Download Disease Informatics: Quality Aspects for Diseases Associated with

Disease Informatics: Quality
Aspects for Diseases
Associated with Viruses
By
Rajendra Prabhakar Deolankar
Prerequisite
 Lecture no. 37971: Disease Informatics: How to handle diseases associated with viruses?, June 19,
2010
 Lecture no. 37141: Assessment of Holistic (Wholistic) Health and Fitness, Disease Informatics.
February 17, 2010
 Lecture no. 36261: Disease Informatics: Living in the Toxic World, November 6, 2009
 Lecture no. 35791: Disease Informatics: The burden of disease, September 11, 2009
 Lecture no. 34141: Disease Informatics: Brush up the terms describing techniques and resources,
February 19, 2009
 Lecture no. 34011: Disease Informatics: Terms and Jargon to begin with, February 1, 2009
 Lecture number -31981: Disease Informatics: ICD-11 at the doorstep, February 26, 2008
 Lecture number-30331: Disease Informatics: Phytates driving from the back-end to Influenza,
Encephalitis, Hepatitis, Anemia at the front-end, July 10, 2007
 Lecture number-28921: Disease Informatics: Host factors simplified, February 07, 2007
 Lecture number-25381: DIG for Disease Informatics group; Part-II, November 07, 2006
 Lecture number-25371: DIG for Disease Informatics group; Part-I, November 07, 2006
Fundamental Quality Check:
Definition of the Disease
Earlier, we had a longitudinal view of “How to handle diseases
associated with viruses” [Lecture no. 37971].
The purpose of defining diseases are to understand exactly
what they are so that they can be prevented or reversed;
public health strategies, by and large, depend on a disease
defined on the basis of component cause while personal
health strategies should consider sufficient causes and
comprehensive disease definition.
Let us now see some additional aspects of an exemplary chronic disease i.e.
AIDS and one acute disease i.e. Acute Encephalitic Syndrome so as to
understand the quality norms for virology laboratory
I. AIDS:
Sulfur Amino Acid Containing Defensin
• Defensin is a family of potent antibiotics made
within the body by neutrophils
and
macrophages
• The defensins play important roles against
invading microbes
• They act against bacteria, fungi and viruses by
binding to their membranes and increasing
membrane permeability
Role of Defensin in
Cervicovaginal Secretions
• Mucosal surfaces of the cervix and vagina are portals
for heterosexual transmission of HIV and, therefore,
play a fundamental role in the pathogenesis of primary
infection
• Cationic
antimicrobial
polypeptides,
including
defensins, are the principal effector molecules of
mucosal innate immunity against microbes and viruses
such as HIV
• Do you think that Good quality definition of AIDS
should take cognizance of the protective principles?
Biomarker Defensin; Continued…
• In cervicovaginal secretions, antimicrobial polypeptides
constitute the majority of the intrinsic anti-HIV activity,
synergism between cationic polypeptides is complex,
and full anti-HIV activity involves the complete
complement of cationic polypeptides
• Periods in which cationic antimicrobial polypeptide
expression is reduced (back-end for HIV infection) are
likely associated with increased susceptibility to HIV
infection. Hormones and bacterial infections can regulate
the expression of defensin
Bacterial Vaginosis and HIV
Connection
• Bacterial vaginosis (back-end for HIV infection in
some cases) was consistently associated with an
increased risk of HIV infection
• High bacterial vaginosis prevalence may result in a
high number of HIV infections being attributable to
bacterial vaginosis (BV) indicating prevention of BV
as also a potential public health strategy for
prevention of AIDS.
• The power of strategy for prevention and treatment
of disease depends upon quality of definition of the
disease
Glutathione
• Glutathione (GSH) is a tripeptide (cysteine, glutamic
acid, glycine); Glutathione deficiency results in early
aging and in the loss of coordination, balance, tremors,
and mental disorders.
• Orally supplemented glutathione is not assimilated.
Cysteine (sulfur amino acid) supplementation improves
glutathione level. Cystine gives two molecules of
cysteine. Cystine as well as cysteine can enter cell;
glutathione cannot.
• Cysteine can be synthesized from methionine. Intestinal
flora converts inorganic sulfur to the sulfur compounds
that can be assimilated.
HIV and Glutathione
• “Glutathione (GSH) deficiency” is common (front-end
mediator of HIV progression) in HIV-infected individuals
and is associated with impaired T cell function and
impaired survival; it must be prevented. N-acetylcysteine
(NAC), a cysteine prodrug, replenishes glutathione in
HIV infection. However, repeated use of NAC further
induces oxidative stress [PMID: 17612979]. Should
quality definition of AIDS progression take cognizance of
GSH deficiency?
• Gandhaka rasayana (sulfur preparation) has been used
on AIDS patients successfully by several doctors,
however, reports of systematic studies are lacking.
Malnutrition in AIDS
• Malnutrition
leads
to
immunodeficiency.
Immunodeficiency makes the host susceptible to
opportunistic infections. Simple multivitamin /
mineral supplement can prolong survival in
HIV/AIDS
• Depletion of cysteine (sulfur amino acid) causing
drop in glutathione (sulfur containing antioxidant)
is a common observation in several AIDS cases
• Dietary
Selenium
strongly
influences
inflammation and immune responses
Continued…
• Furthermore catabolism of tryptophan also
occurs in AIDS
• This is associated with intracellular niacin
deficiency
• All these compose sufficient cause in some
cases and can lead to the front end event of
loss of lean mass typically revealed as
wasting
syndrome,
or
pellagra
or
kwashiorkor like disease
Oxidative Stress-induced
Niacin Sink (OSINS)
Existing evidence supports the hypothesis
that
the
nutrient-related
metabolic
abnormalities in HIV infection regarding
antioxidants, selenium, sulfur, tryptophan
and niacin are interrelated. This has been
described as "oxidative stress-induced
niacin sink" (OSINS) model. The OSINS
model can be used to guide the design of
nutraceutical regimens for AIDS patients
Continued…
• Rectification of malnutrition can be achieved by
correcting the balance of nutrients and/or
reversing the disease process
• Host specific treatment on the basis of Ayurved
could be a strategy to reverse the disease as
well as certain host specific foods and
supplements (nutrigenomics) could cater for
supply of functional principles and nutrients
• A good quality definition of the disease should
provide scope for such treatments
Calophyllum
Anti-HIV Calophyllum: Coumarin is a
compound that smells like vanilla; and
xanthone is a cholesterol lowering
compound commonly extracted from
kokum. Coumarins and Xanthones
extracted from a tree Calophyllum (Known
as Undi in Marathi language) inhibit HIV
reverse transcriptase and HIV replication
Continued…
Mollusk eating Calophyllum: HIV reverse
transcriptase inhibitors have been isolated
from acetone extract of the giant African
snail, Achatina fulica . These snails had
been eating Calophyllum
Lectins in Mollusk
• Lectins are natural compounds found in various foods.
These bind to specific sugar moieties expressed on
human cell surface
• The lectin from a Roman snail Helix pomatia recognizes
terminal sugar (alpha N-acetylgalactosamine) as a part
of glycoprotein residues expressed on the cancer cells.
The expression of the lectin binding glycoproteins by
cancer cells has some value as a marker of metastatic
competence and prognosis of cancer in a range of
common human adenocarcinomas, including those of
breast, stomach, ovary, oesophagus, colorectum, thyroid
and prostate
Recovery From AIDS; A Case
• An AIDS case that could be ranked as stage 4 by WHO
criteria was reversed to stage 1 after eating regularly the
fresh water river snail Pila virens. This was observed by
a senior clinician, Dr. Sharad Joshi, JKRP, Pune, India
• It is a research question whether the benefits are due to
coumarins, xanthones and lectins or something beyond
these. Ayurveda text recommends the mollusk as food
therapy in disease resembling AIDS.
• How would you react to this information?
• Would
you
recommend
compilation
of
such
observations? Why?
Nonprogressors
• AIDS is CD4+ T cell count below 200 per µL of blood or
14% of all lymphocytes in HIV+ve individuals or in terms
of clinical conditions the progression described in 4
stages depending on severity. HIV+ve case could be
with or without AIDS
• AIDS case is a progressor when it is with AIDS (stage-2
onwards). When it is without AIDS (stage-1) it is
nonprogressor
• HIV+ve individuals showing no AIDS more than a
decade without antiretroviral medications are called as
long-term nonprogressors; abbreviated as LTNP
Elite Controllers
• Elite controllers are HIV-positive people whose immune
systems for long periods of time have been able to keep
the virus at undetectable levels without using
antiretroviral drugs
• These patients maintain viral loads below the limit of
detection of commercial assays for many years and
generally do not show any clinical signs of disease
progression
• The mechanisms responsible for this remarkable control
may lead to the design of effective therapy
Viremic Controllers
• Viremic controllers are HIV-positive people
whose immune systems have kept the
virus at barely detectable levels without
antiretrovirals
• What could happen if these controllers are
treated with combination therapy including
HIV protease inhibitors?
Lypodystrophy
Combination therapy including HIV
protease inhibitors (PIs) is associated with
a lipodystrophy syndrome characterized
by selective loss of subcutaneous fat from
the face and extremities and, in some
patients, accumulation of fat around the
neck, dorsocervical region, abdomen, and
trunk
Causation of Lypodystrophy
The pathogenesis is multifactorial, with
contributions from other antiretroviral
medications, patient-related factors, and
HIV itself. Switching to a less toxic highly
active antiretroviral therapy, regimen has
shown partial effectiveness for the
management of fat atrophy and lipid
abnormalities
Associations With Lypodystrophy
Cardiac involvement includes coronary
artery disease, dilated cardiomyopathy,
pericardial
effusion,
pulmonary
hypertension, and ill effects of highly
active antiretroviral therapy in the form of
lipodystrophy,
lipoatrophy,
and
dyslipidemia
Anthropometry
The increased rate of change in waist/hip ratio in HIVinfected men receiving HAART compared with HIVseronegative men is attributable to slower increases in
hip circumference rather than an increased rate of
change in waist circumference. These findings
underscore the importance of body fat composition
changes in the peripheral compartment relative to the
central compartment among HIV-infected men receiving
HAART
II. Childhood Brain Disease
Outbreaks in India
•
•
•
•
High case-fatality
Recurrent, annual, seasonal
Vague clinical descriptions
Floating numerator errors in outbreak
investigations
• Being reported in India for more than 4 to
5 decades, yet to be controlled
successfully
Virus Hypotheses
• Seroconverted denominator is very big,
disease-case numerator is extremely small.
Earlier outbreaks were mostly attributed to
Japanese Encephalitis virus, now attributed to
one or other type of virus. Several viruses have
been associated with the disease
• Virus denial hypotheses: Cassia occidentalis
poisoning [PMID’s: 18515940, 17704552 and
17684305]
Complex Cause Hypotheses
• Virus-aspirin-malathioneneem-deficiency
of
intracellular
protein
UNC93Blow
1,25dihydroxyvitamin D3 as moderator- low estrogenlow DHEA- low melatonin etc some of them working
together to cause said brain disease [10750089,
10750088, 1818875, 2593049, 3440601, 6348317,
6407704,
6618571,
16973841,
17056528,
10696912,
9605130,
17261778,
16099910,
17286740 ]
• Sufficient causes are not worked out and regarding
virus as a sufficient cause is a dogma
Probable Non-viral Component
Causes of AES
• What are the orthologs of Acute Encephalitic Syndrome (AES)
in India?
• How far:
Human microbiome offers protection to AES?
Endocrine anomalies (seasonal or genetical) contribute to
AES?
Nutrient metabolites regulate the genes associated with AES?
Opioid peptides derived from food proteins like gluten
exorphins, beta-casomorphins etc play role in sensitive
individuals?
Host specific treatments in Ayurveda are helpful?
Editorial in Indian Pediatrics
Pinpoints Ignorance
Title: Investigation of Outbreaks in India. How good are we at it?
[PMID: 14581729]
• Often associations have been interpreted as causality
• This has lead to professional disagreement on the
etiology
• Vaguely, CNS related outbreaks in the community have
been labeled as Japanese Encephalitis
• Viral diagnosis is taken for granted until proven
otherwise
• Wrong concepts are common like invasion of virus in
CSF is necessary to cause CNS symptoms
Editorial Also Pinpoints
Mismanagement in Planning
• Investigations lack: Evidence from control
samples, a systematic approach, Analytical
studies and Cooperation between clinical and
public health communities
• Investigations are not well coordinated, shows
discrepancy between clinic and laboratory when
a new disease emerges
• Rivalry for credit sharing, conflicting roles and
inefficient use of NGOs
Quality Check: Are Top Men
Dedicated Epidemiologists?
• How to promote problem based learning?
• How to develop a problem solving approach?
• How to promote public funded labs to work on
non-profitable diseases?
• How to provide simple feasible solutions?
• Quality protocols should check that the persons
having “no answers” to these questions should
not lead or assess or victimize the persons who
“have answers”
Epidemiology is a ProblemSolving Discipline
• The editorial makes it clear by now that outbreak
investigation is handled by top men having dogmatic views
• Strategy planning for outbreak investigation is not only to
know all the components but also to know how they work
together; information is the crux
• Those who claim themselves to be epidemiologists without
having systems approach are pseudoepidemiologists
• Professional epidemiologist applies Information Science in
defining the diseases with least error, identifies most of the
targets to combat a cluster of diseases (Disease Causal
Chain) and designs a holistic solution (Health strategy) to
the problem
Quality Check:
Field and Diseases as Bases
• Is the problem of childhood brain disease in India not
solved because nobody knows who is accountable for
solving the problem? Right To Information (RTI) and Legal
action for “not having the right strategy” are poorly
exploited?
• Are National funds spent on executives rather than the
work? Are donor funds conditional and go to rich superspecialty labs rather than for problem solving NGO
organization? Are committees appointed by a biased view?
• Are workers trained for “the purpose” in the school for
Problem Based Learning? and are they diverted to the field
where problem exists?
Disease Informatics Group to
Take Quality Decisions
• Whether the Disease Informatics Group (DIG) exists
is the main query to be put by the quality auditor
• What are the standard norms for DIG? Is it possible
for an NGO to form DIG? Is there provision for
participation of NGO with Government?
• Is DIG dominated by vested interest?
• Is DIG oriented for solving the disease problem?
• Funds invested are wasted if problem is not solved
Quality Check:
Involvement of Statisticians
• All the members of Disease Informatics
Group (DIG) need to be well trained in
statistics
• It is felt that DIG needs to have at least 15
to 20% professional statisticians
• Statistician should not be dominated,
should be given credit for their work and
should be involved early
Media is Often Blamed for Creating
Panic Leading to Wrong Focus
• Panic α Diversion of attention of masses from sufficient
causes
• Sufficient cause is by and large an unknown word; why?
• Say 1 case results in disease out of 500 cases exposed
to virus; then
Why only the one got the disease?
Which factors other than virus protected other 499?
• Why panic-preventing data is often censored by higher
authorities? Should media get obligations from profit
makers? There is no training course for media people on
disease reporting
Quality of Diagnostic Virology
• The quality program includes Internal Quality
Control (IQC), Internal Quality Assessment (IQA)
and External Quality Assessment (EQA)
• Such program exists in GCLP (Good Clinical
Laboratory Practice) labs
• Lab having no quality program can potentially
mix-up the clinical specimens received from
medical
establishment
and
specialists,
epidemiologists during outbreak of diseases or
samples obtained during clinical trials
Some More Probable Errors
• Labs may also send results on wrong
address
• A data entry error could also occur at
specimen reception
• Virologists not having clinical qualification
tend to interpret results in a wrong manner
• Hence, samples should be sent to GCLP /
GLP (Good Laboratory Practice) certified
labs only
Staffs is the Key for Quality
The quality and education of staff is the
foremost requirement for making reagents
with good quality, maintaining quality of
apparatus, getting good quality clinical
specimens,
maintaining
quality
of
sampling and aliquots, understanding the
suitability of the techniques in use
Training Courses…
Good quality scientific report can be obtained
from well qualified technicians, trained in health
research (Statistics of Bioassay, Training in
Experimental Designing), Diagnostic Virology,
building Professional Charts and Diagrams, and
Database
using
Software
for
Project
Management, Infrastructure Maintenance and
Management, Store and Inventory Management,
Document and Record Management, Bioresource Conservation and Banking, GLP, GCP
(Good Clinical Practice) and GCLP
Impact of Low Quality Diagnosis
• Laboratory diagnosis has to be accurate and
unchallengeable
• Papers published even in good journals are based
on data generated from non-GCLP labs
• Unfortunately, National labs in most of the
developing countries providing viral diagnosis are
yet to be GLP or GCLP certified by accreditation
body
• Quality auditors need to see whether real solutions
to the viral diseases had been researched upon; we
have seen that the answer is “no” for AIDS and
childhood brain disease outbreaks in India
Dispatch of Clinical Sample
• GCLP certified laboratories expect clinical
specimen to be proper, properly collected,
properly labeled and properly packed
• It is customary to publish the Standard
Operating Procedure (SOP) for collecting the
clinical specimen by the diagnostic labs and also
send those to clinical establishments before the
samples are collected
• Several specimens are rejected by diagnostic
lab as found abused during transportation
Doctor’s Requirement
• Doctor may prefer to send specimens to different
labs to know more about different component
causes of the disease
• Whether to send documentation of details of a
patient and provisional diagnosis along with the
specimen is a matter of policy
• Doctor should be clear about what he wants
from virology lab; viral load, viral antigen
detection by PCR, IgM titre, IgG titre, or antigen
titre through ELISA
Serum Specimen for IgM
• IgM antibody is involved in primary
response
• Their presences in high titre in serum
indicate recent infection
• Its presence in a neonate's serum
indicates intrauterine infection (e.g.
congenital rubella)
• It is responsible for the agglutination of red
blood cells
Serum Specimen for IgG
• IgG antibody is involved in the secondary
immune response
• Diagnosis is based on difference in titre of acute
and convalescent serum
• Serological diagnosis is usually retrospective as
paired acute and convalescent sera are required
• Arboviruses and other acute infections are
diagnosed serologically
• Serological diagnosis of Mumps can be easily
made by Complement Fixation Test or by ELISA
Other Specimen
• IgG is present in high concentration in
colostrums
• IgA antibody is found in mucous secretions
(tears, saliva, colostrums, genito-urinary
tract, gastrointestinal tract, prostate and
respiratory epithelium). It is also present in
small amounts in blood
• Stool samples, CSF and tissue biopsies are
rarely used
Continued…
• Enteroviruses like polio, coxsackie B and echoviruses
can be easily identified and cultured from faecal and
throat swab specimens during the acute phase of the
illness
• RSV, influenza A and B, parainfluenza 1-3, non-enteric
adenoviruses and rhinoviruses can often be identified /
isolated from sputum and nasal aspirate
• Throat and nasopharyngeal swabs is not a good
specimen but usually collected because of convenience
• Mumps virus can be isolated from saliva and urine
specimens
Labs Examining the Specimen
• The diagnostic lab detects virus, viral antigen or
viral antibodies
• This is usually done by performing qualitative,
quantitative or both types of assays
• These services are sometimes free as the labs
may isolate virus from clinical specimen and
bank it for further commercial development or
research without the permission of patients or
their doctors
In the Event of Disease Outbreak
• Public health preparedness is the management
of knowledge, information, time and organization
to check the spread of disease and minimize the
morbidity and mortality and not designed for
individuals or families
• A good family doctor or well trained health
worker does not totally depend on the services
provided by Public Health Preparedness but
additionally provides individual and family
strategies to fight the disease
Divya Aushadhi (Panacea): One complete solution to several diseases is a better
strategy than having several incomplete solutions to one disease.