J. Paediatr. Child Health (1992) 28, 331-333
Failure of allogeneic bone marrow transplantation to benefit HIV infection N. GIRI,' M. R. VOWELS and J. B. ZIEGLER'
Departments of Paediatric Haematology and Oncology, and 21mmunology and Allergy; The Prince of Wales Children's Hospital, Randwick, New South Wales, Australia
Abstract A 16 year old boy underwent allogeneic bone marrow transplantation (BMT) from an human leukocyte antigen (HLA)-identical sibling for severe aplastic anaemia. He was symptomatic for 7 years before transplantation and had received multiple red blood cell and platelet transfusions. Conditioning for BMT consisted of cyclophosphamide, antilymphocyte globulin and total lymphoid irradiation. Engraftment was rapid, there was no evidence of rejection despite the history of multiple blood product transfusions and he did not develop acute or chronic graft versus host disease. He was well for the first 8 months after transplantation but then developed fevers, interstital pneumonia, herpes simplex infections and cytomegalovirus enteritis. Serological studies revealed antibodies to human immunodeficiency virus (HIV) and he was considered to have acquired immune deficiency syndrome (AIDS). Retrospective analysis of the serum samples showed that he was seronegative for HIV until approximately 10 months before transplantation when his serum became HIV positive. Lymphocyte function studies done after transplantation suggested immunologic recovery at 3 months post-transplant with a brisk though subnormal response to phytohaemagglutinin stimulation. T cell subset analysis performed subsequently showed complete absence of CD4 positive cells indicating immune incompetence which was associated with clinical features of AIDS. Bone marrow transplantation had failed to produce sustained immunologic reconstitution and prevent the progression of HIV to which he ultimately succumbed.
Key words: acquired immune deficiency syndrome; aplastic anaemia; blood transfusions; bone marrow transplant,
Acquired immunodeficiency syndrome (AIDS) is the most severe clinical manifestation of a spectrum of disorders caused by human immunodeficiency virus (HIV) with a 2 year mortality rate estimated to exceed 80%. There are no reported cases of spontaneous recovery of normal immunological function once opportunistic infections have occurred.' The virus can be transmitted by sexual contact' and from blood or blood products3** Approximately 90% of AIDS patients in developed countries are homosexual or bisexual men, and intravenous drug users5 However recipients of blood or blood products transfused before the systematic screening procedures for donors became available form another group at risk. Infection with HIV has been observed also in a few recipients of allogeneic bone marrow transplants (BMT).~-'O
The present report describes a patient with severe aplastic anaemia who acquired HIV before transplantation by transfusion of an infected blood product. Allogeneic BMT for aplastic anaemia was successful despite the history of multiple blood transfusions but failed to produce a sustained immunologic reconstitution and he died of AIDS 21 months post-transplant.
Correspondence: Dr M. R. Vowels, The Prince of Wales Children's Hospital, Randwick, NSW 2031, Australia.. N.Giri. MD, Clinical Fellow. M. R. Vowels, FRACP, Director, Haematology and Oncology. J. 6.Ziegler. FRACP. Paediatric Immunologist. Accepted for publication 30 January 1992.
CASE REPORT A 9 year old Caucasian boy presented with severe aplastic anaemia in May 1977 with a 2 month history of easy bruising, pallor and prolonged nose bleeds. He was clinically anaemic with petechiae and widespread purpura, and had bleeding from lips, gums and nose. He had no lymphadenopathy or hepatosplenomegaly. Investigations showed a leucocyte count of 1.9 x 109/L, neutrophils 1646, lymphocytes 81%, platelets less than 1 0 . 0 109/L ~ and reticulocyte count less than 0.5%. A bone marrow aspirate was hypocellular, with 86% lymphocytes. Trephine biopsy of bone marrow showed extreme hypocellularity. Lymphocyte subset enumeration showed a normal T cell (E rosetting cells) number. Hepatitis B surface antigen and antibody were not detected. He was treated initially with prednisolone (40 mg/day) and fluoxymesterone (30 mg/day). Over the next 6 years he required red cell and platelet transfusions on aveiage once every 15-20 days, usually for nose and/or gum bleeds. From March 1983 his transfusion requirement increased and he was given repeated red cell and platelet transfusions for severe life threatening bleeding episodes including an intracerebral haemorrhage. In all he received blood products from over 600 random donors during a period of 7 years. Despite the use of desferrioxamine the frequency of red cell transfusions had led to iron overload. The patient had an ABO, HLA A, B and DR identical brother whose cells were mutually non-reactive in mixed leucocyte culture with those of the patient. He received an allogeneic BMT
N. Giri eta/.
332
In the 13 months after AIDS was diagnosed, his clinical condition deteriorated gradually with protean manifestations of the disorder characterized mainly by malaise, cachexia, recurrent fever, infections of the gastrointestinal tract (with CMV, Escherichia coli and Candida albicans). infections of the lower respiratory tract (Pneumocyfis carinii), infections of oral mucosa and lips (herpes simplex, Candida albicans) and progressive retinitis (possibly due to CMV and which failed to respond to ganciclovir). He lost more than 20 kg bodyweight during this period. The platelet and white cell count diminished progressively. He died in March 1986 with bilateral pneumonia and acute renal failure, 21 months after BMT and 13 months after the diagnosis of AIDS. An autopsy was not performed.
from his brother in June 1984. The conditioning therapy consisted of antilymphocyte globulin (12.5 mg/kg per day on alternate days for 3 doses), cyclophosphamide (50 mg/kg per day for 4 days) and total lymphoid irradiation (1200 cGy in 6 fractions over 3 days) with shielding of the myocardium. Graft versus host disease (GVHD) prophylaxis consisted of a short course of methotrexate (15 mg/m2 on day 2, and 10 mg/m2 on days 4,8 and 13). The post-transplant course was uneventful. By day 36, his white cell count rose above 1.4 109/L.the absolute neutrophi1 count was above 0.5.iIO9/L, the bone marrow biopsy/ aspirate was normocellular with regeneration of myeloid and erythroid precursors and megakaryocytes were present. He did not develop acute or chronic GVHD. He received 45 transfusions of irradiated red cells and platelets in the early posttransplant period. He was discharged 6 weeks after transplantation and engraftment was sustained with normalization of his blood count. He remained symptom free and in good general health for a period of 8 months following transplantation. In February 1985, he developed a low grade fever, malaise, tachypnoea and thrombocytopenia. A chest X-ray showed interstitial pneumonia. Bone marrow aspiration showed normal cellularity. After a 3 week course of trimethoprim-sulfamethoxazole the interstitial pneumonia resolved. However he continued to lose weight and developed recurrent infections of the lower respiratory tract presumed to be due to Pneurnocytis cannii. low grade fever, herpes simplex infection of oral mucosa and diarrhoea considered on intestinal biopsy to be due to cytomegalovirus (CMV). At that time antibodies to HIV were found and AIDS was diagnosed. Frozen serum samples obiained at 3 monthly intervals before and after BMT were analysed retrospectively for antibodies to HIV. He was found to have been seronegative until May 1983 and seropositive from August 1983 (10 months before BMT). All serum samples from that time on were found to be positive for HIV antibodies. The marrow donor had no antibodies to HIV at the time of BMT and when retested in February 1985. Survey of blood product donors revealed circumstantial evidence regarding possible HIV infection in one male donor who had donated platelets to this patient in March 1983 and also to another with aplastic anemia at the same time. The other patient has since died of AIDS. and the donor has not been available for HIV testing. Lymphocyte function measured in vifro 3 months after transplantation showed a significant response (75% of normal) to phytohaemagglutin stimulation indicating T cell engraftment. T cell subset enumeration was not done at this stage. Lymphocyte subset analysis after the development of AIDS showed a complete absence of CD4 positive (helperlinducer) T-cells indicating immune incompetence (Table 1).
DISCUSSION This patient received an allogeneic BMT for severe aplastic anaemia. Engraftment was rapid and he remained in good health with normal haematologic parameters for 8 months after transplantation and then showed a steady decline with recurrent and persistent opportunistic infections. Graft rejection did not occur despite the history of multiple transfusions. Phytohaemagglutin stimulation indicated recovering T cell function at 3 months post-transplant. Lymphocyte studies done several months later showed a complete absence of circulating CD4 positive cells indicating immuno-incompetence. Immunologic functions are usually stable by 1 year post-transplant and opportunistic infections are uncommon as late complications in the absence of chronic GVHD."~'* The late occurrence of these infections should raise the suspicion of AIDS. Indeed, the failure of immune reconstitution in our patient was associated with the development of a clinical syndrome that suggested the diagnosis of AIDS and antibodies to HIV were detected in the serum. In contrast to published reports,13 we also noticed a more rapid development of AIDS in this patient. Rate of progression to AIDS is known to be age dependent, being greatest in the very young and the very old. Adolescents with HIV are considered to be the group with the best p r o g n ~ s i s . The ' ~ rapidity of progression in this case thus might be related to the underlying disease or the immunosuppression used for the transplant conditioning. The acquisition of HIV infection and subsequent development of AIDS due to transfusion of blood products from donors at risk is well documented, especially in multiply transfused patient^.^^'^ HIV infection and subsequent AIDS has also been reported in a few recipients of allogeneic BMT."-'O Of these, five patients reported by Vilmer et a/.' and both the patients in Atkinson's report'O were found retrospectively to have been HIV positive before transplantation. With the availability of HIV screening for
Table 1 Immune studies before and after transplant Parameter
At
diagnosis of AA
Lymphocyte+ T cells' T4' T8T 4 / T 8 ratio PHA (46 of normal) 'AIDS was diagnosed
184
0.924 NT NT NT NT
'
~
109/L AA -
Post-transplant3 months
Post-transplant 11 months*
Post-transplant 16 months
Normal value
1.20 NT NT NT NT 75
0.61
0.20 0.11 0 0.09 0 NT
1.O-3.7 0.7-2.1 0.1-1.2 1.3-5.5 100
aplastic anaemia. NT = not tested
0 03 0 0 02 0 NT
1.5-4.0
333
Allogeneic bone marrow transplantation and HIV
all blood donors since 1985, this mode of viral transmission should b e eliminated, and w e are not aware of any reports of HIV infection through blood transfusion after 1985. The retrovirus, HIV, primarily infects helper/inducer (CDA ve) T-cells which play a central role in induction and regulation of immune function. The resulting profound cellular and humoral immunodeficiency is the cause of recurrent and life-threatening infections and neoplastic processes that characterize AIDS.S This has resulted in studies designed to correct the underlying immune defects in patients with AIDS by giving immunomodulators, for example, interferons, peripheral blood lymphocytes or interleukin-2, but without any success.15 In addition, there have been experiments to reconstitute the immune system by giving patients allogeneic lymphocytes,’6 allogeneic BMT” or syngeneic lymphocytes and syngeneic BMT.18 These also have been quite discouraging. Although B M T in our patient was not undertaken with the purpose of curing HIV infection, we would like to highlight that efforts directed towards restoring the immune system by various methods including BMT may be doomed to failure if the causative factor for AIDS (i.e. HIV) cannot be eliminated. Strategies developed to suppress or eliminate HIV by effective antiviral drugs that inhibit reverse transcriptase, the enzyme necessary for retroviral r e p l i ~ a t i o n . ’ ~ along with reconstitution of essential immunologic functions by BMT may offer successful treatment for patients with AIDS in future. Therapeutic trials in this direction are already with varying results. Angelucci ef abZ0 treated an HIV positive thalassaemic child with azidothymidine before transplantation with the aim of reducing the viral load. The patient engrafted but later had florid viral disease. Holland et a/. treated a 41 year old patient with AIDS and non-Hodgkin’s lymphoma with high-dose azidothymidine for 2 weeks before transplantation and continued the drug at a lower maintenance dose after the transplant.*’ This patient became negative for HIV-1 32 days after transplant but died on day 47 from recurrence of lymphoma. Analysis of autopsy tissue showed n o evidence of HIV. This report is encouraging and suggests that the HIV-1 infected recipient cells may have been eradicated secondary to the bone marrow ablative cherno-radiotherapy and that azidothymidine may be able to prevent the establishment of HIV-1 infection in donor haematopoietic lymphoid cells. However it is too early to draw conclusions and additional studies are necessary to determine the ultimate role of BMT and antiviral chemotherapy as a therapeutic modality in patients infected with HIV-1.
+
REFERENCES 1 Update on acquired immune deficiency (AIDS) - United States. Morbid. Mortal. Weekly Rep. 1982; 31: 507-8, 513-14. 2 Harris C.. Butkus S. C..Klein R. S. et a/. Immunodeficiency in female sexual partners of men with acquired immune deficiency syndrome. N. Engl. J. Med. 1983; 308: 1181 -3.
3 Curran J. W., Lawrance D. N., Jaffe H. et a/. Acquired immunodeficiency syndrome (AIDS) associated with transfusions. N. Engl. J . Med. 1984; 310: 69-75. 4 Rajni M. V., Teglmeier G. E.. Levy J. A. eta/. AIDS retrovirus antibodies in hemophiliacs treated with factor Vlll or factor XI concentrates, cryoprecipitate, or fresh frozen plasma: Prevalence, seroconversion rate, and clinical correlation. Blood 1986; 67: 592-5. 5 Fauci A. S., Masur H.. Gelmann E. P., Markham P. D.,Hahn B. H.. Clifford L. H. The acquired immunodeficiency syndrome: An update. Ann. Intern. Med. 1985; 102: 800-13. 6 Bierling P. H., Cordonnier C., Duedari N.. Vernant J. P.. Leibowitch J.. Mathez D. Lymphadenopathy-associatedviruslhuman T lymphotropic virus type Ill in allogeneic bone marrow transplantation (Letter).Ann. Intern. Med. 1986; 104: 131. 7 Vilmer E., Rouzioux C..Barre F. et a/. Screening for lymphadenopathy/AIDSvirus in bone marrow transplant recipients (Letter). N. Engl. J. Med. 1986; 314: 1252. 8 Antin J. H., Smith B. R., Ewenstein B. M. eta/. HTLV-Ill infection after bone marrow transplantation. Blood 1986; 67: 160-3. 9 Verdonck C. K., De Gast G. C., Lange J. M. A., Schuurman H. J.. Dekker A. W., Bast B. J. Syngeneic leukocytes together with Suramin failed to improve immunodeficiency in a case of transfusion-associated AIDS after syngeneic bone marrow transplantation. Blood 1988; 71: 666-71. 10 Atkinson K., Dodds A. J., Concannon A. J.. Biggs J. C. The development of acquired immunodeficiency syndrome after bone-marrow transplantation. Med. J. Aust. 1987; 147: 510-12. 11 Witherspoon R. P.. Lum L. G., Storb R. Immunologic reconstitution after human marrow grafting. Semin. Hematol. 1984; 21: 2-7. 12 Atkinson K., Storb R.. Prentice R. L. et al. Analysis of late infections in 89 long-term survivors of bone marrow transplantation. Blood 1979; 53: 720-31. 13 Goedert J. J.. Kessler C. M.. Aledort L. M. eta/. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with haemophilia. N. Engl. J. Med. 1989; 321: 1141. 14 AIDS-Hemophilia French Study Group. Natural history of primary infection with LAV in multitransfused patients. Blood 1986; 68: 89-94. 15 Lance H. C., Sherwin S. A., Masur H. e l a/. A phase 1 trial of recombinant immune (r) interferon in patients with acquired immune deficiency syndrome (AIDS) (Abstract). Clin. Res. 1985; 33: 408. 16 Davis K. C., Hayward A,, Ozturk G.. Kohler P. F. Lymphocyte transfusion in a case of acquired immunodeficiency syndrome (Letter). Lancet 1983; i:599-600. 17 Hassett J. M., Zaroulis C. G.. Greenberg M. L.. Siegal F. P. Bone marrow transplantation in AIDS (Letter). N. Engl. J. Med. 1983; 309: 665. 18 Lane H. C., Masur H.. Longo D. L. et a/. Partial immune reconstitution in a patient with acquired immunodeficiency syndrome. N. Engl. J. Med. 1984; 311: 1099-103. 19 Yarchoan R.. Broder S. Development of antiviral therapy for acquired immunodeficiencysyndrome and related disorders. N. Eogl. J. Med. 1987; 316: 557-64. 20 Holland H. K., Sara1 R.. Rossi J. J. er a/. Allogeneic bone marrow transplantation, Zidovudine and human immunodeficiency virus type 1 (HIV-1) infection: Studies in a patient with non-Hodgkin lymphoma. Ann. Intern. Med. 1989; 111: 973-81. 21 Angelucci E., Lucarelli G., Baronciani D. el a/. Bone marrow transplantation in an HIV positive thalassemic child following therapy with azidothymidine. Haematologica 1990; 75: 285-7.
Failure of allogeneic bone marrow transplantation to benefit HIV infection N. GIRI,' M. R. VOWELS and J. B. ZIEGLER'
Departments of Paediatric Haematology and Oncology, and 21mmunology and Allergy; The Prince of Wales Children's Hospital, Randwick, New South Wales, Australia
Abstract A 16 year old boy underwent allogeneic bone marrow transplantation (BMT) from an human leukocyte antigen (HLA)-identical sibling for severe aplastic anaemia. He was symptomatic for 7 years before transplantation and had received multiple red blood cell and platelet transfusions. Conditioning for BMT consisted of cyclophosphamide, antilymphocyte globulin and total lymphoid irradiation. Engraftment was rapid, there was no evidence of rejection despite the history of multiple blood product transfusions and he did not develop acute or chronic graft versus host disease. He was well for the first 8 months after transplantation but then developed fevers, interstital pneumonia, herpes simplex infections and cytomegalovirus enteritis. Serological studies revealed antibodies to human immunodeficiency virus (HIV) and he was considered to have acquired immune deficiency syndrome (AIDS). Retrospective analysis of the serum samples showed that he was seronegative for HIV until approximately 10 months before transplantation when his serum became HIV positive. Lymphocyte function studies done after transplantation suggested immunologic recovery at 3 months post-transplant with a brisk though subnormal response to phytohaemagglutinin stimulation. T cell subset analysis performed subsequently showed complete absence of CD4 positive cells indicating immune incompetence which was associated with clinical features of AIDS. Bone marrow transplantation had failed to produce sustained immunologic reconstitution and prevent the progression of HIV to which he ultimately succumbed.
Key words: acquired immune deficiency syndrome; aplastic anaemia; blood transfusions; bone marrow transplant,
Acquired immunodeficiency syndrome (AIDS) is the most severe clinical manifestation of a spectrum of disorders caused by human immunodeficiency virus (HIV) with a 2 year mortality rate estimated to exceed 80%. There are no reported cases of spontaneous recovery of normal immunological function once opportunistic infections have occurred.' The virus can be transmitted by sexual contact' and from blood or blood products3** Approximately 90% of AIDS patients in developed countries are homosexual or bisexual men, and intravenous drug users5 However recipients of blood or blood products transfused before the systematic screening procedures for donors became available form another group at risk. Infection with HIV has been observed also in a few recipients of allogeneic bone marrow transplants (BMT).~-'O
The present report describes a patient with severe aplastic anaemia who acquired HIV before transplantation by transfusion of an infected blood product. Allogeneic BMT for aplastic anaemia was successful despite the history of multiple blood transfusions but failed to produce a sustained immunologic reconstitution and he died of AIDS 21 months post-transplant.
Correspondence: Dr M. R. Vowels, The Prince of Wales Children's Hospital, Randwick, NSW 2031, Australia.. N.Giri. MD, Clinical Fellow. M. R. Vowels, FRACP, Director, Haematology and Oncology. J. 6.Ziegler. FRACP. Paediatric Immunologist. Accepted for publication 30 January 1992.
CASE REPORT A 9 year old Caucasian boy presented with severe aplastic anaemia in May 1977 with a 2 month history of easy bruising, pallor and prolonged nose bleeds. He was clinically anaemic with petechiae and widespread purpura, and had bleeding from lips, gums and nose. He had no lymphadenopathy or hepatosplenomegaly. Investigations showed a leucocyte count of 1.9 x 109/L, neutrophils 1646, lymphocytes 81%, platelets less than 1 0 . 0 109/L ~ and reticulocyte count less than 0.5%. A bone marrow aspirate was hypocellular, with 86% lymphocytes. Trephine biopsy of bone marrow showed extreme hypocellularity. Lymphocyte subset enumeration showed a normal T cell (E rosetting cells) number. Hepatitis B surface antigen and antibody were not detected. He was treated initially with prednisolone (40 mg/day) and fluoxymesterone (30 mg/day). Over the next 6 years he required red cell and platelet transfusions on aveiage once every 15-20 days, usually for nose and/or gum bleeds. From March 1983 his transfusion requirement increased and he was given repeated red cell and platelet transfusions for severe life threatening bleeding episodes including an intracerebral haemorrhage. In all he received blood products from over 600 random donors during a period of 7 years. Despite the use of desferrioxamine the frequency of red cell transfusions had led to iron overload. The patient had an ABO, HLA A, B and DR identical brother whose cells were mutually non-reactive in mixed leucocyte culture with those of the patient. He received an allogeneic BMT
N. Giri eta/.
332
In the 13 months after AIDS was diagnosed, his clinical condition deteriorated gradually with protean manifestations of the disorder characterized mainly by malaise, cachexia, recurrent fever, infections of the gastrointestinal tract (with CMV, Escherichia coli and Candida albicans). infections of the lower respiratory tract (Pneumocyfis carinii), infections of oral mucosa and lips (herpes simplex, Candida albicans) and progressive retinitis (possibly due to CMV and which failed to respond to ganciclovir). He lost more than 20 kg bodyweight during this period. The platelet and white cell count diminished progressively. He died in March 1986 with bilateral pneumonia and acute renal failure, 21 months after BMT and 13 months after the diagnosis of AIDS. An autopsy was not performed.
from his brother in June 1984. The conditioning therapy consisted of antilymphocyte globulin (12.5 mg/kg per day on alternate days for 3 doses), cyclophosphamide (50 mg/kg per day for 4 days) and total lymphoid irradiation (1200 cGy in 6 fractions over 3 days) with shielding of the myocardium. Graft versus host disease (GVHD) prophylaxis consisted of a short course of methotrexate (15 mg/m2 on day 2, and 10 mg/m2 on days 4,8 and 13). The post-transplant course was uneventful. By day 36, his white cell count rose above 1.4 109/L.the absolute neutrophi1 count was above 0.5.iIO9/L, the bone marrow biopsy/ aspirate was normocellular with regeneration of myeloid and erythroid precursors and megakaryocytes were present. He did not develop acute or chronic GVHD. He received 45 transfusions of irradiated red cells and platelets in the early posttransplant period. He was discharged 6 weeks after transplantation and engraftment was sustained with normalization of his blood count. He remained symptom free and in good general health for a period of 8 months following transplantation. In February 1985, he developed a low grade fever, malaise, tachypnoea and thrombocytopenia. A chest X-ray showed interstitial pneumonia. Bone marrow aspiration showed normal cellularity. After a 3 week course of trimethoprim-sulfamethoxazole the interstitial pneumonia resolved. However he continued to lose weight and developed recurrent infections of the lower respiratory tract presumed to be due to Pneurnocytis cannii. low grade fever, herpes simplex infection of oral mucosa and diarrhoea considered on intestinal biopsy to be due to cytomegalovirus (CMV). At that time antibodies to HIV were found and AIDS was diagnosed. Frozen serum samples obiained at 3 monthly intervals before and after BMT were analysed retrospectively for antibodies to HIV. He was found to have been seronegative until May 1983 and seropositive from August 1983 (10 months before BMT). All serum samples from that time on were found to be positive for HIV antibodies. The marrow donor had no antibodies to HIV at the time of BMT and when retested in February 1985. Survey of blood product donors revealed circumstantial evidence regarding possible HIV infection in one male donor who had donated platelets to this patient in March 1983 and also to another with aplastic anemia at the same time. The other patient has since died of AIDS. and the donor has not been available for HIV testing. Lymphocyte function measured in vifro 3 months after transplantation showed a significant response (75% of normal) to phytohaemagglutin stimulation indicating T cell engraftment. T cell subset enumeration was not done at this stage. Lymphocyte subset analysis after the development of AIDS showed a complete absence of CD4 positive (helperlinducer) T-cells indicating immune incompetence (Table 1).
DISCUSSION This patient received an allogeneic BMT for severe aplastic anaemia. Engraftment was rapid and he remained in good health with normal haematologic parameters for 8 months after transplantation and then showed a steady decline with recurrent and persistent opportunistic infections. Graft rejection did not occur despite the history of multiple transfusions. Phytohaemagglutin stimulation indicated recovering T cell function at 3 months post-transplant. Lymphocyte studies done several months later showed a complete absence of circulating CD4 positive cells indicating immuno-incompetence. Immunologic functions are usually stable by 1 year post-transplant and opportunistic infections are uncommon as late complications in the absence of chronic GVHD."~'* The late occurrence of these infections should raise the suspicion of AIDS. Indeed, the failure of immune reconstitution in our patient was associated with the development of a clinical syndrome that suggested the diagnosis of AIDS and antibodies to HIV were detected in the serum. In contrast to published reports,13 we also noticed a more rapid development of AIDS in this patient. Rate of progression to AIDS is known to be age dependent, being greatest in the very young and the very old. Adolescents with HIV are considered to be the group with the best p r o g n ~ s i s . The ' ~ rapidity of progression in this case thus might be related to the underlying disease or the immunosuppression used for the transplant conditioning. The acquisition of HIV infection and subsequent development of AIDS due to transfusion of blood products from donors at risk is well documented, especially in multiply transfused patient^.^^'^ HIV infection and subsequent AIDS has also been reported in a few recipients of allogeneic BMT."-'O Of these, five patients reported by Vilmer et a/.' and both the patients in Atkinson's report'O were found retrospectively to have been HIV positive before transplantation. With the availability of HIV screening for
Table 1 Immune studies before and after transplant Parameter
At
diagnosis of AA
Lymphocyte+ T cells' T4' T8T 4 / T 8 ratio PHA (46 of normal) 'AIDS was diagnosed
184
0.924 NT NT NT NT
'
~
109/L AA -
Post-transplant3 months
Post-transplant 11 months*
Post-transplant 16 months
Normal value
1.20 NT NT NT NT 75
0.61
0.20 0.11 0 0.09 0 NT
1.O-3.7 0.7-2.1 0.1-1.2 1.3-5.5 100
aplastic anaemia. NT = not tested
0 03 0 0 02 0 NT
1.5-4.0
333
Allogeneic bone marrow transplantation and HIV
all blood donors since 1985, this mode of viral transmission should b e eliminated, and w e are not aware of any reports of HIV infection through blood transfusion after 1985. The retrovirus, HIV, primarily infects helper/inducer (CDA ve) T-cells which play a central role in induction and regulation of immune function. The resulting profound cellular and humoral immunodeficiency is the cause of recurrent and life-threatening infections and neoplastic processes that characterize AIDS.S This has resulted in studies designed to correct the underlying immune defects in patients with AIDS by giving immunomodulators, for example, interferons, peripheral blood lymphocytes or interleukin-2, but without any success.15 In addition, there have been experiments to reconstitute the immune system by giving patients allogeneic lymphocytes,’6 allogeneic BMT” or syngeneic lymphocytes and syngeneic BMT.18 These also have been quite discouraging. Although B M T in our patient was not undertaken with the purpose of curing HIV infection, we would like to highlight that efforts directed towards restoring the immune system by various methods including BMT may be doomed to failure if the causative factor for AIDS (i.e. HIV) cannot be eliminated. Strategies developed to suppress or eliminate HIV by effective antiviral drugs that inhibit reverse transcriptase, the enzyme necessary for retroviral r e p l i ~ a t i o n . ’ ~ along with reconstitution of essential immunologic functions by BMT may offer successful treatment for patients with AIDS in future. Therapeutic trials in this direction are already with varying results. Angelucci ef abZ0 treated an HIV positive thalassaemic child with azidothymidine before transplantation with the aim of reducing the viral load. The patient engrafted but later had florid viral disease. Holland et a/. treated a 41 year old patient with AIDS and non-Hodgkin’s lymphoma with high-dose azidothymidine for 2 weeks before transplantation and continued the drug at a lower maintenance dose after the transplant.*’ This patient became negative for HIV-1 32 days after transplant but died on day 47 from recurrence of lymphoma. Analysis of autopsy tissue showed n o evidence of HIV. This report is encouraging and suggests that the HIV-1 infected recipient cells may have been eradicated secondary to the bone marrow ablative cherno-radiotherapy and that azidothymidine may be able to prevent the establishment of HIV-1 infection in donor haematopoietic lymphoid cells. However it is too early to draw conclusions and additional studies are necessary to determine the ultimate role of BMT and antiviral chemotherapy as a therapeutic modality in patients infected with HIV-1.
+
REFERENCES 1 Update on acquired immune deficiency (AIDS) - United States. Morbid. Mortal. Weekly Rep. 1982; 31: 507-8, 513-14. 2 Harris C.. Butkus S. C..Klein R. S. et a/. Immunodeficiency in female sexual partners of men with acquired immune deficiency syndrome. N. Engl. J. Med. 1983; 308: 1181 -3.
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