33  The Syndrome of Combined Pulmonary Fibrosis and Emphysema	565

sis [80, 81]. Emphysema is more prevalent in systemic sclerosis patients with pulmonary brosis than in control smokers without connective tissue disease or IPF, after adjustment for the smoking history [35]. In 470 patients with systemic sclerosis, 43 had CPFE on chest HRCT, including 24 (58%) who had never smoked [36]. Approximately 5–10% of patients with systemic sclerosis-associated ILD have radiological ndings of CPFE [35, 81–83]. The CPFE syndrome may occur in patients with only mild or no smoking history [17, 34, 35, 84, 85], suggesting that systemic sclerosis itself might contribute to the development of emphysema, a hypothesis that remains to be con rmed.

Of note, spontaneous emphysema and right heart hypertrophy develop spontaneously in tight-skin mice that harbor a duplication in the fbrillin-1 gene and exhibit a phenotype that resembles human systemic sclerosis [86, 87]. Modulation of infammatory markers in animal models [88–93] supports the hypothesis that the connective tissue disease per se may play a role in the pathogenesis of the CPFE syndrome, possibly through mechanisms that lead to chronic infammation or epigenetic dysregulation (posttranslational modi cations of histone proteins and hypermethylation) [22, 94].

CPFE has been reported in patients with polymyositis, Sjögren syndrome, mixed connective tissue disease, overlapping connective tissue disease, with consistent antibody pro-les [26]. Emphysematous changes were found in 3 of 65 autopsy cases of polymyositis/dermatomyositis [95]. Tobacco smoking also increases the risk of developing systemic lupus erythematosus [96], however, CPFE seems rare in lupus.

The CPFE syndrome may occur in patients with the so-­ called interstitial pneumonitis with autoimmune features (also referred to as ILD in undifferentiated connective tissue disease [97], autoimmune featured connective tissue disease [98] or lung-dominant connective tissue disease [99]) (e.g. the individualized research condition with manifestations suggestive of connective tissue disease but not satisfying the criteria of any de ned disease entity [100]). For example, a syndrome of CPFE was found in 7% of subjects with lung disease and anti-cyclic citrullinated peptide antibodies but not rheumatoid arthritis [101].

The CPFE syndrome may also develop in patients with systemic vasculitis, especially microscopic polyangiitis [102, 103]. In one study, autoimmune markers including perinuclear anti-neutrophil cytoplasmic antibodies were more frequently found in patients with CPFE than in subjects with IPF and no emphysema, correlating with in ltration of the brotic lungs by clusters of CD20+ B lymphocytes within lymphoid follicles [14]. It is speculated that anti-­ myeloperoxidase antibodies in microscopic polyangiitis may promote the degranulation of neutrophils, with release of reactive oxygen species that may participate in disease pathogenesis.

Table 33.2  Exposures and etiologies that are associated with CPFE

Variables associated
with CPFE		References
Risk factors and	Cigarette Smoking	[13, 21, 23, 26,
demographics		104–111]
	Male sex	[8, 21, 24,
		105–110, 112,
		113]
Diseases	Idiopathic pulmonary	[13–22]
	brosis
	Connective tissue	[26, 34–36, 81, 83,
	disease	95]
	ANCA-associated	[102, 103, 114,
	vasculitis	115]
	Hypersensitivity	[37–40]
	pneumonitis
Inhalational exposure	Coal dusts	[24, 116, 117]
	Asbestos	[118–121]
	Silica and mineral	[122]
	dust
	Agro-chemical	[123]
	compounds
	Talc	[124]
	Other inhalational	[125–127]
	exposures

ANCA anti-neutrophil cytoplasmic antibodies

Other Etiological Contexts

CPFE has been occasionally reported in subjects with exposure to various compounds or a variety of conditions (Table 33.2).

Clinical Manifestations

Patients with the CPFE syndrome have a mean age of 65–70 years [8, 24], with younger individuals overrepresented in those with connective tissue disease or genetic predisposition to ILD (Clinical Vignette). The male:female ratio is greater than 9:1 in CPFE, with 60 men and only one woman in the seminal series [8], and 73–100% male predominance depending on the series [8, 13–22, 105–110, 112, 113]. In patients with connective tissue disease, the CPFE syndrome is less strongly associated with male gender (68% of males), however, male predominance in patients with CPFE does sharply contrast with the female predominance found in series of patients with connective disease and ILD (without emphysema) [128].

Patients with CPFE usually report severe dyspnea at exercise [3, 7, 8, 13, 25, 26, 123, 129–133]. Chronic bronchitis may be present. Clinical examination generally demonstrates basal “velcro” crackles similar to that found in IPF. Finger clubbing is present in one third of the patients [26].

The most frequent comorbidities in patients with CPFE are lung cancer and PH [11, 25]. Coronary artery disease, perivascular artery disease, and diabetes are also frequent [134].

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566	V. Cottin

Pulmonary Function and Physiology

Patients with CPFE syndrome present with limitation to exercise capacity, and severely impaired DLco and transfer coef-cient (Kco), contrasting with subnormal spirometry [24, 26, 135–137]. Spirometric values and lung volumes are preserved, and FVC, TLC, and/or FEV1:FVC are often normal or near normal. The FVC/DLco ratio is increased in most patients [35]. In the seminal series, the mean FVC was 90 ± 18% of predicted value, TLC was 88 ± 17%, FEV1 was 80 ± 21%, FEV1:FVC was 89 ± 13%, whereas DLco was 37 ± 16% of predicted and Kco was 46 ± 19%. In patients with CPFE and associated PH [25], lung volumes were comparable with FVC of 88 ± 18% of predicted, however DLco was only 24 ± 14% of predicted and Kco was 28 ± 16% of predicted.

Data from three merged study populations [8, 25, 26] indicated that only 36% of 132 patients had TLC lower than 80% of predicted values. Only 41% of 132 patients had FEV1:FVC lower than 0.70 (out of whom 11% had FEV1 greater than 80% of predicted, corresponding to GOLD [Global initiative for Obstructive Lung Disease] stage 1); 37% were classi ed as GOLD stage 0 (FEV1:FVC ≥ 0.70 and FEV1 ≥ 80% of predicted) and further 22% were unclassi ed according to GOLD (with FEV1:FVC ≥ 0.70 and FEV1 < 80% of predicted). In another study, smokers with emphysema were less likely to meet GOLD criteria for chronic obstructive pulmonary disease if ILD changes were present at imaging [138]. Compared to isolated IPF, patients with CPFE have higher vital capacity and lung volumes (FVC and TLC), generally comparable FEV1, higher residual volume (RV), lower DLco, lower Kco, and lower PaO2 [4, 13, 15, 20–22, 112, 129, 131, 137, 139–144], even with adjustment for the extent of brosis [4, 131]. Thus, the relative preservation of spirometric values may lead to underdiagnosis of the CPFE syndrome.

These observations are attributed to the counterbalancing effects of the restrictive physiology due to the increased elastic forces imparted by pulmonary brosis (with presumably increased elastic recoil, as well as prevention by traction forces of expiratory airway collapse), and the effects of the alveolar destruction that decreases elastic recoil and the obstructive physiology with propensity to hyperinfation due to emphysema. This is illustrated correction of FEV1:FVC toward normal values as dyspnea and DLco worsen with disease progression [145]. The annual change in FEV1:FVC has been shown to moderately increase in patients with CPFE, as compared to the annual decrease in the ratio that is typical for those with chronic obstructive pulmonary disease alone [146]. TLC correlates positively with the emphysema score at HRCT, and inversely correlates with the brosis score; conversely, FEV1:FVC negatively correlates with the emphy-

sema score at HRCT, and positively correlates with FEV1:FVC [147]. Analysis of respiratory impedance by multi-frequency forced oscillation technique found lower whole-breath, inspiratory or expiratory resistance in CPFE patients than in chronic obstructive pulmonary disease, and lower whole-breath and expiratory resistance in CPFE than in ILD without emphysema, further supporting the hypothesis of pseudo-normalization of lung mechanics in CPFE [148]. Conversely, both disease components lead to reduced alveolar capillary gas exchange through either decreased capillary blood volume or alveolar membrane thickening.

Severe decrease in arterial oxygen saturation and hypoxemia at exercise even of minor intensity is very common, especially when CPFE is complicated by severe PH. In one series [8], the room air partial pressure of oxygen in arterial blood (PaO2) decreased at exercise (20–50 W) by a mean of 1.5 ± 1.6 kPa (11.2 ± 12 mmHg). During a 6-min walk distance test, the arterial oxygen saturation measured by pulse oximetry decreased by 9 ± 6%. In another group of patients with CPFE and PH, the arterial oxygen saturation measured by pulse oximetry decreased by 15 ± 8% [25]. Hence, exercise limitation with decrease in oxygen saturation, and isolated [149] and/or severe [150] reduction in DLco or Kco contrasting with normal or near normal spirometry should raise the suspicion for CPFE syndrome. Hypercarbia occurs only very late in the disease course and patients may die from the physiological consequences of hypoxia before signi cant hypercarbia takes place.

As compared to patients with IPF and no emphysema, those with CPFE have higher lung volumes (FVC and TLC), generally comparable FEV1 and residual volume (RV), lower DLco, and lower PaO2 [4, 13, 15, 139]. The mean FEV1:FVC is within the normal range or close to the lower limit of normal in CPFE, however it is lower than in IPF where it is usually increased (e.g., greater than 0.80) [15, 139]. Comparison of physiology between groups may be hampered by differences between studies in the severity of emphysema, brosis, and emphysema versus brosis, despite attempts to adjust for severity of brosis [13]. Demographics of CPFE and IPF are similar in those studies, however patients with CPFE tend to have greater tobacco smoking history [13, 15]. As expected, FEV1 and FEV1:FVC are preserved in patients with CPFE as compared to those with chronic obstructive pulmonary disease, who also tend to have more hyperinfation and less altered DLco [146].

Importantly, the presence of signi cant emphysema impacts longitudinal lung volume measurement, attenuating the effect of brosis on lung function parameters. Patients with CPFE experience a slower decline in FVC and DLco than IPF patients without emphysema [15, 18, 142]. Therefore, changes in FVC and DLco are not reliable indica-