SCID & CID for FRACP. Theresa Cole 02/06/2014

Transcription

1 SCID & CID for FRACP Theresa Cole 02/06/2014

2 Outline 4 parts with breaks! Some real-life cases SCID Presentation Common forms Management CID Recognising different phenotypes What SCID/CID exam questions might look like

3 The Problem Infancy + early childhood - immune system encounters antigens for first time, mounting immune responses and acquiring memory. Young children mix with other children in families or nursery Exposed to many pathogens. Young children vulnerable to infection - recurrent infection is common. Exposed to many pathogens

4 The Problem Recurrent or persistent infection is major manifestation of primary immunodeficiency (PID). Significant treatment advances make it important to recognize children with PID early, before significant end organ damage occurs to maximize opportunity for successful treatment.

5 Part 1: Real cases from the UK

6 Case 1

7 Background 6 month old male Normal pregnancy & delivery 1 st child, healthy parents Presented to GP in November (Winter) with 2/7 hx cough & vomiting Had signs of respiratory distress Saturations recorded as 75-80% Referred to local hospital

8 Arrival in hospital CVS: HR 160 CRT 3sec RS: RR 36 Sats 80% in air Temp 35.7 BM 4.5 GCS: 15

9 Results FBC: Hb 139 WCC 21.7 Plt 533 Neut 6.6 Biochem normal CRP 0.5

10 What is your diagnosis? Bacterial pneumonia Fungal pneumonia Viral pneumonia/pneumonitis PCP pneumonia Something else

11 local Started optiflow 20ml/kg fluid bolus then maintenance IV fluids Cefotaxime Hypoxic despite optiflow sats mid 80s Marked resp distress Intubated & ventilated at local hospital Transferred to PICU

12 Progress in PICU Ventilated % O2 - High pressures On co-amoxiclav + clarithromycin Resp PCR rhinovirus Blood PCR CMV positive log 3.3 / 1890gEq/ml

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14 Would you investigate further?

15 Further progress Extubated after 9 days of ventilation Discharged from PICU to ward on nasal cannula O2 BAL PCP positive PCR Started high dose cotrimoxazole

16 What immunology investigations would you like to do?

17 Immunology investigations IgG<1.09 IgA <0.05 IgM 0.99 CD3 8554, CD4 5920, CD8 2417, CD , NK 206 Naïve B cells 98%, memory B cells 1%, CSM B cells 0% Lymphocyte proliferations normal Blood CMV PCR log 3.7/ 7387 geq/ml

18 Current status Absent CD40L expression & mutation confirmed Diagnosis = CD40L deficiency Treated with valganciclovir for CMV On co-trimoxazole + azithromycin prophylaxis On SCIg Awaiting HSCT

19 Case 2

20 Presentation 14 month old female, Kurdish Turk 2 nd child, well 4yo brother Presented to local hospital with 3/52 cough & fever Temp 39 o C HR 160 CRT <2 sec RR 40 Sats 95% in air Chest clear on auscultation Perianal ulcer

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22 What is your diagnosis? Bacterial pneumonia Fungal pneumonia Viral pneumonia/pneumonitis PCP pneumonia Something else

23 Background History of developmental delay & irritability from early in life 3 previous admissions to local hospital with LRTI Diarrhoea for first 5-6 months of life Referred to neurologist for investigation of developmental delay & irritability

24 Developmental status Sits in tripod stance Global hypotonia Doesn t transfer objects hand to hand Fixes & follows Smiles occasionally Hearing test normal

25 What investigations would you do?

26 Initial results FBC: Hb 10.1, WBC 0.77, Plt 232, Neut 0.18, lymph 0.1 MCV 67.7 Biochem (13/10): Na 140, K 3.8, Ur 0.9, Creat 29, alb 33, adj Ca 2.45, PO4 1.25, ALP 309, AST 35, ALT 67, CRP 80, cholesterol 5.03, triglycerides 1.42 Urate <6 CSF: 0 wbc, 0 rbc, no organisms seen MRI brain normal

27 Progress at Alder Hey ID/imm requested to review Continued fever Examination unremarkable other than perianal ulcer

28 What immunological investigations would you like to do?

29 Results cont Lymphocyte subsets: CD3 9, CD4 0 CD8 10, CD19 49, NK 184 IgG <1.09, IgM <0.05, IgA <0.05 Blood CMV PCR positive log 4.9/ 71,475 geq/ml Blood EBV PCR positive <250gEQ/ml Resp PCR Rhinovirus positive

30 Diagnosis??

31 Progress PNP deficiency SCID Treated for CMV viraemia and possible fungal pneumonia Unconditioned matched sibling transplant

32 Part 2: SCID

33 What is SCID?

34 Severe COMBINED Immune Deficiency

35 What is SCID? It is not one disease! Characterised by abnormalities in T cell maturation & function With impact on B cell function Multiple different genetic causes X-linked & AR forms Most severe form of primary immunodeficiency Fatal if not recognised and treated More variable phenotype & immunological presentation recognised in recent years

36 Adaptive immune system

37 The classical presentation Well at birth Gradual drop off centiles Present with Persistent respiratory symptoms Chronic diarrhoea Recurrent/persistent oral thrush Bacterial infections less common due to persistent maternal IgG Can have chronic otitis media or serious bacterial infection

38 Examination findings No lymphoid tissue lack of tonsils! Wasted child Head circumference preserved Respiratory signs Tachypnoea Recession Crackles Cyanosis Abdo distension Oral thrush

39 Investigations Lymphopaenia Hypogammaglubulinaemia Remember maternal IgG Thin mediastinum on CXR No thymus

40 The other presentation - Omenn syndrome Rash present from early in life Loss of hair inc eyebrows Failure to thrive Infections including skin eg Staphylococcal or psuedomonas

41 Omenn examination findings Erthymatous exfoliating erythroderma Alopecia Lymphadenopathy Hepatosplenomegaly Miserable -?related to high circulating cytokines Respiratory signs Tachypnoea Recession

42 Omenn investigation findings Lymphocytosis! Eosinophilia High IgE

43 Atypical SCID Increasingly recognised in recent years Children are older Don t present with typical SCID features Severe prolonged infection Autoimmune features Granulomatous skin rashes

44 Comparison of features of different SCID types Classical SCID Omenn Syndrome Atypical SCID Present in infancy Present in infancy Present >12 months of age Persistent viral respiratory +/ gastrointestinal infection Erythroderma Pneumocystis jiroveci pneumonitis Alopecia bronchiectasis Recurrent, severe, prolonged viral infection Disseminated BCG infection Hepatosplenomegaly Autoimmune cytopenias Failure to thrive Massive lymphadenopathy Failure to thrive Superficial candidiasis Inflammatory pneumonitis/enteritis Granulomatous cutaneous lesions Absent lymphoid tissue Raised IgE EBV-associated lymphoproliferation Absent immunoglobulins Eosinophilia Partial or restricted antigen-specific antibody responses Absent T lymphocytes Lymphocytosis Lymphopenia Van der Burg & Gennery. Eur J Pediatr (2011)

45 Investigations for SCID Easy things first: Full Blood Count Lymphopaenia/lymphocytosis (may be normal) Chest X-ray Flow cytometry for lymphocyte subsets Evaluation of T, B & NK cell numbers Need appropriate age related reference range Immunogloblin G, A,M & E T cell repertoire

46 The genetics of SCID

47 Prevention of cell apoptosis DNA replication ADA γc cytokine-dependent signals γc, JAK-3, (IL7Ra) NK Pre-TCR/TCR signalling CD45, CD3δ, ε CD8 HSC CLP THYMUS CD4 V(D)J recombination Rag 1/ 2, Artemis B Adapted from Fisher et al, Immunol Rev 2005

48 Clues about the underlying diagnosis T- B+ B- NK- NK+ NK- NK+ γc, JAK-3 IL7Ra, CD45, CD3δ, ε, Coronin- 1A, ZAP-70, ADA, AK2 RAG1/2, Artemis, Cernunnos

49 Common Gamma Chain SCID Most common form X-linked Mutations in common gamma chain of IL2 receptor Also present in IL4,7,15,21 R Prevents signalling via IL2 & downstream activation AR forms T-B+ SCID due to JAK3 & IL7RA

50 Defects in V(D) J recombination Required for TCR & BCR development First phase lymphoid specific Later phases not specific NHEJ pathway Results in radiation sensitivity

51 Presence of T cells in SCID May be maternal Maternal cells detectable in 50% of B SCID and in 80% of B+ SCID Hypomorphic mutations resulting in oligoclonal T cells with peripheral expansion RAG, Artemis

52 Other forms of SCID

53 Adenine Deaminase deficiency Defect in purine metabolism pathway Results in accumulation of toxic metabolites Leads to premature cell death of lymphocyte precursors Can result in progressive loss of T/B cells Typical costochondral junction flaring Neurological involvement Can be partly corrected with PEG-ADA

54 Purine nucleoside phosphorylase (PNP) deficiency Often less severe but can present as SCID Progressive accumulation of toxic metabolites Results in progressive loss of T cells Neurological involvement

55 Others that can present as SCID MHC II Deficiency ZAP-70 kinase deficiency 22q11 complete DiGeorge

56 Treatment Supportive care Treatment of infections HSCT Outcome depends on: Clinical status Donor diagnosis Gene therapy ADA Common gamma chain

57 Any questions on SCID?

58 Part 3: Combined immunodeficiencies

59 Combined immunodeficiencies Not as severe as SCID Often have associated features that give clues to diagnosis Autoimmunity can be a significant feature Look for clues in the question for the specific phenotype!

60 Conditions to be covered CD40L Deficiency Cartilage Hair Hypoplasia 22q11/CHARGE WAS Ataxia Telangectasia DOCK8 HyperIgE Schimke

61 CD40L deficiency Most common form of Hyper IgM syndrome X linked Expressed on activated CD4+ T lymphocytes Severely reduced IgG & IgA production Half have elevated IgM at presentation (Levy et al 1997) Memory B cells absent or severely reduced in number

62 Clinical manifestations in CD40 ligand deficiency Humoral immunodefieicny results in bacterial infection, particularly sinopulmonary Opportunistic infections relate to impaired T cell interaction with monocytes/macrophages PCP Cryptosporidiosis & sclerosing cholangitis CMV Autoimmunity Malignancy

63 Cartilage Hair Hypoplasia AR Mutationsin RMRP (RNase MRP RNA)involved in processing of mitochondrial RNA and cell cycle control Variable immune phenotype from SCID to normal Predominantly T cell problem Thin, sparse hair Bone marrow failure Results in cytpoaenias Autoimmunity Malignancy risk

64 22q11 De novo mutations (can be AD) Affects thymic development Lymphopaenia Variable presentation with infection from SCID to near normal Cardiac defects Characteristic facies Cleft palate Behavioural difficulties

65 Management of immune defect in 22q11 <1% present with SCID phenotype Thymic transplant curative Others managed with prophylactic antibiotics +/- immunoglobulin replacement Need management of autoimmune features

66 CHARGE syndrome Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies De novo mutation or AD Mutation in CHD7 Also have defect in thymic development Range of immune phenotype T cell lymphopaenia Rarely SCID phenotype

67 Wiscott-Aldrich Syndrome X-linked WASP protein required in actin polymerisation & signalling Thrombocytopaenia Immunodeficiency Malignancy risk Eczema TIME!

68 Presentation of WAS Petechiae in infancy Blood in stool Eczema may be mild Prolonged viral illnesses Severe chicken pox Bacterial infections more problematic over time Progressive immunodeficiency Definitive treatment = HSCT

69 Hyper IgE: Job s syndrome Hyper IgE = a phenotypic description rather than a single diagnosis! Most well described form = STAT3 mutation AD, often de novo mutations High IgE Poor responses to vaccines Bacterial infections eg staphylococcal pneumonia with abscess formation Fungal infection Eczema Fractures Delayed loss of primary teeth Tangye et al. J Immunol. 2009

70 Ataxia telangectasia Form of DNA repair defect AR Due to mutations in ATM Progressive cerebellar ataxia Variable immunological phenotype Progressive lymphopaenia with antibody deficiency Risk of malignancy Death normally early adulthood

71 DOCK 8 AR Mutations in DOCK8 regulator of intracellular actin reorganization Eczema High eosinophils, high IgE Low IgM Impaired T cell proliferation Severe viral & bacterial infections of skin NIH NIAD website

72 Schimke immune-osseus dysplasia AR Mutations in SMARCAL1 involved in chromatin remodelling Short stature associated with spondilo-epiphyseal dysplasia Typical facies History of intrauterine growth retardation Nephropathy with steroid resistant nephrotic syndrome Cerebral ischaemia Develop bacterial, viral, and fungal infections May present as SCID (rare)

73 Management of CIDs Depends on severity of condition! Treat the specific infection Prophylactic antibiotics Immunoglobulin replacement HSCT for some

74 Any questions on CIDs?

75 Part 4: How to approach questions

76 Is this immunodeficiency?

77 Features in the history 10 warning signs of PID Eight or more new ear infections within 1 year Two or more serious infections within 1 year Two or more months on antibiotics with little effect Two or more episodes of pneumonia within 1 year Failure of an infant to gain weight or grow normally Recurrent deep skin or organ abscesses Need for intravenous antibiotics to clear infections Persistent thrush in mouth or fungal infection on skin Two or more deep seated infections e.g. sepsis, meningitis A family history of PID

78 If this is immunodeficiency, what type is it?

79 Infections which may point to a diagnosis Microbial clues Meningococcal (>1 episode, unusual serotype, or +ve family history Pneumococcus (recurrent) Invasive Aspergillus Staphylococcus Respiratory clues Pneumatocoeles Persistent bronchiolitis PJP Interstitial pneumonitis Recurrent pneumonia Bronchiectasis Gastro clues Sclerosing cholangitis Liver abscess Failure to thrive Complement deficiency Asplenia, complement deficiency, antibody deficiency CGD CGD, Hyper IgE Hyper IgE SCID SCID SCID, CD40L, NEMO, MHC II deficiency Antibody deficiency Antibody deficiency CD40L deficiency CGD SCID

80 Are there other clues to help point you in the right direction?

81 Some past questions..

82 Q1 A 6 month-old presents with a two-month history of failure to thrive and loose stools since 2 months of age and recurrent candidal mouth infections. Weight has decreased from the 50 th to the 3 rd centile. The child has a dry cough which has persisted for the last week. A CXR is shown: [Normal heart size with patchy peri-hilar and diffuse changes throughout lung fields] What is the most likely diagnosis? 1) Chronic granulomatous disease 2) SCID 3) XLA 4) Wiscott Aldrich Syndrome 5) DiGeorge syndrome

83 Q2 A boy presents with mild eczema and a thrombocytopenia. Which of the following tests would best distinguish between Wiskott Aldrich Syndrome and ITP? A. IgG B. Immunoglobulins C. Platelet volume D. Platelet antibodies E. T and B cell numbers

84 Q3 A ten year old boy with Hyper IgE syndrome presents with fever and cough. A CXR shows opacities. Which of the following is the most likely causative organism? A) Aspergillus B) Candida C) Staphylococcus Aureus D) Mycoplasma E) Pneumocystis

85 Q4 A 2 month old presents with failure to thrive, oral thrush that recurs whenever oral antifungals are ceased, weight loss and eczema. He has not regained his birthweight. Investigations reveal: Hb 128, WCC 3 (low), Lymphocytes 1 (low), Neutrophils 2.3 (normal), IgG 2.3 (normal), IgM 0.1 (low), IgA 0.5 What is the most likely diagnosis? A. SCID B. Wiskott Aldrich syndrome C. X Linked Agammaglobulinaemia D. Chronic mucocutaneous candidiasis E. Hyper IgE syndrome

86 Who to Investigate? difficult - infection in childhood is very common! High index of clinical suspicion is needed Compared with other children, an immunodeficient child is likely to have: more infections that take longer to resolve or have an atypical course Infections with common organisms may run an unusually severe course, e.g. haemorrhagic chickenpox, or fail to respond to standard treatments

87 Summary for real life

88 Who to Investigate? difficult - infection in childhood is very common! High index of clinical suspicion is needed Compared with other children, an immunodeficient child is likely to have: more infections that take longer to resolve or have an atypical course Infections with common organisms may run an unusually severe course, e.g. haemorrhagic chickenpox, or fail to respond to standard treatments

89 Who to Investigate? Infection should be taken in context with other findings in history & examination and FH When evaluating the number of infections, other factors: parental smoking, attendance at nursery anatomical problems should be considered.

90 Summary for exams Immunodeficiencies are rare in real life but not in exams! Decide which components of immune system are affected according to infection type Look for other clues in the history Know the key features & infections for the main immunodeficiencies

91 Any questions?