Advanced Respiratory

What are common cases seen on general respiratory ward?

1. Chronic Obstructive Pulmonary Disease (COPD)

2. Acute viral pneumonia (including ’Flu and COVID-19)

3. Bronchiectasis (including pseudomonas colonisation and Cystic Fibrosis)

4. Pulmonary Fibrosis (Interstitial Lung Disease)

For this case answer the following questions

• What’s the likely diagnosis?

• What acute treatment does he need?

• What longer term tests / management might you suggest?

COPD steroids?

acute exacerbation of undiagnosed COPD give steroids and some nebulisers acutely and possibly abx

monitor O2 levels and blood glucose levels

long term use long acting preventative meds

diagnosing using spirometry with GP

What are the clinical features of COPD?

• Rare in under 35s

• Dyspnoea

• Chronic cough, may be productive

• Wheeze

• Advanced disease: fatigue, weight loss and anorexia

• Features in history: smoking history, occupational and industrial exposures.

• History of exacerbations

• Co-morbidities

• Impact on patient’s life

What are the clinical signs of COPD?

• Depends on severity / may be normal

• High RR

• Hyperexpanded / barrel chest

• Prolonged expiratory time (>5s), pursed lip breathing

• Use of accessory muscles

• Quiet breath sounds +/- wheeze

• Quiet heart sounds

• Can have basal crepitations

• Signs of cor pulmonale / RHF and CO2 retention: ankle oedema, raised JVP, warm, plethoric conjunctivae, bounding pulse, polycythaemia. Acutely – flapping termor

Define COPD.

• Common: ~12% of all general medical admissions

• Definition: fixed airflow obstruction (FEV1/FVC <0.7), persistent respiratory symptoms

• 95% smoking-related (typically >20 pack/years)

• Genetic susceptibility.

• Environmental and occupational factors

→ Encompasses a number of underlying pathologies including chronic bronchitis and emphysema

→ COPD occurs in 10-20% of smokers

→ Worldwide – biomass fuel exposure. Smoking with marijuana increases risk.

→ Environmental and occupational factors – dusts, chemicals, air pollution

→ Reduced maximal attained lung function due to events during gestation/birth/childhood may also be a risk factor

What is Panacinar emphysema?

dilated airspaces evenly distributed across acini

Centriacinar or proximal emphysema can occur with dilated air spaces in association with respiratory bronchioles

Periacinar or paraseptal emphysema can occur with dilated airspaces at the edge of the acinar unit and abutting a fixed struction such as pleura/vessel

Emphysema

Loss of elasticity, hyper inflammation and increased airspaces

Bronchitis

Mucus overproduction and hyper secretion

Describe and explain the pathology of COPD

• Chronic inflammation and fibrosis of small airways: CD8 lymphocyte, macrophage and neutrophil infiltration with release of pro-inflammatory cytokines

• Reduction in airway lumen

• Airflow limitation leads to gas trapping and static hyperinflation

• Recurrent infections may perpetuate airway inflammation

• Alveolar wall destruction, causing irreversible enlargement of acinar airspaces, subsequent loss of elastic recoil and hyperinflation

• Mucous gland hyperplasia, particularly in large airways

• With mucous gland hypersecretion: chronic productive cough

• Other mucosal damage:

• Squamous metaplasia – replacement of the normal ciliated columnar epithelium by a squamous epithelium

• Loss of cilial function: leads to impairment of normal functioning of mucociliary escalator

→ Chronic productive cough → Worsening of sx when quit smoking

→ emphysema (smoking big cause) and chronic bronchitis 9productive more likely) and respiratory symptoms

→ alveoli destruction tripod: assessors muscles

What are the two types of patient see with COPD?

1. Patient hypoxia and emphysema breathlessness and skinny

2. Bigger cyanotic chronic bronchitis mucus airways respiratory type 2 respiratory failure more non-invasive ventilation

What are the aims of COPD management?

• Smoking cessation

• Minimizing symptoms where possible

• Maintaining QoL

• Minimizing exacerbations

• MDT approach

• No treatment modifies disease progression (except smoking cessation)

Give examples Non-pharmacological management used in COPD.

• Smoking cessation

• Education

• Pulmonary Rehabilitation

• Diet

• Self-management plan

• Psychosocial support

→ Pulmonary rehab: MDT. RCT evidence that it improves ET, QOL, reduces hospital admissions.

→ Muscle mass, esp LL, reduced. Independent predictor of mortality and disability, independent of lung disease. May reflect systemic nature.

→ Graded exercise to improve muscle function, also includes breathing techniques and education.

→ Usually OP basis over several weeks.

→ Wt loss (concurrent OSA/OHS), but also if very breathless, calorific intake may be low and may be catabolic state.

→ Practical support at home, day centres, car disability badge, signs of anxiety + depression

State the Pharmacological management of COPD.

Inhaled therapy:

• Short-acting B2 agonists PRN

• LABA, LAMA or LABA/LAMA

• If 2 exac / year, or one hospital admission – start ICS/LABA. Not ICS monotherapy

• If persistent sx / exac – triple therapy

• Consider nebulizer therapy

• Oral methylxanthines (e.g. theophyllines)

• Oral steroids

• Mucolytics

→ Nebs – if pt unable to use inhalers / disabled or distressed with SOB despite maximal inhaler therapy. Significant placebo effect

→ Theophyllines – only continue if sx improve. Method of action is unclear – may have anti-inflammatory effect. Care regarding therapeutic/toxic levels (esp in elderly)

→ Carbocisteine: 4 week trial period. Meta-analyses – cause significant decrease in number of COPD exac and decrease number of days of disability (may only apply if not on ICS). Worth trying in mod to severe COPD with severe / prolonged exac, or those repeatedly hospitalized. Caution in peptic ulcer disease

What type of inflammation do COPD patient have?

Chronic worsened by smoke and recurrent infections

Describe how the following thing can occur.

Cor Pulmonale / Pulmonary Hypertension secondary to lung disease

• Thickened pulmonary arteriolar wall and remodelling with hypoxia

• Leads to increased pulmonary vascular resistance, pulmonary hypertension and impaired gas exchange

→ Also inactivity and deconditioning, muscle weakness and wasting: vicious cycle

How is COPD diagnosed?

• Spirometry: FEV/FVC <0.7 post bronchodilation

• With respiratory symptoms

• Minimal bronchodilator reversibility (<15%) and minimal steroid reversibility

• Raised TLC, FRC and RV

• Decreased TLco and KCO (emphysema reduces surface area available for gas diffusion)

• Imaging is not necessary for dx but CXR will show hyperinflation

• Consider: alpha1-Antitrypsin levels, FBC, TFT, CRP, ECG/Echo

→ FEV1 measurement of choice to assess progression / prognosis but it correlates weakly with degree of dyspnoea and changes in FEV1 do not reflect decline in pt’s health

→ CXR: hyperinflated lung fields, attenuation of peripheral vasculature ‘black lung sign’: >7 posterior ribs. Flattened diaphragms. More horizontal ribs. May see bullae – can look like pneumothoraces

→ Symptom based

What other pharmacological managements are available for COPD?

• Prophylactic antibiotics:  Azithromycin (no evidence in current smokers). 250mg 3x/week if >/= 4 exac despite optimal inhaled therapy. Prior to start – ECG, LFTs, sputum including NTM. Repeat LFTs after 4 weeks. Assess response 3-6 months. Counsel re: hearing loss / tinnitus

• Long Term Oxygen Therapy (LTOT)

• Vaccination – influenza + pneumococcal

• Palliative care / respiratory sedation: morphine / lorazepam / diazepam

• Phosphodiesterase-4 inhibitors: Roflumilast (FEV1 <50% and >/= 2 exacerbations in past 12 months despite triple therapy)

• MABs/Biologics – watch this space! Dupilumab reduces exacerbations by up to a third in some studies, likely a select patient population

What are COPD exacerbations?

• Acute worsening of symptoms resulting in additional therapy

• Frequency increases with COPD severity

What are the causes of COPD exacerbations?

mainly viral (rhinovirus, RSV, influenza, parainfluenza, coronavirus, human metapneumonovirus and adenovirus). Others – bacterial (commonly Haemophilus influenzae, streptococcus pneumonia and Moraxella catarrhalis) and environment

What are the symptoms of COPD exacerbations?

cough, increased sputum, SOB, wheeze, worsening RVF

Describe the pathophysiology of COPD exacerbations

increased airway resistance due to bronchospasm, mucosal oedema, increased sputum. Worsens expiratory flow limitation, prolonged expiration (further limited by SOB). Promotes dynamic hyperinflation:causes mechanical compromise. Accessory muscles, thoraco-abdominal dyssynchrony

Describe the general management of AECOPD.

• Assess severity

• Controlled oxygen

• Nebulised bronchodilators (salbutamol 2.5mg and ipratroprium250mcg). With air not O2

• Oral steroids (Prednisolone 30mg 5 days – consider wean)

• Consider antibiotics

• (IV aminophylline)

• Consider NIV / ICU

• DVT prophylaxis

• Early mobilization, nutrition

• Consider ‘hospital at home’

What are the Surgical / interventional treatment viable for COPD?

• Lung transplant

• Bullectomy

• Lung volume reduction techniques

• Endobronchial valves – bronchoscopic lung volume reduction surgery (bLVR)

• Other endobronchial treatments

• Lung volume reduction surgery

Based on NICE guidance how should be treat COPD?

• Combo B2 agonist CMP pathway and LAMA cGMP pathway both relax smooth muscle in airways

• High eosinophils use triple therapy inhalers

• small risk using iCS with pneumonia

• if baseline COPD bad nebuliser may make it Asia to get drug in

What is NTM?

Non tuberculosis mycobacteria

ensure NTM not here as if use prophylactic drug can be harder to treat in the future

What biologic has best evidence in COPD?

dupilumab

For this case answer the following questions

• What’s the likely diagnosis?

• What acute treatment does he need?

• What longer term tests / management might you suggest?

viral pneumonia

altixamavir as first line for couple of days

Give O2

Make sure patient gets vaccine and jabs

What is Viral pneumonia?

Abnormalities of oxygen and carbon dioxide gas exchange at the level of the alveoli, secondary to viral-mediated and/or immune response-mediated inflammation.

→ virus reduces ability to fight infection so high risk of getting secondary bacterial infection

What are the complications of Viral pneumonia?

• Superadded bacterial infection / abscess/empyema/pleural effusion

• Sepsis with secondary multi-organ failure

• Acute respiratory failure

• Cardiovascular collapse

• Acute respiratory distress syndrome (ARDS)

What are the outcomes for patients with VIRAL PNEUMONIA?

• Most healthy people with pneumonia recover well

• Prognosis is guarded in immunocompromised/extremes of age

• Several viruses cause severe bronchiectasis

• 10-40% of children suffer irreversible lung damage after adenovirus pneumonia

What populations are at risk of getting viral pneumonia?

Traditionally a disease predominantly of the very young, the elderly, and the immunosuppressed.

Of particular concern in pregnant women

• Longer life spans & early infant survivability

• Increasing number of people taking immunosuppressive treatments for cancer & auto-immune conditions

• HIV

• Increased incidence of organ transplantion

• Obesity

• (COVID-19)

What conditions can predispose someone to viral pneumonia?

• Trauma/severe burns

• Uncontrolled diabetes

• Malnutrition / poverty / Group living

What are the different types of viral pneumonia?

Divided into DNA or RNA as nucleic acid (more useful to divide by clinical syndromes)

• COVID-19: RNA.

• Influenza A, B & C: RNA. Greatest cause of mortality. Multiple subtypes – e.g. Avian (H5N1), Swine (N1N1)

• Respiratory Syncytial virus (RSV): RNA. Most common cause in small children/infants

• Rhinovirus: RNA. Common URTI but uncommon cause of viral pneumonia

• Parainfluenza: RNA. Young children, seasonal.

• Other coronaviruses: RNA. Human bocavirus coronavirus (MERS: initial mortality rate 30%). Human metapneumovirus (SARS).

• Adenovirus: DNA. In people with solid organ/haematological transplantation

• Measles. RNA: in children (rising since vaccination falling)

• Others: Enterovirus, VZV, Hantavirus, EBV, Human Herpesvirus 6&7, HSV, CMV

→ Don’t really need to know

Describe the general pathophysiology of viral pneumonia.

• The submucosa of the alveoli is targeted, causing inflammation and secondary oedema, microhaemorrhage, and cellular immune reaction.

• Cellular reaction consists of mononuclear lymphocytes and progresses to polymorphonuclear neutrophil recruitment. Fibrin is released.

• CD4 and CD8 cells begin a cascade of immune product secretion that can end in increased vascular permeability and oedema.

• May lead to intra-alveolar organization and an obliterans clinical picture.

• Can develop into interstitial pneumonia, pulmonary oedema, and cardiogenic shock

Describe the pathophysiology of influenza.

• 3 subtypes: A, B & C. A more virulent & more frequent. C milder/asymptomatic

• A&B can be further categorised into subtypes depending on principle H & N antigens:

H = hemagglutinin: protein, causes red blood cell agglutination (sticking together)

N = neuraminidase, enzyme that cleaves glycosidic bonds of monosaccharide sialic acid

• There are 18 known types of H and 11 known types of N, so theoretically198 different possible combinations

• •Transmission occurs via droplets, aerosols or direct contact with respiratory secretions: usual incubation is 1-3 days.

• Rarely causes cardiac or neurological complications.

• Usually self-limiting with recovery 2-7 days but can be severe

→ Try and predict

Describe the pathophysiology of Covid 19.

• 4 structural proteins (Spike, Membrane, Envelope, Neucleocaspid): Binds to ACE-2 & Enters cells

• Asymptomatic phase → invasion URT → LRTI → ARDS

• Treatment targeted at two stages of infection response – viral replication and then inflammatory response

• Postmembrane fusion, virus enters pulmonary alveolar epithelial cells + viral contents are released into host cell – replicates (RNA transcription)

• Cytokine storm: inflammatory response to fight virus but causes lung inflammation and lung injury

• White cells sequestered in lung tissue

• Host cell apoptosis

• Diffuse alveolar damage leading to ARDS

→ Binds to ACE2 → why effects lags a lot

ACE 2 prevalent in pulmonary epithelium

How is viral pneumonia diagnosed?

• Used to be a diagnosis of exclusion.

• No specific history clues. Higher clinical suspicion in certain patients. Clues on exam – sx of URTI, rash, physical exam out of keeping with illness. Bilateral findings.

• Blood tests: Generally less rise in WCC. Lymphopenia is common but non-specific. CRP may be raised but less than in bacterial infection.

• Chest x-ray/CT: alveolar infiltrates, patchy bilateral interstitial infiltrates. Or normal chest x-ray.

What tests are there for specific viruses?

• Polymerase chain reaction (PCR) is replacing viral cultures/titres. Much quicker, no need for invasive sampling techniques, more sensitive and specific

• ELISA for specific pathogens e.g. HSV, RSV, ‘flu A&B, CMV. Doesn’t always indicate active disease.

• COVID-19: rapid point of care tests (nucleic acid amplification methods, lateral flow/ELISA/CLIA, biosensors) and PCR.

What specific tests need to be carried out in Covid-19?

1. Bloods:

• Poor prognostic signs: neut:lymph >3, thrombocytopenia <100, High D-dimer (3-4x), CRP >125, High troponin

• Also see mildly raised PT, transient transaminitis, mild AKI

• SARS-COV-2 Spike Antibody

2. ECG / echo – myocarditis/cardiomyopathy/dysrthymia/MI

What are the treatments for viral pneumonia?

Traditionally, the treatment of viral pneumonia was supportive care:

• Supplemental oxygen +/– intubation & ventilation

• Fluid management & replacement

• Temperature control, cough treatment

• Treatment of concomitant bacterial pneumonia

• Meet increased calorie needs

Now, there are specific and effective treatments for certain viruses

• Ribavirin: RSV, Parainfluenza, adenovirus, measles

• Acyclovir: HSV & VZV

• Ganciclovir/foscarnet: CMV

Remember isolation/cohort bay and PPE

Look for and treat superadded bacterial pneumonia

Importance of prevention: immunization, education, prophylaxis

What are the treatments for influenza?

• Usually managed in the community, doesn’t require treatment in the healthy

• For those at risk or pregnant, or complicated infection: Oseltamivir (or zanamivir if resistant strain). Interrupt function of neuroaminidase on virus surface, preventing release of viral particles from infected host cells

• Should start within 48 hours of symptom onset: May help even if up to 5 days but unlicensed

• Some strains more likely to develop resistance to oseltamivir (e.g. A H1N1 pdm09) – higher in the immunosuppressed

• Secondary bacterial infection are a major cause of death: pneumococcus, staph aureus, streptococcus, haemophilus

• Prevention: Annual influenza vaccine and Prophylaxis – for contacts in an at risk group: zanamivir or oseltamivir

What are the pharmacological treatments for covid?

• Antivirals: Paxlovid

• Remdesivir

• Sotrovimab

• Dexamethasone

• Tocilizumab (or Sarilumab)

• Baricitinib

What pathogen factors determine whether TREATMENT FOR COVID-19 is needed?

• Covid variant. There are no current variants of concern. Omicron = variants of interest

• Time course of infection

What risk factors increase the risk for progression to sever disease for Covid 19?

• Down’s syndrome

• Solid cancers

• Haematological diseases, stem cell transplant

• Sickle cell disease, thalassaemia

• Renal disease (transplant, CKD 4 or 5)

• Liver disease

• Solid organ transplant

• Immune-mediated inflammatory disorders

• Asthma – on oral steroids, frequent exacerbation

• COPD home NIV / LTOT, moderate or severe disease (EEV1 <50%)

• ILD

• Immune deficiency

• Neurological disorders and dementia

Outline the Covid 19 therapies flowchart

DONT memorise

What are some of the the other pharmacological treatments/adjuncts for Covid 19?

• Consider Oseltamivir while influenza/viral swab awaited

• Active management of cough and dyspnoea: opioids or benzodiazepines

• Additional Adjuncts to consider: Paracetamol, nebulisers may have a limited role in specific cases (0.9% sodium chloride, salbutamol), Carbocisteine, regular medications

• Nutrition and bowel management

      Many patients with COVID-19 experience diarrhoea).

      Ensure adequate calorific intake.

Describe the use of VTE for the treatment and prophylaxis of Covid 19.

• High reported prevalence of  VTE in COVID-19

• Also other coagulopathy e.g. line clots, DIC, high D-Dimers, high target anti-Xa levels

• Low threshold for CTPA to look for PE

• VTE must be prescribed in absence of CI. Hold if PLT <75 – but consider giving if 50-75 in high risk cases (>25 on ICU)

• For conventional supplemental oxygen – therapeutic dose, for 14 days or until discharge

• HFNO/CPAP (or not on oxgen) – standard prophylactic dose (unless PE/DVT/other reason for high dose)

Describe the use of antibiotics for the treatment of Covid 19.

• ONLY if evidence of superadded bacterial infection (majority will not require) e.g. lobar pneumonia, neutrophilia, productive cough

• CRP can be raised in severe disease which can make it difficult – clinical judgement

• PCT therefore used as an additional aid. Repeat if deteriorates & after 3 days.

What is BRONCHIECTASIS?

Irreversible abnormal dilatation of one or more bronchi, with chronic airway inflammation.

What are the clinical features of BRONCHIECTASIS?

chronic sputum production, recurrent chest infections and airflow obstruction.

Describe the pathophysiology of BRONCHIECTASIS.

Initial (usually infectious) insult – damage to the airway. Disordered anatomy leads to secondary bacterial colonization, perpetuating inflammatory change and damaging mucociliary escalator. Prevents bacterial clearances, leads to further airway damage. Mucosal oedema, inflammation, ulceration. Chronic host inflammatory response

Bronchial neovascularization (hypertrophy and tortuosity of bronchial arteries) may lead to intermittent haemoptysis

Describe and explain the aetiology of BRONCHIECTASIS.

• Many and varied causes

• Idiopathic in c. 50%

• Congenital: pulmonary sequestration

• Post-infective (TB, whooping cough, severe pneumonia, ?NTM)

• Immunodeficiency: primary (e.g. CVID), secondary (HIV, CLL, nephrotic syndrome)

• Mucociliary clearance abnormalities:

• Airway diseases: cystic fibrosis, primary ciliary dyskinesia, COPD, asthma, ABPA

• Toxic insults: aspiration, inhalation (toxic gases, chemicals)

• Mechanical insults: foreign body aspiration, extrinsic lymph node compression, intrinsic obstructing tumour

• Associated diseses: rheumatoid arthritis / other connective tissue disease, ulcerative colitis and Crohn’s, chronic sinusitis, yellow nail syndrome, Marfan’s

Describe the management of BRONCHIECTASIS

• Treatment of underlying medical condition / associated airflow obstruction

• Daily physiotherapy / airway clearance

• Optimize nutrition

• Pulmonary rehabilitation if breathless

• Surgery – rare, localized resection

• Lung transplantation

• Antimicrobials: intermittent for exacerbations, or long term prophylaxis. Based on sputum results (in vivo sensitivity may be different to in vitro). Higher abxdose and for 10-14 days

Describe the management of BRONCHIECTASIS for Pseudomonas colonized patients

• More frequent exacerbations, worse CT appearances, faster decline in lung function

• First isolate of Pseudomonas aeruginosa:

• Initial rx 2/52 PO Ciprofloxacin 500-750mg BD (counsel re: photosensitivity and tendonitis risk, long QT / known vascular aneurysm)

• If fails – IV abx (min 2/42) and nebulized colistin, gentamicin or tobramycin for 3 months

• Combination IV abx (anti-pseudomonal penicillin and aminoglycoside) are only needed if lack of clinical response and/or resistance

• Consider long-term therapy with daily nebulized colistin or gentamicin in colonized patients with frequent exacerbations (may be in combination with macrolide).

• Challenge testing required prior to starting neb abx – risk of bronchoconstriction

Describe and explain the use of Prophylactic Macrolide antibiotics in BRONCHIECTASIS.

• Both antibacterial and immunomodulatory properties

• Decrease mucous production, alter inflammatory mediator release and inhibit pseudomonas virulence factors and biofilm formation

• Reduce exacerbation rates and improve lung function and symptoms

• Counsel re: hearing loss.

• LFTs at 1 months then 8 weekly.

• Avoid if CrCl <30ml/min.

• Avoid concomitant nephrotoxics

• Baseline ECG – QTc

• Exclude NTM

• Azithromycin 25—500mg 3 x/week or 500mg twice weekly

• Antibiotic holiday’ may be taken

What are some of the further managements used in the treatment of BRONCHIECTASIS?

• Self-management plan

• Treatment of associated airflow obstruction / wheeze

• B2 agonists may enhance airway clearance

• Nebulized 7% hypertonic saline – but NB bronchospasm

• Acetylcysteine

• Vaccinations

• Rx reflux and associated rhinosinusitis

• Nutrition

• Immunoglobulin replacement therapy

• Oxygen

• Surgery / transplant

What is Cystic Fibrosis?

• CF is a genetic cause of bronchiectasis. Recessive.

• Multi-system disease due to mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) – a complex chloride channel. Causes inadequate hydration of mucous secretions. Different gene mutations exist which effect different parts of the CFTR and correlate with varying severity – commonest=F508 deletion

• Lungs – causes defective mucociliary clearance, mucus obstruction and colonization with pathogenic bacteria. Recurrent infection leads to bronchiectasis.

• Pancreas – exocrine ducts blocked by secretions, leading to pancreatic destruction, pancreatic enzyme insufficiency, and CF diabetes

• Respiratory management acutely and chronically is largely as for other forms of bronchiectasis

• BUT recent advances with CFTR modulators have transformed the disease

Now, c. 95% of all patients with CF in the UK are eligible for…

modulator therapy

• Pricing and access have been controversial

• Future: gene therapy for cystic fibrosis…(watch this space!)

Describe the use of CFTR modulators in the management of cystic fibrosis.

• Directly target the basic defect underlying CF

• Orally bioavailable drugs, effective in specific mutations

• Small molecule CFTR modulators increase CFTR channel opening at cell surface (’potentiators’), or increase the amount of cell surface CFTR protein (‘correctors’)

• Ivacaftor (Kalydeco) was first - CFTR potentiator effective in patients with gating mutation (c. 5% of CF patients). Then combined to form other drugs:

• Tezacaftor-Ivacaftor (Symkevi/Symdeko) works in patients hetero-zygousfor F508del (or heterozygous with residual function mutation) – the most common mutation

• Lumacaftor-Ivacaftor (Orkambi) – homozygous F580del (c. 50% of CF patients)

What triple therapies are available for the treatment of cystic fibrosis?

• Elexacaftor/tezacaftor/ivacaftor (Kaftrio) the first triple therapy. Demonstrated significant improvements in lung function & QoL & reduction in sx. Must have at least one F580del to qualify

• Vanzacaftor/tezacaftor/deutivacaftor (Alyftrek). At least one F508del variant. As good as Kaftrio maybe better

• Newer triple therapies are often also effective in other, rarer CFTR variants and use is being expanded

For this case answer the following questions

• What’s the likely diagnosis?

• What acute treatment does he need?

• What longer term tests / management might you suggest?

acute exacerbation of PF

possibly try and allude bacterial infection

If survive educate on PF and give Abx if eligible

What are PULMONARY FIBROSIS?

A group of diffuse lung diseases that involve the pulmonary interstitium(hence also called interstitial Lung Disease / ILD). Interstitium=area between alveolae and capillary as well as the fibrous lung framework. 

What are the subtypes of PULMONARY FIBROSIS?

Commonest=Idiopathic pulmonary fibrosis (IPF). Other subtypes are rarer, include e.g. non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP).

What are the clinical features of PULMONARY FIBROSIS?

Can vary slightly with subtype but generally slow and progressive onset, dry cough, sometimes systemic symptoms (e.g. weight loss) over months to years. Inspiratory crackles and squeaks, sometimes clubbing, when advanced can show cyanosis and signs of right heart failure

What things are normally associated to PULMONARY FIBROSIS?

Vary by subtypes but include: smoking; connective tissue diseases (e.g.RA); asbestos exposure; certain drugs e.g. Nitrofurantoin, Amiodarone, Bleomycin; some infections e.g. HIV/PCP

Describe the pathophysiology of PULMONARY FIBROSIS

Largely unknown. Each subtype has its own triggers and pathways but the underlying process of all is one of varying degrees of inflammation and fibrosis.

How is Idiopathic Pulmonary Fibrosis (IPF) diagnosed?

MDT diagnosis – using clinical features, PFTs, HRCT chest and (if biopsy taken) histological features / features from broncho-alveolar lavage

What is the variable prognosis of Idiopathic Pulmonary Fibrosis (IPF)?

• Many are stable/decline slowly

• A subgroup decline more rapidly (usually male smokers)

• 5-20% have rapid progression after an acute exacerbation (often inpatient admission)

State the general principles of the management of Idiopathic Pulmonary Fibrosis (IPF)

• In context of clinical condition, co-morbidities and patient wishes

• Pulmonary rehabilitation

• Supportive treatment E.g. home oxygen, opioids

• Anti-fibrotics – covered on next slides

• Clinical trials

• Lung transplantation if eligible and meets criteria

Describe the use of Anti-fibrotics: Slow progression of fibrosis in PULMONARY FIBROSIS

• Initiation by specialist ILD centres with MDT.

• Initially for those with FVC 50-80%, now FVC >50%

• Initially only for IPF but use is expanding in other forms of ILD

• Exclusions include inability to tolerate side effects (e.g. intolerable diarrhoea / weight loss), interaction with other medications and bleeding risk

• Stop if progression of disease (>10% FVC decline over 12 months)

What Anti-fibrotics are available for PULMONARY FIBROSIS?

• Two drugs currently available:

• Pirfenidone: inhibits collagen synthesis, reduces fibroblast proliferation

• Nintedanib: tyrosine kinase inhibitor

• Both drugs associated with GI side effects (diarrhoeaalmost always present)

• Both can cause LFT derangement. LFT and FBC monitoring monthly for the first 6 months and 3 monthly after.

• Available on a commercial arrangement with drug companies. Nintedanib more expensive - £2,151.10 per pack of 60 capsules, vs £501.92 for 63 capsules (c. £75/day)

Compare Anti-fibrotics: Nintedanib vs Pirfenidone

• Bleeding risk with Nintedanib: Common but usually mild (e.g., epistaxis/bruise), but can be serious, sometimes fatal. Due to inhibition of vascular endothelial growth factor (VEGF). Caution is advised with full-dose anticoagulation

• Drug interactions may dictate choice

• Nintedanib contraindicated in peanut/soya allergy

• Pirfenidone: Increased sensitivity to sunlight (caution with concurrent Doxycycline and must use factor 50 and cover up)

• Religious/vegetarian considerations – some Nintedanib formulations contain gelatin/ porcine products

Describe and explain the management for the acute exacerbations in PULMONARY FIBROSIS.

• An otherwise unexplained acute worsening of dyspnoea in someone with pulmonary fibrosis

• Mechanism is poorly understood, viral infections may act as a trigger.

• Important cause of death in otherwise apparently stable IPF and increasingly recognized in other forms of ILD such as CTD-associated and NSIP

• Inpatient mortality is >60%, rising to 90% within 6 months of discharge

• Outcomes for patients with fibrotic lung disease who undergo intubation and ventilation is poor (mortality approaches 100%) – ICU not usually appropriate

• HRCT typically shows extensive “ground glass” (reflects inflammation) and/or consolidation on a background of fibrotic changes

• Important to exclude/consider/treat for other causes of exacerbation e.g. superimposed bacterial or opportunistic infection, pulmonary embolism, pneumothorax, cardiac dysfunction

• Treatment usually with high dose steroids (e.g. IV Methylprednisolone 750mg-1g for 3 days)

• In practice, infection is often difficult to exclude and often treat with broad-spectrum antibiotics as well

ANTIVIRALS: NIRMATRELVIR AND RITONAVIR (PAXLOVID)

• Nirmatrelvir is a peptidomimetic inhibitor of coronavirus 3C-like protease which prevents multiplication of SARS-CoV-2. Ritonavir inhibits CYP3A-mediated metabolism of nirmatrelvir thereby increasing the plasma concentration of nirmatrelvir.

• 300mg (2 pink) and 100mg (one white) BD for 5 days

• Evidence suggests it reduces hospitalisation and mortality in at risk patients

• £513 for course

• Eligibility:  <5 days of symptoms. Not on oxygen. Increased risk for progression, or age >70, BMI >35, diabetes or heart failure.

• Cautions/CI: Hepatitis, liver disease, uncontrolled HIV

• Adverse effects: diarrhoea, altered taste, vomiting. Reduced efficacy contraception

REMDESIVIR

• Adenosine nucleotide prodrug. RNA polymerase inhibitor – prevents viral multiplication

• 200mg IV loading, maintenance 100mg IV for total 5-10 days (5 on ward, up to 10 on ICU)

• Probably reduces mortality for non-ventilated patients, with or without oxygen. Unclear benefit in those already ventilated. Effectiveness in omicron uncertain.

• Expensive (£1773 for a 5 day course)

• Eligibility: <10 days from symptom onset, requires supplemental oxygen, 40kg and over, eGFR >30ml/min, ALT <5x lower limit of normal.

• Risk assessment: only for use in patients at high risk of progression to severe disease

• Reassess daily: Consider stopping if improves and no longer requires O2 72 hours after rx started/continues to deteriorate despite 48 hours of mechanical ventilation.

• Monitor renal & liver function – stop if ALT >5x ULN (can be restarted when drops), liver inflammation or eGFR<30

• Cautions/CI: (Pregnancy)

• Adverse effects: headache, transaminase elevations, infusion reactions (hypotension, n&v, diaphoresis), hypersensitivity.

SOTROVIMAB

• Engineered human immunoglobulin monoclonal antibody that binds to the spike protein receptor binding domain of SARS-CoV-2, which prevents the virus from entering human cells.

• Evidence: reduced mortality (OR 0.4) and hospitalisation (OR=0.53), mechanical ventilation (OR=0.57), ICU admission (OR=0.33).

• 500mg for 1 dose

• Costs £2209 for one dose

• Eligibility:  Within 5 days of onset. Do not need supplemental oxygen. Increased risk of progression to severe disease. Weight >40kg. Paxlovid contraindicated / unsuitable.

• Adverse effects: Bronchospasm, hypersensitivity, infusion related reaction, skin reaction

DEXAMETHASONE

• 6mg PO/NG/IV OD for 10 days (or until discharge)

• Evidence: Recovery, REMAP-CAP. 28 day mortality lower (OR 0.66)

• For all patients with severe COVID-19 who require supplementary oxygen to maintain saturations >94%

• Monitor blood sugars at least OD in all patients and QDS in people with diabetes.

• PPI

• Cautions: Uncontrolled hyperglycaemia, pt already receiving regular oral corticosteroids

• Adverse effects: Hyperglycaemia, mood/sleep disturbance, hypernatraemia

TOCILIZUMAB

• IL-6 inhibitor used in RA

• Evidence: improved 28 day survival (RR mortality 14% & 24%) & reduced time on ICU by a week

• 8mg/kg IV (total dose not >800mg) single dose over an hour, via Blueteq

• Costs c. £1,000 for one 800mg dose

• Eligibility: CRP >/=75, Sats <92% RA/requires oxygen, or within 24-48 hrs of starting NHF/CPAP/IMV

• CI: Known hypersensitivity to Toci, pregnancy (contraception 3/12 after rx).

  PLT <50, Neut <1, liver enzymes 10x normal

• Cautions: Co-existing infection, ALT >5x ULN, immunosuppression

 Note: CRP levels may be depressed for some time after Toci(missed infeections/atypical presentations of  e.g. GI perforation)

• Adverse effects: URTI, nasopharyngitis, headache, HTN, raised ALT

SARILUMAB

• IL-6 inhibitor used when Tocilizumab not available

• Dose: 400mg one off dose via Blueteq

• Eligibility: CRP >/=75, Sats <92% RA/requires oxygen, or within 24-48 hrs of starting NHF/CPAP/IMV

• CI: Known hypersensitivity to Sari, pregnancy (contraception 3/12 after rx).

  PLT <150, Neut <1, liver enzymes 5x normal

• Cautions: Co-existing infection, immunosuppression

 Note: CRP levels may be depressed for some time after (missed infeections/atypical presentations of  e.g. GI perforation)

BARICITINIB

• Inhibits JAK1 and JAK2 tyrosine kinases

• Evidence: Lower mortality (OR=0.62), lower mechanical ventilation (OR=0.61)

• Costs £805 for one tablet

• Eligibility: Need supplemental oxygen, are receiving corticosteroids, no evidence of bacterial infection and who cannot have tocilizumab or are deteriorating despite tocilizumab

• CI: Lympocytes <0.5, neutrophils <1, haemoglobin <80, active tuberculosis

• Cautions: Active, chronic or recurrent infection, age >65, cardiovascular risk factors, risk factors for VTE, malignancy, diverticulitis or viral reactivation. Live vaccines not recommended during rx

• Adverse effects: abdo pain, dyslipidaemia, headache, herpes zoster, nausea, skin reactions, thrombocytosis, VTE, facial swelling, cardiovascular event, weight gain, GI perforation, hypersensitivity, malignancy