Here we present three cases of chronic DAH initially diagnosed as IPH that subsequently developed ANCA-MPO positivity, and, on HRCT, progressive development of cystic areas in keeping with emphysema, all with a striking perivascular distribution. We believe these three cases are of interest in highlighting the 1) possibility of development of ANCA +/− renal involvement several years down the line from first IPH presentation; 2) the possibility that DAH changes may develop into emphysema.
Development of ANCA MPO antibodies
The development of specific antibodies +/− other typical autoimmune extrapulmonary manifestations after the initial pulmonary presentation have been described in a number of scenarios [
3‐
6]. Specifically, to the development of ANCA MPO positivity, longitudinal assessments have revealed new onset of MPO+ or PR3+ and/or overt vasculitis on follow up in patients initially presenting as idiopathic interstitial pneumonias [
3].
However, there are only a few reports detailing subsequent autoimmune serology (other than ANCA) conversions following an initial diagnosis of IPH [
7,
8]. Le Clainche et al. [
4] report on 15 children diagnosed with IPH, of which only one developed ANCA on follow up (specificity not reported). However, as the children were not screened for ANCA at presentation, it is impossible to conclude whether this was a real seroconversion.
ANCA MPO seroconversion occurring in adulthood in IPH after many years has been described, to our knowledge, only in another case [
5]. However, the patient presented by Freitas et al. was a 21 year old girl diagnosed with IPH at the age of 4, who developed ANCA positivity 12 years after presentation, aged 16, and had a good response to immunosuppression. Furthermore, no emphysematous changes on follow up were mentioned. By contrast, our cases developed ANCA positivity in adulthood, and all continue to require ongoing immunosuppressive treatment to control the DAH, suggesting the possible role played by autoimmune phenomena in this rare disease, even when initially deemed “idiopathic”. In support of this, the second case had positive anti-transglutaminase IgA antibodies and autoimmune thyroiditis and the third case had autoimmune thyroiditis.
Development of emphysema
During follow up, our cases developed cystic opacities consistent with emphysema, not seen at presentation. In the first patient, limited emphysema was first seen 10 years after presentation. The cystic areas became more prominent over the following 6 years, with concurrent isolated reduction in DLCO. The second patient was first noted to have developed emphysematous changes on HRCT 8 years after the initial presentation, and 20 years after having completely stopped smoking, with further significant worsening of radiological emphysema after another 2 years. In parallel, there was marked worsening in gas transfer with persistently normal lung volumes. The third patient was diagnosed with IPH in early childhood and was first noted to have emphysema on HRCT 4 years after the diagnosis, aged 11, with subsequent progression despite the lack of active or passive smoking exposure.
The development of emphysema in the context of interstitial processes even outside of a significant history of smoking is being increasingly recognized. In a cohort of never-smoker patients with rheumatoid arthritis related ILD, 27% had associated emphysema with obstructive functional indices [
6], while in systemic sclerosis related ILD patients with concomitant emphysema, the prevalence of never smokers was 33% [
9]. In a cohort of 233 hypersensitivity pneumonia (HP) patients evaluated for the presence of emphysema and PPFE, 23% of patients with emphysema were never-smokers [
7].
In AAV, development of emphysema has been described in a few retrospective case series and case reports [
8,
10‐
12]. In a cohort of AAV patients with 79 granulomatosis with polyangiitis (GPA) cases and 61 microscopic polyangiitis (MPA) cases, global emphysematous changes incidence was 13% with no significant differences between the two groups [
12]. In the largest published series so far, Yagamata et al. reported emphysematous lesions in 37% of patients in a cohort of MPA patients, more frequently characterized by low attenuation areas rather than cystic lesions, although the Authors did not link the emphysematous lesions with alveolar haemorrhage per se [
13].
The pathogenesis of emphysema on a background of DAH and ANCA positivity is unclear. One possibility is that the emphysema seen in our three cases could be secondary to the inflammatory process present within the capillaries/small vessels leading to the destruction of the alveolar walls though the release of noxious insults including proteolytic enzymes and free oxygen radicals. The observation of a striking peribronchovascular distribution to the emphysema supports this hypothesis. This has been suggested in the context of capillaritis [
14] and in hypocomplementemic urticarial vasculitis, a rare immune complex related small vessel vasculitis, characterized by low C1q and C4 complement levels. Serial histopathological analysis of one case described by Hunt et al. [
15] showed that the initial changes of capillaritis evolved into emphysema, and obstructive airways disease. Several other case reports have presented this association in the context of hypocomplementemic urticarial vasculitis [
16‐
22].
It is also possible that the ANCA antibodies themselves have pathogenic activity. Neutrophils can be activated by MPO-ANCA causing the release of MPO, a cationic protein expressed by several immune cells including neutrophils and macrophages, resulting in an inflammatory response [
23]. In an animal model of smoke-induced emphysema, a myeloperoxidase inhibitor prevented progression of the emphysematous changes [
24] Further support for a role played by autoantibodies and specifically ANCA, comes from the finding of significantly increased proportion of combined pulmonary fibrosis an emphysema (CPFE) among patients with ANA positivity and a higher MPO-ANCA positivity compared to idiopathic pulmonary fibrosis (IPF) patients without emphysema. Furthermore, CPFE patients with ANA and/or ANCA positivity showed an increased number of CD20+ cells forming lymphoid follicles within the fibrotic interstitium in areas adjacent to fibroblastic foci [
25].
In the first two cases, we cannot completely exclude that the development of cystic changes and/or emphysema was related to the previous history of smoking, and certainly cigarette smoking may have contributed to its development. However, the first case had a truly trivial smoking history (one pack year), and stopped by age 21, when her HRCT showed no cystic/emphysematous lesions. The second patient had a 5-pack year history but he stopped and had been a non-smoker for 10 years by the time he had his initial HRCT, which did not reveal any emphysematous destruction. Furthermore, the third patient developed extensive emphysema at a very young age with no exposure to cigarette smoke, supporting a direct link between DAH, ANCA positivity and emphysema.
Further studies are required to better understand the relationship between DAH, ANCA positivity and development of emphysema. ANCA positivity seems to be retrospectively associated with a worse outcome in children with IPH [
26]. Also, the development of emphysema in the contest of CTDs and HP has been associated to a worse prognosis [
6,
7,
9].
IPH is a rare disease and little is known about the mechanisms involved in its development. However, its known association with coeliac disease [
27], its response to immunosuppressive therapy and its possible association with autoimmune features [
4,
28,
29] suggests that a contribution of immunological overactivity, even if a clear cut autoimmune disease is not identified.
Immunosuppressive treatment should always be considered in these patients even in the context of an idiopathic onset. Patients with IPH should have ANCA screening not only at presentation but also during follow up, especially when the response to therapy is poor or in presence of suspected renal involvement. However, it is worth noting that ANCA positivity is not always identified in AAV, such that the presence of ANCA is not essential to confirm the diagnosis or to start immunosuppressive therapy, if needed [
30]. Full lung function tests including DLCO should be monitored frequently even in case of stable spirometric values, as subtle worsening due to development of emphysematous changes could develop even after many years. This could aid in identifying the cases which could benefit from a more aggressive therapy and perhaps prevent the development of complications such as emphysematous changes.