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Title: Disease Informatics: Quality Aspects for Diseases Associated with Viruses


1
Disease Informatics Quality Aspects for Diseases
Associated with Viruses
  • By
  • Rajendra Prabhakar Deolankar

2
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

3
Fundamental Quality CheckDefinition 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

4
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

5
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?

6
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

7
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

8
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.

9
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.

10
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

11
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

12
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

13
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

14
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

15
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

16
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

17
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?

18
Nonprogressors
  • AIDS is CD4 T cell count below 200 per µL of
    blood or 14 of all lymphocytes in HIVve
    individuals or in terms of clinical conditions
    the progression described in 4 stages depending
    on severity. HIVve 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
  • HIVve individuals showing no AIDS more than a
    decade without antiretroviral medications are
    called as long-term nonprogressors abbreviated
    as LTNP

19
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

20
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?

21
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

22
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

23
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

24
Anthropometry
  • The increased rate of change in waist/hip ratio
    in HIV-infected men receiving HAART compared with
    HIV-seronegative 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

25
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

26
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 PMIDs 18515940, 17704552 and
    17684305

27
Complex Cause Hypotheses 
  • Virus-aspirin-malathione- neem-deficiency of
    intracellular protein UNC93B- low
    1,25-dihydroxyvitamin D3 as moderator- low
    estrogen- low 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

28
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?

29
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

30
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

31
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

32
Epidemiology is a Problem-Solving 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

33
Quality CheckField 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 super-specialty 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?

34
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

35
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

36
Media is Often Blamed for Creating Panic Leading
to Wrong Focus
  • Panic a 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

37
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

38
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

39
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

40
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, Bio-resource Conservation and
    Banking, GLP, GCP (Good Clinical Practice) and
    GCLP

41
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

42
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

43
Doctors 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

44
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

45
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

46
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

47
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

48
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

49
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

50
Divya Aushadhi (Panacea) One complete solution
to several diseases is a better strategy than
having several incomplete solutions to one
disease.
Thank you
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