Vertical transmission of Babesia microti, United States.
Subject: DNA (Health aspects)
Disease transmission (Health aspects)
Infection (Health aspects)
Authors: Joseph, Julie T.
Purtill, Kerry
Wong, Susan J.
Munoz, Jose
Teal, Allen
Madison-Antenucci, Susan
Horowitz, Harold W.
Aguero-Rosenfeld, Maria E.
Moore, Julie M.
Abramowsky, Carlos
Wormser, Gary P.
Pub Date: 08/01/2012
Publication: Name: Emerging Infectious Diseases Publisher: U.S. National Center for Infectious Diseases Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 U.S. National Center for Infectious Diseases ISSN: 1080-6040
Issue: Date: August, 2012 Source Volume: 18 Source Issue: 8
Product: Product Code: 2831812 Deoxyribonucleic Acid NAICS Code: 325414 Biological Product (except Diagnostic) Manufacturing
Geographic: Geographic Scope: New York Geographic Code: 1U2NY New York
Accession Number: 299759551
Full Text: Babesiosis is an emerging infection in the United States, principally caused by Babesia microti (1). The most common route of infection is the bite of an Ixodes scapularis tick; transmission can also occur by transfusion of infected blood products, and vertical transmission in animals has been documented (2,3) and is a potential route of transmission for humans. We report a case of babesiosis in an infant for whom vertical transmission was suggested by Babesia spp. antibodies in a heel spot blood sample and confirmed by detection of Babesia DNA in placenta tissue.

The Case-Patient

A 6-week-old girl from Yorktown Heights, New York, was admitted to the hospital on September 16, 2002, with a 2-day history of fever, irritability, and decreased oral intake. The mother was asymptomatic during and after her pregnancy. The infant was delivered vaginally and full term at 3,430 g without complications. The infant's mother had visited parks in Westchester and Dutchess Counties in New York during the pregnancy but was unaware of any tick bites. The infant had no known tick exposure, and neither mother nor infant had a history of blood transfusion.

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During examination, the infant was alert but irritable and pale. Axillary temperature was initially 36.8[degrees]C but increased to 38.1[degrees]C on the same day. Her conjunctivae were icteric, she had a palpable spleen tip, and her liver was palpable 3 cm below the costal margin. Initial laboratory findings included hemoglobin 7.1 g/dL, platelet count 100 x [10.sup.3]/[micro]L, and leukocyte count 19.7 x [10.sup.3] cells/[micro]L with a differential of 4% segmented neutrophils, 80% lymphocytes, and 16% monocytes. Reticulocyte count was 5.5%. Total bilirubin concentration was 2 mg/dL with a direct fraction of 0.4 mg/dL; aspartate aminotransferase level was 66 U/L, alanine aminotransferase level was 50 U/L, and alkaline phosphatase level was 339 U/L. Cultures of blood, urine, and cerebrospinal fluid samples yielded negative results. Lyme disease serologic test result was negative.

Routine examination of a peripheral blood smear showed B. microti in 4% of erythrocytes (Figure); a blood sample from the infant was positive by PCR for B. microti DNA. Total B. microti antibody titer was > 256 by indirect immunofluorescence assay, with a polyvalent secondary antibody (anti-IgG+IgA+IgM) (4) that was presumed to be principally IgG because test results for IgM were negative (online Technical Appendix, wwwnc.cdc.gov/EID/ pdfs/11-0988-Techapp.pdf). The heel-stick blood sample obtained on the infant's third day of life as part of newborn screening was tested and found to be negative for B. microti by PCR (5) and for IgM but total antibody positive (> 128) (online Technical Appendix).

Examination of the placenta showed focal basal decidual inflammation, mild chorangiosis, and villus dys-maturity. Babesia spp. piroplasms were not detected in maternal or fetal blood by histologic examination of hematoxylin and eosin-stained sections of formalin-fixed, paraffin-embedded tissue of the placenta disk, amnion/ chorion, and umbilical cord. Babesia DNA was detected by real-time PCR testing of paraffin-embedded placenta tissue (online Technical Appendix) (6). Cycle threshold values were relatively high (37.1-38.2), indicating that the amount of parasite DNA in the sample was close to the limit of detection; results were reproducible on duplicate testing of DNA samples extracted from separate paraffin blocks. The real-time PCR product was of the correct size, and the melting curve demonstrated melting temperatures within 1[degrees]C from the placenta, the positive control, and a positive sample from an unrelated patient, confirming that the correct product was amplified. At time of the illness in the infant, the mother was negative for Babesia spp. according to PCR and smear but positive for total antibodies (> 256).

The infant was treated with a 9-day course of azithromycin plus atovaquone. A blood transfusion was administered when her hemoglobin concentration fell to 5.2 g/dL. The infant became afebrile by 72 hours and was discharged after a 5-day hospitalization. Repeat blood smears revealed a parasite load of 0.3% at discharge. On final evaluation at 22 months of age, physical examination revealed no abnormalities; hemoglobin level was 11.7 g/dL, Babesia PCR was negative, and total Babesia antibody level was positive at 128.

Conclusions

Congenital babesiosis has been rarely reported (Table) (7-10). This case provided convincing evidence for congenital babesiosis because of prepartum infection involving the placenta in the mother. On the basis of experience with congenital malaria, we assume that Babesia spp. parasites cross the placenta during pregnancy or at the time of delivery (11,12). In congenital malaria, increasing evidence suggests that the malaria parasites are most often acquired antenatally by transplacental transmission of infected erythrocytes (12).

Reported cases of congenital babesiosis share many similarities, including asymptomatic maternal infection and development of fever, hemolytic anemia, and thrombocytopenia in the infant detected between 19 and 41 days after birth. All of the infants responded to antimicrobial drug therapy; 3 were treated with azithromycin plus atovaquone (9,10), the preferred treatment regimen for mild babesiosis (1). All infants required a blood transfusion because of severe anemia. The clinical signs and symptoms for these cases of congenital babesiosis are similar to those of congenital malaria in non-disease endemic areas (11,13).

We found Babesia spp. antibodies on day 3 of life by analyzing the patient's heel-stick blood sample, which likely represented maternal transfer of IgG. Passive transfer of maternal antibodies is regarded as a protective factor against congenital malaria, and some newborns with malaria who are parasitemic at birth spontaneously clear the infection without ever becoming ill (11,14). The temporary presence of maternal IgG in infants has been suggested as an explanation for the typical 3-6 week incubation period of congenital malaria in non-disease endemic areas (14).

The real-time PCR used to find B. microti DNA in placenta tissue is [approximately equal to] 20x more sensitive than microscopic examination of Giemsa-stained blood smears (6). Assuming a blood sample with a parasitemia equivalent to that detected in the placental tissue, a blood smear would contain [less than or equal to] 10 infected cells per slide. Given the low level of Babesia DNA in the placenta tissue, it is not surprising that histologic examination did not reveal piroplasms. Nonetheless, limited evidence of placental abnormalities suggests a pathologic process.

In summary, babesiosis is an emerging infectious disease (15) that can rarely cause congenital infection. This diagnosis should be considered in the differential diagnosis of fever and hemolytic anemia in infants from diseaseendemic areas.

Acknowledgments

The authors thank Steven Smith, Jennifer Calder, Lisa Giarratano, Lenise Banwarie, Ewa Bajor-Dattilo, and Karen Kulas for their assistance.

References

(1.) Vannier E, Gewurz BE, Krause PJ. Human babesiosis. Infect Dis Clin North Am. 2008;22:469-88. http://dx.doi.org/10.1016/j. idc.2008.03.010

(2.) de Vos AJ, Imes GD, Cullen JSC. Cerebral babesiosis in a new-born calf. Onderstepoort J Vet Res. 1976;43:75-8.

(3.) Fukumoto S, Suzuki H, Igarashi I, Xuan X. Fatal experimental transplacental Babesia gibsoni infections in dogs. Int J Parasitol. 2005;35:1031-5. http://dx.doi.org/10.1016/j.ijpara.2005.03.018

(4.) Chisholm ES, Ruebush TK II, Sulzer AJ, Healy GR. Babesia microti infection in man: evaluation of an indirect immunofluorescent antibody test. Am J Trop Med Hyg. 1978;27:14-9.

(5.) Persing DH, Mathiesen D, Marshall WF, Telford SR, Spielman A, Thomfod JW, et al. Detection of Babesia microti by polymerase chain reaction. J Clin Microbiol. 1992;30:2097-103.

(6.) Teal AE, Habura A, Ennis J, Keithly J, Madison-Antenucci S. A new real-time PCR assay for improved detection of the parasite Babesia microti. J Clin Microbiol. 2012;50:903-8. http://dx.doi.org/10.1128/ JCM.05848-11

(7.) Esernio-Jenssen D, Scimeca PG, Benach JL, Tenenbaum MJ. Transplacental/perinatal babesiosis. J Pediatr. 1987;110:570-2. http:// dx.doi.org/10.1016/S0022-3476(87)80552-8

(8.) New DL, Quinn J, Qureshi MZ, Sigler S. Vertically transmitted babesiosis. J Pediatr. 1997;131:163-4. http://dx.doi.org/10.1016/ S0022-3476(97)70143-4

(9.) Sethi S, Alcid D, Kesarwala H, Tolan RW Jr. Probable congenital babesiosis in infant, New Jersey, USA. Emerg Infect Dis. 2009;15:788-91. http://dx.doi.org/10.3201/eid1505.070808

(10.) Aderinboye O, Syed S. Congenital babesiosis in a four-week old female infant. Pediatr Infect Dis J. 2010;29:188. http://dx.doi. org/10.1097/INF.0b013e3181c3c971

(11.) Vottier G, Arsac M, Farnoux C, Mariani-Kurddjian P, Baud O, Aujard Y. Congenital malaria in neonates: two case reports and review of the literature. Acta Paediatr. 2008;97:505-8. http://dx.doi. org/10.1111/j.1651-2227.2008.00690.x

(12.) Malhotra I, Mungai P, Muchiri E, Kwiek JJ, Meshnick SR, King CL. Umbilical cord-blood infections with Plasmodium falciparum malaria are acquired antenatally in Kenya. J Infect Dis. 2006;194:176-83. http://dx.doi.org/10.1086/505150

(13.) Lesko CR, Arguin PM, Newman RD. Congenital malaria in the United States. A review of cases from 1966 to 2005. Arch Pediatr Ado lesc Med. 2007;161:1062-7. http://dx.doi.org/10.1001/archpedi. 161.11.1062

(14.) Hagmann S, Khanna K, Niazi M, Purswani M, Robins EB. Congenital malaria, an important differential diagnosis to consider when evaluating febrile infants of immigrant mothers. Pedi atr Emerg Care. 2007;23:326-9. http://dx.doi.org/10.1097/01. pec.0000270164.78238.7d

(15.) Joseph JT, Roy SS, Shams N, Visintainer P, Nadelman RB, Hosur S, et al. Babesiosis in Lower Hudson Valley, New York, USA. Emerg Infect Dis. 2011;17:843-7.

Dr Joseph is an assistant professor of medicine in the Division of Infectious Diseases at New York Medical College. Her research interests are tick-borne illnesses, particularly babesiosis.

Address for correspondence: Julie T. Joseph, New York Medical College, Division of Infectious Diseases, Munger Pavilion Room 245, Valhalla, NY 10595, USA; email: julie_joseph@nymc.edu

Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the US Department of Health and Human Services.

Julie T. Joseph, Kerry Purtill, Susan J. Wong, Jose Munoz, Allen Teal, Susan Madison-Antenucci, Harold W. Horowitz, [1] Maria E. Aguero-Rosenfeld, [1] Julie M. Moore, Carlos Abramowsky, and Gary P. Wormser

[1] Current affiliation: New York University School of Medicine, New York, New York, USA.

Author affiliations: New York Medical College, Valhalla, New York, USA (J.T. Joseph, K. Purtill, J. Munoz, H.W. Horowitz, M.E. Aguero-Rosenfeld, G.P. Wormser); New York State Department of Health, Albany, New York, USA (S.J. Wong, A. Teal, S. Madison-Antenucci); University of Georgia, Athens, Georgia, USA (J.M. Moore); and Emory University School of Medicine, Atlanta, Georgia, USA (C. Abramowsky)

DOI: http://dx.doi/org/10.3201/eid1808.110988
Table. Comparison of selected clinical and laboratory
data from reported cases of congenital babesiosis in
5 infants *

                                   Reference

Clinical data                          (7)

Year of diagnosis/           Not given/Long Island,
location                            New York

Infant age at time of                  30
symptom onset, d
Clinical findings             Fever, irritability,
                                     pallor,
                               hepatosplenomegaly

Initial babesia                         5
parasitemia level, %
Hospitalization, d                      6
Maternal tick bite            1 wk before delivery

Babesia spp.                    30 d after birth:
serologic and PCR              IgM+/IgG+ (128/128)
results for infant             by IFA; 32 d after
                                birth: IgM+/IgG+
                                (256/512) by IFA;
                                     PCR ND

Babesia spp.                    30 d after birth:
evaluation results                  IgM+/IgG+
for mother                     (2,048/1,024); 32 d
                             after birth: IgM+/ IgG+
                                 (4,096/1,024);
                              peripheral smear--at
                             time of delivery and at
                             30 and 32 d after birth

HGB, g/dL                              9.3
Platelets, x [10.sup.3]/               38
[micro]L Leukocytes/PMN            6,500/1,170
leukocytes, cells/[micro]L
LDH, U/L                               894
Bilirubin indirect,                    3.6
mg/dL
AST, U/L                               90
ALT, U/L                               90
Treatment                    CLI and quinine for 10
                                        d

Follow-up                         Well at 6 mo
                                  posttreatment

Blood transfusion for          Yes, for HCT of 18%
anemia

                                     Reference

Clinical data                           (8)

Year of diagnosis/            Not given/Long Island,
location                             New York

Infant age at time of                   32
symptom onset, d
Clinical findings              Fever, lethargy, poor
                             feeding, pallor, scleral
                               icterus, hepatomegaly

Initial babesia                         4.4
parasitemia level, %
Hospitalization, d                       5
Maternal tick bite             7 wk before delivery

Babesia spp.                 At illness onset: IgG IFA
serologic and PCR                  160; IgM/IgG
results for infant             immunoblot +; PCR ND

Babesia spp.                  7 wk before birth: IgG
evaluation results               IFA <40; IgM/IgG
for mother                   immunoblot -; 2 mo after
                                birth: IgG IFA 640;
                               IgM/IgG immunoblot +;
                               peripheral smear--at
                              delivery and at infant
                                   illness onset

HGB, g/dL                              10.8
Platelets, x [10.sup.3]/                87
[micro]L Leukocytes/PMN                 NA
leukocytes, cells/[micro]L
LDH, U/L                                NA
Bilirubin indirect,                     9.7
mg/dL
AST, U/L                                NA
ALT, U/L                                NA
Treatment                      CLI and quinine with
                              AZT added on day 3; on
                               day 5 changed to AZT
                                 plus quinine for
                                  additional 7 d

Follow-up                        Improved at 2 wk

Blood transfusion for        Yes, for HGB of 7.3 g/dL
anemia

                                              Reference

Clinical data                         (9)                  (10)

Year of diagnosis/               Not given/New        Not given/Long
location                            Jersey              Island, New
                                                           York

Infant age at time of                 19                    27
symptom onset, d
Clinical findings                 Fever, poor          Fever, pallor
                               feeding, gagging,
                             irritability, pallor,
                               scleral icterus,
                                    hepato-
                                 splenomegaly

Initial babesia                       15                     2
parasitemia level, %
Hospitalization, d                     8                    NA
Maternal tick bite                4 wk before           None known
                                   delivery

Babesia spp.                   At illness onset:            NA
serologic and PCR                  IgM+/IgG+
results for infant             (40/256) by IFA;
                                    PCR ND

Babesia spp.                   At infant illness     At infant illness
evaluation results             onset: IgM+/IgG+         onset: PCR+
for mother                      (80/>1,024) by
                                IFA; peripheral
                               smear negative at
                                time of infant
                                 illness onset

HGB, g/dL                             8.8              NA; HCT 24.3%
Platelets, x [10.sup.3]/              34                    101
[micro]L Leukocytes/PMN           9,000/1,890               NA
leukocytes, cells/[micro]L
LDH, U/L                             2535                   NA
Bilirubin indirect,                   5.9                   NA
mg/dL
AST, U/L                              53                    NA
ALT, U/L                              18                    NA
Treatment                       AZT and ATO for        AZT and ATO,
                                     10 d              duration not
                                                           given

Follow-up                      Lost to follow-up            NA

Blood transfusion for           Yes, for HGB of       Yes, for HCT of
anemia                             7.0 g/dL                17.3%

                                    Reference

Clinical data                       This study

Year of diagnosis/               2002/Westchester
location                         County, New York

Infant age at time of                   41
symptom onset, d
Clinical findings             Fever, decreased oral
                              intake, irritability,
                             scleral icterus, pallor,
                                hepatosplenomegaly

Initial babesia                         4
parasitemia level, %
Hospitalization, d                      5
Maternal tick bite                  None known

Babesia spp.                    Newborn screening
serologic and PCR               (heel stick): IgM-
results for infant           (<16); total antibody +
                               (>128) by IFA; PCR-;
                             6 wks after birth: IgM-
                             (<16); total antibody +
                               (>256) by IFA; PCR+

Babesia spp.                  Birth: placenta PCR+;
evaluation results            6 wk after birth: IgM
for mother                     ND; total antibody +
                                    (>256) by
                              IFA; PCR-; peripheral
                                     smear -

HGB, g/dL                              7.1
Platelets, x [10.sup.3]/               100
[micro]L Leukocytes/PMN             19,700/788
leukocytes, cells/[micro]L
LDH, U/L                                NA
Bilirubin indirect,                    1.6
mg/dL
AST, U/L                                66
ALT, U/L                                50
Treatment                      AZT and ATO for 9 d

Follow-up                             22 mo

Blood transfusion for          Yes, for HGB of 5.2
anemia                           g/dL with HCT of
                                      15.8%

* No mothers became ill. NA, not available; +, positive; IFA,
indirect immunofluorescence assay; ND, not done; -, negative;
HGB, hemoglobin; HCT, hematocrit; PMN, polymorphonuclear; LDH,
lactate dehydrogenase level; AST, aspartate aminotransferase;
ALT, alanine aminotransferase; CLI, clindamycin; AZT, azithromycin;
ATO, atovaquone.
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