Nigerian Journal of Paediatrics 2012;39(1): 22 - 26
ORIGINAL
Chimah OU
Levels of serum zinc and severity of
Abhulimhen-Iyoha BI
Ibadin MO
malaria in under-fives: any relationship?
Abiodun P O.
Experience from Benin, Edo State.
DOI: http://dx.doi.org/10.4314/njp.v39i1.5
Received: 27th June 2011
Abstract Background: It remains
Results: Mean serum zinc level of
Accepted: 31st October 2011
uncertain why some individuals
patients with severe/complicated
infected with P l a s m o d i u m
malaria (13.7 ± 9.4µmol/l) was
Chimah OU
( )
falciparum develop severe disease
significantly lower than that
Department of Paediatrics,
while others do not. This may be
o b t a i n e d
i n
n o n -
Federal Medical Center, Asaba,
d u e
t o
d i f f e r e n c e s
i n
severe/uncomplicated malaria
Delta State, Nigeria.
immunological status of the
(17.1±8.0 µmol/l; t =3.67;
p
E-mail: osatomah@yahoo.com
individuals. Zinc levels may play
=0.000). There was a negative
Tel: +234-8037198966.
some roles in the immune
correlation between malaria
competence of such individuals as
parasite density and serum zinc
Abhulimhen-Iyoha BI
manifested in its effects on some
levels (r =
-0.101, p < 0.05). A
Ibadin MO, Abiodun P O
clinical and laboratory parameters.
similar trend was observed between
Department of Child Health,
Objective:
To determine the
zinc levels and degree of pyrexia (r
University of Benin Teaching
relationship between serum zinc
= -0.120; p < 0.05).
Hospital, Benin City Nigeria.
levels and some laboratory and
Conclusion: Patients with severe
clinical parameters in under-five
m a l a r i a
p r e s e n t i n g
w i t h
children with malaria.
h y p e r p y r e x i a
a n d
M e t h o d s :
T h e s t u d y w a s
hyperparasitaemia tended to have
conducted at the University of
lower levels of serum zinc.
Benin Teaching Hospital, Benin
Hypozincaemia is associated with
City between March and
severity of the disease either as a
November 2003 and involved 640
cause or effect.
under-five children. Of these, 384
Recommendation: Similar studies
children had parasitologically
should be conducted in other
proven malaria while 256 were
centres to validate the findings.
healthy controls. Determination of
zinc in sera was done using the
Key Words: Serum Zinc, Malaria
A t o m i c
A b s o r p t i o n
parasite density, Malaria, Under-
Spectrophotometry.
fives.
Introduction
Despite various malaria control programmes,
transmission of malaria in Nigeria is intense and
stable all year round. In the under-five population,
2
Malaria is a major cause of morbidity and mortality
especially amongst children in tropical Africa. In
1,2
infection rate for P lasmodium falciparum is said to
Nigeria, it remains the commonest cause of
rise from zero to two percent during the first three
morbidity and mortality as well as the leading cause
months of life to 90% by one year. Thereafter it
of childhood hospital admissions. In rural areas in
2,3
persists at a high level during early childhood until
The Gambia, Greenwood et al found malaria to be
3
school age when considerable immunity is acquired.
the
commonest cause of childhood deaths in
In endemic areas, the under-five population, known
children aged under five years.
to suffer more from its morbidity and mortality, is
known to have low and unsustained levels of
23
immunity.
4
In recent times, studies have
with sickle cell anaemia
11
and patients with proven
substantiated the need for zinc supplementation in
concomitant bacterial infection or localizing signs of
boosting general immunity of individuals.
5
infections like bronchopneumonia, otitis media, viral
exanthem or enanthem.
12
Controls comprised 256
Zinc is a crucial micronutrient required for normal
apparently healthy children matched for age, sex and
development of the immune system and its
nutritional status seen in the paediatric COPC and
maintenance. It is thus a critical modulator of host
Well Baby Clinic of UBTH. The presence of malaria
resistance to infections caused by viruses, bacteria,
parasite in an apparently healthy child excluded
fungi and protozoa.
5,6
It is involved in both specific
him/her from being recruited as control.
and non-specific aspects of immunity.
5,6
as
buttressed by several studies on zinc
Patients were recruited consecutively into the study.
supplementation in children with diarrhoea and
Severity of malaria in each patient was classified
pneumonia.
7
based on WHO criteria
8
for severe/complicated
malaria. A detailed history was obtained from
It is largely unknown why some individuals infected
accompanying parent(s) or guardian(s) for each
with Plasmodium falciparum in endemic regions
child. This was followed by a thorough physical
develop severe disease while others experience only
examination which was directed at excluding any
mild cases. Possible explanations for this scenario
8
focus of infection. Height of study subjects obtained
were compared to the Jane's standards. Nutritional
13
could include differences in immunological status of
the individuals. Inadequate immunity results in rapid
status was assessed according to the Wellcome
classification.
14
increase in the parasite load and development of
Protein Energy Malnutrition was
complications. In the early months of life the
9
defined as presence of any of the following: Wasting
manifestations of malaria are usually mild, probably
as weight for age less than 80% of expected with or
because of substantial immunity acquired from
without oedema, stunting as height or length less than
immune mothers. Mortality rates in hyperendemic
90% of expected for age or less than the third centile
areas are however, highest during the first two to
and mid upper arm circumference less than 13.5cm.
four years of life when passive immunity has waned
and acquired immunity is low.
8
Findings including temperature readings were
recorded in a proforma designed for the study. Ethical
The exact role(s) of zinc in malaria immunity is not
approval was obtained from the Ethics Committee of
well documented. Suggested mechanisms include
UBTH and written informed consent was obtained
its immune modulating or antioxidant properties or a
from parents/caregivers of subjects and controls.
combination of both. It is hypothesized that in
7
severe disease values of serum zinc would be low
Four millilitres of blood collected in a plain bottle
either as a predisposition or effects. The study
was used for serum zinc analysis in accordance with
methods described by Deric.
15
therefore seeks to evaluate the association between
Other investigation
malaria severity and levels of serum zinc as seen in
done for some patients as determined by clinical
children with malaria.
assessment and suspected form of severe malaria
include blood glucose level, urinalysis, urine
microscopy and culture, cerebrospinal fluid analysis.
Diagnosis of malaria was confirmed on the basis of
Patients and Methods
the presence of asexual forms (trophozoites/ring
forms) of malaria parasites.
8,16
Malaria parasite
The study was a case-control, cross-sectional one
density was determined according to methods
described by Bruce Chwatts.
16
carried out at the Children Emergency Room
(CHER), Paediatric Casualty Unit, Consultant Out-
Patient Clinic (COPC) and Well Baby Clinic of the
The data collected were entered into Statistical
University of Benin Teaching Hospital (UBTH),
Package for Social Science (SSPS) version 10
Benin City between March and November 2003.
software. Student t-test was used for comparison of
means and p value of less than 0.05 (p<0.05) was
Subjects consisted of well-nourished children (six
considered statistically significant.
months to 59 months) with clinically and
parasitologically proven malaria. Excluded from the
study were children with suspected malaria without
Plasmodium falciparum parasitaemia, and children
with conditions associated with hypozincaemia like
in overtly malnourished children (marasmus,
marasmickwashiorkor, kwashiorkor), children
10
24
Results
Table 2: Correlation of mean serum zinc levels and
malaria parasite density in patients with malaria.
Of the 384 subjects recruited into the study, 196
(51.0%) were males while 188 (49.0%) were
Parasite
N
Serum zinc±
females (M: F ratio of 1.04:1).The mean age of study
density
SD ( m
mol/l)
population was 26 ± 16.0 months while the mean
weight and height were 12.0 ± 3.0 kg and 86.3 ± 16.3
+
142
15.9 ± 7.4
cm, respectively. Severe/complicated malaria
++
158
15.2 ± 8.9
accounted for 149 (38.8%) cases, while non-
+++
82
13.5 ± 9.8
severe/uncomplicated malaria was found in 235
++++
2
15.9
(61.2%) cases (Table 1, Fig 1).]
Correlation (r) = - 0.101 p= 0.01
Table 1: Mean serum zinc levels in patients and
Anaemia, hyperparasitaemia and hyperpyrexia as
controls
isolated diagnostic criteria for severe/complicated
Mean Serum zinc ± SD (µmol/l)
malaria were found in 16(10%), 28(18.8%) and
29(19.5%) patients respectively. The corresponding
(n=256)
serum zinc values in these groups of patients was
Controls
18.2 ± 7.0a
respectively 19.3 ± 13.0mol/l, 13.6 ± 7.5mol/l and
16.0 ± 9.5mol/l. In comparison with values obtained
Patients
All patients Uncomplicated/
Complicated
in controls, mean serum zinc in individuals with
non-severe malaria
severe malaria
isolated hyperpyrexia (t = 8.77; p-value = 0.000) and
(n=384)
(n=235) 61.1%
(n=149) 38.8%
hyperparasitaemia (t = 9.56; p-value = 0.000) were
15.8±8.7b
17.1 ± 8.0c
13.7 ± 9.4d
significantly lower. (Table 3).
a vs b; t = 2.694, p = 0.007
Table 3: Mean serum zinc values in patients with
a vs c; p > 0.05
isolated and combined diagnostic criteria for severe
c vs d; t = 3.67, p = 0.000
malaria
Isolated
Multiple
p-value
A m o n g
t h e
1 4 9
s u b j e c t s
w h o
h a d
criteria
criteria
severe/complicated malaria, cerebral malaria
Anaemia
19.3 ±13.0
18.4 ± 13.2
0.76
occurred in isolation in 3(2.0%) patients, anaemia in
n =16
16 (10.0%) and hyperpyrexia in 29 (19.5%). Others
Hyperpyrexia
16. 0 ± 9.5
11.1 ± 7.1
0.01
were isolated hyperparasitaemia, which were
n = 29
identified in 28 (18.8%) and persistent vomiting in
Hyperparasitaemia
13.6 ± 7.5
12.2
± 9.3
0.45
10 (6.7%). Some of the severe/complicated malaria
n =28
diagnostic criteria also occurred in combination with
Controls
18.2 ± 7.0
others.
N = 256
In non-severe/uncomplicated cases, the mean serum
The multiple criteria include various combinations of
z i n c
w a s
1 7 . 1 ± 8 . 0 m o l / L
w h i l e
i n
anaemia, hyperpyrexia, acidosis, hypoglycaemia,
severe/complicated malaria patients; it was 13.7 ±
jaundice.
9.4mol/L. The difference between the mean values
Mean serum zinc correlated negatively with malaria
of non-severe /uncomplicated malaria and
parasite density (barring the 4+ malaria density) and
severe/complicated was statistically significant. (t =
hyperpyrexia implying that serum zinc tended to
3.67; p = 0.000).
decline with increasing malaria parasite density (r = -
0.101; p = 0.01) and increasing body temperature (t=
Mean serum zinc levels in 142 (37.0%) patients with
0.120; p = 0.04). There was, however, no correlation
+ malaria parasite density was 15.9 ±7.4mol/l
between serum zinc and haematocrit in the study
(median 14.8mol/l), in 158 patients with 2+ malaria
subjects. (Table 4).
parasite density of 15.2 ± 8.9mol/l, while that for 82
(21.4%) patients with 3+ was 13.5 ± 9.8µmol/l.
Table 4: Correlation of serum zinc with some
However, the mean serum zinc level in two patients
laboratory and clinical parameters
with heavy malaria parasite density of 4+ was
15.9µmol/l. With the exception of the elevated mean
Parameters of severity
r
p-value
serum zinc in the only two patients with heavy
malaria parasitaemia, serum zinc tended to decline
Low Haematocrit
0.023
0.1
with increasing malaria parasitaemia.(r = -0.0101; p-
Parasite density
-0. 101
0.01
value = 0.01;Table 2).
Hyperpyrexia
-0.120
0.04
25
Discussion
Densities greater than 100,000/L in zinc
supplemented group suggesting that zinc
S e r u m
z i n c
l e v e l s
i n
p a t i e n t s
w i t h
supplementation might protect against severe forms
severe/complicated malaria varied significantly
of malaria.
from those obtained in children with non-
severe/complicated malaria while serum zinc
The morbidities of hyperparasitaemia, hyperpyrexia
concentration in controls was within the commonly
and anaemia were associated with varying mean
quoted range. The substantially low level of serum
12
serum zinc levels. Most profound reductions were
zinc in children with severe/complicated malaria in
found in association with isolated hyperpyrexia and
comparison with their counterparts who had non-
hyperparasitaemia. The apparent high levels of serum
severe/complicated may be attributed to increased
zinc in patients with anaemia might be as a result of
consumption/utilization of zinc resulting from the
the well known high intracellular zinc concentration
enhanced production of tumour necrosis factor and
in red cells which leaves the serum zinc at a relatively
other free radicals produced in the course of severe
normal level following haemolysis of the red blood
malaria. Kulkarni et al had documented that there is
17
cells. It may, therefore, be suggested that children
enhanced production of these free radicals, in
with hyperparasitaemia and hyperpyrexia are at
severe/complicated malaria. It has been suggested
greater risks of having markedly reduced levels of
that lowered zinc level is mediated by exaggerated
zinc and a probable attendant heightened propensity
production of free radicals and may reflect a normal
for complications. It was difficult to assess the
protective mechanism.
18
In addition to increased
relationship between cerebral malaria and serum zinc
consumption/utilisatiion of zinc by free radicals and
levels, as children with isolated cerebral malaria were
oxidants, another plausible explanation for lower
too few for meaningful deductions to be made.
zinc levels in severe/complicated malaria can be pre-
existing zinc deficiency making the child more
susceptible to severe/complicated malaria due to
impaired immunity.
5,18
In 1998 Gibson et al
19
reported that zinc deficiency in Malawian pregnant
Conclusion
women was associated with an increased prevalence
of malaria.
Patients with severe malaria presenting with
hyperpyrexia and hyperparasitaemia tended to have
In this study, with the exception of the two subjects
lower levels of serum zinc. There were negative
with 4+ (which are, however, too few for inferential
correlation between malaria parasite density and
deduction), there was a reduction in the mean serum
serum zinc in under-fives with malaria.
zinc levels in malaria patients with 3+ parasitaemia.
Patients with 1+ and 2+ malaria parasitaemia had
marginal differences in their mean serum zinc levels.
This marginal difference could be as a result of early
presentation at the health facility resulting in parasite
Acknowledgement
clearance at presentation and a subsequent
amelioration of free radicals production. This
We acknowledge the resident doctors and nursing
implies that serum zinc tended to decline with
staff of the Paediatric Emergency Unit of UBTH for
increasing malaria parasitaemia. In 2000, Shanker
their contributions to the management of these
et al
20
reported 29% decline in overall health centre
patients. The children recruited for the study and their
attendance, a 38% reduction in fever associated with
parents/caregivers are also acknowledged for their
Plasmodium
falciparum
parasitaemia, and a
co-operation.
reduction in episodes of hyperparasitaemia with
References
1. Snow RW, Craig M.,
2. Federal Ministry of Health
3. Greenwood BM, Bradley AK,
Deichmann U, Marsh K.
Lagos. Malaria in Nigeria
Greenwood AM. Mortality
Estimating mortality,
Epidemiology and control.
and morbidity from malaria
morbidity and disability due
Nigeria Bulletin of
among children in rural areas
to malaria among Africa's
Epidemiology 1991 Nov; 1:
of Gambia, West Africa. Trans
non-pregnant population. Bull
1-19.
R Soc Trop Med Hyg 1987;
WHO 1999; 77:624-40.
81: 478- 86
26
4. Sowunmi A, Akindele
12. Shakur S, Malek MA,
18. Beck FWJ, Kaplan J, Fine N,
JA.Presumptive diagnosis of
Tarafder SA. Zinc status of
Handschu W, Prasad AS.
malaria in infants in an
Bangladeshi children
Decreased expression of CD
endemic area. Tran R Soc
suffering from respiratory
73 (ecto- 5'- nucleotidase) in
Trop Med J 1984; 15: 69 78.
tract infection. Orion Med J
the CD8+ subset is associated
5. Shanker AH, Prasad AS. Zinc
2000 Jan 5:20-4.
with zinc deficiency in human
and immune function: the
13. Jane MD. Physical growth of
patients. J Lab Clin Med
biological basis of altered
Nigerian Yoruba children.
1997; 1 : 1226-1228.
resistance to infection. Am J
Trop Geogr Med 1974;
19. Gibson RS, Huddle J-M.
Clin Nutri. 1998; 68: 447S-
26:389-398.
Suboptimal zinc status in
63S.
14. Classification of Protein
pregnant Malawian women: its
6.
Abi B. What Does Zinc Do?
Energy Malnutrition.
association with low intakes of
Bri Med Jour. 2002;
Welcome Trust Working
poorly available zinc, frequent
325(7372): 1062
Party on classification of
reproductive cycling, and
7. Bhutta ZA, Black RE, Brown
energy malnutrition. Lancet
malaria. American Journal of
KH, Gardner JM., Gore S,
1970; 11:302-305.
Clinical Nutrition 1998;
.
Hidayat A. Prevention of
15. Mikac-Deric D. A new
67:702709.
diarrhoea and pneumonia by
spectrophotometric method
20. Shankar AH, Genton B,
zinc supplementation in
for the determination of zinc
Baisor M, Paino J, Tamja S,
children in developing
in serum and urine Clin.
Adiguma T, et al. The
countries: Pooled analysis of
Chim Acta. 1969; 23: 499.
influence of zinc
randomized control trial. J
16. Gilles HM. Diagnostic
supplementation on morbidity
Paediatr 1999;135: 689 97 .
methods in malaria. In: Gilles
due to Plasmodium
8. World Health Organisation:
HM. Warrel AD (eds). Bruce
falciparum: a randomized trial
Action Programme on severe
Chwatts Essential
in preschool children in Papua
and complicated malaria
Malariology. London: Arnold,
New Guinea. Am J Trop Med
Trans R Soc Trop Med Hyg.
1993: 81 5.
Hyg 2000; 62:66 3− 669.
2000; 94: pp190.
17. Kulkarni AG, Suryakar AN,
9. Warrel DA. Management of
Sardeshmukh A, Rathi DB.
severe malaria. Parasitologia
Studies on biochemical
41, 287- 94.
changes with special
10. Whitehead RG, Paul AA.
references to oxidant and
Nutritional needs of healthy
antioxidants in malaria
infants In: Jellife, DB.
patients. Indian Journal of
Stanfield, JP.(eds). Diseases
Clinical Biochemistry,
of children in the tropics and
2003:136.
Subtropics. 3 edition
rd
London: Edward Arnold
Publishers 1991. pp344.
11. Bashir NA. Serum zinc,
copper in sickle cell anaemia
and beta thalasaemia in North
Jordan. Ann Trop Paediatr.
1998 Dec 15; 4: 291-3.