Immune Deficiency & Neutropenia (Small Group Session 24) Flashcards
A four year old boy presents with monthly recurrent otitis media. He has also had a skin infection. Both have resolved with antibiotics. 6 months ago he had a thigh abscess and required IV antibiotics. Immunoglobulins were checked. IgG, IgA and IgM were all undetectable. What is the diagnosis? Why are his immunoglobulins undetectable?
The patient has a defect in the antibody producing B cells. In this case, there is abnormal B cell maturation resulting in low B cell numbers. Without B cells, no antibodies can be produced and this is the reason for the undetectable immunoglobulins. The diagnosis is agammaglobulinemia.
Agammaglobulinemia = no Ab = no immunglobulin (absent IgG, IgA, IgM, IgE)
- 85% due to X-linked agammaglobulinemia (XLA or Bruton agammaglobulinemia)
- Mutation of Bruton protein tyrosine kinase (BTK) resulting in a blck in B cell maturation
- Agammaglobulinemia results from an absence of mature B cells
- Autosomal recessive defects cause the remaining forms of agammaglobulinemia
Clinical Presentation
- Recurrent sinopulmonary infections
- Infection with encapsulated organisms
- Presents after 6 months of age, usually early childhood
- May present with neutropenia
- Long term complications include chronic pulmonary disease and bronchiectasis
- Can develop chronic enteroviral infections
Invetsigations
- Decreased number of B cells
- Undetectable serum Igs
- Normal T cell numbers and function
At what age does agammaglobulinemia present?
A gammaglobulinemia presents at 6 months of age. Adult levels of IgG are reached during the 3rd trimester (passively transferred maternal IgG). Premature infants (<28 wks) have low IgG. Healthy neonates have low/absent IgM and IgA.
A two year old boy presents with fever, and a cough with a history of recurrent sinopulmonary infections. Investigations reveal neutropenia, marked decrease in B cells and undetectable serum immunoglobulins and infection with Streptococcus pneumoniae. T cell count is normal.
What is your diagnosis?
Agammaglobulinemia
Clinical presentation:
- Recurrent sinopulmonary infections
- Infection with encapsulated organisms
- After 6 months of age, usually early childhood
- May present with neutropenia
- Long term complications include chronic pulmonary disease and bronchiectasis
- Can develop chronic enteroviral infections
- NO B CELLS = NO LYMPH TISSUE (The majority of a lymph node is made up of B cells so lymph nodes will be tiny on exam)
Investigations:
- Profoundly decreased number of B cells
- Virtually undetectable serum Ig’s
- Normal T cell numbers and function
What is the role of the following isotypes?
IgG
IgA
IgM
IgE
IgG = Memory: provides the majority of Ab-based immunity against invading pathogens. The only Ab capable of crossing the placenta to give passive immunity to the fetus.
IgA = Mucous Membranes: found in mucosal areas, such as the gut, respiratory tract and urogenital tract and prevents colonization by pathogens. Also found in saliva, tears and breast milk
IgM = First Response: expressed on the surface of B cells and in a secreted from with very high avidity. Eliminates pathogens in the early stages of B cell mediated (humoral) immunity before there is sufficient IgG.
IgE = Parasitic Infections, Allergies: binds to allergens and triggers histamine release from mast cells and basophils, and is involved in allergy. Also protects against parasitic worms.
A 15 year old girl presents with an episode of otitis media. She has had 4 pneumonias in the last 2 years, 2 of which required hospital admission and IV antibiotics. She had 1 episode of otitis media this year and 4 episodes of sinusitis last year which were treated with oral antibiotics. Investigations reveal a low IgG, low IgA and normal IgM. Normal B cells on lymphocyte subsets. She is not on any immunosuppressants, or chemotherapy.
What is your diagnosis?
Common Variable Immune Deficiency
- Decreased levels of at least 2 Ig isotypes (usually IgG and IgA)
- Impaired specific Ab productino (poor vaccine responses)
- All other causes of immune deficiency ruled out
- Often have lymphoproliferation with adenopathy, splenomegaly (1/3)
- May have lymphopenia and decreased T cell function
- Family history in 10-20%
- Defects in T-B cell crosstalk
- Incidence is ~1:50000
Which history is suspicious for a humoral defect?
A) 1 yr old boy with hx of an RSV infection, an adenovirus infection with secondary pneumonia, failure to thrive, and recurrent otitis media starting at 2 months of age.
B) 18 month old boy with pneumonia at 8 months, 4 episodes of otitis media starting at 7 months and one skin abscess that grew Staph aureus.
C) 24 year old woman with a cough and fever.
D) 13 year old girl with cervical adenitis growing serratia.
B) 18 month old boy with pneumonia at 8 months, 4 episodes of otitis media starting at 7 months and one skin abscess that grew Staph aureus.
What is a selective Ab deficiency?
Difficulty responding to polysaccharide Ag
- T cell independent response
- Other Ag (proteins, conjugated vaccines) recruit T cells to coach the B cells; T cell dependent responses
- Strep pneumoniae infections: respond to all vaccines except pneumovax
- A milder, more common defect
What is transient hypogammaglobulinemia of infancy?
‘Delayed’ maturation of the immune system
- Rarely have difficulty with infections
- Usually resollves by 3-5 years
- Rarely requires therapy
- Do need to treat fevers, bacterial infections more aggressively
How are humoral immune deficiencies managed?
- Prophylactic immunoglobulin replacement (IVIG or subcutaneous IG) (only indicated for patients with clearly defined deficiency and/or significant difficulties with recurrent infections)
- Prophylactic antibiotics
- Aggressive antibiotic therapy for infections
- Monitoring for long term complications:
- Chronic lung disease: pulmonary function tests, intermittent CT
- Autoimmune complications: CBCD, liver enzymes, screening for SLE, thyroid, renal function, glucose
- High index of suspicion for malignancy
An 18 year old man is referred to you with a history of chronic cough and recurrent pneumonias (usually 2-3 chest X-ray documented pneumonias per year). He has chronic sinusitis and has required 2 ENT procedures in the past. Past history is remarkable for recurrent bilateral otitis media as a young child requring placement of multiple myringotomy tubes. A tonsillectomy and adenoidectomy was done at 3 years of age with no improvement of infections. On physical exam enlarged nodes and spleen is noted. Further investigations reveal normal neutrophils, and low IgG, IgA. What is the most likely diagnosis? What are the three parameters of this diagnosis?
Common Variable Immune Deficiency
- Decreased levels of at least 2 Ig isotypes (usually IgG and IgA)
- Imparied specific Ab production (vaccine titers)
- All other causes of immune deficiency ruled out
An 18 year old man is referred to you with a history of chronic cough and recurrent pneumonias (usually 2-3 chest X-ray documented pneumonias per year). He has chronic sinusitis and has required 2 ENT procedures in the past. Past history is remarkable for recurrent bilateral otitis media as a young child requring placement of multiple myringotomy tubes. A tonsillectomy and adenoidectomy was done at 3 years of age with no improvement of infections. On physical exam enlarged nodes and spleen is noted. Further investigations reveal normal neutrophils, and low IgG, IgA.
The patient reports chronic cough, occasional coughing up of blood and coughing up mucus daily.
What complication is this patient experiencing?
Bronchiectasis
Name 3 of the 10 warning signs of immunodeficiency.
10 Warning Signs of Immunodeficiency
- >4 acute otitis media in 1 year (>2 for adults)
- >2 sinus infections in 1 year
- >2 pneumonias in 1 year
- Failure to thrive (poor growth), chronic diarrhea, weight gain
- IV antibiotics needed to clear infections
- Recurrent viral infections (colds, herpes, warts, etc.)
- Persistent thrus after age 1, fungal infections of skin or internal organs
- Infection with normally harmless tuberculosis-like bacteria
- Positive family history
- Recurrent , deep skin or organ abscesses
Compare and contrast the clinical features of AML vs. ALL.
Acute Lymphoblastic Leukemia (ALL)
- Presents mainly in younge people (kids); 75% of ALL occurs in children <6 yrs old
Clinical Features
- Anemia
- Fatigue, pallor
- B symptoms
- Boney pain
- Gouty arthritis
- Bleeding and bruising
- +/- diffuse lymphadenopathy
- Hepatosplenomegaly
- CNS involvement (1-3%)
From Toronto Notes:
Bone marrow failure: anemia, neutropenia (50% with fever; also infections of oropharynx, lungs, perianal region), thrombocytopenia
Organ infiltration: tender bones, lymphadenopathy, hepatosplenomegaly, meningeal signs (headache, N/V, visual symptoms; especially in ALL relapse)
Acute Myelogenous Leukemia (AML)
- Older people, median age of onset is 65 yr old
Clinical Features
- Anemia
- Fatigue, pallor
- B symptoms
- Gouty arthritis
- Bleeding and bruising
- +/- boney pain
- +/- infections
- +/- fever
- +/- gout
- +/- hepatosplenomegaly
- No lymphadenopathy
Compare and contrast the lab features of AML and ALL.
ALL
Smear: increased blasts, no granules, small nucleoli, less cytoplasm
Blood: increased WBC, general cytopenias, increased uric acid, increased PO4, increased K, increased LDH, decreased Ca (tumor lysis syndrome), increased PTT, increased INR, decreased fibrinogen, D-dimer
Marrow aspirate: hypercellular, >20% blasts
AML
Smear: increased blasts, Auer Rods, lots of cytoplasm, nucleoli, granules
Blood: general cytopenias, increased uric acid, increased PO4, increased K, increased LDH, decreased Ca (tumor lysis syndrome), increased PTT, increased INR, decreased fibrinogen, D-dimer
Marrow aspirate: >20% blasts, hypercellular
What is febrile neutropenia?
Febrile Neutropenia
- A medical emergency!
- Single temperature of >38.3 C or a sustained (>4 hrs) temperature >38 C in a patient with a neutrophil count <0.5 x 109/L
