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Indian Pediatr 2017;54: 489-493 |
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Randomized Controlled Trial Evaluating
Probiotics in Children with Severe Acute Malnutrition.
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Source Citation:
Grenov B, Namusoke H, Lanyero B, Nabukeera-Barungi N,
Ritz C, Mølgaard C, et al. Effect of probiotics on diarrhea in
children with severe acute malnutrition: A randomized controlled study
in Uganda. J Pediatr Gastroenterol Nutr. 2017;64 :396-403.
Section Editor:
Abhijeet Saha
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Summary
This randomized, double-blind, placebo-controlled
trial was conducted involving 400 children hospitalized with severe
acute malnutrition (SAM). Patients received one daily dose of a blend of
Bifidobacterium animalis subsp lactis and Lactobacillus
rhamnosus (10 billion colony-forming units, 50:50) or placebo during
hospitalization followed by an 8- to 12-week outpatient treatment
period, depending on patients’ recovery rate. The primary outcome was
number of days with diarrhea during hospitalization. Secondary outcomes
included other diarrhea outcomes, pneumonia, weight gain, and recovery.
There was no difference in number of days with diarrhea between the
probiotic (n=200) and placebo (n=200) groups during
inpatient treatment (adjusted difference +0.2 days, 95% confidence
interval -0.8 to 1.2, P=0.69); however, during outpatient
treatment, probiotics reduced days with diarrhea (adjusted difference
-2.2 days 95% confidence interval -3.5 to -0.3, P=0.025).
Twenty-six patients died in the probiotic versus 20 in the
placebo group (P=0.38). The authors concluded that these
probiotics had no effect on diarrhea in children with SAM during
hospitalization, but reduced the number of days with diarrhea in
outpatient treatment by 26%.
Commentaries
Evidence-based Medicine Viewpoint
Relevance: Severe malnutrition is a clinically
significant problem with implications for affected individuals,
healthcare system(s), and society at large. The problem is worse in
settings with low-income, poor literacy and other social challenges. A
group of researchers working in Uganda, collaborated with Danish
scientists to examine whether a specific probiotic preparation, could
have beneficial effects on children hospitalized with severe acute
malnutrition (SAM), both during the acute treatment phase, as well as
recovery phase [1]. Although a clear research question has not been
stated in the publication [1], the study was designed to examine the
effect(s) of a combination of two probiotic strains (I=Intervention),
compared to placebo (C=Comparator), on diarrhea, lower respiratory
infection (pneumonia), and nutritional recovery (O=Outcomes), in
children hospitalized for severe malnutrition (P=Population), over a
period of 8-12 weeks (T=time-frame), using a randomized controlled trial
design (S=Study design).
Critical appraisal: Table I
summarizes an outline of the trial. Table II
presents a critical appraisal of the methodological characteristics of
the RCT using the Cochrane Risk of Bias tool [2]. Overall, the trial had
low risk-of-bias.
Table I Summary of the Trial
Study design |
Double blind, placebo-controlled, Randomized controlled trial
(RCT) |
Study setting |
Tertiary care, national-level, referral hospital based in
Kampala, Uganda. |
Study duration
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Participant enrolment from March 2014 to July 2015 (16
consecutive months) and follow-up for 3 months beyond enrolment.
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Sample size |
A
priori sample size calculation was done to detect a difference
in diarrhea duration of 0.3 SD (equivalent to 1 day) between the
two trial arms; with alpha error 5% and beta error 15%. The
calculated sample size was 178 in each arm; hence enrolment was
continued will 200 were recruited in each arm. |
Inclusion criteria |
Children in the age range 6-59 mo, hospitalized with SAM, which
was defined by either (i) weight for height/length z score
<-3.0, or (ii) mid upper arm circumference <11.5 cm, or (iii)
pitting pedal edema. |
Exclusion criteria |
Children with critical illness (shock, severe respiratory
distress), extreme malnutrition (weight < 4 kg), disability,
malignancy, and those with a prior admission for the same
problem. |
Intervention and
Comparison groups
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Intervention (Probiotic group): Combination of Bifidobacterium
animalis subspecies lactis (BB-12) and\Lactobacillus rhamnosus
(LCG) (dose 10 billion colony forming units, in a 1:1 ratio).
The probiotics were delivered in 1 g Maltodextrin.Comparison
(Placebo):1 g Maltodextrin. |
Outcomes |
Primary outcome: Duration of diarrhea during hospitalization
(diarrhea was defined as >3 loose/watery stools per day). |
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Secondary outcomes: In-patient phase of treatment:
(i) Diarrhea: Incidence, Severity; (ii) Pneumonia: Incidence,
Duration and Severity; (iii) Nutritional recovery: Weight gain;
(iv) Days with fever, Days with vomiting; (v) Duration of
hospitalization; (vi) Mortality; (vii) Other adverse events. |
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Out-patient phase of treatment: (i) Diarrhea:
No. of days, Incidence, Severity; (ii) Pneumonia: Incidence;
(iii) Nutritional recovery: Weight gain, weight recovery; (iv)
Days with fever, Days with vomiting; (v) Mortality; (vi) Other
adverse events. |
Statistical analysis |
Modified intention-to-treat (ITT) analysis was undertaken; i.e
patients with available data were included in the analysis
(rather than all who were randomized). Missing values for the
primary outcome were imputed from children with available data,
matched for diarrhea pattern, and days of hospitalization.
Statistical models were adjusted for age, gender, HIV status,
presence of edema, and weight for height/length z scores.
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Main results |
Primary outcome: Duration of diarrhea during hospitalization
(d): 6.9+6.0 (n=187) vs 6.5+6.4 (n=182) |
(Probiotic vs Placebo) |
Secondary outcomes: |
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In-patient phase of treatment |
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•Diarrhea: Incidence: 89% vs 85% (NS); episodes: 299 vs 293;
severity score: 10.2±3.8 vs 9.9±3.7 |
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•Pneumonia: Incidence: 39% vs 41%; Duration (d): 1.9±3.6
vs 2.0 ±3.7; Severity score: 2.6±5.5 vs 2.7±5.3 |
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•Nutritional recovery: Weight gain (g/kg/day): 6.5±4.7 vs
6.1±4.2 |
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•Days with fever: 7.0±5.1 vs 6.7±4.4 |
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•Days with vomiting: 2.1±3.3 vs 2.0±4.4 |
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•Duration of hospitalization (d): 18.3+9.1 vs 18.0+9.3;
Mortality: 23 vs 16 |
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•Other adverse events: None reported |
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Out-patient phase of treatment |
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•Diarrhea: Duration (d): 6.0+8.2 (n=147) vs 8.5+10.9 (n=145);
Incidence: 70% vs 76% (NS); episodes: 354 vs 398;severity score:
4.3+1.7 vs 4.4+1.7 |
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•Pneumonia: Incidence: 5% vs 10% |
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•Nutritional recovery: weight gain (g/kg/day): 3.0+2.1 vs
3.2+2.3; weight recovery: 66% vs 64% |
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•Days with fever: 1.6+2.9 vs 2.0+3.9 |
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•Days with vomiting: 1.2+2.3 vs 1.6+6.0; Mortality: 3 vs 4 |
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•Other adverse events: None reported |
Table II Methodological Appraisal of the Trial
Similarity of groups at
baseline |
The
authors reported similarity of multiple parameters including
age, gender, anthropometric measurements, HIV status, maternal
HIV status, symptoms at presentation, and treatment sought. |
Sequence generation |
A
person not associated with the study, used a computer program to
generate the randomization sequence (Adequate). |
Allocation concealment |
The
sequence was available only to a few personnel including head of
the Unit, and staff packaging the products. None of these
personnel were associated with the study procedures (Adequate).
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Blinding |
Enrolled children, their caregivers, study investigators and
staff; were all blinded. The intervention and placebo were
delivered in similar appearing, similar tasting, and similar
smelling formulations (Adequate). |
Incomplete outcome data |
The
authors used a modified ITT analysis. Rather than including all
randomized children in the denominator, they included those who
had at least some data. Thus the single outcome that showed
statistical significance had less than 75% of the originally
enrolled participants in each arm. The impact of this attrition
is unclear. |
Selective outcome
reporting |
No
evidence of selective outcome reporting. |
Other sources of bias |
The
probiotic manufacturer was one of the two funding agencies; and
‘suggested’ the intervention including dosage and strains of
probiotics, but did not have any further role in the conduct of
the study. |
Overall assessment |
Low
risk of bias |
The investigators introduced several methodological
refinements. Four sets of numbered packages (two each of probiotic or
placebo) were prepared and administered to enrolled children. Although
this method is inferior to administering packages labeled with the
randomization number; it is still better than having only two sets of
packages and administering them by allocation group. The investigators
used standard definitions for most outcomes. They refined outcome
assessment by introducing validated scoring systems for diarrhea
severity. This is important because this outcome hinged on parental
reporting (through a symptom diary). Therefore parents were trained to
use the diary. Follow-up after discharge was strengthened through weekly
telephone calls.
During the course of the study, the primary outcome
was changed from "duration of diarrhea episodes" to "duration of
diarrhea". Although this was done with due approval of the Ethics
Committee, the timing of the change is unclear. Nevertheless, it appears
that this change was not driven by mid-term data analysis.
The criteria for diagnosing pneumonia are not
described; diagnosis was made by the clinical judgment of individual
pediatricians. Likewise, the severity grading criteria are described
differently in the text and the table of the report [1]. Further, even
though the severity grading had a maximum score of 2, it was reported as
the sum of daily scores during the hospitalization period. This makes it
difficult to interpret as children with similar scores need not have
similar severity.
The authors acknowledged some limitations, including
the inability to examine stools for the microbiological etiology of
diarrhea. This is somewhat surprising as the study protocol on the Trial
Registry website [3] shows that additional samples of blood and stool
were to be collected at admission, discharge, and at 8 weeks follow-up
to identify gut microbiota changes and immune response markers. In fact,
the protocol also mentions thymus ultrasonography at these three
time-points. However, these data are not presented.
There was significant attrition of study participants
from both arms, although the inter-arm drop-out rate was comparable
overall. However, one of the reasons for attrition is stated as lack of
data on HIV status. This is again surprising as the table of baseline
parameters clearly shows maternal and child HIV status.
Although the data analysis is described as
intention-to-treat, it was a modified form wherein only those
participants with some data were included. Therefore, the primary
outcome is reported only in about 90% of the enrolled cohort. For
participants with missing data, the method of imputing data have been
clearly described.
Perhaps the most important issue in the critical
appraisal of this RCT is whether the single statistically significant
result favoring probiotic (viz reduction in duration of diarrhea
by about 2 days, during out-patient follow-up) is clinically meaningful.
Careful analysis of a figure provided as a Supplementary file to the
article [4] shows that both arms had a comparable percentage of patients
with diarrhea duration upto 9 days, suggesting lack of benefit of
probiotic for acute diarrhea. In contrast, the probiotic arm had
slightly more patients with diarrhea duration between 10 and 19 days.
However, the percentage of children with total duration of diarrhea
ranging from 20 to >40 days was significantly less in the probiotic
group. This means that the overall statistically significant reduction
in diarrhea duration is not due to decrease in the duration of acute
diarrhea (as the study suggests) but because children in the probiotic
group were less likely to have long(er) duration of diarrhea. This could
be either because of reduction in the number of diarrhea episodes, or
reduced number of days of chronic diarrhea. Since acute diarrhea
episodes last 3-5 days (on average) [5-7], children with total duration
of 20-40 days during 8 weeks follow-up would have had multiple (5 to 10
episodes). A reduction of 2.2 days across this large number of episodes
is not clinically significant. If the children were suffering from
persistent or chronic diarrhea, a reduction of 2.2 days is clinically
insignificant. Therefore, it would have been very helpful if the
investigators had shown the data of diarrhea duration in terms of number
of episodes in each arm, and the duration as well as incidence of
episodes each week after discharge. Otherwise it is difficult to
understand the true meaning of the statistically significant difference
reported [1]. It must be noted that an older trial in Malawi that
compared probiotic (lactic acid bacteria) versus placebo, also
did not find any significant impact of probiotic on diarrhea in severely
malnourished children [8].
Although all the children in the study fulfilled the
definition for SAM, their weight (or length) for age Z-scores suggest
that they were also chronically undernourished. In fact, the enrolled
children had acute-on-chronic malnutrition rather than SAM.
Last but not the least, the study setting has a
reported SAM mortality rate of around 20%; whereas the study population
had an overall mortality rate of less than 10% during hospitalization.
This suggests that the highly controlled research study environment
could be very different from the real-life scenario; thereby limiting
generalizability even within the study setting.
Extendibility: The study setting is
notably different from the setting in our country, in terms of the
profile of enrolled children (two-thirds had kwashiorkor, and 1 in 6
infants were HIV positive). Further, the baseline local in-hospital
morality rate of over 20% in SAM suggests that the children in that
setting present with serious life-threatening illnesses. The
anthropometric measurements also suggest severe wasting and stunting.
For these reasons, it may not be appropriate to directly extrapolate the
study results to other settings even if clinically significant results
had been demonstrated.
Conclusion: This well designed placebo-controlled
randomized trial did not find significant beneficial effects of
administering a specific formulation of probiotics to children during
and after hospitalization for severe malnutrition.
Funding: None; Competing interests: None
stated.
References
1. Grenov B, Namusoke H, Lanyero B, Nabukeera-Barungi
N, Ritz C, Mølgaard C, et al. Effect of probiotics on diarrhea in
children with severe acute malnutrition: A randomized controlled study
in Uganda. J Pediatr Gastroenterol Nutr. 2017;64 :396-403.
2. Cochrane Risk of Bias Tool (modified) for Quality
Assessment of Randomized Controlled Trials. Available from:http://www.tc.umn.edu/~msrg/caseCATdoc/rct.
crit.pdf. Accessed May 14, 2017.
3. Role of Probiotics in Recovery of Children with
Severe Acute Malnutrition. ISRCTN16454889 DOI 10.1186/ISRCTN16454889.
Available from: http://www.isrctn. com/ISRCTN16454889?q=16454889&
filters=&sort=& offset=1&totalResults=1&page=1&pageSize=10&search Type=
basic-search. Accessed May 14, 2017.
4. Supplemental Digital Content 2, Figure. Available
from: http://links.lww.com/MPG/A883. Accessed May 14, 2017.
5. Gharial J, Laving A, Were F. Racecadotril for the
treatment of severe acute watery diarrhoea in children admitted to a
tertiary hospital in Kenya. BMJ Open Gastroenterol. 2017;4:e000124.
6. Teotia N, Upadhyay A, Agarwal S, Garg A, Shah D.
Rotavirus diarrhea in children presenting to an urban hospital in
western Uttar Pradesh, India. Indian Pediatr. 2016; 53 :627-9.
7. Hegar B, Waspada IM, Gunardi H, Vandenplas Y. A
double blind randomized trial showing probiotics to be ineffective in
acute diarrhea in Indonesian children. Indian J Pediatr. 2015; 82
:410-4.
8. Kerac M, Bunn J, Seal A, Thindwa M, Tomkins A,
Sadler K, et al. Probiotics and prebiotics for severe acute
malnutrition (PRONUT study: a double-blind efficacy randomised
controlled trial in Malawi. Lancet. 2009;374:136-44.
Joseph L Mathew
Department of Pediatrics,
PGIMER,
Chandigarh, India.
Email:
[email protected]
Pediatrician’s Viewpoint
Relevance: Diarrhea is one of the most common
co-morbidity with which SAM children may present to a health facility.
The relationship between malnutrition and diarrhea is bidirectional –
while malnutrition predisposes children to a greater incidence and
longer duration of diarrhea, it is also true that malnutrition can be
triggered or worsened by significant diarrhea due to reduced nutrient
and fluid absorption [1].
Critical appraisal: Probiotics especially
Lactobacillus rhamnosus GG and Saccharomyces boulardi have
been reported to decrease duration of acute diarrhea and need of IV
rehydration in well nourished children [2]. Probiotics and prebiotics
have potential to promote healthy gut flora, reduce pathogenic gut
bacteria and immune modulation. Since large proportion of children with
severe acute malnutrition have bacterial overgrowth, it was largely
believed that probiotics may help in improving their outcome in terms of
weight gain and recovery. However in a randomized controlled trial in
Malawi (PRONUT STUDY), 795 SAM children were assigned to ready-to-use
therapeutic food either with or without Synbiotic 2000 forte ,
nutritional cure rates were similar in both the groups (54% vs
51%) [3]. Further, there is concern regarding probiotics causing
invasive infections in presence of increased intestinal permeability.
In present study, authors assessed the effect of
probiotics on diarrhea during in- and outpatient treatment of children
with severe acute malnutrition. Patients received one daily dose of a
blend of Bifidobacterium animalis subsp lactis and
Lactobacillus rhamnosusGG (10 billion CFU,50:50) or placebo.
There was no difference in number of days with diarrhea in probiotics
group during inpatient period. Although probiotics reduced days with
diarrhea during outpatient treatment, there was no effect of probiotics
on diarrhea incidence, severity of pneumonia, weight gain or recovery in
both inpatient and outpatient treatment [4].
Conclusions: Present study results do not
support use of probiotics in children with SAM. Both PRONUT study from
Malawi and present study could not find any significant difference in
weight gain and recovery, which are key outcome indicators of any SAM
management program.
References
1. Irena AH, Mwambazi M, Mulenga V. Diarrhea is a
major killer of children with severe acute malnutrition admitted to
inpatient set-up in Lusaka, Zambia. Nutr J. 2011;10:110.
2. Szajewska H, Guarino A, HojsakI, IndrioF, Kolacek
S, Shamir R, et al. European Society for Pediatric
Gastroenterology, Hepatology, and Nutrition. Use of probiotics for
management of acute gastroenteritis: a position paper by the ESPGHAN
Working Group for probiotics and prebiotics. J Pediatr Gastroenterol
Nutr. 2014;58:531-9
3. Kerac M, Bunn J, Seal A, Thindwa M, Tomkins A,
Sadler K, et al. Probiotics and prebiotics for severe acute
malnutrition (PRONUT study): a double-blind efficacy randomised
controlled trial in Malawi. Lancet. 2009;374:136-44.
4. Grenov B, Namusoke H, Lanyero B, Nabukeera-Barungi
N, Ritz C, Molgaard C, et al. Effect of probiotics on diarrhea in
children with severe acute malnutrition: A randomized controlled study
in Uganda. J Pediatr Gastroenterol Nutr. 2017;64:396-403.
Praveen Kumar
Department of Pediatrics,
LHMC & KSCH, New Delhi, India.
Email: [email protected]
Pediatric Gastroenterologist’s Viewpoint
In this study, the authors report the result of a
randomized controlled trial on the effects of probiotics administration
on the incidence and severity of diarrhea among hospitalized children
with severe acute malnutrition (SAM) [1]. They randomized 400 children
between the ages of 6 months to 59 months admitted in hospital with
severe acute malnutrition to receive one daily dose of a blend of
Bifidobacterium animalis subsp lactis and Lactobacillus rhamnosus
(10 billion colony-forming units, 50:50) or placebo during
hospitalization, followed by an 8- to 12-week outpatient treatment
period. The management of SAM was as per WHO guidelines and all
inpatients received antibiotics. The authors conclude that probiotics
did not affect incidence severity and duration of diarrhea among
inpatients with SAM as these children had more severe gut dysfunction
and were receiving antibiotics thus off-setting the ability of the
probiotics to act. Mortality across groups was similar.
While other probiotic studies have demonstrated a
reduction in days of acute diarrhea in outpatients, most have been in a
developed world setting. This study demonstrates its efficacy in
children with SAM who are more vulnerable to the adverse effects of
prolonged diarrhea. The benefit is still modest, and more research to
identify efficacious probiotics combination and doses are needed before
a recommendation of the use of probiotics in all children with SAM can
be made.
Rohan Malik
Department of Pediatrics, AIIMS, New Delhi, India
Email: [email protected]
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