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

2. 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 (eg, diabetes, HIV), malnutrition, and drugs. Immunocompromised Host

3.  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 Primary immunodeficiency

4.  Genetic immunodeficiencies.  In these disorders both T lymphocytes and often B lymphocytes, regulators of adaptive immunity, are dysfunctional or decreased in number. The main members are various types of severe combined immunodeficiency (SCID).  T-/B+ SCID (T cells predominantly absent)  T-/B- SCID (both T and B cells absent) Combined T and B–cell immunodeficiencies

5.  Agammaglobulinemia: X-Linked and Autosomal Recessive  Common Variable Immune Deficiency  IgG Subclass Deficiency  Selective IgA Deficiency  Specific Antibody Deficiency  Transient Hypogammaglobulinemia of Infancy  Other Antibody Deficiency Disorders Antibody Deficiencies

6.  Severe Combined Immune Deficiency and Combined Immune Deficiency  Wiskott-Aldrich Syndrome  Hyper IgM Syndromes  Ataxia Telangiectasia  DiGeorge Syndrome  Other Primary Cellular Immunodeficiencies Cellular Immunodeficiencies

7. Innate Immune Disorders  Chronic Granulomatous Disease and Other Phagocytic Cell Disorders  Hyper IgE Syndrome  Complement Deficiencies  Innate Immune Defects  NEMO Deficiency Syndrome

8. Diseases of immune dysregulation In certain conditions, the regulation rather than the intrinsic activity of parts of the immune system is the predominant problem.  Immunodeficiency with hypopigmentation or albinism: Chediak-Higashi syndrome  Familial hemophagocytic lymphohistiocytosis: perforin deficiency  X-linked lymphoproliferative syndrome

9. Syndromes with autoimmunity : (a)Autoimmune lymphoproliferative syndrome: type 1a (CD95 defects), type 1b (Fas ligand defects), type 2a (CASP10 defects), type 2b (CASP8 defects) (b) APECED (autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy) (c) IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) (d) CD25 deficiency

10. Examples of primary immune deficiency disorders n Chronic Granulomatous disease CGD occurs when white blood cells called phagocytes are unable to kill certain bacteria and fungi, and mutations in one of five different genes may cause this disease. People with CGD have increased susceptibility to infections Autoimmune lymphoproliferative syndrome : In ALPS, unusually high numbers of white blood cells called lymphocytes accumulate in the lymph nodes, liver, and spleen, which can lead to enlargement of these organs. ALPS can cause numerous autoimmune problems, including low levels of red blood cells, clot-forming platelets, and infection-fighting white blood cells called neutrophils.

11. Examples of primary immune deficiency disorders n Common variable immune deficiency (CVID) is caused by a variety of different genetic abnormalities that result in a defect in the capability of immune cells to produce normal amounts of antibodies. People with CVID experience frequent bacterial or viral infections of the upper airway, sinuses, and lungs. Hyper-Immunoglobulin M (Hyper-IgM) SyndromesHyper-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.

12. Examples of primary immune deficiency disorders n Wiskott–Aldrich syndrome (WAS) is a rare X- linked recessive disease characterized by eczema, thrombocytope, immune deficiency, and bloody diarrhea. It is also sometimes called the eczema- thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954 The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene. Severe Combined Immunodeficiency (SCID) SCID is a group of rare, life-threatening disorders caused by mutations in different genes involved in the development and function of infection-fighting T and B cells. Infants with SCID appear healthy at birth but are highly susceptible to severe infections.

13. Examples of primary immune deficiency disorders n NEMO Deficiency Syndrome The NEMO deficiency syndrome is a complex disease caused by genetic mutations in the X- linked NEMO gene (also known as IKK gamma or IKKG). The most common symptoms are skin disease, ectodermal dysplasia and susceptibility to certain bacterial infections that can be severe and affect virtually any part of the body. Complement Deficiencies Complement is a group of serum proteins that are critically important in our defense against infection. There are deficiencies of each of the individual components of complement. Patients with complement deficiencies encounter clinical problems that depend on the role of the specific complement protein in normal function. Clinical indications for possible complement deficiencies include recurrent mild or serious bacterial infections, autoimmune disease, or episodes of angioedema.

14. Examples of primary immune deficiency disorders n HIV Infection: Human immunodeficiency virus (HIV) is a blood- borne virus typically transmitted via sexual intercourse, shared intravenous drug paraphernalia, and mother-to-child transmission (MTCT), which can occur during the birth process or during breastfeeding. HIV disease is caused by infection with HIV-1 or HIV-2, which are retroviruses in the Retroviridae family, Lentivirus genus. The patient with HIV may present with signs and symptoms of any of the stages of HIV infection. No physical findings are specific to HIV infection; the physical findings are those of the presenting infection or illness. Rate of progression to AIDS and death is related to the viral load; patients with viral loads greater than 30,000/μL are 18.5 times more likely to die of AIDS than those with undetectable viral loads. Electron microscopy of human immunodeficiency virus (HIV)–1 virions.

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

16. 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

17. Diabetes Mellitus ESRD/Hemodialysis Cirrhosis/Hepatic insufficiency Malnutrition ACQUIRED IMMUNOSUPPRESSION: Disorders of biochemical homeostasis

18. ACQUIRED IMMUNOSUPPRESSION: Autoimmune diseases Systemic Lupus Erythematosus Rheumatoid Arthritis

19. ACQUIRED IMMUNOSUPPRESSION Pregnancy Stress Functional splenia Splenectomy Aging

20. Immune deficitCommon causesOrganisms Neutrophil disorders Neutropenia Chemotherapy Leukemia AIDS Felty's syndrome Viral infections Gram-negative bacilli (enteric and nonenteric) Staphylococcus aureus Coagulase-negative Staphylococcus Streptococci Fungi (Aspergillus spp, Candida spp) Neutrophil chemotaxis Diabetes mellitus Cirrhosis, alcoholism Uremia Hodgkin's disease Trauma, burns Lazy leukocyte syndrome S. aureus Candida spp Streptococci Mucorales Organisms associated with infection in individuals with various immune deficits

21. Immune deficit Common causesOrganisms Neutrophil killing Chronic granulomatous disease Myeloperoxidase deficiency S. aureus Escherichia coli T lymphocyte deficiency HIV/AIDS Lymphoma Chemotherapy Transplantation Glucocorticoids Viral infection T cell-depleting antibodies Viruses (latent herpesviruses, papillomaviruses, respiratory viruses) Intracellular bacteria (Legionella spp, mycobacteria) Nocardia spp Fungi (Pneumocystis jirovecii, Cryptococcus spp, Histoplasma capsulatum) Parasites (Strongyloides spp, Toxoplasma spp Organisms associated with infection in individuals with various immune deficits

22. Immune deficit Common causesOrganisms B lymphocyte deficiency Multiple myeloma Acute leukemia Burns Congenital Drugs (anti-B-cell therapies, azathioprine, mycophenylate) Enteropathies Plasmapheresis Glucocorticoids Encapsulated bacteria (Pneumococcus, Haemophilus influenzae, Neisseria meningitides) Salmonella spp Campylobacter Giardia Spleen Splenectomy Sickle cell disease Cirrhosis Encapsulated bacteria (Pneumococcus, H. influenzae, N. meningitidis) Capnocytophaga ComplementCongenital/acquired deficiencies S. aureus Encapsulated bacteria (Pneumococcus, H. influenzae, N. meningitidis) Organisms associated with infection in individuals with various immune deficits

23. Nocardia infection Lung biopsy demonstrated dual infection with cytomegalovirus and Legionella pneumophila. Opportunistic infections in immunocompromized host

24. TB Brain in immunocompromized patient

25. Treatment of X-Linked and AR 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.

26. 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 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. There are several new therapies in use or development that utilize emerging knowledge of TLR biology.

27. 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.

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