Idiopathic Pulmonary Fibrosis (IPF) Treatment & Management

The goal of any disease management strategy should include assessment and treatment of comorbid medical conditions. Common comorbid medical conditions found in patients with idiopathic pulmonary fibrosis (IPF) include chronic obstructive pulmonary disease, obstructive sleep apnea, gastroesophageal reflux disease, and coronary artery disease. Therefore, if any of these comorbid illnesses are present, they should be managed according to current practice guidelines.

Given the high prevalence of gastroesophageal reflux (GER) in patients with idiopathic pulmonary fibrosis, a retrospective study was conducted to investigate the relationship of reflux-related variables and survival time in patients with idiopathic pulmonary fibrosis. Of the 204 included patients, 34% reported symptoms of GER, 45% had a history of GER disease, 47% reported use of medications for GER, and 5% of patients had previously undergone Nissen fundoplication. On adjusted analysis, the use of GER medications was associated with a longer survival time. Additionally, patients taking GER medications had a lower fibrosis score on HRCT. ^[50]

Any patient with idiopathic pulmonary fibrosis who is a current smoker should be encouraged to quit and offered pharmacologic therapy if needed.

Patients with hypoxemia (PaO₂< 55 mmHg or oxygen saturation as measured using pulse oximetry [SpO₂] < 88%) at rest or with exercise should be prescribed oxygen therapy to maintain a saturation of at least 90% at rest, with sleep, and with exertion.

The current clinical practice guidelines from 2011 and 2015 strongly recommend supplemental oxygen therapy for patients with idiopathic pulmonary fibrosis, as oxygen administration reduces exertional dyspnea and improves exercise tolerance. The oxygen prescription should be informed by 6-minute walk tests or treadmill testing of oxygen saturation, as well as by nocturnal oximetry or polysomnography as indicated.

Vaccination against influenza and pneumococcal infection should be encouraged in all patients with idiopathic pulmonary fibrosis.

See Medication for a discussion of the various drugs, experimental and otherwise, used in the treatment of idiopathic pulmonary fibrosis.

See Guidelines for recommendations from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association.

Patients with idiopathic pulmonary fibrosis (IPF) require consideration for lung transplantation owing to the natural progression of the disease. Two main challenges in the process of lung transplantation evaluation are to be considered.

The first challenge is the timing of referral to the transplantation program, as antifibrotic medications attenuate disease progression and make the decision on referral timing more complex as physicians elect to wait longer for those patients with moderate disease, pending a treatment response. Given that idiopathic pulmonary fibrosis is a universally progressive condition, regardless of antifibrotic initiation, one approach is to refer all suitable patients at the time of diagnosis. Another approach is to identify patients who are progressing rapidly and refer them early. Alternatively, studies have identified circulating biomarkers that correlate with disease progression, such as Krebs von den Lungen-6 (more commonly known as KL-6) and surfactant protein D, although these are not used in routine clinical practice. The development of pulmonary hypertension in idiopathic pulmonary fibrosis is an independent marker of poor prognosis and should prompt consideration for referral.

The second challenge is that acute exacerbations are unpredictable, are associated with inpatient mortality rates of more than 50%, and occur more frequently as idiopathic pulmonary fibrosis progresses. ^[51] Although studies have attempted to predict exacerbations on the basis of a previous drop in forced vital capacity (FVC), the evidence remains weak. The inability to accurately predict an event means that future exacerbations cannot be considered when referring for lung transplantation. However, suitable patients who survive an acute exacerbation should be fast-tracked for referral or prioritized if already listed.

The International Society of Heart and Lung Transplantation (ISHLT) suggests criteria for referral of patients with interstitial lung diseases (ILDs), including patients with idiopathic pulmonary fibrosis, which include the following:

• Histopathological or radiographical evidence of usual interstitial pneumonitis (UIP) or fibrosing nonspecific interstitial pneumonitis, regardless of lung function
• FVC less than 80 % of predicted or diffusion capacity less than 40 % of predicted
• Dyspnea or functional limitation attributable to their lung disease
• The requirement for supplemental oxygen, even if only on exertion

However, if every patient meeting these criteria were referred, transplantation services would rapidly become overwhelmed and unable to respond to those with the greatest need.

In May 2005, the lung allocation score (LAS) was implemented, which dramatically changed lung allocation from a system based purely on waiting time to an algorithm based on survival probability on the waiting list and after lung transplantation. ^[52] Therefore, the LAS is used to prioritize patients based on the difference between post-transplant 1-year survival and pretransplant urgency. Consequent to the use of LAS, idiopathic pulmonary fibrosis has now replaced chronic obstructive pulmonary disease as the most common indication for lung transplantation in the United States. ^[53]

Any patient diagnosed with idiopathic pulmonary fibrosis or probable idiopathic pulmonary fibrosis should be referred for lung transplantation evaluation, regardless of the vital capacity. ^[9] After a patient is referred for transplantation evaluation, the appropriate timing to list a patient on the lung transplantation list needs to be determined.

Guidelines for listing a patient with idiopathic pulmonary fibrosis include the following ^[9] :

• Diffusion capacity of carbon monoxide (DL _CO) less than 39% predicted
• A 10% or greater decrement in FVC during 6 months of follow-up
• A decrease in pulse oximetry below 88% during a 6-minute walk test (6MWT)
• Honeycombing on high-resolution computed tomography (HRCT) imaging (fibrosis score >2)

A 2009 retrospective review of the United Network for Organ Sharing data to identify lung transplant recipients with idiopathic pulmonary fibrosis between 2005 and 2007 examined risk for 30-day, 90-day, and 1-year mortality for single lung transplant versus bilateral lung transplant. Data were examined across levels of the LAS (quartile 1, quartile 2, quartile 3, and quartile 4).

Patients in LAS quartile 4 were defined as high risk. A clear inverse relationship between wait-list times and LAS was seen, with a higher LAS score associated with shorter wait-list times. ^[53] Patients in the LAS quartile 4 had a 7.1% lower cumulative survival at 1 year when compared with patients in quartiles 1 to 3. Just over 21% more patients received bilateral lung transplantation in the highest LAS quartile than in the lowest LAS quartile. In the high-risk quartile, bilateral lung transplantation was associated with a 14.4% decrease in mortality 1 year after lung transplantation. ^[53] However, this study is limited by the retrospective nature and the need to see if these trends persist at 3 years and 5 years. The reported 5-year survival rates after lung transplantation in idiopathic pulmonary fibrosis are estimated at 50-56%. ^[1]

Outcomes were published in 2015 comparing single- and double-lung transplantation since the implementation of the Lung Allocation Score. Adults with idiopathic pulmonary fibrosis who underwent lung transplantation between May 04, 2005 and December 31, 2012 were identified in the United Network for Organ Sharing thoracic registry. In total, 4134 patients with idiopathic pulmonary fibrosis underwent lung transplantation. Of these, 2010 patients underwent sing-lung transplantation and 2124 patients underwent double-lung transplantation. After confounders for double-lung transplantation were controlled for with propensity score analysis, double-lung transplant was associated with better graft survival in patients with idiopathic pulmonary fibrosis, with an adjusted median survival of 65.2 months versus 50.4 months in single-lung transplant (P < .001). ^[54]

Further inpatient care

The clinical course of patients with idiopathic pulmonary fibrosis (IPF) is generally marked by a decline in pulmonary function over time. Increasingly, patients have been recognized as having an acute, and often fatal, clinical deterioration, termed an acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). ^[55] Up to one in five patients with idiopathic pulmonary fibrosis experience an acute exacerbation each year.

The following are diagnostic criteria for an AE-IPF ^[56] :

• Previous or concurrent diagnosis of idiopathic pulmonary fibrosis

• Unexplained worsening or development of dyspnea within 30 days

• High-resolution computed tomography (HRCT) scan with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with a usual interstitial pneumonia pattern

• Worsening hypoxemia from a known baseline arterial blood gas measurement

• No evidence of pulmonary infection by endotracheal aspiration or bronchoalveolar lavage (BAL)

• Exclusion of alternative causes, including left-sided heart failure, pulmonary embolism, and an identifiable cause of acute lung injury

In a retrospective review, of 461 patients with idiopathic pulmonary fibrosis, 20.8% of all subjects experienced an AE-IPF during the median follow-up period of 22.9 months. Approximately 50% of patients hospitalized for an AE-IPF died during the hospitalization. The 1-year and 5-year survival rates from the initial diagnosis of an AE-IPF were 56.2% and 18.4%, respectively. ^[57] Therefore, an AE-IPF has a serious impact on the overall survival of patients with idiopathic pulmonary fibrosis.

Despite the high morbidity and mortality associated with AE-IPF, there are limited data to guide management decisions. Supportive care and symptom management, most notably with supplemental oxygen, are well-accepted approaches. However, only very low-quality evidence is available to direct the use of specific treatment strategies, including antibiotics, antacid therapies, and corticosteroids. Corticosteroids are arguably the most controversial of these options.

Patients with idiopathic pulmonary fibrosis who develop an acute clinical deterioration often require hospitalization. These patients should undergo HRCT imaging of the chest to document the interval development of significant ground-glass opacities, which are suggestive of an AE-IPF. Additionally, a BAL may be completed to examine the possibility of infectious etiologies if clinically appropriate. Support with supplemental oxygen should be given to alleviate hypoxemia. ^[56]

Corticosteroids are recommended for the treatment of “the majority of patients with AE-IPF” by the most recent international idiopathic pulmonary fibrosis treatment guidelines in 2018. The guidelines are transparent about the lack of evidence and state that the recommendation is based largely on small, uncontrolled case series. Complicating this recommendation is evidence from clinical trials demonstrating that corticosteroids, in combination with immunomodulatory therapy, cause harm in chronic idiopathic pulmonary fibrosis, as previously mentioned.

In a 2020 retrospective observation of 82 AE-IPF subjects by Farrand et al, 37 patients (45%) received corticosteroids for the management of AE-IPF. It was noted that AE-IPF subjects treated with corticosteroids were more likely to require ICU level care and mechanical ventilation. There was no statistically significant association between corticosteroid treatment and in-hospital mortality. However, the overall survival was reduced in AE-IPF subjects receiving corticosteroids (hazard ratio, 6.17; 95% confidence interval, 1.35-28.14; P = .019). ^[58]

If a patient with an AE-IPF develops respiratory failure and requires invasive mechanical ventilation, plateau pressures should be maintained at less than 30 cm water. ^[56] It is of note that patients with idiopathic pulmonary fibrosis who require mechanical ventilation have a poor prognosis.

In a review published in 2008 by Mallick, ^[59] patients from nine studies consisting of 135 patients with established diagnosis of idiopathic pulmonary fibrosis who were admitted to the intensive care unit and required mechanical ventilation were evaluated. Only patients who were ventilated in intensive care were included from these studies. The pooled data showed an aggregated mortality of 118 (87%) among 135 idiopathic pulmonary fibrosis patients ventilated in intensive care units. The short-term mortality (mortality within 3 months of hospital discharge) was 127 (94%). The mean duration of mechanical ventilation was 8.6 days. Of the very few patients who survived, respiratory failure was precipitated by surgery/anaesthesia in two patients, one had undergone lung transplantation, and three patients were lost in follow-up.

Transfer

Lung transplantation for idiopathic pulmonary fibrosis has been shown to confer a survival benefit over medical therapy. Any patient diagnosed with idiopathic pulmonary fibrosis or probable idiopathic pulmonary fibrosis should be referred to a lung transplantation center for lung transplant evaluation, regardless of the vital capacity unless contraindications for transplantation exist. ^[9]

Patients with idiopathic pulmonary fibrosis should be referred to institutions where they can be counseled regarding enrollment in a trial of an investigational agent for the treatment of idiopathic pulmonary fibrosis.

Chronic cough is a distressing and disabling symptom with a major impact on quality of life. Progress has been made in gaining insight into the pathogenesis of cough in idiopathic pulmonary fibrosis, which is most probably multifactorial and influenced by mechanical, biochemical, and neurosensory changes, with an important role for comorbidities as well.

Conventional antitussive therapy is often not beneficial; furthermore, low-dose steroids were studied in the management of chronic cough; low doses of prednisone are sometimes tried in daily practice to relieve cough, and later are slowly tapered if beneficial. However, no effect on quality of life and survival has been reported in the literature, and the possible adverse effects also must be taken into consideration. A 24-week, single-center, double-blind cross-over study with thalidomide for the treatment of cough showed a positive effect on quality of life, as measured with the Cough Quality of Life Questionnaire. ^[60] However, only 20% of the screened subjects completed the study and the potential adverse effects of thalidomide can be severe. Finally, an inhaled cromolyn preparation was shown to ameliorate cough in patients with idiopathic pulmonary fibrosis. ^[61]

Early palliative care referral is recommended as an adjunct to disease-focused care in idiopathic pulmonary fibrosis (IPF). The UK National Institute for Health and Care Excellence defines palliative care in terms of patient and care-giver involvement, psychological support, symptom management and control, and spiritual support.

In the absence of palliative support, a large proportion of patients with end-stage lung disease die in a critical care environment, receiving care that might not be focused on comfort.

Differentiating between idiopathic pulmonary fibrosis (IPF) and non–idiopathic pulmonary fibrosis diagnosis in the workup of patients with interstitial lung disease (ILD) is of extreme importance. In addition, establishing an accurate diagnosis is paramount. The 2018 American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus statement on the diagnosis of idiopathic pulmonary fibrosis strongly recommends a multidisciplinary evaluation in establishing the diagnosis that includes a pulmonologist, a radiologist, and a pathologist if a lung biopsy was pursued. ^[3] The importance of such evaluation is highlighted by observations that isolated radiographic or histologic UIP can represent processes other than idiopathic pulmonary fibrosis and that idiopathic pulmonary fibrosis does not always demonstrate radiographic or histologic UIP. Discussion among these specialists has been well-studied and has been shown to improve diagnostic agreement, ^[62] and it has become a cornerstone of evaluation at ILD referral centers.

Whether ILD is best diagnosed in a community or academic setting remains controversial. Flaherty and colleagues conducted an investigation of clinicians, radiologists, and pathologists from community and academic settings to determine the level of diagnostic agreement in evaluating ILD. ^[63] Using a stepwise approach that provided an increasing amount of clinical, radiographic, and histopathologic information, the authors demonstrated that diagnostic agreement has increased in both groups with each step. The authors noted that the greater agreement among academic versus community physicians was likely influenced by the fact that these individuals had collaborated on previous projects, including consensus statements, and that the community clinician with the most ILD experience tended to agree more often with the academicians.

Currently, early referral of patients to an ILD specialty center is highly recommended when multidisciplinary evaluation cannot be performed locally, or when diagnostic doubt exists following community multidisciplinary evaluation. Referral has the added advantage of providing patients access to specialized care, including clinical trial enrollment and lung transplantation evaluation. Whether referral of patients to an ILD center improves outcomes is unknown, however, and remains an interesting area for further investigation.

Any patient with idiopathic pulmonary fibrosis who is overweight should be encouraged to meet with a nutritionist and make dietary changes to achieve ideal body weight. Maintaining adequate nutritional intake is important for quality of life in patients with idiopathic pulmonary fibrosis.

Improving quality of life is an important goal in disease management. ^[64] Deconditioning and subsequent functional impairment is a common problem in patients with idiopathic pulmonary fibrosis (IPF) and negatively impacts quality of life. Two controlled trials of pulmonary rehabilitation in idiopathic pulmonary fibrosis have demonstrated an improvement in walk distance and symptoms or quality of life. ^[1] Therefore, patients with idiopathic pulmonary fibrosis should be evaluated for pulmonary rehabilitation and encouraged to participate in regular exercise to maintain a maximal degree of musculoskeletal conditioning. ^{[2, 65]} More evidence of pulmonary rehabilitation to improve exercise capacity and health-related quality of life for patients with idiopathic pulmonary fibrosis was published in 2017. ^[42]

The rate of decline and progression to death in patients with idiopathic pulmonary fibrosis (IPF) may take several clinical forms, including slow physiologic deterioration with worsening severity of dyspnea, rapid deterioration and progression to death, or periods of relative stability interposed with periods of acute respiratory decline sometimes manifested by hospitalizations for respiratory failure. ^[11] Therefore, all patients with idiopathic pulmonary fibrosis should be seen by a pulmonologist on a regular basis for a complete history and physical examination. Patients must undergo disease-specific monitoring with serial assessments of lung physiology, gas exchange, exercise performance, and HRCT to further refine prognosis and management decisions. Patients must be asked about adverse medication effects.

Any patient with idiopathic pulmonary fibrosis who is a current smoker should be encouraged to quit and offered pharmacologic therapy if needed.

Vaccination against influenza and pneumococcal infection should be encouraged in all patients with idiopathic pulmonary fibrosis.

Patients with idiopathic pulmonary fibrosis should be evaluated for pulmonary rehabilitation and should be encouraged to participate in regular exercise to maintain a maximal degree of musculoskeletal conditioning.

Although current guidelines recommend the use of antacid therapy to treat idiopathic pulmonary fibrosis, ^[3] there are no data from clinical trials to support this recommendation. In two studies, antacid use was associated with a slower decline in lung function and a lower mortality rate. ^{[66, 67]} These observational studies of treatment effect are, by nature, confounded by indication and should not be used to inform clinical practice. ^[68] Other data suggest that antacid therapy may increase the risk of respiratory infections in patients with idiopathic pulmonary fibrosis. ^[69]

A growing knowledge of the biologic underpinnings of fibroproliferation has opened new therapeutic avenues. Gorina and colleagues report the safety and efficacy of pamrevlumab, a human monoclonal antibody against connective-tissue growth factor, in a randomized, double-blind, placebo-controlled phase 2 trial on patients with idiopathic pulmonary fibrosis and showed slowing in the decline in FVC, as compared with placebo, over a period of 48 weeks. ^[70] A phase 3 trial targeting 340 participants is expected to be completed by December 2022 (Clinicaltrials.gov, NCT03955146).

GLPG1690, which targets autotaxin, an enzyme responsible for lysophosphatidic acid production, was also examined in a phase 2 trial in 2018 and may reduce circulating lysophosphatidic acid levels while influencing lung function and findings on functional respiratory imaging. ^[71]

Multiple other studies are being conducted to evaluate the safety and efficacy of other therapeutic options for the management of idiopathic pulmonary fibrosis and are yet to be reported. ^{[72, 73]}

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/trimethoprim or doxycycline. ^{[74, 75]} The CleanUP-IPF study is a randomized double-blinded clinical trial with a target of approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care, with a primary endpoint of the time to first nonelective respiratory hospitalization or all-cause mortality. ^[76]