CMV sinusitis, especially in HIV patients (1Y4, 7). Inhaled steroids could be used as an alternative, with less potentially less immunosuppressive effects.
To our knowledge this is the first case report of CMV sinusitis occurring in an HIV-negative patient after solid organ transplantation, suggesting that this is a rare complication. We have demonstrated successful treatment of the disease with a combination of surgery, antiviral treatment, and immunosuppression reduction.
ISSN: 0041-1337/14/9709-e54 DOI: 10.1097/TP.0000000000000114
REFERENCES 1.
2. 3.
Anuksha Gujadhur1 Napier Thomson1 Ar Kar Aung2 Catriona Mclean3 Solomon Menahem1 1
Department of Renal Medicine Alfred Hospital, Melbourne, Australia 2 Department of Infectious Diseases Alfred Hospital, Melbourne, Australia 3 Department of Anatomical Pathology Alfred Hospital Melbourne, Australia The authors declare no conflicts of interest. Address correspondence to Solomon Menahem, M.D., Ph.D., Department of Renal Medicine, Alfred Hospital, Commercial Rd, Prahran 3181, Melbourne, Australia. E-mail: [email protected] Received 10 December 2013. Accepted 6 February 2014. Copyright * 2014 by Lippincott Williams & Wilkins
e57
4. 5.
6.
7.
8.
Williams JD, Kieserman SP, Tavin E. Cytomegalovirus sinusitis in a patient with acquired immunodeficiency syndrome. Otolaryngol Head Neck Surg 1995; 112: 750. Marks SC, Upadhyay S, Crane L. Cytomegalovirus sinusitis. A new manifestation of AIDS. Arch Otolaryngol Head Neck Surg 1996; 122: 789. Yoskovitch A, Cantrell H. Cytomegalovirus infection presenting as chronic sinusitis and nasal polyposis: a case report. Ear Nose Throat J 1998; 77: 35. Jutte A, Fatkenheuer G, Hell K, et al. CMV sinusitis as the initial manifestation of AIDS. HIV Med 2000; 1: 123. Rayes A, Sahni K, Hanna C, et al. Cytomegalovirus sinusitis in a child with chronic myelogenous leukemia following bone marrow transplantation. Pediatr Blood Cancer 2011; 56: 1140. Mortellaro C, Barat V, Nesi F, et al. Intercurrent infectious diseases in post-stem cell transplant patients: paranasal sinusitis. J Craniofac Surg 2012; 23: 153. Morre TD, Clement PA, PipeleersMarichal M. Cytomegalovirus as precipitating factor of acute bacterial sinusitis in an immunocompetent patient. A case report. Acta Otorhinolaryngol Belg 1996; 50: 37. Poole MD, Postma D, Cohen MS. Pyogenic otorhinologic infections in acquired immune deficiency syndrome. Arch Otolaryngol 1984; 110: 130.
Cerulomycin A: A Potent Novel Immunosuppressive Agent he immune system is the body’s paramount defense mechanism against pathogens and foreign and self-antigens. It can precisely distinguish self from nonself with the help of lymphocytes known as T cells and B cells. T cells play cardinal role in orchestrating the immune system in effectively eliminating the pathogens. Immune response to self-antigen in autoimmune diseases, immune attack against alloantigens in graft rejection, inflammatory disorders, and hypersensitivity responses to allergens are considered manifestations of immune dysregulation (1, 2). The immune response elicited by alloreactive T cells is tremendously upsetting during graft rejection. In such cases, the only way to anergize alloreactive T cells is by immunosuppressive drugs. Currently, cyclosporine A, tacrolimus, rapamycin, azathioprine, cyclophosphamide, methotrexate, prednisone, and so on are immunosuppressive drugs in clinical application for suppressing the immune system and reducing the chances of
T
transplant rejection (3). Although these drugs have provided significant benefits to the patients, they also possess several disadvantages. For example, cyclosporine A and tacrolimus has feeble oral bioavailability, poor solubility, and side effects like nephrotoxicity and malignancy (4Y7). Furthermore, their mode of action is nonspecific, which results in wide range of toxic side effects; tolerated dosages do not provide complete suppression of belligerent cells of immune system, lifelong intake is necessary to maintain the acceptance of transplanted organ and nonaffordable cost (8Y10). Consequently, regardless of the availability of many immunosuppressive drugs, neither the gradient of graft rejection nor the occurrence is ameliorated. Thus, there still exists an urgent need and challenge for scientific community to discover novel immunosuppressive drugs that could provide safer and enhanced efficiency, better tolerability, and eventually improved sustenance of organ transplants.
Therefore, we made an attempt to discover a novel immunosuppressive molecule, which could be safer and endowed with better pharmacological activity. Consequently, we screened various bioactive compounds secreted by microorganisms collected from various niches of India. We discovered a bioactive compound caerulomycin A (CaeA) from culture extract of a novel strain of actinomycetes Actinoalloteichus spitiensis that expressed immunosuppressive activity. The role of T cells is well established in the graft rejection (11Y13). It is therefore quite crucial to either tolerize or suppress alloreactive T cells. Hence, we analyzed the immunosuppressive activity of CaeA on the proliferation of alloreactive T cells and prolongation of allogeneic skin grafts. Interestingly, we observed significant (PG0.0001) decline in the in vitro proliferation of anti-CD3 and CD28 AbsYstimulated T cells when cultured with CaeA (Fig. 1A). Furthermore, we also noticed that CaeA substantially (PG0.0001)
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
* 2014 Lippincott Williams & Wilkins
when the donor is female (8, 9, 13). The risk of PLS is dependent on the likelihood of transfer of donor-derived lymphocytes and is more common in hemopoietic cell transplants followed by heart and lung, liver, and finally kidney transplants (2). Anti-D is characteristically an IgG antibody which causes extravascular hemolysis. Conversely, intravascular hemolysis is typically the result of an IgM antibody which can link two antigen sites on the red cell membrane and activate complement. To date, in previous cases of PLS after renal transplantation, only IgG anti-D has been identified on DAT testing, in keeping with extravascular hemolysis. In our case, in addition to IgG, C3d and IgM were detected, raising the possibility of intravascular hemolysis. Rarely, severe hemolytic reactions associated with anti-D have been reported in the setting of immune thrombocytopenia. Postulated mechanisms to explain the severe reactions include the overexpression of the D antigen on recipient red cells allowing IgG molecules to link and activate complement, the presence of trace amounts of IgM anti-D, or the overloading of the extravascular clearance mechanism allowing free hemoglobin to spill into the circulation (10). In our case, any of these mechanisms would seem possible and may have been augmented by P. aeruginosa UTI on postoperative day 9 (3). Although the presence of C3d on the red cell surface may have indicated an augmented hemolytic reaction as postulated above, conversely this may simply have reflected immune stimulation associated with his previous infection. Given the apparent rare occurrence of antiYD-mediated PLS, and equally im-
portantly the self-limiting nature of the condition, in our opinion, routine screening of donors or risk stratification (if it were possible) of recipients is unlikely to have an acceptable risk-versus-benefit profile. Renal transplants can safely be performed in this scenario as long as the clinical teams caring for the patient are aware of the possibility of PLS as a selflimiting cause of anemia 7 to 14 days after transplantation with an ABO or Rhesus-D mismatched donor. Prashanth Karanth, MRCP1 Janet Birchall, FRCPath2 Sarinder Day, Phd1 David J Unsworth, Phd1 Rommel Ravanan, MD1
4.
5.
6.
7.
1
Renal Transplant Centre Southmead Hospital Bristol, UK 2 NHS Blood & Transplant and North Bristol NHS Trust Bristol, UK The authors declare no funding or conflicts of interest. Address correspondence to: Prashanth Karanth, M.D., 26 Efford Road, Plymouth, Devon, UK. E-mail: [email protected] Received 9 December 2013. Accepted 31 January 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9709-e53 DOI: 10.1097/TP.0000000000000100
8. 9.
10.
11.
12.
REFERENCES 1.
2. 3.
Ramsey G, Israel L, Lindsay GD, et al. Anti-Rho (D) in two Rh-positive patients receiving kidney grafts from an Rh immunized donor. Transplantation 1986; 41: 67. Ramsey G. Red cell antibodies arising from solid organ transplants. Transfusion 1991; 31: 76. Nadarajah L, Ashman N, Thuraisingham R, et al. Literature review of passenger lym-
13.
14.
e55
phocyte syndrome following renal transplantation and two case reports. Am J Transplant 2013; 13: 1594. Knoop C, Andrien M, Antoine M, et al. Severe hemolysis due to a donor anti-D antibody after heart-lung transplantation. Association with lung and blood chimerism. Am Rev Respir Dis 1993; 148: 504. Cserti-Gazdewich CM, Waddell TK, Singer LG, et al. Passenger lymphocyte syndrome with or without immune hemolytic anaemia in all Rh-positive recipients of lungs from rhesus alloimmunized donors: three new cases and a review of the literature. Transfus Med Rev 2009; 23: 134. doi: 10.1016/j.tmrv. 2008.12.003. Fung MK, Sheikh H, Eghtesad B, et al. Severe hemolysis resulting from D incompatibility in a case of ABO-identical liver transplant. Transfusion 2004; 44: 1635. Swanson J, Sebring E, Sastamoinen R, et al. Gm allotyping to determine the origin of the anti-D causing hemolytic anaemia in a kidney transplant recipient. Vox Sang 1987; 52: 228. Saba NF, Sweeney JD, Penn LC, et al. AntiD in a D-positive renal transplant patient. Transfusion 1997; 37: 321. Ainsworth CD, Crowther MA, Treleaven D, et al. Severe hemolytic anaemia post-renal transplantation produced by donor anti-D passenger lymphocytes: case report and literature review. Transfus Med Rev 2009; 23: 155. Despotovic JM, Lambert MP, Herman JH, et al. RhIG for the treatment of immune thrombocytopenia: consensus and controversy. Transfusion 2012; 52: 1126. Schwartz D, Gotzinger P. Immune-haemolytic anaemia (IHA) after solid organ transplantation due to rhesus antibodies of donor origin: report of 5 cases. Beitr Infusionsther 1992; 30: 367. Frohn C, Jabs WJ, Fricke L, et al. Hemolytic anaemia after kidney transplantation: case report and differential diagnosis. Ann Hematol 2002; 81: 158. Pomper GJ, Joseph RA, Hartmann EL, et al. Massive immune hemolysis caused by antiD after dual kidney transplantation. Am J Transplant 2005; 5: 2586. Solheim BG, Albrechtsen D, Berg KJ, et al. Auto-antibodies against erythrocytes in transplant patients produced by donor lymphocytes. Transplant Proc 1987; 19:4520.
CMV Sinusitis in a HIV-Negative Renal Transplant Recipient 53-year-old Sudanese woman was admitted to our hospital with a 4-week history of headache, nasal congestion, and bilateral periorbital pain 11 months after deceased-donor renal transplant. Her past medical history included hypertension, gastroesophageal reflux, treated cerebral tuberculosis, and end-stage renal disease secondary to IgA nephropathy. Before transplantation she had been on hemodialysis for 6 years.
A
The transplant had been uncomplicated apart from 2 weeks of delayed graft function. Immunosuppression included induction therapy with basiliximab and ongoing triple maintenance therapy with tacrolimus, mycophenolate mofetil (MMF), and prednisolone. With respect to the CMV match, the donor was of equivocal status, whereas the recipient was CMV positive. The patient had received 5 months of prophylactic oral valganciclovir therapy
and had undetectable CMV virus by PCR on routine screening throughout this period and up until 3 months before her presentation. At the time of presentation, immunosuppression included tacrolimus 7 mg bd (level 4.7 Kg/L), MMF 750 mg bd, and prednisolone 5 mg daily. Steroid dose had been gradually weaned from 20 mg at the time of transplantation and MMF dose had been recently reduced from
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e56
www.transplantjournal.com
Transplantation
FIGURE 1. CT scan showing near-complete opacification of the patient’s right paranasal and maxillary sinuses with associated maxillary wall destruction and lesser involvement of the left side. 135135 mm (9696 DPI).
1000 mg bd because of anemia (hemoglobin, 77 g/L) and lymphopenia (lymphocyte count, 0.13 10^9/L) without neutropenia. Serum creatinine was 1.92 mg/dL. On examination, the patient was afebrile with extremely tender forehead and facial bones and significant nasal congestion. A CT scan of her sinuses revealed near-complete opacification of the right paranasal and maxillary sinuses with associated maxillary wall destruction and lesser involvement of the left side (Fig. 1). She subsequently underwent surgical debridement and washout of her sinuses. Smears and cultures for bacterial, fungal, and acid fast organisms were all
negative. Histologic examination of the sinus tissue revealed active chronic inflammation with numerous intracellular cytomegalic inclusions immunoreacting with CMV antibodies diagnostic for active CMV sinusitis (Fig. 2A and B). There was no other clinical or investigative evidence of disseminated CMV infection. HIV serology was negative as was HIV PCR. The patient was commenced on intravenous ganciclovir (2.5 mg/kg/day) as well as intravenous antibiotics for possible superimposed bacterial infection of her sinuses. Her prednisolone dose was increased to 50 mg daily because of her active sinusitis, MMF dose was reduced to
& Volume 97, Number 9, May 15, 2014 250 mg bd, and tacrolimus dose was decreased to 6 mg bd (level, 3.0Y4.5 Kg/L). For the first 2 weeks of therapy, CMV viral load continued to increase and peaked at 32,320 copies/mL. She had daily nasal washouts and required further surgical debridement. By week 3, CMV viral load began to fall and the patient’s symptoms subsided. She continued on intravenous ganciclovir for a total of 4 weeks and was converted to oral valganciclovir (450 mg/day) when her CMV viral load had fallen to 1,175 copies/mL. At last review, 3 months after presentation, the patient’s CMV viral load was undetectable, and her symptoms had completely resolved. She remains on valganciclovir 450 mg daily, as well as MMF 250 mg bd, tacrolimus 6 mg bd (level 5.1 Kg/L), and prednisolone 10 mg daily. Last serum creatinine was 2.24 mg/dL. In light of the uncommonness of the clinical presentation, follow-up testing was performed to assess the patient’s immune competency. The patient was not known to have any immune deficiency prior to transplantation and had responded appropriately while on dialysis to vaccination for hepatitis B. Subsequent testing confirmed normal quantitative immunoglobulin levels but B and T cell lymphopenia. CD19+ (B Cells) were 28 KL (normal, 80Y400/KL) and CD3+ (T-cells) were 390/KL (normal, 530Y2030/KL). These abnormalities improved following dose reduction in MMF. CMV sinusitis is an uncommon clinical entity and has been reported in patients with impaired cellular immunity mainly in association with HIV infection (1Y4) and more rarely, in patients undergoing bone marrow transplant
FIGURE 2. A, Chronic active sinusitis with numerous intracellular CMV inclusions (arrow) (H & E), 173129 mm (300300 DPI). B, CMV inclusions present in cells (CMV immunoperoxidase). 173129 mm (300300 DPI).
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Letters to the Editor
* 2014 Lippincott Williams & Wilkins
for hematologic malignancies (5, 6). A review of the literature revealed one case report of CMV sinusitis in an immunocompetent patient in association with bacterial infection (7). In line with published reports of CMV sinusitis in HIV-infected individuals, our case demonstrates that early surgical intervention as a diagnostic and therapeutic modality with timely initiation of ganciclovir is necessary in advanced sinus infections (8). The correlation between plasma CMV viral load and disease activity in CMV sinusitis remains unclear, although we were guided by the evolution of clinical symptoms and viral load when defining treatment response and duration. High-dose steroids were used to treat localized inflammation of the sinus mucosa in our patient. This may explain the initial rise in the patient’s CMV viral load that was observed, despite the simultaneous reduction in MMF and tacrolimus dose. Literature review confirmed that steroids have not been part of the treatment of CMV sinusitis, especially in HIV patients (1Y4, 7). Inhaled steroids could be used as an alternative, with less potentially less immunosuppressive effects.
To our knowledge this is the first case report of CMV sinusitis occurring in an HIV-negative patient after solid organ transplantation, suggesting that this is a rare complication. We have demonstrated successful treatment of the disease with a combination of surgery, antiviral treatment, and immunosuppression reduction.
ISSN: 0041-1337/14/9709-e54 DOI: 10.1097/TP.0000000000000114
REFERENCES 1.
2. 3.
Anuksha Gujadhur1 Napier Thomson1 Ar Kar Aung2 Catriona Mclean3 Solomon Menahem1 1
Department of Renal Medicine Alfred Hospital, Melbourne, Australia 2 Department of Infectious Diseases Alfred Hospital, Melbourne, Australia 3 Department of Anatomical Pathology Alfred Hospital Melbourne, Australia The authors declare no conflicts of interest. Address correspondence to Solomon Menahem, M.D., Ph.D., Department of Renal Medicine, Alfred Hospital, Commercial Rd, Prahran 3181, Melbourne, Australia. E-mail: [email protected] Received 10 December 2013. Accepted 6 February 2014. Copyright * 2014 by Lippincott Williams & Wilkins
e57
4. 5.
6.
7.
8.
Williams JD, Kieserman SP, Tavin E. Cytomegalovirus sinusitis in a patient with acquired immunodeficiency syndrome. Otolaryngol Head Neck Surg 1995; 112: 750. Marks SC, Upadhyay S, Crane L. Cytomegalovirus sinusitis. A new manifestation of AIDS. Arch Otolaryngol Head Neck Surg 1996; 122: 789. Yoskovitch A, Cantrell H. Cytomegalovirus infection presenting as chronic sinusitis and nasal polyposis: a case report. Ear Nose Throat J 1998; 77: 35. Jutte A, Fatkenheuer G, Hell K, et al. CMV sinusitis as the initial manifestation of AIDS. HIV Med 2000; 1: 123. Rayes A, Sahni K, Hanna C, et al. Cytomegalovirus sinusitis in a child with chronic myelogenous leukemia following bone marrow transplantation. Pediatr Blood Cancer 2011; 56: 1140. Mortellaro C, Barat V, Nesi F, et al. Intercurrent infectious diseases in post-stem cell transplant patients: paranasal sinusitis. J Craniofac Surg 2012; 23: 153. Morre TD, Clement PA, PipeleersMarichal M. Cytomegalovirus as precipitating factor of acute bacterial sinusitis in an immunocompetent patient. A case report. Acta Otorhinolaryngol Belg 1996; 50: 37. Poole MD, Postma D, Cohen MS. Pyogenic otorhinologic infections in acquired immune deficiency syndrome. Arch Otolaryngol 1984; 110: 130.
Cerulomycin A: A Potent Novel Immunosuppressive Agent he immune system is the body’s paramount defense mechanism against pathogens and foreign and self-antigens. It can precisely distinguish self from nonself with the help of lymphocytes known as T cells and B cells. T cells play cardinal role in orchestrating the immune system in effectively eliminating the pathogens. Immune response to self-antigen in autoimmune diseases, immune attack against alloantigens in graft rejection, inflammatory disorders, and hypersensitivity responses to allergens are considered manifestations of immune dysregulation (1, 2). The immune response elicited by alloreactive T cells is tremendously upsetting during graft rejection. In such cases, the only way to anergize alloreactive T cells is by immunosuppressive drugs. Currently, cyclosporine A, tacrolimus, rapamycin, azathioprine, cyclophosphamide, methotrexate, prednisone, and so on are immunosuppressive drugs in clinical application for suppressing the immune system and reducing the chances of
T
transplant rejection (3). Although these drugs have provided significant benefits to the patients, they also possess several disadvantages. For example, cyclosporine A and tacrolimus has feeble oral bioavailability, poor solubility, and side effects like nephrotoxicity and malignancy (4Y7). Furthermore, their mode of action is nonspecific, which results in wide range of toxic side effects; tolerated dosages do not provide complete suppression of belligerent cells of immune system, lifelong intake is necessary to maintain the acceptance of transplanted organ and nonaffordable cost (8Y10). Consequently, regardless of the availability of many immunosuppressive drugs, neither the gradient of graft rejection nor the occurrence is ameliorated. Thus, there still exists an urgent need and challenge for scientific community to discover novel immunosuppressive drugs that could provide safer and enhanced efficiency, better tolerability, and eventually improved sustenance of organ transplants.
Therefore, we made an attempt to discover a novel immunosuppressive molecule, which could be safer and endowed with better pharmacological activity. Consequently, we screened various bioactive compounds secreted by microorganisms collected from various niches of India. We discovered a bioactive compound caerulomycin A (CaeA) from culture extract of a novel strain of actinomycetes Actinoalloteichus spitiensis that expressed immunosuppressive activity. The role of T cells is well established in the graft rejection (11Y13). It is therefore quite crucial to either tolerize or suppress alloreactive T cells. Hence, we analyzed the immunosuppressive activity of CaeA on the proliferation of alloreactive T cells and prolongation of allogeneic skin grafts. Interestingly, we observed significant (PG0.0001) decline in the in vitro proliferation of anti-CD3 and CD28 AbsYstimulated T cells when cultured with CaeA (Fig. 1A). Furthermore, we also noticed that CaeA substantially (PG0.0001)
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
