Comment
might have been due to differences in dose (number
of sessions or contacts), frequency or duration of the
interventions, the involvement of parents in FITNET
but not usual care, or some other difference that was
not measured. The other main issue is how to define
recovery from an illness that includes symptoms
that are sometimes reported by healthy people.8 The
investigators defined recovery post hoc. However, the
criteria used to define recovery were not stringent and
some individuals who entered the study were already
attending school fairly frequently. The investigators
also used liberal criteria, such as the population mean
plus two rather than one standard deviation, as their
thresholds for recovery by continuous measures such
as fatigue. Therefore, the 63% of patients reported
as recovered might have included those who had
a significant improvement rather than being fully
recovered. This proportion of patients does not detract
from the still impressive difference from the 8% of
participants who were judged to be recovered after
usual care.
There are some difficulties with generalisability,
since only 30% of the world’s population have internet
access (percentages are higher in Europe [58%] and
North America [78%]).9 Patients and parents need to be
reasonably literate, with no language barriers. The results
of the trial cannot be generalised to adults. However, the
investigators should be congratulated on testing a way
to deliver an already effective treatment more efficiently.
They have added to an increasing evidence base which
shows that therapist-aided, internet-based cognitive
Bolus-dose vitamin D and prevention of childhood pneumonia
Vitamin D deficiency is highly prevalent in children
in southern Asia,1 where an association with suscept-
ibility to pneumonia—the leading cause of child
mortality in the region2—has been reported.3,4 Oral
boluses of vitamin D induce large and rapid rises in
circulating concentrations of calcifediol, the major
circulating vitamin D metabolite, which supports
broad-spectrum innate immune responses to microbes
in vitro.5 The case to undertake trials of bolus-dose
vitamin D supplementation for pneumonia prevention
in this setting is therefore compelling. In The Lancet,
Semira Manaseki-Holland and colleagues6 report results
www.thelancet.com Vol 379 April 14, 2012
behavioural therapy is an effective treatment for many
similar disorders.10
*Peter D White, Trudie Chalder
Barts and The London School of Medicine and Dentistry, Queen
Mary University of London, St Bartholomew’s Hospital,
London EC1A 7BE, UK (PDW); and Academic Department of
Psychological Medicine, King’s College London, London, UK (TC)
p.d.white@qmul.ac.uk
PDW has done paid and voluntary consultancy for the UK Departments of Health
and Work and Pensions and a re-insurance company. TC is the author of self-help
books about fatigue.
1 Paprotka T, Delviks-Frankenberry KA, Cingöz O, et al. Recombinant origin of
the retrovirus XMRV. Science 2011; 333: 97–101.
2 Cohen J, Enserink M. False positive. Science 2011; 333: 1694–701.
3 Nijhof SL, Bleijenberg G, Uiterwaal CSPM, Kimpen JLL, van de Putte EM.
Effectiveness of internet-based cognitive behavioural treatment for
adolescents with chronic fatigue syndrome (FITNET): a randomised
controlled trial. Lancet 2012; published online March 1. DOI:10.1016/S0140-
6736(12)60025-7.
4 Crawley EM, Emond AM, Sterne JAC. Unidentified chronic fatigue
syndrome (CFS/ME) is a major cause of school absence: surveillance
outcomes from school-based clinics. BMJ Open 2011; 1: e000252.
5 Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G.
Cognitive behaviour therapy for adolescents with chronic fatigue
syndrome: randomised controlled trial. BMJ 2005; 330: 14.
6 Chalder T, Deary V, Husain K, Walwyn R. Family-focused cognitive
behaviour therapy versus psycho-education for chronic fatigue syndrome
in 11- to 18-year-olds: a randomized controlled treatment trial. Psychol Med
2010; 40: 1269–79.
7 Castell BD, Kazantzis N, Moss-Morris RE. Cognitive behavioural therapy and
graded exercise for chronic fatigue syndrome: a meta-analysis.
Clin Psychol Sci Pract 2011; 18: 311–24.
8 Pawlikowska T, Chalder T, Hirsch SR, Wallace P, Wright DJ, Wessely SC.
Population based study of fatigue and psychological distress. BMJ 1994;
308: 763.
9 Internet world stats. Usage and population statistics. http://www.
internetworldstats.com/stats.htm (accessed Jan 13, 2012).
10 Cuijpers P, van Straten A, Andersson G. Internet administered cognitive
behavior therapy for health problems: a systematic review. J Behav Med
2008; 31: 169–77.
of such a trial, but show no beneficial effect. They Published Online
April 10, 2012
randomly assigned 3046 infants aged 1–11 months DOI:10.1016/S0140-
in Kabul, Afghanistan, to receive a quarterly dose of 6736(12)60405-X
2·5 mg (100 000 IU) colecalciferol or placebo over See Articles page 1419
18 months. Vitamin D supplementation did not affect
the incidence of first episodes of pneumonia (incidence
rate ratio 1·05, 95% CI 0·88–1·25); indeed, an excess
of repeat episodes of pneumonia was recorded in the
intervention group (0·06 vs 0·04 episodes per child
per year).
Does this result spell the end for the hypothesis
that vitamin D supplementation might prevent
1373
 Comment
pneumonia? Certainly the trial has important strengths:
it is the largest to assess this question published so far;
power calculation assumptions regarding low baseline
vitamin D status and high pneumonia incidence in
the study population were fulfilled; and the dose of
vitamin D given was generous. The interpretation that
the hypothesis is flawed must therefore be considered.
However, the possibility remains that investigation of
a different dosing regimen of vitamin D in a different
population might yet yield a positive result.
The first reason to consider this possibility relates to
the pharmacokinetics of calcifediol response to quarterly
administration of large bolus doses of vitamin D to
infants. This resulted in a rapid increase in circulating
calcifediol concentrations—to supraphysiological con-
centrations in some cases—with a subsequent slow
decline to concentrations similar to those recorded in
unsupplemented children.6 Such peaks and troughs
could have potentially deleterious effects on the
immune response: concentrations of calcifediol greater
than 140 nmol/L have been associated with impaired
immunity to infection,6 possibly related to the fact that
vitamin D can suppress adaptive responses to infection
as well as boosting innate responses.7 Moreover, chronic
exposure to falling calcifediol concentrations has been
postulated to cause an imbalance between the activity
of enzymes that synthesise and catabolise calcitriol in
extra-renal tissues, resulting in reduced concentrations
of this active metabolite at sites of disease.8 Either
or both of these events could have contributed to
the excess of recurrent pneumonia recorded in the
Corbis
1374
intervention group of the study. Giving lower doses of
vitamin D more often could induce sustained elevation
of calcifediol concentrations into the physiological
range; this might have more favourable effects on
immune function.
The second issue to be considered relates to the
generalisability of study results. Malnutrition was
common in the study population: more than one in
six participants had Z scores of weight-for-age of less
than –2. Participants might therefore have been at
high risk of deficiencies in other micronutrients such
as calcium and vitamin A, both of which could modify
effects of vitamin D supplementation; results of this
study cannot necessarily be applied to better nourished
populations. Caution should also be exercised in
extrapolating results of this study to older children:
pulmonary expression of pattern recognition receptors
is reduced in early life, and responses to their ligation are
attenuated.9 The ability of calcifediol to support innate
antimicrobial responses in vitro is dependent on the
expression of such receptors;5 consequently vitamin D
supplementation might be more effective at enhancing
immune function in older children than in infants.
A third explanation for the lack of benefit reported
in this trial relates to the possibility that a subgroup
of participants might have benefited from vitamin D
supplementation, but that this effect was obscured
by a larger group of less responsive participants.
Protective effects might have been restricted to those
with profound deficiency, as recently reported in a trial
of vitamin D supplementation in adults with chronic
obstructive pulmonary disease;10 alternatively, genetic
variation in pathways of vitamin D metabolism, trans-
port, or signalling could have modified the effects
of vitamin D status on immunity to respiratory
pathogens, as previously shown for tuberculosis.11,12
Understanding such effect modification has clinical
relevance where resources are sufficient to establish
the phenotype and genotype of patients in detail, but
they are of more academic interest in low-resource
settings where incidence of childhood pneumonia is
highest. Doing a pragmatic trial to assess effectiveness
of bolus vitamin D dosing in a population with
high prevalence of deficiency and high incidence of
pneumonia was therefore a logical point of departure,
and the negative outcome of this study is important—
not because it definitively excludes a role for vitamin D
www.thelancet.com Vol 379 April 14, 2012

supplementation in pneumonia prevention, but because
it informs the design of future studies. Further trials of
more frequent dosing regimens in other age groups
with lower rates of malnutrition, characterising poten-
tial effect modifiers such as baseline vitamin D status
and genetic factors, are now indicated.
Adrian R Martineau
Centre for Primary Care and Public Health, Barts and The London
School of Medicine and Dentistry, Queen Mary University of
London, London E1 2AB, UK
a.martineau@qmul.ac.uk
I am supported by a National Institute of Health Research (NIHR) programme
grant on vitamin D supplementation to prevent acute respiratory illness. I declare
that I have no conflicts of interest.
1 Arabi A, El Rassi R, El-Hajj, Fuleihan G. Hypovitaminosis D in developing
countries—prevalence, risk factors and outcomes. Nat Rev Endocrinol 2010;
6: 550–61.
2 Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of
child mortality in 2008: a systematic analysis. Lancet 2010; 375: 1969–87.
3 Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin
D deficiency with severe acute lower respiratory infection in Indian children
under 5 y. Eur J Clin Nutr 2004; 58: 563–67.
www.thelancet.com Vol 379 April 14, 2012
Comment
4 Roth DE, Shah R, Black RE, Baqui AH. Vitamin D status and acute lower
respiratory infection in early childhood in Sylhet, Bangladesh. Acta Paediatr
2010; 99: 389–93.
5 Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin
D-mediated human antimicrobial response. Science 2006; 311: 1770–73.
6 Manaseki-Holland S, Maroof Z, Bruce J, et al. Effect on the incidence of
pneumonia of vitamin D supplementation by quarterly bolus dose to
infants in Kabul: a randomised controlled superiority trial. Lancet 2012;
published online April 10. DOI:10.1016/S0140-6736(11)61650-4.
7 Nielsen NO, Skifte T, Andersson M, et al. Both high and low serum vitamin
D concentrations are associated with tuberculosis: a case-control study in
Greenland. Br J Nutr 2010; 104: 1487–91.
8 Vieth R. How to optimize vitamin D supplementation to prevent cancer,
based on cellular adaptation and hydroxylase enzymology. Anticancer Res
2009; 29: 3675–84.
9 Levy O. Innate immunity of the newborn: basic mechanisms and clinical
correlates. Nat Rev Immunol 2007; 7: 379–90.
10 Lehouck A, Mathieu C, Carremans C, et al. High doses of vitamin D to
reduce exacerbations in chronic obstructive pulmonary disease:
a randomized trial. Ann Intern Med 2012; 156: 105–14.
11 Martineau AR, Leandro AC, Anderson ST, et al. Association between
Gc genotype and susceptibility to TB is dependent on vitamin D status.
Eur Respir J 2010; 35: 1106–12.
12 Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D3
during intensive-phase antimicrobial treatment of pulmonary tuberculosis:
a double-blind randomised controlled trial. Lancet 2011; 377: 242–50.
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