Download Treatment of Infections

The PNP’s Guide to
Primary Immunodeficiencies
…So How Many Ear Infections Are too Many?
M. Elizabeth M. Younger CRNP, PhD
Assistant Professor, Pediatrics
The Johns Hopkins University
School of Medicine
Baltimore, Maryland
Presented by: M. Elizabeth M. Younger CRNP, PhD
May 25, 2017
1
Disclosures
• Consultant, CSL Behring
• Speaker, CSL Behring
• Advisory Boards:
– CSL Behring
– RMS Medical Products
– Immune Deficiency Foundation
• Chair, Nurse Advisory Committee
Systemic Responses to Infection
• Host Defenses
– Skin
– Mucus Membranes
– Normal Flora
• Non-Specific Responses
– Complement
– Phagocytes
– Natural Killer Cells
• Specific Responses
• Antibody Formation
• Cellular Immunity
May 25, 2017
4
Cells of the Immune System
Primary Immunodeficiencies
• ~150 recognized defects of
immunologic function
• Another 39 disorders of which
immunodeficiency is recognized as a
component
• May present at any age
• Do not always present with severe
infections
May 25, 2017
6
Primary Immunodeficiencies
• Disorders of Humoral Immunityaffecting B cell differentiation and
antibody production
• Disorders of Cellular Immunity-T cell
defects
• Combined T cell and B cell defects
• Phagocytic Defects
• Complement Deficiencies
May 25, 2017
7
Does your patient
have a primary
immunodeficiency?
May 25, 2017
8
May 25, 2017
10
Things to consider…
•
•
•
•
What kinds of infections
How frequently
Co-morbidities
Factors that might contribute to
infections (e.g. day care!)
• Family history
May 25, 2017
11
Imperatives for the Primary Care
Provider
• Accurate record of immunizations
• Maintain accurate and ongoing
growth charts
• Complete family history with
genogram
• Follow-up after antibiotic treatment
(i.e. did what you prescribed work?)
May 25, 2017
12
Screening Tests for Primary
Immunodeficiencies
Suspected Abnormality
Diagnostic tests
Antibody
Serum IgG, IgA, IgM
Antibody response to vaccines
Cell-mediated immunity
Lymphocyte count
T cell enumeration (CD4, CD8)
HIV serology/PCR
Complement
Total hemolytic complement (CH50)
Alternative Pathway (AH50)
Mannan Binding Lectin
Phagocytes
Neutrophil count
Dihydrorhodium (DHR) test
Nitroblue tetrazolium (NBT) dye test
…But always start with a CBC
Range
Units
2/28/03
Age-4 mos
3/17/03
3/21/03
WBC
5.7K-17.7K
/cu mm
13,600
6500
4470
RBC
3.1-4.5
M/cu mm
3.26
3.54
3.87
Hgb
9-20
g/dL
7.6
8.0
7.9
Hct
29-41
%
25.3
26.1
25.7
Lymph %
43-73
%
1
3
6
Mono %
3-9
%
5
6
7
Neutro %
17-49
%
92
90
86
Eo %
1-4
%
2
1
1
Baso %
0-2
%
0
0
0
# Lymph
2.5K-12.9K
/cu mm
136
195
280
# Mono
200-1600
/cu mm
680
390
290
ANC
1000-8500
/cu mm
13,600
5,850
3,830
Rule of 2/3’s
For a child under the age of 3 years:
2/3 of WBC should be lymphocytes
2/3 of lymphocytes should be T cells
2/3 of T cells should be CD4 cells
For someone older than 3 yoa
2/3 of WBC should be neutrophils
2/3 of lymphocytes should be T cells
2/3 of T cells should be CD4 cells
15
Normal Ranges of Immunoglobulins
Immunoglobulins (mg/dL)
Age
Newborn
1-3 months
4-6 months
7-9 months
10-12 months
1 year
2 years
3 years
4-5 years
6-8 years
9-10 years
Adult
IgG
636-1606
176-906
172-814
217-904
294-1069
345-1213
424-1051
441-1135
463-1236
633-1280
608-1572
639-1349
IgA
1-4
1-53
4-84
11-90
16-84
14-106
4-123
22-159
25-154
33-202
45-236
70-312
IgM
6-25
17-105
27-108
34-126
41-149
43-173
18-168
47-200
43-196
48-207
52-242
56-352
Clinical Features of Immunodeficiency
• Increased susceptibility to infection
• Predisposition for autoimmune or inflammatory
diseases, e.g.
- Inflammatory bowel disease
- Autoimmune cytopenias
- Type I Diabetes
- Juvenile rheumatoid arthritis
• Predisposition for lymphoreticular cancers
• Syndrome complex
May 25, 2017
17
Infections
in Immunodeficient Patients
• Chronic/recurrent infections without
other explanation
• Infection with organisms of low virulence
• Infection of unusual severity
• Any site of infection is possible, but
different kinds of infection are
characteristic of the specific
immunodeficiency suspected
May 25, 2017
18
Disorders of Humoral Immunity
1. Transient Hypogammaglobulinemia of
Infancy
2. X-linked Agammaglobulinemia
(Bruton’s Agammaglobulinemia, BTK
deficiency, X-LAG)
3. Common Variable Immunodeficiency
(CVID)
4. Selective IgA deficiency
May 25, 2017
19
Transient Hypogammaglobulinemia of
Infancy
•
Characterized by
– Low serum immunoglobulins
– Little antibody response to vaccines
– Frequent sinopulmonary infections
• Condition may last into pre-school years
• Diagnosis can only be made definitively
in retrospect
May 25, 2017
20
Care and Treatment of the Child with
Suspected Transient Hypogam
• Serial monitoring of immunoglobulins and antibody
titers
• Reimmunization may be necessary
• PNP needs to be aware that infections may require
longer courses of antibiotics for treatment than usually
prescribed
• Gamma globulin is seldom necessary
• Any fever of 101.5F or greater requires that the child
have a CBC, blood culture and physical exam
• Live viral vaccines should be held until
immunocompetency is demonstrated
May 25, 2017
21
X-linked Agammaglobulinemia
•
•
•
•
1:200,000 live births
No/few B cells, normal T cells
No tonsils, small lymph nodes
Usually not diagnosed until after 4
months when maternal immunity wanes
May 25, 2017
22
Common Variable
Immunodeficiency (CVID)
• Approximately 20% of these patients are
diagnosed under the age of 16
• Characterized by low serum immunoglobulins
and susceptibility to infections because of
impaired antibody responses
• Sinopulmonary infections are most common
• Predisposition for autoimmune diseases
May 25, 2017
23
Treatment of
Humoral Immune Disorders
• Regular infusions of pooled human
gamma globulin (either IV every 3-4
weeks or subq weekly)
• Aggressive treatment of infections
• Surveillance for co-morbidities
May 25, 2017
26
Primary Care of the Child with
Humoral Immunity Defects
• Low tolerance for fever, signs of infection
• No live viral vaccines (Varivax, MMR, ProQuad, Flu-Mist, Rota-Teq)
• Because of the increased incidence of
autoimmune disease in this population,
monitor growth curves, carefully assess new
complaints or signs and symptoms of
problems
• Do not need routine immunization since they
do not make protective levels of antibodies
May 25, 2017
27
Disorders of Cellular Immunity
1. Severe Combined Immunodeficiency
(SCID)
May 25, 2017
28
Severe Combined
Immunodeficiency (SCID)
• Severe impairment of humoral and cellmediated immune function
• Susceptibility to infection by virtually any
microbe
• Unless treated, usually fatal within the first
year of life
• 12 known genetic causes
45% X-linked
15% Adenosine Deaminase Deficiency
May 25, 2017
29
Treatment of SCID
• Bone Marrow transplant
• Gamma globulin replacement therapy
• Antibiotic prophylaxis for PCP and
fungal infections
• Gene therapy
• PEG-ADA (Adagen) IM 2 or 3 times per
week (if etiology is ADA deficiency)
• Nutritional support
May 25, 2017
30
Combined T cell and B cell
disorders
1. DiGeorge Syndrome
2. Wiskott-Aldrich Syndrome
3. Ataxia Telangiectasia
May 25, 2017
31
DiGeorge Syndrome
•
•
•
•
22q11.2 deletion syndrome
Velocardiofacial (VCF) syndrome
Conotruncal anomaly face syndrome
Autosomal dominant Opitz-G/BBB
Incidence 1 in 3,000 live births
:
May 25, 2017
32
Fluorescence in situ Hybridization
Korf B, N Engl J Med 1995;332:1219
DiGeorge Syndrome
Catch 22 Mnemonic
C ardiac defects (75%)
A bnormal facies (70%)
T hymic a- or hypoplasia
(60-77%)
C left palate (69-100%)
H ypocalcemia (17-60%)
22- chromosome 22
May 25, 2017
34
C-Cardiac Defects
•
•
•
•
Tetralogy of Fallot (17-22%)
Interrupted Aortic Arch (14-15%)
Ventriculoseptal defect (13-14%)
Truncus arteriosus (7-9%)
May 25, 2017
35
A-Abnormal Facies
•
•
•
•
•
•
•
•
Ocular hypertelorism
Lateral displacement of inner canthus
Short palpebral fissure
Low nasal bridge
Nasal dysmorphism
Small mouth
Low set ears
Cleft lip
May 25, 2017
36
T-Thymic aplasia or hypoplasia
• Thymic aplasia requires thymic or bone
marrow transplant
• Those with thymic hypoplasia must be
protected from live viral vaccines,
transfusions of unirradiated blood, and
opportunistic infections until T cell numbers
normalize
• 10% have delayed production of IgG
• 2 - 4 % have IgA deficiency
May 25, 2017
37
C-Cleft Lip/Palate (velopharyngeal
abnormality associated issues)
• Cleft palate (submucous cleft is
common)
• Recurrent otitis media and sinusitis
• Problems with speech articulation
May 25, 2017
38
H-Hypocalcemia
• Neonatal hypocalcemia occurs in 50-70% of
patients
• Problem generally resolves with increased
dietary calcium intake and growth of
parathyroid glands
• Hypocalcemia can develop in older patients
who are stressed by acute medical illnesses,
trauma or cardiopulmonary bypass
May 25, 2017
39
Variability of Phenotype
Driscoll et al. J Med Genet 1993;30:813
May 25, 2017
40
In a study of 195 patients:
Associated Manifestations
• Speech delay and other
neurodevelopmental problems (75%)
• Kidney and urinary tract defects (36%)
• Skeletal defects (18%)
• Feeding problems
• Psychiatric problems (onset of
schizophrenia during adolescence)
May 25, 2017
41
Autoimmune Disease in
DiGeorge Patients
• Immune thrombocytopenia
– 200x  over rate in general population
• Juvenile rheumatoid arthritis
– 20x  over rate in general population
• Skin disease (psoriasis, vitiligo)
• Autoimmune hemolytic anemia
• Inflammatory bowel disease
May 25, 2017
42
Neurodevelopmental Problems
• Delayed acquisition of language milestones
– At 2 y/o, 90% nonverbal or used only single words
– At 3 y/o, 80% nonverbal or used only words and
simple phrases
– At 4 y/o, 30% nonverbal or not speaking in
sentences
• Articulation disorders
• Cognitive abnormalities
May 25, 2017
43
Primary Care of the DiGeorge
Patient
• Once 22q11 deletion syndrome is identified,
be prepared for a multi-dimensional approach
– Complex medical needs
– School problems
• Refer for genetic counseling
• Routine immunization if immunocompetent
• Antibiotic prophylaxis if T-cell numbers are
low
May 25, 2017
44
Wiskott-Aldrich Syndrome
• X-linked
•
•
Clinical Presentation
Small platelets (Low MPV) and/or
thrombocytopenia
Impaired antibody responses
Recurrent bacterial, viral and fungal
infections
Eczema
Associated Problems
Increased incidence of autoimmune disease
Increased incidence of malignancies, especially
leukemias and lymphomas
May 25, 2017
45
Primary Care of the
Child with Wiskott-Aldrich Syndrome
• Vigilance for signs of bleeding
• Low tolerance for fever, signs of
infection
• Treat eczema aggressively to prevent
suprainfection
May 25, 2017
46
Treatment of
the Wiskott-Aldrich Patient
• Gamma globulin replacement therapy if antibody
production is impaired
• Treatment of acute thrombocytopenia
– Platelet transfusion for acute bleed
– IV Gamma globulin
– Anti CD20 monoclonal antibody therapy (e.g.
rituximab)
• Treatment of chronic thrombocytopenia
– Steroids
– Splenectomy
May 25, 2017
47
Ataxia Telangiectasia
•
•
•
•
•
•
•
Autosomal recessive disease
Ataxia (wobbly, scissor type gait)
Telangiectasias of eyes and skin
Cellular and humoral immunodeficiencies
Predisposition to lymphoreticular cancers
Effects cerebellar function
Progressive neurologic deterioration
May 25, 2017
48
Care of the Child with AT
•
Gamma globulin replacement therapy if
indicated
• Need a team of care providers (i.e. primary
care, neurology, immunology, nutritionist,
pulmonologist, developmentalist)
• Supportive care
Use X-rays ONLY when absolutely necessary
as exposure to x-rays causes cell death or
chromosomal breakage
May 25, 2017
49
Disorders of Phagocytes
1. Chronic Granulomatous Disease
2. Leukocyte Adhesion Deficiency
3. Chédyak-Higashi Syndrome
May 25, 2017
50
Chronic Granulomatous Disease
(CGD)
• Phagocytes have normal function, EXCEPT they
cannot make an oxidative burst
• So…phagocytes successfully defend against some
organisms, but not those that require an oxidative
burst to kill them; these are usually catalase-postive
bacteria and fungi
May 25, 2017
51
Frequent Pathogens
• Staph aureus ~ 30-56% of clinical isolates
• Other Gram positives e.g. Nocardia
• Gram negative ~ 30%
e.g. E. coli, Serratia marcescens,
Klebsiella, Enterobacter species,
Burkholderia, Salmonellae,
Pseudomonas
• Fungi: ~ 20%
Aspergillus ~ 78%
Candida species
May 25, 2017
53
Diagnosis: Nitroblue Tetrazolium Test
negative
positive
Clinical Presentation of CGD
• X linked or, more rarely, autosomal
recessive)
• Recurrent bacterial infections of any organ
system or tissue
• Pneumonias: (50% are fungal, frequently
caused by Aspergillis)
• Other frequent infections include
lymphadenitis, retropharyngeal and liver
abscesses, osteomyelitis
May 25, 2017
55
Primary Care of CGD
• Bacterial prophylaxis with trimethoprim/sulfamethoxazole
Dose: 5-10 mg/kg/day divided BID
• Fungal prophylaxis with Itraconazole
Dose: 2-5 mg/kg/dose BID
• Interferon 
Dose: 50 μg/m2 sq 3x/week or 1.5 mcg/kg if < 0.5 m2
• Routine primary care and immunization are critical
• Infections need to be treated for a long time and may
require parenteral antibiotics
May 25, 2017
56
Complement Deficiencies
Activation of the Complement System:
– Classical Pathway
– Alternative Pathway
– Lectin Pathway
May 25, 2017
57
Problems for Complement
Deficient Patients
• Higher susceptibility to bacterial
infections, especially with encapsulated
organisms
• N. meningitidis particularly problematic
for those with deficiencies of C5,6,7,8,
or 9
• Higher propensity for autoimmune
diseases, especially SLE or
glomeronephritis
May 25, 2017
58
Primary Care across the
Spectrum of Primary
Immunodeficiencies
May 25, 2017
59
Role of the PNP in
Pediatric Primary Immunodeficiency
• Routine primary care is critical, particularly in
the assessment of growth and development
Toddlers and pre-schoolers should be seen at
least twice a year for well-child visits (on an
alternate schedule with the immunologists so that
they are seen every three months)
School-age children and adolescents should be
seen yearly (on an alternate schedule with the
immunologists so that they are seen every six
months)
• Insure immunization when appropriate
May 25, 2017
60
Vaccines
Antibody Deficient Child
(e.g. CVID, SCID)
Complement Deficiency
or Asplenia
• Unnecessary as child
does not make antibody
and receives gamma
globulin therapy
• Need all immunizations
including an annual flu
vaccination
Phagocytic Defect
(e.g. CGD)
• Need all immunizations
including an annual flu
vaccination
• Live vaccines are
ABSOLUTLEY
contraindicated
• Family members need
influenza vaccine
May 25, 2017
61
Treatment of Infections
Antibody Deficient Child
(e.g. CVID, SCID)
Complement Deficiency
or Asplenia
• May need a longer
• Any child with a fever
course of antibiotics than
> 100.5 needs an urgent
usual
(i.e. same day) physical
exam, a CBC and Blood
culture and, if he
appears ill, he will also
need a dose of
Ceftriaxone
May 25, 2017
Phagocytic Defect
(e.g. CGD)
• May need a longer
course of antibiotics than
usual
• Need to follow WBC
count and CRP, as well
as the physical exam
62
Use of Steroids
Antibody Deficient Child
(e.g. CVID, SCID)
Complement Deficiency
or Asplenia
Phagocytic Defect
(e.g. CGD)
• CVID/XLA: Usually okay, • Usually okay, if indicated • Try to avoid steroid use,
if indicated
especially inhaled
• Avoid in SCID patients
steroids
May 25, 2017
63
Diagnostics
Antibody Deficient Child
(e.g. CVID, SCID)
• PCR’s, Not serologies
• CRP, Not ESR
Complement Deficiency
or Asplenia
• Routine diagnostics
(CBC with differential,
ESR or CRP, cultures)
are appropriate
Phagocytic Defect
(e.g. CGD)
• Try to get cultures and
sensitivities before
treating infection
• Remember that the
infection may be fungal
rather than bacterial
May 25, 2017
64
Co-morbidities
Antibody Deficient Child
(e.g. CVID, SCID)
• Autoimmune disease,
including IBD, JRA, and
cytopenias
May 25, 2017
Complement Deficiency
or Asplenia
• SLE
•Glomerulonephritis
Phagocytic Defect
(e.g. CGD)
• GI disease secondary to
granuloma formation in
the gut
• Urinary tract obstruction,
secondary to granuloma
formation
65
Antibiotic Prophylaxis
Antibody Deficient Child
(e.g. CVID, SCID)
• Usually not needed for
Agammaglobulinemia
or CVID patients
•For children with SCIDneed PCP prophylaxis:
Bactrim 4-5 mg/kg/day
divided BID on 3
consecutive days/week
May 25, 2017
Complement Deficiency
or Asplenia
• Penicillin 125-250 mg
BID
Phagocytic Defect
(e.g. CGD)
• Bacterial prophylaxis:
usually Bactrim 4-5
mg/kg/day divided BID
•May need fungal
prophylaxis: usually
Itraconazole 2-5
mg/kg/day as a single
dose
66
Routine Medications
Antibody Deficient Child
(e.g. CVID, SCID)
• Gamma globulin
IV: 400-500 mg/kg/month
SQ: 100-125 mg/kg/week
May 25, 2017
Complement Deficiency
or Asplenia
Phagocytic Defect
(e.g. CGD)
• Interferon gamma
50 mcg/m2 sq TIW or
1.5 mcg/kg if BSA < 0.5 m2
67
Environmental Issues
Antibody Deficient Child
(e.g. CVID, SCID)
Complement Deficiency
or Asplenia
Phagocytic Defect
(e.g. CGD)
• Need to avoid:
-outside play near mulch
-swimming in fresh water
-being around new
construction or
remodeling projects
May 25, 2017
68