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The second generation of HIV-1 vertically exposed infants: a case series from the Italian Register for paediatric HIV infection

  • Carmelina Calitri1,
  • Clara Gabiano1,
  • Luisa Galli2,
  • Elena Chiappini2,
  • Carlo Giaquinto3,
  • Wilma Buffolano4,
  • Orazio Genovese5,
  • Susanna Esposito6,
  • Stefania Bernardi7,
  • Maurizio De Martino2,
  • Pier-Angelo Tovo1Email author and
  • the Italian Register for HIV Infection in Children
BMC Infectious Diseases201414:277

DOI: 10.1186/1471-2334-14-277

Received: 7 January 2014

Accepted: 9 April 2014

Published: 20 May 2014

Abstract

Background

In the Highly Active Antiretroviral Therapy (HAART) era, the prognosis of children perinatally infected with HIV-1 has significantly improved, so the number of perinatally-infected females entering child-bearing age and experiencing motherhood is increasing.

Methods

A description of the medical history and pregnancy outcomes of women with perinatal acquired HIV-1 infection enrolled in the Italian Register for HIV infection in Children.

Results

Twenty-three women had 29 pregnancies. They had started an antiretroviral therapy at a median of 7.7 years (interquartile range, IQR 2.3 - 11.4), and had experienced a median of 4 therapeutic regimens (IQR 2–6). Twenty women (87%) had taken zidovudine (AZT) before pregnancy, in 14 cases as a starting monotherapy. In 21 pregnancies a protease inhibitor-based regimen was used. At delivery, the median of CD4+ T lymphocytes was 450/μL (IQR 275–522), and no viral load was detectable in 15 cases (reported in 21 pregnancies). Twenty-eight children were delivered through caesarean section (median gestational age: 38 weeks, IQR 36–38, median birth weight: 2550 grams, IQR 2270 – 3000). Intravenous AZT was administered during delivery in 26 cases. All children received oral AZT (median: 42 days, IQR 31 – 42), with no adverse events reported. No child acquired HIV-1 infection.

Conclusions

Despite a long history of maternal infection, multiple antiretroviral regimens and, perhaps, the development of drug-resistant viruses, the risk of mother-to-child transmission does not seem to have increased among the second-generation of HIV-1 exposed infants.

Keywords

HIV-1 Drug-resistant virus AZT Vertical transmission

Background

The introduction of Highly Active Antiretroviral Therapy (HAART) has significantly improved the quality of life and prognosis of children with perinatally acquired HIV-1 infection in resource-rich countries [1, 2]. As a result, an increasing number of these children are entering adolescence and young adulthood, with a consequent proportion of females becoming sexually active and pregnant. These mothers presented with a long history of HIV-1 infection and sometimes AIDS complications. They had a wide exposition to antiretroviral (ART) drugs and to their, primarily metabolic, chronic side effects. They experienced multiple ART regimens, which were often sub-therapeutic until the advent of HAART, with a consequent risk of acquiring drug-resistant viruses.

Therefore, it has since become crucial to define the pregnancy outcome and effectiveness of ART therapy in preventing mother-to-child HIV-1 transmission (MTCT) in this 2nd generation of HIV-1 exposed infants. Reports from Europe [3, 4], Puerto Rico [5], India [6], USA [710], and Brazil [11] describe favourable maternal and neonatal outcomes, with a MTCT rate varying from 0 to 7.7%, detected in cases of poor adherence to therapy [10].

Here, we describe the clinical aspects of pregnancy in women with perinatally acquired HIV-1 infection enrolled over the years in the Italian Register for HIV Infection in Children.

Methods

The Italian Register for HIV infection in children (ITLR) is a nationwide, multicentre, prospective study set up by the Italian Association of Paediatrics in 1985. At the moment of patient’s enrolment, written informed consent is obtained from the patient’s guardians; data are treated anonymously as each patient is identified by an alphanumerical code. The study was approved by the review boards and ethics committees of each participating institution, as described in detail elsewhere [1, 12]. A retrospective analysis of perinatally HIV-1 infected females, enrolled in the ITLR from its institution and who had a child, was carried out. Information included: the women’s demographic and clinical characteristics, such as their mothers’ risk factors for HIV-1 infection, perinatal ART use, HIV-1 related diseases and comorbidities; the number and types of ART regimens both before and during pregnancy; age at delivery, number of CD4+ T-lymphocytes and viral load at delivery, the mode of delivery; infants’ characteristics (gestational age, sex, birth weight, congenital malformations, any other acute or chronic diseases, adverse events for MTCT prophylaxis, HIV-1 infection status). SPSS (version 20.0) software for Windows was used for data management.

Results

Between 2001 and 2012, 29 children were born to 23 women with perinatal HIV-1 infection. One woman had 3 pregnancies and four women had 2 pregnancies each. See Tables 1, 2 and 3 for data concerning mother-child pairs.
Table 1

Characteristics of HIV-1 vertically infected women

N.

Birth order

Risk factors for HIV infection in grandmothers

Year of birth

Age (years) at start of ART therapy

AZT monotherapy

No of regimens experienced

Years of ART therapy (before the first pregnancy)

Clinical and immunological category at last observation

Age (years) at AIDS onset

Age (years) at delivery

Case 1

1st

Drug abuse

1982

14.6

No

4

13.2

A 1

 

28.4

Case 2

1st

Sexual intercourse with drug abuser, Drug abuse

1982

10.6

Yes

5

7.7

B 3

 

24.6

 

2nd

        

26.9

Case 3

1st

Risk sexual intercourse

1983

7.7

Yes

6

17.5

B 3

 

26.1

Case 4

1st

Drug abuse

1983

11.4

Yes

7

7

B 3

 

23.9

Case 5

1st

Unknown

1983

21.7

No

1

0

B 3

 

22

 

2nd

        

23.7

 

3th

        

24.7

Case 6

1st

Drug abuse

1984

6.6

Yes

6

9.7

B 2

 

17

 

2nd

        

18.3

Case 7

1st

Sexual intercourse with drug abuser

1985

3.1

No

2

20.5

N 2

 

24.3

Case 8

1st

Drug abuse

1985

3

Yes

15

17.7

C 3

11.5

22.4

Case 9

1st

Sexual intercourse with drug abuser, Drug abuse

1986

12.2

No

2

9.5

C 2

13.1

22.2

Case 10

1st

Sexual intercourse with drug abuser

1986

6.6

Yes

6

14.8

C 3

6.6

22.1

Case 11

1st

Unknown

1986

10.2

No

6

11.1

A 3

 

22

Case 12

1st

Sexual intercourse with drug abuser

1986

10

Yes

3

6.3

A 2

 

21.1

 

2nd

        

22.2

Case 13

1st

Unknown

1986

13.3

No

1

11

A 1

 

25

Case 14

1st

Sexual intercourse with drug abuser

1987

2.3

Yes

3

21.6

B 2

 

24.5

Case 15

1st

Unknown

1988

14.4

No

2

10.3

B 1

 

22.6

Case 16

1st

Unknown

1988

1.9

Yes

2

6.2

A 2

 

19.2

Case 17

1st

Sexual intercourse with drug abuser

1989

1.8

Yes

5

18

A 1

 

20.3

Case 18

1st

Sexual intercourse with drug abuser, Drug abuse

1990

1.7

Yes

5

14.4

B 2

 

20.1

Case 19

1st

Drug abuse

1990

5.4

Yes

8

13.9

B 3

 

20

Case 20

1st

Unknown

1990

8.6

No

4

11.6

A 3

 

20.8

 

2nd

        

21.7

Case 21

1st

Sexual intercourse with drug abuser

1991

1.2

Yes

3

17.3

B 1

 

19.3

Case 22

1st

Drug abuse

1991

0.6

Yes

7

19.2

C 3

0.2

20.4

Case 23

1st

Sexual intercourse with drug abuser, Drug abuse

1991

8.2

No

2

9.9

A 2

 

20

Legend. ART = antiretroviral; AZT = zidovudine.

Table 2

Pregnancy features

N.

Birth order

ART therapy at conception

ART therapy interruption at first trimester

ART regimen during pregnancy

Gestational week at start

Gestational week at end

CD4+ at delivery

VL at delivery

AZT intrapartum

Type of delivery

Case 1

1st

No

No

AZT + 3TC + ATV/rtv

5

37

525

Undetectable

Yes

EC

Case 2

1st

Yes

Yes (from 5th to 12th week)

DDI + 3TC + NVP

1

4

480

157

Yes

EC

    

AZT + 3TC + NVP

13

38

    
 

2nd

Yes

No

FTC + TDF + FPV/rtv

1

38

520

Undetectable

Yes

EC

Case 3

1st

Yes

No

FTC + TDF + ATV/rtv

1

38

125

Undetectable

Yes

EC

Case 4

1st

No

No

No

  

Unknown

Unknown

Yes

EC

Case 5

1st

No

No

AZT + 3TC + LPV/rtv

23

34

307

Unknown

Yes

EC

 

2nd

Yes

No

AZT + 3TC + LPV/rtv

1

37

480

15332

Yes

EC

 

3th

Yes

No

AZT + 3TC + LPV/rtv

1

Unknown

Unknown

Unknown

Yes

EC

Case 6

1st

No

No

AZT + 3TC + NVP

6

36

Unknown

Unknown

No

EC

 

2nd

No

No

AZT + 3TC + NVP

6

40

Unknown

Unknown

No

EC

Case 7

1st

Yes

No

ABC + 3TC + ATV

1

34

323

Undetectable

Yes

EC

    

ABC + 3TC + ATV/rtv

35

38

    

Case 8

1st

Yes

No

FTC + TDF + DRV/rtv

1

38

450

Undetectable

Yes

EC

Case 9

1st

Yes

No

ABC + DDI + LPV/rtv

1

16

312

7653

Yes

EC

    

AZT + 3TC + LPV/rtv

17

36

    

Case 10

1st

Yes

Yes (from 6th to 12th week)

FTC + TDF + EFV

1

5

240

Undetectable

Yes

EC

    

AZT + 3TC + LPV/rtv

13

38

    

Case 11

1st

Unknown

No

ABC + TDF + LPV/rtv

Unknown

39

Unknown

Undetectable

Yes

EC

Case 12

1st

No

No

No

  

Unknown

Unknown

Yes

UC

 

2nd

Yes

No

AZT + 3TC + LPV/rtv

1

38

95

Unknown

Yes

EC

Case 13

1st

Yes

No

FTC + NVP

1

39

673

Undetectable

Yes

EC

Case 14

1st

Yes

No

AZT + 3TC + ABC

1

35

564

Undetectable

Yes

EC

Case 15

1st

Yes

No

FTC + TDF + DRV/rtv

1

37

501

Undetectable

Yes

EC

Case 16

1st

No

No

FTC + TDF + ATV/rtv

16

36

522

Undetectable

Yes

EC

Case 17

1st

No

No

FTC + TDF + ATV

13

37

770

Undetectable

Yes

EC

Case 18

1st

Yes

No

3TC

1

28

440

13099

Yes

LC

    

FTC + TDF + DRV/rtv

29

36

    

Case 19

1st

No

No

FTC + TDF + ATV/rtv

6

38

501

Undetectable

Yes

EC

Case 20

1st

No

No

FTC + TDF + DRV/rtv + RAL

38

40

200

Undetectable

Yes

EC

 

2nd

Unknown

Unknown

Unknown

  

99

Unknown

Unknown

Unknown

Case 21

1st

Yes

No

FTC + TDF + ATV/rtv

1

38

776

615

Yes

EC

Case 22

1st

Yes

No

AZT + DDI + LPV/rtv

1

35

435

Undetectable

Yes

EC

Case 23

1st

Yes

Yes (from 3rd to 9th week)

FTC + TDF + LPV/rtv

1

3

275

20000

Yes

EC

    

FTC + TDF + LPV/rtv

10

38

    

Legend. VL: viral load (copies/ml); AZT: zidovudine; 3TC: lamivudine; ABC: abacavir; FTC: emtricitabine; TDF: tenofovir; DDI: didanosine; NVP: nevirapine; LPV: lopinavir; ATV: atazanavir; FPV: fosamprenavir; DRV: darunavir; rtv: ritonavir booster; RAL: raltegravir; EC = elective caesarean section; UC = unspecified caesarean section; LC = caesarean section after labour.

Table 3

HIV-1 exposed children features

N.

Birth order

Year of birth

Gender

Gestational age (weeks)

Weight at birth (grams)

 

ART prophylaxis

Duration of postnatal ART prophylaxis (days)

HIV-1 status

Other pathological conditions

Case 1

1st

2010

M

37

2590

 

AZT

42

SR

 

Case 2

1st

2007

F

38

2550

 

AZT

45

SR

 
 

2nd

2009

M

38

3240

 

AZT

19

SR

 

Case 3

1st

2009

F

38

3100

 

AZT

28

SR

 

Case 4

1st

2007

F

38

2920

 

AZT

36

SR

 

Case 5

1st

2005

F

34

1975

 

AZT

42

SR

 
 

2nd

2007

F

37

1960

SGA

AZT

42

SR

HCV infection

 

3th

2008

F

Unknown

Unknown

 

AZT

28

SR

 

Case 6

1st

2001

F

36

1880

SGA

AZT

44

SR

 
 

2nd

2002

F

40

3080

 

AZT

42

SR

 

Case 7

1st

2009

M

38

2530

 

AZT

42

SR

 

Case 8

1st

2008

F

38

2450

 

AZT

43

SR

 

Case 9

1st

2008

F

36

2520

 

AZT

42

SR

 

Case 10

1st

2008

M

38

3250

 

AZT

31

SR

 

Case 11

1st

2008

F

39

2770

 

AZT

41

SR

 

Case 12

1st

2007

M

35

2270

 

AZT + 3TC + NVP

31

SR

 
 

2nd

2008

M

38

3000

 

AZT + 3TC + NVP

42

SR

 

Case 13

1st

2011

M

39

3100

 

AZT

41

SR

 

Case 14

1st

2011

F

35

1190

SGA

AZT

18

SR

 

Case 15

1st

2011

M

37

3190

 

AZT

42

SR

 

Case 16

1st

2008

F

36

2760

 

AZT

42

SR

 

Case 17

1st

2009

M

37

2520

 

AZT

29

SR

Cryptorchidism

Case 18

1st

2010

M

36

2180

 

AZT

42

SR

 

Case 19

1st

2010

F

38

2500

 

AZT

14

SR

 

Case 20

1st

2011

F

40

2380

SGA

AZT

45

SR

 
 

2nd

2012

F

Unknown

Unknown

 

Unknown

Unknown

SR

 

Case 21

1st

2010

F

38

2750

 

AZT

42

SR

 

Case 22

1st

2012

M

35

2160

 

AZT

42

SR

 

Case 23

1st

2011

M

38

2690

 

AZT

33

SR

 

Legend. M = male; F = female; AZT = zidovudine; 3TC = lamivudine; NVP = nevirapine; SR = seroreverter; SGA= small for gestational age.

The median maternal age at first delivery was 22 years (interquartile range (IQR) 20.1-24.3); the oldest mother was born in 1982, the youngest in 1991. No infected mother was perinatally exposed to antiretroviral drugs, as ART prophylaxis was not used at that time. The grandmothers’ risk factors for HIV-1 infection were known for 17 women: 11 had had high risk sexual intercourse and 6 had been IV drug users. All but one woman had ART therapy during childhood or adolescence. The median age at the start of ART therapy was 7.7 years (IQR 2.3-11.4). The median number of regimens for each woman was 4 (IQR 2–6). Twenty (87%) women were given zidovudine (AZT), in 14 cases as a starting monotherapy for a median period of 4.4 years (IQR 2.0-5.2); 12/14 patients were later shifted to a dual therapy containing AZT (median period 2.4 years, IQR 1.0-3.4). All but 2 women received HAART before pregnancy, with a combination of 3 or more drugs, containing at least one protease-inhibitor (PI) in 16 cases. The median time of the mothers’ exposure to ART drugs before their first pregnancy was 11.6 years (IQR 9.5-17.5). Four women developed an AIDS defining condition (at a median age of 9.0 years, IQR 1.8-12.7); 10 women were classified, according to the CDC paediatric classification, in clinical category B, 8 in category A, 1 in category N. As far as the immunological status is concerned, 5 were in category 1, 8 in category 2, and 10 in category 3.

Ten mothers did not have any ART therapy at the time of conception; of the ten, 2 continued without therapy throughout their pregnancy, 4 started ART therapy in the first trimester and 4 after the 12th week of gestation, including one woman who started a rescue therapy including the integrase inhibitor raltegravir at the 38th week of gestation. In the other pregnancies, the women were already undergoing ART treatment at conception, and 3 of them discontinued therapy in the first trimester (see Table 2). In one case, efavirenz (EFV) was continued during the first 5 weeks of gestation, with a switch to a lopinavir/ritonavir containing combination after the 12th week. A PI-based regimen was used in a total of 21 pregnancies. No complications related to pregnancy were noticed. There was a median of 450/μL (IQR 275–522)CD4+ T lymphocytes at the last check before delivery (reported in 23 of the 29 pregnancies); all women with a previous AIDS-defining condition had > 200 CD4+/μL. The viral load at delivery (reported in 21 pregnancies) was undetectable in 15 cases. Intravenous AZT was administered during 26 (89.6%) deliveries. Twenty-eight children were born through caesarean section, which was elective in 26 cases. No neonatal complications for children at birth were reported; 17 (58.6%) were females; their median gestational age was 38 weeks (IQR 36–38) and the median birth weight was 2550 grams (IQR 2270–3000). Eight were preterm (<37 weeks of gestation), and 4 were small for the gestational age (SGA) (Table 3) [13]. No infant was breastfed. Twenty-six infants received oral AZT as MTCT prophylaxis; 2 brothers received a combined regimen (AZT + 3TC + NVP single dose): the first child because of lack of maternal ART therapy during pregnancy, the second one because of severe maternal immunosuppression (CD4+ T-lymphocytes at labour: 95 cell/ μL). Neonatal ART prophylaxis was administered for a median period of 42 days (IQR 31–42) with no major adverse events.

No child acquired HIV-1 infection. One patient was HCV infected and one presented cryptorchidism. The median age at the last check was 3 years (IQR 1.3-4.3), with nine children followed over 4 years of age.

Discussion

There are few studies exploring the pregnancy outcome in HIV-1 perinatally-infected women. Despite the limited number of pregnancies enrolled and limited amount of available data, ours is one of the largest cohorts with detailed information on the entire maternal history.

The results are reassuring, since none of the 29 exposed infants acquired the infection. Indeed, of the 134 children born to HIV-1 perinatally-infected mothers described in this and other studies [311], only 2 acquired the infection, for a total MTCT rate of 1.5%, comparable to that observed in the first-generation of exposed infants with the adoption of the same preventive measures, such as ART therapy during pregnancy, elective caesarean section, ART prophylaxis in the child, and bottle-feeding [12, 14, 15].

Among 601 women with perinatally acquired HIV-1 infection enrolled in the ITLR, 383 are alive and over 16 years old at the last check. Thus, the 23 described in this case-series represent 6% of those with a similar child-bearing age. It is worth noting that 5 had more than one child. In spite of the prolonged history of HIV-1 infection and of targeted therapies, the good quality of life and a longer life expectancy presumably allowed these women to live motherhood with fewer distressing concerns. The low probability of HIV-1 transmission to the offspring is an additional important factor supporting such women having children. We have no documentation about the possible birth control methods adopted by these women, or whether these pregnancies were planned. However, the median age of our parturients was rather lower than the 32.3 years observed in the general Italian population [16]. This low median age at delivery is consistent with other reports [3, 5, 6, 10], and, perhaps, mirrors the fear that the chronic disease could deprive them of the special female role of motherhood. This growing desire of motherhood among seropositive women clearly emerges from our Register, where the number of HIV-1 perinatally-exposed children is around 350–400 per year, with an increasing multiparity rate, reaching 25% in recent years (data not shown).

In this scenario, the management of HIV-1 perinatally-infected pregnant women and their children will be an important challenge for clinicians in the near future. A crucial aspect will be the choice of the best ART regimen to prevent MTCT. None of our mothers was perinatally exposed to ART drugs, as they were born before the ACTG 076 protocol [17, 18]. However, the majority received ART therapy during childhood and experienced several sub-therapeutic regimens. Although resistance data were not available, these conditions are well known to favour the development of drug resistant viruses, with a consequent possible higher risk of MTCT, a phenomenon that fortunately does not emerge from the available data. As far as AZT is concerned, it is worth noting that over half of our mothers started AZT as a monotherapy during childhood, then shifted to a dual therapy including AZT, continuing with such combinations for several years. Six of these 14 women continued to receive AZT also during pregnancy, as did all their children as a prophylaxis, apparently with success, since the majority of the mothers had undetectable viral loads at delivery and no child acquired the infection. This casts doubts on the suggested exclusion of AZT during pregnancy if there had been a prolonged monotherapy during childhood [10]. Indeed, in a recent case series the role of intrapartum intravenous AZT for the prevention of MTCT in women with virological failure has been stressed [19]. AZT may be effective in the prevention of MTCT through other mechanisms besides its direct antiviral effect [18, 20].

The possible impact of a prolonged ART therapy on maternal and child health is a further important aspect. Even in this context, our results are reassuring. No congenital abnormalities were noticed, including the child exposed to EFV in the first 5 weeks of gestation [21, 22]. Since maternal and neonatal complications due to ART drugs do not seem to be higher in perinatally-infected women, indications should not differ from those commonly recommended in seropositive mothers, for instance HAART should start as soon as possible [15], while stopping ART during pregnancy should be discouraged [12]. In fact, fearing a possible teratogenicity, 3 women discontinued ART treatment during the first trimester of pregnancy and their viral load was detectable at delivery. On the other hand, the experience of several therapeutic regimens during childhood and adolescence will presumably lead to the use of new antiretroviral drugs during pregnancy, such as integrase inhibitors, the impact of which on pregnant women and their foetuses still needs to be elucidated.

Conclusions

The outcome of second-generation HIV-1 exposed infants seems favourable. In spite of a long course of maternal infection, multiple ART regimens, and a possible development of drug-resistant viral strains, MTCT continues to be efficiently controlled by the commonly adopted preventive strategies, even though an adequate surveillance of pregnancy among this unique population is highly recommended.

Authors’ information

Co-Authors: Giacomo Faldella (Bologna), Raffaele Badolato, Chiara Monfredini (Brescia), Cristina Gotta (Genoa), Vania Giacomet (Milan), Monica Cellini (Modena), Osvalda Rampon (Padua), Maura Agnese (Naples), Piero Valentini (Rome), Carlo Scolfaro, Silvia Garazzino (Turin), Antonio Mazza (Trento).

Declarations

Acknowledgements

All principal investigators and sites who participate in the ITLR have been previously published [1] and are listed below. The Authors are grateful to Andrew Martin Garvey for editorial assistance and to Federica Messina for data management.

The "Italian Register for HIV infection in children" principal investigators by site are: Patrizia Osimani (Ancona), Domenico Larovere (Bari), Maurizio Ruggeri (Bergamo), Andrea Pession, Giacomo Faldella (Bologna), Francesca Capra, Sara Pulcini, Valentina Zattoni (Brescia), Maurizio Dedoni (Cagliari), Antonia Aliffi (Catania), Elisa Anastasio (Catanzaro), Elisa Fiumana (Ferrara), Paola Gervaso, Carlotta Montagnani (Florence), Antonio Di Biagio, Laura Ambra Nicolini, Laura De Hoffer, Maria Sole Acutis, Elisabetta Bondi (Genoa), Paola Erba, Valentina Fabiano, Giulia Ramponi, Filippo Salvini, Rita Lipreri, Susanna Esposito, Anna Plebani, Claudia Tagliabue (Milan), Francesca Giubbarelli (Modena), Emanuele Nicastro, Andrea Lo Vecchio, Wilma Buffolano, Maura Agnese (Naples), Amelia Romano (Palermo), Carlo Giaquinto, Osvalda Rampon, Martina Pennazzato (Padua), Rita Consolini (Pisa), Icilio Dodi (Parma), Anna Maccabruni (Pavia), Orazio Genovese, Paolo Palma, Giuseppe Pontrelli, Hyppolite Tchidjou (Rome), Paolina Olmeo (Sassari), Antonio Mazza (Trento), Erika Silvestro, Silvia Virano (Turin), Vincenzo Portelli (Trapani), Marco Rabusin (Trieste), Antonio Pellegatta (Varese).

Authors’ Affiliations

(1)
Department of Paediatrics, University of Turin
(2)
Department of Health Sciences, University of Florence
(3)
Department of Paediatrics, Padua University
(4)
Coordinating Centre for Perinatal Infection of Campania Region, Translational Medical Sciences Department of Federico II University
(5)
Department of Emergency, Catholic University of Rome
(6)
Paediatric Clinic 1, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
(7)
Department of Immunology and Infectious Diseases, "Bambino Gesù" Children’s Hospital

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    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/14/277/prepub

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