Critical deterioration of chronic eosinophilic pneumonia during pregnancy

Abstract

Chronic eosinophilic pneumonia (CEP) is a rare, idiopathic interstitial lung disease characterised by the accumulation of eosinophils in the pulmonary interstitia and alveoli. Patients with CEP respond well to systemic corticosteroid therapy and infrequently progress to end-stage lung disease. We report a case of a woman in her 40s with previously stable, steroid-responsive CEP who experienced a critical deterioration of her CEP at 25 weeks of gestation during her third pregnancy. The patient was admitted to the intensive care unit due to respiratory failure requiring intubation and mechanical ventilation. Follow-up investigation revealed advanced fibrotic lung disease requiring long-term oxygen therapy and referral for double lung transplantation. While CEP infrequently advances to permanent parenchymal damage, this case demonstrates the potential for severe exacerbations in the setting of pregnancy and highlights pregnancy as a potential risk factor for disease progression, reinforcing the need for further research to define optimal monitoring and treatment strategies.

Background

Chronic eosinophilic pneumonia (CEP) is a rare lung disease accounting for 0.2–2.7% of interstitial lung diseases (ILDs), with a peak incidence between ages 30 and 40 years.¹ It affects females twice as frequently as males.^{2 3} While the pathophysiology remains unclear, aberrant Th2-cell-mediated inflammation is hypothesised to result in eosinophilic accumulation in the alveoli and pulmonary interstitia.^4–6 Unlike acute eosinophilic pneumonia (AEP), which typically presents with a rapid onset of severe symptoms over days to weeks, CEP has a more indolent course. Patients may present with a history of worsening exertional dyspnoea, cough, fever, weight loss or wheezing over weeks to months; however, no symptoms are specific to CEP.^{7 8} CEP rarely progresses to hypoxaemic respiratory failure.⁸ On imaging, CEP is characterised by bilateral pleural-based, non-segmental opacities. Conversely, AEP presents with diffuse parenchymal opacities.⁹ Diagnosis of both AEP and CEP is made by bronchoalveolar lavage, with a cell count of>25% eosinophils and the exclusion of other causes of eosinophilia.

The first-line therapy for CEP is oral corticosteroids, which provide significant clinical and radiological improvement in most patients.^{10 11} However, while most patients are stable on low-dose corticosteroids, approximately 51% experience acute exacerbations and 54% require indefinite prednisolone therapy.⁸ Progression to end-stage lung disease is uncommon.^{7 8} To reduce patients’ steroid burden and minimise the sequelae of chronic steroid use, azathioprine, mycophenolate, inhaled corticosteroids and anti-IL5/5R monoclonal antibodies such as omalizumab, mepolizumab and benralizumab can be considered. However, evidence regarding the use of these agents for CEP is limited.^12–15

Pregnancy poses unique challenges to CEP management. Physiological respiratory changes and a shift from a Th1- to Th2-predominant immunological profile during pregnancy could theoretically worsen disease control.^16–18 However, no studies have systematically evaluated the course of CEP during pregnancy or defined optimal management approaches for these patients.

Case presentation

A previously well woman in her 30s presented with a 2-month history of worsening exertional dyspnoea and productive cough in the postpartum period of her first pregnancy. The patient denied recent travel, changes in medications or exposure to dust, toxins and allergens. She was an ex-smoker of 3.5 pack-years and had no definitive history of asthma. The patient had quit smoking 2 years prior to her presentation. Investigation with bronchoalveolar lavage revealed hypercellularity with 55% eosinophils. In the absence of autoimmune antibodies, systemic manifestations of disease or exposures known to cause eosinophilic lung disease, she was diagnosed with CEP.

The patient was managed with oral prednisolone, 50 mg daily, which was weaned to a maintenance dose of 5 mg. Over the following 4 years, the patient experienced exacerbations every 2–3 months, which were managed with short courses of 50 mg oral prednisolone. She did not require hospitalisation for these exacerbations and maintained her premorbid function. During this period, the patient had an uncomplicated second pregnancy, and any exacerbations were treated with oral corticosteroids. Pulmonary function tests following her second pregnancy, however, noted an established ILD with a moderate-severe restrictive ventilatory defect (FEV1=49% predicted and FVC=45% predicted). High-resolution computed tomography (HRCT) demonstrated stable ground-glass opacities bilaterally, sub-pleurally based cystic changes and mild fibrosis in the mid- and upper zones bilaterally (figure 1A,B).

Figure 1.

Baseline CT chest coronal view (A) and axial view (B) 17 months prior to admission, follow-up imaging 2 months prior to admission CT chest coronal view (C) and axial view (D) and admission CT chest coronal view (E) and axial view (F). Studies show a progressive increase in ground-glass opacities in all lobes without subpleural sparing and the presence of anterior subpleural blebs.

After entering her third pregnancy with reduced respiratory reserves, the patient presented at 16 weeks of gestation with a 3-week history of exertional dyspnoea, fatigue and a non-productive cough that was unresponsive to a 3-day course of 50 mg oral prednisolone. She saw improvement with intravenous hydrocortisone over a 3-day hospital admission and was discharged with high-dose prednisolone. At 25 weeks, the patient presented with type 1 (hypoxaemic, normocapnic) respiratory failure. When assessed by paramedics, she was centrally cyanosed with an SpO2 of 88%, tachypneic at 44 breaths per minute and tachycardic at 139 beats per minute.

Despite treatment with hydrocortisone and empiric antibiotics, on the fourth day of admission, the patient’s oxygen requirements increased from an FiO2 of 32% to 40%. An arterial blood gas performed at a FiO2 of 32% noted a respiratory alkalosis (pH=7.44, pCO2=31 mmHg, pO2=84 mmHg, lactate=2.3 mmol/L) with an A-a gradient of 105 mmHg. The patient was transferred to the intensive care unit (ICU) and intubated the following day for mechanical ventilation in the setting of increasing respiratory distress, agitation and restlessness.

Investigations

HRCT demonstrated bilateral ground-glass opacities that had significantly progressed since previous imaging (figure 1).

Serial bronchoalveolar lavages (figure 2) revealed an initial eosinophilia of 25%, suggesting an exacerbation of the patient’s CEP. Additionally, elevated neutrophils from day 1 (63%) to 5 (72%) were thought to have occurred secondary to her exacerbation of CEP as well. A second elevation of neutrophils from 14% to 70% across days 12–19 occurred in the context of a superimposed bacterial pneumonia.

Figure 2.

Change in bronchoalveolar lavage cell count composition throughout the patient’s hospital admission. Initial eosinophilia of 25% declined to 1% in response to treatment. 70% of neutrophils in the final bronchoalveolar lavage suggested deterioration secondary to superimposed bacterial hospital-acquired pneumonia.

Bronchoscopy samples were tested negative for Pneumocystis jiroveci (PJP) on PCR. Invasive aspergillosis was considered given the patient’s prolonged steroid use and radiographic changes. However, fungal PCR and cultures were negative. Bacterial cultures from bronchial washes showed growth of Staphylococcus epidermidis and Staphylococcus hominis; however, they were thought to represent contaminants.

Autoantibodies including antinuclear antibody (ANA), extractable nuclear antigen (ENA), rheumatoid factor (Rf), antineutrophilic cytoplasmic antibody (ANCA), and complements were negative. Haematological review and bone marrow analysis did not support primary or secondary eosinophilic syndromes. Echocardiography showed mild RV dilation with preserved function.

Differential diagnosis

An acute infectious exacerbation was the primary differential, followed by a progression or acceleration of the patient’s underlying CEP. Infections including PJP and invasive aspergillosis were considered but deemed less likely with negative PCRs and cultures. Other differentials including heart failure, thromboembolic disease and obstetric complications such as obstetric sepsis and HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelets) were excluded.

Treatment

The patient was intubated and managed for acute respiratory distress syndrome with protective low tidal volume ventilation. Moreover, while the fetus remained viable, efforts were made to balance maternal and fetal outcomes—stabilising the patient with fetal-safe therapy to maximise gestational age. To do so, permissive hypercapnia and hypoxaemia were not permitted to ensure adequate transplacental oxygen transfer, and neuromuscular junction blocking agents were avoided to minimise the risks of arthrogryposis.^{19 20}

A multidrug regimen included intravenous methylprednisolone 500 mg once, followed by hydrocortisone 100 mg four times daily. Following discussion between respiratory and immunology teams, mepolizumab was prescribed in response to the patient’s severe eosinophilic inflammation that had failed to respond adequately to high-dose corticosteroids. Mepolizumab was dosed according to the management of eosinophilic granulomatosis with polyangiitis: 100 mg initially, followed by 200 mg. Empiric antibiotics included intravenous piperacillin-tazobactam 4.5 g three times daily and meropenem 1 g three times daily. Antifungal therapy with intravenous voriconazole 200 mg twice daily was instituted to cover possible fungal infection.

Despite efforts to prolong the pregnancy, the patient’s respiratory status continued to decline. After multidisciplinary discussions between critical care, obstetrics, and neonatology, a decision was made to pursue an emergency caesarean section at 26+5/40 weeks given the high risk of fetal distress syndrome. The delivery was uncomplicated, and the postpartum obstetric examination was unremarkable.

Outcome and follow-up

The patient was extubated after a 23-day ICU admission, and oxygen requirements improved on the ward to an FiO2 of 28%. CT chest showed improving ground-glass opacities and resolving consolidation. The patient was discharged to a rehabilitation service in the setting of critical illness myopathy and referred to a transplant service for a double lung transplantation evaluation.

Follow-up HRCT 1 month later demonstrated upper zone and peripheral predominant fibrosis and honeycombing consistent with advanced fibrotic lung disease secondary to CEP (figure 3).

Figure 3.

CT chest 1 month postadmission, coronal view (A) and axial view (B), follow-up imaging 10 months post-admission, coronal view (C) and axial view (D) and most recent CT 2 years post-admission, coronal view (E) and axial view (F). CT (A) and (B) demonstrate an improvement in the density of ground-glass opacities. CT (C) and (D) demonstrate persistent ground-glass infiltrates, again without subpleural sparing and subpleural cystic changes (marked with arrows in B (D and E). CT (E) and (F) demonstrate a reduction in lung volume, with diffuse ground-glass changes.

Pulmonary function tests demonstrated a stable moderate-severe restrictive ventilatory defect. However, there was a significant reduction in the patient’s diffusing capacity for carbon monoxide (DLCO) from 56% to 16% when compared with 17 months prior. Over 2 years of follow-up, the patient’s median FEV1 was 41% predicted, FVC was 43% predicted and DLCO was 19%. Serial 6-min walk tests showed a median distance of 220 m and median nadir oxygen saturation of 86%, reflecting a significant functional limitation.

The patient is currently managed with long-term oxygen therapy, monthly 100 mg mepolizumab injections, oral prednisolone (unable to wean below 22.5 mg), prophylactic trimethoprim-sulfamethoxazole, and esomeprazole. Cyclophosphamide was trialled but ceased after two of six cycles due to recurrent infection. And, despite adding mycophenolate mofetil and monthly intravenous immune globulin (IVIg) to optimise her candidacy for transplantation, the patient remains highly sensitised with a panel reactive antibody of 85%. Such a high burden of anti-human leukocyte antigen antibodies against the population has limited the patient’s eligibility for transplant. Consequently, while immunosuppressed, she has experienced recurrent infections, each requiring hospitalisation and severely limiting her functional capacity (figure 4).

Figure 4.

A timeline of the patient’s disease progression and intensive care unit admission from the date of chronic eosinophilic pneumonia diagnosis.

Discussion

Exacerbations of CEP during pregnancy have been described in four case reports: two gestational exacerbations and two postpartum relapses.^21–24 Unlike the case presented in this report, each experienced good maternal and fetal outcomes. Davies et al.’s report of a postpartum exacerbation of CEP in a woman aged 23 years noted a mild decline in the patient’s respiratory function (FVC=90% predicted and FEV1=70% predicted).²¹ Otherwise, all other cases experienced a full recovery without complication or long-term fibrotic changes. A fifth report by Kotani et al. described a woman aged 24 years diagnosed with AEP at 34+6 weeks of gestation. This resulted in an emergency caesarean section after fetal distress syndrome was diagnosed. The patient was managed with oxygen therapy and systemic corticosteroids, making a full recovery.²⁵ Such reports indicate that pregnant patients may be susceptible to CEP exacerbations. And, while premature birth may occur, prognosis is typically positive with minimal long-term sequelae.^21–25

The pathophysiology of CEP remains unclear; however, an aberrant Th2-mediated immune response may be involved. IL5, IL-25 and C-C chemokine receptor type 3 chemokines such as eotaxin-2 and monocyte chemoattractant protein-4 are increased in the bronchoalveolar lavage fluid of patients with CEP.5 6 26 27 It is hypothesised that IL-25 may stimulate IL-5 production in allergen-primed memory Th2 cells, promoting eosinophil activation and survival, and thus, the pulmonary consolidation, tissue injury and fibrosis characteristic of CEP.4 5 26 28 During gestation, Th1 and Th17 responses are suppressed by higher concentrations of progesterone and oestrogen.^{16 18} It could be hypothesised, therefore, that a shift from a Th1- to Th2-predominant immunological profile during gestation may increase the risk of eosinophilic inflammation and, thus, CEP development or exacerbation.

Physiological changes in pregnancy may also exacerbate CEP. Increased metabolic demands during gestation result in an increase in minute ventilation by 40–50% and oxygen consumption by 20%.^{29 30} Furthermore, as the uterus enlarges, the elevation of the diaphragm by up to 5 cm reduces lung volumes, and plasma volume expansion by 30–50% may predispose pulmonary oedema.³⁰ It is unclear whether such pathophysiological mechanisms contributed to this case report, and no studies have investigated the contribution of pregnancy to CEP disease progression. However, in synthesising available evidence, pregnancy may pose a theoretically increased risk of CEP relapse and respiratory distress.³¹

The reported case also demonstrates the potential for irreversible pulmonary fibrosis in the setting of a CEP relapse during pregnancy. CEP has a median relapse rate of 52.4%.2 3 7 8 11 32 33 Known risk factors for relapse include an elevated serum surfactant protein D at the time of diagnosis (HR=1.008) and the presence of centrilobular opacities on HRCT (HR=3.203).³⁴ Smoking history, sex, asthma and age do not appear to influence the rate of CEP relapse.³⁴ Pulmonary fibrosis occurs in up to 37% of patients with CEP and imparts a 9.53-fold increased risk of mortality.³⁵ Advanced age and male sex confer an increased risk of fibrosis, while a history of asthma reduces risk.³⁵ Pregnancy has not been investigated as a predictive factor for CEP relapse or long-term fibrotic changes; however, it may warrant further consideration.^21–24 As described in this report, the patient’s acute exacerbation and critical deterioration occurred during her third pregnancy; however, this was on a background of moderate-severe restrictive ILD established over two prior pregnancies

There is limited research guiding ILD management during the peripartum period.^{36 37} Pregnancy, however, is an important consideration for many patients with ILD. Moreover, while maternal morbidity and mortality are low in this population, complications such as preterm delivery, pre-eclampsia and the need for early delivery due to maternal disease flares are common in patients with severe lung disease.^{36 37} This emphasises the need for a comprehensive, multidisciplinary approach to optimise maternal and fetal outcomes.

To do so, preconception counselling including a discussion of the impacts of pregnancy on patients’ respiratory function is critical.³⁶ This should include a collaborative discussion with patients to ensure that drugs that are unsafe during pregnancy are modified/withheld, while appropriate symptomatic relief and disease stability are achieved.³⁶ Maximising baseline respiratory function prior to conception could, theoretically, increase the patient’s tolerance of the physiological changes during pregnancy and, thus, improve outcomes. Additionally, education regarding the signs of respiratory deterioration may increase patients’ recognition of disease progression and promote early hospital presentations.

During the gestational period, close monitoring via a regular follow-up schedule to enable the early detection of respiratory deterioration may also be useful.³⁶ If patients with CEP present without rapidly progressive respiratory failure, oral administration of prednisone at 0.5 mg/kg daily is standard. In progressive disease or respiratory failure, high-dose intravenous glucocorticoids can precede oral therapy. However, given that pregnancy may act as an accelerating risk factor for CEP progression, clinicians should have a high index of suspicion and a low threshold for treatment escalation. Accordingly, management should occur at a centre equipped for high-risk pregnancies and involve a multidisciplinary approach.

In a patient with a viable fetus, a joint discussion between the patient and the multidisciplinary team should establish a treatment plan that aims to stabilise and support the patient through fetal-safe therapy while prolonging gestation to optimise fetal outcomes. However, if the risk-benefit ratio for continued pregnancy is no longer favourable for both the patient and fetus, provisions for early delivery should be outlined.³⁸ Following delivery, maternal and newborn outcomes can be addressed independently, allowing for the utilisation of more aggressive immunosuppressive medications and transplantation options that were previously contraindicated.

For pregnant patients who fail to respond to corticosteroids, azathioprine and anti-IL-5/5R biologics such as mepolizumab may be considered.^{12 13 39} Both have been shown in case reports and case series to reduce CEP exacerbations; however, randomised controlled trials in acute CEP exacerbations are lacking.^{12 13 39} These agents appear safe in pregnancy; however, data regarding the safety of anti-IL5/5R biologics are limited to case reports.^{39 40} Mycophenolate has shown similarly favourable long-term outcomes in patients with ILD; however, no data exist for CEP, and it is not safe during gestation.¹⁴ In addition to supporting maternal outcomes, theoretically, these agents may also facilitate a reduction in patients’ steroid burden, thereby decreasing fetal corticosteroid exposure and associated risks of intrauterine growth restriction, cleft lip and impaired fetal ontogeny.^{41 42} However, this outcome remains unstudied.

Without established clinical guidelines, this case highlights the need for an increased understanding of the relationship between pregnancy and CEP disease progression to establish an evidence-based approach for patient management to ensure safe and healthy pregnancies.

Patient’s perspective.

I was diagnosed with CEP 8 years ago during my first pregnancy.

Life prior was full - long hours of a stressful job that I loved, balanced with personal training and boxing sessions multiple times a week. Although, I couldn’t do any of that after my diagnosis. Over 6 years, I saw three lung specialists. There wasn’t much they could do besides monitor me and put me on prednisolone when I had flare-ups. So, I ended up thinking “that’s it, no one can help” and got on with life. I worked and had another baby. But, as time went on, it got harder.

Things turned when I fell pregnant with our third. At his 24 week mark, I kept turning blue and couldn’t breathe. I had our son at 26 weeks while in the ICU, then I was off to rehab before heading home on full-time oxygen.

Life changed. My husband became my full-time career, I couldn’t shower the girls or attend to them, I couldn’t even pick up our newborn or do anything for him. Now, I spend time in hospital away from family constantly, I can’t go far without wheelchair assistance, and most days I spend a lot of time in bed. You have constant insomnia, and you feel so helpless because everyone is catering for you.

I’m not one to sit around - I’m a young mother of three. But trying to do simple things like talk, eat and walk get harder over time. It’s mentally challenging, exhausting, and emotional. And, while I can do some things, my husband does everything else with no complaints. He’s absolutely amazing.

I’ve been on the transplant waitlist for over 2 years now. I can’t tell you how many times I’ve wanted to give up - feeling like I’m suffocating every day. It gets harder, but I look at my family and I’m grateful for waking up every day.

There have been a lot of tears shed, but also a lot of gratitude and grateful moments. We have put our lives on hold, and we have a very unknown future ahead of us. But, with a positive mind set, faith, good routines, and a supportive family, I believe I can keep going no matter what. Yes, my disease is terminal, but we don’t look at it that way and live each day one at a time.

Learning points.

• Chronic eosinophilic pneumonia (CEP) is a rare diagnosis that may be considered as a differential for investigation in patients presenting with dyspnoea or cough during the peripartum period.

• While CEP generally carries a good prognosis, irreversible fibrotic lung disease can occur in a minority of patients. Pregnancy may be an unidentified risk factor for exacerbations and progression to end-stage lung disease.

• Educating patients to recognise CEP disease progression and ensuring scheduled follow-up may assist in identifying and preventing deterioration during the peripartum period.

• Early escalation of treatment and multidisciplinary care at a centre equipped for high-risk pregnancies may be warranted in patients who experience exacerbations, even in those previously stable on low-dose steroids. However, optimal management approaches remain undefined.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).