Legal Medicine 16 (2014) 44–47

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Case Report

Sudden, unexpected infant death due to pulmonary arterial hypertension Yui Igari a,⇑, Tadashi Hosoya a, Yoshie Hayashizaki a, Tsukasa Ohuchi a, Akihito Usui b, Yusuke Kawasumi b, Masaki Hashiyada a, Masato Funayama a a b

Department of Forensic Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan Department of Diagnostic Analysis, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan

a r t i c l e

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Article history: Received 24 September 2013 Received in revised form 31 October 2013 Accepted 1 November 2013 Available online 11 November 2013 Keywords: Pulmonary arterial hypertension (PAH) Right ventricular hypertrophy Sudden death in infancy

a b s t r a c t A 3-year-old girl with no particular medical history complained of a stomachache and died on the way to the hospital. The autopsy revealed marked right ventricular hypertrophy and dilation with no other cardiac abnormalities. Microscopically, the pulmonary small arteries showed marked medial hypertrophy and varying degrees of intimal and adventitial thickening. We supposed that the cause of death was attributable to pulmonary arterial hypertension (PAH). PAH is a rare disease that can cause sudden, unexpected death at any age. Forensic pathologists should consider PAH in the differential diagnosis of sudden death. Ó 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

3. Postmortem radiological findings (Fig. 1)

Pulmonary arterial hypertension (PAH) is a rare disease characterized by high pulmonary vascular resistance and arterial pressure that can lead to right heart failure and death [1]. PAH is a progressive disease with poor prognosis, and sudden death is not unusual [2,3]. PAH occurs mainly in young adult women, but can affect individuals of any age [1,2]. We herein report an autopsy case of PAH in an apparently healthy 3-year-old girl.

A chest radiograph revealed enlargement of the cardiac silhouette. Horizontal long-axis computed tomography (CT) showed right ventricular wall thickening and right atrial enlargement. The enlarged right ventricle was also clearly demonstrated on short-axis CT. A lung image showed irregular consolidation around the hilum of the lungs. The bronchovascular bundle was thickened. These findings indicated the presence of pulmonary congestion and edema. A ground-glass opacity was seen in the peripheral region of the lungs. In particular, nodular ground-glass opacities were present, possibly representing inflammation of the bronchi or bronchioles. CT images were reconstructed with soft tissue and lung kernels to provide 1.0-mm slices each.

2. Case report A 3-year-old girl complained of a stomachache and shoulder pain at dinner, and these symptoms immediately worsened upon lying down. She was noted to be cyanotic and breathing shallowly when the ambulance arrived. She was taken to the emergency room, but could not be resuscitated. She died approximately 40 min after the onset of the symptoms. The patient was the firstborn child. One month before her death, she was treated for adenovirus infection. She had a persistent slight cough, but appeared to be well until just before her death.

⇑ Corresponding author. Tel.: +81 22 717 8110; fax: +81 22 717 8112. E-mail address: [email protected] (Y. Igari). 1344-6223/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.legalmed.2013.11.001

4. Autopsy findings The patient’s body was 96 cm in height and weighed 13 kg. Apart from some needle marks on her neck, there were no apparent antemortem injuries. Her heart weighed 112 g, and her right ventricle showed prominent hypertrophy and dilation with a wall thickness of 0.5 cm (Fig. 2). The widths of the aortic valve, pulmonary valve, mitral valve, and tricuspid valve were 3.8, 4.0, 6.5 and 7.5 cm, respectively. The foramen ovale was closed, and we found no other cardiac abnormalities.

Y. Igari et al. / Legal Medicine 16 (2014) 44–47

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Fig. 1. (a) Supine anteroposterior chest radiograph shows an enlarged cardiac silhouette exceeding 50% of the cardiothoracic ratio. (b) In order to be able to visualize the small density differences within cardiac wall and cavity, quite narrow image window arranged (window width = 90 Hounsfield unit (HU), window level = 50 HU). Horizontal longaxis heart multiplanar reconstruction (MPR) computed tomography (CT) image (i.e., four-chamber view) shows thickening of the right ventricular wall (double-headed arrow), a dilated tricuspid annulus (arrow), and an enlarged right atrium (star). The blood in the heart is separated into two layers due to postmortem hypostasis. (c) Shortaxis heart MPR CT image shows an enlarged right ventricle (double asterisk) and thickening of the interventricular septum (double-headed arrow). The left ventricle is normal in size (asterisk). (d) Coronal lung MPR CT image shows consolidation around the bilateral hilar area and a thickened bronchovascular bundle (arrows). A ground-glass opacity is seen in the peripheral region of the lungs.

The patient’s lungs (left, 142 g; right, 163 g) were congested on the dorsal side and slightly edematous. No macroscopic stenosis of the pulmonary trunk or either of the main arteries was seen. There were no abnormal findings in the other organs. 5. Histopathology The lungs showed relatively severe congestion and moderate to severe edema. The pulmonary small arteries showed marked medial hypertrophy and varying degrees of intimal and adventitial thickening. Frequently, many of these arteries were almost completely obstructed by medial hypertrophy and concentric laminar intimal thickening (Fig. 3). Mononuclear inflammatory cell infiltration mainly comprising lymphocytes was seen in and around the bronchial and bronchiolar walls (Fig. 4). These findings were particularly apparent in the right lower lobe. In addition, some peribronchial lymph nodes were swollen and contained germinal centers. Myocardial cell hypertrophy was seen in the right ventricle. There were no apparent findings indicative of myocardial ischemia. No inflammatory cell infiltration was seen in either ventricle.

Fig. 2. The right ventricle (left side of figure) is markedly enlarged and its wall is thickened (0.5 cm).

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Y. Igari et al. / Legal Medicine 16 (2014) 44–47

6. Discussion PAH is a rare, progressive disease characterized by raised pulmonary vascular resistance and high arterial pressure. Its estimated prevalence is 15–50 cases per million people [4]. PAH is defined as an increase in mean pulmonary arterial pressure of P25 mmHg at rest [1–5]. PAH represents Group 1 within the Pulmonary Hypertension World Health Organization clinical classification system (Dana Point 2008) and is divided into five types: idiopathic PAH (IPAH), heritable PAH (HPAH), drug- and toxin-induced PAH, associated PAH (APAH), and persistent pulmonary hypertension of the newborn (PPHN). IPAH is one of the more common types of PAH, accounting for about 40% of cases [6]. IPAH is characterized by sporadic disease in which there is neither a family history of PAH, nor an identified risk factor. HPAH, which accounts for 6% of cases of PAH, includes PAH that occurs in two or more family members and simplex PAH with causative gene mutations [7–9]. In the present case, we obtained information that the family had a second child who was 2 years old. The forensic pathologist (M.F.) advised the parents to consult with a pediatrician in a general hospital about their child. The arterial lesions of PAH are divided into two groups: constrictive lesions and complex lesions. Constrictive lesions demonstrate medial hypertrophy, intimal thickening, and adventitial thickening, which result in obstruction of small pulmonary arteries. Complex lesions include plexiform lesions, dilatation lesions, and arteritis [10]. Children with PAH have more severe medial hypertrophy, less severe intimal thickening, and fewer plexiform lesions [2,3]. Indeed, medial hypertrophy was the most prominent histological change in the present case, and many arteries were almost completely obstructed by concentric laminar intimal thickening. Therefore, we presume that the pulmonary vascular resistance of the deceased patient was markedly increased.

Fig. 4. Mononuclear inflammatory cell infiltration is seen in and around the walls of the bronchioli.

In PAH, blood flow through the pulmonary arteries is restricted, and the right ventricle attempts to compensate for this increased afterload by hypertrophying to maintain sufficient pulmonary blood flow. Initially, the right ventricle is able to sustain normal cardiac output. When the right ventricle can no longer compensate for this increased resistance, right ventricular failure ensues, leading to the common symptoms of PAH. Dyspnea is the most frequent symptom of PAH in adults as well as in some children [1–3]. Syncope occurs more frequently in children than in adults, which implies a severely limited cardiac output [2]. Exercise-related syncopal episodes are sometimes the only presenting symptoms in the early stage of PAH, and the presence of PAH can be overlooked in such cases [2,3]. In contrast to adults, right ventricular failure is rare in young children [3]. We found no signs of right ventricular failure in our case.

Fig. 3. Histology of small pulmonary arteries. (a) Medial hypertrophy and adventitial thickening. (b) Concentric laminar intimal thickening with medial hypertrophy. (c) This small artery is almost obstructed by marked medial hypertrophy.

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The prognosis for PAH is poor, and the median survival duration after diagnosis in children is only 10 months. The two most frequent mechanisms of death are progressive right ventricular failure and sudden death [2,3]. The mechanisms for sudden death include bradyarrhythmias, tachyarrhythmias, acute pulmonary emboli, massive pulmonary hemorrhage, and sudden right ventricular ischemia [2,3,11]. Furthermore, sudden death is more likely to occur in patients with severe hypoxia [11]. Younger children in general appear to have a more reactive pulmonary vascular bed relative to both pulmonary vasodilation and vasoconstriction, and severe acute pulmonary hypertensive crises occur in response to pulmonary vasoconstrictors more often than in older children or adults [2]. Hypoxia is one of these vasoconstrictors. Therefore, pneumonia can be fatal as a result of alveolar hypoxia, which causes further pulmonary vasoconstriction and an inability to maintain adequate cardiac output, resulting in cardiogenic shock and death [2,3]. In our case, inflammatory cell infiltration was seen in the walls of the bronchi and bronchioli, indicating that the deceased patient had had bronchiolitis. Such findings were seen mainly in the right lower lobe and hardly in the other lobes. Therefore, we suppose that the bronchiolitis alone could not have been the cause of death but that it might have increased the pulmonary vascular resistance by the above-described mechanism, resulting in a severe acute pulmonary hypertensive crisis. Finally, we concluded that the cause of death was attributable to acute heart failure accompanied by PAH and that PAH might have worsened secondary to the bronchiolitis. In conclusion, PAH can present at any age and may result in sudden, unexpected death. However, its diagnosis may be difficult

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because prior signs or symptoms are often absent. Forensic pathologists should consider PAH as a cause of sudden, unexpected death. References [1] Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet 2003;361: 1533–44. [2] Widlitz A, Barst RJ. Pulmonary arterial hypertension in children. Eur Respir J 2003;21:155–76. [3] Rubin LJ. Primary pulmonary hypertension. Chest 1993;104:236–50. [4] Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007;30:104–9. [5] Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S55–66. [6] Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023–30. [7] Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43–54. [8] Aldred MA, Vijayakrishnan J, James V, Soubrier F, Gomez-Sanchez MA, Martensson G, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 2006;27:212–3. [9] Cogan JD, Pauciulo MW, Batchman AP, Prince MA, Robbins IM, Hedges LK, et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:590–8. [10] Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43:25S–32S. [11] Rajdev A, Garan H, Biviano A. Arrhythmias in pulmonary arterial hypertension. Prog Cardiovasc Dis 2012;55:180–6.

Sudden, unexpected infant death due to pulmonary arterial hypertension.

A 3-year-old girl with no particular medical history complained of a stomachache and died on the way to the hospital. The autopsy revealed marked righ...
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