CROSS CANADA ROUNDS THE LONG CASE
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1 CROSS CANADA ROUNDS THE LONG CASE pollev.com/ww278 Dr. Wallace Wee, PGY-4 February 16, 2018
2 INTRODUCTION Objectives Exposure to an interesting clinical case Understand the management of this disease Outline Case presentation Background about disease and pulmonary sequelae
3 CASE: REFERRAL 12 year old M had recurrent pneumonia and was referred to respirology for PFT Unable to complete PFT Looks very fragile so CXR was ordered
4 W H AT D O E S T H I S C X R S H O W? p o l l e v. c o m / w w 2 7 8
5
6 A N Y ADD N I N F O Y O U WA N T T O K N O W? p o l l e v. c o m / w w 2 7 8
7 CASE: BACKGROUND Past Medical History CNS: HIE, CP, Global developmental delay, Strabismus S/P 2008 Resp:?sinus infection, Recurrent pneumonias, 2-3x per year sometimes requiring antibiotics CVS: pulmonary HTN, resolved PFO GI: Mild Hepatomegaly Heme: Pancytopenia, Splenomegaly Immunology: Hypogammaglobulinemia,?CMPA resolved,?prev Contact dermatitis of cheeks unclear history, no other eczema MSK: Bilateral club feet S/P 2007
8 CASE: BACKGROUND Past Medical History CNS: HIE, CP, Global developmental delay, Strabismus S/P 2008 Resp:?sinus infection, Recurrent pneumonias, 2-3x per year sometimes requiring antibiotics CVS: pulmonary HTN, resolved PFO GI: Mild Hepatomegaly Heme: Pancytopenia, Splenomegaly Immunology: Hypogammaglobulinemia,?CMPA resolved,?prev Contact dermatitis of cheeks unclear history, no other eczema MSK: Bilateral club feet S/P 2007 Pregnancy/Birth History GA 38+6, BW 2 kg C/S: breech, placental abruption APGAR: 2, 6, 8 Req d resus for resp. distress Had HIE, noted PTx (conservative) NICU 5/52; NGT Feeds 4/52, CPAP but no surfactant
9 CASE: BACKGROUND Medications occasionally flovent and ventolin Allergies: NKDA Immunizations: UTD
10 CASE: BACKGROUND Medications occasionally flovent and ventolin Allergies: NKDA Immunizations: UTD Family History Mother has history of asthma. Maternal FHx: asthma in grandma and aunty, great uncle has immunodeficiency NYD (who died of pancreatic cancer Dad has history of hypertension and hyperlipidemia. Brother has history of environmental allergies.
11 CASE: HISTORY History of RTI 2-3 per year Req d antibiotics for >1 RTI?Sinusitis?History of constitutional symptoms Recent History May/2016: LTRI Sx, Abx, 2/52 July/2016: Similar Nov/2016: RTI Sx, CXR, Abx April/2017: Same May/2017: IVIG for Hypogam Aug/2017: RTI, same CXR Sept/2017: Presented to HSC
12 CASE: PHYSICAL EXAM Cooperative but looks unwell, somewhat cachectic HR , RR 24, BP 100/70, O2Sat > 95%, Afebrile H/N: shoddy cerv LN, dysmorphic, very prominent jugular pulse Resp: BS ALL, decr. to bases, crackles to left anterior Cardiac: S1, S2 loud, Systolic grade 2 ejection murmur Abdo: ++ distension,?fluid wave, splenic area is dull, NT Skin: No axillary LN, no clubbing
13 D I F F E R E N T I A L D I A G N OS E S? p o l l e v. c o m / w w 2 7 8
14 DIFFERENTIAL DIAGNOSIS Infectious Organizing pneumonia Oncologic Lymphoma Pulmonary Metastases Inflammatory Sarcoidosis Vasculitis Immunodeficiency Metabolic?Syndromic/Genetic
15 W H AT A R E T H E N E X T S T E P S? p o l l e v. c o m / w w 2 7 8
16 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed
17 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed Bloodwork Hgb 80, MCV 74, Plt 80, WBC 1.9 ANC 0.9, Lymph 0.8 Na 138, K 4.5, Cl 100, Glc 5.2 Cr 47, BUN 5.4 Urate 434, LDH 508 ica 1.24, PO4 1.3, Mg 0.73 INR 1.0, PTT 31
18 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered
19 C T C H E S T F I N D I N G S? p o l l e v. c o m / w w [ ] C T C H E S T. AV I
20 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis
21 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis U/S Abdomen + Pelvis Mild hepatomegaly, marked splenomegaly CT Abdomen + Pelvis Gross splenomegaly, LAD, small volume ascites Concerning for lymphoproliferative disorder
22 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis ECHO
23 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis ECHO ECHO Significant phtn, RVSP > 63 mmhg (SBP 92 mmhg) No VSD/PDA Good biventricular systolic function
24 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis ECHO Overnight oximetry
25 O V E R N I G H T O X I M E T R Y?
26 Desat event index: 13.5 Longest Sat <90%: 8 48 sec
27 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis ECHO Overnight oximetry Bronchoscopy and BAL
28 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis ECHO Overnight oximetry Bronchoscopy and BAL Flow cytometry shows majority of lymphocytes are mature T cells. No hemosiderin-laden macrophages, no malignancy. No fungal elements. Infectious panel negative
29 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis ECHO Overnight oximetry Bronchoscopy and BAL LN Biopsy, BMA, BM Biopsy
30 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis ECHO Overnight oximetry Bronchoscopy and BAL LN Biopsy, BMA, BM Biopsy LN Biopsy Right inguinal LN biopsy Benign/reactive LN, no malignancy Bone Marrow Aspirate and Biopsy No clear morphological evidence of malignant infiltration
31 CASE: ACUTE MANAGEMENT Admitted to hospital Concern for lymphoma Managed as Tumor Lysis Syndrome Bloodwork completed CT Chest Ordered CT and US Abdomen + Pelvis ECHO Overnight oximetry Bronchoscopy and BAL LN Biopsy, BMA, BM Biopsy LN Biopsy Right inguinal LN biopsy Benign/reactive LN, no malignancy Bone Marrow Aspirate and Biopsy No clear morphological evidence of malignant infiltration
32 REVISITING DIFFERENTIAL Infectious Organizing pneumonia Oncologic Lymphoma Pulmonary Metastases Inflammatory Sarcoidosis Vasculitis Immunodeficiency Metabolic?Syndromic
33 REVISITING DIFFERENTIAL Infectious Organizing pneumonia Oncologic Lymphoma Pulmonary Metastases Inflammatory Sarcoidosis Vasculitis Immunodeficiency Metabolic?Syndromic/Genetic
34 REVISITING DIFFERENTIAL Infectious Organizing pneumonia Oncologic Lymphoma Pulmonary Metastases Inflammatory Sarcoidosis Vasculitis Immunodeficiency Metabolic?Syndromic/Genetic
35 CASE: FURTHER W/U Ruled out Malignancy and Tumor Lysis Syndrome Infection Immunoglobulins
36 CASE: FURTHER W/U Ruled out Malignancy and Tumor Lysis Syndrome Infection Immunoglobulins Immunoglobulin Quantification Sept/2017 IgA <0.1, IgG 6.7, IgM 0.5, IgE <25 Sept/2017 IgA <0.07, IgG 4.70, IgM 0.41 Aug/2017 IgA <0.07, IgG 5.00, IgM 0.35 July/2017 IgA <0.07, IgG 5.02, IgM 0.3 June/2017 IgA <0.07, IgG 3.99, IgM 0.29 IVIG started May/2017 IgA <0.07, IgG 0.37, IgM 0.16 April/2017 IgA <0.07, IgG 0.34, IgM 0.18, CH50 >60
37 CASE: FURTHER W/U Ruled out Malignancy and Tumor Lysis Syndrome Infection Immunoglobulins Lymphocyte Immunophenotyping
38 CASE: FURTHER W/U Ruled out Malignancy and Tumor Lysis Syndrome Infection Immunoglobulins Lymphocyte Immunophenotyping
39 CASE: FURTHER W/U Ruled out Malignancy and Tumor Lysis Syndrome Infection Immunoglobulins Lymphocyte Immunophenotyping Neutrophil Oxidative Burst Index PHA Stimulation Test CD40/CD40L Metabolic workup Genetic workup
40 Lung Biopsy CASE: FURTHER W/U Ruled out Malignancy and Tumor Lysis Syndrome Infection Immunoglobulins Lymphocyte Immunophenotyping Neutrophil Oxidative Burst Index PHA Stimulation Test CD40/CD40L Metabolic workup Genetic workup
41 Lung Biopsy CASE: FURTHER W/U Ruled out Malignancy and Tumor Lysis Syndrome Infection Immunoglobulins Lymphocyte Immunophenotyping Lung Biopsy Lymphocytes, majority are T cells with no significant antigen loss. Features of GLILD and BOOP Neutrophil Oxidative Burst Index PHA Stimulation Test CD40/CD40L Metabolic workup Genetic workup
42 CASE: LUNG BIOPSY Figure 1: Interstitial lymphocytic infiltrate and pneumocyte hyperplasia Figure 2: Lymphocytic infiltrate and non-necrotizing granulomas Lymphocytes, majority are T cells with no significant antigen loss. Features of GLILD and BOOP
43 W H AT D O E S I T A L L M E A N?
44 DIFFUSE LUNG DISEASE Kurland, ATS, 2013
45 DIFFUSE LUNG DISEASE Kurland, ATS, 2013
46 DIFFUSE LUNG DISEASE Kurland, ATS, 2013
47 DIFFUSE LUNG DISEASE Kurland, ATS, 2013
48 DIFFUSE LUNG DISEASE: PID Primary immune deficiency (PID) from genetic abnormality in immunity Phenotype comprises of 1+ of: Infection Auto-immunity Auto-inflammation Allergy Tumors Increase in PID detection due to whole exome sequencing Classification by the International Union of Immunological Societies (IUIS) Expert Committee for Primary Immunodeficiencies 2015, ~300 single-gene inborn errors of immunity have been identified Slide courtesy of Dr. Schaballie
49 Boushifa, J Clin Immun, 2015
50 CVID Common Variable Immunodeficiency Disorders (CVID) Primary antibody deficiency Hypogammaglobinaemia impaired production of specific antibodies after immunization increased susceptibility to infections Genetics: Phenotypical and genetic heterogeneity Epidemiology: Rarer in Children Monogenic forms probably count for only 2-10% of patients with CVID Pulmonary Sequelae: LIP GLILD Slide courtesy of Dr. Schaballie Hurst, J Allergy Clin Immun Pract, 2017
51 LY M P H O I D I N T E R S T I T I A L P N E U M O N I A
52 LIP: BACKGROUND Etiology: Unknown History 1973 Liebow and Carrington describe LIP with hypogam Levinson et al, describe triad of CVID, pernicious anemia, LIP 1982 Kohler et al. report a case of nodular LIP with CVID and intestinal nodular lymphoid hyperplasia Up to date: Lymphocytic interstitial pneumonia in children Deheinzelin, Am J Respir Crit Care Med, 1996
53 LIP: HISTOLOGY Histology: Extensive interstitial (alveolar septa) infiltration of lymphocytes, plasma cells and histiocytes Polyclonality of infiltrates (whereas lymphoma will have mono-clonal expansion) Up to date: Lymphocytic interstitial pneumonia in children
54 LIP: HISTOLOGY Histology: Extensive interstitial (alveolar septa) infiltration of lymphocytes, plasma cells and histiocytes Polyclonality of infiltrates (whereas lymphoma will have mono-clonal expansion) Abnormal Lung Kendig s, Figure 63-5 Up to date: Lymphocytic interstitial pneumonia in children
55 LIP: HISTOLOGY Abnormal Lung Normal Lung Kendig s, Figure 63-5
56 LIP: HISTOLOGY Abnormal Lung Normal Lung Lymphoid Nodule Kendig s, Figure 63-5
57 LIP: HISTOLOGY Septal Thickening Up to date: Lymphocytic interstitial pneumonia in children
58 LIP: CLINICAL PRESENTATION Symptoms (slowly progressive) Asymptomatic, cough, dyspnea, weight loss, fever, pleuritic CP, fatigue, arthralgias Physical Exam Clubbing, HSM, LAD Crackles, tachypnea Park, Clin. Imm., 2010
59 LIP: INVESTIGATIONS CXR CT Immunoglobulin Lung Biopsy Other: PFT Up to date: Lymphocytic interstitial pneumonia in children Kendig s, Figure 63-6
60 LIP: PROGNOSIS Prognosis: unknown Treatment:?Steroids?Pneumocystis prophylaxis?azathioprine, cyclophosphamide, cyclosporine, rituximab?bronchodilators?ivig in CVID Arish, Thorax, 2006 Park, Clin. Imm., 2010
61 G R A N U LO M AT O U S LY M P H O C Y T I C I N T E R S T I T I A L L U N G D I S E A S E
62 GLILD Definition: Non-infectious, diffuse lung disease complications that develop in CVID patient Exhibit both granulomatous and lymphoproliferative histologic patterns consisting of LIP, follicular bronchiolitis, lymphoid hyperplasia Granulomas are nonnecrotizing and non-caseating Pathogenesis: Not clearly understood?impaired T-cell function leading to abnormal sequestration of antigen and formation of granulomas Associated: CVID, Infection (HHV-8, EBV, CMV),?TNF-alpha Prevalence: 8-22% of CVID pts Jesenak, Frontiers in Peds, 2014 Park, Clinical Immunology, 2010
63 GLILD: PREDICTORS Hartono, et al., Ann Allergy Asthma Imm, 2017
64 GLILD: HISTOLOGY Jesenak, Frontiers in Peds, 2014 Rao, Hum Pathol, 2015
65 GLILD: IMAGING CXR HRCT Chest Jesenak, Frontiers in Peds, 2014 Rao, Hum Pathol, 2015
66 GLILD: PROGNOSIS Population 69 patients with CVID > 16 years old; divided into 3 groups based on respiratory symptoms and radiographically Intervention Retrospective study Comparison (See Table 1) Outcome (Median Survival) Group 1, 2, 3B: 28.8 years Group 3A: 13.7 years P < Bates, J Allergy Clin Imm, 2004
67 GLILD: MANAGEMENT British Lung Foundation and UK PID Network Consensus Statement Treatment Prednisone PO minimum 10 to 20 mg/d, to a maximum of 1-2 mg/kg/d. Commonly used second agent Azathioprine, Rituximab, MMF Adjust based on symptoms, lung function, imaging No consensus for Prophylactic antibiotics Expectant management Hurst, J Allergy Clin Imm Pract, 2017;5:4
68 B A C K T O PAT I E N T
69 CURRENTLY Currently on a prednisone wean Symptoms have resolved Follow up on CT Chest shows improvement to nodules WES still pending /12/img jpg
70 CONCLUSIONS Objectives Exposure to an interesting clinical case Understand the management of this disease Take Home Points GLILD mainly in adults but can occur in pediatrics Understand that GLILD is a pulmonary manifestation of CVID Recognize that it is associated with increased mortality Management is not yet well-defined
71 REFERENCES Vece, Chest, 2016;149:3 Kurland, Am J Respir Crit Care Med, 2013;188:3 Hime, Ped Pulm, 2015;50 Hurst, J Allergy Clin Imm Pract, 2017;5:4 Bates, J Allergy Clin Imm, 2004;144:2 Rao, Hum Pathol, 2015;46:9 Park, Clin Imm, 2010;134 Hartono, Ann Allergy Asthma Imm, 2017;118 Jesenak, Frontiers in Peds, 2014 Arish, Thorax, 2006 Up to date: Lymphocytic interstitial pneumonia in children Chernick, Kendig s, 2006 Deheinzelin, Am J Respir Crit Care Med, 1996 Boushifa, J Clin Immunol, 2015
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