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might have been due to differences in dose (number behavioural therapy is an effective treatment for many
of sessions or contacts), frequency or duration of the similar disorders.10
interventions, the involvement of parents in FITNET
but not usual care, or some other difference that was *Peter D White, Trudie Chalder
not measured. The other main issue is how to define Barts and The London School of Medicine and Dentistry, Queen
Mary University of London, St Bartholomew’s Hospital,
recovery from an illness that includes symptoms
London EC1A 7BE, UK (PDW); and Academic Department of
that are sometimes reported by healthy people.8 The Psychological Medicine, King’s College London, London, UK (TC)
investigators defined recovery post hoc. However, the
criteria used to define recovery were not stringent and PDW has done paid and voluntary consultancy for the UK Departments of Health
some individuals who entered the study were already and Work and Pensions and a re-insurance company. TC is the author of self-help
books about fatigue.
attending school fairly frequently. The investigators
1 Paprotka T, Delviks-Frankenberry KA, Cingöz O, et al. Recombinant origin of
also used liberal criteria, such as the population mean the retrovirus XMRV. Science 2011; 333: 97–101.
2 Cohen J, Enserink M. False positive. Science 2011; 333: 1694–701.
plus two rather than one standard deviation, as their
3 Nijhof SL, Bleijenberg G, Uiterwaal CSPM, Kimpen JLL, van de Putte EM.
thresholds for recovery by continuous measures such Effectiveness of internet-based cognitive behavioural treatment for
adolescents with chronic fatigue syndrome (FITNET): a randomised
as fatigue. Therefore, the 63% of patients reported controlled trial. Lancet 2012; published online March 1. DOI:10.1016/S0140-
as recovered might have included those who had 6736(12)60025-7.
4 Crawley EM, Emond AM, Sterne JAC. Unidentified chronic fatigue
a significant improvement rather than being fully syndrome (CFS/ME) is a major cause of school absence: surveillance
recovered. This proportion of patients does not detract outcomes from school-based clinics. BMJ Open 2011; 1: e000252.
5 Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G.
from the still impressive difference from the 8% of Cognitive behaviour therapy for adolescents with chronic fatigue
syndrome: randomised controlled trial. BMJ 2005; 330: 14.
participants who were judged to be recovered after 6 Chalder T, Deary V, Husain K, Walwyn R. Family-focused cognitive
usual care. behaviour therapy versus psycho-education for chronic fatigue syndrome
in 11- to 18-year-olds: a randomized controlled treatment trial. Psychol Med
There are some difficulties with generalisability, 2010; 40: 1269–79.
since only 30% of the world’s population have internet 7 Castell BD, Kazantzis N, Moss-Morris RE. Cognitive behavioural therapy and
graded exercise for chronic fatigue syndrome: a meta-analysis.
access (percentages are higher in Europe [58%] and Clin Psychol Sci Pract 2011; 18: 311–24.
North America [78%]).9 Patients and parents need to be 8 Pawlikowska T, Chalder T, Hirsch SR, Wallace P, Wright DJ, Wessely SC.
Population based study of fatigue and psychological distress. BMJ 1994;
reasonably literate, with no language barriers. The results 308: 763.
9 Internet world stats. Usage and population statistics. http://www.
of the trial cannot be generalised to adults. However, the (accessed Jan 13, 2012).
investigators should be congratulated on testing a way 10 Cuijpers P, van Straten A, Andersson G. Internet administered cognitive
behavior therapy for health problems: a systematic review. J Behav Med
to deliver an already effective treatment more efficiently. 2008; 31: 169–77.
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 of such a trial, but show no beneficial effect. They Published Online
April 10, 2012
in southern Asia,1 where an association with suscept- randomly assigned 3046 infants aged 1–11 months DOI:10.1016/S0140-
ibility to pneumonia—the leading cause of child in Kabul, Afghanistan, to receive a quarterly dose of 6736(12)60405-X

mortality in the region2—has been reported.3,4 Oral 2·5 mg (100 000 IU) colecalciferol or placebo over See Articles page 1419

boluses of vitamin D induce large and rapid rises in 18 months. Vitamin D supplementation did not affect
circulating concentrations of calcifediol, the major the incidence of first episodes of pneumonia (incidence
circulating vitamin D metabolite, which supports rate ratio 1·05, 95% CI 0·88–1·25); indeed, an excess
broad-spectrum innate immune responses to microbes of repeat episodes of pneumonia was recorded in the
in vitro.5 The case to undertake trials of bolus-dose intervention group (0·06 vs 0·04 episodes per child
vitamin D supplementation for pneumonia prevention per year).
in this setting is therefore compelling. In The Lancet, Does this result spell the end for the hypothesis
Semira Manaseki-Holland and colleagues6 report results that vitamin D supplementation might prevent Vol 379 April 14, 2012 1373


pneumonia? Certainly the trial has important strengths: intervention group of the study. Giving lower doses of
it is the largest to assess this question published so far; vitamin D more often could induce sustained elevation
power calculation assumptions regarding low baseline of calcifediol concentrations into the physiological
vitamin D status and high pneumonia incidence in range; this might have more favourable effects on
the study population were fulfilled; and the dose of immune function.
vitamin D given was generous. The interpretation that The second issue to be considered relates to the
the hypothesis is flawed must therefore be considered. generalisability of study results. Malnutrition was
However, the possibility remains that investigation of common in the study population: more than one in
a different dosing regimen of vitamin D in a different six participants had Z scores of weight-for-age of less
population might yet yield a positive result. than –2. Participants might therefore have been at
The first reason to consider this possibility relates to high risk of deficiencies in other micronutrients such
the pharmacokinetics of calcifediol response to quarterly as calcium and vitamin A, both of which could modify
administration of large bolus doses of vitamin D to effects of vitamin D supplementation; results of this
infants. This resulted in a rapid increase in circulating study cannot necessarily be applied to better nourished
calcifediol concentrations—to supraphysiological con- populations. Caution should also be exercised in
centrations in some cases—with a subsequent slow extrapolating results of this study to older children:
decline to concentrations similar to those recorded in pulmonary expression of pattern recognition receptors
unsupplemented children.6 Such peaks and troughs is reduced in early life, and responses to their ligation are
could have potentially deleterious effects on the attenuated.9 The ability of calcifediol to support innate
immune response: concentrations of calcifediol greater antimicrobial responses in vitro is dependent on the
than 140 nmol/L have been associated with impaired expression of such receptors;5 consequently vitamin D
immunity to infection,6 possibly related to the fact that supplementation might be more effective at enhancing
vitamin D can suppress adaptive responses to infection immune function in older children than in infants.
as well as boosting innate responses.7 Moreover, chronic A third explanation for the lack of benefit reported
exposure to falling calcifediol concentrations has been in this trial relates to the possibility that a subgroup
postulated to cause an imbalance between the activity of participants might have benefited from vitamin D
of enzymes that synthesise and catabolise calcitriol in supplementation, but that this effect was obscured
extra-renal tissues, resulting in reduced concentrations by a larger group of less responsive participants.
of this active metabolite at sites of disease.8 Either Protective effects might have been restricted to those
or both of these events could have contributed to with profound deficiency, as recently reported in a trial
the excess of recurrent pneumonia recorded in the 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

1374 Vol 379 April 14, 2012


supplementation in pneumonia prevention, but because 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
it informs the design of future studies. Further trials of 2010; 99: 389–93.
more frequent dosing regimens in other age groups 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.
with lower rates of malnutrition, characterising poten- 6 Manaseki-Holland S, Maroof Z, Bruce J, et al. Effect on the incidence of
tial effect modifiers such as baseline vitamin D status pneumonia of vitamin D supplementation by quarterly bolus dose to
infants in Kabul: a randomised controlled superiority trial. Lancet 2012;
and genetic factors, are now indicated. 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
Adrian R Martineau Greenland. Br J Nutr 2010; 104: 1487–91.
Centre for Primary Care and Public Health, Barts and The London 8 Vieth R. How to optimize vitamin D supplementation to prevent cancer,
based on cellular adaptation and hydroxylase enzymology. Anticancer Res
School of Medicine and Dentistry, Queen Mary University of 2009; 29: 3675–84.
London, London E1 2AB, UK 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
I am supported by a National Institute of Health Research (NIHR) programme reduce exacerbations in chronic obstructive pulmonary disease:
grant on vitamin D supplementation to prevent acute respiratory illness. I declare a randomized trial. Ann Intern Med 2012; 156: 105–14.
that I have no conflicts of interest. 11 Martineau AR, Leandro AC, Anderson ST, et al. Association between
1 Arabi A, El Rassi R, El-Hajj, Fuleihan G. Hypovitaminosis D in developing Gc genotype and susceptibility to TB is dependent on vitamin D status.
countries—prevalence, risk factors and outcomes. Nat Rev Endocrinol 2010; Eur Respir J 2010; 35: 1106–12.
6: 550–61. 12 Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D3
2 Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of during intensive-phase antimicrobial treatment of pulmonary tuberculosis:
child mortality in 2008: a systematic analysis. Lancet 2010; 375: 1969–87. a double-blind randomised controlled trial. Lancet 2011; 377: 242–50.
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. Vol 379 April 14, 2012 1375

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