The diagnosis of PCH is based on characteristic lung histology in a patient with pulmonary hypertension. Most PCH patients are aged 10–40,1
with rare cases reported in neonates7
and the elderly. PCH has been reported in association with hereditary haemorrhagic telangiectasia,8
as an incidental finding during surgery11 12
and at autopsy.13 14
The most common presenting symptoms of PCH are dyspnoea, haemoptysis and cough. Physical exam often demonstrates cyanosis, clubbing and stigmata of right ventricular failure.1
Pulmonary function testing most commonly shows restriction with a decreased diffusion capacity in the lung for carbon monoxide.1
Several HRCT findings have been noted, including centrilobular nodular opacities, ground glass attenuation, interstitial infiltrates and septal thickening.1 15 16
Angiography and pulmonary capillary wedge pressure are often normal.1
Pathologically, PCH is characterised by diffuse, patchy distribution of hyperplastic, non-clonal endothelial cells invading the alveolar walls, perivascular spaces and, at times, small airways. Associated arteriolar medial hypertrophy is common.17
A genetic basis for the disease is not yet known, although there is a report of a family with three affected children in an autosomal recessive pattern.18
There is increased expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor-B, platelet-derived growth factor receptor α and β, angiopoetin 1 and CD-117.19–21
Decreased nitric oxide synthase III expression has been reported in PCH patients with severe pulmonary hypertension versus those with normal PAP.22
The mortality is high (80–90%) with death often occurring within 6 months of presentation.1
There are fewer than 60 cases reported in the literature, and the majority of cases were diagnosed at autopsy.1
Given this, we recommend early consideration of lung biopsy.
Regarding therapies, a small series of patients improved with interferon α-2a,2
which disrupts basic fibroblast growth factor (bFGF) and VEGF signalling pathways, theoretically interfering with neoangiogenesis.23 24
There is a report of successful doxycycline therapy, which may inhibit neoangiogenesis through inhibition of matrix metalloproteinase 9 activity.3
Mortality in PCH is due to right heart failure from progressive pulmonary hypertension, presumably caused by a compensatory arteriolar response to limit flow to the pulmonary capillary haemangiomas. For this reason, pulmonary vasodilator therapy should be considered. However, fatal pulmonary oedema has been reported in response to pulmonary vasodilators in patients with PCH.25
Despite pharmacologic treatment, disease resolution is extremely rare. Pharmacologic treatment should be utilised as a bridge to lung transplantation, which remains the only definitive therapy for PCH.
This case demonstrates PCH is difficult to treat medically and that current markers of disease progression are not sufficiently sensitive. We initially wondered if the return to altitude complicated treatment as this child showed improved haemodynamics during the first 3 months of therapy and later deteriorated, but it was clear from the autopsy findings that primary disease progression was the main cause of death. In this case, there was extensive spread of disease despite the use of interferon α-2a and doxycycline. Progressive anaemia, likely caused by interferon therapy, led to a high cardiac output state, which contributed to progressive cardiac dysfunction. In retrospect, we misinterpreted her initial haemodynamic improvement as reflecting a treatment effect of the interferon and doxycycline on her PCH, whereas it was likely secondary to the pulmonary vasodilator therapy. We depended on echocardiographic estimations of RVSP to indirectly assess secondary vascular changes (). Urinary bFGF has been suggested as a potential marker of disease progression, but is not a commonly available assay.3
Our experience has led us to recommend lung biopsy in patients with parenchymal lung disease, pulmonary hypertension and normal cardiac function. In patients who present with severe pulmonary hypertension, many of the arteriolar changes may be irreversible at the time of presentation. Severe, and somewhat unpredictable, decompensation can occur. In patients with the biopsy-proven diagnosis of PCH, interferon α-2a and doxycycline should be considered as a bridge to lung transplant. The combination of poor markers of disease severity, rapid disease progression and a variable response to available therapies underscore the urgency to proceed with lung transplantation.
- Early lung biopsy should be considered in cases with parenchymal lung disease, pulmonary hypertension and normal cardiac function.
- Echocardiographic estimations of right ventricular pressure may not be representative of the degree of paediatric lung disease or pulmonary hypertension.
- PCH is a fatal disease, and lung transplantation is the only definitive treatment at this time.