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Service de Virologie, Centre National de Référence des Enterovirus–Parechovirus, Clermont-Ferrand, FranceUniversité d’Auvergne, EA4843 « Epidémiologie et Pathogénie des Infections à Entérovirus », Faculté de Médecine, Clermont-Ferrand, France
Laboratoire de Parasitologie-Mycologie, Centre de Biologie, CHU Gabriel Montpied, 58, rue Montalembert, F-63003 Clermont-Ferrand, FranceClermont Université, Université Blaise Pascal-Université d'Auvergne-CNRS, UMR 6023 Laboratoire Microorganismes: Génome et Environnement, Clermont-Ferrand, France
Laboratoire de Parasitologie-Mycologie, Centre de Biologie, CHU Gabriel Montpied, 58, rue Montalembert, F-63003 Clermont-Ferrand, FranceClermont Université, Université Blaise Pascal-Université d'Auvergne-CNRS, UMR 6023 Laboratoire Microorganismes: Génome et Environnement, Clermont-Ferrand, France
Human herpes virus type 6 (HHV-6) reactivation could promote the reactivation of Toxoplasma gondii.
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The T. gondii-seropositive patient is at high-risk of reactivation after cord blood transplantation.
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Cord blood transplantation is an important risk factor for opportunistic diseases.
Summary
Background
The case of a central nervous system human herpes virus type 6 (HHV-6) and Toxoplasma gondii co-infection after an umbilical cord blood transplantation in a chronic myelomonocytic leukaemia patient is reported.
Case report
A 65-year-old Caucasian man underwent an umbilical cord blood transplantation within the context of chronic myelomonocytic leukaemia. On day 37 post-graft, he presented with a severe headache; PCRs of cerebrospinal fluid and blood were positive for T. gondii and HHV-6. The patient was treated with pyrimethamine and sulfadiazine associated with ganciclovir.
Conclusion
HHV-6 reactivation can trigger a reactivation of T. gondii. This case suggests that patients who are seropositive for T. gondii and who present with HHV-6 reactivation should be monitored closely for toxoplasmosis.
Reactivation of latent infections are life-threatening diseases in immunocompromised patients. We describe a cerebral toxoplasmosis in a context of human herpes virus type 6 reactivation after an umbilical cord blood transplantation.
2. Case report
A 65-year-old man was hospitalized in the haematology clinic for an umbilical cord blood transplantation within the context of chronic myelomonocytic leukaemia diagnosed in September 2013. The patient underwent 11 courses of azacitidine treatment before transplantation. The patient's medical history revealed him to be seropositive for hepatitis A virus, Epstein–Barr virus, and Toxoplasma gondii.
Immunosuppressive therapy was started on September 15, 2014 with ciclosporin 300 mg daily and mycophenolate mofetil 1 g twice a day. On September 18, 2014 he received two umbilical cord blood transplants, with good tolerance, and remained in aplasia for 27 days. The patient was continued on antimicrobial prophylaxis with fluconazole and aciclovir during aplasia. On day 4 post-graft, the anti-T. gondii IgG value was 91 IU/ml (positive value ≥8 IU/ml; BioMérieux Vidas Toxo IgG) and anti-T. gondii IgM was negative (BioMérieux Vidas Toxo IgM). On day 11 post-graft, a febrile episode associated with an inflammatory reaction (C-reactive protein 129 mg/l; normal value <3 mg/l) was treated successfully with piperacillin. Antibiotic therapy was stopped on day 28 after the recovery of blood marrow suppression. Corticosteroids consisting of prednisone 1 mg/kg daily were started on day 20 after a skin rash appeared on the patient's back and chest, covering more than 50% of his body. Mycophenolate mofetil was stopped on day 35 post-graft and ciclosporin was continued at 210 mg twice a day.
On day 37 post-graft, the patient presented a severe headache and moderate fever. Blood count analysis revealed a leukocyte count of 2.26 × 109 cells/l, with lymphocytes of 0.45 × 109 cells/l. A computed tomography (CT) scan of the brain was performed, but did not highlight any bleeding or infectious lesions. Cerebrospinal fluid (CSF) sampled on day 40 showed an increase in proteins (2.69 g/l; normal range 0.15–0.45 g/l) and lactate (4.9 mmol/l; normal range 0.6–2.2 mmol/l), and 98 × 106 red blood cells/l and 21 × 106 leukocytes/l, with a predominance of monocytes (68%) and lymphocytes (20%). May–Grünwald–Giemsa staining of the CSF highlighted tachyzoites of T. gondii (Figure 1). The T. gondii load measured using quantitative PCR was 1800 parasites/ml in CSF and 960 parasites/ml in blood. Viral investigation of the CSF yielded a positive PCR for human herpes virus type 6 (BioMérieux CMV, HHV-6, 7, 8, R-gene Assay) with a cycle threshold value of 37.6, indicating a low viral load. HHV-6 genome quantification in blood was positive below 1000 copies/ml. The anti-Toxoplasma IgG value was 43 IU/ml. Treatment for cerebral toxoplasmosis comprising pyrimethamine (50 mg daily) and sulfadiazine (500 mg three times daily) was started on day 41, for 6 weeks, associated with antiviral treatment (ganciclovir, 10 mg/kg daily). The patient's clinical condition improved rapidly, with a regression of the headache; he became apyretic on day 45. The anti-Toxoplasma IgG value was 45 IU/ml.
Figure 1Tachyzoites of Toxoplasma gondii inside neutrophils in May-Grünwald-Giemsa-stained CSF samples (x1000).
CSF sampled on day 49 still displayed pleocytosis, with 32 × 106 lymphocytes/l. Toxoplasma real-time PCR was positive (39 parasites/ml), whereas HHV-6 PCR was negative. Magnetic resonance imaging performed on the same day did not show any cerebral abscess indicative of toxoplasmosis, but showed images suggestive of graft-versus-host disease (GVHD). Real-time PCR performed on the blood was positive for HHV-6 (1726 copies/ml) but negative for T. gondii. Complete negativity of the HHV-6 quantitative PCR occurred on day 74. The patient was discharged from hospital on day 64, but was readmitted 10 days later for diarrhoea associated with acute renal insufficiency inducing metabolic acidosis and hyperkalaemia. A colonic biopsy showed grade 3 GVHD and methylprednisolone was increased to 2 mg/kg daily. On day 78, the patient became confused with meningeal syndrome and was transferred to the intensive care unit. Blood cultures were positive for Escherichia coli. CSF analysis showed poor cellularity (2 × 106 red blood cells/l and 4 × 106 leukocytes/l) associated with an increase in lactate (7.2 mmol/l) and proteins (0.96 g/l). Real-time PCR for T. gondii and HHV-6 performed on both CSF and blood were negative. Empirical antibiotic therapy was started with piperacillin–tazobactam and gentamicin. The patient died on day 82 of multiorgan failure.
3. Discussion
Umbilical cord blood transplantation (CBT) is an alternative source of haematopoietic stem cells and is used in both paediatric and adult cancer patients. The complete immaturity of the immune system at birth has the advantages of inducing fewer immunological complications and not requiring a perfect match between the donor and recipient.
Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are especially susceptible to severe toxoplasmosis, with an estimated incidence of between 0.4% and 8.7% according to the endemicity.
In HSCT patients, toxoplasmosis mainly results from the reactivation of a latent infection rather than primary infection. CBT is associated with an additional delay in immune reconstitution, which is an important risk factor for toxoplasmosis and other opportunistic diseases. The rate of severe toxoplasmosis has been reported to be significantly higher in CBT patients than in those undergoing other types of allogeneic HSCT.
In most cases, reactivation occurs during the second or third month post-HSCT. To monitor the reactivation of toxoplasmosis, a weekly PCR follow-up in blood is recommended, particularly during the high-risk periods and for patients who are not receiving prophylaxis.
Indeed, the administration of primary chemoprophylaxis should be considered in high-risk HSCT recipients and should be maintained for 6 months post-HSCT.
PCR is the most powerful tool for the diagnosis of cerebral toxoplasmosis, as direct staining is rarely positive and serology can give false results in the immunosuppressed patient.
HHV-6 encephalitis appears to occur more frequently in patients undergoing CBT.
Some studies have suggested that the increased prevalence of HHV-6 reactivation may be due to the large number of immature T-cells present in umbilical cord blood. HHV-6 represents an important emerging pathogen responsible for central nervous system (CNS) complications accompanying HSCT.
The diagnosis of HHV-6 meningoencephalitis includes neurological manifestations and positive detection of HHV-6 DNA in the CSF, in the absence of any other identifiable pathogen.
Initially developed to target human cytomegalovirus infection, ganciclovir has been shown to be effective against HHV-6 in both in vitro and in vivo studies. Thus, the American Society of Transplantation recommends the use of ganciclovir and foscarnet as first-line therapy for HHV-6 encephalitis.
The concomitant detection of DNA for both T. gondii and HHV-6 in the CSF has only been reported once, in a retrospective analysis of 181 CSF samples from patients with suspected viral meningitis.
Simultaneous detection of viruses and Toxoplasma gondii in cerebrospinal fluid specimens by multiplex polymerase chain reaction-based reverse hybridization assay.
This co-infection was observed in an HIV-infected patient, but no detailed description of the neurological signs was mentioned in that report. A case of unilateral panuveitis associated with HHV-6 and T. gondii co-infection has also been described.
Clinical symptoms were suggestive of ocular toxoplasmosis and the evolution was favourable after anti-Toxoplasma and antiviral combination treatment. The pathogenicity of HHV-6 is not well understood, but it could participate in the reactivation of T. gondii.
The primary risk factor for toxoplasmosis in the patient presented here was CBT without anti-Toxoplasma prophylaxis. However, although transient, the concomitant reactivation of HHV-6 could have played a role in the occurrence of the toxoplasmosis. Both HHV-6 and T. gondii show neurotropism and a latency stage in the CNS, and HHV-6 is also known to replicate in CD4+ cells and deplete T-cells, which may favour intracellular opportunistic pathogens such as Toxoplasma.
Acute MCMV infection in mice was associated with a striking decrease in lung CD4+ cells and an increased rate of pulmonary toxoplasmosis.
In conclusion, the first case of a CNS T. gondii and HHV-6 co-infection in a CBT recipient is reported herein. This case suggests that patients who are seropositive for Toxoplasma and who present with HHV-6 reactivation should to be monitored closely for toxoplasmosis. Data on HHV-6 and Toxoplasma co-infection are scarce and further clinical studies are required to clarify the link between HHV-6 and Toxoplasma reactivations.
Conflict of interest: None.
References
Hakko E.
Ozkan H.A.
Karaman K.
Gulbas Z.
Analysis of cerebral toxoplasmosis in a series of 170 allogeneic hematopoietic stem cell transplant patients.
Simultaneous detection of viruses and Toxoplasma gondii in cerebrospinal fluid specimens by multiplex polymerase chain reaction-based reverse hybridization assay.
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