LEVELS.html

ORIGINAL ARTICLE

Levels of procalcitonin, C-reactive protein and neopterin in patients with advanced HIV-1 infection

P Bipath, MSc

M Viljoen, PhD, PhD

Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria

P F Levay, MSc, MB ChB, MMed (Internal)

Department of Internal Medicine, Kalafong Hospital and School of Medicine, Faculty of Health Sciences, University of Pretoria

Corresponding author: M Viljoen (mviljoen@webafrica.org.za)

Objectives.
To compare the value of procalcitonin, C-reactive protein (CRP) and
neopterin as indicators of immune deficiency, co-infection, efficacy of
treatment, and disease progression, in patients with advanced HIV-1
infection.

Design.
Cross-sectional, investigating baseline blood measurements and clinical
observations in 82 HIV-positive patients divided into an antiretroviral
treatment (ART) group and an ART-naïve group.

Setting. Secondary general hospital in Pretoria.

Results.
Procalcitonin and CRP levels showed no significant differences between
the ART and ART-naïve groups, and no correlations with CD4 counts or
viral loads. CRP levels were significantly higher with TB co-infection (p<0.05).
Neopterin levels were raised above normal in 92% of the ART-naïve group
and in 75% of the ART group. The levels were significantly higher (p<0.05)
in the ART- naïve group. Negative correlations were found between
neopterin and CD4 counts for the total patient group (r=-0.482; p<0.001). Neopterin was significantly (p<0.05)
higher in the HIV/TB co-infection group than in those without TB.
Higher neopterin levels at baseline were associated with a decline in
CD4 counts over the ensuing 6-month period, and patients with higher
baseline neopterin levels developed more complications over the 6-month
period.

Conclusions.
Compared with procalcitonin and CRP, neopterin appears to be associated
with the degree of immunodeficiency and of co-infection with TB.
Neopterin levels may be investigated further as a measure of disease
progression or treatment response.

S Afr J HIV Med 2012;13(2):78-82.

Procalcitonin, C-reactive protein (CRP) and
neopterin are three of the markers most commonly used, with varying
degrees of success, as diagnostic or prognostic indicators to monitor
disease progression and to estimate the efficacy of therapeutic
interventions in infectious diseases and non-infectious inflammatory
conditions. All three are, to a lesser or greater extent, used among
HIV-positive patients.

Procalcitonin is the pro-hormone of calcitonin. In normal
conditions, transcription of the procalcitonin gene occurs in the
C-cells of the thyroid under conditions of hypercalcaemia and
neoplastic disease.1 However, in the presence of bacterial infection or endotoxins, virtually all cells produce calcitonin precursors.1
Recent indications are that, in infectious or inflammatory conditions,
procalcitonin may in fact be considered an acute phase reactant, with
the liver being the major source of procalcitonin.2
Procalcitonin levels increase in certain pro-inflammatory conditions,
especially bacterial infections, but are thought not to show
significant increases with viral and non-infectious inflammatory
conditions.3 The levels are
often used to differentiate between patients with sepsis and those with
systemic inflammatory response syndrome (SIRS).4
Procalcitonin levels have been recommended for distinguishing between
bacterial and non-bacterial infections, and therefore as a guideline in
the prescription of antibiotics.5
,
6
One disadvantage in the use of procalcitonin is that the levels in
healthy individuals are below the reliable detection limit (10 pg/ml)
of most clinical assays.

C-reactive protein is an acute-phase protein, and its levels are
upregulated in viral, bacterial and fungal infections, as well as in
non-infectious inflammatory conditions. The cytokine profile found with
raised CRP levels is predominantly pro-inflammatory, and CRP levels are
often used as a non-specific indicator of inflammatory activity,
irrespective of the cause.7
The levels of CRP in bacterial and viral infections differ, and high
levels (e.g. >100 mg/l) can be found with bacterial infections,
while lower levels (usually <10 mg/l) are more commonly associated
with viral infections.8 As
an acute-phase reactant, macrophage- and perhaps adipocyte-derived IL-6
is a major stimulant for the production of CRP, and liver failure is
the major cause for a decline in CRP synthesis.9
,
10

Neopterin (6-D-erythro-hydroxy propyl pteridine) is a catabolic
product of the purine nucleotide guanosine triphosphate. Neopterin is
produced in macrophages from guanosine 5’-triphosphate (GTP)
which is cleaved by GTP-cyclohydrolase 1 to 7,8-dihydroneopterin
triphosphate, followed by conversion of 7,8-dihydroneopterin
triphosphate to neopterin and 7,8-dihydroneopterin under the influence
of phosphatases.11
GTP-cyclohydrolase 1 is stimulated, predominantly, by T-helper cell
type-1 derived interferon-g, but co-stimulation by tumour necrosis
factor alpha may contribute.11
Neopterin is used as indicator of both macrophage function and
cell-mediated immunity. When cell-mediated immunity dominates,
circulating neopterin levels are usually high and, when humoral
immunity dominates, neopterin levels are low.11
Increased neopterin levels are found with viral infections,
intracellular bacterial infections, intracellular parasites, a number
of auto-immune diseases, malignancies, rheumatoid arthritis, systemic
lupus erythromatosus, acute cellular graft rejection or graft-v.-host
disease, and in almost every condition where cellular immunity
dominates.12
,
13 In HIV-1 infection, serum neopterin has been described as an immune activation marker and predictor of disease progression.14

In HIV/AIDS, plasma HIV-1 RNA concentration reveals the degree of
viral replication, and CD4 counts reflect the degree of immune
deficiency and, it is speculated, end-organ damage. The outcome is,
however, largely influenced by the co-existence of other complications,
especially co-infection with TB. Although viral load and CD4 counts are
considered the diagnostic gold standards for HIV, soluble markers may
add valuable information about immune activation status and prognosis.
In addition, cost-effective reliable serum markers would be of benefit
in resource-limited settings where restrictions are placed on the
frequency of laboratory investigations such as viral loads. The aim of
this investigation was to compare the associations of procalcitonin,
C-reactive protein and neopterin and measures of HIV disease status and
co-infection with TB.

Methods

HIV-positive outpatients were randomly recruited
from the Immunology Clinic at the Kalafong Hospital, Pretoria. The
study took place during 2010 - 2011, and patients were followed-up 6
months after baseline, wherever possible.

Informed consent was obtained from 82 adult patients who were
attending the clinic on a Friday, who freely gave informed consent to
take part, and who were not ruled out by the exclusion criteria.
Exclusion criteria included patients <18 years of age, patients with
CD4 counts >400 cells/µl, patients on antiretroviral treatment
(ART) for <2 months, treatment defaulters from the ART group and,
for the ART-naïve group, patients previously on any ART. Ethical
approval was obtained from the Faculty of Health Sciences Research and
Ethics Committee, University of Pretoria.

The patients were firstly divided into a group on active ART (N=57) and a group not on ART (ART-naïve; N=25).
The ART group was further subdivided into groups depending on their
time on treatment prior to baseline investigation (2 months - 1 year; 1
- 2 years, and >2 years). At the 6-month follow-up, patients were
subdivided into 2 groups according to baseline neopterin levels, and
the groups were compared in terms of the CD4 counts and development of
complications diagnosed by the attending physician and confirmed by the
specialist involved in the study.

Blood specimens collected at baseline were centrifuged on site; plasma aliquots were stored at -70oC
until analysis. Procalcitonin (RayBiotech Inc., USA) and neopterin
(Immuno-Biological Laboratories Inc., USA) were measured by commercial
enzyme-linked immune-absorbent assay (ELISA) kits. CRP and other
routine blood investigations (CD4 count, WBC count, haemoglobin etc.)
at baseline were determined according to standard procedures of the
National Health Laboratory Service (NHLS), and results were extracted
from the laboratory reports and patient files.

Student’s t-test
and nonparametric Mann-Whitney U-test were used to determine group
differences. Kruskal-Wallis one-Way ANOVA indicated variance across
multiple groups. Correlations were determined by regression analysis
and Spearman rank correlation co-efficient. Statistical analysis was
performed using NCSS/PASS (Hintze J 2001) software, and all testing was
done at a significance level <0.05 unless otherwise specified.

Results

The demographic profiles for the patient groups are
presented in Table 1. The 2 groups were comparable in age, body mass
index (BMI), gender distribution, race and employment status. Results
of the baseline blood measurements and the comparison between the ART
and ART-naïve groups are presented in Table 2. Neopterin levels
were significantly higher (p=0.0096)
in the ART-naïve group than in the ART group. Negative
correlations were found between neopterin and CD4 counts for the total
group of patients (r=-0.482; p<0.0001; N=82), as well as for the ART group (r=-0.451; p=0.0045; n=57). Neopterin also correlated negatively with haemoglobin levels for the total patient group (p=-0.597; p<0.0001; N=82).

Six months after the baseline
measurements, 47 of the original 82 patients were still available and
could be followed up with regard to CD4 counts and the development of
complications. A comparison between patients with complications and
those without complications, at baseline and at follow-up, is shown in
Table 3. Additional complications at follow-up consisted of TB (n=6, 2 of whom had extrapulmonary disease); pneumonia (n=5); severe lymphadenopathy (n=4); cardiac/renal disease (n=4) and haematological complications such as anaemia, thrombocytosis or neutrophilia (n=10).

The relationship between
neopterin and CD4 counts over the 6-month period following the baseline
assessments was examined. Patients who developed additional
complications, stopped taking anti-retroviral drugs or ART-naïve
patients who started ART during this period were excluded. Seven
patients stopped ART over this period; the reasons included
non-compliance and drug side-effects. This cessation resulted in a
drastic decline in sample sizes, i.e. 11 patients (8 on ART) had a
decrease, and 9 (all on ART) had an increase in CD4 over the period.
Mean baseline neopterin was significantly higher in the patients whose
CD4 counts were decreased at follow-up (35.09 v. 10.82 nmol/l; p=0.035).
In the group whose CD4 counts decreased over the 6-month period,
baseline neopterin levels correlated negatively with both baseline CD4
count (r=-0.68; p=0.03) and follow-up CD4 count (r=-0.58; p=0.07).

As shown in Fig. 1, the patients
were subdivided into groups according to the period of time they had
been on treatment prior to the baseline investigations. Analysis of
variance showed that neopterin levels were significantly (p<0.01) lower and CD4 counts significantly higher (p<0.001) in the patients who had been on treatment >1 year.

Discussion

This study examined the associations of 3
laboratory markers of disease in HIV-positive patients. The key
findings are that neopterin is more strongly associated with the degree
of immunodeficiency and of co-infection with TB than CRP or
procalcitonin. Higher neopterin levels at baseline were associated with
a decline in CD4 counts and the development of more complications over
the ensuing 6-month period.

Limitations of this study include the fact that not all patients
could be traced for the 6-months follow-up, that the groups became
progressively smaller as patients who had a change in treatment over
this period were excluded from the statistical comparisons, and that
disease progression could only be estimated from CD4 counts and not
viral loads.

The results of this study
suggest that CRP levels are not specifically associated with immune
deficiency, the effects of ART, or disease progression. These results
are in agreement with those of a study in India in which CRP
measurement in HIV-positive patients was found neither to be of value
as diagnostic aid nor as prognostic marker in HIV/AIDS.15
However, in view of the fact that CRP levels in HIV-positive
individuals are generally significantly lower in viral than in
bacterial infection, significantly raised levels of CRP could be an
indication to investigate for a possible co-infection, keeping in mind
that other conditions marked by a pronounced pro-inflammatory response
can also lead to increases in the levels of CRP. This finding is in
line with the results of a South African study by Wilson et al.
who showed that normal CRP levels, in combination with clinical
evaluation, could be useful to rule out TB in populations with a high
prevalence of HIV.16

Procalcitonin (PCT) is known for
its increase in bacterial infections and is used by some to
differentiate between viral and bacterial infections.17
One explanation as to why procalcitonin levels remain low in purely
viral infections is based on the fact that the production of PCT is
primarily stimulated by tumour necrosis factor. It is suggested that
increases in procalcitonin do not occur with viral infections because
alpha interferon, synthesised as a result of viral infections, inhibits
synthesis of tumour necrosis factor.1
Should this be true, the question remains whether procalcitonin would
be of much use for the detection of bacterial co-infection in
HIV-positive patients. In developing countries such as South Africa,
co-infections with TB and other bacterial infections in HIV-positive
individuals are common – even major sources of morbidity and
mortality – especially at CD4 counts <200 cells/µl. The
level of circulating PCT in normal healthy individuals is generally
below the limit of detection (10 pg/ml) of most clinical assays.18 According to sensitive research assays, the normal level for plasma/serum PCT is 33±3 pg/ml.1
The analytical sensitivity for the assay of this study was typically
below 30 pg/ml and, from linear extrapolation, individual PCT levels
were all >10 pg/ml. However, the mean PCT levels for the total group
of patients were normal, with no significant difference between the ART
and ART-naïve groups, and no significant correlations between PCT
and CD4 counts or viral loads. Although the value of PCT as a reliable
marker of active TB has on occasion been questioned,19 the overriding assumption is that PCT is indeed a valuable marker of Mycobacterium tuberculosis in non-immunocompromised patients.20
The procalcitonin findings of this study are in line with studies that
showed suppression of the procalcitonin response in HIV-positive
individuals.20
,
21
Although some diagnostic and prognostic value for the measurement of
PCT in HIV/TB-co-infection has been described in a South African study,
only 58% of their HIV-positive patients with TB had PCT levels
marginally above 100 pg/ml.22
This is, in view of better performing markers, not adequate for
clinical use in individual patients. Although procalcitonin induction
in HIV-positive individuals is known to occur in sepsis, and reports
exist of significant increases in procalcitonin in pneumococcal and a
number of other non-viral infections,23
it would appear that secondary infections in HIV-positive patients do
not in general trigger overt increases in procalcitonin synthesis,21
,
23 provided that the infections are localised or organ-related without systemic inflammation.

Neopterin levels were increased
above normal (10 nmol/l) in 92% of the ART-naïve group and in 75%
of the ART group. The levels were significantly higher (p<0.01)
in the ART-naïve group and were inversely associated with CD4
counts. These results confirm the value of neopterin levels as a
reflection of the degree of immunodeficiency. Fig. 1 shows the increase
in CD4 counts that occurred over the same periods on ART as the
decrease in neopterin. This implication (that neopterin may be an
indicator of the efficacy of ART) warrants further investigation.

Among the 18 patients (>26%
of the study population; 50% on ART) in whom active TB-co-infection was
confirmed at the baseline investigations, neopterin levels were
significantly higher (p<0.001), and CD4 counts significantly lower (p=0.028),
than among the patients without TB co-infection. These results are in
agreement with previous indications that neopterin levels are
significantly higher in HIV-positive patients with TB-co-infections and
that, although neopterin levels may decrease with anti-TB therapy, high
levels of neopterin persist with progression of the immune deficiency
and a poor prognosis.24

As neopterin levels reflect the
degree of immune deficiency in HIV-positive patients, and perhaps the
response to ART, the question was asked whether neopterin has indeed,
as claimed elsewhere, prognostic value concerning disease progression.25 Baseline neopterin was significantly higher (p<0.01)
in the group of patients in whom other complications were present 6
months after baseline investigations, than patients who progressed well
(53.9±39.9 v. 10.8±7.6 nmol/l; p<0.01).
When all patients who stopped ART over the 6-month period were
excluded, the mean neopterin levels were significantly higher in the
group with complications than in the group without complications (59.29
v. 30.9 nmol/l; p=0.018).
When those patients who did not change antiretroviral status were split
into groups, the mean neopterin levels were significantly higher in the
group that developed complications than those who did not, both for the
ART (45.9 v. 24.13 nmol/l; p=0.04) and the ART-naïve (75.02 v. 30.99 nmol/l; p=0.001)
groups. Although these results do not necessarily imply a direct
relationship, they warrant further investigation. The possibility that
neopterin levels could perhaps be predictive of disease progression was
further examined by looking at the changes in CD4 counts. The baseline
neopterin values were compared between patients whose CD4 counts
decreased and those that increased over the 6-month period following
baseline assessments. To minimise the number of confounding factors,
any patient who had additional complications or a change in ART during
the 6 months was excluded. This resulted in a drastic decline in sample
sizes, i.e. 11 patients (8 on ART)
had a decrease, and 9 (all on ART) had an increase in CD4 counts over
the period. Mean baseline neopterin levels were significantly higher in
patients whose CD4 counts decreased, and significantly lower in
patients whose CD4 counts increased. In the group whose CD4 count
decreased over the 6-month period, baseline neopterin levels correlated
with both baseline CD4 counts (r=-0.68; p=0.03) and follow-up CD4 counts (r=-0.58; p=0.07).
Although the group divisions, owing to the exclusion criteria, were
small, the association of neopterin levels with CD4 counts is
nonetheless seen. These results warrant further investigation into the
value of neopterin as a possible predictor of disease progression.

In view of the stimulatory role of IFN-γ in neopterin synthesis,11
the link between chronic elevation of IFN-γ and HIV-1
progression, as well as the active role of neopterin in the disease,25
the value of neopterin is not surprising. Neopterin has previously been
described as one of the better immunological markers in patients with
HIV-1 infections.14
,
25 It has even been said that neopterin levels increase before other markers of HIV infections have risen.25
In the present study, 40% of ART, and 75% of ART-naïve, patients
had CD4 counts <200 cells/µl, and all had CD4 counts <400
cells/µl. Therefore, with regard to patients in the advanced
stages of the disease, the results of this study support the notion of
neopterin as an inexpensive indicator of CD4 status and as an indicator
of bacterial co-infection. The results warrant further investigation
into neopterin as an indicator of disease progression and of the
success of ART.

Acknowledgements.Financial
support was received from The Medical Research Council of South Africa
(MRC grant A0S541) and the South African Sugar Association (SASA grant
213).

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Table 1. Patient demographic information at baseline

ART

ART-naïve

Females

35 (61.4%)

15 (60%)

Age (years)

36.6±8.2

36.8±10.8

Race

57 black

25 black

BMI

Married

Employed

Alcohol (number of patients)

Smoking (number of patients)

Average months on treatment

TB positive at baseline

22.6±5.0

10 (17.5%)

22 (38.6%)

3 (5.3%)

9 (15.8%)

13.6±16.2

(2 - 63)

10 (17.5%)

21.2±3.5

7 (28%)

12 (48%)

3 (12%)

5 (20%)

8 (32%)

Table 2. Comparison of baseline blood measurements for the two groups

ART

ART-naïve

p-value

Procalcitonin (pg/ml)

13.2±3.3

12.9±1.5

0.767

Neopterin (nmol/l)

39.5±38.9

64.4±39.4

0.001*

CRP (mg/l)

25.3±38.5

34.9±82.9

0.567

CD4 count (cells/µl)

288.2±196.4

157.5±181.9

0.027*

Viral load (log10 copies/ml)

2.4±0.9

3.6±1.7

0.005*

Red cell count (x1012 /l)

3.6±0.5

3.9±0.7

0.048*

Haemoglobin (g/dl)

14.2±15.2

11.1±2.0

0.345

White cell count (x109 /l)

4.9±1.5

5.7±2.8

0.107

Neutrophils (x109 /l)

2.7±1.2

3.8±2.7

0.026*

Lymphocytes (x109 /l)

1.6±0.8

1.4±0.8

0.211

CD4 % of lymphocytes

17.4±7.6

9.2±7.3

0.0006*

Note: Viral load measured within 2 months of baseline (*p<0.05; mean±SD).

Table 3. Comparisons for patients who were followed up after 6 months

Complications after

6 months

No complications after 6 months

29 (61.7%)

18 (38.3%)

ART

12 (41.4%)

15 (83.3%)

Baseline CD4 count (cells/µl)

6 month CD4 count (cells/µl)

Baseline viral load (log10 copies/ml)

Baseline CRP (mg/l)

Baseline neopterin (nmol/l)

Baseline PCT (pg/ml)

237.0

232.5

2.34±0.9

43.2±87.4

53.9±33.9

13.7±4.5

327.7

325.1

2.3±1.0

9.5±0.7

10.8±7.6

12.6±0.43

Fig. 1. Box plots illustrating neopterin and CD4 levels for patients after 0 years (n=25), <1 year (n=30), 1 - 2 years (n=10) and >2 years (n=10) on ART.

ORIGINAL ARTICLE