CONTENTS

• Gastroenterology
  • Inflammatory bowel disease
  • Cirrhosis
    • Hepatopulmonary syndrome
    • Hepatic hydrothorax ➡️
    • Spontaneous bacterial pleuritis ➡️
    • Portopulmonary hypertension ➡️
  • Pancreas-related pleural effusions ➡️
• Hematology
  • TRALI (transfusion-related acute lung injury)
  • Complications after hematopoietic stem cell transplantation
  • Sickle cell disease
    • Acute chest crisis ➡️
    • Pulmonary hypertension ➡️
  • Leukostasis due to leukemia ➡️
• Questions & discussion

abbreviations used in the pulmonary section: 7

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid fast bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OHS: Obesity hypoventilation syndrome 📖
• OP: Organizing pneumonia 📖
• OSA: Obstructive sleep apnea 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans cell histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: Tumor necrosis factor
• UIP: Usual interstitial pneumonia 📖

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respiratory disorders in patients with inflammatory bowel disease

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Inflammatory bowel disease (IBD) is associated with various inflammatory lung disorders, which likely have the same underlying pathophysiologic causes. The possibility of IBD-associated lung disease is supported by active extraintestinal manifestations of inflammatory bowel disease (e.g., arthropathies, uveitis, episcleritis, pyoderma gangrenosum, and/or erythema nodosum). (33678282; 33036115) IBD-associated lung disease correlates less closely with active inflammatory bowel disease (respiratory symptoms typically don't parallel exacerbations of bowel disease). (ERS handbook 3rd ed.)

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pulmonary abnormalities associated with inflammatory bowel disease

airway disease

• Stenotic lesions:
  • (1) Epiglottitis.
  • (2) Subglottic stenosis.
  • (3) Stenosis involving the mainstem bronchus, lobar, or segmental bronchi:
    • Stenosis is usually circumferential, with exuberant mucosal inflammation. (37164585) 
    • The differential diagnosis may include: granulomatosis with polyangiitis, sarcoidosis, tracheobronchial amyloidosis, and tracheobronchopathia osteochondroplastica.
    • Treatment may include systemic and inhaled steroid, steroid-sparing agents (e.g., azathioprine), and/or interventional pulmonology therapies (e.g., stenting/dilation).
• Bronchiectasis: Associated with ulcerative colitis more than with Crohn disease. (Teneback 2022)
• Necrotizing tracheobronchitis. (32252936)
• Chronic bronchitis (substantial purulent sputum production can occur).
• Bronchiolitis obliterans.
• Diffuse panbronchiolitis.

parenchymal lung disease is overall uncommon

• Parenchymal lung disease is uncommonly due directly to inflammatory bowel disease. Thus, parenchymal lung disease may raise concern for superinfection or drug toxicity.
• Related directly to inflammatory bowel disease:
  • Organizing pneumonia is most frequent (up to ~10%). (33036115, 33678282)
  • NSIP (nonspecific interstitial pneumonia).
  • Sarcoidosis and/or noncaseating granulomas.
  • Eosinophilic pneumonia.
  • Pulmonary fibrosis.
  • Esophagobronchial or colobronchial fistula causing pneumonia.
  • Necrobiotic pulmonary nodules resembling rheumatoid arthritis.
• Infection:
  • The risk of infection may be increased by numerous IBD medications (e.g., steroid, anti-TNF agents, azathioprine, methotrexate).
  • Common considerations include endemic fungal infections, Pneumocystis, or reactivation of tuberculosis. The differential will vary depending on the medications and dosage being used.
• Drug-induced lung disease (Pneumotox.com ↗️)
  • Methotrexate pneumonitis.
  • Mesalamine or sulfasalazine may cause a variety of lung disorders, with a wide range of onset following drug initiation (e.g., between one months and eight years). (31573346, 36865931)
    • Eosinophilic pneumonia, eosinophilic pleural effusion.
    • Organizing pneumonia.
    • NSIP (nonspecific interstitial pneumonia).
    • Many other forms of injury (e.g., obliterative bronchiolitis, large airway inflammation).
  • TNF-inhibitors may cause acute lung injury, or a sarcoidosis-like granulomatous disease.
  • Azathioprine and 6-mercaptopurine infrequently cause pulmonary toxicity that usually occurs within one month of drug initiation. (31573346)

pulmonary vascular diseases

• Pulmonary embolism (3-fold increased risk, especially during a disease flare).
• CTEPH (chronic thromboembolic pulmonary hypertension).
• Pulmonary vasculitis. (Murray 2022)

serositis (pleural effusion and/or pleuropericarditis)

• Serositis usually occurs during a flare of gastrointestinal disease, but may occur without gastrointestinal involvement. (31174661)
• Pleural fluid is exudative with a neutrophilic predominance. (31174661)
• Treatment may involve NSAIDs (nonsteroidal anti-inflammatory drugs), but these risk causing a flare of gastrointestinal disease. Another option is steroid (e.g., ~0.5 mg/kg/day for a month, followed by a rapid taper). (31174661)

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hepatopulmonary syndrome

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basics

• Cirrhosis causes marked vasodilation of capillary beds in the lungs. This causes hypoxemia via numerous mechanisms:
• (#1) Shunt physiology (with right-to-left shunting of deoxygenated blood into systemic circulation).
• (#2) Ventilation-perfusion mismatch (due to vasodilation of capillaries in poorly ventilated parts of the lung).
• (#3) Diffusion limitation (the capillaries may have a ten-fold increase in diameter, causing inadequate diffusion of oxygen into the capillary lumen).

epidemiology

• Hepatopulmonary syndrome usually occurs in the context of cirrhosis (with a prevalence of ~15%).
• However, hepatopulmonary syndrome may also occur in other situations:
  • Acute liver failure (ALF).
  • Chronic non-cirrhotic hepatitis. (ERS handbook 3rd ed.)
  • Budd-Chiari syndrome.
  • Non-cirrhotic portal hypertension (presumably due to shunting of endogenous vasodilators around the liver to the lungs). (35680317)
• Hepatopulmonary syndrome doesn't typically coexist with portopulmonary hypertension (since vasodilation of the pulmonary capillaries actually decreases the pulmonary arterial pressure – so that would treat portopulmonary hypertension!).

clinical presentation

• Dyspnea with hypoxemia, including:
  • Desaturation that is exacerbated in an upright position (orthodeoxia, discussed further below).
  • Dyspnea may worsen with standing (platypnea).
• Clinical features of vasodilation:
  • Digital clubbing.
  • Spider nevi.
  • High-output heart failure (hyperdynamic circulation with reduced diastolic blood pressure).

CT scan

• Two patterns have been described on CT scan:
• Type I (~85% of patients):
  • Peripheral pulmonary arteries are dilated, especially at the lung bases.
  • Arteries may be seen extending to the pleural surface (figure below).
• Type II (~15% of patients):
  • Discrete AVMs (arteriovenous malformations) are seen.
• (Splenomegaly and hepatic abnormalities may also be visible.)

echocardiogram with bubble contrast

• Echocardiogram with injection of agitated saline is the most commonly utilized test to evaluate for right-to-left shunting.
• Hepatopulmonary syndrome will cause an intrapulmonary shunt. This causes bubbles to appear within the left-sided heart chambers after 3-6 heartbeats.
• For patients with orthodeoxia or platypnea (exacerbation in an upright position), echocardiography is more sensitive if performed upright.

differential diagnosis: pulmonary dysfunction related to cirrhosis

• Hepatopulmonary syndrome.
• Portopulmonary hypertension.
• Hepatic hydrothorax.
• Restrictive lung disease due to ascites.

differential diagnosis of orthodeoxia: 📖

treatment

• Oxygen therapy is generally utilized (although it may not be entirely effective in restoring oxygenation, due to shunt physiology).
• There is no treatment for hepatopulmonary syndrome other than liver transplantation. Liver transplantation should generally cure hepatopulmonary syndrome, although improvement typically occurs over a time frame of ~6-12 months after transplantation. (Fishman 2023)
  • Hepatopulmonary syndrome is an indication for liver transplantation. Average survival without transplantation is about two years.
  • If hepatopulmonary syndrome is confirmed with bubble contrast echocardiography and the patient's PaO2 is <60 mm, an application for a MELD exception may be submitted to expedite transplantation. (Fishman 2023)

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TRALI (transfusion related acute lung injury)

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basics

• TRALI is a leading cause of death due to blood transfusion.

epidemiology

• The risk of TRALI from different products:
  • 1/8,000 units of FFP (fresh frozen plasma).
  • 1/5,000 PRBC (packed red blood cells) transfusion.
  • 1/2,000 plasma-containing components.
  • 1/500 units of whole blood-derived platelets.
• The epidemiology of TRALI is unclear, since it's a diagnosis of exclusion and definitive diagnosis is often elusive.

clinical presentation

• Timing:
  • Respiratory distress occurs within <6 hours of transfusion (usually <1-2 hours and typically occurring within minutes of transfusion).
  • Onset is often strikingly abrupt.
• Clinical features:
  • Dyspnea or respiratory distress requiring oxygen is universal.
  • Features of systemic inflammation may be seen:
    • Fever may occur.
    • Hypotension may occur.
  • Patients often require mechanical ventilation. If already intubated, pink frothy airway secretions may be noted.

imaging

• Findings vary, but imaging will generally resemble that of other forms of ARDS.
• By definition, bilateral lung opacities are required for the diagnosis of TRALI.

laboratory studies

• Transient neutropenia may occasionally be seen (likely related to pulmonary sequestration of neutrophils).
• Overall, laboratory studies are relatively noncontributory to the diagnosis of TRALI. However, they may help exclude alternative diagnoses.
• A transfusion reaction panel will generally be sent to help exclude alternative diagnoses. Tests may include:
  • Complete blood count.
  • Haptoglobin.
  • Bilirubin.
  • Direct antiglobulin test (Coombs test).
  • Brain natriuretic peptide.

differential diagnosis

• TACO (transfusion-associated circulatory overload). A diagnosis of TACO may be favored by the following features:
  • Underlying cardiac dysfunction.
  • Examination consistent with volume overload; vital signs may show hypertension.
  • Imaging more suggestive of cardiogenic pulmonary edema.
  • Clinical improvement following diuresis.
• Anaphylaxis following transfusion. 📖
• Acute hemolytic transfusion reaction may also cause ARDS following blood transfusion.
• Aspiration pneumonitis.
• Any other cause of ARDS: 📖

diagnostic criteria for TRALI

• Various definitions exist, but the core elements are as follows: 
• (1) Acute onset of hypoxemic respiratory failure occurring within <6 hours of transfusion.
• (2) Bilateral opacities on chest imaging.
• (3) Not felt to reflect heart failure.
• (4) Not felt to reflect ARDS due to another etiology (e.g., respiratory status should be stable in the 12 hours prior to transfusion and/or no alternative risk factors for ARDS are present). (30993745) 

treatment

• Management is supportive. It's unknown whether steroid may be beneficial and this usually isn't recommended.
• Respiratory support:
  • This is essentially the management of ARDS, which is discussed further here: 📖
  • Most patients may require mechanical ventilation.
• Hemodynamic optimization:
  • Hypotension can occur, which may require vasopressor support.
  • For patients who are hemodynamically stable, gentle diuresis may be attempted.
• The blood bank should be notified and involved in evaluation and management. Additional blood product donations from the same donor should be avoided. However, there doesn't seem to be an increased risk of subsequent TRALI if the patient receives blood products from different donors. (Murray 2022)

prognosis

• TRALI is generally a self-limited process that resolves within about two days. Chest radiograph usually normalizes in four days (unlike many other types of ARDS). (Murray 2022)

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pulmonary complications after hematopoietic stem cell transplantation

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early noninfectious complications (usually <100 days)

• Upper airway complications due to severe mucositis.
• Pulmonary edema.
• Diffuse alveolar hemorrhage. 📖
• Thrombotic microangiopathy (TMA). 📄
• Peri-engraftment respiratory distress syndrome (PERDS). 📖
• Idiopathic pneumonia syndrome (IPS). 📖
• Acute respiratory distress syndrome.
  • TRALI (transfusion related acute lung injury). 📖
• Pulmonary embolism.
• PVOD (pulmonary veno-occlusive disease) ➡️

late noninfectious complications (usually >100 days)

• BOS (bronchiolitis obliterans syndrome). ➡️
• Organizing pneumonia.
  • Usually a late complication occurring after >100 days, possibly related to GVHD (graft-versus-host disease).
  • Presentation is usually acute with dyspnea, dry cough, and fever. (ERS handbook 3rd ed.) If misdiagnosed as infectious pneumonia, this may progress to acute respiratory failure. (Murray 2022)
  • Treatment is similar to cryptogenic organizing pneumonia (e.g., steroid at 0.75 mg/kg with very slow taper).
• PPFE (pleuroparenchymal fibroelastosis). ➡️
• Eosinophilic pneumonia.
• Pulmonary alveolar proteinosis (PAP). ➡️
• PVOD (pulmonary veno-occlusive disease). ➡️
• DPTS (delayed pulmonary toxicity syndrome). 📖

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peri-engraftment respiratory distress syndrome (PERDS) 

• Basics: Capillary leak syndrome in the context of neutrophil recovery.
• Epidemiology:
  • Timing coincides with recovery of neutrophil counts (typically ~9-16 days post transplantation). (Fishman 2023)
  • This is mostly described in autologous stem cell transplantation (~5%), but is rarely reported in allogeneic stem cell transplantation as well. (Fishman 2023)
• Clinical features:
  • Fever.
  • Skin rash.
  • Noncardiogenic pulmonary edema (dyspnea, cough, hypoxemia). Roughly 20% of patients require intubation. (Fishman 2023)
• Evaluation:
  • Most patients don't undergo bronchoscopy, unless already on mechanical ventilation. (Fishman 2023)
  • CT scan may show bilateral ground-glass opacities and smooth thickening of the interlobular septa. (ERS handbook 3rd ed.)
• Diagnostic criteria:
  • New bilateral pulmonary infiltrates.
  • Hypoxemia.
  • Clinical syndrome not fully explained by an infectious process, fluid overload, or heart failure.
  • Occurring within 5 days on either side of the neutrophil engraftment (defined as the first of three consecutive days in which the absolute neutrophil count is >500/uL).
• Management: This generally responds to steroid (e.g. 1-2 mg/kg methylprednisolone twice daily for three days, followed by a rapid taper). (Fishman 2023)

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idiopathic pneumonia syndrome (IPS)

definition

• IPS refers to widespread alveolar injury in a hematopoietic stem cell recipient in absence of infection, heart failure, or volume overload.
• Idiopathic pneumonia syndrome is an umbrella term which includes some other entities:
  • DAD (diffuse alveolar hemorrhage).
  • Peri-engraftment syndrome.
  • AFOP (acute fibrinous and organizing pneumonia).

epidemiology

• Incidence of ~3%. (Murray 2022)
• The median time of onset is 30 days after transplantation, with most episodes occurring within <120 days. (Fishman 2023)
• Risk factors may include: (ERS handbook 3rd ed.)
  • Total body irradiation.
  • Graft-versus-host disease.
  • Older age.

clinical presentation

• Acute or subacute dyspnea usually occurs.
• Cough may occur.
• Progressive hypoxemia.
• Bilateral pulmonary opacities.

diagnosis

• CT shows diffuse parenchymal disease.
• Bronchoscopy is often needed to exclude infection and evaluate for diffuse alveolar hemorrhage.

diagnostic criteria

• Multilobar opacities on either chest radiograph or CT scan.
• Signs and symptoms of pneumonia.
• Hypoxemia.
• Absence of lower respiratory tract infection (as determined by a negative bronchoalveolar lavage).
• Clinical syndrome not fully explained by fluid overload or heart failure.

management

• Supportive care is generally the primary therapy.
• The utility of steroid is unknown, but steroid is often trialed (e.g., 1-4 mg/kg/day methylprednisolone).
• Etanercept (a TNF-alpha inhibitor) was evaluated in a small trial and didn't improve outcomes.

prognosis

• Mortality is high, with poor one-year survival.

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diffuse alveolar hemorrhage (DAH) s/p bone marrow transplantation

basics

• Noninfectious DAH (diffuse alveolar hemorrhage) after stem cell transplantation is a recognized syndrome. The etiology is unknown.

epidemiology

• This may occur after ~2% of hematopoietic stem cell transplantations. (Fishman 2023)
• Timing after transplantation seems to be variable, with a median of 126 days. (Fishman 2023)
• Risk factors:
  • High-dose chemotherapy and/or irradiation prior to transplantation.
  • Older age.
  • Autologous stem cell transplantation.
  • Severe GVHD (graft-versus-host disease).
  • (Although thrombocytopenia is often present, it isn't thought to be causal.)

clinical presentation

• Dyspnea and cough are common symptoms.
• Hemoptysis is uncommon (<20%), even if hemorrhage is extensive.
• Hypoxemia usually occurs, which often may require intubation.

investigations

• Radiologic findings:
  • Ground-glass opacity is often seen, with a central distribution.
  • Additional discussion on the radiology of DAH: 📖
• Hemoglobin may decrease.
• Bronchoscopy is the cornerstone of diagnosis (to confirm the presence of DAH and exclude infection). More on the use of bronchoscopy to diagnose DAH here: 📖

differential diagnosis

• Opportunistic infections (e.g., CMV, Aspergillus).

management

• Optimal therapy is largely unknown.
• Steroid:
  • Steroid is commonly utilized, but it's unclear whether it is actually beneficial. A moderate dose of steroid could be reasonable (e.g., 125 mg/day methylprednisolone).
  • A retrospective series suggested worse outcomes with high-dose steroid. (25531284)
• Coagulopathy management:
  • Coagulopathies or anticoagulants should be reversed, if this can be done safely.
  • Thrombocytopenia is common, but it isn't the cause of DAH. The value of platelet transfusion is unclear. Thrombocytopenia may be difficult to treat in some patients with consumptive coagulopathy, so it may be difficult to know whether repeated platelet transfusions pose a greater risk or benefit. (Fishman 2023)

prognosis

• Mortality may be high (~50%).

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delayed pulmonary toxicity syndrome (DPTS)

• This refers to acute lung injury followed by fibrosis after engraftment, in the context of an auto-SCT (autologous stem cell transplantation) patient who received bis-chloroethyl nitrosourea (carmustine, aka BCNU) as a conditioning agent prior to transplantation.
• Currently, the incidence has decreased.
• If DPTS occurs, it is usually responsive to steroid therapy.

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questions & discussion

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