Unexplained PAH: the importance of an early and correct diagnosis. M.T.R. Roofthooft Pediatric cardiologist Center for CHD UMCG Groningen

Transcription

1 The Third European conference on neonatal and pediatric pulmonary vascular disease October 2017 Unexplained PAH: the importance of an early and correct diagnosis M.T.R. Roofthooft Pediatric cardiologist Center for CHD UMCG Groningen

2 What does it mean: Unexplained not described or made clear Synonyms: non-specific, undeterminate not accounted for or attributable to an identified cause Synonyms: unclear, mysterious, puzzling

3 Simonneau, et a l. JACC 2013

4 My mission To explain the unexplained: looking for clues and cases

5 Unexplained PAH pubmed search PAH in pediatric patients with hematopoetic stemcell transplantation associated thrombotic micoangiopathy Jodele S et al Biol Blood Marrow Transplant Feb;19(2) Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients J. Etemadia et al. Rev Port Pneumol Jan-Feb;18(1)

6 PAH in pediatric patients with hematopoetic stemcell transplantation associated thrombotic micoangiopathy Jodele S et al Biol Blood Marrow Transplant Feb;19(2) Introduction The pathogenesis of PAH in HSCT is poorly understood and the diagnosis requires a high degree of suspicion HSCT-associated thrombotic microangiopathy (TA-TMA): endothelial injury causes microangiopathic hemolytic anemia and platelet consumption, resulting in thrombosis and fibrin deposition in the microcirculation and end-organ injury.

7 PAH in pediatric patients with hematopoetic stemcell transplantation associated thrombotic micoangiopathy Jodele S et al Biol Blood Marrow Transplant Feb;19(2) Report case series of 5 pediatric allogeneic HSCT recipients diagnosed with hypoxemic respiratory failure and PAH with clinical and histologic evidence of pulmonary TA-TMA PAH definition: echocardiographic evidence of right ventricular dysfunction, dilatation, and/or elevated pressure (RV pressure 50% of the systemic pressure), or histologic evidence of PVD on lung biopsy or autopsy as evidenced by vascular proliferation and remodeling of all 3 levels of the arteriolar wall with obstructive changes including endothelial, smooth muscle cells, and fibroblasts

8 PAH in pediatric patients with hematopoetic stemcell transplantation associated thrombotic micoangiopathy Jodele S et al Biol Blood Marrow Transplant Feb;19(2) TA-TMA: de novo microangiopathic anemia with the presence of schistocytes on peripheral blood smear, de novo thrombocytopenia, elevated lactate dehydrogenase (LDH), low haptoglobin, doubling of serum creatinine, evidence of neurologic symptoms, and/or histologic evidence of microangiopathy on tissue biopsy or autopsy N=209 patients underwent HSCT, 21% (45 patients) developed hypoxemic respiratory failure requiring mechanical ventilation 5 had clinical and/or histologic diagnosis of PAH after HSCT Only 1 patient underwent cardiac catheterization, which demonstrated an elevated mean PA pressure and increased pulmonary vascular resistance.

9 PAH in pediatric patients with hematopoetic stemcell transplantation associated thrombotic micoangiopathy Jodele S et al Biol Blood Marrow Transplant Feb;19(2) PAH was diagnosed a median of 76 days (range, days) after a diagnosis of TA-TMA. Despite aggressive medical management, including inhaled nitric oxide, 4 of the 5 patients died. One patient recovered from PAH after 11 months of sildenafil therapy Three of the 4 deceased patients underwent autopsies, which demonstrated severe pulmonary vascular disease. In all cases, lung histology was consistent with acute and subacute TA-TMA, with endothelial separation noted in the pulmonary arterioles

10 PAH in pediatric patients with hematopoetic stemcell transplantation associated thrombotic micoangiopathy Jodele S et al Biol Blood Marrow Transplant Feb;19(2) Discussion TA-TMA may be associated with pulmonary vascular injury, leading to: Persistent endothelial injury damaging the small blood vessels of the pulmonary vasculature ( microthombi formation, fibrin deposition, and damage from RBC and platelet fragments) Persistent inflammation and vasoconstriction would then promote vascular wall proliferation, leading to the increased vascular resistance seen in PAH An acute stressor, such as active hemolysis, could promote vascular spasm contributing to a rapid elevation in PA resistance It is also possible that pulmonary vascular endothelial trauma may significantly interrupt normal nitric oxide production and metabolism, and alter the response of endothelin receptor function

11 Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients J. Etemadia et al. Rev Port Pneumol Jan-Feb;18(1) Introduction PAH is a newly recognized disease in patients with renal disease 2000: Yigla and coworkers first noted unexplained PAH in some long-term hemodialysis (HD) patients during an epidemiologic study shunting of blood from the left to the right side of the heart and increased cardiac output and pulmonary blood flow are common medical conditions resulting in PAH

12 Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients J. Etemadia et al. Rev Port Pneumol Jan-Feb;18(1) retrospective review of the medical records of 278 chronic HD and 145 chronic PD patients Laboratory findings were documented Transthoracic Doppler echocardiography was used to determine the pulmonary artery pressure (PAP). PAH was defined as a systolic pulmonary artery pressure (SPAP) 35 mmhg. To rule out secondary PAH, patients with cardiac disease, pulmonary disease, collagen vascular disease, volume overload at the time of echocardiography and positive HIV test were excluded.

13 Results PAH was more frequent in patients undergoing HD (41.1%) than in patients of PD group (18.7%)

14 Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients Discussion In HD patients numerous hormonal and metabolic disorders contribute to vasoconstriction of pulmonary vessels and pulmonary artery calcification Impaired NO production and reduced sensitivity to NO is described in chronic renal failure; in HD as PD An increase in cardiac output and pulmonary blood flow due to AV access may change shear stress, and may alter endothelial function or release of mediators through induction of gene expressions patterns Finally microbubbles obstruct capillaries in the lungs, may cause tissue ischemia, an inflammatory response and complement activation No explanation for laboratory test differences

15 Unexplained PAH Back to our Dutch Pediatric PAH Registry

16 index patient Boy, 2 years of age at presentation severe PAH and hematuria/proteinuria Kidney biopsy: irregular basal membrane and intracapillary thrombi in accordance with thrombotic microangiopathy Pulmonary hypertensive crisis during biopsy procedure and resuscitation setting on the PICU led to a fatal outcome

17 index patient Post mortem: Lungs: broadening of alveolar septa without remarkble inflammation, with fibrin deposition in alveoli and some alveolar macrophages Pathology conclusion: extended diffuse alveolar damage, applicable to acute interstitial pneumonia (DD ARDS). The vasculopathy most presumably due to hypoxia PAH and renal microangiopathy

18 The power of coincidence Boy, 9 years of age Presentation of pulmonary hypertension (age 9 years) High resolution CT: in accordance with PVOD CO-diffusion rate:28% of normal His medical history: Renal failure after atypical Hemolytic Uremic Syndrome (age 4 years) / biopsy>>renal TMA: hemodialysis by Cimino shunt Kidney transplantation (age 8 years)

19 The power of coincidence Differential diagnosis: pulmonary microangiopathy Pulmonary veno-occlusive disease Pulmonary fibrosis due to immunosuppressants, opportunistic infections, posttransplant lymphoproliferative disease, Nitrofurantoïne shunting of blood from the left to the right side of the heart and increased cardiac output and pulmonary blood flow Right heart catheterization: Resting condition (28% oxygen): AP 44/23 mean 30 mm Hg/ aorta 81/50 mean 61 mmhg. mean wedgepressure 7 mmhg. cardiac index 4.7 l/min/m². PVRi 3.6 resistent U.m², PVR/SVR-ratio 0.4. Cimino-shunt blocked by manchet, pressure 30 mmhg above aortic pressure: lower mpap mean 19 mm Hg, cardiac index 3.9 l/min/m², PVRi 3.7 Condition 3 (100% oxygen/open Cimino): PA 41/17 mean 27 mm Hg /aorta 89/55 mean 68 mm Hg, mean wedgepressure 7 mmhg. PVRi 2.5 resistent U.m², cardiac index van 5.9 l/min/m².

20 The power of coincidence hyperkinetic circulation (Classification group 5 (Unclear and/or Multifactorial Mechanism) - Cimino shunt was closed - sildenafil/oxygen therapy was started 60 days later: progressive severe pulmonary hypertension - Plasmapheresis - Respiratory-circulatory insufficiency - Intubation/inotropics with persistent low cardiac output/hypoxemia and finally fatal outcome - Emergency laboratory test: high homocysteinemia and malonic acid DIAGNOSIS: Cobalamin C deficiency

21 Cobalamin C deficiency Most common inherited form of a defect in Vitamin B12- metabolism, with a wide phenotype spectrum autosomal recessive inheritance (mutation methylmalonic aciduria and homocystinuria type C protein) gene Cbl C disease is related to ahus: by hyperhomocysteinemia impairment of the nitric oxide dependent inhibition of platelet aggregation,or the procoagulant state of the endothelium leading to the formation of microthrombi (< 20 patients reported to have r-tma and presented with ahus)

22 Sister of the index patient 2009: initial PH Screening: negative hematuria /hypertension»»kidney biopsy: chronic r-tma 2011: Hemolytic anemia with atypical HUS: plasmapheresis (-) positive screening cobalamin C deficiency Echocardiography: subtile elevated AP-pressures Right heart catheterization: Condition 1 (Fi ): mean PAP 26mmHg; PVRi 4,1 WU.m2 Condition 2 (Fi02 0,28 + NO 40ppm): mpap 20mmHg, PVRi 2,4 WU.m2 Condition 3 (Fi02 1,0 + NO 40ppm): mpap 19mmHg PVRi 1.4 WU.m2 Condition 4 (Fi ): mpap 26mmHg; CI 5.7 L/min/m2; PVRi 2.5 WU.m2 start targeted PAH therapy: bosentan Hydroxy Cobalamine and Cystadane ACE inhibitor/amlodipin (CCB) to hypertension

23 Sister of the index patient no clinical improvement Progression of PH: mpap 33; PVRi 6,3; SVR 10,4 prostacyclin iv. CT-Thorax: combination of enlarged pulmonary arteries, groundglass phenomena, noduli and broadening of interlobular septa Diagnosis: PVOD Despite maximum therapy further detoriation: parents decided to pull out option of lungtransplantation Patient was send home to depart this life: prostacyclin was stopped

24 Combined Pulmonary Arterial Hypertension and Renal TMA in five children with Cobalamin C deficiency Komhoff et al. Pediatrics Aug;132(2) Patient 1 (IP) Patient 2 Patient 3 Patient 4 Patient 5 A RHC PVR (RU: <2,5) Mean PAP (< 20 mm Hg) B Histology Renal biopsy Lung autopsy - - TMA PAH TMA PAH/ PVOD TMA PAH/ PVOD TMA - C Genetic evaluation Parental Nationalities MMACHC Spanish/Turkish (c.276g>t/ c.271dupa) (p.glu92asp/ p.arg91lysfsx11) Dutch (c.276g>t/ c.442_444delinsa) (p.glu92asp/val148 MetfsX33/ Spanish/Turkish (c.276g>t/ c.271dupa) (p.glu92asp/ p.arg91lysfsx14) Dutch (c.464g>a/ c.464g>a) (p.gly155glu/ p.gly155glu) Italian (c.276g>a/ c.14_24del11 (p.glu92glu /p.val5glufsx25 )

25 conclusions active searching for a diagnosis is worthwile in PH patients, albeit in infrequent cases Structural diagnostic PH work-up remains invaluable From time to time reassessing patients diagnosis can result in new diagnosis and treatment options It ain t over till it s over (Lenny Kravitz)