The role of C – reactive protein and Pentraxin 3 in HIV-associated pre-eclampsia

doi:10.21203/rs.3.rs-3771614/v1

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The role of C – reactive protein and Pentraxin 3 in HIV-associated pre-eclampsia

https://doi.org/10.21203/rs.3.rs-3771614/v1

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Objectives

To compare the expression of inflammatory proteins, pentraxin 3 and c-reactive proteins in HIV-associated normotensive and preeclamptic pregnancies.

Methods

Both HIV status (HIV-positive and HIV-negative) and pregnancy type (normotensive pregnant and preeclampsia) were used to stratify the study population (n = 80). Using a ProcartaPlex™ immunoassay technique, the plasma concentrations of pentraxin 3 and c-reactive protein were measured.

Results

An up-regulation of c-reactive protein was demonstrated in pre-eclamptic versus normotensive women; HIV-positive versus HIV-negative, and across the study population. albeit non-significant. Pentraxin 3 was significantly higher in preeclamptic versus normotensive women (p < 0.0001), irrespective of HIV status. However, no significance was found in HIV status, regardless of pregnancy type. When compared across all groups pentraxin 3 concentrations was significantly different between normotensive HIV-negative versus pre-eclamptic HIV-negative groups (p = 0.0001); and normotensive HIV-negative versus pre-eclamptic HIV-positive groups (p = 0.0049).

Conclusions

This novel study demonstrated pentraxin 3 concentrations to be significantly higher in pre-eclampsia compared to normotensive pregnant women, emanating from oxidative stress and inflammation. C-reactive protein was higher in the normotensive pregnant women compared to pre-eclampsia. This difference may stem from hepatic dysfunction, gestational age, disease severity, interleukin-6 production, and/or sample size.

HIV infection

Pre-eclampsia

inflammation

Pentraxin 3

C- reactive protein

Pre-eclampsia (PE) is a pregnancy-specific disorder, that occurs after 20 weeks of gestation and may be identified by new-onset hypertension (≥ 140/90 mmHg on two or more occasions) and/or proteinuria and multi-organ dysfunction [1]. It can also cause foetal distress and growth restriction and in some cases foetal death [2]. Globally, PE is the leading cause of mortality and morbidity in pregnancies [3]. In South Africa, PE accounts for the majority of hypertensive related maternal deaths [4]

The pathophysiology of PE is described as having abnormal placentation and endothelial injury [5]. This results from abnormal cytotrophoblast invasion and absence of myometrial spiral arteriole transformation [6]. This leads to reduced blood flow, hence insufficient nutrient and oxygen supply to the neonate [7]. Inflammatory and angiogenic mediators are released systemically as a result of this oxidative stress environment [8].

C – reactive protein (CRP) is a pentameric protein, synthesized in the liver, with its structural gene found on chromosome 1 [9]. The level of CRP rise in response to a wide range of inflammatory conditions and thus act as an early innate defence system against infections [10]. Moreover, CRP binds to specific molecules on the surface of bacteria, viruses, and damaged cells, thereby activating the complement system to remove pathogens and damaged cells from the body. Furthermore, CRP may also interact with other immune cells, such as monocytes and macrophages, thus stimulating the production of cytokines, initiating an immune response [11].

The normal level of CRP is 0 to 10 mg/l; however, inflammation causes an increase in concentration [9]. Within two hours of triggering an immune response, CRP levels can spike up to 350–400 mg/l [10]. Systemic CRP levels correlate with the severity of endothelial cell injury, which makes it a good predictor of PE [12].

Numerous cells, including monocytes, macrophages, epithelial cells, polymorphonuclear cells, endothelial cells, dendritic cells, and fibroblasts, synthesize pentraxin 3 (PTX3), which is located on chromosome 3q25. [13, 14]. It would hence have the potential predictor test value for endothelial dysfunction and inflammation in PE [15]. Endothelial dysfunction leads to the production of inflammatory factors, such as growth factors and cytokines, inducing promoting PTX3 synthesis [13]. The normal level of PTX3 in women are around 2.4 x 10^− 3 mg/l but may rise to 0.200 mg/l to 0.800 mg/l in 6 to 8 hours following the initiation of pro-inflammatory mediators [16, 17].

Pentraxin 3 is involved in the immune response against both viral and bacterial infections by binding to virus-infected cells, thus inhibiting the replication of specific viruses, Additionally, PTX3 is also involved in reducing inflammation and aiding in the elimination of viruses. Although its exact mechanism of action is not fully understood, it is known to be involved in the recognition of viral proteins and the activation of immune cells [11].

Human immunodeficiency virus (HIV) is an infection that primarily infects CD4 + T cells, macrophages, and dendritic cells, weakening a body’s immunity against opportunistic infections [18, 19]. Globally, approximately 38 million people suffer from HIV, of which 54% reside in South Africa. [20]. Within the South African population, 24% of HIV infections occur in women between the ages of 15 to 49 years old [21]. Approximately 90% of the women in Eastern and Southern Africa have access to antiretroviral therapy (ART) [20]. HIV treatment remains the same for both pregnant and non-pregnant women, however, the risk of mother-to-child transmission may be reduced by ART throughout pregnancy [22].

In light of the high maternal mortality emanating from PE and HIV infection it is imperative that we understand the synergy of both conditions. Thus, it is crucial to identify the association of biomarkers PTX 3 and CRP within the endothelial damaged hyperinflammatory micro-environment of PE co-morbid with HIV. This understanding is essential for early detection, enabling improved and timely management of this co-morbidity.

Ethics Approval

This prospective study received institutional ethics approval (BE/5735/2023) for use of retrospectively collected plasma samples (BCA338/17). Women were recruited from a large regional hospital in eThekwini, KwaZulu-Natal, South Africa.

Study Population

Sample size

The sample size was determined after consultation with an institutional biostatistician using G*Power statistical software. A sample of size of 80 pregnant women was required to detect a median effect size of 0.3 between the two larger groups: normotensive and pre-eclamptic or HIV positive and HIV negative, assuming equal groups (n = 40 per group). To compare four groups: normotensive (HIV-positive versus HIV-negative) and preeclamptic (HIV-positive versus HIV-negative); assuming equal groups (n = 20 per group) to detect a large effect size of 0.45. All calculations are with a probability of 95% and a power of 80%. Sample size calculated.

Irrespective of CD4 cell count, all HIV-positive study participants received ART and PMTCT therapy during pregnancy and breastfeeding. Women with CD4 counts < 500 cells/mm3 were also given ongoing ART after nursing. Women receiving ARV treatment were given either a single medication, such as zidovudine, often referred to as azidothymidine (AZT), or a combination of many medications, including efavirenz (EFV), tenofovir disoprovil fumarate (TDF, Viread), and emtricitabine (FTC, Emtriva). In accordance with South African National HIV guidelines, an alternate medicine combination consisting of Abacavar (ABC, Ziagen), Lamivudine (3TC, Epivir), and Efavirenz (EFV) was given to a few patients together with PMTCT (nevirapine). Nevirapine prophylaxis was given to newborns exposed to HIV for 4–6 weeks.

Inclusion criteria - Women diagnosed with early on-set pre-eclampsia (EOPE); blood pressure reading of ≥ 140/90 mmHg and incidence of proteinuria. Women with normotensive pregnancy. HIV status is known; both HIV-positive and HIV-negative women were considered in the study.

Exclusion criteria - Women who did not consent to participate and did not provide informed consent; women without antenatal care; Women with an unknown HIV status; women diagnosed with late on-set pre-eclampsia (LOPE); and Women with the following ailments: polycystic ovarian syndrome; eclampsia; pre-existing seizure disorders; intrauterine death; abruption placentae; chorioamnionitis; chronic hypertension; gestational diabetes; chronic diabetes; systemic lupus erythematous; chronic renal disease; thyroid disease; sickle cell disease; antiphospholipid antibody syndrome; cardiac disease; connective tissue disorder; asthma was excluded from the study.

Immunoassay

Plasma samples, stored at -80℃, were used and underwent an immunoassay using ProcartaPlex™ kits [ThermoFisher, HU basic kit (EPX010-10420-901); HU CRP simplex (EPX01A-10288-901); HU PTX3 simplex (EPX010-12281-901)]. Only CRP samples underwent a dilution of 1:500.

Statistical analysis

GraphPad Prism 5.00 for Windows was used to analyse the data. Because of the non-parametric nature of the distribution, the results are shown as the median and interquartile range (IQR). The statistical significance of each pregnancy type (normotensive versus PE) and HIV status (negative versus positive) was assessed using the Mann-Whitney U test. One-way ANOVA was performed to evaluate statistical significance for each group, and the Kruskal-Wallis test was employed. The reported statistical significance was p < 0.05.

Data analysis techniques

Data obtained in this study was captured using a Bio-plex 200 instrument equipped with Bio-Plex® MAGPIX™ Multiplex system and analysed using Bio-Plex Manager™ analysis software version 6.1. A standard curve of each analyte was generated using the known concentration (pg/ml) by plotting the median fluorescent intensity (MFI) signal against concentration. The standard curve was then used to interpolate the concentration of the unknown samples. This data was then imported into an Excel spreadsheet for statistical analysis and converted from pg/ml to mg/l.

Patient demographics and clinical characteristics

Patient demographics and clinical characteristics (Table 1) were non-parametrically distributed hence, represented by median and interquartile range (IQR). Significant differences were observed in maternal age (p = 0.0163); parity (p < 0.0001); gravidity (p < 0.0001); gestational age at birth (p = 0.0001); systolic blood pressure (p < 0.0001); diastolic blood pressure (p = 0.0043); Body Mass Index (BMI) (p = 0.0102); and baby weight (p = 0.0044) across the study groups. However, there were no significant differences of placental weight (p > 0.1000) across the study groups.

Table 1

Patient demographics across the study group
	Normotensive HIV – (n = 20)	Normotensive HIV + (n = 20)	Pre-eclamptic HIV – (n = 20)	Preeclamptic HIV + (n = 20)	p-value
Maternal age (years)	24 (26 − 19)	27 (30 − 23)	27.5 (30.50-19.75)	28 (30 − 23)	0.0163 (*)
CD4 + count	-	404 (585 − 253)	-	413 (514.5–292)	> 0.1000 (ns)
Parity	1 (1 − 0)	2 (2 − 1)	1.5 (2.250-0)	1 (2 − 0)	< 0.0001 (****)
Gravidity	2 (2 − 1)	3 (3 − 2)	2.5 (3 − 1)	2 (3 − 1)	< 0.0001 (****)
Gestation age at birth (weeks)	40 (40.50–37.50)	39 (39.25-37.00)	31 (34.50–28)	31.5 (36.75–29.25)	0.0001 (***)
Systolic BP (mmHG)	119 (128 − 106)	117 (123 − 110)	167 (180.8-159.3)	171 (180 − 162)	< 0.0001 (****)
Diastolic BP (mmHG)	70.5 (82 − 66)	72 (77 − 70)	102.5 (112.8-94.25)	104 (114 − 97)	0.0043 (**)
BMI	33 (36 − 31)	28 (31 − 26)	29.5 (33.50-25.75)	28 (36 − 26)	0.0102 (*)
Baby weight (kg)	3.64 (3.843–3.110)	3.16 (3.300–2.970)	1.8 (2.5-1.195)	1.4 (2.590–0.98)	0.0044 (**)
Placental weight (g)	0.67 (0.713 − 0.586)	0.59 (0.650 − 0.500)	0.485 (0.643 − 0.338)	0.42 (0.568 − 0.318)	> 0.1000 (ns)
Data is represented as the median (IQR)
BP = blood pressure; BMI = body mass index; ns = non-significant
ns = 0.1234; * -= 0.0332; -= 0.0021; * < 0.0001

Table 2

Plasma concentrations of CRP and PTX 3 (ng/ml) across all study groups.
	Normotensive pregnancy		Pre-eclamptic pregnancy
	HIV –	HIV +	HIV –	HIV +
CRP (mg/l) (n = 80)	43.30 (43.30-2.661)	44.13 (70.61–2.650)	38.58 (38.58–4.176)	37.54 (37.54–6.234)
PTX 3 (mg/l) (n = 80)	0.040 (0.061 − 0.028)	0.076 (0.202 − 0.047)	0.258 (0.833 − 0.119)	0.299 (0.519 − 0.062)
All values are represented as median (IQR); CRP = c - reactive protein; PTX 3 = pentraxin 3; HIV = human immunodeficiency virus

Plasma concentration of Pentraxin 3

Pregnancy type

Pentraxin 3 concentrations were significantly higher in PE [0.279 mg/l; IQR = 0.651 − 0.103 mg/l] compared to normotensive [0.049 mg/l; IQR = 0.111 − 0.039 mg/l] groups, irrespective of HIV status [Mann-Whitney U = 353; p = < 0.0001; FIGURE 1A]

HIV status PTX 3 concentrations showed no significance in HIV-negative [0.100 mg/l; IQR = 0.289 − 0.039 mg/l] compared to HIV-positive [0.148 mg/l; IQR = 0.4594 − 0.04750 mg/l] groups, irrespective of pregnancy type [Mann-Whitney U = 635; p = 0.371; FIGURE 1B]

Across all groups

PTX 3 concentrations was significantly different between normotensive HIV-negative [0.040 mg/l; IQR = 0.061 − 0.028 mg/l] versus PE HIV-negative [0.258 mg/l; IQR = 0.833 − 0.119 mg/l] groups (p = 0.0001); and normotensive HIV-negative [0.040 mg/l; IQR = 0.061 − 0.028 mg/l] versus PE HIV-positive [0.299 mg/l; IQR = 0.519 − 0.062 mg/l] groups (p = 0.0049) [Kruskal-Wallis statistic = 20.05; FIGURE 1C]

Plasma concentration of c-reactive protein

Pregnancy type

C- reactive protein concentrations was not statistically different between normotensive pregnant [43.30 mg/l; IQR = 63.78–2.650 mg/l] and PE [ 37.540 mg/l; IQR = 38.58–5.3 mg/l] groups, irrespective of HIV status [Mann-Whitney U = 602; p = 0.055; FIGURE 2A]

HIV status

Based on HIV status, CRP concentrations was not significantly different between HIV-negative [38.580 mg/l; IQR = 43.30–3.600 mg/l] versus HIV-positive [37.540 mg/l; IQR = 62.34–3.176 mg/l] groups, irrespective of pregnancy type [Mann-Whitney U = 769; p = 0.767; FIGURE 2B].

Across all groups

C-reactive protein concentrations did not differ across the study population; Normotensive HIV-negative [43.300 mg/l; IQR = 43.30-2.661 mg/l]; normotensive HIV-positive [44.130 mg/l; IQR = 70.61–2.650 mg/l] groups, PE HIV-negative [38.580 mg/l; IQR = 38.58-4.176g/l]; and PE HIV-positive [37.540 mg/l; IQR = 37.54–6.234 mg/l] groups [Kruskal-Wallis statistic = 4.264; p = 0.230; FIGURE 2C]

Pentraxin 3

A main finding of this study was a significance up-regulation of PTX 3 in PE compared to normotensive pregnancy, regardless of HIV status (p < 0.0001) and across the study population (p = 0.0002). These findings are consistent with previous studies [23–25]. Our results are also corroborated by Cetin et al (2009) who observed a significantly higher PTX3 level in PE compared to normotensive pregnancy (p = 0.0046). Furthermore, a meta-analysis study highlighted that PTX3 concentration in EOPE or severe PE is up-regulated compared to LOPE or mild PE (p = 0.01) [25].

In PE a failure to establish adequate uteroplacental blood flow causes hypoxia, promoting a state of oxidative stress and exaggerated inflammation [26]. This excessive inflammation increases the levels of pro-inflammatory factors such as interleukin-1 (IL-1) and TNF- α, which synthesize PTX3 and activate vascular and placental endothelial cells thereby leading to endothelial dysfunction [25].

Pentraxin 3 is produced at sites of inflammation, and it is intimately linked to endothelial dysfunction [27]. Since PE is a hyperinflammatory condition concomitant with endothelial injury it is expected that the concentrations of this inflammatory marker as observed in our study would be exacerbated in the synergy of PE co-morbid with HIV infection. The complement system is also activated during endothelial dysfunction, PTX 3 directly binds to C1q, which serves as the initial component of the pathway. Inflammation causes PTX 3 release in PE co-morbid with HIV infection, which activates C1q release and boosts C3 and C4 deposition. This induces the release of cytokines, including IL-1, IL-6, and TNF-α. [28, 29].

Furthermore, opsonization of apoptotic cells by PTX3 affects the clearance of lipid-loaded macrophages and foam cells [25]. PTX3 may promote T lymphocyte transformation into type 1 T helper cells and hinder the recognition ability of dendritic cells on late apoptotic cells. This could result in an imbalance of apoptosis, which may contribute to the development of PE. As a result, it is suggested that PTX3 may increase the risk of PE by impairing the function of placental vascular endothelial cells [25]. It is plausible that the elevated PTX3 in PE as observed in our study may explain the elevated apoptosis; moreover severe PE is characterised by vascular foam cells within athetotic lesions [30]. Xiong et al (2020) suggests that PTX3 may be a novel marker for EOPE.

We also report that HIV infection did not influence PTX 3 concentration, irrespective of pregnancy type (p = 0.371). It is well established that ART reconstitutes immune response thereby influencing TNF-α and IL-1 which inhibits PTX3 activation. Previous studies have shown that HIV-infected patients have a lower concentration of PTX3 than those who are ART naïve [31, 32]. However, Minami et al (2020) found that low plasma PTX3 concentrations correlated with the duration of ART, however, HIV-related variables such as CD4 + T cell counts, HIV-RNA load before ART, and the type of ART did not correlate with plasma PTX3 levels [33]. Nonetheless, PTX 3 specifically binds to virus-infected cells, rather than uninfected cells, implicating a selective impact during viral infection [34].

C – reactive protein

During normal pregnancy CRP levels vary across trimesters (2.39 mg/l, 2.44 mg/l, 4.12 mg/l, respectively) [35]. CRP levels in PE compared to normotensive pregnancies are variable, being both up-regulated [23, 36–38] and down-regulated [39] in PE. In our study we observed a borderline, non-significant difference of CRP concentration between PE and normotensive pregnancies (p < 0.055). This difference is supported by the afore-mentioned studies; however, it may also reflect the sample size, disease severity and gestational age. C-reactive protein levels are associated with lower birth weight hence would be compromised in EOPE [40]. Moreover, in EOPE the low levels of IL-6, a pre-requisite for CRP synthesis may pre-empt a dysregulation of CRP. [41]. Nonetheless, CRP is an inflammatory marker and was expected to be elevated in PE, a hyperinflammatory condition. It has been reported that the absence of variation in CRP levels during EOPE may indicate that the maternal inflammatory response in the second trimester of pregnancy is not heightened before the appearance of clinical signs of PE [38].

Our study also demonstrates that HIV infection, regardless of pregnancy type does not affect CRP concentration (p = 0.371) with CRP levels being higher in HIV infection than HIV naïve groups. It is controversial that this acute phase protein is elevated in HIV infection compared to HIV naïve patients [42, 43]. Previous studies have reported that the high apoptosis, as occurs in HIV infection may promote the production of CRP, a scavenger for chromatin released from apoptotic cells [44, 45].

It is plausible that ART usage may have influenced CRP concentration in the HIV cohort since ART is a standard of care for HIV infection in South Africa. A higher CRP concentration has been associated with AIDS progression, independent of Highly active antiretroviral treatment usage however, lower levels of CRP are believed to predict longer survival rates of HIV infected patients [46]. Switching antiretrovirals, may have a substantial effect on inflammation [47]. Antiretroviral therapy reduces systemic inflammation. However, levels do not eliminate the inflammatory response. Integrase inhibitors reduces inflammation to a greater extent than NNRTIs [48]

Silva et al (2013) reported that patients who switched from enfuvirtide to raltegravir had significant decreases in CRP, D-dimer, and IL-6 levels [49]. The same was observed when patients switched from a ritonavir-boosted PI or NNRTI treatment to raltegravir [50]. In contrast, Hileman and Funderburg (2017) reported elevated CRP levels in patients receiving efavirenz.

PIs such as lopinavir, darunavir and NNRTIs like nevirapine have known to cause hepatitis, with NNRTIs having the most severe reactions [51].

In the synergy of PE co-morbid with HIV infection, hepatic dysfunction may exist. HIV is known to cause non-alcoholic fatty liver disease [52], whilst EOPE is associated with elevated liver enzymes and/or liver damage [26, 39]. Since CRP is produced in the liver [9], liver dysfunction may be responsible for the elevated CRP concentrations in the EOPE positive compared to the normotensive positive and negative groups in our study.

The novel study demonstrates a significant up-regulation of PTX3 concentrations in normotensive versus PE, regardless of HIV status. This elevation may originate from the oxidative stress micro-environment which predisposes vascular foam cells and IL1-6 release withing the hyperinflammatory condition of PE. CRP concentrations were similar by pregnancy type, HIV status and across study groups, possibly attributed to hepatic dysfunction, IL-6 production, sample size, gestational age and/or disease severity. In the synergy of HIV infection and PE, PTX 3 and CRP concentrations were not significantly different across groups and may be attributable to highly active antiretroviral treatment and switching of ART regimens during pregnancy (Fig. 3).

Acknowledgements

The authors would like to express their gratitude to Dr Shoohana Singh and Ms Catherine Connolly for their assistance with data and statistical analysis.

Funding

This project was funded by the Productivity Fund of Prof Thajasvarie Naicker.

Ethics approval

Ethical approval was obtained from the institutional Biomedical Research Ethics Committee.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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No competing interests reported.

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The role of C – reactive protein and Pentraxin 3 in HIV-associated pre-eclampsia

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Abstract

Objectives

Methods

Results

Conclusions

Figures

Introduction

Methods and materials

Ethics Approval

Study Population

Sample size

Immunoassay

Statistical analysis

Data analysis techniques

Results

Patient demographics and clinical characteristics

Plasma concentration of Pentraxin 3

Plasma concentration of c-reactive protein

Discussion

Pentraxin 3

C – reactive protein

Conclusion

Declarations

References

Additional Declarations

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