Disseminated Echovirus Infection Complicating Bone Marrow Transplantation DAVIDD. BIGGS,M.D., BEHNAZC.TOORKEY,M.D., M.D., Milwaukee, Wisconsin
DONALD R.CARRIGAN,P~.D.,GERALDA.
pportunistic viral infections occur frequently in bone marrow transplant recipients and are a ma0 jor cause of morbidity and mortality. Cytomegalovirus (CMV), herpes simplex, varicella zoster, Epstein-Barr, and adenovirus infections have been well described in this patient setting [l-3]. Other viral pathogens in marrow transplant patients include respiratory syncytial virus [4], influenza and parainfluenza [5], papovavirus [6], and Coxsackie A [7]. In this report, we describe the clinical and pathologic findings in a fatal case of disseminated echovirus infection, which is, to our knowledge, the first documentation of serious echovirus infection complicating marrow transplantation.
CASE REPORT A 38-year-old woman with a malignant lymphoma, small-cell cleaved type, was admitted for an allogeneic bone marrow transplant for persistent pancytopenia of 4 months’ duration following chemotherapy. Her total leukocyte count on admission was less than 0.6 X log/L. The patient underwent transplantation with marrow from a sibling donor mismatched for a single HLA-B locus antigen (Patient HLA type: A1,2; B8(w6)-; Cw2,7; DR1,3(w52); DQwl,w2. Donor HLA type: A1,2; B8(w6),27(w4); Cw2,7; DR 1,3(w52); DQwl,w2). Ten days before transplantation, the patient began to receive prophylactic oral acyclovir, ketoconazole, and trimethoprim-sulfa. She received intravenous immunoglobulin (Sandoglobulin@, Sandoz Pharmaceuticals, East Hanover, New Jersey) at 30 g every week. Her induction therapy, per a regimen described previously [8], consisted of cytosine arabinoside 2 g/m2 every 12 hours for six doses, cyclophosphamide 30 mg/kg every 24 hours for two doses, and 1,400 cGy total-body irradiation in nine fractions over 3 days prior to transplant; 2 g/dose intravenous methylprednisolone was given in four doses during the 2 days before transplant. She underwent transplantation with 6.4 X lo7 marrow mononuclear cells/kg that were depleted of CD3-positive marrow T cells [8]. Administration of cyclosporin A was begun on the day of transplant and continued until 45 days after transplant. The dose of cyclosporin was adjusted to maintain serum levels close to 200 ng/mL. To treat grade II acute graft-versus-host disease, methylprednisolone was initiated at 2 mglkglday on Day 28 after transplantation and tapered over 3 weeks. From the Departments of Internal Medicine (DDE. RCA) and Pathology (BCT. DRC, GAH), and the Bone Marrow Transplant Program, MedIcal College of Wisconsin, Mtlwaukee, Wlsconsln. This work was supported In part by funds from the Medical College of Wisconsin. the Koehrlng Foundation. Sandoz Research Instttute. the Cutter Corporation. Caremark Homecare, and the Freedman Memorial Fund. Requksts for reprints should be addressed to Robert C. Ash, M.D., Department of Medicine, MedIcal College of Wisconsin. 8700 West Wisconsin Avenue, Milwaukee, Wisconsin 53226. Manuscript submitted June 22, 1989, and accepted in rewsed form September 13, 1989.
HANSON,M.D., ROBERTC.ASH,
On the day after transplant, the patient developed noncardiogenic pulmonary edema, which resolved with diuretics and fluid management. However, patchy infiltrates remained on chest radiograph, and bronchoscopy with bronchoalveolar lavage (BAL) was performed on the third day after transplant. No pathogens were found. The pulmonary infiltrates persisted throughout the posttransplant course. By 4 weeks after transplantation, the patient had trilineage myeloid engraftment and was progressing well hematologically (Figure 1). On the 46th day after transplant, the patient had significant deterioration in her cardiopulmonary status, and on Day 48 was found to have cardiac tamponade. Pericardiocentesis revealed serosanguinous fluid with negative Gram stain, cytology, and bacterial cultures; viral cultures were positive for echovirus type 11 (ECHO 11). On Day 49 a new pulmonary infiltrate was observed. BAL was again performed; lavage fluid cultured ECHO 11. The patient’s respiratory status deteriorated and mechanical ventilatory support was begun. An open lung biopsy was performed from which cultures were also positive for ECHO 11 (Figure 1). CMV was isolated from sputum samples on the 62nd and 67th days following bone marrow transplant. Although it was believed that CMV was probably not the primary pathogen responsible for this patient’s disease, ganciclovir (DHPG, Syntex Laboratories, Inc., Palo Alto, California) therapy was begun. In an effort to treat the patient’s echovirus infection, intravenous immunoglobulin was increased to 30 mg twice weekly and a-interferon was begun at 3 x lo6 units subcutaneously three times per week, beginning on Day 46. After an approximately lo-day trial of interferon with no apparent response, ribavirin (Virazole@,Viratek, Inc., Costa Mesa, California) was begun according to a Food and Drug Administrationand Institutional Review Board-approved compassionateuse protocol, and administered at 40 mglkg on Day 57 after transplant and 25 mglkg on Days 58 to 67 after transplant. Despite this treatment, the patient required pericardial stripping to relieve constrictive pericarditis and developed adult respiratory distress syndrome. She died 68 days after bone marrow transplant of progressive respiratory failure. Pathologic Findings Postmortem examination revealed a large heart weighing 720 g. The pericardium and epicardium showed a fibrinous pericarditis grossly and microscopically. There was a microscopic focus of myocardial fibrosis, but no evidence of acute infarction, hemorrhage, or viral inclusions. The pleural surfaces showed fibrinous pleuritis without pleural effusion. The right lung weighed 1,000 g and the left lung 950 g. Both lungs were firm and yellow-gray with focal hemorrhagic lesions. Microscopically, there were findings of organizing alveolar April
1990
The American
Journal
of Medicine
Volume
88
421
ECHOVIRUS
INFECTION
IN MARROW
TRANSPLANTATION
/ BIGGS ET AL
5
02
Biopsy ‘003
04
8 1007
0’
6
06 09
Throat Naso@-wwx Sputum Urine Saliva Stool -
W;te;eil
4
‘Ooo
per mm3
BMT
5ooc
3ooc
Days after transplant Symbols:
m
Pretransplant conditioning
q
I.V.
Ribaviron
and interstitial pneumonitis and extensive intra-alveolar hemorrhage. The abdomen contained 2,000 mL of yellow, strawcolored fluid. The enlarged liver weighed 2,200 g, and was firm and homogeneously yellow-brown in appearance. Histologic findings included veno-occlusive disease, hemosiderosis, and centrilobular hepatocellular necrosis. No viral inclusions or areas of hemorrhage were noted. Congestive splenomegaly without focal lesions and acute tubular necrosis of the kidney were other significant findings. The brain showed small foci of subdural and subarachnoid hemorrhages as well as subependymal hemorrhage in the lateral ventricles and occipital lobe hemorrhage at the calcarine fissure. No histopathologic stigmata specific for ECHO 11 were seen in any tissue, although the virus was isolated from samples of brain, cerebrospinal fluid, spleen, and heart. CMV was cultured from the lung, and typical cytomegalic cells with prominent nuclear inclusions were found in a single small focus in one section of lung tissue. Virus Isolation and Identification The presence of CMV in patient specimens was detected using a shell vial procedure with a monoclonal antibody specific for a viral immediate-early antigen [9]. This allowed CMV detection even in the presence of high levels of echovirus. For virus isolation, patient specimens were inoculated onto monolayers of diploid human fibroblasts (MRC-5) and primary rhesus monkey kidney cells, which were observed for the appearance of viral cytopathic effects (CPE). This combination of cell cultures has been established to be permissive for a broad range of viral pathogens [lo]. Medium from CPE-positive cultures was passaged onto MRC-5 monolayers in culture flasks for the preparation of viral stock materials, which were aliquoted and frozen at -7O’C. Two such stocks were prepared. One was derived from a sputum specimen taken on the ninth day after bone marrow transplantation while the 422
April
1990
The American
Journal
of Medicine
Volume
88
Figure 1. Summary of patient’s clinical course, white blood cell counts, viral isolations, and antiviral treatments. Positive isolation of echovirus is denoted by plus signs, whereas virus-negative samples are shown by minus signs. Samples from which CMV was isolated are designated. Biopsy specimens are as follows: (1) BAL; (2) esophagus; (3) duodenum; (4) rectum; (5) pleural fluid; (6) thoracic cavity; (7) lung; (8) pericardium; (9) pericardial fluid. BMT = bone marrow transplantation; I.V. = intravenous.
other was prepared from a pleural fluid sample obtained on the 51st day. The original identification of the isolated virus as ECHO 11 by neutralization with reference antibodies was performed by Dr. Gerald Sedmak of the Virology Laboratory of the Milwaukee City Health Department. National Institutes of Health research reference reagent ECHO 11 (Gregory strain-NIAID VO44-OOl047) was obtained from the American Type Culture Collection (ATCC). This material was passaged once in MRC-5 cells to prepare a stock. A horse reference antiserum specific for ECHO 11 (NIAID VO44-501560) and the corresponding preimmune control serum were obtained from the ATCC. The reported neutralization titer of this reagent was 320 to 640, which agreed reasonably well with the titer observed in the studies reported here. For the determination of the echovirus 11 neutralizing titers shown in Table I, serial twofold dilutions, beginning at 1:s and going through 1:1,024, of the antibody or serum to be titered were prepared in microtiter culture plate wells using culture medium containing 2% fetal calf serum. Samples were analyzed in duplicate. To each well was added 100 TCIDso of the appropriate virus stock in a volume of 0.1 mL, and the entire plate was incubated at 37°C for 1 hour. The actual viral input was confirmed in all experiments by back-titration of the stock dilution used. The contents of each well were then transferred into a new well containing a confluent monolayer of MRC-5 cells, which was observed for 2 weeks for the appearance of viral CPE. The neutralization titer was defined as the highest viral dilution that completely neutralized the virus in both of the wells inoculated. To ensure quantitative reliability, comparisons among different antibody preparations were only made when the titrations were performed at the same time using matched MRC-5 monolayers and viral stock dilutions.
COMMENTS Echovirus is a human enterovirus similar to the po-
ECHOVIRUS
lio and coxsackie viruses. It is a recognized pathogen in neonates [ll-131 and patients with X-linked agammaglobulinemia [14,15]. To our knowledge, this is the first reported case of echovirus complicating bone marrow transplantation. In this patient, an initial isolate of ECHO 11 was recovered in the stool during pretransplant conditioning. This most likely represented a primary infection since a stored serum sample taken 3 weeks before transplant showed no significant antibodies (titers less than 1:8) to ECHO 11. The initiation of pretransplant chemoradiotherapy during this primary infection presumably caused sufficient incremental immunosuppression to allow widespread dissemination of the virus in this patient. The course of the viral infection was unrelenting. Each new site from which ECHO 11 was isolated remained positive for the virus throughout the remainder of the patient’s hospital course. This suggests that no significant host immune response was mounted, despite good marrow engraftment. Several factors may have contributed to this continuing immunosuppression. Bone marrow transplants from HLA-mismatched marrow, such as the one this patient received, have been reported to have a high incidence of infectious complications [16,17]. The cyclosporin A and methylprednisolone administered to this patient also certainly inhibited the immune response. Pooled human immunoglobulin was given to this patient throughout her transplant course. Antibody preparations with neutralizing titers of 1:32 have been reported to successfully treat echovirus infections in newborns and patients with X-linked agammaglobulinemia 1181.Interestingly, by the 60th day after transplantation this patient’s serum had a neutralizing titer of 1:32 when measured against standard ECHO 11. However, when the same serum sample was tested against a culture of the virus retrieved from this patient, the titer was barely detectable at a value of 1:8. Likewise, the preparation of pooled immunoglobulin used in the patient was shown to have a lower neutralizing titer against the patient’s virus as compared to neutralizing titers obtained versus standard ECHO 11 (Table I). Similar differences of neutralizing titers were seen with two other commonly used immunoglobulin preparations when tested against patient echovirus as compared with standard echovirus. Therefore, the ECHO 11 infecting the patient was either an unusual, nonprime virus or had undergone one or more mutations during the course of the infection, which altered the antigenicity of the epitopes involved in viral neutralization by antibodies. The continuous passive administration of IgG to the patient throughout her course may have provided the immunologic pressure for such mutations. Neither of the antiviral agents (a-interferon and ribavirin) used to treat this patient’s echovirus infection had any measurable effect. Interferon has been described to inhibit enterovirus growth in vitro [19], but no reports exist on its use in a clinical setting against enteroviruses. Ribavirin has been used clinically against respiratory syncytial virus and adenovirus [20], but has likewise not been reported to be successful clinically against echovirus. Literature reports concerning the pathology of echovirus infections in other settings are compared with the findings observed in this patient in Table II. Several aspects of the pathology in this case deserve
INFECTION
IN MARROW
3
TRANSPLANTATION
/ BIGGS ET AL
Titers of Neutralizing Antibody Preparations against Standard Echovwus-11 and Patient Viral Isolate
Sauce of Antibody
Neutralization Standard Echovirus 11
Reference antiserum Patlent serum7 Patient serum* Sandoglobulin IgG§
256
DONALD R.CARRIGAN,P~.D.,GERALDA.
pportunistic viral infections occur frequently in bone marrow transplant recipients and are a ma0 jor cause of morbidity and mortality. Cytomegalovirus (CMV), herpes simplex, varicella zoster, Epstein-Barr, and adenovirus infections have been well described in this patient setting [l-3]. Other viral pathogens in marrow transplant patients include respiratory syncytial virus [4], influenza and parainfluenza [5], papovavirus [6], and Coxsackie A [7]. In this report, we describe the clinical and pathologic findings in a fatal case of disseminated echovirus infection, which is, to our knowledge, the first documentation of serious echovirus infection complicating marrow transplantation.
CASE REPORT A 38-year-old woman with a malignant lymphoma, small-cell cleaved type, was admitted for an allogeneic bone marrow transplant for persistent pancytopenia of 4 months’ duration following chemotherapy. Her total leukocyte count on admission was less than 0.6 X log/L. The patient underwent transplantation with marrow from a sibling donor mismatched for a single HLA-B locus antigen (Patient HLA type: A1,2; B8(w6)-; Cw2,7; DR1,3(w52); DQwl,w2. Donor HLA type: A1,2; B8(w6),27(w4); Cw2,7; DR 1,3(w52); DQwl,w2). Ten days before transplantation, the patient began to receive prophylactic oral acyclovir, ketoconazole, and trimethoprim-sulfa. She received intravenous immunoglobulin (Sandoglobulin@, Sandoz Pharmaceuticals, East Hanover, New Jersey) at 30 g every week. Her induction therapy, per a regimen described previously [8], consisted of cytosine arabinoside 2 g/m2 every 12 hours for six doses, cyclophosphamide 30 mg/kg every 24 hours for two doses, and 1,400 cGy total-body irradiation in nine fractions over 3 days prior to transplant; 2 g/dose intravenous methylprednisolone was given in four doses during the 2 days before transplant. She underwent transplantation with 6.4 X lo7 marrow mononuclear cells/kg that were depleted of CD3-positive marrow T cells [8]. Administration of cyclosporin A was begun on the day of transplant and continued until 45 days after transplant. The dose of cyclosporin was adjusted to maintain serum levels close to 200 ng/mL. To treat grade II acute graft-versus-host disease, methylprednisolone was initiated at 2 mglkglday on Day 28 after transplantation and tapered over 3 weeks. From the Departments of Internal Medicine (DDE. RCA) and Pathology (BCT. DRC, GAH), and the Bone Marrow Transplant Program, MedIcal College of Wisconsin, Mtlwaukee, Wlsconsln. This work was supported In part by funds from the Medical College of Wisconsin. the Koehrlng Foundation. Sandoz Research Instttute. the Cutter Corporation. Caremark Homecare, and the Freedman Memorial Fund. Requksts for reprints should be addressed to Robert C. Ash, M.D., Department of Medicine, MedIcal College of Wisconsin. 8700 West Wisconsin Avenue, Milwaukee, Wisconsin 53226. Manuscript submitted June 22, 1989, and accepted in rewsed form September 13, 1989.
HANSON,M.D., ROBERTC.ASH,
On the day after transplant, the patient developed noncardiogenic pulmonary edema, which resolved with diuretics and fluid management. However, patchy infiltrates remained on chest radiograph, and bronchoscopy with bronchoalveolar lavage (BAL) was performed on the third day after transplant. No pathogens were found. The pulmonary infiltrates persisted throughout the posttransplant course. By 4 weeks after transplantation, the patient had trilineage myeloid engraftment and was progressing well hematologically (Figure 1). On the 46th day after transplant, the patient had significant deterioration in her cardiopulmonary status, and on Day 48 was found to have cardiac tamponade. Pericardiocentesis revealed serosanguinous fluid with negative Gram stain, cytology, and bacterial cultures; viral cultures were positive for echovirus type 11 (ECHO 11). On Day 49 a new pulmonary infiltrate was observed. BAL was again performed; lavage fluid cultured ECHO 11. The patient’s respiratory status deteriorated and mechanical ventilatory support was begun. An open lung biopsy was performed from which cultures were also positive for ECHO 11 (Figure 1). CMV was isolated from sputum samples on the 62nd and 67th days following bone marrow transplant. Although it was believed that CMV was probably not the primary pathogen responsible for this patient’s disease, ganciclovir (DHPG, Syntex Laboratories, Inc., Palo Alto, California) therapy was begun. In an effort to treat the patient’s echovirus infection, intravenous immunoglobulin was increased to 30 mg twice weekly and a-interferon was begun at 3 x lo6 units subcutaneously three times per week, beginning on Day 46. After an approximately lo-day trial of interferon with no apparent response, ribavirin (Virazole@,Viratek, Inc., Costa Mesa, California) was begun according to a Food and Drug Administrationand Institutional Review Board-approved compassionateuse protocol, and administered at 40 mglkg on Day 57 after transplant and 25 mglkg on Days 58 to 67 after transplant. Despite this treatment, the patient required pericardial stripping to relieve constrictive pericarditis and developed adult respiratory distress syndrome. She died 68 days after bone marrow transplant of progressive respiratory failure. Pathologic Findings Postmortem examination revealed a large heart weighing 720 g. The pericardium and epicardium showed a fibrinous pericarditis grossly and microscopically. There was a microscopic focus of myocardial fibrosis, but no evidence of acute infarction, hemorrhage, or viral inclusions. The pleural surfaces showed fibrinous pleuritis without pleural effusion. The right lung weighed 1,000 g and the left lung 950 g. Both lungs were firm and yellow-gray with focal hemorrhagic lesions. Microscopically, there were findings of organizing alveolar April
1990
The American
Journal
of Medicine
Volume
88
421
ECHOVIRUS
INFECTION
IN MARROW
TRANSPLANTATION
/ BIGGS ET AL
5
02
Biopsy ‘003
04
8 1007
0’
6
06 09
Throat Naso@-wwx Sputum Urine Saliva Stool -
W;te;eil
4
‘Ooo
per mm3
BMT
5ooc
3ooc
Days after transplant Symbols:
m
Pretransplant conditioning
q
I.V.
Ribaviron
and interstitial pneumonitis and extensive intra-alveolar hemorrhage. The abdomen contained 2,000 mL of yellow, strawcolored fluid. The enlarged liver weighed 2,200 g, and was firm and homogeneously yellow-brown in appearance. Histologic findings included veno-occlusive disease, hemosiderosis, and centrilobular hepatocellular necrosis. No viral inclusions or areas of hemorrhage were noted. Congestive splenomegaly without focal lesions and acute tubular necrosis of the kidney were other significant findings. The brain showed small foci of subdural and subarachnoid hemorrhages as well as subependymal hemorrhage in the lateral ventricles and occipital lobe hemorrhage at the calcarine fissure. No histopathologic stigmata specific for ECHO 11 were seen in any tissue, although the virus was isolated from samples of brain, cerebrospinal fluid, spleen, and heart. CMV was cultured from the lung, and typical cytomegalic cells with prominent nuclear inclusions were found in a single small focus in one section of lung tissue. Virus Isolation and Identification The presence of CMV in patient specimens was detected using a shell vial procedure with a monoclonal antibody specific for a viral immediate-early antigen [9]. This allowed CMV detection even in the presence of high levels of echovirus. For virus isolation, patient specimens were inoculated onto monolayers of diploid human fibroblasts (MRC-5) and primary rhesus monkey kidney cells, which were observed for the appearance of viral cytopathic effects (CPE). This combination of cell cultures has been established to be permissive for a broad range of viral pathogens [lo]. Medium from CPE-positive cultures was passaged onto MRC-5 monolayers in culture flasks for the preparation of viral stock materials, which were aliquoted and frozen at -7O’C. Two such stocks were prepared. One was derived from a sputum specimen taken on the ninth day after bone marrow transplantation while the 422
April
1990
The American
Journal
of Medicine
Volume
88
Figure 1. Summary of patient’s clinical course, white blood cell counts, viral isolations, and antiviral treatments. Positive isolation of echovirus is denoted by plus signs, whereas virus-negative samples are shown by minus signs. Samples from which CMV was isolated are designated. Biopsy specimens are as follows: (1) BAL; (2) esophagus; (3) duodenum; (4) rectum; (5) pleural fluid; (6) thoracic cavity; (7) lung; (8) pericardium; (9) pericardial fluid. BMT = bone marrow transplantation; I.V. = intravenous.
other was prepared from a pleural fluid sample obtained on the 51st day. The original identification of the isolated virus as ECHO 11 by neutralization with reference antibodies was performed by Dr. Gerald Sedmak of the Virology Laboratory of the Milwaukee City Health Department. National Institutes of Health research reference reagent ECHO 11 (Gregory strain-NIAID VO44-OOl047) was obtained from the American Type Culture Collection (ATCC). This material was passaged once in MRC-5 cells to prepare a stock. A horse reference antiserum specific for ECHO 11 (NIAID VO44-501560) and the corresponding preimmune control serum were obtained from the ATCC. The reported neutralization titer of this reagent was 320 to 640, which agreed reasonably well with the titer observed in the studies reported here. For the determination of the echovirus 11 neutralizing titers shown in Table I, serial twofold dilutions, beginning at 1:s and going through 1:1,024, of the antibody or serum to be titered were prepared in microtiter culture plate wells using culture medium containing 2% fetal calf serum. Samples were analyzed in duplicate. To each well was added 100 TCIDso of the appropriate virus stock in a volume of 0.1 mL, and the entire plate was incubated at 37°C for 1 hour. The actual viral input was confirmed in all experiments by back-titration of the stock dilution used. The contents of each well were then transferred into a new well containing a confluent monolayer of MRC-5 cells, which was observed for 2 weeks for the appearance of viral CPE. The neutralization titer was defined as the highest viral dilution that completely neutralized the virus in both of the wells inoculated. To ensure quantitative reliability, comparisons among different antibody preparations were only made when the titrations were performed at the same time using matched MRC-5 monolayers and viral stock dilutions.
COMMENTS Echovirus is a human enterovirus similar to the po-
ECHOVIRUS
lio and coxsackie viruses. It is a recognized pathogen in neonates [ll-131 and patients with X-linked agammaglobulinemia [14,15]. To our knowledge, this is the first reported case of echovirus complicating bone marrow transplantation. In this patient, an initial isolate of ECHO 11 was recovered in the stool during pretransplant conditioning. This most likely represented a primary infection since a stored serum sample taken 3 weeks before transplant showed no significant antibodies (titers less than 1:8) to ECHO 11. The initiation of pretransplant chemoradiotherapy during this primary infection presumably caused sufficient incremental immunosuppression to allow widespread dissemination of the virus in this patient. The course of the viral infection was unrelenting. Each new site from which ECHO 11 was isolated remained positive for the virus throughout the remainder of the patient’s hospital course. This suggests that no significant host immune response was mounted, despite good marrow engraftment. Several factors may have contributed to this continuing immunosuppression. Bone marrow transplants from HLA-mismatched marrow, such as the one this patient received, have been reported to have a high incidence of infectious complications [16,17]. The cyclosporin A and methylprednisolone administered to this patient also certainly inhibited the immune response. Pooled human immunoglobulin was given to this patient throughout her transplant course. Antibody preparations with neutralizing titers of 1:32 have been reported to successfully treat echovirus infections in newborns and patients with X-linked agammaglobulinemia 1181.Interestingly, by the 60th day after transplantation this patient’s serum had a neutralizing titer of 1:32 when measured against standard ECHO 11. However, when the same serum sample was tested against a culture of the virus retrieved from this patient, the titer was barely detectable at a value of 1:8. Likewise, the preparation of pooled immunoglobulin used in the patient was shown to have a lower neutralizing titer against the patient’s virus as compared to neutralizing titers obtained versus standard ECHO 11 (Table I). Similar differences of neutralizing titers were seen with two other commonly used immunoglobulin preparations when tested against patient echovirus as compared with standard echovirus. Therefore, the ECHO 11 infecting the patient was either an unusual, nonprime virus or had undergone one or more mutations during the course of the infection, which altered the antigenicity of the epitopes involved in viral neutralization by antibodies. The continuous passive administration of IgG to the patient throughout her course may have provided the immunologic pressure for such mutations. Neither of the antiviral agents (a-interferon and ribavirin) used to treat this patient’s echovirus infection had any measurable effect. Interferon has been described to inhibit enterovirus growth in vitro [19], but no reports exist on its use in a clinical setting against enteroviruses. Ribavirin has been used clinically against respiratory syncytial virus and adenovirus [20], but has likewise not been reported to be successful clinically against echovirus. Literature reports concerning the pathology of echovirus infections in other settings are compared with the findings observed in this patient in Table II. Several aspects of the pathology in this case deserve
INFECTION
IN MARROW
3
TRANSPLANTATION
/ BIGGS ET AL
Titers of Neutralizing Antibody Preparations against Standard Echovwus-11 and Patient Viral Isolate
Sauce of Antibody
Neutralization Standard Echovirus 11
Reference antiserum Patlent serum7 Patient serum* Sandoglobulin IgG§
256
