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Measles Mortality and Vitamin A
Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore,
Maryland, USA. rdsemba@jhmi.edu
Vitamin A deficiency is associated with increased morbidity and mortality from
diarrheal disease, measles, and malaria. It has been proposed that vitamin A
supplementation could be linked with childhood immunization programs to improve
child health. We conducted a randomized, double-blind, placebo-controlled
clinical trial to evaluate the impact of linking vitamin A supplementation with
the Expanded Programme on Immunization on morbidity and child growth. In West
Java, Indonesia, 467 six-week-old infants were randomized to receive 7.5 mg
retinol equivalent (RE), 15 mg RE, or placebo with childhood immunization
contacts at 6, 10, and 14 wks and 9 mo of age. Child growth was assessed
through anthropometry, and morbidity histories were obtained. Vitamin A
supplementation had no apparent impact upon linear or ponderal growth or
infectious disease morbidity in the first 15 mo of age when integrated with the
Expanded Programme on Immunization. CONCLUSION: Although improving vitamin A nutriture is of general
importance in reducing diarrheal and measles morbidity and mortality in
developing countries, this clinical trial showed no apparent benefit of
vitamin A capsules for infant health when given through childhood immunization
programs.
Micronutrients as adjunct therapy of acute
illness in children: impact on the episode outcome and policy implications of
current findings.
Mahalanabis D, Bhan MK.
Society for Applied Studies, Calcutta and All India Institute of Medical
Sciences, New Delhi, India. dmahalanabis@vsnl.com
Role of micronutrients namely vitamin A, zinc and folate, as adjunct therapy of
illness episodes in children in developing countries have been discussed in the
light of health policy. Apart from a selective review, attempts have been made
to statistically combine results of several studies to address policy issues.
In children, vitamin A
supplementation during illness has (a) a profound effect in reducing mortality
in measles, (b) possibly a significant effect in reducing persistent
diarrhea episodes in children with acute diarrhea, and (c) no benefit in
pneumonia. Use of large dose vitamin A is recommended during measles episodes
but not in non-measles pneumonia. Its use in acute diarrhea is debatable but
recommended in persistent diarrhea and in severe malnutrition as a component of
a micronutrient mixture. Large dose vitamin A supplementation should be used with
caution in young infants as there are unresolved concerns about its safety
particularly, bulging fontanelle observed in infants when co-administered at
immunization. In children, zinc supplementation during illness, (a) had a
marked effect in reducing prolonged episodes and a modest effect on episode
duration in acute diarrhea, (b) resulted in reduced rate of treatment failure
and death in persistent diarrhea, (c) had no effect in measles and non-measles
pneumonia, and (d) probably had a detrimental effect of increasing death rate
when a large dose was used in severely malnourished children. The desirability
of routine zinc supplementation therapy of undernourished children with acute
diarrhea should be assessed further. Concerning policy, zinc supplementation as
a component of a micronutrient mixture is recommended in the rehabilitation of
severely malnourished children and in persistent diarrhea. However,
recommendation for its routine use in all cases of acute diarrhea in children
needs additional studies on effectiveness, cost, operations and safety. In two
randomized controlled trials folate has been evaluated in acute and persistent
diarrhea and found to have no beneficial effect. Folate is not recommended as
adjunct therapy of diarrhea. Role of folate in preventing severe disease and/or
death deserves further evaluation.
Mortality during a famine--Gode district,
Ethiopia, July 2000.
Recurrent famine has been a major cause of mortality in the Horn of Africa. In
Ethiopia, three consecutive years of drought led to widespread loss of
livestock, population displacement, and malnutrition, placing an estimated 10
million persons at risk for starvation in 2000. A large proportion of the
population of the Gode district in Somali region was displaced in a search for
food and food aid (CDC, unpublished data, 2000). From April through July 2000,
nongovernmental organizations (NGOs) opened feeding centers in the Gode
district. Because no vital statistics or public health surveillance system
existed in the district, and no representative mortality or morbidity data were
available, during July 2000, CDC, in collaboration with Save the Children U.S.,
the Office of Foreign Disaster Assistance of the U.S. Agency for International
Development, and the United Nations Children's Fund (UNICEF), conducted a
mortality survey. This report summarizes the results of this survey, which
found persistently high levels of mortality, with measles representing an
important cause of mortality in children aged <5 years and 5-14 years. Mass measles vaccination with
vitamin A distribution is an important intervention during the acute phase of
famines in sub-Saharan Africa.
Unprecedented decline in measles morbidity
and mortality in Calabar, south-eastern Nigeria.
Ekanem EE, Ochigbo SO, Kwagtsule JU.
Department of Paediatrics, College of Medical Sciences, University of Calabar,
Nigeria. emmanuel@unical.anpa.net.ng
The features of measles presenting at the University of Calabar Teaching
Hospital, in south-eastern Nigeria between January 1992 to December 1996, were
compared with those of a previous period (January 1984 to December 1987) in the
same institution. The aim was to detect any changes in trends, morbidity and
mortality from the infection in this environment. There were only 36 cases (7.2
per year) in the current period compared with 436 (109 per year) in the
previous period (chi2=48.4, P<0.001).There were also highly significant
falls in the incidence of malnutrition and bronchopneumonia (P<0.05) in the
current period. Notably, there were no cases of dehydration or keratomalacia in
the current period.The case fatality rate was 2.8% compared with 20.0% in the
previous period (P<0.02).These unprecedented changes in the incidence,
morbidity and mortality from measles are attributed to the continuing Expanded
Programme on Immunization, oral rehydration therapy, appropriate nutritional
management and vitamin A prophylaxis.With maintenance and strengthening of
these strategies, the elimination of measles and measles deaths in the near
future is feasible in this environment.
Vitamin A supplementation: implications for
morbidity and mortality in children.
Villamor E, Fawzi WW.
Departments of Nutrition and Epidemiology, Harvard School of Public Health,
Boston, Massachusetts 02115, USA.
Vitamin A deficiency impairs epithelial integrity and systemic immunity and
increases the incidence and severity of infections during childhood. However,
findings from vitamin A supplementation trials are not consistent.
Supplementation has resulted in significant reductions in mortality in several
(but not all) large community-based trials among apparently healthy children. In hospital-based studies,
vitamin A supplements have been consistently found to reduce the severity of
measles infection, but no effect on nonmeasles respiratory infections
has been observed. In some cases, the supplements were associated with an
apparently increased risk of lower respiratory infection. Vitamin A supplements
also reduced the severity of diarrhea in most (but not all) trials. Potential
explanations for the differences in efficacy across trials are reviewed. While
vitamin A supplementation is effective in reducing total mortality and
complications from measles infections, it is likely to be more effective in
populations suffering from nutritional deficiencies.
[Malnutrition and infections in children--a
destructive interplay with global dimensions]
[Article in Norwegian]
Bohler E, Wathne KO.
Barnemedisinsk avdeling Ulleval sykehus, Oslo.
BACKGROUND: Seven out of ten deaths among the world's children are caused by
infectious diseases. Malnutrition is a contributing cause in more than half of
the children's deaths. At present, interventions against such diseases in
children are the most cost-effective way of reducing the world's morbidity and
mortality. MATERIAL AND METHODS: This paper discusses how nutritional status
affects the immune defence, and vice versa. General protein and energy malnutrition
and some specific nutrients are discussed. The paper is based on review of
recent literature found in Medline, and key references in the papers
identified. RESULTS: Malnutrition is the most common cause of acquired immune
deficiency in children. Malnourished children are especially prone to develop
persistent diarrhoea, which in turn aggravates the nutritional status. Iron
deficiency may be caused or worsened by hookworm and a number of other
gastrointestinal infections. There are indications that iron deficiency in
itself reduces the immune defence. Vitamin A supplements have reduced the mortality of measles and other
infectious diseases. Some studies have shown reduced vertical
transmission of HIV when pregnant women get vitamin A supplements. Chronic
diarrhoea may cause zinc deficiency which may aggravate the diarrhoea. In areas
where the general population's zinc status is marginal, zinc supplementation
has reduced the incidence and duration of persistent diarrhoea. INTERPRETATION:
The interaction between malnutrition and common infections in children causes a
considerable fraction of the global burden of disease, yet so far this is not
reflected in research, which mainly targets the diseases of the rich.
Division of Pediatric Infectious Diseases, Children's Hospital, University of
Texas, Galveston 77555-0371, USA.
Dietary micronutrients such as vitamins and trace minerals are known modulators
of host immune responses against common pathogens. In this respect, vitamin A
and zinc have recently received increased attention. Several in vivo and in
vitro studies suggest that vitamin A may be a critical player in the mucosal
immune responses in the respiratory and gastrointestinal tracts, particularly
in undernourished children. The effect may be mediated primarily by
stabilization of the membrane of mucosal epithelial cells, as well as enhanced
leukocyte functions. The
beneficial effect of vitamin A therapy in reducing measles-associated morbidity
and mortality suggests its crucial role in defenses against viral
pathogens. Zinc is also known affect leukocyte functions such as phagocytosis
and T-lymphocyte-mediated immune responses. However, unlike vitamin A, zinc has
been investigated primarily for its effects on bacterial infections. Dietary
supplementation or therapeutic treatment with vitamin A and zinc may be a cheap
yet effective means of preventing or treating infections in highly susceptible
populations. Additional studies, however, are required to better define the
types of pathogens and the specific human populations that may benefit from
such therapy.
Malnutrition, morbidity and mortality in
children and their mothers.
Tomkins A.
Centre for International Child Health, Institute of Child Health, 30 Guilford
Street, London WC1N 1EH, UK. a.tomkins@ich.ucl.ac.uk
While being underweight or stunted is recognized as an important risk factor
for increased prevalence and severity of infection and high mortality rates,
there is increasing evidence for an independent role for micronutrient
deficiency. Improving vitamin A status reduces mortality among older infants
and young children and reduces pregnancy-related mortality; it also reduces the
prevalence of severe illness and clinic attendance among children. Improving Zn
status reduces morbidity from diarrhoeal and respiratory infection. Treatment of established
infection with vitamin A is effective in measles-associated complications,
but is not as useful in the majority of diarrhoeal or respiratory syndromes. Zn
supplements, however, have significant benefit on the clinical outcome of
diarrhoeal and respiratory infections. Concerns that Fe supplements might
increase morbidity if given in malarious populations appear to be decreasing,
in the light of new studies on Fe supplements showing improved haemoglobin
without an increase in morbidity. Breast-feeding, well known to protect against
diarrhoea, is also important in protecting against respiratory infection,
especially in the young infant. Transmission of human immunodeficiency virus
(HIV) in breast milk is recognized, but new data showing reduced transmission in
infants who receive exclusive breast-feeding rather than mixed feeding
reinforces the importance of promoting this practice in areas where
environmental contamination precludes the safe use of other infant feeding
regimens. The presence of subclinical mastitis, now recognized to occur in
approximately 20 % of mothers in several developing countries, has been shown
to increase the concentration of HIV in breast milk. Preliminary findings
suggest that the prevalence of subclinical mastitis is reduced by dietary
supplements containing antioxidants. Governments and international agencies now
have a strong scientific basis to be much more active and innovative in the
introduction of focused nutrition interventions especially micronutrients, for
the control of infection.
Vitamin A and immunity to viral, bacterial
and protozoan infections.
Semba RD.
Department of Ophthalmology, Johns Hopkins University School of Medicine,
Baltimore, MD 21205, USA. rdsemba@jhmi.edu
Studies in animal models and cell lines show that vitamin A and related
retinoids play a major role in immunity, including expression of mucins and
keratins, lymphopoiesis, apoptosis, cytokine expression, production of
antibody, and the function of neutrophils, natural killer cells, monocytes or
macrophages, T lymphocytes and B lymphocytes. Recent clinical trials suggest that vitamin A
supplementation reduces morbidity and mortality in different infectious
diseases, such as measles, diarrhoeal disease, measles-related pneumonia,
human immunodeficiency virus infection and malaria. Immune responses vary
considerably during different infections, and the available data suggest that
the modulation of immune function by vitamin A may also vary widely, depending
on the type of infection and immune responses involved.
The role of vitamin A in reducing child
mortality and morbidity and improving growth.
Ramakrishnan U, Martorell R.
Department of International Health, Rollins School of Public Health, Emory
University, Atlanta, GA 30322, USA.
This is an update of knowledge on the role of the vitamin A status in
determining child mortality, morbidity and growth. Recent information confirms
the earlier conclusion of Beaton et al. that a 23% reduction in young child
mortality results following improvements in the vitamin A status. Studies show that the mortality
effect is primarily due to reductions in deaths due to acute gastroenteritis and
measles but not acute respiratory infections (ARI) and malaria. While
improvement of the vitamin A status enhances the survival of older preschool
children, it remains unclear whether it benefits infants (i.e. < 6 months).
Vitamin A supplementation does not reduce the overall incidence and prevalence
of common childhood illness; however, it reduces the incidence of more severe
episodes of diarrhea. Also, vitamin A supplementation either during and/or
immediately after the illness does not improve its symptomatology. Finally,
contrary to earlier expectations, recently completed, placebo-controlled
randomized interventions have failed to detect improvements in child growth.
Meta-analysis of trials of prophylactic
antibiotics for children with measles: inadequate evidence.
Shann F.
Intensive Care Unit, Royal Children's Hospital, Parkville Victoria, Australia.
OBJECTIVE: To assess whether antibiotics should be given to all children with
measles in communities with a high case fatality rate. DESIGN: Meta-analysis of
randomised controlled trials that compared routine antibiotic prophylaxis with
no antibiotic treatment or selective treatment of pneumonia or sepsis.
SUBJECTS: Six trials of children admitted to hospital with measles: five in
Glasgow, London, or New York between 1939 and 1954; and one in India in 1967.
MAIN OUTCOME MEASURES: Incidence of pneumonia or sepsis, and mortality.
RESULTS: All but one of the trials were unblinded, and randomisation was either
not described or was by alternate allocation. In four studies, the incidence of
pneumonia or sepsis in the control group was similar to that in the antibiotic
prophylaxis group; in the other two studies, the incidence of pneumonia or
sepsis was unusually high in the control group so these children had a higher
complication rate than the antibiotic group. Four of the 764 children given
antibiotics died compared with one of the 637 controls (exact odds ratio 4.0,
mid-P corrected 95% confidence interval 0.5 to 101.6). CONCLUSION: The quality
of the trials reviewed was poor, and they provide weak evidence for giving
antibiotics to all children with measles. Available evidence suggests that, when mortality from
measles is high, all children with measles should be treated with vitamin A
but antibiotics should be given only if a child has clinical signs of pneumonia
or other evidence of sepsis.
Measles is an important acute childhood viral infection having severe
consequences on the nutritional status. The adverse nutritional effects of
measles are experienced by both the well-nourished and the malnourished
children. However, the severe nutritional deficiencies like
kwashiorkor/marasmus are precipitated only in children who are already
malnourished. As high as 3-4 per cent of children with measles suffered from
these clinical nutritional syndromes in their post-measles period. Though
malnutrition is widespread among Asian children also, measles appears to run a
milder course with low mortality rates in developing Asian countries, as
compared to African children. The associated secondary infections which
apparently complicate the primary illness in malnourished children might be
responsible for higher mortality and could be due to socioeconomic and
environmental causes that are associated with poverty and malnutrition rather
than due to malnutrition or measles per se. Measles related blindness is of multifactorial
aetiology. While acute measles triggers corneal ulceration through viral
proliferation in the cornea, nutritional keratomalacia is often the cause of
blindness in the post-measles period. Measles vaccination is the major
preventive measure. However,
timely use of local antibiotic therapy to the eyes and administration of
vitamin A supplements offer protection to the child who already has measles.
Response of malnourished children to live attenuated measles vaccine has been
found to be safe and effective. Neither malnutrition nor tuberculosis which are
widespread among malnourished children of developing countries appear to be
contraindications for measles vaccination. Thus, the beneficial effects of the
measles vaccination should be fully exploited by adequate supply of potent
vaccine and coverage of all susceptible children.
Measles in infants: a review of studies on
incidence, vaccine efficacy and mortality in east Africa.
Burstrom B, Aaby P, Mutie DM.
Department of International Health and Social Medicine, Karolinska Institute,
Sundbyberg, Sweden.
Control of measles in developing countries is complicated by high incidence and
mortality among infants. Hospital-based and community-based studies from East
Africa were reviewed with respect to the reported incidence and mortality of
measles and vaccine efficacy/seroconversion rates after the administration of
measles vaccine to infants. The studies reviewed confirm that measles is
particularly severe in infants, and some indicate that vaccination before 9
months with standard vaccine could be effective and have beneficial effects for
children aged 6-9 months, while other studies refute this finding. Due to the
high incidence and mortality of measles in infants, alternative control
strategies are essential to reduce measles mortality. Further studies are
needed on the effects of a two-dose schedule vaccinating at 6 and 9 months,
which in mathematical modelling shows considerable benefit. Improved management of measles
cases, including the administration of vitamin A could be considered as a
complementary strategy for reducing measles mortality, especially in infants.
Potential interventions for the prevention of
childhood pneumonia in developing countries: a meta-analysis of data from field
trials to assess the impact of vitamin A supplementation on pneumonia morbidity
and mortality. The Vitamin A and Pneumonia Working Group.
Reported are the results of a meta-analysis (12 large-scale field trials in
seven countries) of the impact of vitamin A supplementation on pneumonia
morbidity and mortality, undertaken as part of a wider review process of a
range of possible potential interventions for the prevention of childhood
pneumonia. The summary estimate of the relative risk for the impact of vitamin
A supplementation on pneumonia incidence was 0.95 (95% confidence interval (CI)
= 0.89, 1.01), and for pneumonia mortality, 0.98 (95% CI = 0.75, 1.28). - This is in marked contrast to
the substantial impact of vitamin A supplementation on all cause mortality (combined rate
ratio (RR) = 0.77, 95% CI = 0.71, 0.84), and on diarrhoea-specific and
measles-specific mortality. There was no evidence for a differential
impact on pneumonia mortality by age. Since the majority of pneumonia deaths
occur in the first year of life, we complemented the paucity of data on
pneumonia-specific mortality among this age group with a detailed examination
of all-cause mortality among infants. The mortality reduction in the 6-11 month
age group was consistent with that observed for older age groups (RR = 0.69;
95% CI = 0.54, 0.90), but there was no reduction for 0-5 month-olds (RR = 0.97;
95% CI = 0.73, 1.29).
Impact of massive dose of vitamin A given to
preschool children with acute diarrhoea on subsequent respiratory and
diarrhoeal morbidity.
Bhandari N, Bhan MK, Sazawal S.
Department of Paediatrics, All India Institute of Medical Sciences, New Delhi.
OBJECTIVE--To assess the impact of vitamin A supplementation on morbidity from
acute respiratory tract infections and diarrhoea. DESIGN--Double blind
randomised placebo controlled field trial. SETTING--An urban slum area in New
Delhi, India. SUBJECTS--900 children aged 12-60 months attending a local health
facility for acute diarrhoea of less than seven days' duration randomly
allocated to receive vitamin A 200,000 IU or placebo. MAIN OUTCOME MEASURES--Incidence
and prevalence of acute lower respiratory tract infections and diarrhoea during
the 90 days after termination of the enrolment diarrhoeal episode measured by
twice weekly household surveillance. RESULTS--The incidence (relative risk
1.07; 95% confidence interval 0.92 to 1.26) and average number of days spent
with acute lower respiratory tract infections were similar in the vitamin A
supplementation and placebo groups. Among children aged 23 months or less there was a significant reduction
in the incidence of measles (relative risk 0.06; 95% confidence interval 0.01
to 0.48). The incidence of diarrhoea was also similar (relative risk
0.95; 0.86 to 1.05) in the two groups. There was a 36% reduction in the mean
daily prevalence of diarrhoea associated with fever in the vitamin A
supplemented children older than 23 months. CONCLUSIONS--Results were
consistent with a lack of impact on acute lower respiratory tract related
mortality after vitamin A supplementation noted in other trials and a possible
reduction in the severity of diarrhoea.
Vitamin A supplementation in post-measles
complications.
Madhulika, Kabra SK, Talati A.
V. S. General Hospital, Ahmedabad, India.
One-hundred-and-seventy-seven children with post-measles complications divided
into two comparable groups were studied for the effect of Vit.A
Supplementation. Eighty-nine children received Vit.A in doses of 200,000 units
daily on two consecutive days in addition to antibacterials and other
supportive care and 88 did not reveice Vit.A. The case fatality rate was 16 per cent in those who
received VIT.A, while the same was 32 per cent in those who did not receive
Vit.A (P < 0.02). There was no statistical difference in the
mortality rate among two groups when the children were suffering from severe
malnutrition or encephalopathy (P > 0.1).
Dana Center, Department of Immunology and Infectious Diseases, Baltimore,
Maryland.
Although a role for vitamin A in immunity to infectious diseases has long been
suggested, only in the last decade have epidemiological, immunologic, and
molecular studies yielded substantial evidence for a central role. The recent
discovery of retinoic acid and retinoid X receptors has provided a molecular
basis for the action of vitamin A and its metabolites at the level of gene
activation. At least a
dozen clinical trials have now demonstrated that vitamin A supplementation
reduces severe morbidity and mortality from infectious diseases among children
who have acute measles or who are from areas in which vitamin A deficiency is
endemic. Vitamin A deficiency is an immunodeficiency disorder
characterized by widespread alterations in immunity, including pathological
alterations in mucosal surfaces, impaired antibody responses to challenge with
protein antigens, changes in lymphocyte subpopulations, and altered T- and
B-cell function. Vitamin A and its metabolites are immune enhancers that have
been shown to potentiate antibody responses to T cell-dependent antigens,
increase lymphocyte proliferation responses to antigens and mitogens, inhibit
apoptosis, and restore the integrity and function of mucosal surfaces. Vitamin
A and related retinoids may have potential applications in therapy for some
infectious diseases.
Measles associated diarrhea and pneumonia in
south India.
Deivanayagam N, Mala N, Ahamed SS, Shankar VJ.
Advanced Centre for Clinical Epidemiological Research and Training (ACCERT),
Institute of Child Health, Madras.
A prospective study was undertaken from April 1988 to April 1989, to assess the
diarrheal and respiratory complications of measles. Standard definitions were
used for the cases, Measles Associated Diarrhea (MAD) and Measles Related
Pneumonia (MRP). Children with diarrhea not related to measles were recruited
for comparison for MAD. There was a total of 454 cases, measles 53 (11.7%),
measles associated diarrhea (MAD) 113 (24.9%), measles related pneumonia (MRP)
186 (41.0%) and MAD with MRP 102 (22.5%). Children under 10 months and 24
months were 11% and 51.5%, respectively. Altogether 215/401 (53.6%) and 288/401
(71.8%) had diarrhea and pneumonia. Children who had been measles vaccinated
were 8.4%. The overall case fatality was 4.2%. Case fatality in pneumonia was
1.1%. There was no statistically significant difference between the MAD and
diarrhea in relation to religion, water supply, the method of excreta disposal,
nutritional status and immunization status other than measles vaccination.
There was significant difference in the nature of stools between the two
groups, the stools of MAD were more of dysenteric in nature (p < 0.005).
Vitamin A deficiency as evidenced by eye signs, was significantly more in MAD
than in diarrhea (p < 0.001). It is recommended that Vitamin-A be given to all children with
measles, complication due to diarrhea be promptly and adequately treated
and to consider measles vaccination earlier than 9 months.
Physiological role of antioxidants in the
immune system.
Bendich A.
Hoffmann-LaRoche Inc, Nutley, NJ 07110.
Diets contain naturally occurring antioxidant compounds that can stabilize
highly reactive, potentially harmful molecules called free radicals. Free
radicals are generated during normal cellular metabolism and result from the
metabolism of certain drugs or xenobiotics. Exposure to UV light, cigarette
smoke, and other environmental pollutants also increases the body's free
radical burden. The harmful activities of free radicals are associated with
damage to membranes, enzymes, and DNA. The ability of antioxidants to destroy
free radicals protects the structural integrity of cells and tissues. This
review focuses on data indicating that the functions of the human immune system
depend on the intake of micronutrients, which can act as antioxidants. Recent
clinical trials have found that antioxidant supplementation can significantly
improve certain immune responses. Specifically, supplementation with vitamins
C, E, and A or beta-carotene increased the activation of cells involved in
tumor immunity in the elderly. Supplementation with the antioxidant vitamins
also protected immune responses in individuals exposed to certain environmental
sources of free radicals. Supplementation
with vitamin A, a relatively weak antioxidant, decreases morbidity and
mortality associated with measles infections in children.
Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Brooklyn,
NY 11201.
Findings on the benefits and mechanism of action of vitamin A in measles and
other infectious diseases and immunocompromised states are discussed. Vitamin A
deficiency is one of the world's major malnutrition problems and is most
commonly found in children under the age of five years. An association between
vitamin A status and immune function has been suggested by community studies
and animal experiments. Mortality and susceptibility to infection and diarrhea
are higher in children with vitamin A deficiency. The association between increased mortality and morbidity
and vitamin A deficiency is strongest in children with measles. Vitamin A
supplementation reduces mortality and complications resulting from measles.
Measles may increase the body's utilization of vitamin A, possibly because of
the rapid destruction of epithelial surfaces. Vitamin A may boost immune
responses in the elderly, persons with high exposure to ultraviolet light,
patients who have undergone surgery, and persons with parasitic infection, but
more studies are needed. The immune defect caused by vitamin A deficiency may
be due to alterations in the glycoproteins of the lymphocyte membrane, an
adverse effect on helper T-cell function, the effect on epithelial tissue, or
some other mechanism. Vitamin
A therapy is relatively safe, and its effectiveness in children with measles
and possibly other groups appears to justify public health campaigns to
eliminate vitamin A deficiency. Vitamin A apparently has important
immunomodulating properties, notably in patients with measles.
Measles severity and serum retinol (vitamin
A) concentration among children in the United States.
Butler JC, Havens PL, Sowell AL, Huff DL, Peterson DE, Day SE, Chusid MJ,
Bennin RA, Circo R, Davis JP.
Section of Acute and Communicable Disease Epidemiology, Wisconsin Division of
Health, Madison.
BACKGROUND. Studies in developing countries have shown that children with
measles have low serum retinol concentrations and that lower retinol levels are
associated with measles-related mortality. Vitamin A therapy has been shown to
reduce mortality among African children with acute measles. OBJECTIVES. To
determine whether serum retinol concentration is low among children with
measles in the United States and to determine whether retinol concentration is
associated with illness severity. SETTING. Pediatric referral hospital and
clinic in Milwaukee, WI, during the measles outbreak of 1989-1990. PATIENTS.
One hundred fourteen patients < or = 5 years of age evaluated for
serologically confirmed measles with serum obtained within 5 days following
rash onset. METHODS. Serum retinol concentration was determined by
high-performance liquid chromatography. Clinical data were collected by
hospital record review. A modified Pediatric Risk of Mortality (PRISM) score
was used to assess physiologic instability as a measure of illness severity.
RESULTS. Retinol concentrations ranged from 0.25 to 1.18 mumol/L (median 0.58
mumol/L); 82 (72%) patients had low retinol concentration (< or = 0.70
mumol/L). Median retinol concentrations were lower among hospitalized patients
(0.56 vs 0.70, P = .006) and patients with pneumonia (0.52 vs 0.64, P = .02)
but higher among children with otitis media (0.63 vs 0.54, P = .01). Higher
modified PRISM scores, reflecting greater physiologic instability, were
associated with lower retinol concentration (beta coefficient -.0147, P =
.025). In multivariate analysis, higher modified PRISM scores were associated
with lower retinol concentration (beta coefficient -.0144, P = .025) even after
controlling for hospitalization, presence of complications, race, age, receipt
of Aid to Families With Dependent Children, gender, and interval from rash
onset until serum was collected. CONCLUSIONS. Among these children with measles in an urban United
States community, retinol concentrations were depressed, and the degree of
depression was associated with illness severity. Vitamin A therapy should be
considered for children with measles in the United States who require
hospitalization.
Vitamin A, infectious disease, and childhood
mortality: a 2 solution?
Sommer A.
School of Hygiene and Public Health, Johns Hopkins University, Baltimore,
Maryland 21205-2179.
Vitamin A was first discovered in 1913. Its deficiency was soon associated in
animal models and case reports with stunting, infection, and ocular changes
(xerophthalmia) resulting in blindness. The ocular consequences dominated
clinical interest through the early 1980s. A longitudinal prospective study of
risk factors contributing to vitamin A deficiency and xerophthalmia revealed a
close, dose-response relationship between the severity of mild preexisting
vitamin A deficiency and the subsequent incidence of respiratory and diarrheal
infection (relative risk [RR], 2.0-3.0) and, most dramatically, death (RR,
3.0-10.0). Subsequent
community-based prophylaxis trials of varying design confirmed that vitamin A
supplementation of deficient populations could reduce childhood (1-5 years old)
mortality by an average of 35%. Concurrent hospital-based treatment trials with
vitamin A in children with measles revealed a consistent reduction in
measles-associated mortality in Africa of at least 50%. It is now estimated
that improving the vitamin A status of all deficient children worldwide would
prevent 1-3 million childhood deaths annually.
Vitamin A supplementation and child
mortality. A meta-analysis.
Fawzi WW, Chalmers TC, Herrera MG, Mosteller F.
Department of Nutrition, Harvard School of Public Health, Boston, MA 02115.
OBJECTIVE--A two-part meta-analysis of studies examining the relationship of
vitamin A supplementation and child mortality. DATA SOURCES--We identified
studies by searching the MEDLARS database from 1966 through 1992 and by
scanning Current Contents and bibliographies of pertinent articles. STUDY
SELECTION--All 12 vitamin A controlled trials with data on mortality identified
in the search were used in the analysis. DATA EXTRACTION--Data were
independently extracted by two investigators who also assessed the quality of
each study using a previously described method. DATA SYNTHESIS--We formally
tested for heterogeneity across studies. We pooled studies using the
Mantel-Haenszel and the DerSimonian and Laird methods and adjusted for the
effect of cluster assignment of treatment groups in community-based studies.
Vitamin A supplementation to hospitalized measles patients was highly
protective against mortality (DerSimonian and Laird odds ratio, 0.39; 95%
confidence interval, 0.22 to 0.66; P = .0004) (part 1 of the meta-analysis).
Supplementation was also protective against overall mortality in
community-based studies (DerSimonian and Laird odds ratio, 0.70;
clustering-adjusted 95% confidence interval, 0.56 to 0.87; P = .001) (part 2 of
the meta-analysis). CONCLUSIONS--Vitamin A supplements are associated with a significant reduction in
mortality when given periodically to children at the community level. Factors
that affect the bioavailability of large doses of Vitamin A need to be studied
further. Vitamin A supplements should be given to all measles patients in
developing countries whether or not they have symptoms of vitamin A deficiency.
Vitamin A supplementation in infectious
diseases: a meta-analysis.
Glasziou PP, Mackerras DE.
Department of Social and Preventive Medicine, Medical School, University of
Queensland, Herston, Australia.
OBJECTIVE--To study the effect of vitamin A supplementation on morbidity and
mortality from infectious disease. DESIGN--A meta-analysis aimed at identifying
and combining mortality and morbidity data from all randomised controlled
trials of vitamin A. RESULTS--Of 20 controlled trials identified, 12 trials
were randomised trials and provided "intention to treat" data: six
community trials in developing countries, three in children admitted to
hospital with measles, and three in very low birth weight infants. Combined
results for community studies suggest a reduction of 30% (95% confidence
interval 21% to 38%; two tailed p < 0.0000001) in all cause mortality.
Analysis of cause specific mortality showed a reduction in deaths from
diarrhoeal disease (in community studies) by 39% (24% to 50%; two tailed p <
0.00001); from respiratory disease (in measles studies) by 70% (15% to 90%; two
tailed p = 0.02); and from other causes of death (in community studies) by 34%
(15% to 48%; two tailed p = 0.001). Reductions in morbidity were consistent
with the findings for mortality, but fewer data were available. CONCLUSIONS--Adequate supply of vitamin A,
either through supplementation or adequate diet, has a major role in preventing
morbidity and mortality in children in developing countries. In developed
countries vitamin A may also have a role in those with life threatening
infections such as measles and those who may have a relative deficiency, such
as premature infants.
Vitamin A supplementation enhances specific
IgG antibody levels and total lymphocyte numbers while improving morbidity in
measles.
Coutsoudis A, Kiepiela P, Coovadia HM, Broughton M.
Department of Paediatrics and Child Health, University of Natal, Durban, South
Africa.
The effect of vitamin A supplementation on selected factors of immunity was
tested in African children (ages 4 to 24 months with complicated measles)
during a randomized double-blind intervention trial. Placebo (n = 31) and
treated groups (n = 29) had similar baseline characteristics. The supplemented
group had significant reductions in morbidity (expressed as integrated
morbidity scores) during the acute (Day 8, P = 0.006) and chronic (Day 42, P =
0.02; 6 months; P = 0.002) phases. In the treated group there was an increase
in total number of lymphocytes (Day 42, P = 0.05) and measles IgG antibody
concentrations (Day 8, P = 0.02), both of which have consistently been
previously shown to correlate more closely with outcome in measles than other
immunologic, clinical and radiologic factors. Interleukin 2 and plasma
complement values were unaffected by vitamin A supplementation. These findings reinforce results
from animal studies that show that the pathways of vitamin A activity in
decreasing morbidity and mortality are partly founded on selective
immunopotentiation.
The effects of vitamin deficiencies on increased morbidity and mortality from
infectious disease were noted very soon after the discoveries of the vitamins. Repletion and, in numerous
instances, supplementation with the deficient vitamin resulted in clinically
relevant immunoenhancement. However, communication of the importance of vitamin
status, especially in children with measles complications, has not progressed
to the point that micronutrient assessment and intervention, when appropriate,
occurs on a routine basis.
Childhood mortality after a high dose of
vitamin A in a high risk population.
Daulaire NM, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR.
International Center for the Prevention and Treatment of Major Childhood Disease
(INTERCEPT), Hanover, New Hampshire 03755.
OBJECTIVES--To determine whether a single high dose of vitamin A given to all
children in communities with high mortality and malnutrition could affect
mortality and to assess whether periodic community wide supplementation could
be readily incorporated into an ongoing primary health programme.
DESIGN--Opportunistic controlled trial. SETTING--Jumla district, Nepal.
SUBJECTS--All children aged under 5 years; 3786 in eight subdistricts given
single dose of vitamin A and 3411 in remaining eight subdistricts given no
supplementation. MAIN OUTCOME MEASURES--Mortality and cause of death in the
five months after supplementation. RESULTS--Risk of death for children aged 1-59 months in
supplemented communities was 26% lower (relative risk 0.74, 95% confidence
interval 0.55 to 0.99) than in unsupplemented communities. The reduction in
mortality was greatest among children aged 6-11 months: death rate
(deaths/1000 child years at risk) was 133.8 in supplemented children and 260.8
in unsupplemented children (relative risk 0.51, 0.30 to 0.89). The death rate
from diarrhoea was also reduced (63.5 supplemented v 97.5 unsupplemented;
relative risk 0.65, 0.44 to 0.95). The extra cost per death averted was about
$11. CONCLUSION--The
results support a role for Vitamin A in increasing child survival. The
supplementation programme was readily integrated with the ongoing community
health programme at little extra cost.
A randomized, controlled trial of vitamin A
in children with severe measles.
Hussey GD, Klein M.
Department of Paediatrics and Child Health, University of Cape Town, South
Africa.
BACKGROUND. Measles kills about 2 million children annually, and there is no
specific therapy for the disease. It has been suggested that vitamin A may be
of benefit in the treatment of measles. METHODS. We conducted a randomized,
double-blind trial involving 189 children who were hospitalized at a regional
center in South Africa because of measles complicated by pneumonia, diarrhea,
or croup. The children (median age, 10 months) were assigned to receive either
vitamin A (total dose, 400,000 IU of retinyl palmitate, given orally; n = 92)
or placebo (n = 97), beginning within five days of the onset of the rash. At
base line, the characteristics of the two groups were similar. RESULTS.
Although clinically apparent vitamin A deficiency is rare in this population,
the children's serum retinol levels were markedly depressed (mean [+/- SEM],
0.405 +/- 0.021 mumols per liter [11.6 +/- 0.6 micrograms per deciliter]), and
92 percent of them had hyporetinemia (serum retinol level less than 0.7 mumols
per liter [20 micrograms per deciliter]). Serum concentrations of
retinol-binding protein (mean, 30.1 +/- 2.0 mg per liter) and albumin (mean,
33.4 +/- 0.5 g per liter) were also low. As compared with the placebo group,
the children who received vitamin A recovered more rapidly from pneumonia
(mean, 6.3 vs. 12.4 days, respectively; P less than 0.001) and diarrhea (mean,
5.6 vs. 8.5 days; P less than 0.001), had less croup (13 vs. 27 cases; P =
0.03), and spent fewer days in the hospital (mean, 10.6 vs. 14.8 days; P =
0.01). Of the 12 children who died, 10 were among those given placebo (P =
0.05). For the group treated with vitamin A, the risk of death or a major
complication during the hospital stay was half that of the control group
(relative risk, 0.51; 95 percent confidence interval, 0.35 to 0.74).
CONCLUSIONS. Treatment
with vitamin A reduces morbidity and mortality in measles, and all children
with severe measles should be given vitamin A supplements, whether or not they
are thought to have a nutritional deficiency.
Vitamin A levels and mortality among
hospitalized measles patients, Kinshasa, Zaire.
Markowitz LE, Nzilambi N, Driskell WJ, Sension MG, Rovira EZ, Nieburg P,
Ryder RW.
Treatment with high dose vitamin A has recently been recommended for children
with measles in communities where vitamin A deficiency is a recognized problem.
However, the relationship between vitamin A and measles mortality has not been
clearly established. We studied serum vitamin A levels in 283 children less
than or equal to 5 years of age admitted to Mama Yemo and Kalembe Lembe
Hospitals in Kinshasa, Zaire, between January and March, 1987. Vitamin A levels
were determined by high performance liquid chromatography. Vitamin A levels
ranged from less than 5 to 63 micrograms/dl (median, 8). The overall
case-fatality rate was 26 per cent. On univariate analysis, age less than 24 months, pneumonia on
admission, lymphopenia (less than 2000/mm3), and lower vitamin A levels were
associated with death during hospitalization. In a multivariate logistic
regression model, a vitamin A level less than 5 micrograms/dl was associated
with fatal outcome for children younger than 24 months old (relative risk =
2.9, 95 per cent CI 1.3, 6.8), but not for older children. Further studies are
needed to determine whether low vitamin A levels predispose children to severe
measles and the role of vitamin A supplements in the prevention of measles
mortality.
Measles prevention and control in emergency
settings.
Toole MJ, Steketee RW, Waldman RJ, Nieburg P.
Outbreaks of measles continue to be a common occurrence among refugee and
famine-affected children in emergency relief camps. Extremely high
measles-associated mortality rates have been reported from refugee camps--where
undernutrition is common--in several countries over the past 10 years.
Mortality from measles is, however, preventable, and immunization against the
disease is a high priority in emergency relief programmes, second only in
importance to the provision of adequate food rations. All children aged 6
months to 5 years should be immunized with measles vaccine as soon as they
enter an organized camp or settlement. Should supplies of measles vaccine be
inadequate, children in feeding centres, or those otherwise identified as
undernourished, are the top priority for immunization. The occurrence of
measles in a camp is not a contraindication to conducting an immunization
campaign. Strong coordination by a designated lead agency is needed if such
campaigns are to be successful; however, cooperation with the local expanded
programme on immunization is essential to ensure that existing cold chain
equipment, training protocols, and management manuals are used. If additional
equipment is necessary, a complete immunization kit developed by the Office of
the United Nations High Commissioner for Refugees, the World Health
Organization, and Oxfam can be procured from Oxfam headquarters in the United
Kingdom. Vitamin A supplements should be given routinely at the time of measles
immunization in situations where malnutrition is severe. Mortality and morbidity in
children with clinical measles can be reduced by administering high doses of
vitamin A.
PMID: 2805216 [PubMed - indexed for MEDLINE]
Br Med J (Clin Res Ed) 1987 Jan 31;294(6567):294-6
Vitamin A supplements and mortality related
to measles: a randomised clinical trial.
Barclay AJ, Foster A, Sommer A.
One hundred and eighty children admitted with measles were randomly allocated
to receive routine treatment alone or with additional large doses of vitamin A
(200,000 IU orally immediately and again the next day). Baseline
characteristics of the two groups were virtually identical for age, severity of
measles, and vitamin A and general nutritional states. In 91% of the children
serum vitamin A concentrations were less than 0.56 mumol/l. Of the 88 subjects given
vitamin A supplements, six (7%) died; of the 92 controls, 12 (13%) died (p =
0.13). This difference in mortality was most obvious for children aged under 2
years (one death out of 46 children receiving supplements versus seven deaths
out of 42 controls; p less than 0.05) and for cases complicated by croup
or laryngotracheobronchitis. Mortality was several times higher in marasmic
than in better nourished children, regardless of study allocation (p less than
0.01).
Vitamin A for treating measles in children
(Cochrane Review).
D'Souza RM, D'Souza R.
National Centre for Epidemiology and Population Health, The Australian National
University, Canberra, ACT, AUSTRALIA, 0200. rennie.dsouza@anu.edu.au
BACKGROUND: Measles is a leading cause of childhood morbidity and mortality.
Vitamin A deficiency is a recognised risk factor for severe measles. The World
Health Organization (WHO) recommends administration of an oral dose of 200,000
IU (or 100,000 IU in infants) of vitamin A per day for two days to children
with measles in areas where vitamin A deficiency may be present. OBJECTIVES:
The purpose of this review is to determine whether vitamin A when commenced
after measles has been diagnosed, is beneficial in preventing mortality,
pneumonia and other complications in children. SEARCH STRATEGY: MEDLINE and the
Cochrane Library, Issue 4, 1999 were searched. SELECTION CRITERIA: Only
randomized controlled trials in which children with measles were given vitamin
A or placebo along with standard treatment were considered. DATA COLLECTION AND
ANALYSIS: Studies were assessed independently by two reviewers. The analysis of
dichotomous outcomes was done using the StatExact software package. Sub-group
analyses were done for dose, formulation, age, hospitalisation and pneumonia
specific mortality. Weighted mean difference with 95% CI were calculated for
continuous outcomes. MAIN RESULTS: The relative risks (RR) and 95% Confidence
Intervals (CI) are based on the estimates from the StatExact software package.
There was no significant reduction in mortality in the vitamin A group when all
the studies were pooled together (RR 0.60; 95% CI 0.32 to 1.12)(Statexact
estimate). There was a 64% reduction in the risk of mortality in children who
were given two doses of 200,000 IU of vitamin A (RR=0.36; 95% CI 0.14 to 0.82)
as compared to placebo. Two doses of water based vitamin A were associated with
a 81% reduction in risk of mortality (RR=0.19; 95% CI 0.02 to 0.85) as compared
to 48% seen in two doses of oil based preparation (RR=0.52; 95% CI 0.16 to
1.40). Two doses of oil and water based vitamin A were associated with a 82%
reduction in the risk of mortality in children under the age of 2 years
(RR=0.18; 95% CI 0.03 to 0.61) and a 67% reduction in the risk of pneumonia
specific mortality (RR=0.33; 95% CI 0.08 to 0.92). There was no evidence that
vitamin A in a single dose of 200,000 IU was associated with a reduced risk of
mortality among children with measles (RR=0.77; 95% CI 0.34 to 1.78).
Sub-groups like age, dose, formulation, hospitalisation and case fatality in
the study area were highly correlated and there were not enough studies to separate
out the individual effects of these factors. There was a 47% reduction in the
incidence ofcroup (RR=0.53; 95% CI 0.29 to
0.89), while there was no significant reduction in the incidence of pneumonia
(RR=0.92; 95% CI 0.69 to 1.22) or of diarrhoea (RR=0.80; 95% CI 0.27 to 2.34).
Duration of diarrhoea was measured in days and there was a reduction in its
duration of almost two days WMD -1.92, 95% CI -3.40 to -0.44. Only one study
evaluated otitis media and found a 74% reduction in its incidence (RR=0.26, 95%
CI, 0.05 to 0.92). We did not find evidence that a single dose of 200,000 IU of
vitamin A per day, givne in oil-based formuation in areas with low case
fatality, was associated with reduced mortality among children with measles.
However, there was evidence that the same dose given for two days was
associated with a reduced risk of overall mortality and pneumonia specific
mortality. REVIEWER'S CONCLUSIONS: Although we did not find evidence that a single dose of 200,000 IU of
vitamin A per day was associated with reduced mortality among children with
measles, there was evidence that the same dose given for two days was
associated with a reduced risk of overall mortality and pneumonia
specific mortality. The effect was greater in children under the age of two
years. There were no trials that compared a single dose with two doses,
although the precision of the estimates of trials that used a single dose were
similar to the trials that used two doses.
PMID: 11405993 [PubMed - in process]
This article may, in fact, support the notion that
vitamin A reduces mortality from measles.It looks like the group was only given one day of the recommended 2-day
dose where the finding was made of no reduction in measles mortality. - SM
Randomised trial to assess benefits and safety of vitamin
A supplementation linked to immunisation in early infancy. WHO/CHD
Immunisation-Linked Vitamin A Supplementation Study Group.
BACKGROUND: The benefits and safety of vitamin
A supplementation linked to immunisation in infancy need to be assessed
before it can be widely recommended. We assessed the safety and benefits of
maternal postpartum and infant vitamin A supplementation administered with
each of the three diphtheria-tetanus-pertussis (DPT) and poliomyelitis
immunisations and with a fourth dose with measles immunisation. METHODS:
From January, 1995, we enrolled 9424 mother-infant pairs from Ghana, India,
and Peru in this randomised, double-blind, placebo-controlled trial. 4716
mothers of infants in the vitamin A group received 200000 IU vitamin A, and
their infants were given 25000 IU vitamin A with each of the first three
doses of DPT/poliomyelitis immunisation at 6, 10, and 14 weeks. In the
control group, 4708 mothers and their infants received placebo at the same
times. At 9 months, with measles immunisation, infants in the vitamin A
group were given a further dose of 25000 IU and those in the control group
received 100000 IU vitamin A. Infants were followed up to age 12 months. The
primary outcome measures were vitamin A status, signs of acute toxic
effects, anthropometric indicators, and severe morbidity. Analysis was by
intention to treat. FINDINGS: 3933 (93%) of the eligible 4212 infants on
vitamin A and 3938 (93%) of the eligible 4227 controls received all four
study doses. At the 6-month follow-up, there was a small decrease in vitamin
A deficiency in the vitamin A group compared with controls (serum retinol
< or =0.70 micromol/L 101 [29.9%] vs 122 [37.1%; 95% CI of the difference
-14.3% to -0.2%]). This effect was no longer apparent at 9 and 12 months. There
were no significant between-group differences in mortality throughout the
study. The rate ratio to compare all deaths up to age 9 months in the
two groups was 0.96 (95% CI 0.73 to 1.27). Fewer than 1% of the infants had
bulging fontanelle. The intervention had no effect on anthropometric status,
or on overall or severe morbidity. INTERPRETATION: The trial confirmed the
safety of the intervention, but shows no sustained benefits in terms of
vitamin A status beyond age 6 months or infant morbidity.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 9788455 [PubMed - indexed for MEDLINE]
Without the inclusion of an
actual control group that had not been vaccinated at all, there is no way to
know if the apparent lack of difference between the groups re: mortality was
because vitamin A does not reduce it, or because it could not overcome the
effects of vaccination. - SM
Measles incidence, case fatality, and delayed
mortality in children with or without vitamin A supplementation in rural Ghana.
Dollimore N, Cutts F, Binka FN, Ross DA, Morris SS, Smith PG.
London School of Hygiene and Tropical Medicine, United Kingdom.
Data on measles incidence, acute case fatality, and delayed mortality were
collected on 25,443 children aged 0-95 months during the course of a
community-based, double-blind, placebo-controlled, randomized trial of vitamin
A supplementation in rural, northern Ghana between 1989 and 1991. Measles
vaccine coverage in these children was 48%. The overall estimated measles
incidence rate was 24.3 per 1,000 child-years, and acute case fatality was
15.7%. There was not significantly increased mortality in survivors of the
acute phase of measles compared with controls (rate ratio = 1.22, 95%
confidence interval (CI) 0.65-2.30). Reported incidence rates and case fatality
were higher in families with low paternal education, in the dry season, and in
unvaccinated children, and case fatality was higher in malnourished children.
There was no sex difference in incidence, but acute case fatality was somewhat
higher in girls than boys (adjusted odds ratio = 1.3, 95% CI 0.9-2.1). Measles
incidence was lower in vitamin A-supplemented groups (23.6 per 1,000
child-years) than in placebo groups (28.9 per 1,000 child-years), but this
difference was not statistically significant (p = 0.33). Among 946 measles cases in
clusters randomized to receive vitamin A or placebo, there was no marked
difference in acute measles case fatality between vitamin A-supplemented and
placebo groups (15.4% vs. 14.5%, respectively). The biologic effects of
vitamin A supplemented on the subsequent clinical manifestations and severity
of measles need further elucidation.
"A foolish faith in authority is the worst enemy of truth."
-- Albert Einstein, letter to a friend, 1901
"I know of no safe depository of the ultimate powers of the society but the people themselves, and if we think them not enlightened enough to exercise control with a wholesome discretion, the remedy is not to take it from them, but to inform their discretion by education."
-- Thomas Jefferson, letter to William C. Jarvis, September 28, 1820
"What's the point of vaccination if it doesn't protect you from the unvaccinated?"
-- Sandy Gottstein
"Who gets to decide what the greater good is and how many will be sacrificed to it?"
Books,
