Case Based Introduction to Adult Disease and Management.pdf

Cys$c 'brosis Noel G McElvaney Learning outcomes Recognise adult symptoms of cys8c 9brosis, and conduct a pa8ent's history and examine Evaluate therapeu8c and surgical op8ons for advanced CF  CF: Presenta$on in childhood Birth/ Infancy Failure to thrive Meconi...

Cys$c 'brosis Noel G McElvaney Learning outcomes Recognise adult symptoms of cys8c 9brosis, and conduct a pa8ent's history and examine Evaluate therapeu8c and surgical op8ons for advanced CF  CF: Presenta$on in childhood Birth/ Infancy Failure to thrive Meconium ileus/ intes8nal obstruc8on Tes8ng – sibling with CF Newborn screening (2012 – onwards) Childhood Failure to reach growth milestones Recurrent chest infec8ons Abdominal cramps/ diarrhoea  CF: Clinical Manifesta$ons in adults Liver disease Pan-Bronchiectasis Distal intestinal obstruction syndrome Pancrea8cobstruc8on/ Intes8nal insuPciencyDIOS Nasal Polyps/Sinusi8s CBAVD Congenital bilateral absence of Vas Deferens CF related Diabetes Osteoporosi s CF Renal disease  CF: Respiratory Disease Decreased mucociliary clearance Recurrent pulmonary exacerba8ons DiVuse Pan-broncheictasis Mucus plugging Obstruc8ve airways disease Respiratory failure Symptoms of lung disease in CF Cough with increased volume and purulence of sputum Ques8ons Do you have a cough, is it chronic or comes and goes , what brings on the cough? How much phlegm (sputum) do you produce a day- 1cup, 2 cups, a spoonful? Is the sputum produc8on constant throughout the day What colour is the phlegm? Is there any blood in the phlegm? How much blood, is it mixed in with the phlegm, is it bright red or dark? CF Lung symtpoms Are you short of breath? On exer8on? Or at rest? How far can you walk on a \at surface before you become short of breath? Can you walk and talk at the same 8me? Have you shortness of breath going up hills or inclines Do you wheeze? Is it worse in the morning or evening? Is it aVected by weather? Is it worse on exposure to dusts or deodorants/perfumes Do certain foods make it worse? Have you any skin rashes? Other respiratory symptoms Chest pain What type of pain? Is it on one side? Is it worse on breathing in or coughing Are you SOB with the pain? Could it be mucus plugging or pneumothorax Sinus problems Is your nose frequently blocked? Do you get sinus headaches? Do you get frequent sinus infec8on?  CF: Exacerba$on Symptoms Respiratory symptoms  Produc8ve cough Sputum -  volume,  purulence,  viscidity  SOB  Wheeze  Haemoptysis Nasal/ sinus symptoms Dura8on of onset – few days- couple of weeks (Absence of febrile symptoms – common)  CF: Gastrointes$nal & Pancrea$c disease Condi8on Prevalence Malabsorp8on 85% GORD 25-80% Rectal prolapse 20% DIOS 16% Meconium ileus 6-20%  CF: GI manifesta$ons Pancrea8c insuPciency (present in the majority) Fady in9ltra8on of pancreas from birth (seen on U/S) Ques8ons: Have you diPculty keeping your weight up? Do you have any problems with your bowels? Any diarrhea, do you have diPculty \ushing your stools? Do you have any abdominal cramps? Is that associated with cons8pa8on or intermident diarrhea? Do you have abdominal pain? Is it constant or intermident? Recurrent Pancrea88s – only seen in PWCF with mild CF muta8ons, who are pancrea8c suPcient Do you ever have heartburn or indiges8on?  CF: Gastrointes$nal disease Large bowel Cons8pa8on Colonic carcinoma (in older pa8ents  30 years) Small bowel Distal intes8nal obstruc8on syndrome (DIOS) – recurrent abdo pain, no de9ni8ve clinical 9ndings, abdominal CT diagnosis Upper GI Vomi8ng, GORD – common with coughing Advanced disease – delayed gastric emptying – early sa8ety and vomi8ng  CF: Other manifesta$ons Liver disease – focal biliary cirrhosis, fady in9ltra8on, can lead to cirrhosis with splenomegaly, varices Any jaundice, itch, abdominal pain )gallstones), hematemesis CF related diabetes Polyuria, polydipsia, lack of energy, failure to gain weight Low bone mineral density/ osteoporosis – usually assymptoma8c, signi9cance unknown, no increase in incidence of fractures Growth retarda8on/ Delayed puberty Obstruc8ve azospermia – func8onal sterility in males (due to CBAVD) Do you have any children? CF Renal disease – dis8nct en8ty, compounded by aminoglycoside usage, and diabetes CF: Non-infec$ous respiratory complica$ons Haemoptysis – can be intermident, mild/moderate/severe Pneumothorax (pleuradiesis contraindicated) Allergic bronchopulmonary aspergillosis – wheeze, unresponsive to an8bio8cs, thick mucus plugs, raised IgE Atelectasis – due to mucus plugging. Can cause acute SOB and hypoxaemia (desatura8on) Advanced disease – Type II Respiratory failure, Pulmonary hypertension with Cor Pulmonale Past History Do you get a lot of chest infec8ons? How oien do you require an8bio8cs +/- steroids How oien would you require IV an8bio8cs? How oien do you have to go into hospital? Did you ever require help to breath like a ven8lator device? Can you remember whether you were in hospital much as a child? Were you in hospital for bowel problems as a child or adult Were you ever diagnosed with diabetes? Or osteoporosis? Do you ever get hypoglycemic adacks? Speci'c CF ques$ons Do you know what type of CF you have? Do you know what your last FEV1 was? Do you know what types of bacteria/fungi are in your sputum? How is your diabetes control? Do you know your HBA1C Have you had a recent dexa scan? Did you veer have a PEG tube inserted? Did you ever have a portocath? Have you ever been assessed for transplant? Did you ever have a thoracostomy/pleurodesis, thoracotomy Family history/social history When were you diagnosed with CF? Has anyone else in the family been diagnosed with CF? What do you work at? Have you any pets? Any hobbies? Do you smoke cigaredes? When did you start, when did you stop, how many a day for how long? Do you take recrea8onal/illicit drugs? Do you drink alocohol? How much: units , how oien, binging  CF: Maintenance Treatments What medica8ons are you on? Nebulized/Inhaled therapies Nebulized an8-pseudomonal an8bio8cs – Tobramycin, Colis8n, Aztreonam Nebulized DNAase – Dornase Alpha (‘Pulmozyme’) Nebulized 7% Hypertonic Saline Inhaled/ Nebulized bronchodilators – Salbutamol, Ipratropium Concurrent asthma – ‘Sere8de’ (Salmeterol/Flu8casone) or ‘Symbicort’ (Formoterol/Budesonide) An8-in\ammatories Azithromycin (orally, alternate days)  CF: Maintenance Treatments Allergic Bronchopulmonary Aspergillosis Daily oral prednisolone or Monthly iv Methylprednisolone ± Oral Itraconozole (12-18 months) Malabsorp8on Pancrea8c enzyme tablets – ‘Creon’ Vitamin ADEK – ‘Aquadek’ Proton pump inhibitors Oral nutri8onal supplements PEG feeds – ‘Pera8ve’, ‘Nutrison’ Diabetes: Insulin Liver disease Ursofalk  CF: Physical Findings General Inspec8on BMI, Delayed puberty Clubbed, Cyanosis +/- oxygen Tremor Tachypnea, using accessory muscles of respira8on Chest Hyperin\a8on, Portacath Crepita8ons, Wheeze Abdomen  Hepatosplenomegaly  PEG tube Diabetes: ** Occasionally there may be no added respiratory sounds, even during an exacerba8on  CF: Outpa*ent Monitoring FEV1 BMI Sputum CF culture *Compare with last results and trends  CF: Outpa*ent Monitoring Annual Measurements OGTT (or Hb A1C) Liver U/S Vitamin Levels Bone Densitometry CXR (Review date of last HRCT) IgE, RAST Aspergillus FBC, U&E, LFT’s, Ca/Phos, Protein, Albumin Chest X-Ray 8ndings CF: Respiratory Microbiology  CF: Respiratory Microbiology Pseudomonas Aeruginosa Staph Aureus Stenotrophomonas Maltophilia Burkholderia Cepacia Complex Atypical Mycobacteria Aspergillus Candida  CF: Improving Outcomes MulTdisciplinary team/ CF centers Aggressive anTbioTc tx/ nutriTonal supplementaTon/ airway clearance measures Adherence and aUenTon to detail Stringent infecTon control policy PaTent & parent educaTon Close Tes with Paediatric Referral Centers How do we predict morbidity/mortality? Mortality vs. FEV1% Kerem et al NEJM 1992 Is FEV1 alone enough? Clinical experience would demonstrate that many paTents survive beyond 2 years with an FEV1 40 60 Meq/L considered abnormal – Majority of CF children > 80mEq/L – Adults may have high false posiTve sodiums GeneTc tesTng a necessity now – 2 know mutaTons Neonatal screening  Clinical progress AUended CF centre Yearly infecTons as a child PancreaTc insuncient Went on holidays at age 19 – Severe respiratory tract infecTon – Treated with inappropriate anTbioTcs – Respiratory failure – Airliied home  On examinaTon Cachexia Clubbing Type 2 Respiratory failure – Using accessory muscles of respiraTon – Wheeze – Crackles throughout both lungs Very signiqcant mucus producTon Abnormal liver funcTon tests  CF: Respiratory Disease Decreased mucociliary clearance Recurrent pulmonary infecTons Diruse Pan-broncheictasis Mucus plugging ObstrucTve airways disease Respiratory failure  Diagnosis of acute exacerbaTons Increased cough Increased sputum Increased congesTon Increased dyspnea Increased faTgue Decreased appeTte Change in sputum Decreased FEV1  CF: Respiratory Microbiology Pseudomonas Aeruginosa Staph Aureus H.Insuenzae Burkholderia Cepacia Stenotrophomonas Aspergillus/Candida Atypical Mycobacteria  Treatment Intravenous anTbioTcs Chest physiotherapy NutriTonal supplementaTon DieteTc advice re pancreaTc supplementaTon Liver ultrasound Dexa scan  Intravenous an,bio,cs Select based on in vitro suscep,bility For Ps aeruginosa – Tobramcyin + an,-pseudomonal semi-synthe,c penicillin or 3rd genera,on cephalosporin or carbapenem Stenotrophomonas: sulphamethoxazole/trimethoprim-Septrin MRSA use vancomycin or linezolid. If MSRA use Gucloxacillin  CF: Respiratory Infec,ons Acute Treatment i.v. an,bio,cs – 2 weeks/ 2 agents Intensive airway clearance/chest physio Maintenance Treatment Daily airway clearance/ physiotherapy Nebulized an,bio,cs – Tobramycin/ Colomycin Azithromycin po Nebulized Dornase Alpha (rhDNase) Nebulized hypertonic saline (7%) Asthma treatments: Inhaled ICS/LABA NIPPV  Recombinant Dnase in CF 968 pa,ents –24 weeks Two diZerent dosing schedules vs. placebo T-Updra\ II Neb-u- mist neb, PulmoAide compressor Fuchs et al NEJM 1994 Chronic therapies  EZect of hypertonic saline on PFTs FEV and FVC increased during 1st 4 weeks with HTS No diZerence in linear slope of PFTs Absolute level of lung func,on from 4-48 weeks higher with HTS Elkins et al , NEJM 2006  Nutri,onal Management Majority have pancrea,c insubciency – Can test for faecal elastase Need pancrea,c enzymes-enteric coated Take with meals Titrate dosage Very high dosages , 15000 units per kg per day associated with complica,ons  Supplements and Vitamins ADEK CF pa,ents need 102% of calories of non CF child Scandishakes, for,sips, calogen etc.  Follow Up for CF Review every 3 months with sputum/ spirometry Every 6 months nutri,onal screen plus above One year evalua,on –includes CXR, Abdominal US Admit for exacerba,ons  CF: Monitoring Spirometry: FEV1 BMI Sputum CF culture Vitamin levels Oral glucose tolerance test RAST/IgE LFT’s Bone densitometry Liver U/S HRCT Thorax (Baseline)  Staphylococcus aureus May predominate in irst few years of life Debate as to need for prophylac,c an, staph. medica,on Seven year randomised placebo controlled trial of oral cepalexin from ,me of Dx – Decreased prevalence of S. aureus – Incidence of Ps. Aeruginosa increased – No evidence of clinical beneit  Pseudomonas Aeruginosa Associated with increased morbidity and mortality Once established dibcult to eradicate Treat aggressively at irst isolate  Early eradica,on Australia – 2 weeks i.v. tobramycin with either ,carcillen/clavulanate or ce\azidime – Followed by 2/12 of inhaled tobramycin – And oral ciproGoxacin p.o. for 1/12 Pseudomonas eradicated but emergence of other organisms-Aspergillus United States: CFF trail inhaled tobramycin b.d. for 28 days +/- ciproGoxacin for 14 days  Why is pseudomonas so bad? Resistant to an,bio,cs Virulence factors – Elastase – Alkaline protease Pro-inGammatory Dry powder tobramycin Aztreonam Modulators of CFTR Func2on Potentiators Increase CFTR gating Normal Gating Defect Increased Ion Levels of Low Chloride Flow Surface CFTR Flow  Changes from Baseline CFTR potentiator therapyrough Week 48 in Sweat Chloride, According to Study Group. 150mg q 12 hrs Double blinded placebo 84/83 48 weeks Primary endpoint FEV1 % predicted through 24 weeks Ramsey BW et al. N Engl J Med 2011;365:1663-1672 CFTR poten,ator therapy  Back to our pa,ent 40 years of age FEV1 c30% Desatura,ng on exercise Sputum – Stenotrophomonas – Occasionally pseudomonas BMI: 23  Clinical progress Despite ivaca1or – Severe exacerba5on – Intubated/ven5lated Tracheostomy Placed on transplant list In hospital long term as too debilitated to go home  Interim status p.Gly551Asp homozygote on ivaca1or Severely compromised pulmonary func5on Chronic Pseudomonas and Stenotrophomonas Tracheostomy in situ On ac5ve transplant list  COVID Pronounced and rapid deteriora5on within 2 days of symptom onset Respiratory rate 48 breaths/min Hypotension, tachycardic, febrile COVID swab posi5ve  CTs and CXRs A B C D McElvaney OJ, et al. Manuscript under review. Table 1a. Clinical and biochemical characteristics at time of ICU admission Variable Normal value or range Heart rate (beats/minute) 108 Respiratory rate 48 (breaths/minute) Blood pressure (mmHg) 103/68 Temperature (oC/oF) 39.5/103.1 Peripheral oxygen saturation 91 (%) Arterial blood gas PaO2 (kPa) 7.7 11.1-14.4 PaCO2 (kPa) 6.9 4.3-6.0 pH 7.45 7.35-7.45 PaO2:FIO2 (mmHg) 96 400-500 Lactate (mmol/l) 1.2 0.5-1.0 C-reactive protein (mg/l) 372 0-5 White cell count (109/l) 5.69 4.0-11.0 Neutrophils 4.59 2.0-7.5 Lymphocytes 0.87 1.0-4.0 Monocytes 0.21 0.2-1.0 Eosinophils 0.02 0.04-0.4 Hemoglobin (g/dl) 9.8 11.5-16.5 Alanine aminotransferase (IU/l) 13 0-41 Aspartate aminotransferase 36 0-40 (IU/l) Albumin (IU/l) 34 35-52 Urea (mmol/l) 3.2 2.8-8.1 Creatinine (µmol/l) 36 45-84 Lactate dehydrogenase (U/l) 704 135-225 Ferritin (ng/ml) 1646 13-150 Fibrinogen (g/l) 7.8 1.9-3.5 Procalcitonin 0.56 0-0.49 D-Dimer 3.2 0-0.5 Alpha-1 antitrypsin (g/l) 2.64 0.9-2.0 McElvaney OJ, et al. Manuscript under review. Table 1b. Inflammatory cytokines and neutrophil elastase activity levels relative to baseline Inflammatory mediators Baseline Most recent COVID-19† severe IECF* Blood cytokines (pg/ml) IL-1β 12.1 20.7 141.4 IL-6 63.8 97.4 571.3 IL-8 88.3 119.9 238.7 sTNFR1 2870.9 3615.1 4092.5 Airway cytokines (pg/ml) IL-1β 202.6 299.0 374.6 IL-6 104.7 198.4 633.9 IL-8 492.2 658.3 788.1 Airway NE activity (nM) 741.9 905.6 1298.8 McElvaney OJ, et al. Manuscript under review. McElvaney OJ, et al. Manuscript under review. McElvaney OJ, et al. Manuscript under review. A B C D McElvaney OJ, et al. Manuscript under review.  Post ICU Pa5ent extubated Back to wards: on bi-pap, extensive physiotherapy Transplant reassessment – S5ll COVID PCR posi5ve Eventually cleared COVID Transplanted 3 months post ICU discharge  What about more common muta5ons? 15.7% PWCF in Ireland G551D 6.5% R117H 54% of PWCF in Ireland F508 homozygotes 37.3% F508 heterozygotes 8.4% no copies of F508  Trika1a People with CF with – Single F508 and minimal func5on genotype – Elexaca1or, Tezaca1or, Ivaca1or Randomized double blind placebo controlled trial 24 weeks FEV1, exacerba5ons Exacerba5ons What about Lung In`amma5on? A B 0.0079 0.0208 0.0074 0.0212 0.0017 100 0.0060 10000 NE Activity level nM 8000 Neutrophils (106/ml) 80 0.6154 0.8445 60 6000 0.0086 0.1431 0.4055 0.1561 40 4000 20 2000 0 0 C 0.0024 D 0.0175 0.0107 0.0202 10000 15000 0.0180 Cat G Activity level nM PR3 Activity level nM 8000 0.0066 0.9771 10000 6000 0.3407 0.9434 0.1376 4000 0.7967 0.6305 5000 2000 0 0  Post Trika1a cytokines A B C 0.4001 0.0242 0.1113 0.0141