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

2. 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.

3. 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

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

5. 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

6. 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

7. 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

8. 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)

9. 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

10. 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

11. 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

12. 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.

13. 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. 

14. 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

15. 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

16. 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.

17. 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

18. 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)

19. 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

20. 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).

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.