2009년 4월 23일~5월 15일까지  임상적으로 신종플루로 인해 사망했을 것으로 추정되는 사망자 15명의 부검을 실시했음. 멕시코(the Institute of Epidemiological Diagnosis and Reference)로부터 폐조직 샘플을 소량 획득함. 그 중 5명의 사망자는 RT-PCR로 Swine influenza A H1N1으로 확정 진단을 내림. 5명의 사망자는 모두 멕시코시티 거주자로 그 중 4명은 22, 26, 28, 37세였음. 이들 환자들은 모두 초기에 항생제 치료를 받음. 5번째 사망자는 뇌출혈(cerebral hemorrhage) 진단을 받은 83세의 여성으로 독감증상을 보이지는 않았으나 출혈성 폐렴 소견을 보임. 5명의 환자들은 독감 증상 발현 후 7~13일 후 사망함.

부검결과 5명의 사망자들은 좌폐와 우폐의 무게가  각각 650~1200g 으로 증가(정상 450 g)했으며, solid consistency가 나타남. 4명의 사망자에서는 후두와 기관의 안쪽면의 상부호흡기에 부종, 출혈, 괴사가 확인됨(계절성 독감 사망자에서도 나타났던 소견). 5명의 사망자들은 모두 폐의 손상과 급성 간질성 병변이 나타났음.(조류독감 사망자에서도 나타났던 소견)

4명의 사망자들에게서 hyaline membranes, alveolar septal edema, hyperplasia of type II pneumocytes, fibrin thrombus in the vascular lumen, and necrosis of the bronchiolar walls 확인됨. 3명의 사망자들에게서 inflammatory infiltrate below the endothelium and partial loss and adherence of the endothelium in the medium- and small-caliber intrapulmonary blood vessels 확인됨. 3명의 사망자들에게서  pneumonia foci with intraalveolar exudates without evidence of bacterial colonies 확인됨. 모든 사망자들이 항생제 투여를 받았음에도 불구하고 2명이 사망자들에서 erythrophagocytosis and phagocytosis of inflammatory cells in the liver, spleen, and bone marrow 나타남.(조류독감 사망자들에게 나타난 소견과 유사함)

1명의 사망자에게선 focal centrilobular necrosis of the liver and hemorrhagic necrosis of the adrenal gland cortex이 나타났으며, 다른 사자들에게서 나타났던 acute tubular necrosis 확인됨.

 실질성 뇌출혈(parenchymal cerebral hemorrhage)로 사망한 1명의 사망자는 부검결과 폐에서는 septal edema and extensive hemorrhage with scarce fibrin thrombi 확인됨. 간질성 병변은 초기였으며, 출혈이 지배적인 특징을 보였음. 이러한 소견은 삼출기(exudative phase)에서 증식기(proliferative phase)로 아직 진행되지 않은 급성 폐병변의 초기 단계를  보여주는 것으로 추정됨.
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Volume 361:2001-2003 November 12, 2009 Number 20

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To the Editor: Between April 23, 2009, and May 15, 2009, we performed 15 autopsies on deceased patients in whom probable influenza had been diagnosed either clinically or macroscopically. Small samples of lung tissue were obtained and taken for analysis to the Institute of Epidemiological Diagnosis and Reference in Mexico City. Five infections with the 2009 pandemic influenza A (H1N1) virus were confirmed with the use of a real-time reverse-transcriptase–polymerase-chain-reaction assay, after it was determined that these patients were seronegative for influenza B virus, respiratory syncytial virus, parainfluenza virus (types 1, 2, and 3), and adenovirus.¹ From these five patients, organ samples were collected, fixed in 10% formalin, embedded in paraffin, and stained with hematoxylin and eosin. In the remaining 10 patients in whom the 2009 H1N1 virus was not detected, histopathological analyses identified bacterial pneumonia.

All five patients with diagnosed 2009 H1N1 influenza had been residents of Mexico City. Four of them were young adults (ages 22, 26, 28, and 37 years) who were hospitalized with the presumptive diagnosis of influenza. These patients were initially treated with antibiotics for bacterial pneumonia. The fifth patient was an 83-year-old woman with a diagnosis of cerebral hemorrhage, who had no clinical signs of influenza but showed characteristics of hemorrhagic pneumonia on macroscopic evaluation. The patients had died 7 to 13 days after the onset of influenza symptoms.

On autopsy for all five patients, the right and left lungs had increased in weight (650 to 1200 g for each lung; normal, 450 g) and had a solid consistency (see Fig. 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In four patients, zones of edema, hemorrhage, or necrosis were observed in the upper respiratory tract on the internal surface of the larynx and trachea, as reported in previous cases of seasonal influenza.^2,3 All five patients showed evidence of pulmonary damage and signs of acute interstitial lesions, as noted in patients with avian influenza A (H5N1) virus infection.^3,4

In four patients, we observed hyaline membranes, alveolar septal edema, hyperplasia of type II pneumocytes, fibrin thrombus in the vascular lumen, and necrosis of the bronchiolar walls; three patients had inflammatory infiltrate below the endothelium and partial loss and adherence of the endothelium in the medium- and small-caliber intrapulmonary blood vessels (Figure 1). These histologic changes are characteristics of influenza though not pathognomonic. In three patients, we observed pneumonia foci with intraalveolar exudates without evidence of bacterial colonies; however, nearly all the patients had received antibiotic treatment. In two patients, we observed erythrophagocytosis and phagocytosis of inflammatory cells in the liver, spleen, and bone marrow, which is similar to observations in lethal cases of infection with the avian influenza A (H5N1) virus² (Fig. 2 and 3 in the Supplementary Appendix). One patient had focal centrilobular necrosis of the liver and hemorrhagic necrosis of the adrenal gland cortex, and acute tubular necrosis was observed in another patient.

View larger version (105K): [in this window] [in a new window]   Figure 1. Micrographs of Lung Tissue from Five Patients with Fatal 2009 H1N1 Influenza. Panel A shows hyaline membranes (arrows). Panel B shows a thickened alveolar septum associated with predominant edema (arrows). Panel C shows hyperplasia of type II pneumocytes (arrows). Panel D shows an inflamed, necrotized bronchiole wall with partial loss of the coating epithelium (arrow). Panel E shows inflammatory infiltrate in the intima of the wall of a medium-caliber blood vessel, below and between the endothelial cells (endotheliitis) (arrow).

 
The cause of death in one patient was parenchymal cerebral hemorrhage. Histologic evaluation of the lungs showed only septal edema and extensive hemorrhage with scarce fibrin thrombi. The interstitial lesion was incipient, and hemorrhage was the predominant characteristic. These observations may represent an early stage of an acute pulmonary lesion that had not yet transitioned from the exudative phase to the proliferative phase.

M. Virgilia Soto-Abraham, M.D.
Juan Soriano-Rosas, M.D.
Hospital General de México
Mexico City, Mexico
virgiliasoto@yahoo.com

Alberto Díaz-Quiñónez, Ph.D.
Instituto de Diagnóstico y Referencia Epidemiológicos
Mexico City, Mexico

Juan Silva-Pereyra, Ph.D.
Universidad Nacional Autónoma de México
Mexico City, Mexico

Patricia Vazquez-Hernandez, M.D.
Oralia Torres-López, M.D.
Hospital General de México
Mexico City, Mexico

Alfonso Roldán, M.D.
Hospital Central Militar
Mexico City, Mexico

Ana Cruz-Gordillo, M.D.
Patricia Alonso-Viveros, M.D.
Francisco Navarro-Reynoso, M.D.
Hospital General de México
Mexico City, Mexico

References

1. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605-2615. [Erratum, N Engl J Med 2009;361:102.] [Free Full Text]
   
2. Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu Rev Pathol 2008;3:499-522. [CrossRef][Web of Science][Medline]
   
3. Korteweg C, Gu J. Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. Am J Pathol 2008;172:1155-1170. [Free Full Text]
   
4. Guarner J, Paddock CD, Shieh WJ, et al. Histopathologic and immunohistochemical features of fatal influenza virus infection in children during the 2003-2004 season. Clin Infect Dis 2006;43:132-140. [CrossRef][Web of Science][Medline]