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

Immunocompromised Host 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.

Primary immunodeficiency Combined T and B–cell immunodeficiencies Predominantly antibody deficiencies Other well defined immunodeficiency syndrome Diseases of immune dysregulation Congenital defects of phagocyte number, function, or both Defects in innate immunity Autoinflammatory disorder Complement deficiencies

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

ACQUIRED IMMUNOSUPPRESSION: Immunosuppressive Therapy 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 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

DISORDERS of T CELLS DiGeorge's syndrome: It the most understood T-cell immunodeficienc y Also known as congenital thymic aplasia/hypoplasia Associated with hypoparathyroidism, congenital heart disease, fish shaped mouth. Defects results from abnormal development of fetus during 6th-10th week of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed

T cell deficiencies with variable degrees of B cell deficiency (Ataxia-telangiectasia) A-T affects many parts of the body: It impairs certain areas of the brain including the cerebellum, causing difficulty with movement and coordination. It weakens the immune system, causing a predisposition to infection. It prevents repair of broken DNA, increasing the risk of cancer. Ataxia is apparent early but worsens in school to pre-teen years Oculomotor apraxia Involuntary movements Telangiectasia (dilated blood vessels) Problems with infections, especially of the ears, sinuses and lungs Increased incidence of cancer primarily, lymphomas and leukemias)

Wiskott-Aldrich syndrome: The disease occurs only in males. The first signs of WAS are usually petechiae and bruising, resulting from a low platelet count. Spontaneous nose bleeds and bloody diarrhea are common. Eczema develops within the first month of life. Recurrent bacterial infections develop by three months. Enlargement of the spleen is not an uncommon finding. The majority of WAS children develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients. Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated

MHC DEFICIENCY (Bare lymphocyte syndrome): Bare lymphocyte syndrome is a condition caused by mutations in certain genes of the major histocompatibility complex or involved with the processing and presentation of MHC molecules. It is a form of severe combined immunodeficiency Patients have fewer CD4 cells and are infection prone !. There are also individuals who have a defect in their transport associated protein (TAP) gene and hence do not express the class-I MHC molecules and consequently are deficient in CD8+ T cells. Diarrhea can be among the associated conditions Though BLSII is an attractive candidate for gene therapy, bone marrow transplant is currently the only treatment

Defects of the phagocytic system Defects of phagocytic cells (numbers and/or functions) can lead to increased susceptibility to a variety of infections. Cyclic neutropenia: It is marked by low numbers of circulating neutrophil approximately every three weeks. The neutropenia lasts about a week during which the patients are susceptible to infection. The defect appears to be due to poor regulation of neutrophil production. The diagnosis of cyclic neutropenia is established by documentation of an absolute neutrophil count <200/microL on at least three to five consecutive days per cycle of each of three regularly spaced cycles and a nadir <200/microL

Chronic granulomatous disease (CGD): Chronic granulomatous disease is the name for a genetically heterogeneous group of immunodeficiencies. The core defect is a failure of phagocytic cells to kill organisms that they have engulfed because of defects in a system of enzymes that produce free radicals and other toxic small molecules. CGD is characterized by marked lymphadenopathy, hepato splenomegaly and chronic draining lymph nodes. In majority of patients with CGD, the deficiency is due to a defect in NADPH oxidase that participate in phagocytic respiratory burst.

Leukocyte Adhesion Deficiency: Leukocyte adhesion deficiency (LAD), is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also known as LAD-1/variant. In LAD3, the immune defects are supplemented by a Glanzmann thrombasthenia-like bleeding tendency Leukocytes lack the complement receptor CR3 due to a defect in CD11 or CD18 peptides and consequently they cannot respond to C3b opsonin. These molecules are involved in diapedesis and hence defective neutrophils cannot respond effectively to chemotactic signals. 

Chediak-Higashi syndrome: Is a rare autosomal recessive disorder that arises from a mutation of a lysosomal trafficking regulator protein, which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism and peripheral neuropathy. Neuropathy often begins in the teenage years and becomes the most prominent problem. Infections in CHS patients tend to be very serious and even life-threatening; few patients with this condition live to adulthood. Most children with Chédiak–Higashi syndrome ultimately reach a stage known as the accelerated phase, also known as the lymphoma-like-syndrome

Common variable immune deficiency (CVID) CVID is a clinically heterogeneous disease. Its main features are hypogammaglobulinemia and recurrent infections. Hypogammaglobulinemia manifests as a significant decrease in the levels of IgG antibodies, usually alongside IgA antibodies; IgM antibody levels are also decreased in about 50% of patients  Hyper-Immunoglobulin M (Hyper-IgM) Syndromes Hyper-IgM syndromes are conditions in which the immune system fails to produce normal immunoglobulin A (IgA), IgG, and IgE antibodies but can produce normal or elevated IgM. Infants with a hyper-IgM syndrome usually develop severe respiratory infections within the first year of life. n

Disorders of complement system Deficiencies in late components (C3-C9) predispose patients to recurrent infections, especially pneumococcal and H. influenzae (with C3 deficiency) and Neisserial infections The management of complement-deficient patients involves vigilance for early signs of infection and vaccination against the organisms to which the patient is susceptible The main clinical manifestations are recurrent infections with encapsulated bacteria, systemic SLE, or both. Deficiencies in the early components of the classical complement pathway (i.e., C1q, C1r, C1s, C4, and C2) predispose patients to autoimmune disorders, particularly SLE. Recurrent infections may also be seen.

SEVERE COMBINED IMMUNODEFICENCY In about 50% of SCID patients the immunodeficiency is x-linked whereas in the other half the deficiency is autosomal. They are both characterized by an absence of T cell and B cell immunity and absence (or very low numbers) of circulating T and B lymphocytes. SCID is the most severe form of primary immunodeficiencies, and there are now at least nine different known genes in which mutations lead to a form of SCID SCID patients are usually affected by severe bacterial, viral, or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea, and failure to thrive

Initial and Additional Laboratory Tests for Immunodeficiency Type Initial tests Additional 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 Type Initial tests Additional 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

Treatment of X-Linked & Agammaglobulinemia 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 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 consists mostly of IgG and contains all the important antibodies present in the normal population.

Specific Therapy of Severe Combined Immune Deficiency 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.

Treatment of Innate Immune Defects 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. 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.

Treatment of Complement Deficiencies 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 Chronic Granulomatous Disease 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.