Acute exacerbation of pleuroparenchymal fibroelastosis with lower lobe usual interstitial pneumonia: An autopsy case

Abstract

An 87-year-old man presented with dyspnea. Computed tomography revealed progressive subpleural consolidation in the apex, reticular shadows in the lower lobes, and bilateral ground glass opacifications. He died of respiratory failure on day 3. The post-mortem examination showed exudative stage diffuse alveolar damage and pulmonary edema. Intraalveolar collagenous fibrosis and subpleural elastosis were observed in the upper lobes, accompanied by interlobular septal and pleural thickening and lung architecture remodeling in the lower lobes. He was diagnosed with acute exacerbation of pleuroparenchymal fibroelastosis with lower lobe usual interstitial pneumonia, which can be fatal.

1. Introduction

Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia characterized by fibrosis of the pleura and subpleural lung parenchyma, predominantly in the upper lobes [1]. Most PPFE patients were in 40–70 years age range, without sex difference. Common symptoms are progressive breathlessness and cough. Pneumothorax and pneumomediastinum are frequent complications of PPFE [2]. Although PPFE is progressive, pulmonary apical cap (PAC) mimics PPFE pathologically and radiologically, whereas PAC is localized without extension to other lobes [3].

PPFE consists of idiopathic pulmonary upper lobe fibrosis (Amitani disease) or idiopathic pulmonary upper lobe dominant fibrosis with lower lobe involvement. The pathologic features of lower lobe fibrosis in PPFE patients include less marked PPFE changes than the upper lobe, usual interstitial pneumonia (UIP), and others [3]. Although several reports describe acute exacerbation of PPFE (AE-PPFE) [4,5] and an autopsy case of AE-PPFE involving only the upper lobe was reported [6], no autopsy reports described AE-PPFE with lower lobe fibrosis. Herein, we report an autopsy case of AE-PPFE with lower lobe UIP.

2. Case report

An 87-year-old man was admitted to our hospital due to 4-day history of dyspnea on exertion and anorexia. He had a history of left pneumothorax two years ago, and was simultaneously diagnosed with interstitial pneumonia at that time. However, interstitial pneumonia was observed due to age and his coexisting diseases. In addition, he had a history of angina pectoris, myocardial infarction, chronic heart failure, left ventricular thrombosis, dyslipidemia, subdural hygroma, and Alzheimer's disease. He had no history of mycobacterium infection or connective disease, and had not previously received radiation, chemotherapy, or bone-marrow transplantation. Moreover, he was a never smoker and had no remarkable history of occupational exposure or familial history of respiratory diseases.

On admission, his peripheral arterial oxygen saturation (SpO₂) was 94% on a 2 L/min nasal cannula. Upon performing chest auscultation, bilateral coarse crackles were noted. A chest X-ray showed a worsening pre-existing bilateral apical cap and elevation of the hilum and diaphragm. Consolidation and reticular shadows emerged predominantly in the bilateral middle and lower lung fields (Fig. 1A and B). The right costophrenic angle was dull. High-resolution computed tomography (HRCT) revealed worsened bilateral dense subpleural consolidation with traction bronchiectasis in the apex (Fig. 2A and B). Consolidation and ground glass opacifications (GGOs) with reticular shadows were observed and honeycomb lesions were enlarged in the lower lobes (Fig. 2C–F). Bilateral pleural effusion was also observed.

Fig. 1.

Chest X-ray images from 8 years before admission (A) and on admission (B).

The chest X-ray on admission showed worsened pre-existing bilateral apical cap and elevation of the hilum and diaphragm. Consolidation and reticular shadows appeared predominantly in the bilateral middle and lower lung fields.

Fig. 2.

Computed tomography images from 3 years before admission (A, C, E) and on admission (B, D, F).

A, B) Bilateral dense subpleural consolidation with traction bronchiectasis in the apex was worse. C–F) Consolidation and GGOs with reticular shadows appeared and honeycomb lesions were enlarged in the lower lobes. Bilateral pleural effusion was also detected.

GGOs: ground glass opacifications.

Clinical data on admission are shown in Table 1. White blood cells (WBC), C-reactive protein, and lactate dehydrogenase (LDH) were elevated. No elevations in Krebs von den Lungen 6 (KL-6) or surfactant protein D (SP-D) were observed, and serum autoantibodies associated with connective tissue disease were negative. The sputum, blood, and urine cultures were negative for bacteria and fungi.

Table 1.

Laboratory Data on admission.

Hematology			Chemistry			Venous BGA (FiO2 0.3)
WBC	10,400 (3300–8600)	/μL	TP	7.3 (6.5–8.0)	g/dL	pH	7.39
Neutro	86.7 (38.5–80.5)	%	Alb	3.5 (3.5–5.2)	g/dL	PaCO2	36.2	mmHg
Lym	4.1 (16.5–49.5)	%	AST	31 (10–50)	IU/L	PaO2	20.2	mmHg
Mono	8.7 (2.0–10.0)	%	ALT	15 (5–45)	IU/L	HCO3	21.7	mmHg
RBC	369 (430–560)	× 104/μL	LDH	268 (100–220)	IU/L	Lactate	22	mg/dL
Hb	11.8 (13.5–17.0)	g/dL	Na	134 (135–147)	mEq/l	Immunology
Hct	34.3 (40.0–51.0)	%	K	3.9 (3.5–5.0)	mEq/l	IgG	1462 (870–1700)	mg/dL
Plt	16.1 (15.0–35.0)	× 104/μL	Cl	98 (98–108)	mEq/l	IgG4	56.4 (4.5–117.0)	mg/dL
Coagulation			BUN	65 (8–20)	mg/dL	KL-6	366 (0–499)	U/mL
PT-INR	1.88 (0.85–1.15)		Cre	1.33 (0.60–1.20)	mg/dL	SP-D	94.3 (0–110)	ng/mL
APTT	62.1 (24.0–45.0)	s	CPK	340 (24–195)	IU/L	sIL2-R	1000 (157–474)	U/mL
D-Dimer	1.8 (0.0–1.0)	μg/mL	CRP	16.2 (0.0–0.20)	mg/dL	RF	<5 (0–15)	IU/mL
			NT-proBNP	1112 (0–125)	pg/mL	ANA	<40 (<40)
			Infection			Autoimmune antibodies		(−) (−)
			β-d-glucan	14.9 (0.0–19.9)	pg/mL	MPO-ANCA	<1.0 (0.0–3.4)	U/mL
			CMV pp65	(−) (−)		PR3-ANCA	<1.0 (0.0–3.4)	U/mL

Alb: albumin, ALT: alanine aminotransferase, ANA: anti-nuclear antigen, aPTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BGA: blood gas analysis, BNP: B-type natriuretic peptide, CMV: cytomegalovirus, CPK: creatine phosphokinase, Cre: creatinine, CRP: C-reactive protein, FiO₂: fraction of inspired oxygen, Hb: hemoglobin, HCO₃: bicarbonate, Hct: hematocrit, IgG: immunoglobulin G, KL-6: Krebs von den Lungen 6, LDH: lactate dehydrogenase, MPO-ANCA: Myeloperoxidase-antineutrophil cytoplasmic antibody, NT-proBNP: N-terminal prohormone of brain natriuretic peptide, PaCO₂: partial pressure of carbon dioxide in arterial blood, PaO₂: partial pressure of oxygen in arterial blood, Plt: platelet, PR3-ANCA: proteinase 3 antineutrophil cytoplasmic antibody, PT-INR: prothrombin time-international normalized ratio, RBC: red blood cell, RF: rheumatoid factor, sIL2-R: soluble interleukin-2 receptor, SP-D: surfactant protein D, TP: total protein, UN: urea nitrogen, WBC: white blood cell.

The patient was diagnosed with AE-PPFE, and methylprednisolone (40 mg/day) were initiated on day 1 of admission. Bronchoalveolar lavage (BAL) was not performed due to age. Since bacterial infections could not be ruled out by BAL, piperacillin/tazobactam (9 g/day) was also administered as an empiric antibiotic therapy. However, productive cough emerged, and his respiratory condition deteriorated and he received a 10 L/min reservoir mask on day 2. CT on day 2 showed worsening GGOs in both lungs and bilateral pleural effusion. Accordingly, methylprednisolone pulse (1000 mg/day for 3 days) and recombinant human soluble thrombomodulin (380 U/kg) were administered. Furosemide was also started because N-terminal prohormone brain natriuretic peptide increased to 1576 pg/mL. However, his respiratory condition continued to worsen, and he died of respiratory failure on day 3. He was not intubated due to his choice.

Microscopic examination of the lungs revealed an exudative phase of diffuse alveolar damage with hyaline membranes composed of fibrin on the alveolar walls (Fig. 3A). Pulmonary edema and pulmonary congestion were also observed. No indications of infections were detected. The left lower lobe exhibited pleural and interlobular septal thickening with collagen fibers. In addition, simplification of lung architecture and airspace enlargement were observed (Fig. 3B). This histopathology pattern was considered probable UIP according to the idiopathic pulmonary fibrosis (IPF) clinical practice guidelines [7]. In contrast, intraalveolar collagenous fibrosis was demonstrated in the left upper lobe (Fig. 3C). This fibrosis exhibited an abrupt transition to the adjacent normal lung parenchyma. Increasement of subpleural elastic fibers were observed in the left apex (Fig. 3D). Accordingly, this patient was diagnosed with AE-PPFE with lower lobe UIP and pulmonary edema.

Fig. 3.

Autopsy findings in the lungs.

A) Exudative phase of diffuse alveolar damage with a hyaline membrane (black arrows) and pulmonary edema are shown (HE stain × 40). B) Pleural and interlobular septal thickening with collagen fibers can be observed. Simplification of lung architecture and airspace enlargement can also be observed (Left lower lobe, EVG stain × 20). C) Collagenous fibrosis-filled alveolar spaces (Left lower lobe, EVG stain × 20). D) Elastosis is shown in the subpleural lesion (Left apex, EVG stain × 12.5).

HE: Hematoxylin-Eosin, EVG: Elastica van Gieson.

3. Discussion

We experienced a challenging case of an elderly patient who died from rapidly progressive acute hypoxemic respiratory failure. The patient had imaging features of PPFE with superimposed GGOs suggestive of AE-PPFE; ultimately, the autopsy report confirmed the diagnosis of AE-PPFE with lower lobe UIP. PPFE has a poor prognosis, especially when lower lobe UIP is involved. The median survival time (MST) of patients with PPFE is significantly shorter when UIP in the lower lobes is involved (12 M vs. 62 M, p = 0.001) [8]. In addition, MST of patients with PPFE and lower lobe UIP tends to be shorter compared to IPF in a study with relatively small number of patients (31.5 M vs. 82.1 M, p = 0.13) [9]. AE has been reported in PPFE patients, with and without lower lobe UIP [6,10]. AE tends to occur less often in patients with PPFE with or without lower lobe fibrosis compared to patients with IPF and is usually not the cause of death [4].

A consensus for the diagnostic criteria for PPFE has not been reached. Reddy proposed radiological and histological criteria for PPFE, and these criteria are widely used [3]. In this case, pathological examination met the histological criteria of “definite PPFE,” because upper zone pleural fibrosis with subjacent intraalveolar fibrosis accompanied by alveolar septal elastosis was observed. Since upper lobe subpleural consolidation was progressive over 3 years, an apical cap was denied. Accordingly, we determined this patient had PPFE. No underlying diseases or treatments were noted that would cause secondary PPFE, such as radiation, chemotherapy, bone-marrow transplantation, mycobacterium infection, or connective disease. Therefore, this patient was diagnosed with idiopathic PPFE. Several definite risk factors of AE-IPF were reported, such as low respiratory function (both forced vital capacity and diffusing capacity for carbon monoxide), pulmonary hypertension, and low 6-min-walk distance. Regarding this patient, these findings were not demonstrated prior to AE. However, this patient had several candidate risk factors of AE; comorbid coronary artery disease and East Asian [11].

Nintedanib is an intracellular tyrosine kinase inhibitor used to treat IPF. Nintedanib significantly slows the decline in forced vital capacity (FVC) and may reduce AE in patients with IPF [12]. In a recent study of progressive fibrosing interstitial lung diseases (PF-ILD) other than IPF, nintedanib also significantly reduced FVC decline and AE or death [13]. PPFE patients accounted for 10% of the study population in this study. Moreover, 9 PPFE patients treated with nintedanib (3 with definite or probable UIP patterns on HRCT) showed significantly slower FVC declines compared to patients without treatment [14]. Meanwhile, another study showed no effect of nintedanib on the decline of FVC or the fibrosis score on CT in PPFE patients although 10 out of 15 patients had lower lobe UIP [15]. Thus, the efficacy of nintedanib in patients with PPFE is controversial. Regarding the treatment of AE-ILD, corticosteroid is an only possible therapeutic agent according to the 2022 IPF clinical practice guidelines [7]. Nevertheless, initiation of nintedanib has been reported to be significantly associated with a lower risk of in-hospital death and shorter length of hospitalization in patients with AE of fibrosing ILDs [16]. Therefore, nintedanib is a potential treatment for patients with PPFE with lower lobe UIP, since fibrosis of PPFE with lower lobe UIP consists not only of elastic fibers but also collagen fibers, especially in the lower lobes.

4. Conclusion

In summary, the autopsy demonstrated that the patient had idiopathic PPFE in the upper lobe and probable UIP in the lower lobes. AE occurred mainly in the lower lobes. PPEE with lower lobe UIP can cause AE and the prognosis is poor compared to patients without UIP.

The authors state that they have no conflict of interest.

Grants

None.

Declaration of competing interest

The authors state that they have no conflict of interest.

Handling Editor: DR AC Amit Chopra