An interesting case of progressive dyspnoea and diffuse mediastinal adenopathy in a 25-year-old man

Discussion

PVOD was first described by Julius Hora in the 1930s and later distinguished from IPAH in 1966 by Heath et al. [2, 3]. Due to its rarity and the lack of effective treatment options, PVOD is classified as an orphan lung disease, with an estimated prevalence of 1–2 cases per million inhabitants [3]. While PVOD can be heritable in nature, it is also associated with connective tissue diseases, such as systemic sclerosis and specific drugs, chemotherapeutic agents and toxins [3–5]. Heritable PVOD typically presents at a younger age, with an average age of disease onset of 26 years, and has an equal sex distribution due to its recessive nature. This differs from sporadic disease which presents later, typically in the 6th decade and exhibits a male predominance, which is potentially linked to specific occupational exposures [3–5].

Once considered separate clinical entities, PVOD and pulmonary capillary haemangiomatosis (PCH) are now classified together as “Group 1.6: PAH with overt features of venous/capillaries (PVOD/PCH) involvement” [1]. This updated classification following the 6th World Symposium on Pulmonary Hypertension reflects an appreciation for shared characteristics between PVOD/PCH and PAH, as venous pathology may also be observed in PAH and separation of these conditions into different subgroups may be an oversimplification of a spectrum of pulmonary vascular disease [4, 6, 7]. The patient in this case was classified as group 1.6 heritable PVOD due to biallelic EIF2AK4 mutations, with the reported gene variants previously described in association with PVOD [8–10]. The importance of this gene in the pathogenesis of PVOD was first reported by the French Pulmonary Hypertension Network in 2014, when they performed whole-exome sequencing in 13 families with heritable PVOD [11]. Recessive mutations in EIF2AK4 were identified in all of these families and in additional sporadic cases of PVOD, which was a major breakthrough in our understanding of this rare condition [11]. The EIF2AK4 gene encodes a kinase that controls phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (EIF2α), which can induce changes in gene expression and protein synthesis. These gene mutations can be homozygous or compound heterozygous such as in this case. Further work is required to fully elucidate the exact genotype–phenotype relationship and link with specific pulmonary vascular changes [3, 8, 9, 11, 12].

Clinically PVOD can be difficult to distinguish from IPAH, as both present with progressive dyspnoea, fatigue and right heart failure if left untreated. Clinical findings that should alert the clinician to the potential diagnosis of PVOD include high supplemental oxygen requirements, pulmonary oedema during vasoreactivity testing and a poor response to PAH targeted therapies. Relevant investigations that may also suggest the diagnosis include severe reductions in T_LCO, <50% of predicted values, mediastinal adenopathy with associated septal line thickening and centrilobular ground glass opacities on computed tomography, and occult haemorrhage on bronchoalveolar lavage [2, 3, 10]. Interestingly RHC is not helpful to differentiate PVOD from other causes of Group 1 PAH, as it typically demonstrates a precapillary pattern, even though the principle anatomical abnormality is located on the postcapillary side. This is related to the technique used to obtain a PAWP during RHC. In order to obtain a PAWP, a small balloon is wedged into a medium-sized pulmonary artery; this creates a static column of blood downstream, to similarly sized pulmonary veins and the resultant pressure is the reported PAWP. In PVOD, these larger veins are typically spared, as the anatomical abnormalities are more proximal, in the post capillary venules and small veins [10]. Therefore if the condition is suspected, gene testing for EIF2AK4 mutations is recommended, as RHC is not specific for the condition and histological confirmation with lung biopsy is not practical or safe [6]. The histopathology of PVOD has been clearly described in post mortem and post-transplant lung specimens. It is characterised by diffuse intimal thickening and fibrosis of venules and small veins, with associated vessel narrowing and obliteration. Luminal thrombosis, recanalised thrombotic lesions termed “colander-like lesions”, haemosiderin deposition, occult haemorrhage and secondary angioproliferation of alveolar capillaries are frequently seen. Lymphatic abnormalities are also described, but importantly plexiform lesions are not observed, which is a key differentiator from IPAH [3].

PVOD is frequently associated with a poor response to targeted PAH medications. In this case, our patient tolerated double oral combination therapy with an ERA and PD5 inhibitor with no adverse events, but he remained intermediate risk, oxygen dependent and functional class III. Additional parenteral prostacyclin could also be considered with cautious titration given the associated risk of pulmonary oedema. Supportive measures, such as supplemental oxygen, vaccinations, diuretics and treatment of comorbidities are important to consider, but double lung transplant remains the only curative option for these patients. Interestingly, our patient has a small PFO, which technically could offload the right ventricle by shunting blood from right to left if the right atrial pressure exceed that of the left, acting like a balloon atrial septostomy (BAS). Evidence for BAS in PVOD is lacking, as theoretically profound hypoxaemia in PVOD precludes BAS, though anecdotal evidence suggests that BAS could be combined with veno–venous ECMO as a bridge to transplant in highly selected cases [13, 14].

Unfortunately the prognosis of this condition is poor, with a mean time from diagnosis to death or lung transplantation of 11.8 months [3]. Genetic counselling and testing should be offered to siblings of affected individuals for this recessive condition, as evidence suggests that early diagnosis of PAH and prompt intervention may translate into better long-term clinical outcomes [9].