Disseminated Congenital Toxoplasma Infection With a Type II ... : The Pediatric Infectious Disease Journal (original) (raw)

The risk of mother-to-child transmission of toxoplasmosis increases later in the term when the pregnant mother acquires a primary infection, whereas the severity of fetal infection decreases. More than 80% of the congenital infections acquired in the third trimester are subclinical.1 Cases of congenital disseminated toxoplasmosis are unusual and are associated with atypical Toxoplasma genotypes.2 We report a case of disseminated congenital toxoplasmosis that was acquired after a third trimester maternal primary infection with a type II strain.

Case Report.

The mother was a 37-year-old woman with no particular relevant history; she had 2 previous healthy children. In the beginning of the pregnancy, her HIV serology was negative. She was nonimmune for toxoplasmosis. The monthly serologic testing for toxoplasmosis remained negative until 27 weeks' gestation. Systematic serology performed at 33 1/2 weeks' gestation detected _Toxoplasma_-specific immunoglobulin G (200 IU/mL by HS agglutination) and immunoglobulin M (12/12 index by ISAGA). Fetal ultrasounds, including the final one carried out at 31 1/2 weeks' gestation, were normal. The mother was hospitalized at 34 weeks' gestation for spontaneous preterm labor, and she gave birth to a boy by vaginal delivery. His birth weight was 2600 g (50th percentile) and his head circumference was 33.5 cm (75th percentile). The Apgar score was 1 at 1 minute. After resuscitation, he was given exogenous surfactant and was transferred to the intensive care unit.

Upon admission, he had diffuse edema, purpura, hepatosplenomegaly, ascites, and severe respiratory distress syndrome that required ventilation with 80% oxygen. His chest radiograph showed nonconfluent mottled opacities. Echocardiography revealed persistent pulmonary hypertension. He had thrombocytopenia with a platelet count of 22,000/mm3 and a leukocyte count of 26,000/mm3. Initial treatment consisted of intermittent positive ventilation with inhaled nitric oxide and antimicrobial therapy (amoxicillin, cefotaxime, and amikacin).

The respiratory distress syndrome evolved with refractory hypoxemia and hypercapnia to persistent pulmonary hypertension that responded poorly to inhaled nitric oxide. Severe disseminated intravascular coagulation with macroscopic hematuria required 2 platelet transfusions and administration of freshly frozen plasma. Oliguric renal failure was treated by volume expansion with normal saline, dopamine, and hydrocortisone. An exchange transfusion was done on day 4 due to severe icterus (total bilirubin: 477 μmol/L; conjugated: 166 μmol/L). All bacterial cultures were negative.

Congenital Toxoplasma infection was established by the detection of specific immunoglobulin M in serum (12/12 index in ISAGA) and by positive results of the real-time quantitative polymerase chain reaction (PCR) using the 529-base pair fragment3 on various specimens: serum (3800 parasites/mL), tracheal aspirates (2000 parasites/mL), urine (250 parasites/mL), and ascitic fluid (250 parasites/mL), collected on the third day of life. Head ultrasound showed diffuse echogenic areas. Ophthalmologic examination results were normal for the right eye but showed macular bleeding and edema in the left eye. Treatment with intravenous sulfamethoxazole (30 mg/kg/d) and trimethoprim (6 mg/kg/d) was begun on day 4. On day 9, quantitative PCR analysis of the serum and tracheal aspirates remained positive but were greatly reduced to <20 parasites/mL.

The infant died on day 10 because of severe refractory hypoxemia. Postmortem examination showed interstitial pneumonitis, myocarditis, focal myositis, and myelomeningoencephalitis without necrosis.

The Toxoplasma strain genotype was determined by the French National Reference Center for Toxoplasmosis, Pôle Souche (Limoges University). It was found to be a type II (BRC TgH 20059A).

Comment.

Disseminated congenital toxoplasmosis mimics severe septic shock with multi-organ failure and differs from usual forms of congenital toxoplasmosis. Including ours, a total of 9 cases have been described.2,4 Other than its rarity, the primary interest in this form of infection is to try to understand its pathogenesis for identifying fetuses that are at high risk for developing the disseminated congenital form.

The time of gestation when maternal infection is acquired is the main risk factor for the incidence and the severity of congenital infection. Congenital infections acquired after a third trimester maternal infection are subclinical in more than 80% of cases.1 In contrast, all cases of congenital disseminated toxoplasmosis occurred after a primary maternal infection of the third trimester.2,4 A relatively short period between maternal infection and birth seems necessary for this occurrence.

Among the 9 published cases of disseminated congenital toxoplasmosis, a favorable outcome was observed in 2 of the 3 cases that included prenatal treatment and in 2 of 6 cases that lacked prenatal treatment. In studies published ≥40 years ago, when prenatal treatment was not offered to pregnant women in France, systemic symptoms at birth were frequent (eg, pneumonia occurred in 8 and 41% of infants and splenomegaly in 56 and 90%).5 By contrast, in recent large studies such as SYROCOT (Systematic Review on Congenital Toxoplasmosis), extraophthalmic or intracranial lesions were considered too rare to be taken into account in the analysis.6 The decreasing frequency of systemic signs in European countries may reflect the widespread use of prenatal treatment in seroconverting pregnant women. However in the United States, although severe manifestations of toxoplasmosis are the general rule, septic shock, ARDS, and disseminated intravascular coagulation are rarely recognized as being due to congenital toxoplasmosis.

Parasite load may be another important factor that correlates with the reduced Toxoplasma gondii seroprevalence observed in many developed countries in recent decades.1 The size of the parasite inoculum in cases of primary infection may have become smaller recently, resulting in infections that are less severe and have fewer systemic signs. Conversely, a massive maternal ingestion of parasites followed by the passage of large numbers of parasites through placenta could be a risk factor for the development of disseminated toxoplasmosis. In our case, quantitative PCR showed high parasite loads, with parasite concentrations to a maximum of 3800/mL. It has been shown that Toxoplasma concentrations higher than 100/mL in amniotic fluid are associated with poor outcomes for congenital toxoplasmosis following a maternal infection acquired before 20 weeks' gestation.7

Disseminated Toxoplasma infection is a severe complication for immunocompromised subjects, particularly in patients with AIDS or after a transplantation.1 In immunocompetent adult subjects, disseminated forms of severe acquired toxoplasmosis have been recently reported. The isolated strains were highly virulent in mice and genotypic analysis showed them to be atypical.8 Previous cases of disseminated congenital toxoplasmosis were also associated with an atypical strain genotype.2 The type II strain found in our case is the one most frequently identified in congenital infections in Europe. To our knowledge, this is the first report of disseminated congenital toxoplasmosis that has been proven to be due to a type II strain. In the absence of an atypical virulent strain or an immunodeficiency, host genetic and epigenetic factors could have contributed. Polymorphisms in 2 genes implicated in juvenile retinal dystrophies have been associated with ocular disease or brain disease in children having congenital toxoplasmosis. More recently, polymorphisms at the gene that encodes a pro-inflammatory receptor on the macrophage cell surface (the purinergic P2X7 receptor) and at the gene ERAP1 of an endoplasmic protease (the endoplasmic reticulum-associated aminopeptidase, ERAAP) have been shown to influence susceptibility to congenital T. gondii infection.9

Usually, postnatal treatment for congenital toxoplasmosis consists of pyrimethamine combined with sulfadiazine.1 As these drugs are not available intravenously and the illness severity of our case made the enteral route impossible, the infant was treated with trimethoprim and sulfamethoxazole. In vitro, trimethoprim is much less active than pyrimethamine on T. gondii,10 but the clinical efficacies of trimethoprim plus sulfamethoxazole versus pyrimethamine plus sulfadiazine are similar in patients with AIDS.1 The substantial decrease in parasite load, as measured by quantitative PCR analysis of the serum and tracheal aspirates after 5 days of treatment, suggests that the cause of death was not secondary to an uncontrolled toxoplasma infection but rather to its hemodynamic and respiratory consequences.

Disseminated congenital toxoplasmosis at birth is acquired after a maternal primary infection of the third trimester. Despite rapid postnatal administration of antiparasitic treatment, the disease is life-threatening. Disseminated forms are caused not only by atypical strains; type II strains can also be involved. The roles of the maternal parasite load and of host-parasite interactions remain to be clarified.

ACKNOWLEDGMENTS

The authors acknowledge the Biologic Resource Centre for Toxoplasma, University of Limoges, for typing the strain.

REFERENCES

1. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363:1965–1976.

2. Delhaes L, Ajzenberg D, Sicot B, et al. Severe congenital toxoplasmosis due to a Toxoplasma gondii strain with an atypical genotype: case report and review. Prenat Diagn. 2010;30:902–905.

3. Homan WL, Vercammen M, De Braekeleer J, et al. Identification of a 200- to 300-fold repetitive 529 bp DNA fragment in Toxoplasma gondii, and its use for diagnostic and quantitative PCR. Int J Parasitol. 2000;30:69–75.

4. Armstrong L, Isaacs D, Evans N. Severe neonatal toxoplasmosis after third trimester maternal infection. Pediatr Infect Dis J. 2004;23:968–969.

5. Hayde M, Pollak A. Clinical picture. Neonatal signs and symptoms.In: Ambroise-Thomas P, Petersen E, eds. Congenital Toxoplasmosis. Berlin, Germany: Springer; 2000:153–164.

6. SYROCOT (Systematic Review on Congenital Toxoplasmosis) study group, Thiébaut R, Leproust S, Chêne G, Gilbert R. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data. Lancet. 2007;369:115–122.

7. Romand S, Chosson M, Franck J, et al. Usefulness of quantitative polymerase chain reaction in amniotic fluid as early prognostic marker of fetal infection with Toxoplasma gondii. Am J Obstet Gynecol. 2004;190:797–802.

8. Carme B, Bissuel F, Ajzenberg D, et al. Severe acquired toxoplasmosis in immunocompetent adult patients in French Guiana. J Clin Microbiol. 2002;40:4037–4044.

9. Lees MP, Fuller SJ, McLeod R, et al. P2X7 receptor-mediated killing of an intracellular parasite, Toxoplasma gondii, by human and murine macrophages. J Immunol. 2010;184:7040–7046.

10. Derouin F, Chastang C. In vitro effects of folate inhibitors on Toxoplasma gondii. Antimicrob Agents Chemother. 1989;33:1753–1759.

Announcement of new section: Pediatric HIV/AIDS

The Journal is pleased to announce the launching in January 2012 of a new section dedicated to pediatric HIV topics. This section will be edited by Dr George K. Siberry, Medical Officer, Pediatric, Adolescent, and Maternal AIDS (PAMA) Branch, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, Bethesda, MD. The section will solicit high-quality, high-impact original articles and brief reports of epidemiologic, clinical, translational, and implementation science studies pertaining to the prevention, treatment, and outcomes of HIV infection in infants, children, and adolescents.

The scope and focus of articles published in this section will include:

Keywords:

Toxoplasma gondii; congenital toxoplasmosis; genotype

© 2011 Lippincott Williams & Wilkins, Inc.