Acute exacerbations of idiopathic pulmonary fibrosis

INTRODUCTION — Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without a clear etiology. Peripheral and basal predominant pulmonary fibrosis with histopathologic and/or computed tomography (CT) findings consistent with usual interstitial pneumonia (UIP) are diagnostic of the disease. Patients with IPF have a poor prognosis: multiple retrospective series demonstrate a median survival of two to three years from diagnosis [1-5]. However, data from clinical trials indicate this may be an underestimate of the true median survival [6-10]. Regardless, the individual clinical course is quite variable; some individuals have stable or slow progression, others demonstrate rapid progression, and still others develop episodic acute declines in lung function, known as "acute exacerbations" (AE) of IPF (AE-IPF) (figure 1).

The following questions will be discussed:

●How often does AE occur and what are the potential triggers?

●What are the presenting signs and symptoms of an AE?

●What are the current recommendations for evaluation and management of AE-IPF?

●What are typical outcomes for those who have an AE?

●What are the future directions for research in AE?

The risk factors, clinical manifestations, evaluation, diagnosis, and management of AE-IPF will be reviewed here. The clinical manifestations, diagnosis, and management of IPF are discussed separately. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis" and "Treatment of idiopathic pulmonary fibrosis".)

DEFINITION — The exact definition of AE-IPF is a work in progress. In 2007, the Idiopathic Pulmonary Fibrosis Network (IPFnet) proposed a definition to better delineate a particular subset of these acute declines in function [11]. A revised "conceptual framework" was proposed by an international working group in 2016 [12].

The 2007 proposed definition of an "acute exacerbation" (AE) of IPF included all of the following:

●A previous or concurrent diagnosis of IPF

●Deterioration within 30 days

●New bilateral ground glass opacities and/or consolidation on a background of reticular or honeycomb pattern consistent with usual interstitial pneumonia (UIP)

●No evidence of pulmonary infection by endotracheal aspiration or bronchoalveolar lavage

●Exclusion of alternative causes including left heart failure, pulmonary embolism, or an identifiable cause of acute lung injury

The 2016 revised criteria more accurately reflect today's knowledge of AE-IPF and should allow for better insights into the etiology, treatment, and outcomes of this process [12]. Similar to the definition in 2007, this newly proposed framework defines an AE as "an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality," but does not set an exact 30 day limit for symptom onset and does not require exclusion of infection. The following diagnostic criteria are proposed:

●A known diagnosis of IPF (diagnosis may be made at the time of acute respiratory deterioration)

●Acute worsening, "typically less than one month's duration"

●CT of the chest with new bilateral ground glass opacification and/or consolidation superimposed on a background of findings consistent with usual interstitial pneumonia (bibasilar reticular opacities associated with honeycomb changes and traction bronchiectasis) (see 'Imaging' below)

●Heart failure or fluid overload does not fully explain the worsening.

Based on our understanding that these events may be triggered similar to acute lung injury in the non-IPF patient population, events are further classified into "triggered" (ie, postprocedure, drug toxicity, infection, aspiration) versus "idiopathic" (ie, no inciting event identified). This new classification will allow for a more complete picture of these patients.

EPIDEMIOLOGY — Understanding the precise epidemiology has been problematic due to differences in diagnostic criteria, patient populations, baseline disease severity, follow-up time, and statistical methodology. Retrospective cohorts typically report a higher incidence and prevalence and may be hampered by bias to over-report acute deteriorations with a known cause (eg, pulmonary embolism, heart failure) as an AE-IPF [13]. Prospective trials, on the other hand, may have missing data hampering accurate diagnosis of an AE [14], as well as differing prevalence when reported by central reviewers versus the principal investigators [8,15]. A meta-analysis of seven multicenter prospective trials described an overall rate of 26.3 per 1000 patient-years (range of 8.9 to 206.3 per 1000 patients-years) [16]. As prospective clinical trials often exclude patients with advanced disease and comorbidities and as the risk of AE increases with severity of IPF, true rates of AE may be higher than the estimate from prospective trials.

PATHOPHYSIOLOGY AND RISK FACTORS — While our current understanding of the pathophysiology of AE-IPF is limited, AE has clinical similarities to acute respiratory distress syndrome (ARDS). Both have increased oxygen needs, bilateral ground glass opacities and/or consolidation on imaging, and histopathology demonstrating diffuse alveolar damage [17-20]. We know that there are multiple causes for ARDS and it is likely the same for those with AE-IPF. Further, IPF patients likely have maladaptive responses to lung injury, demonstrated by altered responses of IPF versus control fibroblasts to stimuli in vitro [21,22].

There are multiple examples of lung injury that subsequently develop into an AE-IPF [23-26].

●Infections – Direct lung injury due to pulmonary infection is a common cause of ARDS and likely contributes to AE-IPF as well. Lower respiratory viral infections are present in a significant minority of cases of AE-IPF [27].

●Microaspiration of gastric contents – Microaspiration of gastric contents is a proposed risk factor for exacerbations and progression of IPF. There is weak evidence for a potential benefit from pharmacologic treatment [28], but guidelines argue against empiric treatment in asymptomatic patients [29]. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Empiric treatment for asymptomatic gastroesophageal reflux'.)

●Surgery and thoracic procedures – Thoracic procedures, such as surgical lung biopsy, lung cancer resection, and bronchoscopy, have been associated with the development of IPF exacerbations [30-34]. Nonthoracic surgical procedures have also been implicated in development of exacerbations [33]. Potential mechanisms include administration of high concentrations of oxygen and volutrauma or barotrauma during mechanical ventilation. However, a causal relationship between IPF exacerbations and procedures is difficult to ascertain due to the retrospective analysis of the studies.

●Advanced lung disease – Clinical factors of physiologically advanced IPF are associated with increased rates of AE, including: lower FVC, diffusing capacity of the lung for carbon monoxide (DLCO), and six-minute walk distance [25,35,36].

●Other – A number of other potential contributors have been implicated, such as evidence of pulmonary hypertension, higher body mass index, coronary artery disease, and treatment with immunosuppressive therapy [10,36-38].

CLINICAL MANIFESTATIONS — In patients with IPF, an acute exacerbation typically presents with shortness of breath or worsening exercise tolerance that develop over days to weeks, but generally less than one month [12,39]. In a small series of 11 patients, the time from onset of symptoms to hospital admission averaged approximately 13 days [13]. Cough (with or without sputum production) is common; fever and flu-like symptoms may also be present.

On physical examination, the patient may be tachypneic and will typically have bibasilar crackles consistent with the underlying diagnosis of IPF.

Patients typically demonstrate impaired gas exchange, as evidenced by an arterial oxygen tension to fraction of inspired oxygen ratio (PaO₂/FiO₂) of less than 225 mmHg or a decrease in the PaO₂ of 10 mmHg or more from baseline.

As noted above, high-resolution computed tomography (HRCT) reveals bilateral ground glass or consolidative opacities superimposed on a background of typical HRCT features of IPF (eg, bibasilar reticular opacities, honeycomb changes, traction bronchiectasis). (See 'Definition' above and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Chest imaging'.)

DIAGNOSTIC EVALUATION — The presenting symptoms and signs of AE-IPF are not specific, and the evaluation should exclude alternate diagnoses (eg, pneumothorax, heart failure, venous thromboembolism) and identify potential triggers of AE-IPF, such as lung infection or a recent lung procedure.

Laboratory testing — There are no laboratory studies specific to the diagnosis of AE in IPF. As identification and management of comorbidities is fundamental to the management of these patients, careful evaluation for potential contributing or alternate diagnoses is critical. We typically obtain complete blood and differential cell counts, brain natriuretic peptide, serial troponin tests, procalcitonin, and sensitive D-dimer. The role of serum markers of inflammation and lung injury is unclear [12,40]. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are nonspecific and have not proved helpful.

Testing for potential lung infection typically includes blood cultures, urinary antigen assays for Streptococcus pneumoniae and Legionella, rapid influenza antigen test on respiratory secretions (in the appropriate season), and multiplex polymerase chain reaction (PCR) test for respiratory viruses [27,41,42]. The rapid influenza tests have a specificity of >95 percent, but the sensitivity is only about 50 to 60 percent, so a negative result does not rule out influenza [43,44]. Real-time reverse-transcriptase PCR is the test of choice to diagnose influenza but requires a laboratory and a laboratory technician. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

Of note, troponins, while typically used to look for evidence of an acute myocardial infarction, can be elevated in patients with a moderately large pulmonary embolism. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Laboratory tests'.)

Imaging — The first step is often a conventional chest radiograph to exclude a pneumothorax or other abnormality that requires immediate attention. High-resolution computed tomography (HRCT), with or without a rule-out pulmonary embolism protocol, is necessary for appropriate classification of the parenchymal abnormalities [12]. We have a very low threshold to perform CT pulmonary angiogram to exclude pulmonary embolism due to the significantly increased risk of venous thromboembolism in IPF [45-47]. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Diagnosis'.)

HRCT in patients with an AE-IPF will demonstrate typical chronic background findings of a usual interstitial pneumonia pattern (eg, reticulation, traction bronchiectasis, honeycomb changes) in combination with more acute abnormalities of increased ground glass opacity and/or consolidation. Three HRCT distribution patterns have been described: peripheral, multifocal, and diffuse [48]. (See 'Definition' above.)

For patients who are unable to undergo CT pulmonary angiography due to kidney disease, an alternative approach is to obtain ventilation-perfusion (V/Q) scanning, possibly with lower extremity compressive ultrasonography if the V/Q scan is indeterminate. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Ventilation perfusion scan'.)

Flexible bronchoscopy — Flexible bronchoscopy with bronchoalveolar lavage (BAL) is part of our standard evaluation of patients with AE-IPF, as long as the patient is clinically able to tolerate the procedure. The main role is to identify and characterize any infection or malignancy. When performing a BAL for this purpose, we select a subsegment that appears to be involved based on the HRCT findings. BAL samples are sent for a broad spectrum of microbiologic tests, including stains and cultures for bacteria, mycobacteria, and fungi, as well as multiplex PCR testing for respiratory viruses. (See "Basic principles and technique of bronchoalveolar lavage".)

Transbronchial biopsies are generally not helpful due to their small size and are not part of our standard work-up [12].

Avoidance of surgical lung biopsy — Surgical lung biopsy is of minimal value in AE-IPF. Given the high surgical risk in this patient population, we do not recommend it [20,49,50]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Interstitial lung disease presenting with acute respiratory failure'.)

DIAGNOSIS — The diagnosis of AE-IPF is generally made in a patient with known or concurrently diagnosed IPF and the following features [12] (see 'Definition' above):

●An acute, clinically significant respiratory deterioration typically <1 month in duration

●High-resolution computed tomography (HRCT) demonstrating new bilateral ground-glass opacification and/or consolidation superimposed on a background of findings consistent with usual interstitial pneumonia

●Exclusion of heart failure and fluid overload as significant contributors to the deterioration

Flexible bronchoscopy with bronchoalveolar lavage (BAL) is used to identify infectious agents and exclude malignancy. While the 2007 criteria for AE-IPF required the exclusion of infection, the 2016 criteria do not exclude potential triggers, such as infection, lung procedures/operations, drug toxicity, and aspiration [11,12]. These potential triggers should be noted, but do not exclude AE-IPF.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of AE-IPF includes venous thromboembolism, infection, and heart failure. A pneumothorax can complicate IPF, but would usually be recognized on a conventional chest radiograph. Pulmonary hypertension developing as a consequence of IPF is also in the differential diagnosis of worsening dyspnea, but would not have the new radiographic opacities associated with AE-IPF.

●Venous thromboembolism – IPF is associated with a significantly increased risk of venous thromboembolism (VTE) [45-47]. The suspicion for VTE is increased in patients with obesity, immobilization, malignancy, and prior or family history of VTE. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

●Infection – For patients who can tolerate the procedure, our standard practice is to perform a full investigation for potential lung infection and to initiate empiric antibiotics for pneumonia while studies are pending, as described (see 'Diagnostic evaluation' above). The choice of antibiotics for community-acquired pneumonia is described separately. (See "Treatment of community-acquired pneumonia in adults who require hospitalization".)

●Heart failure – Given the average age of individuals with IPF, careful cardiac assessment for heart failure or myocardial infarction is appropriate. We typically begin with serial troponin, brain natriuretic peptide (BNP), and an electrocardiogram. An echocardiogram is not typically a first line assessment, but may be useful to evaluate for heart failure in a subset of patients, such as those with extrathoracic clinical features of heart failure or an elevated BNP. (See "Heart failure: Clinical manifestations and diagnosis in adults".)

●Pulmonary hypertension – Pulmonary hypertension (group 3), a well-known complication of IPF, also presents with worsening dyspnea, but without increased radiographic opacities. The diagnosis is often suspected in patients with worsening gas transfer without evidence of worsening interstitial lung disease. Plasma BNP is often increased, and Doppler echocardiography can provide an estimate of pulmonary artery systolic pressure. A firm diagnosis requires right heart catheterization. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

TREATMENT — Optimal therapy for AE-IPF has not been established. All patients require supportive care to relieve hypoxemia and alleviate symptoms of shortness of breath and cough. Most experts, including ourselves, administer systemic glucocorticoids, although randomized trial data are lacking.

Other therapies to treat AE-IPF have been reported in case series, but the study design and small numbers limit clear conclusions regarding efficacy and safety of these interventions and emphasize the need for randomized trials [12]. Preliminary studies with these agents are described below. (See 'Investigational approaches' below.)

Supportive measures

Routine — Supportive measures for all patients with AE-IPF include provision of supplemental oxygen and relief of dyspnea. Standard measures for prevention of VTE and stress gastropathy are prudent.

●Oxygenation – Patients with AE-IPF often have a high oxygen requirement to maintain a pulse oxygen saturation above 88 percent and their high inspiratory flow rate may make oxygenation with standard low-flow nasal cannula difficult.

High-flow oxygen therapy by nasal cannula may be a reasonable alternative for patients with acute hypoxemic respiratory failure without hypercapnia who are not able to achieve an adequate SpO₂ with low-flow oxygen. (See "Continuous oxygen delivery systems for the acute care of infants, children, and adults", section on 'Nasal cannula'.)

●Relief of dyspnea – For some patients, treating hypoxemia with supplemental oxygen is sufficient to treat dyspnea, but dyspnea due to IPF may be refractory. Palliative care strategies may help alleviate dyspnea, as described below. (See 'Palliative care' below.)

●Prevention of venous thromboembolism – Patients who are hospitalized with an AE-IPF are at increased risk of venous thromboembolism. Routine measures used to prevent VTE in hospitalized patients should be employed. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

●Anti-acid therapy – As noted above, acid aspiration has been implicated as a potential contributor to AE-IPF based on analysis of data from the placebo arms of three randomized trials [28]. A randomized trial of laparoscopic Nissen fundoplication in 58 individuals with stable IPF and abnormal acid gastroesophageal reflux did not decrease rates of acute exacerbation [51]. Data are not available regarding a potential role for anti-acid therapy in the context of AE-IPF. We typically continue any anti-acid therapy that the patient has been taking. For patients not on anti-acid therapy at the time of admission, we usually follow guidelines for stress ulcer prophylaxis. (See 'Pathophysiology and risk factors' above and "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'Prophylaxis'.)

Mechanical ventilation — The role and efficacy of noninvasive positive pressure ventilation and low tidal volume mechanical ventilation have not been formally studied in AE-IPF. We believe that mechanical ventilation is of limited value in the IPF patient with an acute deterioration without a defined treatable trigger, based on high mortality rates and the poor outcomes reported for mechanical ventilation in IPF [52]. Thus, we make every effort to communicate the limitations of mechanical ventilation to the patient and their family. (See 'Palliative care' below.)

Multiple cohorts demonstrate poor short-term prognosis for patients with AE-IPF admitted to the ICU and/or mechanically ventilated [52-55]. In a large database study of patients with IPF who were hospitalized in the United States, 1703 patients were treated with mechanical ventilation and 778 were treated with noninvasive ventilation [52]. Among those with a primary diagnosis of IPF, the mortality rate was 49 percent regardless of the type of ventilatory support. In other studies, mortality has reached 96 percent [56]. If the patient chooses to pursue a trial of invasive mechanical ventilation, it may be helpful to outline parameters for discontinuing ventilatory support should the patient fail to improve.

Hopefully, all patients with IPF will have had the opportunity to have discussions about goals of care with their physicians prior to the onset of an AE, so the patient, family, and clinician can make decisions that are in concert with the patient's values and preferences. (See "Palliative care for adults with nonmalignant chronic lung disease", section on 'Advance care planning' and 'Palliative care' below.)

Glucocorticoids — The international evidence-based guidelines for AE-IPF suggest administering systemic glucocorticoids in the majority of patients with AE-IPF [56]. No clinical trials have been performed, so the guidelines put a high value on anecdotal reports of benefit. We typically treat AE-IPF with glucocorticoids in the range of prednisone 1 mg/kg per day orally to methylprednisolone 1 gram per day intravenously for three days followed by a taper, based on severity of disease and response to therapy. For those individuals who appear to a have a clinical response to glucocorticoids, we will typically taper them slowly over the course of weeks to months ensuring there is no recurrence with close follow up.

Multiple reports outline glucocorticoid use as monotherapy [12,53,57-59]. On the other hand, some investigators have reported an immunosuppression-free approach with similar outcomes in AE [60].

While autopsy and biopsy data from this cohort typically demonstrate usual interstitial pneumonia with diffuse alveolar damage (DAD), a few reports describe concomitant organizing pneumonia, which may respond to glucocorticoids. Further, one may hypothesize that activation of the immune response plays a role in the acute deterioration of these patients.

Antibiotics — Broad-spectrum antibiotics are typically initiated upon presentation as the radiographic findings overlap with pneumonia. Given the severity of disease and poor prognosis, many experts complete a seven day course even if all cultures are negative. Our approach is to cover broadly at presentation, including atypical coverage. If cultures/testing identify a specific pathogen, we narrow the coverage appropriately. For those without a pathogen, we limit the antibiotics to a seven-day course.

In addition to broad-spectrum antibiotics, we support antiviral treatment for proven viral respiratory infections. Patients with IPF are designated by the United States Centers for Disease Control and Prevention (CDC) as persons at risk for severe COVID-19 (coronavirus disease 2019) (table 1), and therefore qualify for prioritized access to antiviral therapies including nirmatrelvir/ritonavir and remdesivir. Neuraminidase inhibitors should be used in patients with influenza infection.

Biologic markers, such as procalcitonin and C-reactive protein (CRP), are sometimes used to try to distinguish between bacterial and nonbacterial causes of pneumonia. One randomized trial evaluated the use of procalcitonin (PCT)-guided antibiotic treatment versus standard clinician determined care in 61 patients with AE-IPF [61]. This trial demonstrated shorter duration of antibiotic use with PCT monitoring while the duration of mechanical ventilation and overall mortality were unchanged [12]. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Serum biomarkers'.)

Nintedanib and pirfenidone — Accumulating data suggest that the antifibrotic agents, nintedanib and pirfenidone, help prevent AEs [8,12,62,63]. Unfortunately, the value of adding or continuing nintedanib or pirfenidone during an AE remains unknown. Our practice is to continue the patient on their established therapy. For patients not on one of these agents, it may be reasonable to initiate one of the antifibrotic agents after resolution of the AE. The effect of nintedanib and pirfenidone on disease progression and mortality is discussed separately. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Medical therapies'.)

Lung transplantation — Lung transplantation provides a survival benefit for selected patients who have IPF, but are not in the midst of an AE. For those with an acute deterioration, perioperative risks of transplantation are clearly greater. For individuals with AE-IPF transplanted in the context of mechanical ventilation or ICU stay, both one- and three-year survivals after lung transplantation appear decreased compared with stable patients undergoing elective transplantation [64]. In contrast, 25 patients with an AE-interstitial lung disease (ILD; not limited to IPF) who underwent lung transplant had similar one-year survival compared with 67 patients with stable ILD transplanted during the same period (96 percent versus 92.5 percent, respectively) [65]. In the latter study, the majority of patients were supported with high flow nasal cannula rather than invasive mechanical ventilation; only one patient was on extracorporeal membrane oxygenation (ECMO) at the time of transplant.

For individuals who have yet to undergo assessment by a transplant center, urgent lung transplantation may not be available due to limited time and resources, and would depend on discussions with regional lung transplant center. Rarely, in patients who have already been listed for transplantation and are hospitalized at a transplant center, extracorporeal membrane oxygenation can be used as a bridge to transplant.

The best recommendation remains that patients with IPF who are potential candidates for lung transplantation should be referred for evaluation early in the course of their disease, so that full assessments may be made while the patient is stable. (See "Lung transplantation: General guidelines for recipient selection".)

Palliative care — Given the poor prognosis of patients with AE-IPF, palliative care consultation to provide relief from symptoms and stress for the patient and family is vital. We routinely use palliative care services as an extra layer of psychosocial support for these patients. (See "Palliative care for adults with nonmalignant chronic lung disease".)

Palliation of dyspnea is an important component of end-of-life care. Palliative strategies to reduce dyspnea in an individual patient may include relaxation techniques, facial cooling with a fan, opiates, benzodiazepines, and sometimes noninvasive ventilation. A few studies have suggested a role for noninvasive ventilation to reduce dyspnea, although this requires a clear discussion of goals of care, especially in patients who prefer not to pursue life-prolonging treatments. Palliation of dyspnea is discussed separately. (See "Assessment and management of dyspnea in palliative care".)

Cough can also be a troubling symptom that may benefit from a palliative approach. (See "Palliative care: Overview of cough, stridor, and hemoptysis in adults", section on 'Cough'.)

PROGNOSIS — AE-IPF portends a poor prognosis for patients with this progressive fibrotic lung disease. AE precedes approximately 40 percent of IPF deaths [36,66], and the median survival following an AE is approximately three to four months [14,25]. More severe disease (lower baseline forced vital capacity and diffusing capacity of the lung for carbon monoxide) as well as more extensive computerized tomography findings and worse oxygenation at presentation are associated with worse outcome [48,67]. Respiratory failure resulting in the need for mechanical ventilation or noninvasive ventilation has an extremely poor prognosis [52-55].

Serum markers such as lactate dehydrogenase, Kerbs von Lungren 6 antigen, neutrophil elastase, circulating fibrocytes, and antiheat shock protein antibodies may have prognostic value but are not recommended for routine clinical use until more studies validate their usefulness [68,69].

AGENTS WITHOUT BENEFIT

●Cyclophosphamide – A phase 3 multicenter randomized trial (EXAFIP) evaluated the efficacy of adding cyclophosphamide (600 mg/m² intravenous pulses) or placebo to high-dose glucocorticoids in 119 patients with AE-IPF [70]. The three-month mortality was higher in the cyclophosphamide group than in the control group even after adjusting for IPF severity. The rate of infectious complications was similar between the groups.

INVESTIGATIONAL APPROACHES — Observational studies have examined the following treatments, sometimes using historical or parallel untreated controls. These interventions require additional study prior to widespread implementation. Information about ongoing clinical trials can be obtained at clinicaltrials.gov. It is hoped that the revised definition of AE-IPF will enable researchers to test novel hypotheses of the pathophysiologic mechanisms and also novel approaches to detection and treatment in well-designed clinical trials [12]. (See 'Definition' above.)

●Cyclosporine – Small retrospective series have suggested a slight survival benefit to cyclosporine added to systemic glucocorticoids compared with those managed without cyclosporine [71-73]. However, a large retrospective series (7989 patients) found no mortality benefit with the addition of cyclosporine to high-dose methylprednisolone in patients with acute exacerbations of IPF [74].

●Rituximab with therapeutic plasma exchange – In a small series of seven critically-ill patients with AE-IPF, therapeutic plasma exchange (TPE) was performed on day one and four to eight additional times, and rituximab was administered twice (roughly on days 5 and 15) [75]. Pulse methylprednisolone was administered on day 1 followed by a prednisone taper over 3 weeks. An additional four patients received TPE, rituximab, glucocorticoids, and also intravenous immune globulin 0.5 mg/kg/day on days 16 to 19. One year survival was 46 +/-15 percent compared with 5 percent among the historical controls.

●Tacrolimus – Fifteen patients with AE-IPF were treated with methylprednisolone pulse therapy with (n = 5) or without (n = 10) oral tacrolimus [76]. Four patients in the tacrolimus group survived compared with one of the non-tacrolimus group.

●Hemoperfusion with polymyxin-B immobilized fiber – Hemoperfusion with polymyxin-B immobilized fiber was developed to remove endotoxin, but may also remove cytokines that contribute to lung injury [77-79]. In a retrospective series of 160 patients with AE-IPF who underwent this therapy, oxygenation improved after the second treatment [77]. The one and three month survival rates were 70 and 34 percent, respectively. The majority of the patients also received high dose systemic glucocorticoids.

●Intravenous recombinant thrombomodulin – One hypothesis is that disordered coagulation and fibrinolysis contribute to the pathogenesis of AE-IPF. Recombinant human soluble thrombomodulin alpha (rhTM) has anti-inflammatory, anticoagulant, and antifibrinolytic properties that might ameliorate these processes. While preliminary studies suggested a beneficial effect in AE-IPF [80-82], rhTM did not improve survival at 90 days in a randomized trial with 82 participants [83]. Bleeding adverse events were higher with rhTM than placebo. The results of this trial suggest that rhTM should not be used for the treatment of AE-IPF.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest).

●Basics topic (See "Patient education: Idiopathic pulmonary fibrosis (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Definition – The exact definition of AE-IPF is a work in progress, but the following features are proposed (see 'Definition' above): a known diagnosis of IPF (diagnosis may be made at the time of acute respiratory deterioration); acute worsening (typically less than one month's duration); CT of the chest with new bilateral ground-glass opacification and/or consolidation superimposed on a background of findings consistent with usual interstitial pneumonia (bibasilar reticular opacities associated with honeycomb changes and traction bronchiectasis); and heart failure or fluid overload does not fully explain the worsening.

●Risk factors – AE-IPF likely arises from maladaptive responses to direct lung injury. Known and suspected risk factors include respiratory infections, aspiration, mechanical ventilation, and immunosuppressive therapy. (See 'Pathophysiology and risk factors' above.)

●Diagnostic evaluation – Evaluation of patients presenting with AE should focus on identifying contributing or alternate causes of decline, such as venous thromboembolism (VTE), infection, and heart failure.

•Laboratory testing typically involves obtaining a complete blood count and differential cell count, brain natriuretic peptide, serial troponin tests, procalcitonin, and sensitive D-dimer. For potential lung infection, we perform blood cultures, urinary antigen assays for S. pneumoniae and Legionella, rapid influenza antigen test on respiratory secretions (in the appropriate season), and polymerase chain reaction (PCR) tests for respiratory viruses, including COVID-19. (See 'Diagnostic evaluation' above.)

•Imaging should include high-resolution computed tomography (HRCT) in all patients. We have a low threshold for obtaining a CT pulmonary angiogram to rule out pulmonary embolism. (See 'Imaging' above.)

•Bronchoscopy with bronchoalveolar lavage (BAL) is often helpful to evaluate for lung infection if the patient will tolerate the procedure. Transbronchial biopsies or open lung biopsies are not indicated. (See 'Diagnostic evaluation' above.)

●Approach to treatment

•Supportive Measures – Initial management of AE in all patients should consist of supplemental oxygen and palliation of shortness of breath. Current evidence-based guidelines and our own practice advise against the use of mechanical ventilation given the extremely poor prognosis. Early discussions about goals of care are appropriate, and decisions should be made on an individual basis. (See 'Mechanical ventilation' above and 'Palliative care' above.)

•Glucocorticoids – We suggest a trial of empiric treatment with systemic glucocorticoids in patients with AE-IPF (Grade 2C). The usual dose ranges from prednisone 1 mg/kg per day orally to methylprednisolone 1 gram per day for three days followed by a prednisone taper, based on severity of disease and response to therapy. (See 'Glucocorticoids' above.)

•Antibiotics – We initiate broad-spectrum antibiotics, including atypical coverage, upon presentation. Antibiotic treatment is tailored if an organism is identified and we typically continue antibiotics for a seven-day course. (See 'Antibiotics' above.)

•Antifibrotics – There are no data examining a role for nintedanib or pirfenidone during an AE-IPF. Our practice is to continue patients on their baseline regimen but not to initiate de novo therapy during the acute exacerbation. (See 'Nintedanib and pirfenidone' above.)

•Lung transplantation – Lung transplantation for AE-IPF is occasionally possible in patients who have previously undergone transplant evaluation. However, it carries significant risk and is usually not feasible in the midst of an AE-IPF. (See 'Lung transplantation' above.)

•Palliative care – Given the poor prognosis of patients with AE-IPF, palliative care consultation to provide relief from symptoms and stress for the patient and family is vital. We routinely use palliative care services as an extra layer of psychosocial support for these patients. (See 'Palliative care' above.)

●Prognosis – AE-IPF precedes approximately 40 percent of IPF deaths and portends a poor prognosis. The median survival following an AE-IPF is approximately three to four months. (See 'Prognosis' above.)