267

Toxoplasmosis in Bone Marrow-Transplant Recipients: Report of Seven Cases and Review Francis Derouin, Agnes Devergie, Pierre Auber, Eliane Gluckman, Bernadette Beauvais, Yves J. F. Garin, and Michel Lariviere

From the Laboratoire de Parasitologie-Mycologie, Unite de Greffe de Moelle. Hiipital Saint-Louis. Paris. France

Toxoplasmic encephalitis is a frequent, life-threatening opportunistic infection in patients with AIDS, but it can also affect patients with other types of immunosuppression, particularly iatrogenic [I]. In such patients, severe toxoplasmosis usually results from reactivation of chronic infection, although some cases of transmission have been reported in recipients of heart, kidney, and liver transplants [2-4]. We have previously reported high rates of cerebral and disseminated toxoplasmosis following allogeneic bone marrow transplantation (BMT). Four cases were observed among 80 consecutive recipients; all occurred in patients previously seropositive for Toxoplasma gondii who were receiving marrow from a seronegative donor [5]. We report seven additional cases and review the relevant literature in an attempt to identify risk factors of toxoplasmosis following BMT.

Patients and Methods The seven cases of cerebral or disseminated toxoplasmosis were observed during a period in which transplantation was performed for 296 patients at our center. The BMT procedure and conditioning therapy were as previously described [6]. After BMT, patients were maintained in laminar airflow rooms for at least 30 days and received nonabsorbable antibiotics for gut decontamination, ketoconazole for prophylaxis of fungal infections, and acyclovir for the prevention of her-

Received 26 December 1991 ~ revised 28 February 1992. Reprints or correspondence: Dr. F. Derouin. Laboratoire de Parasitologie-Mycologie, Hopital Saint-Louis. I, Avenue Claude Vellefaux, 75010 Paris. France. Clinical Infectious Diseases 1992;15:267-70 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1502-0006$02.00

pesvirus infections. Prophylactic trimethoprim-sulfamethoxazole was not given during the 2 months following BMT. All blood products were irradiated (40 Gy). Diagnosis oftoxoplasmosis. Cerebral or visceral toxoplasmosis was diagnosed on the basis ofat least one of the following criteria: demonstration of tachyzoites and cysts in tissue sections; presence of typical brain lesion scans on computed tomography (CT) and isolation of Toxoplasma from blood, bone marrow, or CSF; and resolution of clinical symptoms and brain lesions on CT scan while the patient was receiving pyrimethamine-sulfadiazine therapy. Demonstration of Toxoplasma. Toxoplasma was identified in either cerebral biopsy specimens or autopsy material with use of the hematoxylin or Giemsa staining method. In two patients with clinically suspected toxoplasmosis, isolation of Toxoplasma was attempted by inoculating mice [7] or tissue cultures [8] with blood leukocytes or CSF. Serology. Specific IgG antibodies to Toxoplasma were quantified with use of an ELISA (Platelia G, Diagnostics Pasteur, Marnes, France); titers were expressed in international units per milliliter (IV /rnl.). Patients were considered seropositive if titers were ~ 10 IV /mL. IgM antibodies were quantified with use ofan immunosorbent agglutination assay (ISAGA; Bio-Merieux, Lyon, France) and an IgM-immunocapture ELISA (Platelia M, Diagnostics Pasteur). Results were expressed as positive if the ISAGA index was ~9 or the ELISA index was ~3. Otherwise results were considered to be negative. Donors and recipients underwent serological testing before BMT, and recipients were retested at periodic intervals after BMT.

Case Reports The characteristics of the patients with cerebral or disseminated toxoplasmosis are shown in table I. Infections oc-

Downloaded from http://cid.oxfordjournals.org/ at University of New South Wales on September 1, 2015

We report seven cases of cerebral or disseminated toxoplasmosis that occurred following bone marrow transplantation (BMT) and review the other 24 cases described in the literature. For all the cases, toxoplasmosis occurred within 6 months of BMT, with the highest incidence in the second and third months. Twenty-four of 26 recipients tested serologically before BMT were positive for Toxoplasma gondii, a finding that supports the view that such cases result from reactivation of latent infection. At the onset of clinical symptoms, IgG antibody titers were unchanged or decreased in 23 of 25 documented cases, and IgM antibodies were detected in two cases. Antemortem diagnosis was made in 16 cases and was based on the response to specific therapy in six cases and/or the demonstration of the parasite in body fluids or tissues in 10 cases. Autopsy was performed in 19 cases and revealed that infection was not restricted to the brain but either involved lung or heart tissue or was disseminated in 14 cases.

Derouin et al.

268

CID 1992; 15 (August)

Table 1. Toxoplasmosis in recipients of bone marrow transplants. Antibody titer (IU/mL for IgG) Case no.

Pretransplantation Donor/recipient

Age (y)/sex

CGL

37/M

0/40*

Decreased

2

CGL

28/M

0/80*

Decreased

3

CGL

36/F

0/20*

Unchanged

4

CGL

40/M

o/r.ooo'

5

CGL

44/M

6

ALL

7

ALL

Posttransplantation

Clinical symptoms Brain abscess, confusion

Onset (d)

Diagnostic indicator

60

PIS therapy, parasitemia (day 65)

NE

74

Autopsy (brain, lungs, heart)

NE

82

Autopsy (disseminated)

Decreased

Fever. meningitis, abscess

55

Toxoplasma gondii in CSF. blood. and BALF

2,000*/600*

Decreased

Fever, hemiparesis, brain abscess

55

Cerebral biopsy (day 85)

12/M

0/150*

Decreased

Hemiparesis, brain abscess

180

PIS therapy

19/F

0/200*

Decreased

Confusion, brain abscess

96

PIS therapy

Outcome and probable cause of death Died on day 117; pneumonitis + cerebral toxoplasmosis; no autopsy Died on day 74; CMV pneumonitis + toxoplasmosis Died on day 105; renal insufficiency + toxoplasmosis Died on day 290; pneumonitis + cerebral toxoplasmosis (relapse); no autopsy Died on day 87; sepsis + cerebral toxoplasmosis; no autopsy Died on day 214; pneumonitis; no autopsy Died on day 269; CMV pneumonitis; no autopsy

NOTE. For autopsy studies, the main localizations of Toxoplasma are specified in parentheses. CGL = chronic granulocytic leukemia; PIS = pyrimethamine/sulfadiazine; ALL = acute lymphoblastic leukemia; NE = not evaluable (patients had no clinical symptom suggestive oftoxoplasmosis and the diagnosis was made at autopsy); CMV cytomegalovirus; and BALF = bronchoalveolar lavage fluid. * IgM antibody titer = O. t IgM antibody titer was positive.

curred between days 55 and 180 after BMT (median, 74 days). Cerebral toxoplasmosis was suspected in five patients on the basis of neurological signs including hemiparesis (two cases), confusion (two cases), meningitis (one case), and typical abscess lesions detected on CT examination of the brain. Two patients had clinical signs not suggestive oftoxoplasmosis, and the diagnosis was not suspected before death (cases 2 and 3). The underlying disease was chronic granulocytic leukemia (CGL) in five cases and acute lymphoblastic leukemia (ALL) in two cases. Definitive evidence of infection was obtained in five cases by identification of T. gondii. In three cases, cysts and tachyzoites were found in sections of cerebral biopsy specimens (one case) or autopsy material (two cases); in two cases, autopsy revealed that the lungs and heart were also infected. Parasitemia was demonstrated by tissue culture or inocula-

tion of mice with blood at the time neurological symptoms appeared in two cases (cases I and 4); in one ofthese patients (patient 4), parasites were also demonstrated in bronchoalveolar lavage fluid and CSF. The diagnosis of cerebral toxoplasmosis was established in two cases by the resolution of clinical and radiological symptoms after administration of pyrimethamine/sulfadiazine therapy. Before BMT, serological evidence of past toxoplasmic infection was found for six patients; IgG antibody titers ranged between 20 and 1,000 IV/mL and were stable on two determinations; no specific IgM was detected. A recently acquired infection was suspected prior to BMT in one case, since the IgG titer was 1,000 IV /ml, 2 months before transplantation and increased to 1,500 IV /ml. 2 weeks before transplantation; IgM was also present. Only one donor was seropositive; the IgG titer was 2,000 IV /rnl. and no IgM was present. At

Downloaded from http://cid.oxfordjournals.org/ at University of New South Wales on September 1, 2015

Underlying disease

Toxoplasmosis and Bone Marrow Transplantation

CtD 1992~ 15 (August)

269

Table 2. Summary of data from casesof toxoplasmosis in recipients of bone marrow transplants reported in the literature.

Serology Case No. [reference]

Age/sex

Underlying disease

Recipient Donor

(pretransplan tation/postransplantation)

Onset of symptoms (d)

18/M 14/M 25/M IO/F 15/M 23/M

AA AA AA AA AA COL

Negative Negative Negative ND ND ND

Positive/decreased Positive/unchanged Positive/decreased Positive/increased Positive/nega tive NO/positive

74 123 180 9 NO

7 [18] 8 [19] 9 [20] 10 [20] II [21] 12 [22] 13 [22] 14 [5] 15 [10] 16 [l0] 17 [12] 18[14] 19 [20] 20[20] 21 [10] 22 [13] 23[17]

15/M 34/F 33/F 32/F 46/M 25/M 32/F 42/M 44/M 29/F 38/F 23/M 33/F 21/M IO/M II/M 16/F

COL COL COL COL COL COL COL AML AML AML AML AML AML AML ALL ALL ALL

ND Negative ND ND ND Negative Negative Negative Positive Positive NO Positive ND ND Negative ND Negative

Positive/unchanged Positive/increased (IgO and IgM) ND/ND ND/ND Positive/decreased Positive/unchanged Positive/unchanged Positive/IgG unchanged; IgM increased Positive/unchanged Positive/unchanged Positive/decreased Positive/decreased NO/ND NO/NO Positive/unchanged Positive/ND Negative/ND

63 44 30 148 50 33 51 50 55 42 88 75 55 67 50 38 90

24[16]

16/M

Lymphoma

Negative

Negative/negative

72

39

Brain biopsy Autopsy (brain) Brain biopsy; parasitemia Brain abscess; PIS therapy Brain biopsy Toxoplasma gondii in BALE autopsy (lungs) Autopsy (brain) Brain abscess; P/S therapy Autopsy (heart) Autopsy (brain) Autopsy (disseminated) Autospy (lung) Autopsy (brain) Brain abscess; autopsy (disseminated) Parasitemia; autopsy (heart) Parasitemia Brain abscess; autopsy (brain andheart) Autopsy (brain and heart) Autopsy (brain andheart) Autopsy (heart) Parasitemia; autopsy (disseminated) Autopsy (disseminated) Brain abscess; PIS therapy; autopsy (brain) T. gondii in CSF

NOTE. For autopsy studies, the main localizations of Toxoplasma are specified inparentheses. AA = aplastic anemia (n 5); NO not documented; PIS 8); BALF = bronchoalveolar lavage fluid; AML = acute myeloid or nonlymphoblastic leukemia (n 7); andALL = acute lymphoblastic leukemia(n "" 3). = pyrimethamine + sulfadiazine; COL = chronic granulocytic leukemia (n

the onset of clinical signs of toxoplasmosis, IgG titers decreased in six patients and remained stable in one.

Discussion and Review Toxoplasmosis has been considered a rare opportunistic infection in recipients ofallogeneic bone marrow transplants [9, 10], Twenty-four documented cases of clinical toxoplasmosis have so far been reported in the literature (table 2); the cases described herein bring the total to 31. We have reviewed all the reported cases and describe the main features of toxoplasmosis following BMT. Thirty cases were observed within 6 months ofBMT (data unavailable in one case), In one case, infection occurred 9 days after BMT; in 24 cases, it occurred between days 30 and 90-a period during which acute graft-versus-host disease and cytomegalovirus infection are also frequent [9]; and in five cases, it occurred more than 3 months after BMT. Toxoplasmosis was observed mainly in patients who were seropositive before BMT: 24 of 26 patients tested pre-BMT were positive. This finding supports the view that such cases

result from reactivation of latent infection. This higher incidence among seropositive recipients may explain the frequency of toxoplasmosis at our institution compared with that at other institutions [10, 22, 23] and may reflect the high endemicity of toxoplasmosis within the population of France. The donor's serological status was known for 20 of the seropositive recipients who developed toxoplasmosis: 16 donors were seronegative and four were seropositive. These results suggest that toxoplasmosis is not restricted to a specific group of patients but occurs more frequently in patients who are seropositive for Toxoplasma before BMT and who receive marrow from a seronegative donor. The source of infection was not determined in the two reported cases of seronegative recipients of marrow from seronegative donors. A predisposing role for the underlying disease cannot be established, although 13 of the 31 cases of visceral toxoplasmosis occurred in patients with CGL; possibly, the older ages of these patients (mean, 32.7 years) (compared with those with other underlying diseases [mean, 22 years]) may be associated with increased risk of previous infection by Toxoplasma and thereby increased risk of reactivation.

Downloaded from http://cid.oxfordjournals.org/ at University of New South Wales on September 1, 2015

1[5] 2 [5] 3 [5] 4 [II] 5 [13] 6 [15]

Diagnostic indicator

270

Derouin et al.

Acknowledgments

The authors wish to thank T. Pautet, C. Chottin, M. C. Lambert, and A. Cousin for their expert technical assistance and B. Luft and D. Young for reviewing the manuscript. References I. Ruskin J, Remington JS. Toxoplasmosis in the compromised host. Ann Intern Med 1976;84: 193-9. 2. Renoult E, Chabot F, Aymard B, et al. Generalized toxoplasmosis in two renal transplant recipients who received a kidney from the same donor [letter]. Rev Infect Dis 1991; 13:18D-1.

3. Mason Jc, Ordelheide KS, Grames GM, et at. Toxoplasmosis in two renal transplant recipients from a single donor. Transplantation 1987;44:588-91. 4. Speirs GE, Hakim M, Caine RY, et al. Relative risk ofdonor-transmitted Toxoplasma gondii infection in heart, liver and kidney transplant recipients. Clin Transpl 1988;2:257-60. 5. Derouin F, Gluckman E, Beauvais B, et at. Toxoplasma infection after human allogeneic bone marrow transplantation: clinical and serological study of 80 patients. Bone Marrow Transplant 1986;1:67-73. 6. Gluckman E, Devergie A, Lokiec F. Use ofcyclosporine for prevention ofgraft-versus-host disease after allogeneic bone marrow transplantation. Transplant Proc 1988;20:461-9. 7. Remington JS, Desmont G. Toxoplasmosis. In: Remington JS, Klein J, eds. Infectious diseases of the fetus and newborn infant. Philadelphia: WB Saunders, 1990:89-195. 8. Derouin F, Sarfati C, Beauvais B, Iliou MC, Dehen L, Lariviere M. Laboratory diagnosis of pulmonary toxoplasmosis in patients with acquired immunodeficiency syndrome. J Clin Microbiol 1989; 27: 1661-3. 9. Meyers JD. Infections in marrow transplant recipients. In: Mandel GL, Douglas RG Jr, Bennett JE, eds. Principles and practice ofinfectious disease. New York: Churchill Livingstone, 1990:2291-4. 10. Shepp DH, Hackman RC, Conley FK, Anderson JB, Meyers JD. Toxoplasma gondii reactivation identified by detection of parasitemia in tissue culture. Ann Intern Med 1985; 103:218-21. II. Emerson RG, Jardine DS, Milvenan ES, et al. Toxoplasmosis: a treatable neurologic disease in the immunologically compromised patient. Pediatrics 1981;67:653-5. 12. Lowenberg B, van Gijn J, Prins E, Polderman AM. Fatal cerebral toxoplasmosis in a bone marrow transplant recipient with leukemia. Transplantation 1983;35:30-4. 13. Hirsch R, Burke BA, Kersey JH. Toxoplasmosis in bone marrow transplant recipients. J Pediatr 1984; 105:426-8. 14. Jehn U, Fink M, Gundlach P, et al. Lethal cardiac and cerebral toxoplasmosis in a patient with acute myeloid leukemia after successful allogeneic bone marrow transplantation (letter). Transplantation 1984;38:430-3. 15. Maguire GP, Tatz J, Giosa R, Ahmed T. Diagnosis of pulmonary toxoplasmosis by bronchoalveolar lavage. NY State J Med 1986;88:2045. 16. Fisher MA, Levy J, Helfrich M, August CS, Starr SE. Luft BJ. Detection of Toxoplasma gondii in the spinal fluid ofa bone marrow transplant recipient. Pediatr Infect Dis J 1987;6:81-3. 17. Bergin M, Menser MA, Procopis PG. Roy LP, Shaw PJ, Stevens MM. Central nervous system toxoplasmosis and hemolytic uremic syndrome [letter]. N Engl J Med 1987;317: 1540-1. 18. Tang TT, Harb JM, Dunne WM Jr. et al. Cerebral toxoplasmosis in an immunocompromised host: a precise and rapid diagnosis by electron microscopy. Am J Clin PathoI1986;85: 104-10. 19. Ackerman ZVI, Or R, Maayan S. Cerebral toxoplasmosis complicating bone marrow transplantation. Isr J Med Sci 1986;22:582-6. 20. Beelen DW. Mahmoud HK, Mlynek ML, et al. Toxoplasmosis after bone marrow transplantation. Hamatol Bluttransfus 1987;30:574-8. 21. Heurkens AHM, Koelma lA, de Planque MM, Polderman AM, van der Meer JWM. Failure to diagnose fatal disseminated toxoplasmosis in a bone marrow transplant recipient: the possible significance of declining antibody titres. J Infect 1989; 18:283-8. 22. Pendry K, Tait RC, McLay A, Ho Yen D, Baird D, Burnett AK. Toxoplasmosis after BMT for CML [letter]. Bone Marrow Transplant 1990;5:65-6.

Downloaded from http://cid.oxfordjournals.org/ at University of New South Wales on September 1, 2015

Serological follow-up of recipients was of limited diagnostic value. In 23 ofthe 25 documented cases of visceral toxoplasmosis, IgG antibody titers remained unchanged or decreased at the onset of clinical symptoms, and specific IgM antibodies were detected before the onset of symptoms in two cases. The definitive proof of infection was obtained usually by the demonstration of Toxoplasma in blood or tissues. For 10 patients, an antemortem diagnosis was made on the basis of results of tissue culture or mouse inoculation or of histologic examination of smears or tissue sections. The presence of parasitemia in six cases suggests the potential value of blood cultures in the diagnosis ofacute toxoplasmosis in this setting. Toxoplasmosis was the probable cause of death in 21 cases. Autopsies, performed in 19 cases, showed that the brain was the most common localization (14 cases), but other organs (heart and/or lung) were involved in 14 cases. The excessive morbidity and mortality associated with the reactivating form of toxoplasmosis in recipients of bone marrow transplants mandate preventive measures, especially in countries such as France where toxoplasmosis is endemic. Pretransplantation serological tests of donors and recipients may help in evaluating the potential risk. When the recipient is seronegative, the risk ofsevere toxoplasmosis appears to be negligible; however, a potential for transmission exists at the time of donation if the donor has just become infected and, worse yet, is parasitemic. It would thus seem preferable to perform at least two serological tests before donation. Suspected, recently acquired infection would be an indication for delaying BMT and perhaps for treating the donor. Recipients seropositive before BMT are at a higher risk oftoxoplasmosis due to reactivation of latent infection. For these patients, preventive chemoprophylaxis during the period in which the risk of reactivation is maximal, i.e., from the second to the sixth month after BMT, could be beneficial given the frequently severe nature of toxoplasmosis in these patients.

CID 1992; 15 (August)