CONTENTS

• Basics
• Causes of ARDS
  • ARDS due to DAD
  • ARDS without DAD
• Clinical presentation
• Radiology
• Bronchoscopy
• Investigation
• Diagnosis
• Management
• Questions & discussion

abbreviations used in the pulmonary section:

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• 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 📖
• 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 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• 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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basics

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(1) what is diffuse alveolar damage (DAD)? 

• DAD is defined pathologically as a specific form of diffuse alveolar injury that results in hyaline membrane formation (figure above). It is termed “diffuse” because it involves transmural damage to the alveolar-capillary unit (including the alveolar epithelium, capillary endothelium, and interstitium). (37289644)
• Clinically:
  • DAD may be caused by a variety of insults to the lung.
  • Patients with DAD usually present clinically with ARDS (acute respiratory distress syndrome).
• Historically, ARDS was intended to be a constellation of clinical criteria that would identify patients with DAD. However, clinical ARDS criteria are not very effective at identifying which patients actually have DAD (e.g., one study found DAD in only about half of patients who met the Berlin definition of ARDS). (23370917) With recently re-defined and broadened criteria for ARDS, only a minority of patients with ARDS will have DAD.

(2) what is acute interstitial pneumonia (AIP, aka Hamman-Rich syndrome)?

• AIP refers to the development of DAD without any identifiable cause. It is an acute process that is histologically homogeneous and affects patients without pre-existing lung disease.
• Patients with AIP have probably been exposed to some trigger for DAD which we are unable to detect. (37289644) For example:
  • Inhalational exposure that wasn't noted and reported.
  • Aspiration event which was clinically silent.
  • Viral infection that couldn't be identified.
  • Rheumatological disorder that hasn't yet fully manifested.
• AIP isn't a single disease, but rather it refers to idiopathic DAD resulting from a collection of different triggers.
• Most historical cases of AIP probably reflect infectious or rheumatologic disorders that clinicians didn't have the tools to diagnose (e.g., serologic panels and multiplex PCR weren't available). Hamman and Rich first described AIP in 1935, a time when diagnostic studies were largely nonexistent.
• Sometimes, the term “AIP” is loosely used to refer to DAD which is caused by a definable trigger. This isn't technically correct, but it's not terribly wrong either.

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causes of ARDS

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Although this chapter is about DAD and AIP, it may be helpful to provide a broader perspective of all diseases that can cause ARDS:

(#1/2) ARDS due to DAD 

direct pulmonary injury causing DAD

• Aspiration:
  • Gastric aspiration.
  • Drowning.
  • Hydrocarbon aspiration (e.g., following toxic ingestion).
• Inhalational exposures:
  • EVALI (E-cigarette and vaping associated lung injury).
  • Smoke inhalation.
  • Heroin, cocaine.
  • Chlorine gas, phosgene, nitrogen dioxide.
  • Oxygen toxicity.
• Pneumonia: (23001802)
  • Viral:
    • Influenza.
    • HSV-1.
    • CMV.
    • Adenovirus.
    • RSV.
  • Fungal:
    • Pneumocystis.
    • Disseminated histoplasmosis.
    • Cryptococcal pneumonia.
  • Nontuberculous mycobacteria.
  • (Severe bacterial pneumonia generally doesn't cause DAD).
• PGD (primary graft dysfunction) following lung transplantation.

nonpulmonary injury causing DAD

• Acute exacerbation of an ILD (especially acute exacerbation of IPF).
• Connective tissue disease-related ILD (CTD-ILD), especially:
  • Myositis-associated ILD (particularly antisynthetase syndrome, anti-MDA5 disease).
  • Acute lupus pneumonitis.
  • Rheumatoid arthritis.
  • Scleroderma.
  • Mixed connective tissue disease.
  • Sjogren syndrome.
• Septic shock.
• Severe trauma.
• TRALI (transfusion related acute lung injury).
• Medications most commonly implicated (comprehensive listing at PneumoTox.com: 🌊)
  • Amiodarone, dronedarone.
  • Aspirin.
  • Azathioprine.
  • Cancer therapies:
    • Chemotherapy (bleomycin, busulfan, carmustine (BCNU), cyclophosphamide, cytarabine, docetaxel, etoposide, FOLFOX, gemcitabine, hydroxyurea, irinotecan, leflunomide, methotrexate, nitrosoureas, oxaliplatin-based regimens, teniposide, topotecan, vinblastine).
    • Targeted therapies (cetuximab, crizotinib, erlotinib, gefitinib, panitumumab, sorafenib).
    • Immune checkpoint inhibitors.
  • Hydralazine.
  • Infliximab.
  • Interferon alpha/beta.
  • Nitrofurantoin.
  • Paroxetine.
  • Rifampicin.
  • Sirolimus.
  • Sulfasalazine.
  • Trimethoprim-sulfamethoxazole.

(#2/2) ARDS without DAD

• DAH (diffuse alveolar hemorrhage).
• Pneumonias that don't cause DAD (probably most pneumonias, including typical bacterial pneumonias).
• OP (organizing pneumonia).
• AEP (acute eosinophilic pneumonia).
• Acute HP (hypersensitivity pneumonia).
• Acute sickle chest syndrome.
• Fat emboli syndrome (traumatic or following orthopedic surgery).

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clinical presentation of DAD

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general presentation of DAD

• Patients with DAD generally present with hypoxemic respiratory failure (the clinical syndrome of ARDS).
• Acute respiratory failure usually develops within <3-7 days following an acute insult.
• Respiratory failure is often severe, requiring intubation. However, intubation is not invariably required.
• Among patients with ARDS, some features may suggest the presence of DAD: (26972901)
  • More severe hypoxemia.
  • Persistence over several days (as opposed to recovery within 1-2 days).
  • Reduced lung compliance on mechanical ventilation.
  • CT scan consistent with ARDS (not merely bilateral infiltrates on chest radiograph).

Acute Interstitial Pneumonia (AIP)

• AIP may be indistinguishable from other cases of DAD, as described above. However, some differences are often reported:
• (#1) AIP may be more subacute in nature. Some patients may have symptom evolution over several weeks.
• (#2) A prodromal illness often occurs before AIP, with features of a viral upper respiratory tract infection (e.g., fever, chills, myalgias, arthralgias). This may be followed by a dry cough and, subsequently, rapidly progressive respiratory failure. (Walker 2019)

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radiology of DAD

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acute exudative phase

• Bilateral ground glass opacities (GGO) are invariably seen, usually as a predominant feature.
  • Focal sparing of lung lobules may result in a geographic appearance. (Walker 2019)
• Interlobular septal thickening is frequent superimposed on GGO, leading to a crazy-paving pattern. (Walker 2019)
• Consolidation may also occur:
  • Initially consolidation is often patchy, but in later stages it tends to become more homogeneous.
  • Consolidation often occurs predominantly in the dependent portions of the lung. However, it may also have a peripheral distribution. (Walker 2019)

fibroproliferative phase

• Ground glass opacities may improve in some areas.
• Features suggestive of fibrosis may evolve:
  • Traction bronchiectasis and traction bronchiolectasis.
  • Coarse reticulation may be superimposed on ground glass opacities.
  • Cystic airspaces may develop (honeycombing).
  • ⚠️ Contraction of consolidated areas with traction bronchiectasis doesn't necessarily represent worsening, but may simply represent the natural course of DAD followed by eventual recovery. (37289644)

involvement of previously spared areas

• DAD often follows a temporally uniform pattern, as described above. However, some patients may suffer from repeated episodes of acute alveolar injury. This causes new areas of acute exudative DAD to emerge in previously spared parts of the lung.
• The result from sequential bouts of alveolar injury may be a scan that has some areas of fibroproliferative DAD and other areas of acute exudative DAD. (37289644)
• The differential diagnosis for new infiltrates includes:
  • Superimposed nosocomial pneumonia.
  • Pulmonary infarction(s), as a consequence of pulmonary emboli.

chronic persistent abnormalities

• Findings are variable, depending on the disease extent and additional lung injuries incurred by mechanical ventilation. These may include:(37289644)
• Persistent airspace opacities (ground glass opacities more frequently than consolidation).
• Imaging findings suggestive of fibrosis (parenchymal bands, traction bronchiectasis, rarely honeycombing).
• Parenchymal destruction (focal emphysema).
• Pneumatoceles.
• Sometimes residual fibrosis is distributed in an anterior fashion (affecting the “baby lung” which was subject to atelectrauma during mechanical ventilation).

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bronchoscopy

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diagnostic role of bronchoscopy

• The need for bronchoscopy is assessed on an individual patient basis. For most patients with ARDS, bronchoscopy is relatively low-yield.
• The primary role of bronchoscopy is to exclude alternative diagnoses.
• Diagnoses for which bronchoscopy is especially helpful:
  • Diffuse alveolar hemorrhage (e.g., due to ANCA vasculitis).
  • Acute eosinophilic pneumonia (AEP).
  • Immunocompromise with opportunistic infection (e.g., PJP, aspergillus).
• Risks of bronchoscopy include worsening hypoxemia, as well as risks of barotrauma.

typical findings on bronchoalveolar lavage in DAD

• Differential cell counts:
  • Neutrophilia is generally the predominant finding (a nonspecific finding in the context of acute lung injury).
  • Occasionally, lymphocyte count may be elevated.
• Cytology may rarely reveal findings suggestive of DAD:
  • Atypical hyperplastic type II pneumocytes may be seen.
  • Fragments of hyaline membranes may occasionally be seen.

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investigation

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• The initial investigation is largely identical to the diagnostic approach towards a patient with ARDS (discussed further here: 📖).
• If initial evaluation reveals no clear etiology, then a more detailed investigation for underlying connective tissue diseases is warranted, including careful examination, review of systems, and a serologic panel (discussed further here: 📖).

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diagnosis

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diagnosis of AIP (acute interstitial pneumonia)

• Diagnosis of AIP is extremely challenging (which may explain why hardly any cases are reported in the literature).
• Definite diagnosis of AIP requires:
  • (1) Acute onset of severe hypoxemia with bilateral infiltrates (i.e., clinical ARDS).
  • (2) A surgical lung biopsy revealing DAD (transbronchial biopsy doesn't provide sufficient tissue).
  • (3) A comprehensive evaluation that excludes any potential cause of DAD.
• Unfortunately, most patients with AIP are usually too ill to tolerate a surgical biopsy.
• A possible diagnosis of AIP might be considered if clinical and radiological features suggest DAD, and a comprehensive evaluation reveals no cause of DAD.

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management of DAD

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getting started: 

• (1) High-quality supportive care is essential. This is essentially the same as for patients with ARDS: 📖
• (2) Any causative etiology should be treated.

steroid +/- immunosuppressive therapies:

• The role of steroid is generally unknown. The optimal immunosuppressive regimen likely varies, depending on the cause of DAD. Overall, DAD histology is generally less steroid-responsive than OP (organizing pneumonia) or cellular NSIP (nonspecific interstitial pneumonia).
• Acute interstitial pneumonia (AIP):
  • Steroid is generally utilized. (Fishman 2023)
  • For acutely ill patients, this commonly begins with a pulse dose of methylprednisolone. Steroid therapy may be slowly tapered over weeks to months. Unfortunately, the optimal steroid dose is unknown.
• DAD due to an exacerbation of ILD:
  • Steroid is generally utilized (discussed further in the chapter on acute exacerbation of interstitial lung disease: 📖).
  • Patients with connective tissue disease-related ILD may benefit from complex immunosuppressive regimens (e.g., patients with myositis-associated ILD: 📖).

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questions & discussion

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