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Pulmonary Venoocclusive Disease in Childhood

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Neumologia Neumologia pediatrica tromboembolia pulmonar
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    journal.publications.chestnet.org   167 Pulmonary Venoocclusive Disease in Childhood Cornelia Woerner , MD ; Ernest Cutz , MD ; Shi-Joon Yoo , MD , PhD ; Hartmut Grasemann , MD ; and Tilman Humpl , MD , PhD BACKGROUND:  Pulmonary venoocclusive disease (PVOD) is a rare lung disease, diagnosed in 5% to 10% o patients with pulmonary hypertension (PH). Te incidence, prevalence, and etiology o PVOD in children are not well de󿬁ned. Te mortality remains high, related, at least partly, to the limited treatment options. METHODS :  Tis retrospective analysis (1985-2011) summarizes symptoms, associated actors, treatment, and outcomes o nine pediatric patients (󿬁ve girls, our boys) with histologic con-󿬁rmation o PVOD. RESULTS:  PH was diagnosed at a mean age o 13.5 years (range, 8-16 years), ollowed by the de󿬁nitive diagnosis o PVOD at a mean age o 14.3 years (range, 10-16 years). Symptoms such as decreased exercise tolerance (n 5  6) and/or shortness o breath (n 5  9) preceded the diag-nosis by 21 months on average; the mean survival time afer diagnosis was 14 months (range, 0-47 months). C scans o the lungs showed typical radiologic eatures. reatment included supplemental home oxygen (n 5  5), diuretics (n 5  9), wararin (n 5  4), and pulmonary vaso-dilators (n 5  4). Four children were listed or lung transplantation, and three have undergone transplantation. Eight patients died, including two afer lung transplantation. One patient with lung transplant survived with good quality o lie. CONCLUSIONS:  PVOD is an important differential diagnosis or pediatric patients with PH. C scanning is a valuable tool to image lung abnormalities; the de󿬁nitive diagnosis can only be made by examination o lung biopsy specimens, which subjects the patient to additional risk. Early listing or lung transplantation is essential, as the mean survival time is only 14 months. CHEST 2014; 146(1):167-174 [   Original Research   Pulmonary Vascular Disease ]   Manuscript received January 22, 2013; revision accepted January 2, 2014 ; srcinally published Online First February 6, 2014. ABBREVIATIONS: NYHA 5  New York Heart Association; PAP 5  pul-monary artery pressure; PF 5  pulmonary unction test; PH 5  pulmo-nary hypertension; PVOD 5  pulmonary venoocclusive disease AFFILIATIONS:  From the Department o Pediatrics, Division o Cardi-ology (Drs Woerner, Yoo, and Humpl), Department o Laboratory Medicine and Pathobiology (Dr Cutz), Department o Pediatrics, Divi-sion o Respiratory Medicine (Dr Grasemann), Department o Crit-ical Care Medicine (Dr Humpl), and Department o Medi cal Imaging (Dr Yoo), University o oronto, Hospital or Sick Children, oronto, ON, Canada. FUNDING/SUPPORT:  Te authors have reported to CHES   that no unding was received or this study. CORRESPONDENCE   TO: ilman Humpl, MD, PhD, he Hospital or Sick Children, Critical Care and Cardiology, 555 University Ave, oronto, ON, M5G 1X8, Canada; e-mail: tilman.humpl@sickkids.ca  © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction o this article is prohibited without written permission rom the American College o Chest Physicians. See online or more details. DOI:  10.1378/chest.13-0172    168 Original Research [  146#1 CHEST  JULY 2014 ]  Results Nine patients were identi󿬁ed; demographic data are shown in able 1 . Te average time interval rom onset o symptoms until the diagnosis o pulmonary hyper-tension (PH) and PVOD was 14 months and 21 months, respectively (range, ,  1 month to 7 years). Te mean survival time afer diagnosis with PVOD was 14 months (range, ,  1-47 months). Initial symptoms included atigue, decreased exercise tol-erance, and shortness o breath on exertion. Other symp-toms were cough, dizziness, chest pain with exercise, palpitations, syncope, and nonspeci󿬁c symptoms such as headache, poor appetite, pallor, perioral cyanosis, and hemoptysis ( able 2 ). Four children were previously diag-nosed with a different pulmonary dis ease: three with bronchial asthma and one with allergic alveolitis. Additional diagnoses affecting other organs were pre-sent in three children and included bilateral renal dys-plasia, ichthyosis, velopharyngeal incompetence, severe developmental delay, and congenital heart dis ease. One patient was diagnosed with Myhre syndrome, con-󿬁rmed by mutational analysis o SMAD4  . 14  wo patients received long-term immunosuppressive treatment (tacrolimus and tacrolimus, azathioprine and prednisone) afer (nonlung) solid organ transplantation. Other risk actors, such as tobacco consumption, were not documented. One patient was taking an antidepres-sant drug, three patients were treated with bronchodila-tors (puffers), and three were not on any medications. Te physical examination was unremarkable in one patient; the others presented with abnormal 󿬁ndings ( able 2 ). NYHA class at presentation ranged rom I to Pulmonary venoocclusive disease (PVOD) is a rare lung disease that affects the postcapillary venous pulmo-nary vasculature and accounts or 5% to 10% o cases with “idiopathic” pulmonary arterial hyper tension. 1-5  It carries a high risk o developing right-sided heart ailure secondary to elevated pulmonary artery pressure (PAP) ollowed by death. Histopathologic 󿬁ndings in PVOD have previously been well characterized. 2  Te main ea-tures include involvement o preseptal venules and small septal veins with vary ing degree o luminal oblit-eration due to intimal 󿬁brous prolieration that can be loose initially and later becoming dense or sclerotic. Te media o the veins can become arterialized with an increase in smooth muscle cells and elastic 󿬁bers in their walls. Further progression may lead to pulmonary arterioles with medial hypertrophy, capillary angiecta-sia, and even capillary prolieration. Parenchymal changes begin with interstitial edema and can progress to 󿬁brosis. 2 Incidence, prevalence, and etiology o PVOD are not well de󿬁ned, treatment is limited, and the mortality remains high. Tere are a number o reports about adult patients, 3,6-8  but, to our knowledge, only a ew case reports exist about children. 9-13  We undertook a single-center retro-spective review to summarize symptoms, associated ac-tors, treatment, and outcomes in children with PVOD. Materials and Methods Te cardiology, radiology, and pathology databases were searched or patients with clinical suspicion o PVOD between 1985 and 2011. Final patient selection or this study was based on histologic con󿬁rmation o PVOD. Patients with clinical signs o PVOD but without histologic 󿬁ndings were excluded. Paper and electronic patient charts were reviewed, and data including initial symptoms, age at presentation with symptoms, time o diag-nosis, additional diagnoses, risk actors, New York Heart Association (NYHA) unctional class, and physical examination at presentation were collected. Additionally, the results o the ollow ing investigations were evaluated: ECG, echocardiogram, chest radiograph, 6-min walk test, pulmonary unction test (PF), C scan o the lung, cardiac cath-eterization, bronchoscopy, lung biopsy specimen examination, and autopsy. Te lung samples were 󿬁xed in buffered ormalin and embedded in paraffi n. In addition to routine stains with hematoxylin and eosin, we also used special stains, including elastic trichrome to visualize vascular changes, stain or iron or assessment o hemosiderosis, or stains or microorganisms where indicated. Due to the small number o patients and the large variation in their clinical course, statistical analysis was not perormed. Tis study was approved by the Research Ethics Board at the Hospital or Sick Chil-dren, oronto, Ontario, Canada (No. 100010504). TABLE 1   ]  Demographic Data of Patients With PVOD Demographic Variable Age at diagnosis, alive or postmortem, mean (range), y14.3 (10-16) Age at diagnosis of pulmonary hypertension, mean (range), y13.5 (8-16) Age at onset of symptoms, mean (range), y12.4 (7-15) Sex, female:male5:4 Postmortem diagnosis, No.3 PVOD 5  pulmonary venoocclusive disease.    journal.publications.chestnet.org   169    T   A   B   L   E   2                   ]     S  y  m  p  t  o  m  s  a  n   d   C   l   i  n   i  c  a   l    F   i  n   d   i  n  g  s  o   f   P  a  t   i  e  n  t  s  a  t   I  n   i  t   i  a   l    P  r  e  s  e  n  t  a  t   i  o  n 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A, Frontal chest radiograph shows mild cardiomegaly with markedly dilated main pulmonary arterial segment o the lef upper heart border due to pulmonary hypertension. Both lungs are diffusely hazy and show increased interstitial markings with blurred vessel margins. B, C images reconstructed in axial and coronal planes show diffuse ground-glass opacity with a mosaic pattern, thickened septal lines extending to the pleura (black arrows), and peribronchial thickening (white arrows). Note that there are low density areas in the mediastinum and hila (asterisks), which represent sof tissue edema or lymphatic dilatation. Extensive edematous tissue in the posterior mediastinum is well appreciated in the coronal plane. Te pulmonary arteries in the mediastinum and hila are dilated. IV ( able 2 ). ranscutaneous oxygen saturation ranged rom 85% to 98% on room air (mean, 92%). Hypocap-nia was present in 66% (n 5  6); the pH was within nor-mal limits. PFs were perormed in seven patients at our institu-tion and revealed a restrictive pattern in all cases (in one patient, the PF was done at another hospital, and the results were not available). In all patients, the FVC and FEV 1  were decreased, with a mean o 50% (range, 20%-81%) and 51% (range, 18%-81%), respectively. Te diffusing capacity o the lung or carbon monoxide was reduced in the our patients tested (67%, 62%, 26%, and 83%), ranging rom 5.9 mL/min/mm Hg to 14.2 mL/min/mm Hg. Five children completed a 6-min walk test with a mean distance o 263 m (range, 19-382 m). Eight patients had abnormal ECG 󿬁ndings, with re-quent right-axis deviation, signs o right atrial enlarge-ment, and right ventricular hypertrophy. ransthoracic echocardiography showed a dilated right ventricle with 󿬂attening or bowing o the interventricular septum, sug-gesting elevated right ventricular pressure in all patients. Te estimated right ventricular systolic pressure ranged rom more than one-hal systemic to sys temic (n 5  5) to suprasystemic (n 5  3). In one patient, only mean PAP could be estimated and exceeded 25 mm Hg. Te initial chest radiograph showed a prominent pul-monary arterial segment o the lef heart border in all cases and increased interstitial markings, ground-glass haziness o both lungs, or blurring o vessel margins suggestive o pulmonary venous hypertension in eight o nine cases. C scan indings are summarized in able 3 and illustrated in Figure 1 . A diagnostic cardiac catheterization with acute vasodi-lator testing was perormed in our patients and showed elevated PAP ( able 4 ). During testing with pulmonary  vasodilators, one patient developed acute pulmonary edema. Bronchoscopy with BAL was perormed in only two patients and did not reveal signi󿬁cant 󿬁ndings. Four chil-dren underwent elective lung biopsy; two had samples taken rom the explanted lungs at the time o transplanta-tion, and three patients had the diagnosis o PVOD estab-lished at autopsy ( able 5 ). Te main histologic 󿬁ndings included extensive changes o PVOD similar to those pre- viously described. 1,2,13,15-17  Tese changes were character-ized by extensive and diffuse occlusion o pulmonary  veins by 󿬁brous tissue, which, in some areas, was loose and edematous, while in others it was dense and sclerotic ( Fig 2A ). Te intimal thickening involving venules and small veins exhibited an eccentric pattern resembling organizing arterial thrombi. In most cases, the pulmonary arterioles showed moderate to severe medial thickening without plexiorm lesions. In addition, several cases showed variable interstitial thickening with ocal 󿬁brosis and moderate to marked pulmonary hemosiderosis ( able 5 ). In the two patients who underwent solid organ transplantation, the lung biopsy specimens, in addition to
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