Infectious Diseases
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Antibodies against pneumococcal capsular polysaccharide in Malawian HIV-positive mothers and their HIV-exposed uninfected children Silvia Baroncelli, Clementina Maria Galluzzo, Sandro Mancinelli, Mauro Andreotti, Haswell Jere, Roberta Amici, Maria Cristina Marazzi, Stefano Vella, Leonardo Palombi & Marina Giuliano To cite this article: Silvia Baroncelli, Clementina Maria Galluzzo, Sandro Mancinelli, Mauro Andreotti, Haswell Jere, Roberta Amici, Maria Cristina Marazzi, Stefano Vella, Leonardo Palombi & Marina Giuliano (2015): Antibodies against pneumococcal capsular polysaccharide in Malawian HIV-positive mothers and their HIV-exposed uninfected children, Infectious Diseases, DOI: 10.3109/23744235.2015.1115895 To link to this article: http://dx.doi.org/10.3109/23744235.2015.1115895
Published online: 26 Nov 2015.
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Date: 07 December 2015, At: 14:12
INFECTIOUS DISEASES, 2015 http://dx.doi.org/10.3109/23744235.2015.1115895
ORIGINAL ARTICLE
Antibodies against pneumococcal capsular polysaccharide in Malawian HIV-positive mothers and their HIV-exposed uninfected children Silvia Baroncellia, Clementina Maria Galluzzoa, Sandro Mancinellib, Mauro Andreottia, Haswell Jerec, Roberta Amicia, Maria Cristina Marazzid, Stefano Vellaa, Leonardo Palombib and Marina Giulianoa Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanita`, Rome, Italy; bDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; cDREAM Program, Community of S. Egidio, Blantyre, Malawi; dLUMSA University, Rome, Italy
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a
ABSTRACT
ARTICLE HISTORY
Background: HIV-exposed uninfected children have a higher risk of infection and mortality compared to HIV-unexposed children and the reasons for this vulnerability are still under investigation. Aim: This study aimed to evaluate the influence of maternal HIV parameters on the passive transfer of anti-pneumococcal capsular polysaccharide (PCP) IgG and to determine whether the concentrations of specific IgG might be related to the morbidity and mortality in HIV-exposed uninfected children. Methods: One hundred and twenty-six Malawian HIV-infected pregnant women and their uninfected children were studied. Antiretroviral treatment-naive women started a nevirapine-based triple combination regimen from the third trimester of pregnancy until at least 6 months of exclusive breastfeeding. Mother/child pairs were followed until 2 years after delivery. Plasma anti-PCP IgG titers (in mothers at 26 weeks of gestation and in infants at 1 and 6 months) were determined by an enzyme-linked immunosorbent assay. None of these women and children had received any vaccination against pneumococcal polysaccharides. Results: Maternal anti-PCP IgG concentration was independent from viral load (p ¼ 0.848), CD4 count (p ¼ 0.740) and WHO stage (p ¼ 0.450). However, the child/mother ratio of anti-PCP IgG measured at 1 month among infants was significantly reduced in pairs whose mothers had HIV-RNA410 000 copies/ml (p ¼ 0.043) and CD45350 cells/ml (p ¼ 0.090) before antiretroviral therapy (ART). No clear associations between anti-PCP IgG and respiratory-related deaths were found, but respiratory infection episodes were more frequent among children with lower anti-PCP IgG ratio (p ¼ 0.046). Conclusion: This study indicates that HIV pre-ART conditions in mothers may influence the rate of specific immunoglobulins transfer, increasing infants vulnerability to respiratory infections.
Received 24 July 2015 Revised 21 October 2015 Accepted 23 October 2015 Published online 26 November 2015 KEYWORDS
HIV exposed infants; antipneumococcal IgG; passive transfer; Malawi
Introduction The implementation of antiretroviral prophylaxis in HIVinfected pregnant women has resulted in a drastic reduction of HIV paediatric infections, both in western and in resourcelimited countries. As a consequence, HIV-exposed uninfected children are becoming an increasing population, especially in sub-Saharan Africa, where antenatal HIV infection can reach 10–20% of prevalence.[1–3] Every year 1.5 million of HIV-exposed uninfected children are born to HIV positive mothers [4]. Recent studies have reported a significant increase in morbidity and mortality in these children when compared to children born from HIV-uninfected mothers.[5–8] In subSaharan Africa, 2-year mortality in HIV-exposed uninfected children is 2–3-times greater than in healthy children [9] and the main causes of death are related to gastrointestinal and respiratory infections [10,11]. The higher vulnerability of HIV exposed uninfected children to viral and bacterial infections could be multifactorial, including HIV exposure itself,[12] CONTACT Dr Silvia Baroncelli Elena, 299, 00161 Rome, Italy
[email protected]
ß 2015 Society for Scandinavian Journal of Infectious Diseases
severity of maternal HIV clinical status and pre-natal exposure to antiretroviral drugs.[13–16] Many reports indicated inadequate maternal transplacental transfer of specific IgG in HIV exposed uninfected children,[17– 20] that could be responsible for high susceptibility to pathogens in the first months of life. Similarly, reduced passive antibody transfer has also been observed in antenatal vaccine programmes for poliovirus,[18] tetanus toxoid [21] and Haemophilus influenza type B [22] in HIV pregnant women. Many factors might be involved in this process and the mechanisms are still under investigation. Abnormalities of B cells, including polyclonal activation and hypergammaglobulinemia observed in advanced stages of HIV disease,[23] could interfere with the transfer of maternal antibodies across the placenta that is mediated by Fc receptors.[24,25] In this study we aimed to explore the influence of maternal HIV infection on the passive transfer of specific antibodies against the capsular polysaccharide of Streptococcus pneumoniae (PCP), one of the most common causes of lower
Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanita`, Viale Regina
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respiratory tract infections (LRTI) in sub-Saharan Africa.[15] The specific aims of this study were (1) to evaluate the anti-PCP IgG concentrations in mothers and their HIV exposed uninfected children and to determine the influence of maternal HIV conditions on the passive transfer of anti-PCP IgG; and (2) to determine whether different child/maternal IgG ratios might be related to an increased vulnerability to respiratory infections in HIV-exposed uninfected children.
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Methods Study setting and population The present study population included 126 mother/child pairs and it is nested in a larger observational study aimed to assess safety and pharmacokinetics of maternal antiretroviral therapy (ART) administration during breastfeeding [Safe Milk for African Children (SMAC) study],[26] conducted within the DREAM (Drug Resource Enhancement against AIDS and Malnutrition) Program of the Community of S. Egidio. Criteria to include patients in this sub-study were: availability of plasma samples from mothers at the enrolment and from children at the first month of life and complete clinical records for all pairs. Children diagnosed with HIV infection were excluded.
Diagnostics, Deerfield, IL) were performed at the local DREAM laboratories in Malawi. This study received ethics approval by the National Health Research Committee in Malawi.
Anti-pneumococcal capsular polysaccharide IgG determination Levels of Pneumococcal Capsular Polysaccharide (PCP) specific IgG were evaluated in serum or plasma at baseline for mothers (26 weeks of gestation) and at month 1 in infants. In infants, when samples were available, plasma levels of anti-PCP IgG were measured also at month 6 (n ¼ 33). Anti-PCP IgG were measured using the VaccZyme Human Anti-PCP Enzyme Immunoassay kit (The Binding Site Ltd, Birmingham, UK). Microwells in the pneumococcal assay were pre-coated with pneumococcal capsular polysaccharide antigens 1-5, 6B, 7F, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F. This commercial kit, designed to measure antibody response to vaccination and to natural exposition to Streptococcus pneumoniae, determines a global response to 23 polysaccharide antigens accounting for 80% of virulent serotypes.[29] The IgG data are presented as a collective response to multiple serotypes, as indicated by the assay instructions and reported by others in similar studies.[17,30,31] The values are expressed in mg/L.
Study procedures HIV-infected pregnant women, treatment-naive (with the exception of single dose-nevirapine) were introduced to antiretroviral therapy from week 26 of gestational age. If meeting the criteria for treatment (CD4 + cell count5350 cells/ mm3), they received a combination of stavudine (30 mg twice daily), lamivudine (150 mg twice daily) and nevirapine (200 mg twice daily) (first-line regimen recommended in Malawi at the time of the study) and continued indefinitely; in the case of a CD4 + count4350/mm3, were treated with a regimen consisting of zidovudine (300 mg twice daily), lamivudine and nevirapine (the preferred preventive strategy used by the DREAM programme) [27] until 6 months post-partum. Infants were exclusively breastfed for the first 6 months of life. Women and children enrolled in this study did not receive any vaccination against pneumococcal polysaccharides.
Clinical visits and laboratory analysis Clinical visits were scheduled monthly during the first 12 months after delivery, then every 3 months until 24 months post-partum. Supplemental clinical care was offered to all women and children when needed also outside the scheduled visits. All LRTIs were diagnosed at the clinical sites. Due to the limitation of diagnostic tools available, respiratory infections were diagnosed by clinical judgement, on the basis of symptoms such as fever and malaise, cough, pleuritic chest pain, dyspnoea or tachypnoea and by the auscultation of the chest, as suggested by the guidelines.[28] Laboratory analysis and plasma samples collection were performed at months 1, 3 and 6 and then every 3 months. CD4 cell count (Epics XL-MCL, Beckman Coulter, Brea, CA) and HIV RNA determinations (branched DNA version 3.0 assay, Siemens
Statistical analysis Statistical analysis was performed using SPSS (v.22, IBM, Somers, NY). The Mann Whitney and Wilcoxon tests were used to compare geometric mean concentration (GMC) of antiPCP IgG. The Spearman’s test was used for correlations and the Fisher exact test for proportions.
Results Study population One hundred and twenty-six mother/child pairs were included in this analysis, based on the availability of maternal and child plasma samples. Characteristics of the study population are reported in Table 1. At enrolment (median ¼ 26 week of pregnancy) median level of HIV RNA was 4.09 log copies/ml and over half the women (55.6%) had a CD4 cell count below 350/mm3. Their antiretroviral therapy was based on a backbone of zidovudine-lamivudine (n ¼ 56, 44.4%) or stavudine-
Table 1. Maternal characteristics (n ¼ 126) at the enrolment (median ¼ 26th gestational week). Values are expressed as median and interquartile range (IQR) or percentage. Patients characteristics Age (years) Maternal weight (Kg) Hb levels (g/dl) WHO I/II/III stage (%) CD4 (below 350 cell/mm3) (%) CD4 (cells/mm3) HIV RNA (log copies/mL) Pregnancy week of ART initiation Caesarian section (n, %)
Values 26.5 (23.0–30.0) 57.9 (51.8–65.3) 10.2 (9.1–11.0) 69.4/21.8/8.9 70 (55.6) 320 (214–482) 4.09 (3.38–4.51) 26 (24–29) 7 (5.6%)
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lamivudine (n ¼ 70, 55.6%) plus nevirapine. Most of the women (94.4%) had vaginal delivery. At the time of delivery plasma HIV RNA was determined only for a small number of women, but 1 month after delivery only six out of 126 (4.8%) women had viral load41000 copies/ml, showing the efficacy of the antiretroviral therapy. Median neonatal weight was 3300 g (IQR ¼ 2800–3500). All except three neonates were singletons. Only data from the first born were considered in this study. Women and children enrolled in this study did not receive any vaccination against pneumococcal polysaccharides.
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Maternal and infant IgG antibodies specific for pneumococcal capsular polysaccharide At enrollment (third trimester of pregnancy, before the introduction of ART) all 126 mothers had concentrations of PCP IgG above the detection limit (higher than 3.3 mg/L). The geometric mean concentration of specific anti-PCP IgG was 57.4 mg/L (IQR ¼ 28.8–115.5) in mothers and 10.3 mg/L (IQR ¼ 4.2–18.6) and 6.8 mg/L (IQR ¼ 3.4–9.8) in 1 and 6 months old infants, respectively (Table 2). Medians of infant/ maternal PCP IgG ratio were 0.165 mg/L (IQR ¼ 0.111–0.256) and 0.103 (IQR ¼ 0.051–0.190) at months 1 and 6, indicating the physiological decline in passively acquired specific anti-PCP antibodies during the first 6 months of life. The maternal PCP IgG levels were directly correlated to infant levels at 1 month (r ¼ 0.704, p50.001), remaining significantly associated at 6 months (r ¼ 0.410, p ¼ 0.018).
Maternal and infant follow-up: respiratory morbidity and mortality A total of 35 women and 30 children (27.8% and 23.8%, respectively) had episodes of lower respiratory tract infections. Eight children had two or more episodes of LRTI during the 24month follow-up. Generally, most of the children LRTIs (n ¼ 32, 24.6%) and the four deaths for respiratory infections occurred in the first 12 months and decreased in the second year of life (n ¼ 8, 8.3%). The number of maternal respiratory infections was 18 (14.3%) and 16 (13.7%) episodes in the first and second year, respectively. A strong correlation was also observed between occurrence of maternal and children LRTI infections; almost 50% of children from mothers experiencing LRTIs also had episodes of respiratory infections, compared with 14% of children from mothers with no LRTI episodes (p50.001).
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Association between maternal HIV immunovirological conditions and passive transfer of anti-PCP IgG The maternal concentrations of anti-PCP IgG were not influenced by the HIV immunovirological profile before the start of therapy. No significant correlations were observed between anti-PCP IgG levels and maternal CD4 cell count (p ¼ 0.740), HIV-RNA levels (p ¼ 0.848) or WHO stage (p ¼ 0.450). The maternal age, weight or haemoglobin levels did not influence the concentration of anti-PCP IgG. However, the transplacental transfer of maternal anti-PCP IgG to infants was lower in mothers with a more advanced stage of disease: the PCP IgG ratio at 1 month was significantly lower in pairs whose mothers had sustained viral replication (410 000 HIV RNA copies/ml) and with lower CD4 cell count (5350 cell/ml) before ART initiation (p ¼ 0.043 and p ¼ 0.090, respectively). While anti-PCP IgG concentrations were not associated to the episodes of LRTI, children with reduced transplacental antibody transfer were more susceptible to respiratory infections. In fact, while antibody levels were similar in mothers (55.6 and 62.3 mg/L respectively, p ¼ 0.628) and children (10.19 and 10.32 mg/L, respectively, p ¼ 0.800) experiencing or not LRTI, anti-PCP IgG ratio at month 1 was significantly lower in children with at least one episode of respiratory infection in the first 12 months of life (p ¼ 0.046, Figure 1). A lower anti-PCP IgG ratio was still observed in 6 months old children experiencing one or more LRTI episodes between months 6 and 24 (p ¼ 0.075).
Discussion In this study we investigated the passive transfer of antipneumococcal capsular polysaccharide IgG (anti-PCP IgG) in 1 and 6 month old HIV-exposed uninfected children, in a context of ART-treated HIV infection in Malawian women. Our results showed that, although maternal antibody levels are within normal values, maternal pre-ART viro-immunological parameters can affect child/mother anti-PCP IgG ratio. No clear
Table 2. Antibody levels and ratio in mother and infant plasma. Antibodies values are expressed in geometric mean and interquartile range (IQR). n maternal PCP IgG (mg/L) infant PCP IgG (mg/L) 1 month 6 months Infant/maternal ratio at 1 month Infant/maternal ratio at 6 months
geometric mean, IQR
126
57.4 (28.8–115.5)
126 33 126 33
10.3 (4.2–18.6) 6.8 (3.4–9.8) 0.165 (0.111–0.256) 0.103 (0.051–0.190)
Figure 1. Infant/maternal ratio at 1 month, in children with (n ¼ 21) or without (n ¼ 105) lower respiratory tract infections in the first 12 months of life. Values are expressed as median and IQR.
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association between anti-PCP IgG and respiratory-related deaths were found, but a lower PCP IgG ratio was significantly correlated to a higher vulnerability to respiratory infections in children. In this study the choice to measure specific anti-PCP IgG was based on the high frequency of Streptococcus pneumoniae infections, responsible for a considerable proportion of childhood morbidity and mortality worldwide and specifically in African countries.[5,15,32,33] The GMC of anti-PCP IgG concentrations of mothers was 57.4 mg/L, which is within the reported parameters for HIV-infected [17] and healthy populations.[30] It is reasonable to consider that the normal levels of maternal anti PCP IgG found in our HIV + women could reflect the repeated natural exposition to the antigens of S. pneumoniae in Malawi, where there is a high frequency of pneumococcal exposure.[34] Normal values of specific IgG concentrations have already been observed by others in the HIV infected population;[25,35] Jones et al.[31] reported antibody titers to pertussis, Hib, tetanus and pneumococcus within the normal range in HIV infected women at the time of delivery, but reduced transplacental transfer of specific IgG. We did not find any correlation between maternal anti-PCP IgG levels and pre-ART CD4 cell count and viral load. Conversely, in our study maternal HIV immunovirological parameters seem to influence the rate of passive transfer of specific IgG, as confirmed by the observation that higher maternal HIV-RNA replication and lower CD4 cell count in the pre-ART period were correlated with reduction of anti-PCP IgG ratio. Regardless of maternal IgG levels, impairment of transplacental passage of specific immunoglobulins has already been observed in HIV-infected mother children dyads.[5,19,24,31,36,37] Recently, Gupta et al.[19] demonstrated a reduction ranging from 56–90% of antibody concentration against most of the PCP serotypes in cord serum of HIV-exposed uninfected neonates compared to healthy neonates. A variety of conditions could interfere with transplacental IgG transfer; in this regard, many studies reported that the hypergammaglobulinemia in HIV could inhibit IgG transfer across the placenta, leading to a reduction of specific IgG in neonates.[24] The maternal hypergammaglobulinemia might be responsible for saturation and blocking of the active transport mechanism of specific IgG via Fc neonatal receptors on the placenta.[24,38] Unfortunately, we could not verify this hypothesis, since no total IgG levels were determined in mothers. In our study pulmonary infections occurred commonly in HIV-exposed uninfected children, as already observed by others,[15] and most of the reported episodes of LRTI occurred in the first 12 months of life, when the infants antibody levels still depend strongly on maternal transmission. The levels and the child/maternal ratio of anti-PCP IgG in the four children who died for pulmonary infection did not differ from those of the other children, but the low number of cases could have limited the statistical power to detect significant differences. Although we did not find a clear association between specific IgG absolute concentrations and an increase in morbidity/ mortality in HIV-exposed uninfected children, the reduction of passive transfer of maternal PCP IgG (ratio) was associated to
an increased risk of respiratory infection in children in the first 12 months of life. These results are not conflicting: the measurement of specific antibody concentrations does not necessarily correlate with their functional activity [39] and one of the major limits of this study is the lack of functional tests regarding antibody responses. Moreover, the alteration in transplacental passage could also be responsible for a preferential passage of IgG sub-classes.[24] In particular, antibodies against encapsulated bacteria such as S. pneumoniae in which IgG2 prevail are transferred with less efficiency in children exposed to viral and parasitic infections [24,40] and might influence their susceptibility to the infections. Our results seem to indicate that the increased children vulnerability to respiratory infections could be a consequence of inadequate maternal transfer of protective antibodies, possibly correlated to the maternal immune dysfunction. This study has important limits. One of the major limits could be inherent to the problem of obtaining an aetiological diagnosis in most cases reported as pneumonia; since respiratory infections were diagnosed and treated at the clinical sites, we had limited information on other possible aetiological agents. Second, the sample size of the mother/child pairs was small, particularly at 6 months, due only to the limited availability of children plasma samples. In conclusion, our study indicates that pre-ART conditions in mothers may influence the rate of passive transfer of specific immunoglobulins. The identification of factors that can contribute to the high rate of morbidity and mortality in HIVexposed uninfected children could be important to develop preventive strategies. In this sense the implementation of the new strategy of life-long ART administration to all pregnant women, regardless of the immunological stage (Option B-Plus approach), by generally improving mothers’ conditions, could also be beneficial for their children.
Acknowledgements We thank Alessandra Mattei for providing secretarial help, Tonino Sofia for providing comments and help in the revision of the final manuscript, Marco Mirra, Massimiliano Di Gregorio, Stefano Lucattini and Luca Fucili for IT support and Ferdinando Costa and Patrizia Cocco for technical support.
Declaration of interest This work was supported by funds from Istituto Superiore di Sanita` Rome, Italy (Grant N. 528c/28c7); by a grant from the Italian Research Program on AIDS of the Ministry of Health 2009–2010 (N. 3H/33); and by Esher-Italy, Ministry of Health 2009–2010 (Grant N. 9M34). No funding was received for this work from any of the following organizations: National Institutes of Health (NIH); Wellcome Trust; and the Howard Hughes Medical Institute (HHMI). Stefano Vella has received honoraria from ViiV, Gilead and Merck for scientific board membership. All other authors report no conflicts of interest.
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ISSN: 2374-4235 (Print) 2374-4243 (Online) Journal homepage: http://www.tandfonline.com/loi/infd20
Antibodies against pneumococcal capsular polysaccharide in Malawian HIV-positive mothers and their HIV-exposed uninfected children Silvia Baroncelli, Clementina Maria Galluzzo, Sandro Mancinelli, Mauro Andreotti, Haswell Jere, Roberta Amici, Maria Cristina Marazzi, Stefano Vella, Leonardo Palombi & Marina Giuliano To cite this article: Silvia Baroncelli, Clementina Maria Galluzzo, Sandro Mancinelli, Mauro Andreotti, Haswell Jere, Roberta Amici, Maria Cristina Marazzi, Stefano Vella, Leonardo Palombi & Marina Giuliano (2015): Antibodies against pneumococcal capsular polysaccharide in Malawian HIV-positive mothers and their HIV-exposed uninfected children, Infectious Diseases, DOI: 10.3109/23744235.2015.1115895 To link to this article: http://dx.doi.org/10.3109/23744235.2015.1115895
Published online: 26 Nov 2015.
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INFECTIOUS DISEASES, 2015 http://dx.doi.org/10.3109/23744235.2015.1115895
ORIGINAL ARTICLE
Antibodies against pneumococcal capsular polysaccharide in Malawian HIV-positive mothers and their HIV-exposed uninfected children Silvia Baroncellia, Clementina Maria Galluzzoa, Sandro Mancinellib, Mauro Andreottia, Haswell Jerec, Roberta Amicia, Maria Cristina Marazzid, Stefano Vellaa, Leonardo Palombib and Marina Giulianoa Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanita`, Rome, Italy; bDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; cDREAM Program, Community of S. Egidio, Blantyre, Malawi; dLUMSA University, Rome, Italy
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ABSTRACT
ARTICLE HISTORY
Background: HIV-exposed uninfected children have a higher risk of infection and mortality compared to HIV-unexposed children and the reasons for this vulnerability are still under investigation. Aim: This study aimed to evaluate the influence of maternal HIV parameters on the passive transfer of anti-pneumococcal capsular polysaccharide (PCP) IgG and to determine whether the concentrations of specific IgG might be related to the morbidity and mortality in HIV-exposed uninfected children. Methods: One hundred and twenty-six Malawian HIV-infected pregnant women and their uninfected children were studied. Antiretroviral treatment-naive women started a nevirapine-based triple combination regimen from the third trimester of pregnancy until at least 6 months of exclusive breastfeeding. Mother/child pairs were followed until 2 years after delivery. Plasma anti-PCP IgG titers (in mothers at 26 weeks of gestation and in infants at 1 and 6 months) were determined by an enzyme-linked immunosorbent assay. None of these women and children had received any vaccination against pneumococcal polysaccharides. Results: Maternal anti-PCP IgG concentration was independent from viral load (p ¼ 0.848), CD4 count (p ¼ 0.740) and WHO stage (p ¼ 0.450). However, the child/mother ratio of anti-PCP IgG measured at 1 month among infants was significantly reduced in pairs whose mothers had HIV-RNA410 000 copies/ml (p ¼ 0.043) and CD45350 cells/ml (p ¼ 0.090) before antiretroviral therapy (ART). No clear associations between anti-PCP IgG and respiratory-related deaths were found, but respiratory infection episodes were more frequent among children with lower anti-PCP IgG ratio (p ¼ 0.046). Conclusion: This study indicates that HIV pre-ART conditions in mothers may influence the rate of specific immunoglobulins transfer, increasing infants vulnerability to respiratory infections.
Received 24 July 2015 Revised 21 October 2015 Accepted 23 October 2015 Published online 26 November 2015 KEYWORDS
HIV exposed infants; antipneumococcal IgG; passive transfer; Malawi
Introduction The implementation of antiretroviral prophylaxis in HIVinfected pregnant women has resulted in a drastic reduction of HIV paediatric infections, both in western and in resourcelimited countries. As a consequence, HIV-exposed uninfected children are becoming an increasing population, especially in sub-Saharan Africa, where antenatal HIV infection can reach 10–20% of prevalence.[1–3] Every year 1.5 million of HIV-exposed uninfected children are born to HIV positive mothers [4]. Recent studies have reported a significant increase in morbidity and mortality in these children when compared to children born from HIV-uninfected mothers.[5–8] In subSaharan Africa, 2-year mortality in HIV-exposed uninfected children is 2–3-times greater than in healthy children [9] and the main causes of death are related to gastrointestinal and respiratory infections [10,11]. The higher vulnerability of HIV exposed uninfected children to viral and bacterial infections could be multifactorial, including HIV exposure itself,[12] CONTACT Dr Silvia Baroncelli Elena, 299, 00161 Rome, Italy
[email protected]
ß 2015 Society for Scandinavian Journal of Infectious Diseases
severity of maternal HIV clinical status and pre-natal exposure to antiretroviral drugs.[13–16] Many reports indicated inadequate maternal transplacental transfer of specific IgG in HIV exposed uninfected children,[17– 20] that could be responsible for high susceptibility to pathogens in the first months of life. Similarly, reduced passive antibody transfer has also been observed in antenatal vaccine programmes for poliovirus,[18] tetanus toxoid [21] and Haemophilus influenza type B [22] in HIV pregnant women. Many factors might be involved in this process and the mechanisms are still under investigation. Abnormalities of B cells, including polyclonal activation and hypergammaglobulinemia observed in advanced stages of HIV disease,[23] could interfere with the transfer of maternal antibodies across the placenta that is mediated by Fc receptors.[24,25] In this study we aimed to explore the influence of maternal HIV infection on the passive transfer of specific antibodies against the capsular polysaccharide of Streptococcus pneumoniae (PCP), one of the most common causes of lower
Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanita`, Viale Regina
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respiratory tract infections (LRTI) in sub-Saharan Africa.[15] The specific aims of this study were (1) to evaluate the anti-PCP IgG concentrations in mothers and their HIV exposed uninfected children and to determine the influence of maternal HIV conditions on the passive transfer of anti-PCP IgG; and (2) to determine whether different child/maternal IgG ratios might be related to an increased vulnerability to respiratory infections in HIV-exposed uninfected children.
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Methods Study setting and population The present study population included 126 mother/child pairs and it is nested in a larger observational study aimed to assess safety and pharmacokinetics of maternal antiretroviral therapy (ART) administration during breastfeeding [Safe Milk for African Children (SMAC) study],[26] conducted within the DREAM (Drug Resource Enhancement against AIDS and Malnutrition) Program of the Community of S. Egidio. Criteria to include patients in this sub-study were: availability of plasma samples from mothers at the enrolment and from children at the first month of life and complete clinical records for all pairs. Children diagnosed with HIV infection were excluded.
Diagnostics, Deerfield, IL) were performed at the local DREAM laboratories in Malawi. This study received ethics approval by the National Health Research Committee in Malawi.
Anti-pneumococcal capsular polysaccharide IgG determination Levels of Pneumococcal Capsular Polysaccharide (PCP) specific IgG were evaluated in serum or plasma at baseline for mothers (26 weeks of gestation) and at month 1 in infants. In infants, when samples were available, plasma levels of anti-PCP IgG were measured also at month 6 (n ¼ 33). Anti-PCP IgG were measured using the VaccZyme Human Anti-PCP Enzyme Immunoassay kit (The Binding Site Ltd, Birmingham, UK). Microwells in the pneumococcal assay were pre-coated with pneumococcal capsular polysaccharide antigens 1-5, 6B, 7F, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F. This commercial kit, designed to measure antibody response to vaccination and to natural exposition to Streptococcus pneumoniae, determines a global response to 23 polysaccharide antigens accounting for 80% of virulent serotypes.[29] The IgG data are presented as a collective response to multiple serotypes, as indicated by the assay instructions and reported by others in similar studies.[17,30,31] The values are expressed in mg/L.
Study procedures HIV-infected pregnant women, treatment-naive (with the exception of single dose-nevirapine) were introduced to antiretroviral therapy from week 26 of gestational age. If meeting the criteria for treatment (CD4 + cell count5350 cells/ mm3), they received a combination of stavudine (30 mg twice daily), lamivudine (150 mg twice daily) and nevirapine (200 mg twice daily) (first-line regimen recommended in Malawi at the time of the study) and continued indefinitely; in the case of a CD4 + count4350/mm3, were treated with a regimen consisting of zidovudine (300 mg twice daily), lamivudine and nevirapine (the preferred preventive strategy used by the DREAM programme) [27] until 6 months post-partum. Infants were exclusively breastfed for the first 6 months of life. Women and children enrolled in this study did not receive any vaccination against pneumococcal polysaccharides.
Clinical visits and laboratory analysis Clinical visits were scheduled monthly during the first 12 months after delivery, then every 3 months until 24 months post-partum. Supplemental clinical care was offered to all women and children when needed also outside the scheduled visits. All LRTIs were diagnosed at the clinical sites. Due to the limitation of diagnostic tools available, respiratory infections were diagnosed by clinical judgement, on the basis of symptoms such as fever and malaise, cough, pleuritic chest pain, dyspnoea or tachypnoea and by the auscultation of the chest, as suggested by the guidelines.[28] Laboratory analysis and plasma samples collection were performed at months 1, 3 and 6 and then every 3 months. CD4 cell count (Epics XL-MCL, Beckman Coulter, Brea, CA) and HIV RNA determinations (branched DNA version 3.0 assay, Siemens
Statistical analysis Statistical analysis was performed using SPSS (v.22, IBM, Somers, NY). The Mann Whitney and Wilcoxon tests were used to compare geometric mean concentration (GMC) of antiPCP IgG. The Spearman’s test was used for correlations and the Fisher exact test for proportions.
Results Study population One hundred and twenty-six mother/child pairs were included in this analysis, based on the availability of maternal and child plasma samples. Characteristics of the study population are reported in Table 1. At enrolment (median ¼ 26 week of pregnancy) median level of HIV RNA was 4.09 log copies/ml and over half the women (55.6%) had a CD4 cell count below 350/mm3. Their antiretroviral therapy was based on a backbone of zidovudine-lamivudine (n ¼ 56, 44.4%) or stavudine-
Table 1. Maternal characteristics (n ¼ 126) at the enrolment (median ¼ 26th gestational week). Values are expressed as median and interquartile range (IQR) or percentage. Patients characteristics Age (years) Maternal weight (Kg) Hb levels (g/dl) WHO I/II/III stage (%) CD4 (below 350 cell/mm3) (%) CD4 (cells/mm3) HIV RNA (log copies/mL) Pregnancy week of ART initiation Caesarian section (n, %)
Values 26.5 (23.0–30.0) 57.9 (51.8–65.3) 10.2 (9.1–11.0) 69.4/21.8/8.9 70 (55.6) 320 (214–482) 4.09 (3.38–4.51) 26 (24–29) 7 (5.6%)
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lamivudine (n ¼ 70, 55.6%) plus nevirapine. Most of the women (94.4%) had vaginal delivery. At the time of delivery plasma HIV RNA was determined only for a small number of women, but 1 month after delivery only six out of 126 (4.8%) women had viral load41000 copies/ml, showing the efficacy of the antiretroviral therapy. Median neonatal weight was 3300 g (IQR ¼ 2800–3500). All except three neonates were singletons. Only data from the first born were considered in this study. Women and children enrolled in this study did not receive any vaccination against pneumococcal polysaccharides.
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Maternal and infant IgG antibodies specific for pneumococcal capsular polysaccharide At enrollment (third trimester of pregnancy, before the introduction of ART) all 126 mothers had concentrations of PCP IgG above the detection limit (higher than 3.3 mg/L). The geometric mean concentration of specific anti-PCP IgG was 57.4 mg/L (IQR ¼ 28.8–115.5) in mothers and 10.3 mg/L (IQR ¼ 4.2–18.6) and 6.8 mg/L (IQR ¼ 3.4–9.8) in 1 and 6 months old infants, respectively (Table 2). Medians of infant/ maternal PCP IgG ratio were 0.165 mg/L (IQR ¼ 0.111–0.256) and 0.103 (IQR ¼ 0.051–0.190) at months 1 and 6, indicating the physiological decline in passively acquired specific anti-PCP antibodies during the first 6 months of life. The maternal PCP IgG levels were directly correlated to infant levels at 1 month (r ¼ 0.704, p50.001), remaining significantly associated at 6 months (r ¼ 0.410, p ¼ 0.018).
Maternal and infant follow-up: respiratory morbidity and mortality A total of 35 women and 30 children (27.8% and 23.8%, respectively) had episodes of lower respiratory tract infections. Eight children had two or more episodes of LRTI during the 24month follow-up. Generally, most of the children LRTIs (n ¼ 32, 24.6%) and the four deaths for respiratory infections occurred in the first 12 months and decreased in the second year of life (n ¼ 8, 8.3%). The number of maternal respiratory infections was 18 (14.3%) and 16 (13.7%) episodes in the first and second year, respectively. A strong correlation was also observed between occurrence of maternal and children LRTI infections; almost 50% of children from mothers experiencing LRTIs also had episodes of respiratory infections, compared with 14% of children from mothers with no LRTI episodes (p50.001).
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Association between maternal HIV immunovirological conditions and passive transfer of anti-PCP IgG The maternal concentrations of anti-PCP IgG were not influenced by the HIV immunovirological profile before the start of therapy. No significant correlations were observed between anti-PCP IgG levels and maternal CD4 cell count (p ¼ 0.740), HIV-RNA levels (p ¼ 0.848) or WHO stage (p ¼ 0.450). The maternal age, weight or haemoglobin levels did not influence the concentration of anti-PCP IgG. However, the transplacental transfer of maternal anti-PCP IgG to infants was lower in mothers with a more advanced stage of disease: the PCP IgG ratio at 1 month was significantly lower in pairs whose mothers had sustained viral replication (410 000 HIV RNA copies/ml) and with lower CD4 cell count (5350 cell/ml) before ART initiation (p ¼ 0.043 and p ¼ 0.090, respectively). While anti-PCP IgG concentrations were not associated to the episodes of LRTI, children with reduced transplacental antibody transfer were more susceptible to respiratory infections. In fact, while antibody levels were similar in mothers (55.6 and 62.3 mg/L respectively, p ¼ 0.628) and children (10.19 and 10.32 mg/L, respectively, p ¼ 0.800) experiencing or not LRTI, anti-PCP IgG ratio at month 1 was significantly lower in children with at least one episode of respiratory infection in the first 12 months of life (p ¼ 0.046, Figure 1). A lower anti-PCP IgG ratio was still observed in 6 months old children experiencing one or more LRTI episodes between months 6 and 24 (p ¼ 0.075).
Discussion In this study we investigated the passive transfer of antipneumococcal capsular polysaccharide IgG (anti-PCP IgG) in 1 and 6 month old HIV-exposed uninfected children, in a context of ART-treated HIV infection in Malawian women. Our results showed that, although maternal antibody levels are within normal values, maternal pre-ART viro-immunological parameters can affect child/mother anti-PCP IgG ratio. No clear
Table 2. Antibody levels and ratio in mother and infant plasma. Antibodies values are expressed in geometric mean and interquartile range (IQR). n maternal PCP IgG (mg/L) infant PCP IgG (mg/L) 1 month 6 months Infant/maternal ratio at 1 month Infant/maternal ratio at 6 months
geometric mean, IQR
126
57.4 (28.8–115.5)
126 33 126 33
10.3 (4.2–18.6) 6.8 (3.4–9.8) 0.165 (0.111–0.256) 0.103 (0.051–0.190)
Figure 1. Infant/maternal ratio at 1 month, in children with (n ¼ 21) or without (n ¼ 105) lower respiratory tract infections in the first 12 months of life. Values are expressed as median and IQR.
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association between anti-PCP IgG and respiratory-related deaths were found, but a lower PCP IgG ratio was significantly correlated to a higher vulnerability to respiratory infections in children. In this study the choice to measure specific anti-PCP IgG was based on the high frequency of Streptococcus pneumoniae infections, responsible for a considerable proportion of childhood morbidity and mortality worldwide and specifically in African countries.[5,15,32,33] The GMC of anti-PCP IgG concentrations of mothers was 57.4 mg/L, which is within the reported parameters for HIV-infected [17] and healthy populations.[30] It is reasonable to consider that the normal levels of maternal anti PCP IgG found in our HIV + women could reflect the repeated natural exposition to the antigens of S. pneumoniae in Malawi, where there is a high frequency of pneumococcal exposure.[34] Normal values of specific IgG concentrations have already been observed by others in the HIV infected population;[25,35] Jones et al.[31] reported antibody titers to pertussis, Hib, tetanus and pneumococcus within the normal range in HIV infected women at the time of delivery, but reduced transplacental transfer of specific IgG. We did not find any correlation between maternal anti-PCP IgG levels and pre-ART CD4 cell count and viral load. Conversely, in our study maternal HIV immunovirological parameters seem to influence the rate of passive transfer of specific IgG, as confirmed by the observation that higher maternal HIV-RNA replication and lower CD4 cell count in the pre-ART period were correlated with reduction of anti-PCP IgG ratio. Regardless of maternal IgG levels, impairment of transplacental passage of specific immunoglobulins has already been observed in HIV-infected mother children dyads.[5,19,24,31,36,37] Recently, Gupta et al.[19] demonstrated a reduction ranging from 56–90% of antibody concentration against most of the PCP serotypes in cord serum of HIV-exposed uninfected neonates compared to healthy neonates. A variety of conditions could interfere with transplacental IgG transfer; in this regard, many studies reported that the hypergammaglobulinemia in HIV could inhibit IgG transfer across the placenta, leading to a reduction of specific IgG in neonates.[24] The maternal hypergammaglobulinemia might be responsible for saturation and blocking of the active transport mechanism of specific IgG via Fc neonatal receptors on the placenta.[24,38] Unfortunately, we could not verify this hypothesis, since no total IgG levels were determined in mothers. In our study pulmonary infections occurred commonly in HIV-exposed uninfected children, as already observed by others,[15] and most of the reported episodes of LRTI occurred in the first 12 months of life, when the infants antibody levels still depend strongly on maternal transmission. The levels and the child/maternal ratio of anti-PCP IgG in the four children who died for pulmonary infection did not differ from those of the other children, but the low number of cases could have limited the statistical power to detect significant differences. Although we did not find a clear association between specific IgG absolute concentrations and an increase in morbidity/ mortality in HIV-exposed uninfected children, the reduction of passive transfer of maternal PCP IgG (ratio) was associated to
an increased risk of respiratory infection in children in the first 12 months of life. These results are not conflicting: the measurement of specific antibody concentrations does not necessarily correlate with their functional activity [39] and one of the major limits of this study is the lack of functional tests regarding antibody responses. Moreover, the alteration in transplacental passage could also be responsible for a preferential passage of IgG sub-classes.[24] In particular, antibodies against encapsulated bacteria such as S. pneumoniae in which IgG2 prevail are transferred with less efficiency in children exposed to viral and parasitic infections [24,40] and might influence their susceptibility to the infections. Our results seem to indicate that the increased children vulnerability to respiratory infections could be a consequence of inadequate maternal transfer of protective antibodies, possibly correlated to the maternal immune dysfunction. This study has important limits. One of the major limits could be inherent to the problem of obtaining an aetiological diagnosis in most cases reported as pneumonia; since respiratory infections were diagnosed and treated at the clinical sites, we had limited information on other possible aetiological agents. Second, the sample size of the mother/child pairs was small, particularly at 6 months, due only to the limited availability of children plasma samples. In conclusion, our study indicates that pre-ART conditions in mothers may influence the rate of passive transfer of specific immunoglobulins. The identification of factors that can contribute to the high rate of morbidity and mortality in HIVexposed uninfected children could be important to develop preventive strategies. In this sense the implementation of the new strategy of life-long ART administration to all pregnant women, regardless of the immunological stage (Option B-Plus approach), by generally improving mothers’ conditions, could also be beneficial for their children.
Acknowledgements We thank Alessandra Mattei for providing secretarial help, Tonino Sofia for providing comments and help in the revision of the final manuscript, Marco Mirra, Massimiliano Di Gregorio, Stefano Lucattini and Luca Fucili for IT support and Ferdinando Costa and Patrizia Cocco for technical support.
Declaration of interest This work was supported by funds from Istituto Superiore di Sanita` Rome, Italy (Grant N. 528c/28c7); by a grant from the Italian Research Program on AIDS of the Ministry of Health 2009–2010 (N. 3H/33); and by Esher-Italy, Ministry of Health 2009–2010 (Grant N. 9M34). No funding was received for this work from any of the following organizations: National Institutes of Health (NIH); Wellcome Trust; and the Howard Hughes Medical Institute (HHMI). Stefano Vella has received honoraria from ViiV, Gilead and Merck for scientific board membership. All other authors report no conflicts of interest.
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