Necrotizing Pneumonia in a 7 Year Old Boy. Dr. Michal Gur, Dr. Joseph Rivlin Carmel Medical Center Pediatric Pulmonology Meeting

Transcription

1 Unusual Course of Necrotizing Pneumonia in a 7 Year Old Boy Dr. Michal Gur, Dr. Joseph Rivlin Carmel Medical Center Pediatric Pulmonology Meeting October 2012

2 Case Presentation 1 A.S., 7 years old Generally healthy ( ) admitted to Carmel Medical Center 6 days high fever;clinical pneumonia Azenil (outpatient clinic) 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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4 Case Presentation 2 Admitted for IV ampicillin treatment Slow resolution After 3d WBC 20,600, 76% Neut; CRP 19 CXR slightly worse; air bronchogram

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6 Case Presentation 2 Admitted for IV ampicillin treatment Slow resolution: After 3d WBC 20,600, 76% Neut; CRP 19 CXR slightly worse; air bronchogram After 7d fever, improved general condi on, no vomi ng discharged with oral moxypen (7d)

7 Case Presentation one day after cessation of moxypen fever, cough, vomiting CBC WBC 25,300, Neut 80%; referred to hospital PE ill, pale; no fever; normal sat. Lungs air entry lt.; CRP 11.2 CXR worsening LLL infiltrate

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9 (under IV Zinacef)

10 Case Presentation 4 No improvement fever, ill appearing BAL PCR ++ Strep. Pneumoniae Treatment tswitched to ceftriaxone + clindamycin i BUT initially clinical, lab and X ray deterioration Clinical fever 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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13 Case Presentation 5 Continued ceftriaxone + clindamycin Next few days very slow improvement fever gradually ; CRP to normal; WBC 19,000 CXR lt. sideimproving; improving; changesappearonrt appear rt. lung; apparent granulomas

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15 Case Presentation 6 Detailed history Age 4yrs multiple infected lesions following varicella Recurrent perianal abscesses; surgery X 2 Recurrent folliculitis (summer) Suspected immune deficiency Immunoglobulins li + IG IgG subclasses; bl response to immunizations normal Discharged after 20d with moxypen & clindamycin (14d) Ambulatory follow up

16 Follow Up Clinical & lab improvement CXR worsening changes rt.; lt. improving

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18 Follow Up Clinical & lab improvement CXR worsening changes rt.; lt. improving CT cavitary lesion (10mm) left, smaller right; bilateral granulomas; DD pyogenicprocess process ina patient with immune deficiency or a granulomatous disease History& clinical course & imaging suspected CGD

19 CT - 1

20 CT - 2

21 CGD Chronic Granulomatous Disease A rare immunodeficiency disorder 1/200, ,000, live births in the USA (Khanna et al., RadioGraphics 2005) Defect in phagocytic respiratory burst Recurrent infections, usually with low grade pathogens; formation of abscesses & suppurative granulomas; normal humoral and cellular immunityit Usual onset of symptoms first 2 yrs

22 CGD Clinical Features Purulent inflammation due to catalase positive, low grade pyogenic bacteria Recurrent 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; infectious dermatitis; perianal abscesses Deep seated infections: purulent lymphadenitis; HSM; hepatic/perihepatic abscess Microbial prolifera on & leukocyte accumula on granuloma formation

23 CGD Clinical Features 2 GI gingivitis; esophagitis; rectal/ perianal abscess Osteomyelitis metacarpals, metatarsals, spine, ribs Urinary GN; renal abscess;cystitis cystitis Lymphadenitis chronic, suppurative, granulomatous; often requires drainage Skin suppura ve lesions granulomatous nodules CNS brain abscess

24 CGD non infectious complications Pyloric stenosis sterile granulomas in antrum Lesions in bowel abdominal pain, diarrhea, malabsorption, obstruction (DD Crohn s) 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

25 CGD Pulmonary Complications Pneumonia 80% of CGD patients (Kendig s 8 th edition) Pulmonary disease major cause of morbidity & mortality Upto 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

26 CGD Pulmonary Complications 2 CGD registry 368 patients; most common cause of death pneumonia/ sepsis Aspergillus 1 st, B. cepacia 2 nd (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/ panlobular; hard to diagnose in early stages Aggressive treatment to prevent spread into chest wall/ osteomyelitis of ribs

27 Screening assays: CGD - Diagnosis 1) NBT test (nitroblue tetrazolium); NBT is reduced by O 2 converted from yellow to purple Normal >95% cells reduce NBT Carriers 2 population of cells 2) DHR dihydrorhodamine 123; fluorescence based More quantitative also partial reduction A posi ve screening test quan ta ve test Bactericidalassays assays (E.coli, Staph) O 2 consumption, 0 2 production, H 2 O 2 Analysis of oxidase components Genetic analysis

28 NADPH Oxidase Res ng neutrophil NADPH oxidase dormant Phagocytosis ac va on transfer of electrons to molecular oxygen respiratory burst forma on of free oxygen radicals Cytochrome b558 the main catalytic component; in resting 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

29 NADPH Oxidase (Kendig s 8 th edition)

30 CGD Genetics Mutations in one of 4 genes encoding subunits (gp91phox, p22phox, 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 mean 7.8 yrs (Kendig s 8 th edition, Winkelstein et al., Medicine 2000)

31 CGD Treatment Earlydiagnosis; prophylactic antimicrobials; vigorous treatment of infection Prophylactic dil 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 spectrum until culture results); anti fungal Inflammatory conditions/ obstructive lesions respond to steroids

32 HSCT & Gene Therapy HSCT hematopoietic stem cell transplantation mixed results Best predictors of success no overt pre existing infection at time of transplantation; Tx at early stage before end organ damage Consider risk ikvs. benefit Gene therapy still experimental; few reports short lasting positive effect (% normal neutrophils, relief of severe infections) (Malech et al., Proc Natl Acad Sci USA 1997; Ott et al., Nat Med 2006; Kang et al., Blood 2010)

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34 Mean survival 49.6 yrs AR, 37.8 yrs XL van den Berg et al., PLoS one 2009

35 van den Berg et al., PLoS one 2009

36 van den Berg et al., PLoS one 2009

37 van den Berg et al., PLoS one 2009

38 Conclusions CGD a rare immunologic disorder; defect in phagocytic respiratory burst Pulmonary infections most common, significant morbidity & mortality Most commonly X linked recessive; AR milder form Prophylactic AB & aggressive treatment of infections prognosis HSCT consider risk vs. benefit Gene therapy experimental; future hope

39 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) Started on resprim prophylaxis stable CXR (3⅟2 months after 1 st hospitalization) marked improvement; atelectasis LUL ** Should itraconazole be added?

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42 Slovenia summer 2012