IMMUNE COMPROMISED HOST Dr. M. A. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin

An immunocompromised host is a patient who does not have the ability to respond normally to an infection due to an impaired or weakened immune system. This inability to fight infection can be caused by a number of conditions including illness and disease (e.g., diabetes, HIV), malnutrition, and drugs. Immunocompromised Host

There are two types of immunodeficiency disorders: Primary: These disorders are usually present at birth and are usually hereditary. They typically become evident during infancy or childhood. There are more than 100 primary immunodeficiency disorders. All are relatively rare. Secondary: These disorders generally develop later in life and often result from use of certain drugs or from another disorder, such as diabetes or human immunodeficiency virus (HIV) infection. They are more common than primary immunodeficiency disorders. Some immunodeficiency disorders shorten life span. Others persist throughout life but do not affect life span, and a few resolve with or without treatment. Immune Compromised Host

Some Primary Immunodeficiency Disorders Immune System That Is AffectedDisorder Humoral immunity: Problems with B cells (lymphocytes) and their production of antibodies Common variable immunodeficiency Deficiency of a specific antibody (immunoglobulin), such as IgA deficiency Transient hypogammaglobulinemia of infancy X-linked agammaglobulinemia Cellular immunity: Problems with T cells (lymphocytes) Chronic mucocutaneous candidiasis DiGeorge syndrome X-linked lymphoproliferative syndrome Combined humoral and cellular immunity: Problems with B and T cells Ataxia-telangiectasia Hyperimmunoglobulinemia E syndrome Severe combined immunodeficiency Wiskott-Aldrich syndrome Phagocytes: Problems with the movement or killing activity of these cells Chronic granulomatous disease Chédiak-Higashi syndrome (rare) Cyclic neutropenia Complement proteins: Deficiency of complement proteins Complement component 1 (C1) inhibitor deficiency (hereditary angioedema) C3 deficiency C5, C6, C7, C8, and/or C9 deficiency

Causes of Secondary Immunodeficiency: CategoryExamples GIHepatic insufficiency, hepatitis, intestinal lymphangiectasia, protein- losing enteropathy HematologicAplastic anemia, cancers (eg, chronic lymphocytic leukemia, multiple myeloma, Hodgkin lymphoma), graft-vs-host disease, sickle cell disease, splenectomy IatrogenicCertain drugs, such as chemotherapeutic drugs, immunosuppressants, corticosteroids, radiation therapy; splenectomy InfectiousViral infections (eg, cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella-zoster virus), bacterial infections, rare bacterial infections with superantigens (antigens that can activate large numbers of T cells, resulting in massive cytokine production, most notably fromStaphylococcus aureus), mycobacterial infections PhysiologicPhysiologic immunodeficiency in infants due to immaturity of the immune system, pregnancy RenalNephrotic syndrome, renal insufficiency, uremia RheumatologicRA, SLE OtherBurns, cancers, chromosomal abnormalities (eg, Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis

ACQUIRED IMMUNOSUPPRESSION  Immunosuppressive Therapy  Microbial Infection  Malignancy  Disorders of biochemical homeostasis  Autoimmune diseases  Trauma

Immunosuppressants are used to suppress the immune system. Some are used to prevent rejection of a transplanted organ or tissue. Immunosuppressants also suppress the body’s ability to fight infections and perhaps to destroy cancer cells. Chemotherapy and radiation therapy can also suppress the immune system, leading to immunodeficiency disorders Chemotherapy for malignancy- Neutropenia Treatment of autoimmune disorders Bone marrow transplant- ablation, graft vs. host disease Solid organ transplant: induction, maintenance immunosuppression, treatment of rejection ACQUIRED IMMUNOSUPPRESSION: Immunosuppressive Therapy

Disorders of biochemical homeostasis  Diabetes Mellitus  ESRD/Hemodialysis  Cirrhosis/Hepatic insufficiency  Malnutrition  Pregnancy  Stress  Functional splenia  Splenectomy  Aging Autoimmune diseases  Systemic Lupus Erythematosus  Rheumatoid Arthritis ACQUIRED IMMUNOSUPPRESSION

Immunodeficiency manifests as recurrent infections and those infections that are: Severe Complicated In multiple locations Resistant to treatment Caused by unusual organisms Present in family members Initially, URT and LRT infections (eg, sinusitis, bronchitis, pneumonia) and gastroenteritis, Patient presenting with serious bacterial infections (eg, meningitis, sepsis). Diarrhea caused by unusual viruses (adenovirus) or fungi (Cryptosporidium sp). Skin lesions (eg, eczema, warts, abscesses, pyoderma, alopecia), oral or esophageal thrush, oral ulcers, and periodontitis. Approach to the Patient With Suspected Immunodeficiency:

FindingImmunodeficiency 1.Recurrent Streptococcus pneumoniae and Haemophilus influenzae infections Ig, C2, or IRAK-4 deficiency 2.Recurrent Giardia intestinalis (lamblia) infection Antibody deficiency syndromes 3.Familial clustering of autoimmune disorders (eg, SLE, RA, pernicious anemia) Common variable immunodeficiency or selective IgA deficiency 4.Pneumocystis infections, cryptosporidiosis, or toxoplasmosis T-cell disorders or occasionally Ig deficiency 5.Viral, fungal, or mycobacterial (opportunistic) infections T-cell disorders 6.Clinical infection due to live- attenuated vaccines (eg, varicella, polio, BCG) T-cell disorders Some Clues in Patient History to Type of Immunodeficiency

FindingImmunodeficiency 7.Graft-vs-host disease due to blood transfusions T-cell disorders 8.Staphylococcal infections, infections with gram-negative organisms(eg,Serratia or Klebsiella sp), or fungal infections (eg, aspergillosis) Phagocytic cell defects or hyper-IgE syndrome 9.Skin infectionsNeutrophil defect or Ig deficiency 10.Recurrent gingivitisNeutrophil defect 11.Recurrent neisserial infectionsCertain complement deficiencies 12.Recurrent sepsisCertain complement deficiencies or IgG deficiency Some Clues in Patient History to Type of Immunodeficiency

Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders < 6 mo Findings*Disorder Diarrhea, failure to thrive Life-threatening infections (eg, pneumonia, sepsis, meningitis) Severe combined immunodeficiency Maculopapular rash, splenomegaly Severe combined immunodeficiency when accompanied by graft-vs-host disease (eg, caused by transplacentally transferred T cells) Hypocalcemic tetany, a congenital heart disorder, unusual facies with low-set ears, developmental delay DiGeorge syndrome Oculocutaneous albinism, neurologic changes, lymphadenopathy Chédiak-Higashi syndrome Maculopapular rash, splenomegaly Severe combined immunodeficiency when accompanied by graft-vs-host disease (eg, caused by transplacentally transferred T cells) Hypocalcemic tetany, a congenital heart disorder, unusual facies with low-set ears, developmental delay DiGeorge syndrome

Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders 6/12 to 5 yr Findings*Disorder Oculocutaneous albinism, neurologic changes, lymphadenopathy Chédiak-Higashi syndrome Paralysis after oral polio immunizationX-linked agammaglobulinemia Persistent oral candidiasis, nail dystrophy, endocrine disorders (eg, hypoparathyroidism, Addison disease) Chronic mucocutaneous candidiasis > 5 yrAtaxia, recurrent sinopulmonary infections, neurologic deterioration, telangiectasias Ataxia-telangiectasia Recurrent sinopulmonary infections, malabsorption, splenomegaly, autoimmune disorders, giardiasis, lymphoid interstitial pneumonia, bronchiectasis Common variable immunodeficiency Progressive dermatomyositis with chronic echovirus encephalitis X-linked agammaglobulinemia

Primary Immunodeficiency Disorders DisorderInheritanceClinical Findings Humoral immunity deficiencies Common variable immunodeficiencyVariable Recurrent sinopulmonary infections, autoimmune disorders (eg, ITP, AIHA), malabsorption, granulomatous interstitial lung disease, nodular lymphoid hyperplasia of GI tract, bronchiectasis, lymphoid interstitial pneumonia, splenomegaly; in 10%, gastric carcinoma and lymphoma Usually diagnosed in aged 20–40 yr Selective IgA deficiencyUnknown Most often asymptomatic Recurrent sinopulmonary infections, diarrhea, allergies (including anaphylactic transfusion reactions [rare]), autoimmune disorders (eg, celiac disease, inflammatory bowel disease, SLE, chronic active hepatitis) Hyper-IgM syndrome with CD40 ligand deficiency X-linked Similar to X-linked agammaglobulinemia (eg, recurrent pyogenic bacterial sinopulmonary infections) but greater frequency of Pneumocystis jirovecii pneumonia, cryptosporidiosis, severe neutropenia, and lymphoid hypoplasia

Primary Immunodeficiency Disorders DisorderInheritanceClinical Findings Cellular immunity deficiencies Chronic mucocutaneous candidiasis Autosomal dominant or recessive Persistent or recurrent candidal infections, onychomycosis, autosomal recessive autoimmune polyendocrinopathy–candidosis-ectodermal dystrophy (with hypoparathyroidism and adrenal insufficiency) DiGeorge syndromeAutosomal Unusual facies with low-set ears, a congenital heart disorder (eg, aortic arch abnormalities), thymic hypoplasia or aplasia, hypoparathyroidism with hypocalcemic tetany, recurrent infections, developmental delay X-linked lympho- proliferative syndrome X-linked Asymptomatic until onset of Epstein-Barr virus infection, then fulminant or fatal infectious mononucleosis with liver failure, B-cell lymphomas, splenomegaly, aplastic anemia

Primary Immunodeficiency Disorders DisorderInheritanceClinical Findings Combined humoral and cellular immunity deficiencies Ataxia- telangiectasia Autosomal recessive Ataxia, telangiectasias, recurrent sinopulmonary infections, endocrine abnormalities (eg, gonadal dysgenesis, testicular atrophy, diabetes mellitus), increased risk of cancer Wiskott-Aldrich syndrome X-linked recessive Typically, pyogenic and opportunistic infections, eczema, thrombocytopenia Possibly GI bleeding (eg, bloody diarrhea), recurrent respiratory infections, cancer (in 10% of patients > 10 yr), varicella-zoster virus infection, herpesvirus infection Severe combined immunodeficiency Autosomal recessive or X-linked Oral candidiasis, P. jirovecii pneumonia, diarrhea before 6 mo, failure to thrive, graft vs host disease, absent thymic shadow, lymphopenia, bone abnormalities (in ADA deficiency), exfoliative dermatitis as part of Omenn syndrome

Primary Immunodeficiency Disorders DisorderInheritanceClinical Findings Phagocytic cell defects Chédiak-Higashi syndrome Autosomal recessive Oculocutaneous albinism, recurrent infections, fever, jaundice, hepatosplenomegaly, lymphadenopathy, neurologic changes, pancytopenia, bleeding diathesis Chronic granulomatous disease X-linked or autosomal recessive Granulomatous lesions in the lungs, liver, lymph nodes, and GI and GU tract (causing obstruction); lymphadenitis; hepatosplenomegaly; skin, lymph node, lung, liver, and perianal abscesses; osteomyelitis; pneumonia; staphylococcal, gram-negative, and aspergillus infections Leukocyte adhesion deficiency Autosomal recessive Soft-tissue infections, periodontitis, poor wound healing, delayed umbilical cord detachment, leukocytosis, no formation of pus Developmental delay (type 2). Cyclic neutropeniaAutosomal dominant Pyogenic bacterial infections during recurrent episodes of neutropenia (eg, every 14 to 35 days)

Primary Immunodeficiency Disorders DisorderInheritanceClinical Findings Complement deficiencies in the classical pathway C1 Autosomal recessive SLE C2 Autosomal recessive SLE, recurrent pyogenic infections with encapsulated bacteria (especially pneumococcal) that start in early childhood, other autoimmune disorders (eg, glomerulonephritis, polymyositis, vasculitis, Henoch-Schönlein purpura, Hodgkin lymphoma) C3 Autosomal recessive Recurrent pyogenic infections with encapsulated bacteria that start at birth, glomerulonephritis, other antigen-antibody complex disorders, sepsis C4 Autosomal recessive SLE, other autoimmune disorders (eg, IgA nephropathy, progressive systemic sclerosis, Henoch- Schönlein purpura, type 1 diabetes mellitus, autoimmune hepatitis)

TypeInitial testsAdditional tests Humoral immunity deficiency  IgG, IgM, IgA, and IgE levels  Isohemagglutinin titers  Antibody response to vaccine antigens (e.g., Haemophilus influenzae type b, tetanus, diphtheria,)  B-cell phenotyping and count using flow cytometry and monoclonal antibodies to B cells  Flow cytometry for CD40 and CD40 ligand  Evaluation for mutations in genes that encode BTK and NEMO  Sweat test Cellular immunity deficiency  Absolute lymphocyte count  Delayed hypersensitivity skin tests  HIV testing  Chest x-ray for size of thymus in infants only  T-cell phenotyping and flow cytometry and monoclonal antibodies to T cells and subsets  T-cell proliferative response to mitogens  TREC test (a genetic test for abnormal T cells or a low T-cell count due to SCID or other disorders) Initial and Additional Laboratory Tests for Immunodeficiency

TypeInitial testsAdditional tests Phagocytic cell defects Phagocytic cell count and morphology Flow cytometric oxidative burst measurement using dihydrorhodamine 123 (DHR) or nitroblue tetrazolium (NBT) Flow cytometry for CD18 and CD15 Neutrophil chemotaxis Complement deficiency C3 level C4 level CH50 activity (for total activity of the classical pathway) and AH50 activity (for total activity of the alternate complement pathways) C1 inhibitor level and function Specific component assays BTK = Bruton tyrosine kinase; C = complement; CH = hemolytic complement; NEMO = nuclear factor–kappa-B essential modulator; SCID = severe combined immunodeficiency; TREC = T-cell receptor excision circle Initial and Additional Laboratory Tests for Immunodeficiency

 There is no cure patients who have agammaglobulinemia  The defective genes cannot be repaired or replaced.  Agammaglobulinemia can be given some of the antibodies that they are lacking.  The antibodies are supplied in the form of immunoglobulins (or gamma globulins) and can be given directly into the blood stream (intravenously) or under the skin (subcutaneously). Treatment of X-Linked & Agammaglobulinemia

 Immunoglobulin consists mostly of IgG and contains all the important antibodies present in the normal population. Treatment Common Variable Immune Deficiency  The treatment of CVID is similar to that of other disorders with low levels of serum immunoglobulins.  In the absence of a significant T-lymphocyte defect or organ damage, immunoglobulin replacement therapy almost always brings improvement of symptoms.

 Immunoglobulin therapy should be given to all infants with SCID.  Although immunoglobulin therapy will not restore the function of the deficient T- cells, it does replace the missing antibodies resulting from the B-cell defect and is of benefit.  The most successful therapy for SCID is immune reconstitution via stem cell transplantation.  Stem cells for the transplant can be obtained from the bone marrow, peripheral blood or even from cord blood from related or unrelated donors that at least partially match the tissue type of the patient. Specific Therapy of Severe Combined Immune Deficiency

 The usual treatment for these defects is antibiotic therapy to treat acute infection.  Prophylactic antibiotic therapy is also used.  Some also prescribe immunoglobulin therapy as infection prophylaxis.  New treatments of innate immune system defects have included new TLR- based therapies (Toll-like receptors)  There are several new therapies in use or development that utilize emerging knowledge of TLR biology. Treatment of Innate Immune Defects

 Patient should be immunized against the likely candidate microbes.  There are no specific treatments for complement deficiencies.  Infection prevention and appropriate treatment of infections (usually with antibiotics).  Prophylactic antibiotics can be used if the patient experiences repeated infections.  Most of these patients eventually make antibodies against the offending bacteria and do not get sick as often. Treatment of Complement Deficiencies

 Early diagnosis of infection and prompt, aggressive use of appropriate antibiotics is the best way to treat CGD infections.  Initial therapy with antibiotics aimed at the usual suspects makes sense while waiting for results of cultures, but it is important to try to identify the specific infection and not just guess all the way along.  Intravenous antibiotics may be needed for serious CGD infections. Phagocyte transfusions are sometimes used when an infection is especially life threatening. Treatment of Chronic Granulomatous Disease