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Journal of Perinatology (2012) 32, 235–237 r 2012 Nature America, Inc. All rights reserved. 0743-8346/12 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Transplacental of to an HIV-exposed premature neonate

M Patel1, KP Beckerman1,2, S Reznik3, RP Madan1,5 and DL Goldman1,4,5 1Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA; 2Department of Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY, USA; 3Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA and 4Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA

and we were able to document the presence of C. neoformans during pregnancy is well documented, but transmission antigen in the neonatal serum. of to the fetus is rare. We describe a premature neonate born to a mother with congenitally acquired human immunodeficiency (HIV) and active cryptococcosis. Histological examination of the placenta Case revealed Cryptococcus neoformans within the maternal intervillous space Patient PD was a 1080 g male delivered at 28 weeks estimated with focal invasion into the chorionic villi. A positive serum cryptococcal gestational age by cesarean section. His mother, AD, was a 19-year- antigen (1:2) was detected on days 1 and 5 of life. The neonate had no old primigravid woman with perinatally acquired HIV-1 infection evidence of central nervous system disease and was treated with fluconazole and a history of non-adherence to medical therapy. She presented with resolution of antigenemia. This case highlights both the potential to our hospital at 25 weeks gestation with a 1-week history of fever, for transplacental transmission of C. neoformans infection and the cough and shortness of breath, and was admitted with a complexities of caring for pregnant mothers who themselves are presumptive diagnosis of Pneumocystis jiroveci . congenitally infected with HIV. Admission CD4 þ T-cell count and HIV viral load (VL) were Journal of Perinatology (2012) 32, 235–237; doi:10.1038/jp.2011.112 20 cells per ml and 635 copies per ml, respectively. Her initial blood Keywords: cryptococcus; neonate; pregnancy; placenta; congenital HIV culture yielded C. neoformans and her serum cryptococcal antigen titer was 1:4096. A lumbar puncture revealed a cerebrospinal fluid cryptococcal antigen titer of 1:218 and was otherwise negative. Intravenous amphotericin B therapy was initiated; 5-fluorocytosine Introduction was deferred due to maternal pancytopenia and concern for fetal Cryptococcus neoformans is an opportunistic infection that causes toxicity. AD’s pulmonary status improved, but she remained non- substantial morbidity and mortality in immunocompromised adhererent to highly active anti-retroviral therapy despite directly hosts, and can affect most organ systems. With the introduction observed in-patient anti-retroviral (ARV) treatment. HIV genotype/ of highly active anti-retroviral therapy in the 1980s, the phenotype testing confirmed susceptibility to her current ARVs. By of cryptococcosis among human immunodeficiency virus (HIV)- 28 weeks gestation, the VL increased to 72 319 copies per ml, and infected persons has dramatically decreased.1 Reports of pregnancy- she developed severe preeclampsia. Subcutaneous emfuvirtide and associated cryptococcosis in the absence of other underlying intravenous zidovudine were added to her regimen to prevent risk factors, suggest that alterations in immune function during perinatal HIV transmission. pregnancy contribute to an enhanced susceptibility to cryptococcal The infant, PD, was delivered by cesarean section and intubated disease.2 Despite the well-described occurrence of disease during in the delivery room for respiratory distress and bradycardia. His pregnancy, documented congenital cryptococcosis is rare. We report examination was consistent with an estimated gestational age of 28 a case of probable in utero transmission of C. neoformans from weeks. Complete blood count showed a total white blood cell count of 6300 cells per ml with 14% neutrophils, 2% bands, 71% a 19-year-old woman with congenital HIV to her preterm infant. À1 Placental pathology was diagnostic of C. neoformans infection, and 9% monocytes; hemoglobin of 12.6 g dl ; and a platelet count of 217 000 platelets per ml. His Correspondence: Dr DL Goldman or RP Madan, Department of Pediatrics, Albert Einstein demonstrated bilateral lung disease. He received empiric therapy College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. with ampicillin and gentamicin. E-mail: [email protected] or [email protected] 5These authors contributed equally to this article. The infant’s serum cryptococcal antigen titer was positive (1:2) Received 10 December 2010; revised 24 May 2011; accepted 11 July 2011 on the first day of life, and antifungal therapy was initiated with Neonatal cryptococcosis M Patel et al 236

Figure 1 Placental pathology. (a) Immunostaining for cryptococcal polysaccharide reveals large number of C. neoformans and extensive shed polysaccharide. (b) Higher magnification of a focally infected area shows a cluster of organisms invading a villus. (c) Factor VIII staining shows fetal capillaries within the villi. Non-staining organisms within the villi next to a capillary are seen. V refers to vessel. Arrows point to C. neoformans for all figures.

amphotericin B lipid complex. Evaluation of cerebrospinal fluid She expired from within 1 week on the second day of life revealed white blood cell count of of hospitalization. 2 cells per ml and red blood cell count of 50 cells per ml, a negative gram stain and culture, and a non-reactive cerebrospinal fluid cryptococcal antigen. Therapy was changed to fluconazole. Cryptococcal antigen testing of the bronchoalveolar fluid was Discussion negative. Repeat cryptococcal antigen titer was 1:2 at the fifth We consider this a probable case of congenital cryptococcosis that day of life, but was subsequently negative. occurred as a result of transplacental transmission. Over a dozen Owing to his mother’s VL at delivery and extensive history cases of cryptococcosis in early infancy (for example, within of ARV exposure, PD was started on triple ARV therapy with the first 3 months of life) have been reported with a mortality intravenous zidovudine, oral lamivudine and oral lopinavir/ greater than 50% (reviewed in Nakwan et al.4; Sirinavin et al.5) ritonavir on the first day of life. The infant’s HIV-1 DNA PCR (Supplementary Material Table). Disease is typically a multi- and RNA VL tests were non-detectable at 48 h of life. systemic disease, typically with involvement of the central nervous Histological examination of the placenta revealed abundant and respiratory systems. Early (for example, within hours to days of mucin-positive, round budding fungal organisms within the life)6 and late presentations of cryptococcosis (weeks to months)7 maternal intervillous space with focal invasion into the chorionic have been described in neonates. Both the forms of disease are villi (Figure 1a). Lesions were not associated with significant generally presumed to represent congenital infection based on inflammation, and granulomas were not identified. Extensive the lack of environmental exposure in the neonate and the organism-associated polysaccharide and shed polysaccharide within presence of maternal cryptococcosis. Although it is possible that the the intervillous space were demonstrated by immunohistochemical presence of low-level antigenemia in our patient represented only staining (Figures 1b and c). These studies were done as transmission of polysaccharide antigen, we chose to treat this described using a murine monoclonal antibody (18B7) that infant based on: (1) the presence of chorionic invasion, (2) the recognized the polysaccharide component of all cryptococcal high morbidity of congenital cryptococcosis (see Supplementary serotypes as described.3 Factor VIII staining confirmed the Material Table) and (3) the presence of respiratory distress in our localization of C. neoformans within the villi (Figure 1c). patient together with the nonspecific symptoms of congenital PD received HIV prophylaxis with three ARVs for 6 weeks, cryptococcosis. We note that the extremely large size of the and cryptococcosis therapy with fluconazole for 3 months. cryptococcal polysaccharide (B106 Da) makes passive transfer of He was discharged to a pediatric rehabilitation facility at 3 months this molecule very unlikely.8 of age, after a prolonged hospital stay secondary to complications The mechanisms leading to vertical transmission of of prematurity. All HIV DNA PCR tests were non-detectable. cryptococcosis are unknown, but aspiration or swallowing of HIV antibody enzyme-linked immunosorbent assay result was infected material during birth likely accounts for late forms of negative by 18 months of age. neonatal disease. This hypothesis is supported by case reports AD continued to have elevated cryptococcal titers and developed describing the isolation of C. neoformans from the genitourinary cardiomyopathy 4 months postpartum, which improved with tract of pregnant and non-pregnant women. Endocervical fluid supportive management. Although virological control remained contamination with C. neoformans has been reported in a case of suboptimal, her cryptococcal disease did not relapse. At 12 months presumed congenital cryptococcosis.9 Furthermore, C. neoformans postpartum, she was admitted for diarrhea and dehydration has been isolated from the vaginal discharge10 and endometrium11 (CD4 þ T-cell count 3 cells per ml, HIV VL 31 534 copies per ml). of that delivered infected offspring. Endometrial

Journal of Perinatology Neonatal cryptococcosis M Patel et al 237 cryptococcosis has been reported in a 34-year-old female with AIDS Acknowledgments 12 who presented with severe menorrhagia, and as a cause of tubo- We thank Xiaoxiao Li for her help with immunohistochemistry. ovarian abscess13 and vaginal infection.14 The placenta is an extremely effective barrier to fungal infection, and transplacental transmission of fungal , References though reported, is rare. Several lines of evidence suggest that 1 Mirza SA, Phelan M, Rimland D, Graviss E, Hamill R, Brandt ME et al. The changing placental transmission of C. neoformans infection, although rare, epidemiology of cryptococcosis: an update from population-based active surveillance in can occur. This includes: (1) the early presentation of 2 large metropolitan areas, 1992 to 2000. Clin Infect Dis 2003; 36: 789–794. cryptococcosis in neonates (within hours of birth)15, (2) the 2 Ely EW, Peacock Jr JE, Haponik EF, Washburn RG. Cryptococcal pneumonia association with intracranial calcifications in some cases9 and complicating pregnancy. Medicine (Baltimore) 1998; 77: 153–167. (3) histopathological evidence (including our own) of chorionic 3 Casadevall A, Cleare W, Feldmesser M, Glatman-Freedman A, Goldman DL, Kozel TR 16 et al. Characterization of a murine monoclonal antibody to Cryptococcus neoformans villi invasion. Darko et al. reviewed three cases of placental polysaccharide that is a candidate for human therapeutic studies. Antimicrob Agents cryptococcosis. In two cases, infection was limited to the Chemother 1998; 42: 1437–1446. intervillous space without extension, but in the third case extension 4 Nakwan N, Ngerncham S, Srisuparp P, Lapphra K, Chokephaibulkit K. Cryptococcus into the chorionic villi was present. None of the neonates in neoformans septicemia in an immunocompetent neonate: first case report in this series demonstrated evidence of infection. Recently, Rahimi Thailand. Southeast Asian J Trop Med Public Health 2008; 39: 697–700. 17 5 Sirinavin S, Intusoma U, Tuntirungsee S. Mother-to-child transmission of et al. described cryptococcemia that resulted in an incomplete Cryptococcus neoformans. Pediatr Infect Dis J 2004; 23: 278–279. abortion in an HIV-positive patient. Histological examination 6 Miller K, Louie A, Baltch AL, Smith RP, Davis PJ, Gordon MA. Pharmacokinetics of of the dilation and curettage specimen revealed chorionic pentoxifylline and its metabolites in healthy mice and in mice infected with villi invasion without endometrial disease. Taken together, albicans. Antimicrob Agents Chemother 1998; 42: 2405–2409. these studies highlight the importance of placental examination 7 Kaur R, Mittal N, Rawat D, Mathur MD. Cryptococcal in a neonate. Scand J in the evaluation of neonates born to mothers with active Infect Dis 2002; 34: 542–543. 8 McFadden DC, De Jesus M, Casadevall A. The physical properties of the capsular cryptococcosis. polysaccharides from Cryptococcus neoformans suggest features for capsule Our report also underscores the complexities of managing construction. J Biol Chem 2006; 281: 1868–1875. opportunistic infections in HIV-1-infected pregnant women. 9 Neuhauser EB, Tucker A. The roentgen changes produced by diffuse torulosis in the We hypothesize that the profound immunodeficiency associated newborn. Am J Roentgenol Radium Ther 1948; 59: 805–815. with AIDS in our case likely contributed to placental transfer 10 Hodgin EC, Corstvet RE, Blakewood BW. Cryptococcosis in a pup. J Am Vet Med Assoc 1987; 191: 697–698. of the organism. Although reports of pregnancy outcomes among 11 Petrites-Murphy MB, Robbins LA, Donahue JM, Smith B. Equine cryptococcal congenital HIV-1-infected women with adequate prenatal care endometritis and placentitis with neonatal cryptococcal pneumonia. J Vet Diagn Invest are limited, reported rates of HIV vertical transmission remain 1996; 8: 383–386. low (0 to 3.3%) and are comparable to those of non-congenitally 12 Gopal M, McCrosson S, Edmonds P, Klein T. Cryptococcosis of the upper genital tract. infected women. However, congenitally infected women may AIDS Patient Care STDS 2009; 23: 71–73. experience higher risks of morbidity with pregnancy.18 A recent 13 Sing Y, Ramdial PK, Ibrahim T. Cryptococcosis masquerading as a tuboovarian abscess. Int J Gynecol Pathol 2008; 27: 37–40. comparison of pregnant young women with congenitally or 14 Chen CK, Chang DY, Chang SC, Lee EF, Huang SC, Chow SN. Cryptococcal infection of horizontally acquired HIV suggested that congenitally infected the vagina. Obstet Gynecol 1993; 81: 867–869. women were less likely to achieve viral suppression during 15 Miller MJ. Fungal infections. In: Remington JS, Klein JO (eds). Infectious Diseases of the Fetus pregnancy, had lower CD4 þ T-cell counts during pregnancy, and Newborn Infant. Harcourt Brace Jovvanovich Inch: Philadelphia, 1990; 475–500. delivered babies of lower birth weight and were more likely to 16 Darko AD, Dim DC, Taylor G, Watson DC, Sun CC. Placental Cryptococcus neoformans infection without neonatal disease: case report and review of the literature. Pediatr Dev remain viremic with low CD4 þ T-cell counts at 1 month and Pathol 2009; 12: 249–252. 19 1 year postpartum. The mother described in this report 17 Rahimi K, Chetty R, Clarke B. Cryptococcemia resulting in an incomplete abortion in never achieved virological control or CD4 þ T-cell reconstitution an HIV-positive patient. Can J Infect Dis Med Microbiol 2009; 20: e97–e99. and died 12 months postpartum. 18 Centers for Disease Control and Prevention (CDC). Pregnancy in perinatally HIV- infected adolescents and young adults–Puerto Rico, 2002. MMWR Morb Mortal Wkly Rep 2003; 52: 149–151. 19 Phillips U, Dobroszycki J, Katz M, Sansary J, Wiznia A, Abadi J. Poor virologic control in Conflict of interest pregnant adolescents with perinatally acquired HIV infection compared to horizontally infected pregnant women. 15th Conference on and Opportunistic The authors declare no conflict of interest. Infections; Boston, MA 2008.

Supplementary Information accompanies the paper on the Journal of Perinatology website (http://www.nature.com/jp)

Journal of Perinatology