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Clinical and Diagnostic Laboratory Immunology, March 1999, p. 204-208, Vol. 6, No. 2
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Plasma-Soluble CD30 in Childhood Tuberculosis: Effects of Disease
Severity, Nutritional Status, and Vitamin A Therapy
W. A.
Hanekom,1,*
G. D.
Hussey,2
E. J.
Hughes,2
S.
Potgieter,2
R.
Yogev,1 and
I. J.
Check1
Division of Pediatric Infectious Diseases,
Northwestern University Medical School, Chicago, Illinois
60614,1 and Department of
Paediatrics and Child Health, University of Cape Town, Red Cross War
Memorial Children's Hospital, Rondebosch 7700, South
Africa2
Received 27 August 1998/Returned for modification 29 September
1998/Accepted 14 December 1998
 |
ABSTRACT |
Plasma-soluble CD30 (sCD30) is the result of proteolytic splicing
from the membrane-bound form of CD30, a putative marker of type 2 cytokine-producing cells. We measured sCD30 levels in children with
tuberculosis, a disease characterized by prominent type 1 lymphocyte
cytokine responses. We postulated that disease severity and nutritional
status would alter cytokine responses and therefore sCD30 levels.
Samples from South African children enrolled prospectively at the time
of diagnosis of tuberculosis were analyzed. (Patients were originally
enrolled in a randomized, double-blind placebo-controlled study of the
effects of oral vitamin A supplementation on prognosis of
tuberculosis.) Plasma samples collected at the time of diagnosis and 6 and 12 weeks later (during antituberculosis therapy) were analyzed.
sCD30 levels were measured by enzyme immunoassay. The 91 children
included in the study demonstrated high levels of sCD30 at diagnosis
(median, 98 U/liter; range, 11 to 1,569 U/liter). Although there was a
trend toward higher sCD30 levels in more severe disease (e.g.,
culture-positive disease or miliary disease), this was not
statistically significant. Significantly higher sCD30 levels were
demonstrated in the presence of nutritional compromise: the sCD30 level
was higher in patients with a weight below the third percentile for
age, in those with clinical signs of kwashiorkor, and in those with a
low hemoglobin content. There was minimal change in the sCD30 level
after 12 weeks of therapy, even though patients improved clinically.
However, changes in sCD30 after 12 weeks differed significantly when 46 patients (51%) who received vitamin A were compared with those who had
received a placebo. Vitamin A-supplemented children demonstrated a mean (± standard error of the mean) decrease in sCD30 by a factor of 0.99 ± 0.02 over 12 weeks, whereas a factor increase of 1.05 ± 0.02 was demonstrated in the placebo group (P = 0.02). We conclude that children with tuberculosis had high sCD30
levels, which may reflect the presence of a type 2 cytokine response.
Nutritional compromise was associated with higher sCD30 levels. Vitamin
A therapy resulted in modulation of sCD30 levels over time.
| |
INTRODUCTION |
It is estimated that one-third of
the world's population is infected with Mycobacterium
tuberculosis (6). Although only 10% of infected
patients will develop clinical disease, approximately 3 million deaths
were directly attributed to tuberculosis worldwide in 1990 (14). Four hundred fifty thousand of the people who died
were children younger than 15 years of age (14).
The immunopathogenesis of tuberculosis remains incompletely understood.
Host responses to M. tuberculosis in children, who virtually
invariably manifest with the primary form of tuberculosis, may differ
from those in adults, whose disease most commonly results from
reactivation of dormant infection. Although most studies to date have
focused on adults, a better understanding of immune responses in
children may be particularly important for developing novel primary
vaccination and immunotherapeutic strategies.
Type 1 cytokine responses are thought to be central in protective
immunity against tuberculosis in adults (1). In contrast, type 2 cytokine responses may represent deleterious immunity to intracellular bacteria such as M. tuberculosis,
Mycobacterium leprae, and Leishmania major
(1, 17, 21). The role of type 2 responses in tuberculosis is
not clear. Surcel et al. have demonstrated increased numbers of
interleukin 4 (IL-4)-producing cells in tuberculosis patients compared
with numbers in tuberculin-sensitized healthy controls in an ELISPOT
assay (22). There was no difference in gamma interferon
(IFN-
)-producing cells (reflecting a type 1 response) between the
two groups. Sanchez et al. demonstrated increased IL-4 production by
purified protein derivative-stimulated peripheral blood mononuclear
cells (PBMC) when patients were compared with healthy tuberculin
reactors (19). Zhang et al. failed to document increased
type 2 responses in PBMC (24). Instead, patients with
clinical disease had depressed type 1 responses compared with infected
persons without clinical disease, suggesting that depressed type 1 responses rather than enhanced type 2 responses may characterize
ineffective immunity to M. tuberculosis. It is possible
therefore that immunity to M. tuberculosis is analogous to
that to M. leprae, in which patients with milder disease
(tuberculoid leprosy) may manifest type 1 responses whereas more severe
disease (lepromatous leprosy) is characterized by type 2 responses
(21).
We proposed measurement of plasma-soluble CD30 (sCD30) in tuberculosis
patients as a marker of type 2 cytokine responses. CD30 is a member of
the tumor necrosis receptor family and is expressed on
antigen-activated T cells, B cells and NK cells and possibly on
macrophages (4, 7, 10). CD30-CD30-ligand interactions result in a variety of functions, including T-cell costimulation, upregulation of cell surface antigens (such as adhesion molecules), and
enhanced cytokine secretion (4, 7, 10). Human
CD30+ T-cell clones preferentially produce type 2 cytokines
(5); however, type 1 cytokine-producing cells may also
express CD30 in vivo (11). In mice, CD30 expression on
activated CD4+ cells reflected the ability of these cells
to respond to IL-4, a type 2 cytokine (15). Similarly,
CD30-CD30-ligand interaction in mice resulted in IL-5 production (a
type 2 cytokine) but not IFN- production (a type 1 cytokine)
(2). Thus, although CD30 expression may not be an intrinsic
marker of type 2 cytokine-producing cells, it might reflect the
presence of type 2 cytokine-producing cells.
sCD30, an 85-kDa molecule, is the result of proteolytic splicing of the
120-kDa membrane-bound form (7). High levels of sCD30 have
been demonstrated in diseases in which type 2 cytokine responses
predominate, for example, in atopy, advanced human immunodeficiency virus (HIV) infection, measles, systemic lupus erythematosus, and
Ommen's syndrome (18). These data suggest that sCD30
concentration parallels CD30 expression and may be a plasma marker of
type 2 cytokine profiles. Should sCD30 be a marker of type 2 cytokine response, its easy measurement in plasma could offer significant advantages over traditional in vitro cytokine-based assays, including measurement of mRNA, intracellular protein, or secreted protein.
We postulated that deleterious type 2 cytokine responses would be
present in children with more extensive tuberculosis compared with
patients with milder disease, resulting in higher sCD30 levels. We also
postulated that nutritional compromise would modulate sCD30
levels. We measured sCD30 longitudinally over the course of
therapy, postulating that sCD30 levels would return to normal as the
children improved clinically. As all patients in this cohort were
subjects in a separate study of the effect of oral vitamin A therapy on
prognosis in childhood tuberculosis (12), we also investigated effects of this immunomodulator on longitudinal changes in sCD30.
| |
MATERIALS AND METHODS |
Study design.
Children presenting with pulmonary
tuberculosis to the Red Cross War Memorial Children's Hospital in Cape
Town, South Africa, were enrolled prospectively. Pulmonary tuberculosis
was diagnosed on the basis of environmental exposure characteristics,
clinical symptomatology, physical findings, chest roentgenography, and microbiologic investigations for detection and isolation of M. tuberculosis. Only patients meeting World Health Organization criteria of "definite" and "probable" tuberculosis were
enrolled (23). Chest roentgenographic findings were later
redocumented after consensus by two study pediatricians and a pediatric
radiologist, who were blinded at that time. Children infected with HIV
were excluded.
Patients were randomly selected at a ratio of 1:1 by a
computer-generated list to receive either vitamin A or an
identical-appearing placebo at diagnosis in a separate double-blind
study of the effects of this vitamin on clinical outcome
(12). Vitamin A (200,000 IU per dose) was administered
orally on days 0 and 1.
Patients were again assessed after 6 and 12 weeks of standard
antituberculosis therapy. At all three evaluations, plasma was
collected and frozen at
70°C for subsequent sCD30 determination.
At
all evaluations a complete blood count and leukocyte differential
count
(Coulter MACM, Miami, Fla.) and determination of serum electrolytes,
total protein, albumin, transthyretin, bilirubin, liver enzymes,
cholesterol (Cxynchron CX4; Beckmann, Munich, Germany), retinol
(by
spectrofluorometry; spectrofluorophotometer model RF-1501
[Shimadzu,
Kyoto, Japan]), zinc (by atomic absorption spectrophotometry;
Beckman
model 1272M atomic absorptiometer) were also performed.
All specimens
were processed in the same
manner.
Written informed parental consent was obtained for participation in the
study, and the study protocol was approved by the
Research and Ethics
Committee of the University of Cape
Town.
sCD30 assay.
sCD30 was determined by a second-generation
sandwich enzyme-linked immunosorbent assay (DAKO Corp., Glostrup,
Denmark), as described previously (16). Briefly, prediluted
sCD30 calibrators, a curve control, and individual specimens were added
with peroxidase-conjugated mouse anti-CD30 antibody to microtiter wells
precoated with another anti-CD30 monoclonal antibody. After 2 h of
incubation, unbound material was washed away and a chromogenic
substrate was added to the wells. The reaction was stopped, and the
absorbance at 450 nm was measured. A standard curve was obtained from
sCD30 calibrators, while sCD30 concentrations in plasma samples were determined by interpolation from the curve. When results above the
value of the highest sCD30 calibrator were obtained, tests were
repeated with dilutions to bring values within the linear section of
the standard curve. The coefficient of variation of the assay was 9%,
as estimated by duplicate determinations of two specimens at five
separate runs.
Statistical considerations.
Weight measurements were
documented as z scores to account for sex and age.
Correlation of sCD30 with other continuous variables was determined by
Spearman coefficients. Because there was a strong correlation between
age and sCD30 level, all further statistical analyses were corrected
for age. Differences in sCD30 levels in various tuberculosis disease
categories (see Table 2) and nutritional categories (see Table 3) at
baseline were determined by analysis of variance (ANOVA) of mean
log10-transformed sCD30 values. Multiple linear regression,
using log10-transformed values when not normally distributed, was utilized to determine the differential effects of
various disease and nutritional categories and of age on statistically significant ANOVA results and Spearman correlations. Differences between sCD30 levels at baseline and those at subsequent evaluations were determined by paired t tests of
log10-transformed sCD30 values. Analysis was performed with
SPSS software (version 6.1; SPSS Inc., Chicago, Ill.).
| |
RESULTS |
Patient characteristics.
Of the 110 patients initially
enrolled, 19 were subsequently excluded from analysis, because the
final diagnosis was not tuberculosis (n = 8), the
patient was HIV positive (n = 2), or follow-up data were regarded as inadequate (n = 9). Results from 91 patients were therefore included in the final analysis. Seventy-six
patients (84%) attended the 6-week follow-up visit, and 81 (89%)
attended the 12-week follow-up visit. The median age of patients was 39 months (range, 3 to 171 months); the female-to-male ratio was 0.9.
The clinical severity of tuberculosis ranged widely, from 32 cases
(35%) of primary complex disease to 19 patients (21%) with
extrapulmonary disease in addition to pulmonary tuberculosis.
Thirty-two patients (35%) had positive mycobacterial
cultures.
Generally poor nutritional status at diagnosis was demonstrated by a
mean (± standard error of the mean [SEM]) weight
z score
of
1.42 ± 0.14 (normal mean, 0; normal range,
2 to 2).
Clinical
features of kwashiorkor (protein energy malnutrition) were
present
in 10 patients (11%), and serum albumin was below the lower
limit
of normal (<3.5 g/dl) in 62 patients (68%), while 57 patients
(63%) had low vitamin A levels (<20 µg/dl).
Forty-six patients (51%) received vitamin A therapy at presentation,
while 45 patients (49%) received a placebo. There were
no differences
in disease or nutritional characteristics between
the two treatment
groups (Table
1).
sCD30 levels at diagnosis.
The median sCD30 level at baseline
was 98 U/liter (range, 11 to 1,569 U/liter) (Fig.
1). There was a strong negative
correlation between sCD30 level and age (r = 0.6; P < 0.001): younger children had higher sCD30 levels (Fig.
2). We corrected all subsequent data
analysis for age.
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|
FIG. 1.
sCD30 levels at diagnosis and after 6 and 12 weeks of
therapy in 91 children with tuberculosis. There were no differences in
sCD30 levels between evaluations.
|
|
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|
FIG. 2.
A strong negative correlation between sCD30 level and
age was demonstrated in 91 children with tuberculosis (r = 0.6, P < 0.001).
|
|
Patients with additional extrapulmonary disease tended to have higher
sCD30 levels (
P = 0.09, corrected for age) than
patients
with pulmonary tuberculosis alone (Table
2). Similarly, a hemoglobin
level below
10 g/dl, a weight
z score of <
2 (which equals weight
below the third percentile for age), and clinical signs of kwashiorkor
were associated with higher sCD30 levels (
P = 0.04,
P = 0.05,
and
P = 0.07, respectively) (Table
3). When corrected for age,
a negative
correlation between both plasma albumin and cholesterol
with sCD30 was
demonstrated (
P < 0.05).
To determine which factors were most strongly associated with sCD30
levels, we performed linear regression analysis. When
(i) age, (ii)
presence of extrapulmonary disease, (iii) presence
of a hemoglobin
level <10 g/dl, and (iv) presence of kwashiorkor
and of a weight
z score of <
2 were included in regression analysis,
only
age correlated significantly with sCD30 level (
P < 0.001).
When (i) presence of malnutrition and (ii) presence of
extrapulmonary
disease or (i) presence of a hemoglobin level <10 g/dl
and (ii)
presence of extrapulmonary disease were included in regression
analysis, the nutritional variable was more significantly correlated
with sCD30 level (data not shown). These results indicate that
it was
likely that patients with extrapulmonary disease had higher
sCD30
levels because they were younger and because they tended
to have a
poorer nutritional
status.
Change in sCD30 levels during therapy.
Median sCD30 levels did
not change significantly from baseline (98 U/liter; interquartile
range, 66 to 165 U/liter) to 6 weeks (93 U/liter; range, 51 to 177 U/liter) or to 12 weeks (89 U/liter; range, 60 to 145 U/liter) (Fig.
1). No significant changes in individual patients' sCD30 levels could
be demonstrated from baseline to 12 weeks (P = 0.62).
Median sCD30 levels in the vitamin A-treated group decreased from 96 U/liter (interquartile range, 70 to 180 U/liter) at diagnosis
to 73 U/liter (range, 57 to 138 U/liter) at 12 weeks, whereas
median values
remained unchanged in the placebo-treated group
at these time points
(105 U/liter [range, 64 to 166 U/liter] versus
106 U/liter [range,
71 to 166 U/liter]). On an individual patient
basis, vitamin A therapy
was associated with a mean (± SEM) factor
decrease of 0.99 ± 0.02 in sCD30 level from diagnosis to 12 weeks,
whereas there was a
mean factor increase of 1.05 ± 0.02 in the
placebo therapy group
(difference:
P = 0.02, corrected for age).
Similar
changes in the sCD30 level in the vitamin A- and placebo-treated
groups
were demonstrated after 6 weeks of therapy (data not
shown).
Within different tuberculosis disease categories and nutritional
categories (as listed in Tables
2 and
3), no significant
change in
sCD30 level from baseline to follow-up evaluations was
demonstrated
(data not
shown).
| |
DISCUSSION |
We determined sCD30 levels in a well-characterized cohort of
children with tuberculosis. Although we did not have a control group of
healthy children, sCD30 levels were significantly higher than those
previously reported in healthy adults or newborns by use of the same
assay. Levels in healthy adults ranged from 4.6 ± 0.4 U/liter
(8) to 9.9 ± 3 U/liter (9) (mean ± SEM). Levels of sCD30 in newborns were 5.68 ± 3.94 U/liter
(3). Our patients' sCD30 levels were also higher than those
levels reported in adults with asymptomatic HIV infection (52 ± 40.9 U/liter, mean ± standard deviation) (16) and in
adults with hepatitis B infection (mean, 28 U/liter) (8).
A strong negative correlation between sCD30 level and age was
demonstrated (Fig. 2). It is not known whether healthy children have
higher sCD30 levels at younger ages. Alternatively, high sCD30 levels
in our study may reflect the presence of type 2 cytokine responses in
children with tuberculosis.
We postulated that patients with more severe disease would have higher
sCD30 levels, possibly indicating type 2 cytokine responses, than
patients with milder forms of tuberculosis. More severely sick patients
did tend to have elevated levels (Table 2); however, this trend was not
invariably true. For example, no difference in sCD30 levels was found
between patients with positive mycobacterial cultures (reflecting
higher bacterial burdens and usually more severe childhood
tuberculosis) and children with negative cultures (Table 2).
Compromised nutritional status tended to be associated with higher
sCD30 levels (Table 3). Multivariate analysis demonstrated stronger
independent associations between elevated sCD30 levels and markers of
nutritional compromise, such as kwashiorkor, weight below the third
percentile for age, and a low hemoglobin level, than between elevated
sCD30 levels and markers of more severe tuberculosis. Additionally,
there was a significant negative correlation between sCD30 level and
plasma albumin and cholesterol levels, both of which are low in
children with protein energy malnutrition. These findings suggest that
sCD30 levels may be elevated in nutritionally compromised patients and
that elevated sCD30 levels observed in children with more severe
tuberculosis may therefore reflect poorer nutritional status. It is
tempting to speculate that nutritional compromise may predispose a
patient to a type 2 cytokine environment, which may contribute to host
responses that are less effective, resulting in more severe disease.
Although we expected a decrease in sCD30 levels during the course of
antituberculous therapy, no significant change was demonstrated, even
though all patients improved clinically (Fig. 1).
Approximately half the patients received high-dose vitamin A
supplementation at diagnosis in a separate study of the effect of this
intervention on clinical outcome (12). The many
immunomodulatory effects of vitamin A have been demonstrated both in
vitro and in clinical situations (20). For example,
significantly improved mortality and morbidity in children with severe
measles were shown after supplementation with similarly large dosages
of vitamin A (13). In our cohort, megadosages of vitamin A
at diagnosis had no effect on clinical outcome (12) but were
associated with a reduction in the median sCD30 level over time.
However, on an individual patient basis, changes in sCD30 levels were
small and are of doubtful significance.
In conclusion, high levels of sCD30 were demonstrated in our cohort of
children with pulmonary tuberculosis. A strong negative correlation
with age was found. sCD30 levels were still higher than those
previously reported in healthy adults and newborns. Although there was
a weak association between more severe disease and higher sCD30 levels,
more severe nutritional compromise was significantly associated with
higher sCD30 levels. Vitamin A therapy resulted in a change in sCD30
levels over time; however, the significance of this finding is not
clear. Future correlation of PBMC cytokine production with sCD30 levels
in children with tuberculosis will be helpful in determining whether
sCD30 could function as a marker of the cytokine milieu during the infection.
| |
FOOTNOTES |
*
Corresponding author. Present address: Laboratory of
Cellular Physiology and Immunology, Rockefeller University, 1230 York Avenue, New York, NY 10021. Phone: (212) 327-7079. Fax: (212) 327-8875. E-mail: hanekow{at}rockvax.rockefeller.edu.
| |
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Clinical and Diagnostic Laboratory Immunology, March 1999, p. 204-208, Vol. 6, No. 2
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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(2002). A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am. J. Clin. Nutr.
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Abstract
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