Prof. Md. Prof. Md. AkramAkramHossain April April 20122012

ImmunodeficienciesImmunodeficiencies

Prof. Md. Prof. Md. AkramAkram HossainHossain

April April 20122012

12/23/2013 1Prof. Muhammad Akram , Immunodeficiency

What is immunodeficiency?What is immunodeficiency?

Deficiencies of host defense systemsresult in an immunologic imbalancethat can lead to a susceptibility tothat can lead to a susceptibility toinfection, an autoimmune disease, or apredisposition to malignancies.


Types of immunodeficiencyTypes of immunodeficiency

MayMay bebe ofof twotwo typestypes::

1.1. PrimaryPrimary immunodeficiencyimmunodeficiency

isis usuallyusually aa geneticgenetic defectdefect inin thethe immuneimmuneisis usuallyusually aa geneticgenetic defectdefect inin thethe immuneimmuneresponsesresponses thatthat oneone isis bornborn withwith..

2.2. SecondarySecondary oror acquiredacquired immunodeficiencyimmunodeficiency

oneone isis bornborn withwith normalnormal immuneimmune responsesresponsesbutbut somesome secondarysecondary factorfactor oror occurrenceoccurrencecausescauses aa decreasedecrease inin immuneimmune responsesresponses..


Types of immunodeficiency disorders:

1- Primary: Causes inimmune systemcomponent:a. According of component:

i. Complements. ii. Phagocytic. iii. B cells. iv. T Cells.

b. According to the etiology:

i. Congenital (X-linked disease) ii . Acquired (AIDS)

44

i. Congenital (X-linked disease) ii . Acquired (AIDS)

iii. Embryogenesis (Digoerge syndrome). iv. Idiopathic

2- Secondary: NonImmunogenic causes:a. Prematurity. b. Mal nutrition.

c. Hodgkin`s and others malignancy. d. Injury, Burns, Splenectomy.

e. Drugs.


Classification :

Primary (congenital). Secondary (acquired).Its common

Genetic mutations.Genetic polymorphism.

They could be :

malnutrition.Most important cause

viral & bacterial

either Monogenic ( defect in one gene )

or polygenic( defect in more than one gene )

viral & bacterialinfections.

e.g. AIDS which is caused by HIV

Immunosuppressive drugs.(corticosteroids).For long-time use,

it’ll depress the immune system

excessive protein loss,burns, nephrotic syndrome

( loss of cells like RBC and loss of protein liek Ig )12/23/2013 5Prof. Muhammad Akram ,

Immunodeficiency

Primary or acquired.can affect.

Natural immunity(non-specific body defenses).

Acquired immunity.(specific body defenses).(non-specific body defenses). (specific body defenses).

Phagocyticcells.

Complement proteins.

T-cells. B-cells.

12/23/2013 6Prof. Muhammad Akram ,

Immunodeficiency

Primary Primary ImmunodeficienyImmunodeficienyDisorderDisorderDisorderDisorder


Primary ImmunodeficiencyPrimary Immunodeficiency

AA primaryprimary immunodeficiencyimmunodeficiency isis usuallyusually aa geneticgenetic defectdefect

inin thethe immuneimmune responsesresponses whichwhich involvesinvolves thethe

developmentdevelopment ofof BB--lymphocytes,lymphocytes, TT--lymphocytes,lymphocytes, orordevelopmentdevelopment ofof BB--lymphocytes,lymphocytes, TT--lymphocytes,lymphocytes, oror

bothboth.. DependingDepending onon thethe disorder,disorder, thethe lymphocyteslymphocytes inin

questionquestion maymay bebe completelycompletely absent,absent, presentpresent inin veryvery

lowlow levels,levels, oror presentpresent butbut notnot functioningfunctioning normallynormally..


Primary Immunodeficiency: Primary Immunodeficiency: FrequencyFrequency

Phagocytic18%

Combined

Cellular10%

Complement2%

Antibody50%

Combined20%

The overall prevalence of PID is about 1:2000


Frequency of the Primary Frequency of the Primary

Immunodeficiency DiseasesImmunodeficiency Diseases

�� The primary immunodeficiency diseases The primary immunodeficiency diseases were originally thought to be quite rare. were originally thought to be quite rare.

�� some of the primary immunodeficiency some of the primary immunodeficiency �� some of the primary immunodeficiency some of the primary immunodeficiency diseases are relatively common.diseases are relatively common.

�� For example, Selective IgA deficiency For example, Selective IgA deficiency occurs in as many as occurs in as many as 11//500500--11//1000 1000 individuals.individuals.


Frequency of the Primary Frequency of the Primary Immunodeficiency DiseasesImmunodeficiency Diseases

�� OtherOther primaryprimary immunodeficiencyimmunodeficiency diseasesdiseases arearemuchmuch lessless commoncommon andand occuroccur withwith aafrequencyfrequency ofof betweenbetween 11//1010,,000000 andand11//100100,,000000..11//100100,,000000..

�� BecauseBecause therethere areare soso manymany primaryprimaryimmunodeficiencyimmunodeficiency diseases,diseases, whenwhen takentakentogethertogether asas aa groupgroup ofof disorders,disorders, theythey becomebecomeaa significantsignificant healthhealth problem,problem,

�� occurringoccurring withwith aa frequencyfrequency comparablecomparable totoleukemialeukemia andand lymphomalymphoma inin childrenchildren andand fourfourtimestimes asas frequentlyfrequently asas cysticcystic fibrosisfibrosis..


Overview of Immunodeficiency

Disorders.

The defect might beIn the level of

stem cellor

in any otherlevel of tree


Types of Primary immunodeficiencyTypes of Primary immunodeficiency

Types Types

1.1. BB--lymphocytelymphocyte disordersdisorders

2.2. TT--lymphocyte disorderslymphocyte disorders2.2. TT--lymphocyte disorderslymphocyte disorders

3.3. Combined BCombined B-- and Tand T--lymphocyte disorders lymphocyte disorders

(severe combined immunodeficiency disease or (severe combined immunodeficiency disease or

SCID) SCID)

4.4. Phagocyte DeficienciesPhagocyte Deficiencies5.5. Complement DeficienciesComplement Deficiencies


B Cell Immunodeficiencies:B Cell Immunodeficiencies:

�� Bruton’s (XBruton’s (X--linked) Agammaglobulinemialinked) Agammaglobulinemia

�� Autosomal Recessive HyperAutosomal Recessive Hyper--IgM SyndromeIgM Syndrome

�� B Cell Receptor DeficienciesB Cell Receptor Deficiencies�� B Cell Receptor DeficienciesB Cell Receptor Deficiencies

�� Common Variable Immunodeficiency Common Variable Immunodeficiency (CVID)(CVID)

�� Selective IgA DeficiencySelective IgA Deficiency

�� IgG Subclass DeficiencyIgG Subclass Deficiency


T Cell ImmunodeficienciesT Cell Immunodeficiencies

�� “Pure” T Cell Deficiencies:“Pure” T Cell Deficiencies:

�� DiGeorge syndrome DiGeorge syndrome –– Thymic aplasiaThymic aplasia

�� Chronic mucocutaneous candidiasisChronic mucocutaneous candidiasis�� Chronic mucocutaneous candidiasisChronic mucocutaneous candidiasis

�� Hyper IgM syndromeHyper IgM syndrome

�� InterleukinInterleukin--12 receptor deficiency12 receptor deficiency


Combined BCombined B--cell & T cell & T ––cell cell DeficienciesDeficiencies

�� Severe Combined Immunodeficiency (SCID)Severe Combined Immunodeficiency (SCID)

�� WiskottWiskott--Aldrich SyndromeAldrich Syndrome�� AtaxiaAtaxia--TelangiectasiaTelangiectasia�� AtaxiaAtaxia--TelangiectasiaTelangiectasia


Phagocyte Deficiencies:Phagocyte Deficiencies:

�� Chronic granulomatous disease (CGD)Chronic granulomatous disease (CGD)

�� Leukocyte adhesion deficiency (LAD I)Leukocyte adhesion deficiency (LAD I)

�� ChediakChediak--Higashi syndromeHigashi syndrome�� ChediakChediak--Higashi syndromeHigashi syndrome

�� ILIL--1212/IFN/IFNγγ pathwaypathway deficienciesdeficiencies

�� Chronic or cyclic neutropeniaChronic or cyclic neutropenia


Complement Deficiencies:Complement Deficiencies:

�� Hereditary AngioedemaHereditary Angioedema�� Due to deficiency of C1 esterase inhibitorDue to deficiency of C1 esterase inhibitor

�� Recurrent infectionsRecurrent infections�� Recurrent infectionsRecurrent infections�� Due to deficiency of C1, C3, C5 or C6,C7, C8Due to deficiency of C1, C3, C5 or C6,C7, C8

�� Autoimmune diseasesAutoimmune diseases�� Due to deficiency of C2 & C4 Due to deficiency of C2 & C4 -- SLESLE


T-cell.

Combined T& B cells(SCID).

SCID.

T-cell.

B-cell.

Phagocytes.

B-cell.

Phagocyte.


Immunodeficiency

Types of Secondary immunodeficiencyTypes of Secondary immunodeficiency

1.1. BB--lymphocytelymphocyte disordersdisorders

�� Common Varable HypogammaglobinaemiaCommon Varable Hypogammaglobinaemia

�� MalnutritionMalnutrition

2.2. TT--lymphocyte disorderslymphocyte disorders

�� Acquired Immune deficiency syndrome (AIDS)Acquired Immune deficiency syndrome (AIDS)

�� MeaslesMeasles

33. Complement Deficiencies. Complement Deficiencies�� Liver failureLiver failure�� MalnutritionMalnutrition

44. . Phagocyte deficiencyPhagocyte deficiency�� NeutropeniaNeutropenia�� Chronic fatigue syndrome (Chronic fatigue immune Chronic fatigue syndrome (Chronic fatigue immune

dysfunction syndrome)dysfunction syndrome)12/23/2013 20Prof. Muhammad Akram , Immunodeficiency

Patterns of Infection in Patterns of Infection in Immunodeficiencies:Immunodeficiencies:

� B Cell: recurrent sinopulmonary and GI infectionsbeginning after 3-4 months.

� T Cell and Severe Combined Immunodeficiency(SCID): opportunistic infections beginning early in(SCID): opportunistic infections beginning early ininfancy (thrush, diarrhea, failure to thrive); Milderforms termed Combined Immunodeficiency (CID)

� Phagocyte deficiencies:deep tissue infections withhigh-grade bacterial pathogens

� Complement: some infections, primarily withencapsulated organisms andNeisseriae12/23/2013 21Prof. Muhammad Akram , Immunodeficiency

Primary immunodeficiency: Primary immunodeficiency: IntroductionIntroduction

�� RecurrentRecurrent infectionsinfections areare generallygenerally thethe mostmostcommoncommon presentingpresenting featurefeature ofof primaryprimaryimmunodeficiencyimmunodeficiency diseasesdiseases inin childrenchildren..

�� CarefulCareful historyhistory andand physicalphysical examinationexamination cancangivegive thethe mostmost importantimportant cluesclues thatthat willwill directdirectyouryour investigationsinvestigations andand furtherfurther managementmanagement..


History:History: Age of onset: Age of onset:

�� Usually,Usually, thethe earlierearlier thethe onsetonset thethe moremore thethelikelihoodlikelihood ofof severesevere immunodeficiencyimmunodeficiency..

ForFor exampleexample::

** SCIDSCID (severe(severe combinedcombined immunodeficiency)immunodeficiency)** SCIDSCID (severe(severe combinedcombined immunodeficiency)immunodeficiency)usuallyusually presentspresents inin thethe firstfirst 44--55 monthsmonths ofoflifelife..

** AgammaglobulinemiaAgammaglobulinemia usuallyusually presentspresents atat77--99 monthsmonths ofof lifelife.. (?)(?)


History: Site of infectionHistory: Site of infection

�� InvolvementInvolvement ofof specificspecific sitessites isis moremore commoncommon withwithspecificspecific typestypes ofof immunodeficiencyimmunodeficiency thanthan othersothers..

ExamplesExamples::

-- RecurrentRecurrent GingivitisGingivitis andand skinskin abscessesabscesses:: PhagocyticPhagocytic-- RecurrentRecurrent GingivitisGingivitis andand skinskin abscessesabscesses:: PhagocyticPhagocyticdefectsdefects..

-- RecurrentRecurrent SinopulmonarySinopulmonary infectionsinfections:: BB--cellcell defectsdefects..

-- RecurrentRecurrent MeningitisMeningitis:: complementcomplement defectsdefects..

�� ChronicChronic diarrheadiarrhea shouldshould alwaysalways raiseraise thethe possibilitypossibility ofofimmunodeficiencyimmunodeficiency.. TheThe naturenature ofof thethe infectinginfectingorganismorganism maymay indicateindicate thethe typetype ofof immuneimmune defectdefect..


Type of the infecting organismType of the infecting organism

�� RecurrentRecurrent viral,viral, fungal,fungal, mycobacterialmycobacterial,, ororopportunisticopportunistic infectionsinfections suggestsuggest TT--cellcell defectsdefects..

�� RecurrentRecurrent infectionsinfections withwith invasiveinvasiveencapsulatedencapsulated bacteriabacteria ((ee..gg:: pneumococcuspneumococcus))encapsulatedencapsulated bacteriabacteria ((ee..gg:: pneumococcuspneumococcus))suggestsuggest BB--cellcell defectsdefects..

�� RecurrentRecurrent infectionsinfections withwith bacteriabacteria ofof lowlowvirulencevirulence ((ee..gg:: staph)staph) suggestsuggest aa neutrophilneutrophilabnormalityabnormality..

�� RecurrentRecurrent NisseriaNisseria infectionsinfections suggestsuggest terminalterminalcomplementcomplement defectdefect..


Family HistoryFamily History

�� Most immunodeficiency diseases are Most immunodeficiency diseases are inherited as either AR or XL.inherited as either AR or XL.

�� Examples of XExamples of X--linked immunodeficies:linked immunodeficies:

* Chronic Granulomatous disease * Chronic Granulomatous disease (gp91def.)(gp91def.)

* Wiskott* Wiskott--Aldrich Syndrome.Aldrich Syndrome.

* * γγcc

–– SCID.SCID.

* * btk btk –– agammaglobulinemia.agammaglobulinemia.12/23/2013 28Prof. Muhammad Akram , Immunodeficiency

History of Adverse Reactions to History of Adverse Reactions to VaccinesVaccines

�� LiveLive attenuatedattenuated vaccinesvaccines maymay causecausediseasedisease inin immunodeficientimmunodeficient patientspatients..ForFor example,example, OPVOPV cancan causecause paralysisparalysis ininForFor example,example, OPVOPV cancan causecause paralysisparalysis ininaa patientpatient withwith SCIDSCID ororhypogammaglobulinemiahypogammaglobulinemia ifif hehe receivesreceivesthethe vaccinevaccine oror exposedexposed toto itit throughthroughvaccinatedvaccinated childrenchildren whowho areare stillstillsheddingshedding thethe livelive attenuatedattenuated virusvirus inintheirtheir stoolstool..


Physical ExaminationPhysical Examination

�� Absent tonsils Absent tonsils -------------------------------- B cell defectB cell defect

�� Absent Absent lymphnodeslymphnodes ------------------ T/B cell defectT/B cell defect

�� LymphnodeLymphnode hyperplasia hyperplasia -------- CVID, CGDCVID, CGD�� LymphnodeLymphnode hyperplasia hyperplasia -------- CVID, CGDCVID, CGD

�� BCG scar BCG scar -------------------------------------------- T cell defectT cell defect

�� Delayed separation of the umbilical Delayed separation of the umbilical

cord cord -------------------------------- Leukocyte adhesion defectLeukocyte adhesion defect

�� Others ………Others ………


Assessment of the Assessment of the Immune SystemImmune System


STAGESTAGE--I:I: General nonGeneral non--specific specific evaluation.evaluation.

�� CBC, differential and blood film.CBC, differential and blood film.

�� Quantitative immunoglobulin levels.Quantitative immunoglobulin levels.

�� In newborns, CXR for thymic shadow.In newborns, CXR for thymic shadow.


Absolute lymphocyte count distribution in SCIDAbsolute lymphocyte count distribution in SCID––25 25 newborns with SCID and newborns with SCID and 11 11 healthy newborns at healthy newborns at birth evaluated at Duke University.birth evaluated at Duke University.


Photo Slide


STAGESTAGE--II: II: Evaluation based on the suspected Evaluation based on the suspected type of immune deficiencytype of immune deficiency

A.A. Innate immunity:Innate immunity:

�� Phagocytic function study (NBT, or oxidative Phagocytic function study (NBT, or oxidative burst).burst).

�� CHCH5050, C, C33, C, C44..

�� Flowcytometry for CDFlowcytometry for CD1818..

�� Chemotaxis.Chemotaxis.


NBT in normal neutrophils (D) and in neutrophils from NBT in normal neutrophils (D) and in neutrophils from a patient with CGD (E)a patient with CGD (E)


STAGESTAGE--II: II: Evaluation based on the Evaluation based on the suspected type of immune deficiencysuspected type of immune deficiency

B.B. Specific immunity:Specific immunity:

1.1. Humeral component:Humeral component:1.1. Humeral component:Humeral component:

1.1. Specific antibodies responses to tetanus, Specific antibodies responses to tetanus, hemophilus influenzae, and pneumococcus.hemophilus influenzae, and pneumococcus.

2.2. Isohemagglutinins.Isohemagglutinins.

3.3. IgG subclasses.IgG subclasses.


Complement deficiencies

» Liver failure– By alcoholic cirrhosis or chronic hepatitis B or

HCV can reduce synthesis of complement proteins by the liver.

acquired

proteins by the liver.

» Malnutrition– Severe malnutrition can reduce the supply of

amino acids and thereby reduce the synthesis of complement proteins by the liver

Chronic fatigue syndrome (Chronic fatigue immune dysfunction syndrome)

» Persistent debilitating fatigue lasts for 6 months and not relived by rests .

» Exact Cause is not known

acquired

» Abnormalities in various components of immune system have been reported like » Increased levels of cytotoxic T cells.» Loss of DTH

Case Study-1

l An eight-month-old boy was presented to a pediatrician with fever, aseptic meningitis, left ocular and facial palsy, ocular and facial palsy, and flaccid paralysis of the lower extremities.


Case Study-1 Cont…

l Two months earlier, the child had received an oral poliovirus immunization. A presumptive diagnosis of post-infectious diagnosis of post-infectious polyneuritis was made, but, because of a serum IgG concentration of 9 mg/dl (extremely low), the infant was referred to a pediatric allergist-immunologist. Mature B-cells were absent from the circulation. T-cell immunity was normal. The spinal fluid

Case Study-1 cont…

l Based upon the absence of mature B-cells in the circulation and a state of panhypogammaglobulinemia, a of panhypogammaglobulinemia, a diagnosis of Agammaglobulinemia was made.

l The child has done well on monthly intravenous immunoglobulin replacement therapy, but is hemiplegic.

� Individuals with a primary immunodeficiency should NOT be given live virus vaccines!

Case Study-2

l A four-month-old infant was noted to have persistent oral thrush persistent oral thrush due to Candida albicans.



l A consulting immunologist ordered a barium swallow x-ray, and ulcer craters due to this same organism this same organism were observed throughout the esophagus .



l The child’s serum IgG was normal (maternal IgG) but the IgA and IgM were virtually absent. Few mature were virtually absent. Few mature T-cells could be detected by examination of surface antigen phenotypes by flow cytometry, and there was no response of peripheral blood lymphocytes to stimulation by mitogens.


l A diagnosis of SCID (Severe Combined Immunodeficiency) was made based on the very low T-cell made based on the very low T-cell number and their suppressed function.

l The child survived with a bone marrow transplantation from his HLA-compatible sister.

IVIG in PID

l IVIG (IntraVenousImmunoGlobulin) is purified human IgG prepared from pooled plasma of thousands of donors.donors.

l Mechanism of action: It is estimated that an IVIG preparation contains ten million antibody specificities. This mechanism leads to:» Neutralization of viruses.» Opsonization of bacteria.

IVIG in PID

l Indications:» Agammaglobulinemia.» CVID.» CID.

l Dosage: It is recommended to maintain a trough IgG level of > 500 mg/dl. This can be achieved in most patients by the administration of about 400-500 mg/kg q 3-4 wks intervals

l Monitoring: IgG trough level and liver enzymes q3-6 months. Clinical evaluation q 6 months.

IVIG in PID

l Adverse Effects: non-specific generalized reactions are usually reported in 1-10% of patients, mostly mild.

» Mild: flushing, headache, back pain, chills, myalgia, nausea. Intervention: slow infusion and treat nausea. Intervention: slow infusion and treat symptoms.

» Moderate: urticaria, bronchospasm, vomiting. Intervention: stop infusion and treat symptoms.

» Severe: anaphylaxis/anaphylactoid. Intervention: stop infusion and resuscitate. Very rare. ? IgG or IgE anti IgA antibodies.

l Organ-Specific and idiosyncratic reactions are rare.

l Risk of disease transmission.

Prof. Md. Prof. Md. AkramAkramHossain April April 20122012

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