The hospitalized patient with interstitial lung disease: a hospitalist primer

Laboratory Testing

All patients presenting to the hospital with a suspected ILD should undergo careful assessment for the presence of connective tissue disease, including patients without clear symptoms because ILD can be the presenting manifestation. We routinely test for antinuclear antibody titer and pattern, rheumatoid factor, anticyclic citrullinated peptide, creatinine kinase, and aldolase as the initial screening panel in most patients, with further testing directed by the findings on history and physical examination. Pulmonary function tests are used routinely to monitor disease progression in the outpatient setting; however, in the hospitalized ILD patient, they are often difficult to perform and have no real diagnostic value. Similarly, arterial blood gas is not routinely used as part of the initial inpatient evaluation.

Imaging

All hospitalized patients with a known or suspected ILD should undergo chest imaging, assuming they are stable enough to do so. While the chest radiograph can provide a low-cost initial assessment of the degree of lung involvement and presence of accompanying abnormalities, computed tomography (CT) scanning is the diagnostic test of choice.¹¹ The pattern and distribution of abnormalities on CT scan can greatly assist with the differential diagnosis in patients presenting with a new ILD, while the presence and pattern of new opacities superimposed on chronic changes can inform the differential and the prognosis of an ILD exacerbation.¹² High-resolution CT provides the most sensitive imaging modality for diffuse ILD. The addition of prone and expiratory images are helpful in differentiating mild lung disease from atelectasis and detecting air trapping, respectively.¹³ However, since pulmonary embolism is a common extraparenchymal finding routinely considered in the differential of a patient presenting with a known or suspected ILD, physicians should consider ordering a CT pulmonary angiogram with additional high-resolution images. Most important, radiographic evaluation should include a review of all available prior chest imaging to assess both the tempo and the nature of radiographic findings.

Bronchoscopy

Bronchoscopy (with bronchoalveolar lavage [BAL], transbronchial lung biopsy [TBLB] and/or transbronchial needle aspiration [TBNA]) is not a routinely used diagnostic tool in the hospitalized ILD patient. However, it should be considered in certain circumstances.⁷ Cell count and differential can be helpful in diagnosing AEP (greater than 40% eosinophilia) or acute HP (greater than 50% lymphocytosis), while the addition of microbiologic and cytologic analysis can assist with the diagnosis of infectious etiologies (including pneumocystis pneumonia) or malignancy.^14,15 Bronchoscopy with BAL has limited sensitivity for many infections and the procedure is associated with a small risk of worsened hypoxemia. Transbronchial lung biopsy, and to a lesser extent TBNA, carry the added risk of pneumothorax and bleeding. In the majority of cases of ILD, TBLB and TBNA have limited diagnostic utility given the small amount of lung tissue sampled. In cases of suspected IPF, where the identification of the histologic pattern is needed for definitive diagnosis, tissue from TBLB cannot be used to make a conclusive diagnosis.^16,17 However, both TBNA and TBLB are useful in the diagnosis of granulomatous disorders, such as sarcoidosis, where the diagnostic yield ranges from 80% to 90% and 50% to 75%, respectively.^18,19

A newer bronchoscopic approach to sampling the lung using a bronchoscopically-placed cryoprobe (termed transbronchial cryobiopsy) has uncertain diagnostic utility and safety in the acute setting. This procedure involves intubation, sedation, and bronchoscopy allowing for the passage of an endobronchial cryoprobe through the bronchoscope and into the periphery of the lung. Several cryobiopies are generally taken from the same pulmonary subsegment. Despite a large number of recent publications on this topic, none of them have provided a clear sense of the diagnostic yield and safety.^20,21 Transbronchial cryobiopsy remains a highly controversial procedure in the clinical setting, and we would not recommend its use until further data are available.²²

Surgical Lung Biopsy

In the outpatient setting, a surgical lung biopsy is often useful when the ILD diagnosis cannot be made from the clinical context and imaging. However, patients presenting with acute respiratory failure from ILD are at greatly increased risk of complications from nonelective biopsy including pneumothorax, hemothorax, acute exacerbation of ILD, ICU admission, mechanical ventilation, and in-hospital mortality.^23,24 Acute histological findings can also make it difficult to appreciate the underlying pattern of fibrosis, reducing the diagnostic utility.^25-27 In our experience, surgical lung biopsy rarely alters the treatment of ILD patients presenting in acute respiratory failure. We believe that surgical lung biopsy should be reserved for the rare hospitalized patients in whom the clinician believes the results would clearly change management and that the substantial risk is worth taking.^5,28

The inpatient management of ILD is a large topic and difficult to comprehensively cover in a single review. Therefore, in this section, we will review 6 key management questions that address both general and specific treatment decisions that frequently arise in the care of hospitalized ILD patients (Figure).

When should hospitalized ILD patients be treated with antibiotics?

Infection and acute presentations of ILD have many similar clinical and radiographic features, making it difficult to distinguish between the two, or exclude infection as the causative role in an acute exacerbation.² In many ILD patients, the risk of infection is higher than in the general population, due to the acute and chronic use of immunosuppression. Until firm guidelines on the use of antibiotics in hospitalized patients with acute respiratory symptoms are available, we recommend considering the empiric use of antibiotics in ILD patients in respiratory failure, in addition to a thorough infectious workup.

When should hospitalized ILD patients be treated with corticosteroids?

Clinical experience supports the use of corticosteroids in the acute management of most rapidly progressive ILDs presenting with respiratory failure, including AEP, COP, acute HP, drug-induced ILD, and some cases of CT-ILD. Patients with AEP tend to respond rapidly to corticosteroids. In a series of 137 patients with AEP, 127 (92%) received corticosteroids, with defervescence and improved dyspnea within 48 to 72 hours and resolution of all symptoms after a median of 7 (4 to 10) days.²⁹ Cryptogenic organizing pneumonia is similarly corticosteroid-responsive, with patients typically started on doses of 1mg/kg of prednisone followed by a slow taper due to the risk of relapse.³⁰ For the majority of acute CT-ILD, oral prednisone is the initial treatment, often in combination with a second immunosuppressive agent such as mycophenolate.

No proven therapies are available for acute exacerbations of IPF (AE-IPF), including the use of corticosteroids. The most recent international guidelines on the management of AE-IPF conditionally recommends the use of corticosteroids, although this recommendation is largely based on anecdotal reports and clearly states that randomized studies are needed.³ When corticosteroids are used, we recommend high doses (eg, 1 to 2 mg/kg of prednisone) with close clinical monitoring. Consider stopping corticosteroids after 3 to 5 days if there is no evidence of clinical improvement. Prolonged courses of corticosteroids should be avoided.

What additional pharmacologic therapies should be considered in the treatment of hospitalized ILD patients?

Immunomodulators. Patients presenting acutely with a new-onset ILD or with an acute exacerbation of a chronic ILD often receive corticosteroids, sometimes in concert with an immunomodulator. This is most commonly seen in the acute management of CTD- ILD and in chronic HP, where mycophenolate mofetil, and to a lesser extent, cyclophosphamide and azathioprine for CT-ILD are used in combination with corticosteroids. The rationale for this is both therapeutic synergy and a desire to limit the long-term exposure to corticosteroids. Similarly, multiple observational cohort studies have investigated the role of combination or tandem immunosuppression in the treatment AE-IPF. Although cyclosporine, cyclophosphamide, azathioprine, rituximab and tacrolimus have all been studied, their efficacy remains uncertain.³ Until these therapies are better studied, they have no routine role in the management of AE-IPF.

Antifibrotics. Nintedanib and pirfenidone are 2 antifibrotic agents approved for the treatment of IPF. Clinical trials suggest that, in addition to slowing disease progression, these therapies may help prevent AE-IPF. The data are most robust in studies of nintedanib. A phase 2 trial with 432 subjects demonstrated a delay in time to the first investigator-reported acute exacerbation.³¹ Two follow-up phase 3 trials showed a reduction in centrally adjudicated AE-IPF in the pooled nintedanib groups compared to placebo.³² An initial phase 2 trial of pirfenidone showed a reduction in acute exacerbations in patients on pirfenidone, but this finding was not replicated in follow-up studies.^33-35 Because of their potential role in preventing acute exacerbations and emerging evidence to suggest that continuation of antifibrotics may lead to better outcomes during an acute exacerbation, these drugs should not generally be stopped during a hospitalization for ILD. However, no evidence supports their initiation during acute exacerbations, and we do not recommend starting antifibrotics in the hospitalized setting for newly diagnosed patients. Starting and stopping antifibrotics should be reserved for outpatient management.

When should noninvasive and mechanical ventilation be considered?

We recommend carefully considering the use of noninvasive ventilation (NIV) and intubation in every ILD patient in respiratory distress, as an acutely reversible process may be present. In patients requiring mechanical ventilation, every effort should be made to minimize potential damage by reducing the fraction of inspired oxygen (to prevent potential hyperoxic injury) and reducing tidal volumes (to minimize barotrauma). Patients with a chronic ILD, particularly IPF, who require NIV or mechanical ventilation will generally have poor outcomes.

Studies suggest that NIV prevents mechanical ventilation in only the minority of patients presenting with an AE-IPF and is associated with high in-hospital mortality and a median survival following hospital discharge of only 60 days.^36-38 The majority of patients with IPF requiring mechanical ventilation will not survive the intensive care unit. In a series of 23 patients presenting with acute respiratory failure and IPF, 22 of the 23 patients died while receiving mechanical ventilation, with a median survival of 3 days. In a more recent study of 34 patients with acute respiratory failure and IPF, 15 subjects underwent mechanical ventilation with an in-hospital mortality rate of 100%.³⁹ Given the overall poor survival associated with AE-IPF, mechanical ventilation should be carefully considered with the patient and family as part of an overall goals-of-care conversation prior to initiation.