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Unusual Course ofUnusual Course of Necrotizing Pneumonia in a 7 g
Year Old Boy
Dr. Michal Gur, Dr. Joseph RivlinCarmel Medical CenterPediatric Pulmonology MeetingOctober 2012October 2012
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Case Presentation 1Case Presentation ‐ 1
• A.S., 7 years old• Generally healthy (…)• 13.11.11 – admitted to Carmel Medical Center• 6 days high fever; clinical pneumonia→ Azenil• 6 days high fever; clinical pneumonia → Azenil (outpatient clinic)No impro ement omiting LUQ abdominal pain• No improvement – vomiting, LUQ abdominal pain
• PE – fever 38.8; sat 98%; pale• Lungs –↓ air entry – lt.• LAB – WBC 20,000, 85% Neut; CRP 20 (0‐0.5), , ; ( )• CXR – LLL pneumonia; patchy atelectasis LUL
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13 11 1113.11.11
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Case Presentation 2Case Presentation ‐ 2
• Admitted for IV ampicillin treatment• Slow resolution –• After 3d – WBC 20,600, 76% Neut; CRP 19CXR li htl i b h• CXR – slightly worse; air bronchogram
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16 11 1116.11.11
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Case Presentation 2Case Presentation ‐ 2
f• Admitted for IV ampicillin treatment• Slow resolution:• After 3d – WBC 20,600, 76% Neut; CRP 19CXR li htl i b h• CXR – slightly worse; air bronchogram
• After 7d – fever ↓, improved general condi on, no vomi ng → discharged with oral moxypen (7d)( )
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Case Presentation 3Case Presentation ‐ 3
• 27.11.11 – one day after cessation of moxypen –fever, cough, vomiting
• CBC – WBC 25,300, Neut 80%; referred to hospitalhospital
• PE – ill, pale; no fever; normal sat.• Lungs ‐ ↓ air entry – lt.; CRP 11.2• CXR – worsening LLL infiltrateg
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27.11.11
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( d IV Zi f)29 11 11 (under IV Zinacef) 29.11.11
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Case Presentation ‐ 4
• No improvement ‐ fever ↑, ill appearingp ↑, pp g• BAL 29.11‐ PCR ++ Strep. PneumoniaeT t t it h d t ft i li d i• Treatment switched to ceftriaxone + clindamycin
• BUT – initially ‐ clinical, lab and X ray deterioration• Clinical – fever ↑• Lab CRP↑↑ (max 30); WBC↑↑ (max 32 000)• Lab – CRP ↑↑ (max 30); WBC ↑↑ (max 32,000)• CXR – severe & worsening changes; consistent with necrotizing pneumonia (presented in pediatric infectious diseases meeting)
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1 12 111.12.11
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3.12.11
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Case Presentation 5Case Presentation ‐ 5
• Continued ceftriaxone + clindamycin• Next few days ‐ very slow improvement – fever y y pgradually ↓; CRP to normal; WBC 19,000
• CXR lt side improving; changes appear on rt lung;• CXR – lt. side improving; changes appear on rt. lung; apparent granulomas
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7.12.11
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Case Presentation ‐ 6• Detailed history –
– Age 4yrs – multiple infected lesions following varicella– Recurrent perianal abscesses; surgery X 2– Recurrent folliculitis (summer)
Suspected immune deficiencyI l b li + I G b l t• Immunoglobulins + IgG subclasses; response to immunizations ‐ normal
• Discharged after 20d with moxypen & clindamycin (14d)
• Ambulatory follow up
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Follow UpFollow Up
• Clinical & lab improvement• CXR – worsening changes rt.; lt. improvingCXR worsening changes rt.; lt. improving
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26.12.11
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Follow UpFollow Up
• Clinical & lab improvement• CXR – worsening changes rt.; lt. improvingg g ; p g• CT – cavitary lesion (10mm) left, smaller right; bilateral granulomas; DD pyogenic process in abilateral granulomas; DD – pyogenic process in a patient with immune deficiency or a
l t digranulomatous disease
• History & clinical course & imaging →→ suspected CGDsuspected CGD
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CT 1CT - 1
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CT 2CT - 2
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CGD – Chronic Granulomatous Disease
• A rare immunodeficiency disorder• 1/200,000‐250,000 live births in the USA (Khanna et / , , (
al., RadioGraphics 2005)
• Defect in phagocytic “respiratory burst”p g y p y• Recurrent infections, usually with low grade pathogens; formation of abscesses & suppurativepathogens; formation of abscesses & suppurative granulomas; normal humoral and cellular i itimmunity
• Usual onset of symptoms – first 2 yrs
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CGD – Clinical FeaturesCGD Clinical Features• Purulent inflammation due to catalase‐positive, low p ,grade pyogenic bacteria
• Recurrent pulmonary infections – the most commonRecurrent pulmonary infections the most common abnormality (Khanna et al., RadioGraphics 2005; Kobayashi et al., Eur J Pediatr 2008; van den Berg et al., PLoS one 2009)
• 2 patterns of infection:– At interface between host & environment – pneumonitis;At interface between host & environment pneumonitis; infectious dermatitis; perianal abscesses
– Deep‐seated infections: purulent lymphadenitis; HSM; p p y p ; ;hepatic/perihepatic abscess
• Microbial prolifera on & leukocyte accumula on → p ygranuloma formation
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CGD – Clinical Features 2CGD – Clinical Features ‐ 2
• GI – gingivitis; esophagitis; rectal/ perianal abscess• Osteomyelitis – metacarpals, metatarsals, spine, y p , , p ,ribs
• Urinary GN; renal abscess; cystitis• Urinary – GN; renal abscess; cystitis• Lymphadenitis – chronic, suppurative, granulomatous; often requires drainage
• Skin – suppura ve lesions → granulomatous pp gnodules
• CNS – brain abscess• CNS – brain abscess
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CGD – non‐infectious complications
• Pyloric stenosis – sterile granulomas in antrum• Lesions in bowel → abdominal pain, diarrhea, → p , ,malabsorption, obstruction (DD – Crohn’s)
• Granulomas in urinary bladder→ obstructive• Granulomas in urinary bladder → obstructive uropathy
• Autoimmune – systemic/ discoid lupus (also x‐linked carriers); ITP; JRA; IgA nephropathy
• Related to abnormal neutrophil apoptosis• Pyloric/ bladder granulomas respond to steroids• Pyloric/ bladder granulomas respond to steroids
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CGD – Pulmonary ComplicationsCGD – Pulmonary Complications
• Pneumonia – 80% of CGD patients (Kendig’s 8th edition)• Pulmonary disease – major cause of morbidity & y j ymortality
• Up to 20% abscess/ empyema• Up to 20% ‐ abscess/ empyema• Usual clinical picture/ few signs & symptoms (esp. fungal infection)
• Staph. aureus (↓ with AB prophylaxis); p (↓ p p y );Aspergillus; B. cepacia – fulminant pneumonia
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CGD – Pulmonary Complications ‐2
• CGD registry – 368 patients; most common cause of death – pneumonia/ sepsis – Aspergillus 1st, B.
dcepacia 2nd (Winkelstein et al., Medicine 2000)
• CXR – extensive infiltration; hilar adenopathy; miliary pattern (hematogenous spread); may be – pleural effusion, pul. abscess, RML atelectasis
• Fungal infection – discrete nodular/ miliary/ pan‐lobular; hard to diagnose in early stages; g y g
• Aggressive treatment – to prevent spread into chest wall/ osteomyelitis of ribswall/ osteomyelitis of ribs
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CGD - Diagnosisg• Screening assays:1) NBT test (nitroblue tetrazolium); NBT is reduced by O2
‐ → converted from yellow to purple Normal ‐ >95% cells reduce NBT Carriers – 2 population of cells
2) DHR – dihydrorhodamine – 123; fluorescence – basedMore quantitative – also partial reduction
• A posi ve screening test → quan ta ve test Bactericidal assays (E.coli, Staph) Bactericidal assays (E.coli, Staph) O2 consumption, 02‐ production, H2O2
Analysis of oxidase components Analysis of oxidase components
• Genetic analysis
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NADPH OxidaseNADPH Oxidase• Res ng neutrophil → NADPH oxidase dormant• Phagocytosis → ac va on → transfer of electrons to
molecular oxygen – “respiratory burst” → forma on of f di lfree oxygen radicals
• Cytochrome b558 – the main catalytic component; in i ll 80 90% i ifi l bi d NA Hresting cells – 80‐90% in specific granules; binds NADPH
• 2 subunits – α (p22phox) and β (gp91phox)• S mula on → fuse with plasma membrane; cri cal for
electron transfer• Cytosolic oxidase – p47phox, p67phox (complex in rest),
p40phox• Interactions – complex‐membrane‐cytoskeletal elements
– critical for oxidase activation
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NADPH OxidaseNADPH Oxidase
(Kendig’s 8th edition)
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CGD ‐ Genetics• Mutations in one of 4 genes encoding subunits (gp91phox, p22phox, p47phox p67phox)p47phox, p67phox)• Most common – x‐linked recessive (gp91phox) – no NADPH oxidase activity• AR variants – milder disease• CGD registry – 76% X‐linked recessive; mean – 3yrs at diagnosis; AR –
7 8 hmean 7.8 yrs (Kendig’s 8th edition, Winkelstein et al., Medicine 2000)
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CGD TreatmentCGD ‐ Treatment• Early diagnosis; prophylactic antimicrobials; vigorous• Early diagnosis; prophylactic antimicrobials; vigorous treatment of infectionP h l ti d il i ↓ b t i l• Prophylactic daily resprim ‐ ↓ severe bacterial infections by 70%
• IFN‐ɤ X3/week – thought to reduce incidence & severity of infections
• Daily itraconazole – no concensus in literature• During infection – aggressive AB treatment (broad g gg (spectrum until culture results); anti fungal
• Inflammatory conditions/ obstructive lesions –• Inflammatory conditions/ obstructive lesions respond to steroids
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HSCT & Gene TherapyHSCT & Gene Therapy
• HSCT – hematopoietic stem cell transplantation –mixed results
• Best predictors of success – no overt pre‐existing infection at time of transplantation; Tx at earlyinfection at time of transplantation; Tx at early stage – before end‐organ damageC id i k b fit• Consider risk vs. benefit
• Gene therapy – still experimental; few reports –short – lasting positive effect (% normal neutrophils, relief of severe infections) (Malech et al., pProc Natl Acad Sci USA 1997; Ott et al., Nat Med 2006; Kang et al., Blood 2010)
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M i l 49 6 AR 37 8 XLMean survival – 49.6 yrs AR, 37.8 yrs XL
van den Berg et al., PLoS one 2009
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van den Berg et al., PLoS one 2009
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van den Berg et al., PLoS one 2009
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van den Berg et al., PLoS one 2009
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ConclusionsConclusions• CGD – a rare immunologic disorder; defect in• CGD – a rare immunologic disorder; defect in phagocytic “respiratory burst”
• Pulmonary infections – most common, significant morbidity & mortality
• Most commonly X‐linked recessive; AR – milder formform
• Prophylactic AB & aggressive treatment of infections prognosis↑infections – prognosis ↑
• HSCT – consider risk vs. benefit• Gene therapy – experimental; future hope…
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Back to Our Patient…Back to Our Patient
• Referred to Prof. Wolach (Meir Medical Center) –confirmed diagnosis of CGD
• DNA analysis – homozygous for the exon 7 mutation in NCF‐1 (579‐G>A 193‐Trp>stop)mutation in NCF 1 (579 G>A 193 Trp>stop)
• Started on resprim prophylaxis → stable• CXR – 28.2.12 (3⅟2 months after 1sthospitalization) – marked improvement; atelectasis LUL
** Should itraconazole be added? Should itraconazole be added?
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28.2.12
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Slovenia summer 2012