Author: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC)
A 55 year-old female with a history of idiopathic pulmonary fibrosis and pulmonary hypertension (prednisone, sildenafil, and bosentan therapy) presents with a three day history of cough, chills, and shortness of breath. As you enter the room, you see the patient leaning forward in her bed, gasping.
The bedside monitor alarms with a HR of 132, RR of 28, SpO2 of 84% on room air. Physical exam is significant for end-expiratory wheezing and accessory muscle use. While opening a non-rebreather mask and starting supplemental oxygen, your mind buzzes with thoughts of NIPPV, an EKG, a chest xray, a VBG, and antibiotics, but is there more that you should consider? Does the patient’s previous diagnosis of idiopathic pulmonary fibrosis (IPF) change your management?
Let’s take a minute to discuss interstitial lung diseases and the importance of identifying acute exacerbations.
Diagnosing an Interstitial Lung Disease
While this piece centers on the management of an acute exacerbation of an interstitial lung disease (ILD), let’s first review the approach to diagnosing an ILD:
The term “interstitial lung disease” currently represents greater than 200 non-malignant pulmonary conditions, characterized by varying degrees of parenchymal and interstitial inflammation and fibrosis.1-5 Individuals suffering from undiagnosed ILD often present to healthcare providers with complaints of shortness of breath, persistent dry cough, chest pain with exertion, and even syncope (described in the setting of an ILD resulting in pulmonary hypertension and subsequent right heart failure).3,6
In this patient population, emergency department (ED) evaluation begins as all others: with an assessment of the ABCs. After initial stabilization, history and physical examination will dictate the requirement of an assessment for: myocardial infarction, aortic dissection, congestive heart failure, myocarditis, pericarditis, endocarditis, pericardial effusion, valvular dysfunction, cardiac arrhythmia, pulmonary embolism, pneumonia, and pleural effusion, among others.3
Depending upon the patient’s hemodynamic status and emergency department findings, settings which incite concern for an underlying primary lung pathology or systemic disease associated with pulmonary compromise, often prompt inpatient or outpatient specialist consultation for advanced imaging, tissue sampling, pulmonary function testing, and laboratory analysis.3
Specialist consultation and evaluation allows for a definitive diagnosis of ILD and performance of subgroup analysis. The subgroup classification system identifies conditions associated with an underlying systemic disorder, those with a known trigger, and those that are idiopathic in nature. Tables 1-3 below contain examples; not all-encompassing.1,3
For an excellent review of historical and clinical clues suggesting ILD upon initial patient encounter, see Keith Meyer’s Diagnosis and Management of Interstitial Lung Disease:
Meyer K. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014; 2:4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215823/
|Associated with a Systemic Disorder1-5|
|Polymyositis||Langerhans Cell Histiocytosis|
|Systemic Lupus Erythematosus||Pulmonary Vasculitis|
|Rheumatoid Arthritis||Gaucher’s Disease|
|Mixed Connective Tissue Disease||Nieman-Pick Disease|
Table 1. ILDs Associated with a Systemic Disorder
|Antibiotics (nitrofurantoin, sulfasalazine)||Silicosis|
|Antiarrhythmics (amiodarone, tocainide, propanolol)||Asbestosis|
|Anti-inflammatories (gold, penicillamine)||Coal Worker’s Pneumoconiosis|
|Chemotherapeutic Agents (mitomycin C, bleomycin, etc.)||Talc Pneumoconiosis|
|Oxygen Toxicity||Stannosis (Tin)|
|Narcotics||Hypersensitivity Pnemoitis (Bird breeder’s or Farmer’s lung)|
Table 2. ILDs with a Known Trigger
|Idiopathic Pulmonary Fibrosis|
|Non-specific Interstitial Pneumonia|
Table 3. Idiopathic ILDs
Note: the term ILD is synonymous with interstitial pulmonary disease, diffuse parenchymal lung disease, and interstitial pneumonia.1,3
The Epidemiology of ILD
As international standards for the diagnosis of ILD are lacking and disease terminology is highly variable, the true incidence and prevalence of ILD is difficult to ascertain.2 The largest U.S. study of ILD (n=2,936; patient population localized to Bernalillo County, NM), utilizing physician referral data, histopathology reports, ICD discharge diagnoses, and death certificate information, identified the incidence of ILD as 31.5 per 100,000/yr in males and 26.1 per 100,000/yr in females, with a male prevalence of 80.9 per 100,000, and a female prevalence of 67.2 per 100,000.7 Autopsy data revealed the estimated prevalence of pre-clinical or undiagnosed ILDs as 1.8% among all deaths.7,8 The most common incident diagnoses amongst both sexes were pulmonary fibrosis and IPF.7
Economic data for the majority of ILD subgroup classifications are lacking; however, a 2002 study of private health insurance medical and pharmacy claims, performed by Weckyer et al., demonstrated the mean patient healthcare charges related to IPF as $33,304 – $40,707 per patient per year, with hospital admissions accounting for 71-73% of these expenses.2,9
Identifying ILD Exacerbations
In a patient with a previously diagnosed ILD, an exacerbation is defined as an acute lung injury (new onset bilateral pulmonary infiltrates, PaO2/FiO2 ≤ 300, and PAWP ≤ 18) in the absence of heart failure, pulmonary infection, pulmonary embolism (PE), aspiration, or drug reaction.4,10-13 Acute exacerbations have been documented in patients with the subgroup classifications of IPF, IPF associated with a connective tissue disease, chronic hypersensitivity pneumonitis, desquamative interstitial pneumonia, and asbestosis.4 Patients with these diagnoses may present to the ED with acute shortness of breath, cough, fever, or wheezing.3,6,10 In addressing this population, the role of the emergency physician is to provide acute resuscitation while initiating an evaluation for the previously detailed underlying etiologies.10,11
As mentioned, ED assessment begins with addressing ABCs, therefore a word on airway and breathing:
Oxygenation and Ventilation Support in Patients with ILD
Gas exchange abnormalities (ABG/VBG) or respiratory distress may dictate the employment of therapeutic options including nasal cannula, non-rebreather, non-invasive positive pressure ventilation, or intubation and mechanical ventilation. The requirement for NIPPV or intubation in a patient with ILD is ominous. Studies of patients with IPF experiencing acute respiratory distress demonstrated no mortality benefit from the utilization of NIPPV,14-16 and an average median survival time of 18.0 days [95% CI 9.0-25.0] in patients failing NIPPV, and 90 days [95% CI 65.0-305.0] in those with successful NIPPV therapy (n = 18, p < 0.0001).12
Ventilation strategies for patient with varying degrees of lung fibrosis previously centered on limiting barotrauma through the utilization of low tidal volumes (similar to the ARDSNet protocol);10 however, a recent case series of 94 patients with IPF demonstrated no improvement in patient outcomes with employment of this strategy.17 Increased levels of PEEP were also associated with increased short-term mortality.16 Overall, the vast majority of patients experiencing respiratory failure secondary to an acute exacerbation of an ILD perish in intensive care units.12,18
Let’s now address our C – Circulation:
Hemodynamic instability in a patient with ILD may occur secondary to the acute exacerbation (hypercapnic respiratory failure resulting in hypoxemia and cardiovascular collapse), heart failure, acute coronary syndrome, infectious pulmonary pathology resulting in sepsis, or PE.10,19
In evaluating the hemodynamically unstable patient consider the following:19
- EKG to evaluate for signs of heart strain, STEMI, NSTEMI, or ST-T changes concerning for ischemia.
- Point of care ultrasound to evaluate for pleural effusions (left-sided heart failure), cardiomegaly (heart failure), right atrial/right ventricular dilation (PE), or right ventricular free wall dilation/ paradoxical septal shift toward the LV during early diastole (pulmonary hypertension20).
- Antibiotic therapy for all patients presenting with SIRS criteria (temperature >38.0°C or <36°C, heart rate >90 bpm, respiratory rate > 20 or PCO2 < 32 Torr).
History, Physical Examination, and Evaluation
History and physical examination are paramount in assessing underlying etiologies of the patient’s symptoms, as treatment goals vary dramatically according to diagnosis (i.e. an acute exacerbation requiring respiratory support and admission to an ICU setting for bronchoalveolar lavage, vs. afterload reduction and potential diuresis in the setting left-sided heart failure, vs. the maintenance of euvolemia in the setting of pulmonary HTN precipitating right-sided heart failure vs. early antibiotic therapy and fluid resuscitation in the setting of sepsis, vs. anticoagulation in the setting of a PE).
When stable, the patient should be questioned regarding:
- His/her specific ILD diagnosis (i.e. – eosinophilic pneumonia, scleroderma, etc.)
- Current medical therapy or changes in medical therapy
- Many patients are treated with chronic corticosteroids or immune modulators (methotrexate, infliximab, mycophenalate, etc.)
- Bosentan, a treatment for pulmonary hypertension, is known to worsen fibrosis.4
- Medical co-morbidities (ACS risk stratification/PE & DVT risk stratification)
- Fevers or viral prodrome
- Symptoms of right- or left-sided heart failure (orthopnea, paroxysmal nocturnal dyspnea, peripheral edema, etc.)
- History of acid reflux (predisposes to aspiration pneumonia and ARDS4)
- Many patients are treated with chronic corticosteroids or immune modulators (methotrexate, infliximab, mycophenalate, etc.)
Of note, studies have demonstrated an increased risk of thromboembolism in patients previously diagnosed with IPF. A review of 218,991 decedent records contained in the US Multiple Cause-of-Death mortality database identified a prevalence of venous thromboembolism of 1.74% in patients with IPF vs. 1.34% (p<0.0001) in the general population (overall OR 1.34, 95% CI 1.29–1.38).21 IPF should be considered an independent risk factor for thromboembolism.
All patients with the diagnosis of an ILD presenting to the ED with chest pain, shortness of breath, fever, cough, or in acute respiratory failure should undergo the following evaluation:19
- CBC, CMP, troponin, BNP, VBG/ABG, and lactate
- Urinalysis, urine culture, and blood cultures are highly recommended for all patients, with or without SIRS criteria, given steroid and immune-modulator therapy.
- Chest radiograph in patients with pre-existing ILD lacks sensitivity in identifying new opacities.10
- High resolution CT (HRCT) is recommended as it demonstrates increased sensitivity in detecting radiographic abnormalities (ground glass opacities or a new organizing pneumonia), lacks iodinated contrast, and is able to differentiate an acute exacerbation of ILD from an interstitial pneumonia, aspiration pneumonia, or ARDS (these conditions lack the traditional honeycombing pattern).20
- CTPA is required for the evaluation of pulmonary embolism if concern is present for PE, and this modality demonstrates a positive predictive value of 96% for pulmonary hypertension in individuals in which the maximum transverse diameter of the pulmonary artery is greater than the diameter of the proximal ascending aorta.22
Disposition and Treatment
At this point in the clinical encounter you have diagnosed an acute lung injury in your patient with a history of ILD. You have ruled out cardiac pathology, pulmonary infection, aspiration, and pulmonary embolism. Depending on the patient’s respiratory and hemodynamic status, your patient may be undergoing a trial of NIPPV or intubated and ventilated. What comes next?
- Experts recommend the initiation of broad-spectrum antibiotic therapy in all patients with an acute exacerbation of an ILD given the potential for immunosuppression.19
- Attempts should me made to temporize with NIPPV. While there is no statistically significant mortality benefit, patients who successfully complete NIPPV may survive to hospital discharge.12
- Consult pulmonology to discuss patient medication regimens, ventilation strategies, the possibility of corticosteroid and immune-modulator treatment, and performance of the recommended bronchoalveolar lavage (samples for culture).10
- As an aside: Randomized controlled trials of corticosteroid therapy for acute exacerbations of ILD (patients with IPF and sarcoidosis) have failed to demonstrate a survival benefit.13,23 Cyclosporin A therapy in the setting of acute IPF exacerbation has also failed to demonstrate mortality benefit.11
- Admit the patient to the ICU – progression to ARDS is common. All-cause mortality associated with acute exacerbations of ILD is estimated as 70%.4
Returning to the Case
Our 55 year-old patient with a history of IPF is in respiratory distress. Based upon our above discussion, we would initiate a trial of NIPPV (guided by mental status examination and serial VBGs), and begin our efforts to rule out underlying etiologies according to our history and physical examination. Our evaluation would include an EKG, +/- an US. HR and RR dictate early antibiotic therapy. HRCT or CTPA would be our imaging modalities of choice. If our laboratory studies and imaging led us to a diagnosis of an acute exacerbation of the patient’s IPF, pulmonology would be consulted, and the patient admitted to the ICU.
Patients with ILD presenting with complaints related to the pulmonary system have a significant risk of mortality. Close monitoring of respiratory status and early disposition may allow survival to hospital discharge.
- Airway and breathing => keep in mind, there is a 70% mortality associated with an acute ILD exacerbation; intubated patients most commonly perish in the ICU.4,12,18
- In the hemodynamically unstable patient, perform an EKG + bedside US.
- Hemodynamic instability in the setting of an ILD exacerbation results from progressive hypercapnia and subsequent hypoxia with cardiovascular collapse.
- In the stable patient, elicit a thorough history – patients with IPF, IPF associated with a connective tissue disease, chronic hypersensitivity pneumonitis, desquamative interstitial pneumonia, and asbestosis may experience acute exacerbations.4
- Initiate an evaluation to rule out cardiac pathology, pulmonary infection, aspiration, pulmonary embolism, and medication effect.
- If the aforementioned evaluation identifies an ALI without etiology => presume ILD exacerbation, initiate broad-spectrum antibiotics, consult pulmonology, and admit to the ICU.
- HRCT is a great chest imaging modality, but if concerned for PE, obtain CTPA.
References / Further Reading
- Mikolasch T, Garthwaite H, Porter J. Update in diagnosis and management of interstitial lung disease. Clin Med. 2016; 16(Suppl 6):s71-s78.
- Raghu G, Nyberg F, Morgan G. The epidemiology of interstitial lung disease and its association with lung cancer. Br J Cancer. 2004; 91(Suppl2): S3-S10.
- Lacamera P. Interstitial Lung Disease. Ferri’s Clinical Advisor 2017. p.690-692. Elsevier, Philadelphia, PA.
- Kim R, Meyer K. Therapies for interstitial lung disease: past, present and future. Ther Adv Respir Dis. 2008; 2(5):319-338.
- Churg A, Wright J, Tazelaar H. Acute exacerbations of fibrotic interstitial lung disease. Histopathology. 2011; 58(4):525-530.
- Wilcox S, Kabrhel C, Channick R. Pulmonary hypertension and right ventricular failure in emergency medicine. Ann Emerg Med. 2015 66(6):619-628.
- Coultas D, Zumwalt R, Black W, Sobonya R. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med. 1994; 150:967-972.
- Coultas D, Hughes M. Accuracy of mortality dat for interstitial lung diseases in New Mexico, USA. Thorax. 1996; 51:717-720.
- Weycker D, Oster G, Edelsberg J, Bradford W, Happel D, et al. Economic costs of idiopathic pulmonary fibrosis. Chest. 2002;122:150S.
- Disayabutr S, Calfee C, Collard H, Wolters P. Interstitial lung diseases in the hospitalized patient. BMC Med. 2015; 13:245.
- Collard H, Moore B, Flaherty K, Brown K, Kaner R, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007:176:636-643.
- Kubo H, Nakayama K, Yanai, Suzuki T, Yamaya M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest. 2005; 128(3): 1475-1482.
- Kim D, Park J, Park B, Lee J, Nicholson A, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J. 2006; 27(1):143-150.
- Vianello A, Arcaro G, Battistella L, Pipitone E, Vio S, et al. Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis. J Crit Care. 2014; 29(4):562-567.
- Yokoyama T, Kondoh Y, Taniguichi H, Kataoka K, Kato K, et al. Noninvasive ventilation in acute exacerbation of idiopathic pulmonary fibrosis. Intern Med. 2010; 49(15):1509-1514.
- Nava S, Rubini F. Lung and chest wall mechanics in ventilated patients with end stage idiopathic pulmonary fibrosis. Thorax. 1999; 54(5):390-395.
- Fernandez-Perez E, Yilmaz M, Jenad H, Daniels C, Ryu J, Hubmayr R, et al. Ventilator settings and outcome of respiratory failure in chronic interstitial lung disease. Chest. 2008; 133:1113-1119.
- Blivet S, Philit F, Sab J, Langevin B, Paret M, Gueri C, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001; 1(20):209-212.
- Papiris S, Manali E, Kolilekas L, Kagouridis K, Triantafillidou C, et al. Clinical review: idiopathic pulmonary fibrosis acute exacerbations – unravelling Ariadne’s thread. Crit Care. 2010; 14(6):246.
- Voelkel N, Quaife R, Leinwand L, et al. Right ventricular function and failure. Circulation 2006; 114: 1883-1891.
- Sprunger D, Olson A, Huie T, Fernandez-Perez E, Fischer A, et al. Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease. Eur Respir J. 2012; 39(1):125-132.
- Fujimoto K, Taniguchi H, Johkoh T, Kondoh Y, Ichikado K, et al. Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. Eur Radiol. 2012. 22:83-92.
- Tan RT, Kuzo R, Goodman LR, et al. Utility of CT scan evaluation for predicting pulmonary hypertension in patients with parenchymal lung disease. Medical College of Wisconsin Lung Transplant Group. Chest 1998;113:1250-1256.