AIDS and Immunodeficiency

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    Today's lecture is about two topics which are very imp.  , so let's begin…

    First of all let's talk about AIDS, which is one of the 4 retroviruses (and those are HIV1,

    HIV2, HTLV1, HTLV2) .  HIV1 is more common and pathogenic than HIV2, and it causes

    more than 90 %of AIDS cases  .HIV2 is widely distributed in Africa but it's somehow

    rare outside it, and relatively it causes slowly aggressive and benign disease  .HTLV1

    human T-cell lymphotropic virus type 1)(  causes what we call ATLL Adult T-cell leukemia/lymphoma)(  

     where the patient has a picture of leukemia, lymphoma, hypercalcemia, skin lesion and

    others, and it's in certain locality . HTLV2 hasn't clearly linked to any disease  .

     

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    ** what you see in the above table is the classification of clinical diagnosis of AIDS "not

    HIV "dr  .said"", according to the revised 1993 system. Obviously we can see that we

    depend on two entities in this classification, 1CD4+  T-  cell count and, 2clinical

    picture.  According to the CD4

    +

    count, we have 3 groups …group 1 (cells count is ≥ 500\µl), group 2 (cells count is between 200-499\ µl) and group 3 (cells count is< 200\ 

    µl). According to the clinical picture, we have also 3 groups A,B,C …and this depends

    on the diseases that the patient has…see the table.  Then when we combine these two

    entities, we end up with 9 groups…. A1, A2……,C3 . And this is imp to know how to deal

     with the patient  .

     

    **here we can see the molecular

    structure of HIV virus, here we have

    multiple proteins: 

     Reverse transcriptasewhich

    trancripes viral RNA into DNA. 

      Integrase   which unites the

    trancriped viral DNA with the cellular

    DNA

      Protease which helps the virus to

    exit the cell through the cell

    membrane. 

     

    gp41 & gp120which help the virus toenter the cell, here gp120 begins the

    process by binding with cd4 receptor,

    and then gp41 bind the chemokine

    receptor, and then the virus enters into

    the cell  . 

    **here in this picture,

    we can see how does

    the virus use its

    proteins to enter the

    cell, proliferate, and

    then exit the cell . 

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    ## another thing that you should know that around 95-97 %of the plasma viral load

    comes from newly activated CD4+T-cells, and around 2-3% of the viral load is in the

    other cells which have cd4 receptor like macrophages and dendritic cells, and the rest1% comes from the memory T-cells, see the pic . below   .

     

    The dr.  skips this slide without

    mention anything about it, so tryto read and understand as much

    as you can …….sorry.

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    ***this virus presents in all body fluids and also within resting cells "this makes the

     virus more prominent to be transmitted", we have multiples routes of transmission  :

      Sexual…hetero  - or homosexual, in hetero sexual, there is more risk to transmit the disease

    from male to female than the opposite  .  Through blood or blood product…you should know that if infected unit is transfused to

    healthy person, the chance that this person will get the disease is almost 100%  . On the other

    hand, needle stick from HIV infected person to the health care worker will result in disease

    transmission in almost 3\1000 only, while in HBV it's 100 times more  .

       Vertical….the chance of the baby to get the infection from his\her infected mother is around

    33% and almost 85  % of those babies get the infection during delivery, bcoz of that there are

    advices in this situation to do caesarean section which will decrease the risk .  The issue of

    lactation depends on the situation, it's better not to lactate unless there is special situation like

    in Africa, where there is no other source for child nutrition  .

     

    ### here are some epidemiological facts the dr .mention them rapidly but they aren't

    in the slides  ...

      In 2000, 55 million people worldwide are HIV infected  .

       Among them, 5 million get AIDS  .

       3 million were already died

      It's a major cause of death in subsaharan Africa  .

     

    ***  now what about the course of HIV infection, how does the infection progress…

    -first of all, we have the acute phase, which may last up to 6 months, in this stage we

    have some characteristics…1 there is very marked viremia, 2 very severe drop in CD4+ 

    T-cells count  (from 1200 to around 500\ µl), 3seeding of lymphoid organs, 4flu-like

    symptoms, so these are not specific symptoms . The thing which is very imp.  is that

    it's somehow difficult to diagnose the patient as HIV infected in this stage, bcoz

    symptoms are not specific  .

     

    -then the patient enters in clinical latency phase, which occurs bcoz of partial control

    of the disease by the immune system,  it may last for many years 1 without any

    symptoms, 2 viral load is very low or not detectable, 3CD4+ T-cells count start to drop

    gradually   .

     

    -after many years the patient enters the stage of AIDS, where there will be

    constitutional symptoms firstly, then increase in opportunistic infections , and

    ultimately death  .In this stage viral load increase rapidly, and T-cells count continue

    in drop .

     

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    ##this is an evidence of the importance

    of viral load regardless of the T -cells

    count….we can notice when viral load is

    low "the upper curve" the survival rate will

    be more, and the with the increase in the

    viral load, the survival rate will

    decrease. 

    ##this is the antiviral AB titers, dr .said

    they aren't imp.  for protection, but we

    use them to detect HIV especially in case

    of blood transfusion, the bad thing is

    that they will ultimately decrease after

    long period, so again you will depend

    completely on viral load and T  -cells

    count for diagnosis. 

    ***dr  .didn't say anything

    about this slide, so just read it

    if you want to . 

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    ***treatment and prevention…although we have very effective drugs but their

    effectiveness decrease with time bcoz of high level of mutation of HIV genome, so we

    usually use combinations  .

     Anyway we have multiple groups of drugs depending on the mechanism of action, wehave 1reverse transcriptase inhibitors, 2integrase inhibitors, 3protease inhibitors, see

    the table. We can notice that there are a lot of side effects, bcoz they are new drugs  .

     

    ## this pic shows how it’s effective to combine

    cytokines "IL-2  " and antiretovirals in treatment

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    **about vaccines….here is a table that gives you a list of vaccine strategies under study,

    nothing is successful until now . If you notice we have different mechanisms, so try to

    read it".dr .again didn't mention anything about it 

    **Dr .started with some revision about the immune system, we should know that we have two forms

    of division...1\a  innate "natural, nonspecific "or  b adaptive"  acquired, specific ".  These two

    types differ from each other by multiple things, like need for previous exposure, immunologic

    memory, amplification process  . 2\a cellular or  b humoral . Also we should know that the newborn

    is born with not fully developed immune system, and he depends in the 1st six months on IgG that

    come from his mother by specific mechanisms through placenta   . On the other hand, the immune

    system weakens with age, so we have relatively weak immune system in extreme ages  .

     

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    **Now, we have two types of Immunodeficiency, primary and secondary…  .

     primary , where we have genetic defect that leads the immunodeficiency, it's rare

     but imp  .  but why?? I\ for us "as students", bcoz it's a favorite Q's in the exam☻, and generally bcoz it's

    imp .For experiments and study to understand how the immune system works  .

     secondary,  which is more common. But in except for HIV, this type is not well studied  .

    *** We should differentiate between immunodeficiency and immune tolerance  .In

    immune tolerance, we have immune unresponsiveness to specific type of antigen,

     with normal immunity against other antigens .On the other hand, immunodeficiency

    is associated with deficient immunity for most antigens  .

    -  let's begin with…

     

    ##we classify it into two types…1specific, which could be cellular "T-cell defect, like:

    DiGeorge syndrome, Wiskott Aldrich syndrome", humoral "B-cell defect, like:  Bruton

     Agammaglobulinemia, Common Variable Immunodefeciency,  Selective IgA deficiency ", or

    combined cellular and humoral "severe combined immunodeficiency (SCID)". 2 nonspecific,

     which also could be cellular "neutrophil defects, like chronic granulomatous disease  " , or

    humoral "complement defects  " …. we'll talk about each one of them in the rest of the lecture  .

    ***let's begin with…DiGeorge Syndrome, the most imp  .signs are absent thymusand parathyroid glands and defects in major blood vessels  .So the typical pic  .is a

    newborn with tetany due to hypercalcemia which is caused hypoparathyroidism .The

    main genetic defect is 3 & 4 pharyngeal pouches defects, and 22q11 deletion  .

     

    **in DS, you should know that most changes

    are dysmorphic changes  "like low set ears  "

    rather than mental defects  .And bcoz it's T  -cell

    defect, DS clinically resembles AIDS . 

    **radiologically, we should

    notice the absence of the

    thymus, which normally

    should appear in newborn. 

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    **Bruton’s Agammaglobulinemia  ...this is X-linked condition  "so it's more

    common in males", leads to the absence of Bruton's tyrosine kinase, which is

    necessary for B-cell production, and this will lead to deficiency of Ig's"agammaglobulinemia  ."It's presented after 1 year of age bcoz of innate maternal

    immunity, and it's characterized by absence of both B-cells & Ig's "and this is how itdiffers from common variable immunodeficiency  (CVID)".

     

    **CVID and Selective IgA Deficiency , these are Acquired genetic defects, means

    that the patient grows and the defects occur Later in life.  All classes of Ig's are

    deficient but there is normal numbers of B cells, Associated with autoimmune

    diseases and lymphomas  .On the other hand, Selective IgA D.  is the commonest

    primary ID in adult, but why we put these two syndromes together? Bcoz the patient

     with CVID may "if he lives enough  "get S  .IgA D. you should know the order of Ig's

    deficiency in CVID as the following..IgM, IgD, IgG, IgE, and then IgA (MD  Get

    Excellent A ttributes)  .

     

    **Severe Combined Immunodeficiency Diseases (SCID)  this isn't a single

    disease, it's a huge group of diseases, each one has distinctive genetic defect, but all ofthem lead to SCID with dysfunction of both B and T cells .The usual picture is a family

     with multiple newborns deaths, without any known cause  .There are many diseases,

    dr .  didn't mention any one, so I'll put them here…

     

    X-  linked SCID  Classical SCID (SCID1  )   CD132 Deficiency SCID   SCID with ADA Deficiency    SCID with NP Deficiency  

     

    SCID with PNP Deficiency 

     

    SCID with ZAP- 

    70 Deficiency   SCID with IL-  7 Receptor Deficiency   SCID with RAG-  1 Deficiency 

      SCID with RAG-  2 Deficiency 

       Bare Lymphocyte Syndrome I

       Bare Lymphocyte Syndrome II

     

    **Chronic Granulomatous Disease,  Defect in the Respiratory Burst killingmechanism  " neutrophil defects", 2/3 X-Linked recessive or 1/3 Autosomal Recessive  .

    It's associated with Granulomas (Muconium ileus, intestinal obstruction, skininfections and abcesses), it's tested by NBT test Nitro blue tetrazolium  " ."

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    ##Now let's shift to

    ** 

    here we have many causes…

      Malnutrition…it's by far the most common cause of secondary ID ., it could be

    protein or calorie deficiency "like children in Africa, where even measles could be fatal",

    or trace elements deficiency "like zinc deficiency   ."

      HIV Infection or even non HIV sometimes  .

      Diabetes mellitus( Multi-factorial)  .

      Radiation  .

      Chemicals and Drugs  .

     Malignancies

     

    .  Burns Surgeries  .

      Foreign Bodies  .

     

    **  Now when to suspect immunodeficiency? We have certain features of ID patients…

     i. Unusual infections…  and this unusualness could be in severity, frequency,

    organisms "like pneumocystis carinii in AIDS", site, resistance…  .

    -The type of infection could help us to identify the part of the immune system

     which is affected, see the table next page… 

    **here it's a pic of NPT test, we have neutrophils and we add NPT on them .In normal

    situation "right pic "the yellow stain "NPT   " won't be reduced and will appear blue in

    color .While in abnormal situation, it will appear like in the left pic  . 

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    ** just two notes about the above graph…  .

    -in CGD, why do we have staph. Infection but not strep. Infection? That's bcoz staph

    is resistant to catalase which is produced by the neutrophil, in contrast to strep  .

    - when we have specifically repetitive niesseria infectionmeans complement defect

    …this is repetitive exam question "dr .said  ."

     

    ii. Unusual Malignancies (Lymphomas, Kaposi Sarcoma  )

     iii. Connective Tissue Disorders (e.g .SLE,,  )

     iv. Syndromic manifestation…like digeorge syndrome.

     

    *** what about laboratory diagnosis…  .

      We have two categories of tests, as follows… 

    • Screening tests, should be readily available, cheap, very sensitive  .  – CBC, Diff (Manual or Counter)  for CMI

      – Immunoglbulins levels (G, M, A and IgE  )

      – C3, C4, CH50 (Immunoassay, or Comp cytotoxicity   )

      – PPD test (Functional test)  for CMI

     

    • Confirmatory Advanced tests, most of them experimental, and not used in all cases .  – Flow cytometry  (T cells CD3, 4, 8, NK cells CD16, and B cells CD19  )

      –  Antigen Vaccination then Antibody titer

      – Experimental methods (Stimulation tests by Superantigens  )

     

    HIV

    Specific Ig's

    immunodeficien

    Neutrophils deficiency

    CGD Complement deficiency

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    ##Lastly….  Management,

      Nutrition, you should be sure that the patient eats the expected amount and

     variable food (Protein, Calorie, and Trace Elements) 

    .   Avoidance of Pathogens….so usually we isolate these patients to prevent them  .

       Antibiotic Prophylaxis (Most from HIV experience  )

      CD4 < 200 for pneumocystis carinii pneumonia, by co-trimoxazole,

    and pentamidine  .

      CD4 < 50 for mycobacterium avium intracellulare )MAI  .(

       Vaccination important and repeated…  you should give repetitive vaccines for them,

     but be careful, never give them live vaccines" v .imp 

    ".

       Antibiotic treatment…early, aggressive and appropriate antibiotic treatment  .

     

    Specific Treatment (like BMT  " for SCID especially if the diagnosis is early ",Interferon gamma  "  whoch might might be helpful in CGD", IVIG  " intravenousimmunoglobulins in agammaglobulinemia).  

    ***Ta7yi kbeere l shabab w sabaya 8roob A9… w b5o9 belthkr

    bakor

     Ya8006☻,mli7an☻, els3di "wla 7ellani a7la", abo- farsa5, elmol8i, abo elshena8, elshare3, w

    la 7abibna mn malysia..3zzat & 2nwar.

     W 27la salam ll ethnen elli msh m5lien 7da mn shrhom… abo el3nan & abo ersheid.

    W akeed l njdawi, hesham yaseen, abo jandal, sub-laban, m07a 7mdan"nrd eldof3a eljdeed", MLM,KJB, 7osam, 5alil, milad, 3amer, mothana, m7mood 6anash, 2yham sha6nawi, abo el3z, hani 3id,

    3la2 elrawashde "elk w7she". 2asf kteer etha nseet 7da….

     

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