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Indian Pediatr 2010;47: 61-66 |
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Zinc Supplementation for Prevention or
Treatment of Childhood Pneumonia: A Systematic Review of
Randomized Controlled Trials |
Joseph L Mathew
From the Advanced Pediatrics Centre, PGIMER, Chandigarh
160012, India.
Email: [email protected]
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Relevance
Community acquired pneumonia (CAP) is reportedly the
leading cause of childhood mortality, accounting for an estimated 1.9
million annual deaths among under-five children(1,2), of which India
contributes nearly 20%. Co-existent HIV/AIDS, measles and other
morbidities increase the burden of childhood pneumonia for individuals and
the community. The WHO and UNICEF have recently prioritized interventions
to reduce the burden of childhood pneumonia(1).
Over the past couple of decades, zinc is being
recognized as an important element in maintaining immune function,
reducing infections, and enhancing growth. Various research studies
supported its role in the management of acute and persistent diarrhea(3),
and it is currently included as the standard of care for this(4,5). This
led investigators to evaluate the role of zinc in childhood pneumonia
through a series of research trials.
The clinical question addressed in this systematic
review of evidence is: "Does zinc supplementation (intervention),
either improve the clinical outcome or prevent the occurrence of community
acquired pneumonia (outcome) in children (population),
compared to no supplementation (comparison)?" Two separate lines of
inquiry are required to determine whether zinc has potential for therapy
and/or prophylaxis. Relevant outcomes to assess therapeutic effect include
reduction in duration and/or severity of pneumonia with zinc
supplementation; the relevant outcome for prophylactic effect is reduction
in occurrence (incidence/prevalence) of CAP and/or associated mortality
and morbidity. Other surrogate outcomes have limited value in facilitating
informed decisions on this issue.
Current Best Evidence
An exhaustive literature search for randomized
controlled trials (RCT) evaluating either a therapeutic or prophylactic
role of zinc in childhood CAP was undertaken and updated on November 22,
2009. A Cochrane Library search using the term "zinc" and filter "Record
Title" yielded 8 Cochrane Systematic Reviews and 2 Protocols, 12 Other
(systematic) Reviews, 1240 (methodologically-appraised) Clinical Trials, 2
Methods studies and 6 Economic Evaluations. Simultaneous Pubmed search
using "zinc pneumonia" and "zinc (respiratory infection)"
with Limits "Clinical trial, randomized controlled trial" yielded
19 and 81 trials, respectively. Hand-searching of the bibliography of
relevant citations yielded an additional 12 papers that were retrieved and
examined.
Altogether 44 studies were short-listed, of which 29
were excluded for the following reasons: (i) pneumonia not
included/reported as an outcome (n=9), (ii) respiratory
infection evaluated but not consistent with pneumonia (n=6), (iii)
not RCT (n=5), (iv) not community acquired pneumonia (n=5),
(v) adult participants (n=2), and (vi) re-analysis of
data from included RCT (n=2). The remaining 15 RCTs comprise
current best evidence.
Table I
Summary of RCTs Examining Zinc Supplementation for Prophylaxis of Childhood Pneumonia
No. |
Participants |
Definition of P, SP, ALRI |
N (Zinc/
placebo) |
Dose and
duration |
Follow-
up |
Outcomes |
Pneumonia episodes/ |
Severe pneumonia |
Ref |
|
|
|
|
|
|
|
person-time |
episodes/ person-time |
|
1 |
1-12mo |
P = tachypnea + crepts. |
809/ 812 |
70mg/wk |
324 d |
P, SP, M |
Zn 0.47 |
Zn 0.04 |
6 |
|
|
SP = additional ID and/ |
|
×12 mo |
|
|
Pl 0.56 |
Pl 0.08 |
|
|
|
or danger sign |
|
|
|
|
Rel Risk = 0.83 (0.73-0.95) |
RR = 0.51 (0.30-0.88) |
|
2 |
3-59mo |
ALRI = cough, breathing
difficulty and rapid |
2483/ 2502 |
20mg/d |
NS |
H, M |
Zn 1543/ 20669 Pl 1700/ |
|
7 |
|
|
breathing or ID
|
|
× 14 d |
|
|
21089 RR = 0.93 (0.78-1.10) |
|
|
3 |
3-5wk old |
ALRI = cough + difficult breathing + fever >1d + |
152/ 149 |
5mg/d x 6mo |
6 mo |
ALRI In, Pr |
Zn 0.7 Pl 0.7
RR = 0.99 |
|
8 |
|
|
rapid breathing or ID |
|
|
|
|
(0.71-1.37) |
|
|
4 |
6-30mo |
ALRI = cough, tachypnea or ID. |
1241/ 1241 |
10mg/d in <1y |
4mo |
ALRI/severe
ALRI In |
Zn 0.53
Pl 0.54 |
Zn 0.08
Pl 0.11 |
9 |
|
|
P = cough + crepts/ bronchial breathing or
ALRI with at least 1 |
|
20mg/d in >1y For 4 mo |
|
|
OR = 0.98 (0.86-1.13)* |
RR = 0.72 (0.56-0.99)* |
|
|
|
severe disease symptom |
|
|
|
|
|
|
|
5 |
12-35 mo |
ALRI = cough + rapid or difficult breathing + |
400/400 |
20mg/d x 14d |
6mo |
ALRI / severe |
Incidence
Zn 1.14, Pl 0.79 |
Incidence
Zn 0.59,
Pl 0.32 |
10 |
|
|
fever Severe ALRI =
ALRI + ID |
|
|
|
ALRI In, Pr |
RR = 1.62 (1.16-2.25) |
RR = 2.03 (1.24-3.33) |
|
|
|
|
|
|
|
|
Prevalence Zn 5.10, Pl 2.94 |
Prevalence Zn 2.13, Pl 1.28 |
|
|
|
|
|
|
|
|
RR = 2.07 (1.76-2.44) |
RR 2.06 (1.60-2.64) |
|
6 |
0.5-15 y |
ALRI = cough +
tachypnea ( rate NS) |
214/ 215 |
20mg/d x 7d |
7 mo |
ALRI |
GEE Risk Ratio = 1.00 (0.27) |
|
11 |
7 |
2-4 wk old
term LBW |
ALRI = cough or
breathing difficulty +
tachypneaSevere ALRI |
1026/ 1026 |
5mg/d
10mg/d<6mo
>6mo |
11.5 mo |
ALRI Pr ** |
ALRI/severe** |
** |
12 |
|
|
= ALRI + 1 or more |
|
Till 12 mo old |
|
|
|
|
|
|
|
severe symptoms |
|
|
|
|
|
|
|
8 |
6-35 mo |
ALRI = cough +
tachypnea or |
298/ 311 |
10mg/d x 4mo |
120 days |
ALRI In. Pr |
*** |
|
13 |
|
|
temperature
>101 deg F |
|
|
|
|
|
|
|
9 |
<6mo |
LRI= fever + cough +
difficult/rapid breathing |
170/ 164 |
10mg/d x 6mo |
6mo |
ALRI +
others |
Zn 3.6
Pl 3.7 |
|
14 |
|
|
(as per mothers’ report) |
|
|
|
|
RR=0.97 (CI ns) |
|
|
10 |
6-36mo,
with >14d diarrhea |
ALRI=cough + tachypnea
P = cough + crepts |
81-83 |
10mg/d x 6 mo |
6mo |
p |
Zn 1.11+0.96
P1 1.26+1.19
RR = 0.88 (CI ns)**** |
|
15 |
11 |
3-24 mo***** |
LRTI = Tachypnea + breathing difficulty +
cough + fever > 38 deg or ID |
76/78 |
20mg/d x 14d |
6mo |
RTI In,
duration, M |
**** |
|
16 |
A LRI = acute lower
respiratory infection, GEE = general estimating equation H =
hospitalization, ID = indrawing, In = incidence, LBW = low birth
weight, M = mortality, NS = not specified, OR = odds ratio, P =
pneumonia, PL = placebo, Pr = prevalence, RTI = respiratory tract
infection (upper and lower), RR = rate ratio, Rel Risk = relative
risk, SP = severe pneumonia, Zn = zinc
*Study definition of ALRI was consistent with WHO pneumonia and study
definition of ‘Pneumonia’ was consistent with WHO ‘severe pneumonia’.
** Pneumonia and severe pneumonia estimated during a 24 hour as well
as a seven-day recall period at four time-points (12 observations), of
which 11 did not show any difference between the groups. *** This
study reported incidence and prevalence per person-time; the
respective odds ratios were 0.55 (0.33-0.90) and 0.59 (0.35-1.00).
**** This study presented data in a figure showing the comparative
difference in incidence of ALRI and pneumonia relative to placebo; the
former was about 3% lower, while the latter was not different. The
study also reported the effect of zinc plus vitamins, which resulted
in a 20% higher incidence of pneumonia. ***** Participants were
recruited for a trial of zinc in persistent diarrhea; this study
followed-up a sub-group of the original participants for respiratory
infection and presented results in an even smaller sub-group of
malnourished infants. Data were combined for URTI and LRTI. |
Eleven RCTs assessed the effect of zinc supplementation
for prevention of CAP. Table I summarizes the trial
characteristics and findings. All were community-based trials in
developing countries. One was a cluster-randomized trial(7). Pneumonia
and/or lower respiratory tract infection were defined in various ways, but
all were consistent with the currently accepted IMNCI
definition/classifi-cation(17). However, three trials did not specify the
respiratory rate for defining tachypnea(11,13,14). Nine of eleven trials
were double-blind and placebo-controlled. Zinc dosage ranged from 5 to 20
mg/day. Two trials used smaller doses for younger infants(9,12). Duration
of supplementation ranged from two weeks(7,16) to 12 months(20). Follow-up
ranged from 4-12 months. The relevant outcomes – occurrence of pneumonia
and/or severe pneumonia – were measured and expressed in various ways
including incidence, prevalence, and episodes per person-time. Three
trials reported mortality, but expressed the results differently(7,8,16).
These differences made it difficult to derive a pooled estimate of effect,
through meta-analysis. However, the balance of evidence (8 trials, 11701
participants) suggests that zinc supplementation does not prevent the
occurrence of pneumonia. Only two trials (2230 participants) reported that
zinc decreased pneumonia(6,13) and one trial (800 participants) showed
that zinc supplementation increased the incidence and prevalence of
pneumonia(10).
Four RCTs looked for a possible therapeutic effect of
zinc supplementation in addition to antibiotic therapy(18-21). All were
hospital-based, double-blind, placebo-controlled RCTs, although the
process of allocation concealment and blinding were not clearly described
in one(18). The trials used various definitions for pneumonia, but these
were consistent with the WHO definitions of pneumonia and severe
pneumonia. All but one(19) reported sample size calculations, and examined
multiple outcomes including time for recovery and/or duration of
hospitalization. Three (18,20,21) compared the time for resolution of
severe pneumonia, and three (18,19,21) evaluated duration of
hospitalization. Since all four RCTs presented results as median duration,
meta-analysis was not possible. The trial characteristics and results are
summarized in Table II. The balance of evidence suggests
that there is no therapeutic benefit of adding zinc to antibiotic therapy.
One trial in Australian indigenous children(19) followed participants for
an additional 120 days and found that zinc supplementation resulted in a
2.4 times higher risk of readmission for pneumonia.
Table II
Summary of RCTs Examining Therapeutic Role of Zinc Supplementation In Childhood Pneumonia
No. |
Setting |
Participants |
Definitions used |
N (Zinc/ |
Dose and |
Outcomes |
Time for |
Duration of |
Ref |
|
|
|
|
placebo) |
duration |
|
resolution of SP |
hospitalization |
|
1 |
Bangladesh |
2-23 mo |
P = cough + |
135/ 135 |
20mg/d till |
TR of SP, H |
Median (95%CI) |
Median (95% CI) |
18 |
|
|
with SP |
tachypnea + crepts; |
|
discharge |
TR of tachypnea,
ID, hypoxia |
Zn: 72 (72-96)
Pl: 96 (72-96) |
Zn: 112 (104-112)
Pl: 112 (111-129) |
|
|
|
|
SP = P + ID or
danger sign |
|
|
|
|
RH 0.75 (0.57-0.99) |
|
2 |
Australia
(indigenous |
<11y |
ALRI = tachypnea |
111/ 104 |
< 12mo
20mg/d > |
Readmission within |
|
Median (range) |
19 |
|
population) |
|
+ fever/ID or
pneumonia on x-ray |
|
12 mo 40mg/d ×5 d |
120d, H, TR of
hypoxia, fever,
tachypnea. |
|
Zn: 5 (1-46)Pl: 5 (1-25) p =
0.75 |
|
3 |
India |
2-23mo
with SP |
SP = tachypnea + crepts + 1
severe symptom |
150/ 150 |
20mg/d till
discharge |
TR of tachypnea, ID, hypoxia,
poor feeding,
fever, cough |
Median (95%CI)
Zn: 111.3 (88.5-138)
Pl: 96.7 (78.2-112.9)
RR 0.86 (0.62-1.18) |
Median (95% CI)
Zn: 71.1 (68.1-88.0)
Pl: 72.3 (67.7-79.6)
RR 0.93 (0.74-1.17) |
20 |
4 |
India |
9mo-15y
with measles + P |
ALRI = tachypnea, ID,
auscultation signs or both |
42/ 43 |
20mg/d x 6
days* |
TR of fever, tachypnea and
“significant illness” as judged by clinician |
Median (quartile)
Zn: 132 (117-139)
Pl: 122 (107-141)
RH 1.07 (0.64-1.78) |
|
21 |
RH = relative hazard, TR = time for resolution; * Both groups received
1 dose vitamin A. |
Critical Appraisal
The fifteen RCTs included in this systematic review had
generally high methodological quality. Some of them included additional
refinements such as direct observation of zinc/placebo intake, frequent
field-worker visits to measure outcomes, multiple/serial outcome
measurements, pre-post estimation of zinc levels in the participants, and
measurement of compliance.
Based on adequacy of randomization and allocation
concealment procedures, blinding of outcome assessors and low attrition
rate, 8 of the 15 RCTs (5 prophylaxis and 3 therapy) had low risk of bias;
6 had moderate risk of bias (1 or 2 of 4 elements unclear) and only 1
trial had high risk of bias. Nine trials reported sample size calculations
for the specific outcomes measured; 5 trials used intention-to-treat
analysis. Therefore, it is reasonable to conclude that the RCT methodology
were robust to support the conclusions stated. However, it was not
possible to pool data through meta-analysis owing to variations in the
measurement and reporting formats.
The findings of this review are contrary to two
previous meta-analyses of a limited number of RCTs(22,23). This is easily
explained by noting that seven additional trials with robust methodology
have been included in this review, and all included studies had
definitions consistent with pneumonia.
Some additional interesting findings were picked up
during the systematic review. There was limited data suggesting benefit of
zinc in zinc-deficient children(8). If this is borne out by further
studies, it may be possible to identify a sub-group of children who could
benefit from zinc supplementation. However, the issue is complicated by
the fact that serum zinc levels do not reflect tissue levels(21), and may
be higher(16) or lower in severe infection. This apparent contradiction is
explained by divergent views on zinc homoeostasis in response to
infection. Besides this, although children in developing countries are
assumed to be zinc deficient, data suggests that this is true only in a
minority(12,13). These data argue strongly against considering
population-based supplementation for pneumonia prophylaxis. Trials
reporting harmful effects of zinc supplementation(10,13,19) advocate
further caution.
A small number of trials used additional vitamin A,
other vitamins, or iron supplementation in addition to zinc in both the
intervention and control groups(12-14,19). From a methodological
standpoint, it is appropriate to combine data from these studies with the
others. However, the exact nature of interaction between zinc and other
nutritional supplements is unclear, as there is evidence for benefit as
well as harm. This may be an avenue for further research.
Should more RCTs be conducted to evaluate a therapeutic
or prophylactic role of zinc? This systematic review shows that rather
than undertaking more trials, it would be prudent to await updates in
statistical methodology, and combine data from the existing RCTs to derive
the pooled estimate. These developments are anticipated from the Cochrane
Collaboration in the near future.
Extendibility
The RCTs in this review shared the common
characteristics of developing-country setting, lower/middle socio-economic
population, clinical definitions of pneumonia, clinical measurement of
outcomes, and standard treatment protocols. Further, two therapeutic
trials and four prophylaxis trials were conducted in our country itself.
Therefore it is easy to extend the results and interpretations to the
Indian context.
Funding: None.
Conflict of interest: None stated.
EURECA Conclusion in the
Indian Context
• There is no benefit of adding zinc to the
standard treatment of childhood community acquired pneumonia.
• The current best evidence does not support zinc supplementation
to prevent childhood pneumonia.
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