What is immune deficiency Primary Immunodeficiency PI

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                  Kenneth Paris, M.D.                                                FACULTY DISCLOSURE

                                                                                     The AAFP has selected all faculty appearing in this program. It is the policy of the AAFP that all CME planning
                                                                                     committees, faculty, authors, editors, and staff disclose relationships with commercial entities upon nomination or
                                                                                     invitation of participation. Disclosure documents are reviewed for potential conflicts of interest and, if identified,
     CME #057 Saturday, 10:30-11:30 a.m. Location: Room 401                          they are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or
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                                                                                     Kenneth Paris, MD, has disclosed a financial relationship with Teva in the area of Asthma and Influenza. He has
      CME #058 Saturday, 1:30-2:30 p.m. Location: Room 401                           also served as a consultant or on the Advisory Board for Baxter and CLS-Behring in the area of Gammaglobulin.




              Learning Objectives/                                                                    How does the immune system 
               Search References                                                                           keep people alive?
                                                                                               Recognizes and responds to DANGER
 • Compare guidelines for identifying patients with immunodeficiency in
   their practice (as defined by the CDC’s Infection Control Guidelines).                                     Cluster of bacterium on a food particle
 • Create a disease management plan for patients with
   immunodeficiency.
 • Assess indications for patient referral to a subspecialist.



  Search References




                                                                            Source: Agricultural Research Service, US Department of Agriculture.                                                              4




      What is immune deficiency?                                                         Primary Immunodeficiency (PI)
• The immune system 
                                                                                 • An inherent defect in immunity
  keeps most people 
                                                                                        – Over 150 individual diagnoses classified as PI1
  healthy most of the 
                                                                                        – This presentation does not represent the entire spectrum 
  time                                                                                    of PI
• Immune deficiency is a                                                                – Focus on clinical patterns consistent with the majority of 
  term to describe what                                                                   diagnoses
  happens when the                                                               • Patients with PI have increased vulnerability to 
  immune system is                                                                 infections
  unable to protect                                                              • You have the ability to find these patients
  against pathogens in the                                                              – Prevalence rate for PI among children is estimated as 1 in 
                                                                                          2000 children2
  environment
                                                                            1. Geha RS, et al. J Allergy Clin Immunol. 2007;120:776-794.
                                                                      5     2. Boyle JM, Buckley RH. J Clin Immunol. 2007;27:497-502.                                                                         6
                        Window of Opportunity                                                                                                         PI is Underdiagnosed
     • Why do you want to find these patients?
           –   Early diagnosis reduces morbidity1                                                                             • US prevalence is ~1 in 1200 persons1
           –   Lifesaving and curative therapies exist1                                                                       • You can change this
           –   Diagnosed and treated patients can lead normal lives1,2
           –   The vast majority of patients with PI present in childhood
                                                                                                                                     – Low yield, high impact
                  • You can distinguish patients with PI from patients presenting for                                                – Consider PI, then rule it out
                    routine “sick” visits 1,3,4
                  • An immunologist can help                                                                                  • This talk will underscore some clinical patterns 
           – Without diagnosis and treatment, children with PI are at risk for                                                  of typical PI presentations
             early death 
1. Bonilla FA, et al. Ann Allergy Asthma Immunol. 2005;94(5 suppl 1):S1-62; 2. Skull S, Kemp A. Arch Dis Child.
1996;74:527-530; 3. Slatter MA, Gennery AR. Clin Exp Immunol. 2008;152:389-396; 4. Carneiro-Sampaio M, Coutinho A.
Infect Immun. 2007;75:1545-1555.




                                                                                                                     7   1. Boyle JM, Buckley RH. J Clin Immunol. 2007;27:497-502.                     8




                               Summary of Case Studies 
                                  to Be Presented                                                                                                               Key Takeaways
      1)    18‐month‐old boy with pneumonia                                                                                   • Children with PI have insufficient immunity 
      2)    16‐year‐old girl with bronchitis                                                                                    and are susceptible to infection1
      3)    9‐month‐old boy failing to thrive                                                                                 • They often have:
      4)    10‐month‐old boy with bronchiolitis                                                                                      – Recurrent infection
                                                                                                                                     – Severe infection
      5)    12‐year‐old girl with sinusitis
                                                                                                                                     – Unusual infection
      6)    8‐month‐old boy with pneumonia
                                                                                                                              • Patterns of infection can provide clues to 
     DISCLAIMER
     The case studies presented herein are fictional and
                                                                                                                                specific diagnosis1
     intended for educational purposes only and do not
     represent actual patient information or records.
                                                                                                                     9   1. Bonilla FA, et al. Ann Allergy Asthma Immunol. 2005;94(5 suppl 1):S1-62.   10




                                                                                                                         Case Study 1


                                                                                                                                   18‐Month‐Old Boy With Pneumonia
                                                                                                                             History of Present Illness
                                                                                                                             • 1 week of cough and fever 
                                                                                                                               (102.0°F)
                                        CASE STUDY 1                                                                         • Increased work of 
                                                                                                                               breathing over last 24 h
                                                                                                                             • Decreased urine output
                     18‐Month‐Old Boy With Pneumonia
                                                                                                                             • Sibling sick at home
                                                                                                                             • Attends day care 3 days/wk



                                                                                                                                                                                                       12
 Case Study 1                                                                   Case Study 1


                          Past Medical History                                                                          Clinical Course
                                                                                    •    Physical examination
     • Uneventful pregnancy and neonatal period                                            – RR = 40, SPO2 94% on RA, T = 102.3°F
                                                                                           – Crackles to auscultation, right > left

     • First episode of otitis media at 6 mo                                        •
                                                                                           – Purulent otorrhea
                                                                                         Chest X‐ray: right lower lobe (RLL) infiltrate
           – Recurrent episodes at 8, 11, 13 mo                                            – Abnormal lung with infiltrate
                                                                                    •    CBC
           – Successfully treated with amoxicillin                                         – WBC: 13.5 × 103 cells/L; 70%N, 28%L

           – Tympanostomy tubes at 13 mo                                            •    Prescribed cefdinir
                                                                                           – Defervescence after 48 hours and RR 
     • Clinical diagnosis of pneumonia at 14 mo                                     •
                                                                                             normalized
                                                                                         Reexamine in 1 week
           – Treated with azithromycin                                                     – Improved aeration RLL
                                                                                           – Otorrhea resolved
     • Weight: 25th percentile for age
                                                                                RR = respiratory rate; SPO2 = saturation of peripheral oxygen; RA = room air; T = temperature;
                                                                           13   CBC = complete blood count; WBC = white blood cell count; N = neutrophil; L = lymphocyte         14




 Case Study 1                                                                   Case Study 1


                  Diagnostic Considerations                                                                                     Evaluation

     • Infections began at 6 mo                                                               Serum IgG, IgA, and IgM levels were
     • Recurrence of sinopulmonary bacterial                                                             undetectable
       infection
           – 2 episodes of pneumonia
           – Concurrence of otitis and pulmonary infection                                                              DIAGNOSIS
     • Appropriate response to antibiotics
                                                                                          X-Linked Agammaglobulinemia
     • Serum IgG, IgA, IgM levels were undetectable


                                                                           15                                                                                                    16




 Case Study 1                                                                   Case Study 1


           X‐Linked Agammaglobulinemia                                                                                   Key Messages
   • Caused by a gene mutation on the X chromosome (BTK)1
   • Results in absence of antibody‐producing lymphocytes (B                         • Onset of bacterial infection at 6 mo suggests 
     cells)                                                                            congenital antibody deficiency1
         – Congenital inability to ever make antibodies                              • Two or more bacterial pneumonias within 12 mo 
   • Treatment with life‐long immunoglobulin replacement                               should prompt consideration for immunodeficiency2
     therapy2                                                                        • Repeated infection and hospitalization for serious 
         – Protects against spread of infection
                                                                                       bacterial infection would be expected
   • Early diagnosis can prevent end organ damage (from 
                                                                                     • Occasionally, a history of pyogenic infections in 
     infection) and reduce mortality
                                                                                       maternal male relatives can be an important clue
1. Väliaho J, et al. Hum Mutat. 2006;27:1209-1217.
2. Jeffery Modell Primary Immune Deficiency Resource Center.
http://www.info4pi.org/aboutPI/index.cfm?                                       1. Bonilla FA, et al. Ann Allergy Asthma Immunol. 2005;94(5 suppl 1):S1-62;
section=aboutPI&content=syndromes&area=4&CFID=33620350&CFTOKEN=23553579.        2. Jeffery Modell Primary Immune Deficiency Resource Center.
                                                                                http://www.info4pi.org/aboutPI/index.cfm?section=aboutPI&content=syndromes&area=4&
                                                                           17   CFID=33620350&CFTOKEN=23553579..                                                                 18
                                                                      Case Study 2


                                                                            16‐Year‐Old Girl With Bronchitis
                                                                        History of Present Illness
                                                                        • Missed the previous week of 
                                                                          work because of “cold”
                                         CASE STUDY 2                   • Symptoms persist despite 
                                                                          following an asthma action plan
                                                                        • Over‐the‐counter decongestants 
                    35‐Year‐Old Woman With Bronchitis                     were somewhat helpful
                                                                        • Now has productive cough with 
                                                                          green sputum



                                                                                                                                                    20




Case Study 2                                                          Case Study 2


                               Past Medical History                                            Clinical Course
    • Up to date with vaccinations                                      • Physical examination
    • Well until age 29 years                                               – Appears thin and tired 
    • Frequent work absences since 30 yo                                    – T = 100.8°F, RR = 18, 
      because of URI                                                          SPO2 = 98% on RA
    • Has received numerous courses of                                      – Purulent nasal discharge
      antibiotics                                                           – Diffuse scant rhonchi R > L
    • ENT evaluation defined chronic                                    • Prescribed azithromycin
      pansinusitis                                                          – Improved in 3 days              Chest CT Scan: Right-sided bronchiectasis
           – Functional endoscopic sinus surgery
                                                                        • Follow‐up visit: rhonchi still present 
    • Intermittent abdominal pain and 
                                                                            – Chest X‐ray: RML, pneumonia
      diarrhea
                                                                            – Bronchiectasis
           – Diagnosed as irritable bowel syndrome
    • Career at risk due to performance at 
      work
ENT = Ear-nose-throat; URI = upper respiratory tract infection   21                                                                                 22




                                                                      Case Study 2


                                        Clinical Course                              Diagnostic Considerations
    • Immunoglobulin levels
                                                                         • Abrupt onset of recurrent infections in a previously well 
           –   IgG = 352 mg/dL,
                                                                           adult
           –   IgA = undetectable,
                                                                         • Need for abundant and longer courses of antibiotics
           –   IgM normal
           –   No antibody present against 
                                                                         • Nonresponsive to appropriate treatment for given 
               tetanus toxoid despite                                      diagnosis (eg, asthma)
               recent vaccination                                        • Inability to mount an antibody response despite recent 
                                                                           vaccination
                                                                         • Elusive GI diagnosis
                                                                         • Presence of end‐organ damage (bronchiectasis)


                                                                 23                                                                                 24
                                                                                                  Case Study 2

                                                                                                           Common Variable Immunodeficiency (CVID)
                                               DIAGNOSIS
                                                                                                      • Defined as impaired antibody quantity and quality
                                                                                                            – Hypogammaglobulinemia with impaired antibody 
                                                                                                              specificity
                                                                                                      • May be seen by multiple specialists
                                                                                                      • Prompt diagnosis and treatment can prevent 
   Common Variable Immunodeficiency                                                                     complications
                                                                                                      • Autoimmune, hematologic, gastrointestinaI, and 
                                                                                                        oncologic comorbidities can occur1,2
                                                                                                      • Treatment options: immunoglobulin replacement, anti‐
                                                                                                        infective prophylaxis, or an organ system–specific 
                                                                                                        therapy
                                                                                                      • Mostly unknown genetic causes
                                                                                                  1. Cunningham-Rundles C, Bodian C. Clin Immunol. 1999;92:34-48.
                                                                                             25   2. Oksenhendler E, et al. Clin Infect Dis. 2008;46:1547-1554.     26




Case Study 2                                                                                      Case Study 2

              Common Variable Immunodeficiency (CVID)
                                                                                                                                        Key Messages
                                                                                                      • Onset of immune deficiency can occur 
                                                     Patient characteristics and referral               later in childhood or in adulthood1,2
                                                                   times
                                                                                                      • Pattern of infections may not differ 
                                                   Number of patients           47                      from the “normal” pediatric 
   • Time from symptom                                                                                  population, but chronicity may trump 
     onset  to diagnosis is 4                      Median age, y (range)        45.5 (22–81)            severity
     years on average (see                         Median age at diagnosis,
                                                                                35.0 (5–72)
                                                                                                      • End‐organ damage may be an 
     table)1
                                                   y (range)                                            indicator of underlying immune 
                                                   Median time from first                               deficiency (bronchiectasis)
                                                   symptoms to diagnosis,       4.0 (0.8–45)
                                                   y (range)
                                                                                                      • Recurrent GI symptoms can be due to 
                                                                                                        immune deficiency and not antibiotics
                                                   Median time until referral
                                                   to an immunologist, y        5.0 (0–12)
                                                   (range)


                                                                                                  1. Cunningham-Rundles C, Bodian C. Clin Immunol. 1999;92:34-48.
1. Thickett KM, et al. QJM. 2002;95:655-662.                                                 27   2. Oksenhendler E, et al. Clin Infect Dis. 2008;46:1547-1554.     28




                                                                                                  Case Study 3


                                                                                                         9‐Month‐Old Boy Failing to Thrive
                                                                                                      History of Present Illness
                                                                                                      • Growth failure decreased 
                                                                                                        from 90th to 25th percentile 
                                        CASE STUDY 3                                                    over 3 months
                                                                                                      • Thrush for past 2 weeks
                       9‐Month‐Old Boy Failing to Thrive                                              • Reduced frequency of 
                                                                                                        breast‐feeding
                                                                                                      • No fever


                                                                                                                                                                    30
Case Study 3                                                                Case Study 3


        9‐Month‐Old Boy Failing to Thrive                                                                 Past Medical History
• Growth failure 
  decreased from 90th to                                                         • Born after uneventful pregnancy — normal newborn 
  25th percentile over                                                             screen
  3 months                                                                       • Normal neonatal course
                                                                                 • Treated with antibiotics 3× for otitis media
                                                                                 • Difficulty with thrush and monilial dermatitis
                                                                                        – Required 4 prescriptions for oral/topical nystatin
                                                                                 • Has been increasingly difficult to feed
                                                                                        – Exclusively breast‐fed
                                                                                 • Brother died of SIDS at 2 mo of age
Adapted with permission from Buckley RH. In: Kliegman RM,
et al, eds. Nelson Textbook of Pediatrics. 18th ed.
Philadelphia, PA: Saunders; 2007.                                      31   SIDS = sudden infant death syndrome                                32




Case Study 3                                                                Case Study 3


                                        Clinical Course                                          Diagnostic Considerations
    • Physical examination
           –   Irritable; thin, sparse hair                                      • Recurrent thrush with 
           –   Vital signs:  T = 98.4°F, RR = 22, SPO2 = 99% RA                    failure to thrive
           –   Good airflow in all lung fields
           –   Oral thrush and diaper dermatitis
                                                                                 • Family history of male 
    • Admitted for evaluation of failure to thrive                                 infant death
           – Nasogastric tube feeds started                                      • Low lymphocyte count1,2
    • Laboratory results:                                                               – Lymphocyte subpopulation 
           – Normal metabolic panel                                                       enumeration
           – CBC: WBC = 6200 cells/µL (80% N, 20% L)                                           • Lymphocyte subset: No T 
           – ANC = 4960 cells/µL, ALC = 1240 cells/µL                                            cells
                                                                                               • All lymphocytes were B 
                                                                                                 cells
                                                                                               • No serum antibodies 
                                                                                                 detected

                                                                            1. Comans-Bitter WM, et al. J Pediatr. 1997;130:388-393.
ANC = absolute neutrophil count     ALC = absolute lymphocyte count.   33   2. Buckley RH. In: Nelson Textbook of Pediatrics, 18th ed. 2007.   34




       Diagnostic Considerations (Cont’d)                                                                                 DIAGNOSIS
           Age-matched reference values for
         blood lymphocyte immunophenotyping
                                     Median Absolute
                                    Lymphocyte Count
    Age Groups (no.                 (× 103/µL; 5th-95th
    studied)                           percentiles)
    Neonatal (20)                     4.8 (0.7 – 7.3)                                Severe Combined Immunodeficiency
    1 wk – 2 mo (13)                  6.7 (3.5 – 13.1)
    2 – 5 mo (46)                      5.9 (3.7-9.6)                                               (SCID)
    5 – 9 mo (105)                    6.0 (3.8 – 9.9)
    9 – 15 mo (70)                    5.5 (2.6 – 10.4)
    15 – 24 mo (33)                   5.6 (2.7 – 11.9)
    2 – 5 y (33)                      3.3 (1.7 – 6.9)
    5 – 10 y (35)                     2.8 (1.1 – 5.9)
    10 – 16 y (23)                    2.2 ( 1.0 – 5.3)
    Adults (51)                       1.8 (1.0 – 2.8)
1. Comans-Bitter WM, et al. J Pediatr. 1997;130:388-393.
2. Buckley RH. In: Nelson Textbook of Pediatrics, 18th ed. 2007.       35                                                                      36
 Case Study 3                                                                               Case Study 3


             Severe Combined Immunodeficiency (SCID)                                                                                 Key Messages
      • True pediatric emergency1                                                                • Failure to thrive should prompt consideration of immune 
             – Absolute risk for death if not diagnosed                                            deficiency1
      • Defined as failure of lymphocytes to expand and function2                                • Common infection (recurrent thrush) might signify underlying 
             – T‐cell function is always reduced                                                   diagnosis in broader clinical context
             – T‐cell number usually greatly reduced                                             • Lymphocyte count is readily available and can be an indicator 
             – Other lymphocyte subsets can be reduced as well                                     of serious immune deficiency
      • Management includes3:                                                                           – Frequently overlooked
             – Immunoglobulin replacement                                                        • Family history of similar symptoms in infancy should raise 
             – Treatment of existing infections                                                    suspicion2
             – Curative hematopoietic stem cell transplantation 
                                                                                                 • Severity of clinical presentation should warrant more 
      • Caused by one of many different gene mutations3                                            aggressive evaluation
1. Rosen FS. J Pediatr. 1997;130:345-346; 2. Geha RS, et al. J Allergy Clin Immunol.
2007;120:776-794;
                                                                                            1. Bonilla FA, et al. Ann Allergy Asthma Immunol. 2005;94(5 suppl 1):S1-62.
3. Buckley RH. Annu Rev Immunol. 2004;22:625-655.                                      37   2. Schatz M, et al. J Allergy Clin Immunol. 2006;117:S495-S523.               38




                                                                                            Case Study 4


                                                                                                          12‐Year‐Old Girl With Sinusitis
                                                                                                History of Present Illness
                                                                                                • Congestion and green nasal 
                                                                                                  discharge for 2 weeks
                                          CASE STUDY 4                                          • 5 days low‐grade fever
                                                                                                • Tried over‐the‐counter 
                             12‐Year‐Old Girl With Sinusitis                                      decongestants
                                                                                                • Patient’s mother requesting 
                                                                                                  antibiotics


                                                                                                                                                                          40




 Case Study 4                                                                               Case Study 4


                               Past Medical History                                                                                 Clinical Course
      • 2 similar episodes of sinusitis this year                                                • Sinus CT scan shows pansinusitis
                                                                                                 • Consultations for allergy and GERD
      • On therapy with nasal steroid spray and oral                                               unrevealing
        antihistamines                                                                           • Initial immunologic evaluation:
      • Required tympanostomy tubes for recurrent                                                  normal IgG quantity, but poor quality
                                                                                                 • Patient vaccinated with unconjugated
        otitis in early childhood                                                                  pneumococcal polysaccharide vaccine (Pneumovax)
                                                                                                        – Antibody titers tested 4 weeks later: still poor 
                                                                                                 • Amoxicillin/clavulanate resolved symptoms for 8 weeks
                                                                                                 • Frequent school absences


                                                                                       41   GERD = gastroesophageal reflux disease                                        42
Case Study 4


                    Diagnostic Considerations                                                                      DIAGNOSIS
     • Recurrent upper respiratory infections since 
       early childhood
     • Failure to mount antibody response to 
                                                                                                         Specific antibody deficiency
       unconjugated pneumococcal polysaccharide 
       vaccine (Pneumovax)                                                                               with normal immunoglobulins
     • Normal IgG quantity, poor immunoglobulin 
       quality


                                                                                     43                                                                   44




Case Study 4                                                                              Case Study 4
                          Specific Antibody Deficiency 
                         With Normal Immunoglobulins                                                             Key Messages
     • Defined as the presence of normal                                                     • Recurrent upper respiratory tract infections can be 
       immunoglobulin quantity, but one or more of                                             due to poor quantity OR quality of antibody
       the IgG subclass levels are below normal                                              • Individual infections do not have to be life 
           – Appears to be transient in many cases                                             threatening or unusual
                                                                                             • Recurrence of infection can cause significant 
     • Treatment is aimed at improving quality of life                                         morbidity
           – Anti‐infective prophylaxis                                                      • Antibody abnormalities can occur in the setting of 
           – Occasionally, immunoglobulin replacement                                          normal immunoglobulin quantity1
     • Genetic cause and mechanism unknown                                                       – Diagnosis: specific antibody deficiency with normal 
                                                                                                   immunoglobulins

1. Immune Deficiency Foundation. In: Patient & Family Handbook for Primary
Immunodeficiency Diseases. 4th ed. Towson, MD: Immune Deficiency Foundation; 2007.   45                                                                   46




                                                                                          Case Study 5


                                                                                             8‐Month‐Old Boy With Pneumonia
                                                                                            History of Present Illness
                                                                                            • Fever and cough for 2 days
                                                                                            • Crackles over right lung
                                        Case Study 5                                          base
                                                                                            • Prescribed antibiotics
                                                                                            • Returns 3 days later with
                    8‐Month‐Old Boy With Pneumonia                                            continued fever
                                                                                            • Chest X‐ray confirms right lower lobe (RLL) infiltrate
                                                                                            • Admit to pediatric ward for parenteral antibiotics


                                                                                                                                                          48
Case Study 5                                                                                                    Case Study 5


                              Past Medical History                                                                                      Clinical Course
     • History of formula intolerance – required                                                                   • Exam — eczema with excoriation and
                                                                                                                     petechiae
       hydrolyzed formula                                                                                          • CBC – elevated white blood cell count
     • Mild‐to‐moderate eczema                                                                                       with thrombocytopenia
                                                                                                                       – Platelet = 35,000
     • Bruises on knees from crawling                                                                                  – Mean platelet volume = 5.2 fL
                                                                                                                   • Oncology consulted for thrombocytopenia
     • 5 episodes of otitis                                                                                            – Bone marrow aspirate – normal cell lineages
     • Maternal uncle died in infancy of                                                                           • Immunology consulted for pneumonia
                                                                                                                     and recurrent infection
       “pneumonia”                                                                                                     – Normal IgG quantity, poor quality
                                                                                                                   • Pneumonia resolves on parenteral antibiotics

                                                                                                           49                                                          50




Case Study 5


                     Diagnostic Considerations                                                                                              DIAGNOSIS
     • Hematologic abnormalities
            – Low platelet number and volume
     • Recurrent otitis
     • Patient antibody evaluation                                                                                             Wiskott‐Aldrich Syndrome
            – Poor antibody quality
     • Family history of death in infancy 



                                                                                                           51                                                          52




Case Study 5                                                                                                    Case Study 5


                     Wiskott‐Aldrich Syndrome                                                                                            Key Messages
     • Defined as triad of:                                                                                        • Pneumonia and otitis can be a hallmark of 
            – Recurrent infection, particularly sinopulmonary
            – Thrombocytopenia                                                                                       immunodeficiency
            – Eczema1,2
                                                                                                                   • Family history of severe infection should 
     • Treatment can include1,3
            – Anti‐infective prophylaxis                                                                             prompt consideration of immunodeficiency
            – Immunoglobulin replacement
            – Hematopoietic stem cell transplantation
                                                                                                                   • Hematologic abnormalities can indicate 
     • Caused by a variety of mutations in the gene encoding the                                                     immunodeficiency
       WAS protein
            – Leads to poor immune cell function2
            – X chromosome linked

1. Sullivan KE, et al. J Pediatr. 1994;125:876-885; 2. Conley ME, et al. Clin Immunol. 2003;109:272-277;
3. Orange JS, et al. Cell Mol Life Sci. 2004;61:2361-2385.                                                 53                                                          54
              Summary of Case Studies
1.   18‐month‐old boy with pneumonia: 
      – X‐Linked (Bruton’s) Agammaglobulinemia
2.   40‐year‐old girl with bronchitis: 
      – CVID
3.   9‐month‐old boy failing to thrive:                                                        When to Pick up the Phone
      – SCID
4.   12‐year‐old girl with sinusitis: 
      – Specific antibody deficiency with normal immunoglobulins
5.   8‐month‐old boy with pneumonia:
      – Wiskott‐Aldrich Syndrome




                                                                      55




           An Immunologist Can Help                                                                          When to Call…
• Immunologists are trained in the diagnosis and                                • Don’t hesitate to call for…
  management of primary immunodeficiency                                                – Infections:
     – The immunologist helps navigate disease complexities                                    • Recurrent, severe (eg, requiring hospitalization), unusual
          •   When/if to vaccinate                                                             • Out of the ordinary for your practice
          •   Specific infections to worry about                                               • Hallmark organisms (eg, Pneumocystis)
          •   Expectant management of comorbidities                                     – Abnormal screening tests
          •   Prophylactic therapies specific to diagnosis                              – Autoimmunity with infections
          •   Decisions about immunologic reconstitution
                                                                                        – Family history of infant death or failure to thrive
          •   Genetic counseling and family evaluation
          •   Management of immunoglobulin replacement                          • “…when something isn’t right, it’s OK to call”
     – Comanagement with the pediatrician is key to patient success             • It is OK if many referrals yield normal results

                                                                      57   1. http://www.info4pi.org/                                                         58




                                                                                               Screening Laboratory Tests
                                                                                • Some basic laboratory tests can raise 
                                                                                  suspicion of immune deficiency
                      Screening Module                                                  – Those you might already have
                                                                                        – Those that you would need to order


                                                                                • It is OK to call for an abnormal result in either 
                                                                                  of the above scenarios


                                                                                                                                                              60
                                               Screening                                                                                                                           Screening
    • Tests you may routinely order                                                                                                    • Tests you might order if you have suspicion of 




                                                        Median Absolute Lymphocyte
          – CBC                                                                      20
                                                                                     18
                                                                                                                                         immune deficiency1
             • Leukocytopenia
                                                                                     16                                                       – Immunoglobulin quantity




                                                              Count (× 10 /μL)
             • Low ANC                                                               14




                                                                         3
                                                                                     12                                                             • IgG < 5th percentile for age‐related norm
             • Low ALC                                                               10
                  – Special attention to infants                                      8
                                                                                      6
                                                                                                                                                    • IgA undetectable
                    with ALC < 5th percentile for
                                                                                      4
                    age‐related norm                                                  2
                                                                                                                                                    • IgM (if elevated in the context of low IgG)
                                                                                      0
          – Chest X‐ray                                                                                                                       – Immunoglobulin quality1
             • Small or absent thymic shadow                                            k- wk




                                                                                         5- y



                                                                                             lt s
                                                                                        5- mo
                                                                                         15 o


                                                                                          2- o

                                                                                        10 y
                                                                                         A 6y
                                                                                        2- mo



                                                                                        -2 o
                                                                                       9- m


                                                                                            m
                                                                                      15 m
                                                                                                                                                    • Low/absent antibody titers against vaccinations




                                                                                             5
                                                                                           10

                                                                                          du
                                                                                          -1
                                                                                     <1


                                                                                          5
                                                                                          9


                                                                                          4
                                                                                          2
    • Referral to an immunologist may be
                                                                                     w
                                                                                     1



      warranted without these tests                                                                                                    • Referral to an immunologist can be based on your 
                                                                             Error bars represent the 5th and 95th percentiles.
                                                                                                                                         suspicion without obtaining these tests
                                                                                                                                   Figure adapted from Dorsey MJ, Orange JS. Ann Allergy Asthma Immunol. 2006;97:590-595.
Comans-Bitter WM, et al. J Pediatr. 1997;130:388-393.                                                                    61        1. Bonilla FA, et al. Ann Allergy Asthma Immunol. 2005;94(5 suppl 1):S1-62.              62




                                                                                                                                                               “Capstone” Messages
                                                                                                                                        • Patients with PI require therapy
                                                                                                                                               – Many genetic PIs are permanent and do not 
                               Conclusion Module                                                                                                 improve


                                                                                                                                        • Certain patterns of common symptoms can 
                                                                                                                                          distinguish patients with PI from general 
                                                                                                                                          population


                                                                                                                                                                                                                            64




                                   Be Sensitive to PI                                                                                                  Benefits of Being Sensitive
     • Sensitivity over specificity
            – You have the power to increase sensitivity                                                                                • Early diagnosis reduces morbidity1
                  • Majority of patients with PI present in childhood
                  • Pediatricians are typically the first to encounter                                                                  • Lifesaving and curative therapies exist1,2
                    patients with PI
                  • Clinical patterns exist that are consistent with primary 
                    immune deficiency                                                                                                   • Diagnosed and treated, patients can lead 
            – The immunologist will work with you to increase                                                                             more normal lives3,4
              specificity and to diagnose patients
                                                                                                                                  1. Bonilla FA, et al. Ann Allergy Asthma Immunol. 2005;94(5 suppl 1):S1-62; 2. Orange
                                                                                                                                  JS, et al. J Allergy Clin Immunol. 2006;117:S525-553; 3. Skull S, Kemp A. Arch Dis
                                                                                                                         65       Child. 1996;74:527-530; 4. Gardulf A, et al. Clin Exp Immunol. 1993 92:200-204.           66
         What to Do Tomorrow…                                                     Thanks to Colleagues/Contributors
                                                                          • Contributors
                                                                            • Jordan Orange, MD, PhD
• Find an immunologist                                                      • Ken Paris, MD

• Think about your patients who demonstrate                                 • Jason Raasch, MD
                                                                            • Lisa Kobrynski, MD
  clinical patterns consistent with PI                                      • Jack Bleesing, MD

• Refer these patients and partner them with an                             • Ramsay Fuleihan, MD
                                                                            • Elena Perez, MD, PhD
  immunologist                                                              • James Verbsky, MD, PhD
                                                                            • Vivian Hernandez-Trujillo, MD
• Save lives!                                                               • Troy Torgerson, MD, PhD




                                                                     67                                               68




                       Resources
• Immunologists are everywhere, but you may need help 
  finding one
   – Immune Deficiency Foundation at www.primaryimmune.org
   – IDF Handbook for Providers, Diagnostic Guidelines
   – Jeffrey Modell Foundation Diagnostic and Referral Centers at 
     www.info4pi.org
• Want more Information on primary immune deficiency?
   – www.immunedisease.com
   – www.nichd.nih.gov/publications/pubs/primary_immuno.cf
   – www. AAAAI.org


                                                                     69

				
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