Download Non HIV/AIDS Immunodeficiency Syndromes

Primary
Immunodeficiency
Syndromes
Welcome to the module on Primary
Immunodeficiency Syndromes
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2
Case 1
63 year old man presents with failure to thrive, dysphagia, diarrhea,
cough, and SOB
He was in his USOH until 6 weeks prior, when he developed watery
diarrhea 4-7x/day
Cough and SOB in the last few days
 Saw his PCP, negative C dif, tried Cipro/azithro, immodium, and
probiotics, without improvement
 Now he is presenting to the ED febrile, ill-appearing, and profoundly
SOB
Past Medical History
Thymoma:
 Initially diagnosed in late 1980’s, when he developed Myasthenia
Gravis (ptosis). He initially had local disease treated w/ resection
1990’s: local recurrence with lung invasion (stage 3 disease),
received surgery, chemotherapy, radiation
2000’s: residual disease burden remains, but fairly inactive and he
was followed by Hematology-Oncology until 12/2013 (his Dr retired)
CT scan 2016
Assessment of the mediastinum reveals para-aortic soft tissue area, 38 x 25
mm, slightly bigger than on the prior study (34 x 18 mm when compared to 22
December 2011 the changes in more pronounced (29 x 18 mm and)
Multiple pleural nodularity as are present,
involving the entire left pleura
Upper Endoscopy
Colonoscopy
 Also found to have giardia via stool DFA, and Salmonella bacteremia
 HIV (3rd gen assay and viral load) negative
 WBC 4.2, with normal differential (no neutropenia or lymphopenia)
Infectious Disease consult
o “Please help us sort out treatment plan”
o “…and figure out if he is immunosuppressed, and if so why”
o “…and what prophylaxis he should be on”
o “…Thanks!”
Overview of
Immunodeficiency Syndromes
o Antibody deficiencies and/or defects: 65%
o Combined antibody and cellular deficiencies: 15%
o Disorders of phagocytes: 10%
o Isolated cellular defects (IE: T-cell problems): 5%
o Disorders of the complement system: 5%
o Other disorders of innate immunity: <1%
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Encapsulated bacterial
infection
“Other” bacterial infection
Disorders of cellmediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Recurrent Neisseria
infections
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Disorders of cellmediated immunity
Disorders of phagocytosis
Disorders of complement
Encapsulated bacterial
infection
Recurrent and severe
sinopulmonary infections with
encapsulated bacterial strains
(Streptococcus pneumoniae,
Haemophilus influenzae)
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Encapsulated bacterial
infection
“Other” bacterial infection
Disorders of cellmediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Recurrent Neisseria
infections
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Severe viral and/or bacterial illnesses or
opportunistic infections*
“Other” bacterial infection
Disorders of cellmediated immunity
Viral infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Encapsulated bacterial
infection
“Other” bacterial infection
Disorders of cellmediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Recurrent Neisseria
infections
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
“Other” bacterial infection
Disorders of cellmediated immunity
Fungal infection
Disorders of phagocytosis
Disorders of complement
Recurrent and severe fungal (Candida
and Aspergillus) and bacterial
(Staphylococcus aureus, Pseudomonas
aeruginosa, Nocardia asteroides,
Salmonella typhi) infections in the skin
and lung
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Encapsulated bacterial
infection
“Other” bacterial infection
Disorders of cellmediated immunity
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Recurrent Neisseria
infections
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Disorders of cellmediated immunity
• Recurrent Neisserial infections at any age
• Multiple family members who have
experienced Neisserial infections
Disorders of phagocytosis
Disorders of complement
Recurrent Neisseria
infections
Overview of
Immunodeficiency Syndromes
o Antibody deficiencies and/or defects: 65%
o Combined antibody and cellular deficiencies: 15%
o Disorders of phagocytes: 10%
o Isolated cellular defects (IE: T-cell problems): 5%
o Disorders of the complement system: 5%
o Other disorders of innate immunity: <1%
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Disorders of cellmediated immunity
Disorders of phagocytosis
Disorders of complement
Encapsulated bacterial
infection
Recurrent and severe
sinopulmonary infections with
encapsulated bacterial strains
(Streptococcus pneumoniae,
Haemophilus influenzae)
Antibody deficiency/defect in
adults
o Deficiency
o Common-variable immunodeficiency (CVID)
o IgA deficiency
o Asymptomatic, to recurrent sinopulmonary and GI bacterial infections
o IgG subclass deficiency
o Sinopulmonary bacterial infections
o Non-specific immunoglobulin loss (bone marrow invasion; nephrotic
syndrome; protein-losing enteropathy)
o Antibodies defective (normal levels but efficacy is poor; lymphoma
good example)
Common-Variable
Immunodeficiency
o Primary immunodeficiency disorder characterized by impaired B cell
differentiation with defective immunoglobulin production
o Markedly reduced IgG, in combination with low levels IgA and/or IgM
o Poor or absent response to immunizations
o 80% of patients diagnosed from age 20-45
o Encapsulated bacterial infection of sino-pulmonary tract is a prominent
feature
o Also at high risk for all bacterial infections (especially GI tract), giardia,
mycobacteria, autoimmune disease, and malignancy
Overview of
Immunodeficiency Syndromes
o Antibody deficiencies and/or defects: 65%
o Combined antibody and cellular deficiencies: 15%
o Disorders of phagocytes: 10%
o Isolated cellular defects (IE: T-cell problems): 5%
o Disorders of the complement system: 5%
o Other disorders of innate immunity: <1%
Overview of
Immunodeficiency Syndromes
o Antibody deficiencies and/or defects: 65%
o Combined antibody and cellular deficiencies: 15%
o Disorders of phagocytes: 10%
o Isolated cellular defects (IE: T-cell problems): 5%
o Disorders of the complement system: 5%
o Other disorders of innate immunity: <1%
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
“Other” bacterial infection
Disorders of cellmediated immunity
Fungal infection
Disorders of phagocytosis
Disorders of complement
Recurrent and severe fungal (Candida
and Aspergillus) and bacterial
(Staphylococcus aureus, Pseudomonas
aeruginosa, Nocardia asteroides,
Salmonella typhi) infections in the skin
and lung
Disorders of phagocytosis
o Chronic Granulomatous Disease (CGD)
o Recurrent, life-threatening bacterial and fungal infections with granuloma
formation
o Skin and lung most common sites of infection
o Failure of “oxidative burst” means phagocytes cannot kill bacteria/fungi with
H2O2 as usual
o Nitroblue tetrazolium (NBT) reduction test directly measures oxidative burst
o Management: early treatment of infections; prophylaxis with Bactrim, azole,
and even interferon. Patients now living to middle-age.
o Chediak-Higashi syndrome
o Aberrant fusion of neutrophil vesicles
o “Giant” inclusion bodies
Overview of
Immunodeficiency Syndromes
o Antibody deficiencies and/or defects: 65%
o Combined antibody and cellular deficiencies: 15%
o Disorders of phagocytes: 10%
o Isolated cellular defects (IE: T-cell problems): 5%
o Disorders of the complement system: 5%
o Other disorders of innate immunity: <1%
Match the deficiency with the
clinical picture
Disorders of antibodies
(number or quality)
Severe viral and/or bacterial illnesses or
opportunistic infections*
“Other” bacterial infection
Disorders of cellmediated immunity
Viral infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Defects in cellular immunity
o T-cell defects lead to B-cell defects, so often immunoglobulin problems
as well
o Can use a T-cell functional assay: “cutaneous delayed-type
hypersensitivity” test
o Analogous to PPD
o Subcutaneous Candida antigen, measure in 48-72 hours. Induration > 5mm
is positive test
o More advanced: take peripheral T-cells in a tube, add a known antigen
and radiolabeled thymidine, see how much thymidine is taken up
(marker for appropriate clonal expansion)
oFlow cytometry accurately defines T-cell subpopulation deficiency and
can be helpful
Flow Cytometry can be helpful for defining
cell-mediate immunodeficiency
Overview of
Immunodeficiency Syndromes
o Antibody deficiencies and/or defects: 65%
o Combined antibody and cellular deficiencies: 15%
o Disorders of phagocytes: 10%
o Isolated cellular defects (IE: T-cell problems): 5%
o Disorders of the complement system: 5%
o Other disorders of innate immunity: <1%
Back to the case
63yoM, history of thymoma with possible recurrence, HIV negative,
now admitted with: Candida esophagitis, CMV colitis, PCP, Salmonella
bacteremia, giardia
How to work him up?
Disorders of antibodies
(number or quality)
Encapsulated bacterial
infection
“Other” bacterial infection
Viral infection
Disorders of cellmediated immunity
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Recurrent Neisseria
infections
Disorders of antibodies
(number or quality)
- Immunoglobulin levels
- IgG subclass levels
- Response to tetanus and
pneumococcal (PCV13 vaccine)
Disorders of cellmediated immunity
- T-cell lymphocyte panel
- T-cell functional assay
Encapsulated bacterial
infection
Disorders of antibodies
(number or quality)
“Other” bacterial infection
Viral infection
Disorders of cellmediated immunity
Opportunistic infections
Course continued
 Severe immunoglobulin deficiency found (IgG level 76)
 Poor IgG response to tetanus and PCV13 vaccination
 T-cell sub-population panel shows CD4 count 231
 T-cell functional assay shows minimal induration
 Combined immunoglobulin and T-cell level/function deficiency
diagnosed
Thymoma-associated
paraneoplastic disorders
 Good’s syndrome (thymoma with immunodeficiency) is
a rare cause of combined B and T cell immunodeficiency
in adults.
 The clinical characteristics of Good’s syndrome are
increased susceptibility to bacterial infections with
encapsulated organisms and opportunistic viral and
fungal infections
Patient outcome
He is started on ganciclovir, fluconazole, ceftriaxone, Bactrim, and
metronidazole
 Discharged home after 35 day admission on valgancyclovir,
fluconazole, and Bactrim prophylaxis
 His recurrent thymoma is treated
 Several more infections, though overall doing well
Work-up to Immunodeficiency
o Thorough infectious disease history. Figure out what categories they
fall into
o Eg: “recurrent sinopulmonary bacterial infection”, “recurrent skin
infections”, “opportunistic infections”
Encapsulated bacterial
infection
“Other” bacterial infection
Viral infection
Fungal infection
Opportunistic infections
Recurrent Neisseria
infections
Work-up to Immunodeficiency
oMatch each category to expected immune system deficiency
o If recurrent encapsulated sinopulmonary infection, think immunoglobulin
deficiency; if recurrent viruses and OI’s, think T-cells
Disorders of antibodies
(number or quality)
Disorders of cellmediated immunity
Encapsulated bacterial
infection
“Other” bacterial infection
Viral infection
Fungal infection
Disorders of phagocytosis
Opportunistic infections
Disorders of complement
Recurrent Neisseria
infections
Work-up to Immunodeficiency
o Assay those parts of the immune system
Disorders of antibodies
(number or quality)
Disorders of cellmediated immunity
- Immunoglobulin levels
- IgG subset levels
- Response to tetanus/PCV13
vaccination
- T-lymphocyte panel
- T-cell functional assay
Disorders of phagocytosis
Disorders of complement
- Oxidative burst assay (NBT)
- Blood smear
- Convalescent complement
levels
Work-up to Immunodeficiency
o Once you’ve defined what components of the immune system are down,
considering the patients age and clinical context, hit the books (or
UpToDate) to see what specific syndrome is a match
Congratulations
on finishing the Primary Immunodeficiency Module!
Please take this brief pre-module quiz
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