Vitamin Information Center

Causation
HRISTINA VLAJINAC
Institute of Epidemiology, School of Medicine,
University of Belgrade, Belgrade, Serbia
kristiv@eunet.yu
Synonyms
Causality
Definition
A cause of a disease can be defined as an event, condition,
or characteristic that plays an essential role in producing
an occurrence of the disease (Rothman 1986).
The most important aim of epidemiology is to identify
the causes and the  risk factors of a disease, and to
improve public health by reducing or eliminating exposure
to these factors.
Basic Characteristics
Epidemiological – EcologicalModels
A disease is a result of the  interaction of host factors
and the environment. Several models have been developed
in order to depict the ways in which these interactions
influence the occurrence of the disease: the triangle,
the wheel, and the web of causation.
The triangle – Thismodel consists of three components,
 agent, host, and environment, which are in a kind of
dynamic equilibrium. Change in any of these components
will alter an existing equilibrium and increase or
decrease the frequency of the disease. This model has
been the most frequently applied to infectious diseases
in which infectious organismswere separated from other
environmental factors and identified as agents.
For diseases that have not been linked to specific agents,
two other models have been developed.
The Wheel – In this model, the host, with its genetic
make-up as its core, is presented as the hub of the
wheel, surrounded with the environment, which is separated
into biological, social and physical components.
This separation is artificial since these three parts of the
environment are closely interrelated with one another
and with host factors.
The Web – The web model emphasizes the concept that
effects never depend on single causes but develop as the
result of causal chains, which make the web. Each link
in the web is the result of antecedents, and breaking
of the web at any level can prevent occurrence of the
disease. This means that full knowledge of etiology is
not needed for effective disease prevention and control.
(Mausner, Kramer 1985; Bhopal 2002)
Search for Causal Relationship
There are two approaches to testing hypotheses about
causes of disease, experimental and observational.
Experimental study can establish the causal relationship
of a factor with a disease more conclusively, but
since experiments in epidemiology are performed on
humans, for ethical reasons the effects of some possible
causal factors cannot be investigated directly.
Observational studies have therefore been providing the
major contribution to the understanding of many diseases.
The first step in an investigation of causal relationship
is to see whether there is an  association between
a disease and a postulated causal factor. If an association
exists, it does not necessarily mean that it is
a causal one. It can be: a) spurious ( spurious association),
b) secondary ( secondary association), or c)
causal. Before an association is assessed for the possibility
that it is causal, other alternative explanations,
such as chance, selection bias, information bias, and
confounding, have to be excluded.
A Concept of Necessary and Sufficient Cause
“A causal factor whose presence is required for the
occurrence of the effect” (Last 2001), that is, without
which the disease never develops, is the necessary
cause. Sufficient cause is a “minimum set of conditions,
factors or events needed to produce a given outcome;
minimal implies that none of the conditions or events is
superfluous” (Rothman 1986). A sufficient cause is not
usually a single factor, but often comprises several components
– component causes or contributing causes.
A disease can have several sufficient causes and these
may have one or more contributing causes in common.
Types of Causal Relationship A causal factor can be
either necessary or sufficient, both, or neither:
1. Necessary and sufficient
A factor can be both necessary and sufficient, which
means that the disease never develops without that factor,
and that factor always produces the development
of the disease. This type of causal relationship occurs
rarely. For example, a person who has three copies of
chromosome 21 instead of two will inevitably be mentally
retarded – Down’s syndrome (Bhopal 2002).
2. Necessary but not sufficient
The factor, although necessary, cannot produce the disease
without the presence of some other factors, called
component or contributory causes. For clinically manifest
tuberculosis, in addition to the bacillus, which is
the necessary cause, contributing causes such as poor
nutritional and socio-economic conditions are needed.
3. Sufficient but not necessary
Although sufficient for producing the disease, the factor
(usually more than one) is not necessary because there
are some other factors that can also produce the disease.
Either radiation exposure or benzene exposure can
produce leukemia independently of each other (Gordis
2004).
4. Neither sufficient nor necessary
Smoking is a cause of lung cancer but not everyonewho
smokes develops this type of cancer and not everyone
who develops lung cancer has smoked.
Guidelines for Causal Reasoning in Epidemiology
Although epidemiologic evidence by itself is insufficient
to establish causality, Bradford Hill (Hill, 1965)
suggested that the following attributes (criteria) of an
association be considered in assessment of the possibility
that it is a causal one.
1. Strength of the association – The strength of association
is measured by the relative risk (odds ratio), that is
the ratio of disease rates for those exposed and those not
exposed to the hypothesized causal factor. The stronger
the association, the more likely it is that the relation is
causal. However, it does not mean that a weak association
cannot be judged to be a causal one. “The strength
of an association is not a biologically consistent feature,
but rather a characteristic that depends on the relative
prevalence of other causes” (Rothman, 1986).
2. Dose-response relationship – A dose-response is
established when, with increasing level of exposure
(“dose” or duration), the risk of disease also increases.
The absence of a dose-response relationship does not
rule out the possibility of causal association since, for
some causes, a threshold may exist and a disease may
not develop unless a certain level of exposure is present.
3. Consistency of the association – A cause-effect relationship
is supported when similar results are obtained
in a number of studies performed in various populations
or population groups, by different investigators,
and with different methodology. The causal relationship
might not be found in some studies because “the
effect of a causal agent cannot occur unless the component
causes act, or have already acted, to complete
a sufficient cause” (Rothman 1986).
4. Temporality – Exposure to the postulated causal factor
must precede the onset of disease by a period of
time consistent with the proposed biologic mechanism
( induction,  incubation,  latency). In some diseases,
especially chronic and those with a long period
of latency, temporality cannot always be easy to establish.
Although the only indispensable attribute among
all Hill’s conditions, a temporally correct association
between two events does not necessarily mean that it is
that of cause and effect. They could both be generated
by the same factor.
5. Biologic plausibility – The existence of a causeeffect
relationship is enhanced if it is coherent with the
current body of biologic knowledge. This, of course,
depends on the state of scientific information at a given
time. An association that is biologically implausible at
one time may eventually prove to be plausible.
6. Experimental evidence – Causal understanding can
be greatly advanced by “in-vivo” and animal experiments,
but data obtained in that way must be integrated
with observations in the human population. Because of
ethical reasons, experimental evidence is seldom from
the human population. However, evidence for a causal
relationship is supported if reduction or elimination of
exposure to a certain factor (postulated causal factor) is
related to decline of disease frequency.
7. Coherence – Coherence implies that a cause-effect
interpretation of an association does not conflict with
the generally known facts of the natural history and
biology of the disease.
8. Specificity of the association – An association is
specific when a certain exposure is associated with
only one disease. Taking into account the multifactorial
nature of disease and the fact that one factor can
cause more than one disease, the specificity is the least
important criterion to satisfy, and “should be probably
deleted from the list” (Gordis 2004).
In making decisions about causation, the list of criteria
presented above should be considered only as guidelines.
If temporality is viewed as part of the definition
of causation, “there is no necessary or sufficient criterion
for determining whether an observed association is
causal” (Rothman, Greenland 1998; Rothman, Greenland
2005). Decisions about causation must always
remain a matter of judgment based on all available evidence
“achievable through hypothesis generation and
testing, with data interpreted using a logical framework
of analysis, which draws on multidisciplinary perspectives”
(Bhopal 2002).
Hill himself pointed out that these “viewpoints” cannot
be used as criteria for causal inference, but can help
to make a judgment, and to act on the premise that
a causal relationship exists rather than awaiting further
evidence: “All scientific work is incomplete – whether it
be observational or experimental. All scientific work is
liable to be upset or modified by advancing knowledge.
That does not confer upon us a freedom to ignore the
knowledge we already have, or to postpone the action
that it appears to demand at a given time”.
Most definitions are taken from the last edition of Last’s
Dictionary of Epidemiology (Last, 2001).We are much
obliged to Professor Last for his kind consent.
Cross-References
 Agent (of Disease)
 Association
 Incubation
 Induction
 Interaction
 Latency
 Risk Factor
 Secondary Association
 Spurious Association
References
Bhopal R (2002) Concepts of Epidemiology: An integrated introduction
to the ideas, theories, principles and methods of epidemiology.
Oxford University Press, Oxford
Gordis L (2004) Epidemiology. Elsevier Saunders, Philadelphia
Hill B (1965) The environment and disease: Association or causation.
Proc Roy Soc Med 58:295–300
Last J (2001) A Dictionary of Epidemiology, 4th edn. Oxford
University Press, New York
Mausner J, Kramer S (1985) Epidemiology. WB Saunders,
Philadelphia
Rothman K (1986) Modern Epidemiology. Little Brown, Boston
Rothman K, Greenland S (1998) Modern Epidemiology, 2nd edn.
Lippincott – Raven Publishers, Philadelphia
Rothman K, Greenland S (2005) Basic Concept. In: Ahrens W,
Pigeot I (ed) Handbook of Epidemiology. Springer, Berlin,
pp 45–

Antibodies
Synonyms
Immune globulins; Immunoglobulins
Definition
Antibodies or immune globulins are proteins which
react specifically against substances foreign to the
organism. Their structure was described first in 1959
by G. Edelmann and R. Porter. From all immune globulins
the types IgG, IgM, IgD, IgA and IgE can be differentiated.
While IgD and IgE do not play a role in
the defence of infectious diseases, IgA has an important
function concerning non-specific defence mechanisms,
particularly in viral infections. The immune globulins
of the types G and M interact specifically with the different
pathogens. As IgM is responsible for the primary
immune response, it is the first immune globulin
detected in the blood after contact with a pathogen. IgG
is produced a little later. This type of immune globulin,
which reacts very specifically against the antigen,
becomes part of the immune memory. If there is a new
contact with the same pathogen defence mechanisms
are quickly available. In contrast to IgM antibodies,
antibodies of the IgG type can pass through the placenta
and thus protect the unborn baby in the womb from a number of infectious diseases (see also  nest protection).
Cross-References
 Immunization, Passive

Anthelminthic Therapy
Synonyms
Anthelminthic drugs; Medicinal treatment of worm
infections; Therapeutics against worm infections
Cross-References
 Therapy of Infectious Diseases

Acute Life-Threatening Infections
MONIKA KORN
Klinik für Kinder und Jugendmedizin,
Friedrich Ebert Krankenhaus,
Neumünster, Germany
hkorn80663@aol.com
Synonyms
Highly dangerous infectious diseases; Infectious diseases
with a critical course
Definition
Acute life-threatening infectious diseases are characterized
by the fact that they can take a lethal course within
a few hours or a couple of days. The pathogens or their
toxins can cause a cardiocirculatory shock, a failure of
the functions of the central nervous system, respiratory
insufficiency or multiorganic failure.
Basic Characteristics
Reasons for Life-Threatening Courses of Infections
Whether an infectious disease takes a life-threatening
course or not, depends on various factors. The severity of an infection is determined by the virulence of
the pathogens and the organs or organic systems that
are involved; deadly courses have to be feared in cases
where impairment of vital functions or multiorganic
failure occur. The development of serious infections
is facilitated by a weakened immune status or underlying
(chronic) disease. Further important aspects are
the prophylactic and therapeutic possibilities. Avoidable
severe or even deadly courses can occur due to
a neglect of preventive measures, especially due to
missing active vaccinations ( immunization, active).
Other reasons for a treatable disease taking a lethal
course can be a lack of effective drugs (due to a shortage
of resources), or the late onset of therapy. The quick
introduction of treatment is highly significant in cases
of infections with toxin-building germs, like tetanus,
 anthrax infection and  gas gangrene. If there is no
therapy against a number of infecting organisms or their
toxins one has to be prepared for a lethal outcome.
 Hemorrhagic fevers belong to this category of infectious
disease.
Sepsis
A sepsis is an inflammatory reaction, which involves
the whole organism (SIRS=systemic inflammatory
response syndrome). Characteristic symptoms are bacteremia,
tachycardia, abnormal rapid breathing (tachypnea),
a changed body temperature (fever or hypothermia)
as well as changes in white blood cell count
(> 12/nl or < 4/nl). The various pathogens have typical
places of entrance, like wounds, the respiratory,
the urinary or the gastrointestinal tracts. From there
they reach the circulatory system and spread into other
organs. In 70–80% cases of sepsis, gram-negative
bacteria are responsible, and in 20–30% gram-positive.
Poisons (toxins), which are set free by the bacteria, play
an important role in the course of the sepsis. During
the destruction of gram-negative germs endotoxins are
released, and in the case of gram-positive pathogens
exotoxins are released. Staphylococci are responsible
for the  staphylococcal toxic-shock syndrome (TSS)
and streptococci for the  streptococcal toxic-shock
syndrome (STSS). In sepsis, substances, which mediate
inflammations (cytocines, interleukines), start a cascade
process that leads to a condition of life-threatening
shock. A complex impairment of immunological,
endocrinological, cardiovascular and metabolic functions results. Uncontrollable cardiocirculatory problems
(extreme decrease of blood pressure), serious
coagulation defects (consumption coagulopathy, disseminated
intravascular coagulation = DIC) and organic
failure of the lungs and kidneys are responsible
for the lethal course of septic shock. Besides
combined antibiotic treatment, surgical interventions
(drainage of abscesses, removal of necrotic material)
as well as intensive care measures (intravenous substitution
of volume deficits, cardiocirculatory therapy,
application of oxygen, mechanical ventilation) may
be required. A typical example of an infectious disease
leading to septic shock is meningococcal sepsis,
which is also known as Waterhouse-Friderichsen syndrome.
Encephalitis
Encephalitis is the inflammation of brain tissue. Most
frequently, the pathogens reach the brain via the blood
vessels (hematogenic); some germs can also get into
the central nervous by nerve tracts. Besides fever and
headache, impairment of central nervous functions,
cerebral seizures, neurological failure (pareses), impaired
consciousness or changes in behavior are all possible
symptoms of encephalitis. Therapy depends on the
pathogen responsible. Even if treatment is possible and
the course of the infection is not lethal, encephalitis is
always a serious condition. Neurological defects can
persist, which is not only a severe burden for the patient
and his relatives but also may lead to the need for costly
follow-up treatments. An extremely dreaded infection
is herpes-simplex encephalitis Without treatment,
it takes a lethal course in about 70% of cases. Prognosis
depends on the level of consciousness at the onset
of therapy. A lethality of 20–50% has to be assumed in
cases of Japan encephalitis. The prognosis is also bad
when encephalitis occurs as a complication of malaria
or  measles.
Meningitis
Meningitis is an inflammation of the membranes that
envelop the central nervous system. Diagnosis is confirmed
by an examination of cerebrospinal fluid. In general,
the micro-organisms come from the nose-throat
area and reach the meninges from the blood vessels. In
most cases, the course of a viral meningitis is not harmful.
Of the bacterial inflammations of the meninges 60–70% occur in childhood. In newborns, impaired breathing
is the most conspicuous symptom. In older babies,
fever, vomiting and agitation predominate. From the
age of one year, meningitis is characterized by fever,
headache, vomiting and nuchal rigidity (meningism);
cerebral seizures and an impairment of consciousness
can appear. Bacterial meningitis demands antibiotic
therapy; from the age of four weeks, ceftriaxone,
a 3rd generation cephalosporine, is the preferred
form of treatment. Even though a great number of
pathogens can cause meningitis, after the seven weeks
of age only three pathogens are of clinical relevance:
Neisseria meningitidis (meningococci), Streptococcus
pneumoniae (pneumococci) and Haemophilis influenzae
type B (Hib). Pneumococci are responsible for 6–
20% of meningitis deaths; meningococci or Hib cause
less than 5%. Possible long-term effects are impaired
hearing, impaired motor and neurophysiological development,
cerebral seizures and pareses.
Tetanus
Tetanus is caused by Clostridium tetani, a toxin- and
spore-building bacterium, which exists worldwide and
is found in the soil. Usually, infection is due to dirty
wounds. In newborn babies, the navel is the main route
of entry. Following an incubation period of 3 days to
3 weeks, in newborns after a short interval, tetanus
infection is primarily characterized by muscular spasms
and increased muscle tonus. The mouth cannot be
opened completely, and a characteristic facial expression
results, called “risus sardonicus”. The cardiac muscle
is damaged. Furthermore, hyperactivity of the sympathic
nervous system and impairment of carbohydrate
metabolismdevelop.After the onset of the disease, only
 symptomatic therapy can be carried out. To avoid
a further build up of toxins, excision of the wound
has to be performed. Death is primarily due to respiratory
insufficiency and cardiovascular complications.
Although 57 countries are known to have a high risk of
tetanus, 90% of all infections occur in only 27 of them.
The highest incidence of tetanus is found in the Middle
East (Iraq, Yemen), in Africa, South Asia (Afghanistan,
Bangladesh, India, Nepal, Pakistan), East Asia and in
the Pacific region (China, Indonesia, Cambodia). The
risk of a tetanus infection is extremely high if nonimmunized
women give birth to children under insufficient
hygienic circumstances (http://www.who.int/vaccines/en/neotetanus.shtml). Through wounds (for
example, when cutting through the umbilical cord) bacteria
can reach the blood circulation of mothers and
newborn babies. Every year about 250 000 newbornes
and 30 000 women die after birth due to a tetanus infection.
In newborn babies the infection takes a lethal
course in 70%. Thus it is responsible for 14% of deaths
in newborns. Prognosis, depends on the onset interval;
if this interval is less than 24 hours, lethality is 100%.
However, tetanus lethality is also high when the disease
occurs later in life. Depending on the incubation
period, it is 25–60%. The most important prophylactic
measure is active tetanus vaccination ( tetanus vaccination,
active). Under certain circumstances, a passive
tetanus vaccination ( tetanus vaccination, passive) or
a  simultaneous vaccination is indicated. To prevent
tetanus, it is necessary to carry out births under good
hygienic conditions.
Rabies
Rabies is a viral infection with a deadly course, which
is transmitted by the bite of an infected animal or by
contact with contagious spittle. Animals with suspected
rabies, show abnormal behavior: thus pets can be
aggressive, while wild animals appear tame and trusting.
The average incubation time of rabies is 3–8 weeks;
it is shorter in injuries near the head than in those distant
from the head. Initially, the virus affects muscle
cells and then later passes along the nerve tracts to
the brain. Finally, it gets into the salivary glands. In
humans the course of rabies shows three phases. At
the onset of the disease there are nonspecific symptoms
like fever and exhaustion, the area of the bite
is very sensitive to pain. During the following acute
neurological phase, fear and agitation appear as well
as changes in the frame of mind (aggressions, depressions).
As swallowing induces pharyngeal cramps, the
patients become afraid of drinking. To avoid swallowing,
they let the spittle flow out of their mouths. Even
the perception of water – visually or acoustically –
leads to agitation and cramps. This state, which is typical
of rabies, is called hydrophobia (or aquaphobia,
fear of water). During the final phase of the infection
the cramps decrease and progressive pareses inevitably
lead to death. As there is no chance of cure after the
onset of the disease, therapy should begin immediately
after the patient has been bitten by an animal suspected of having rabies. An active ( rabies vaccination,
active), and – if necessary – a passive rabies vaccination
( rabies vaccination, passive), is carried out.
Persons at risk, like veterinarians and hunters, should
receive an active rabies vaccination as a prophylactic
measure. It has to be recommended to be careful
with unknown and, particulary, free running animals
especially, if the animal cannot be caught for examination.
These precautionary measures should also be
taken seriously by travelers in regions with a high
incidence of rabies (http://www.cdc.gov/ncidod/dvrd/
rabies/).
Cross-References
 Anthrax Infection
 Gas Gangrene
 Immunization, Active
 Japan Encephalitis
 Malaria
 Measles
 Rabies Vaccination, Active
 Rabies Vaccination, Passive
 Simultaneous Vaccination
 Staphylococcal Toxic-Shock Syndrome (TSS)
 Streptococcal Toxic-Shock Syndrome (STSS)
 Symptomatic Therapy
 Tetanus Vaccination, Active
 Tetanus-Vaccination, Passive
 Tropical Diseases
 Tropical Diseases and Travel Medicine
Waterhouse–Friederichsen Syndrome
References
Behrman RE, Kliegman RM, Jenson HB (2003) Nelson Textbook
of Paediatrics, 17th edn. W.B. Saunders Company, Philadelphia
Gorbach SL, Bartlett JG, Blacklow NR (2004) Infectious diseases,
3rd edn. Lippincott Williams & Wilkins, Philadelphia
Hay WW, Myron Lewin MJ, Sondheimer JM, Deterding RR
(2005) Current pediatric diagnosis &treatment, 17th edn.Mc
Graw-Hill, New York
Kliegman RM, Greenbaum LA, Lye PS (2004) Practical strategies
in pediatric diagnosis and therapy, 2nd edn. Elsevier
Saunders, Philadelphia
Osborn LM, Thomas DeWitt TG, First LR, Zenel JA (2005) Pediatrics,
1st edn. Elsevier Mosby, Philadelphia
http://www.cdc.gov/ncidod/dvrd/rabies/
http://www.who.int/mediacentre/factsheets/fs114
http://www.who.int/vaccines/en/neotetanus.shtml
http://www.emedicinehealth.com/toxic_shock_syndrome/
article_em.htm

With More Than 50 percent of Americans Vitamin D Deficient, Dr. Karl Gruber
  Says the Sun is the Best Solution - but for Only 10 Minutes Weekly; Wear
Sunscreen With UVA and UVB Protection to Avoid Melanoma and Premature Aging

    CHARLESTON, S.C., March 4 /PRNewswire/ -- As many as half of all U.S.
children and adults are vitamin D deficient and new evidence shows a link
between low vitamin D levels and cancer, autoimmune and infectious
diseases, according to experts. Researchers and doctors say the vitamin D
problem can be solved if people spend more time outside on a sunny day.

    Karl Gruber, M.D., a South Carolina-based surgical pathologist and CEO
of LUCA Sunscreen, providing the highest UVA rating available, agrees that
the sun can help people reap the benefits of vitamin D, but not without
precaution.

    "There's no doubt the sun is the quickest way to obtain important
vitamin D," says Dr. Gruber. "However, to simply prescribe sunshine without
prescribing sunscreen is irresponsible. It's imperative that people
understand that ample vitamin D is produced with finite limited amounts of
UVB rays, but there are no beneficial effects from the more dangerous UVA
rays. People need to block the UVA rays with sunscreen everyday -- even
when trying to obtain vitamin D from the sun."

    Vitamin D is produced by exposure to the sun's UVB rays. According to
Dr. Gruber, the SPF system rates a sunscreen's protection from these rays.
For example, an SPF 15 blocks 94 percent of the sun's UVB rays so a person
wearing an SPF 15 sunscreen will need to stay in the sun for two hours to
obtain the vitamin D benefits they would receive in eight minutes without
sunscreen protection. Although a person obtains UVB exposure while wearing
sunscreen, they increase their risk of exposure to dangerous UVA rays that
are closely linked to melanoma and premature aging.

    Dr. Gruber suggests that people concerned about getting enough vitamin
D should plan 10 minutes of sun exposure once a week on parts of the body
that are not chronically sun exposed, such as the back and stomach. During
this time, Dr. Gruber says to use sunscreen -- with a high UVA rating such
as 370nm or higher -- on the face, neck and arms or body parts chronically
in sunshine.

    "People should wear sunscreen daily on these highly exposed body parts
as a vital defense against the damaging effects of chronic sun exposure,
including solar aging and cancer," says Dr. Gruber. "I'm seeing skin cancer
in younger and younger patients and everyone needs to wear sunscreen daily
and take doing so seriously."

    Dr. Gruber created LUCA Sunscreen as a daily wear moisturizing solar
protection that is water resistant, hypoallergenic, fragrance free and
specially formulated for children and adults with sensitive skin. Featuring
breakthrough Polycrylene(R) technology, LUCA(TM) Sunscreen is better at
blocking UVA radiation than other sunscreens sold in the U.S. and it is the
first sunscreen on the U.S. market to back up its UVA protection claims
with a critical wavelength value printed on the bottle. With this unique
formulation, LUCA is effective for up to six hours in intense sunlight.

    Critical wavelength is an international rating system for UVA
protection and LUCA's critical wavelength of 383nm is the highest available
in the U.S. The FDA has not yet adopted a standard by which to measure
protection against UVA radiation, however, it considers any product with a
critical wavelength over 370nm to provide excellent UVA coverage.

    Because there are no tangible symptoms of vitamin D deficiency, people
are encouraged to ask their physicians to check their vitamin D levels
during annual check-ups. Ensuring the proper vitamin D levels will help the
body fight cancer, autoimmune and infectious diseases, according to
experts.

    Dr. Gruber says the farther you live from the equator and the less
opportunity you have for regular sun exposure, the more likely you are to
be deficient. Older adults and people who are obese or who have liver or
kidney disease also are at risk. In addition, African Americans and people
with darker skin are more at risk, because their skin is less able to
synthesize Vitamin D from the sun.