当前位置: X-MOL 学术Am. J. Transplant. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Acute hepatitis and adenovirus infection among children—Alabama, October 2021–February 2022
American Journal of Transplantation ( IF 8.8 ) Pub Date : 2022-07-05 , DOI: 10.1111/ajt.16665
Julia M Baker 1, 2 , Markus Buchfellner 3 , William Britt 3 , Veronica Sanchez 3 , Jennifer L Potter 3 , L Amanda Ingram 4 , Henry Shiau 5, 6 , Luz Helena Gutierrez Sanchez 5, 6 , Stephanie Saaybi 5 , David Kelly 6, 7 , Xiaoyan Lu 1 , Everardo M Vega 1 , Stephanie Ayers-Millsap 8 , Wesley G Willeford 8 , Negar Rassaei 9 , Hannah Bullock 9, 10 , Sarah Reagan-Steiner 9 , Ali Martin 4 , Elizabeth A Moulton 11, 12 , Daryl M Lamson 13 , Kirsten St George 13, 14 , Umesh D Parashar 1 , Aron J Hall 1 , Adam MacNeil 1 , Jacqueline E Tate 1 , Hannah L Kirking 1
Affiliation  

During October–November 2021, clinicians at a children's hospital in Alabama identified five pediatric patients with severe hepatitis and adenovirus viremia upon admission. In November 2021, hospital clinicians, the Alabama Department of Public Health, the Jefferson County Department of Health, and CDC began an investigation. This activity was reviewed by CDC and conducted consistent with applicable federal law and CDC policy.1

Clinical records from the hospital were reviewed to identify patients seen on or after October 1, 2021, with hepatitis and an adenovirus infection, detected via real-time polymerase chain reaction (PCR) testing on whole blood specimens, and no other known cause for hepatitis. An additional four children were identified, for a total of nine patients with hepatitis of unknown etiology and concomitant adenovirus infection during October 2021–February 2022. On February 1, 2022, a statewide health advisory2 was disseminated to aid in the identification of cases at other facilities in Alabama; no additional patients were identified.

All nine children were patients at Children's of Alabama. These patients were from geographically distinct parts of the state; no epidemiologic links among patients were identified. The median age at admission was 2 years, 11 months (IQR = 1 year, 8 months to 5 years, 9 months) and seven patients were female (Table 1). All patients were immunocompetent with no clinically significant medical comorbidities.

TABLE 1. Demographics, clinical characteristics, laboratory testing results, and clinical outcomes in a cluster of pediatric patients with acute hepatitis and adenovirus infection (N = 9)—Alabama, October 2021–February 2022
Demographic No.
Age at admission, years
0–2 5
3–4 1
5–6 3
Sex
Female 7
Male 2
Race
White 9
Other 0
Ethnicity
Hispanic 6
Non-Hispanic 3
Initial sign/symptom
Vomiting 7
Diarrhea 6
Fever 5
Upper respiratory symptomsa a Upper respiratory symptoms were identified when taking the patient's history and conducting an initial physical exam. Upper respiratory symptoms can include nasal congestion, nasal discharge, cough, sore throat, wheezing, and dyspnea, among other symptoms.
3
Initial physical exam
Scleral icterus 8
Hepatomegaly 7
Jaundice 6
Hepatic encephalopathy 1
Splenomegaly 1
Ascites 0
Liver function testing on admission, median (range)b b Normal ranges are ALT = 9–25 U/L; AST = 21–44 U/L; total bilirubin = 0.1–1.0 mg/dL.
ALT (U/L) 1724 (603–4696)
AST (U/L) 1963 (447–4000)
Total bilirubin (mg/dL) 7 (0.23–13.5)
Pathogen testing performed
Blood viral PCR 9
Hepatitis A/B/C 9
Epstein–Barr Virus, blood viral PCR 9
Epstein–Barr Virus, IgM 8
Respiratory panel testingc c The respiratory viral panels (ePlex Respiratory Pathogen Panel [GenMark] or BioFire Respiratory Panel [Biomérieux]) were used to test for adenovirus, coronavirus 229E, coronavirus HKU1, coronavirus NL63, coronavirus OC43, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A/H1, influenza A/H1–2009, influenza A/H3, influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, respiratory syncytial virus A, respiratory syncytial virus B, Chlamydia pneumoniae, Mycoplasma pneumoniae, Bordetella parapertussis (BioFire only), and Bordetella pertussis (BioFire only).
8
Blood culture 4
Urine culture 4
Stool culture 1
Pathogen testing result, no. positive/total no.
Adenovirus (whole blood) 9/9
EBVd d Positive EBV test results were based on PCR testing, but all patients received negative test results for EBV IgM antibodies (except one patient who did not have IgM testing) suggesting that infections were likely not acute but rather potential low-level reactivation of previous infections.
6/9
Enterovirus/Rhinovirus 4/8
Metapneumovirus 1/8
Respiratory syncytial virus 1/8
Human coronavirus OC43 1/8
SARS-CoV-2e e All patients received testing for SARS-CoV-2 using nucleic acid amplification tests.
0/9
Hepatitis A/B/C 0/9
Outcome
Recovered without transplant 7
Required transplant and recovered 2
Died 0
  • Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; EBV, Epstein-Barr virus; IgM, immunoglobulin M; PCR, polymerase chain reaction.
  • a Upper respiratory symptoms were identified when taking the patient's history and conducting an initial physical exam. Upper respiratory symptoms can include nasal congestion, nasal discharge, cough, sore throat, wheezing, and dyspnea, among other symptoms.
  • b Normal ranges are ALT = 9–25 U/L; AST = 21–44 U/L; total bilirubin = 0.1–1.0 mg/dL.
  • c The respiratory viral panels (ePlex Respiratory Pathogen Panel [GenMark] or BioFire Respiratory Panel [Biomérieux]) were used to test for adenovirus, coronavirus 229E, coronavirus HKU1, coronavirus NL63, coronavirus OC43, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A/H1, influenza A/H1–2009, influenza A/H3, influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, respiratory syncytial virus A, respiratory syncytial virus B, Chlamydia pneumoniae, Mycoplasma pneumoniae, Bordetella parapertussis (BioFire only), and Bordetella pertussis (BioFire only).
  • d Positive EBV test results were based on PCR testing, but all patients received negative test results for EBV IgM antibodies (except one patient who did not have IgM testing) suggesting that infections were likely not acute but rather potential low-level reactivation of previous infections.
  • e All patients received testing for SARS-CoV-2 using nucleic acid amplification tests.

Before admission, among the nine patients, vomiting, diarrhea, and upper respiratory symptoms were reported by seven, six, and three patients, respectively. At admission, eight patients had scleral icterus, seven had hepatomegaly, six had jaundice, and one had encephalopathy (Table 1). Elevated transaminases were detected among all patients3 (alanine aminotransferase [ALT] range = 603–4696 U/L; aspartate aminotransferase [AST] range = 447–4000 U/L); total bilirubin ranged from normal to elevated (range = 0.23–13.5 mg/dL, elevated in eight patients). All patients received negative test results for hepatitis viruses A, B, and C, and several other causes of pediatric hepatitis and infections were ruled out including autoimmune hepatitis, Wilson disease, bacteremia, urinary tract infections, and SARS-CoV-2 infection. None of the children had documented history of previous SARS-CoV-2 infection.

Adenovirus was detected in whole blood specimens from all patients by real-time PCR testing (initial viral load range = 991–70 680 copies/mL). Hexon gene hypervariable region sequencing was performed on specimens from five patients, and adenovirus type 41 was detected in all five specimens. Low viral loads precluded sequencing among three patients, and residual specimens were not available for sequencing for one patient. Seven patients were coinfected with other viral pathogens (Table 1). Six received positive test results for Epstein–Barr virus (EBV) by PCR testing but negative test results for EBV immunoglobulin M (IgM) antibodies (one patient did not have IgM testing), suggesting that these were likely not acute infections but rather low-level reactivation of previous infections. Other detected viruses included enterovirus/rhinovirus, metapneumovirus, respiratory syncytial virus, and human coronavirus OC43.

Liver biopsies from six patients demonstrated various degrees of hepatitis with no viral inclusions observed, no immunohistochemical evidence of adenovirus, or no viral particles identified by electron microscopy. Three patients developed acute liver failure, two of whom were treated with cidofovir (off-label use) and steroids, and were transferred to a different medical facility where they underwent liver transplantation. Plasma specimens from these two patients were negative for adenovirus by real-time PCR testing upon arrival at the receiving medical facility, but both patients received positive test results when retested by the same real-time PCR test using a whole blood specimen. All patients have recovered or are recovering, including the two transplant recipients.

Adenovirus type 41 is primarily spread via the fecal-oral route and predominantly affects the gut. It is a common cause of pediatric acute gastroenteritis typically with diarrhea, vomiting and fever, often accompanied by respiratory symptoms (1). Adenovirus is recognized as a cause of hepatitis among immunocompromised children (2). It might be an underrecognized contributor to liver injury among healthy children (3); however, the magnitude of this relationship remains under investigation.

This cluster, along with recently identified possible cases in Europe (4-6), suggests that adenovirus should be considered in the differential diagnosis of acute hepatitis of unknown etiology among children. Clinicians and laboratorians should be aware of possible differences in adenovirus test sensitivity for different specimen types; tests using whole blood might be more sensitive than those using plasma. CDC is monitoring the situation closely to understand the possible cause of illness and identify potential efforts to prevent or mitigate illness. Enhanced surveillance is underway in coordination with jurisdictional public health partners. Clinicians are encouraged to report possible cases of pediatric hepatitis with unknown etiology occurring on or after October 1, 2021, to public health authorities for further investigation.4



中文翻译:

儿童急性肝炎和腺病毒感染——阿拉巴马州,2021 年 10 月至 2022 年 2 月

2021 年 10 月至 11 月期间,阿拉巴马州一家儿童医院的临床医生在入院时发现了 5 名患有严重肝炎和腺病毒血症的儿科患者。2021 年 11 月,医院临床医生、阿拉巴马州公共卫生部、杰斐逊县卫生部和 CDC 开始了调查。此活动已由 CDC 审查并按照适用的联邦法律和 CDC 政策进行。1个

审查了医院的临床记录,以确定 2021 年 10 月 1 日或之后就诊的患者,他们患有肝炎和腺病毒感染,通过对全血样本进行实时聚合酶链反应 (PCR) 检测,并且没有其他已知的肝炎原因. 在 2021 年 10 月至 2022 年 2 月期间,又确定了 4 名儿童,总共 9 名患有不明原因肝炎并伴有腺病毒感染的患者。2022 年 2 月 1 日,在全州范围内发布了健康咨询2以帮助确定病例阿拉巴马州的其他设施;没有发现其他患者。

这九名儿童都是阿拉巴马州儿童医院的患者。这些患者来自该州地理上不同的地区;未发现患者之间存在流行病学联系。入院时的中位年龄为 2 岁 11 个月(IQR = 1 岁 8 个月至 5 岁 9 个月),7 名患者为女性(表 1)。所有患者均具有免疫功能,没有临床上显着的医学合并症。

表 1.一群患有急性肝炎和腺病毒感染的儿科患者(N  = 9)的人口统计学、临床特征、实验室检测结果和临床结果——阿拉巴马州,2021 年 10 月至 2022 年 2 月
人口统计 不。
入院年龄,岁
0–2 5个
3–4 1个
5–6 3个
性别
女性 7
男性 2个
种族
白色的 9
其他 0
种族
西班牙裔 6个
非西班牙裔 3个
初始体征/症状
呕吐 7
腹泻 6个
发热 5个
上呼吸道症状 a 在询问患者病史和进行初步体检时发现了上呼吸道症状。上呼吸道症状包括鼻塞、流鼻涕、咳嗽、喉咙痛、喘息和呼吸困难等症状。
3个
初步体检
巩膜黄染 8个
肝肿大 7
黄疸 6个
肝性脑病 1个
脾肿大 1个
腹水 0
入院时肝功能检测,中位数(范围)b b 正常范围是 ALT = 9–25 U/L;AST = 21–44 U/L;总胆红素 = 0.1–1.0 mg/dL。
ALT(上/下) 1724 (603–4696)
AST (U/L) 1963 (447–4000)
总胆红素 (mg/dL) 7 (0.23–13.5)
进行病原体检测
血液病毒PCR 9
甲型/乙型/丙型肝炎 9
Epstein-Barr 病毒,血液病毒 PCR 9
爱泼斯坦-巴尔病毒,IgM 8个
呼吸面板测试c c 呼吸道病毒组(ePlex 呼吸病原体组 [GenMark] 或 BioFire 呼吸组 [Biomérieux])用于检测腺病毒、冠状病毒 229E、冠状病毒 HKU1、冠状病毒 NL63、冠状病毒 OC43、人偏肺病毒、人鼻病毒/肠道病毒、甲型流感病毒, 流感 A/H1, 流感 A/H1–2009, 流感 A/H3, 流感 B, 副流感 1, 副流感 2, 副流感 3, 副流感 4, 呼吸道合胞病毒 A, 呼吸道合胞病毒 B, 肺炎衣原体, 肺炎支原体, 博德特氏菌parapertussis  (仅限 BioFire)和 Bordetella pertussis  (仅限 BioFire)。
8个
血培养 4个
尿培养 4个
大便培养 1个
病原体检测结果,没有。阳性/总数
腺病毒(全血) 9/9
EB病毒d d 阳性 EBV 检测结果基于 PCR 检测,但所有患者的 EBV IgM 抗体检测结果均为阴性(一名未进行 IgM 检测的患者除外)表明感染可能不是急性感染,而是先前感染的潜在低水平再激活.
6/9
肠道病毒/鼻病毒 4/8
偏肺病毒 1/8
呼吸多核体病毒 1/8
人类冠状病毒 OC43 1/8
SARS-CoV-2病毒 e 所有患者都接受了使用核酸扩增试验进行的 SARS-CoV-2 检测。
0/9
甲型/乙型/丙型肝炎 0/9
结果
无需移植即可恢复 7
需要移植并康复 2个
死了 0
  • 缩写:ALT,谷丙转氨酶;AST,天冬氨酸转氨酶;EBV,Epstein-Barr 病毒;IgM,免疫球蛋白M;PCR,聚合酶链反应。
  • a 在询问患者病史和进行初步体检时发现了上呼吸道症状。上呼吸道症状包括鼻塞、流鼻涕、咳嗽、喉咙痛、喘息和呼吸困难等症状。
  • b 正常范围是 ALT = 9–25 U/L;AST = 21–44 U/L;总胆红素 = 0.1–1.0 mg/dL。
  • c 呼吸道病毒组(ePlex 呼吸病原体组 [GenMark] 或 BioFire 呼吸组 [Biomérieux])用于检测腺病毒、冠状病毒 229E、冠状病毒 HKU1、冠状病毒 NL63、冠状病毒 OC43、人偏肺病毒、人鼻病毒/肠道病毒、甲型流感病毒, 流感 A/H1, 流感 A/H1–2009, 流感 A/H3, 流感 B, 副流感 1, 副流感 2, 副流感 3, 副流感 4, 呼吸道合胞病毒 A, 呼吸道合胞病毒 B, 肺炎衣原体, 肺炎支原体, 博德特氏菌parapertussis  (仅限 BioFire)和 Bordetella pertussis  (仅限 BioFire)。
  • d 阳性 EBV 检测结果基于 PCR 检测,但所有患者的 EBV IgM 抗体检测结果均为阴性(一名未进行 IgM 检测的患者除外)表明感染可能不是急性感染,而是先前感染的潜在低水平再激活.
  • e 所有患者都接受了使用核酸扩增试验进行的 SARS-CoV-2 检测。

入院前,9名患者中分别有7名、6名和3名患者出现呕吐、腹泻和上呼吸道症状。入院时,8 名患者出现巩膜黄染,7 名患者出现肝肿大,6 名患者出现黄疸,1 名患者出现脑病(表 1)。所有患者均检测到转氨酶升高3(丙氨酸转氨酶 [ALT] 范围 = 603–4696 U/L;天冬氨酸转氨酶 [AST] 范围 = 447–4000 U/L);总胆红素范围从正常到升高(范围 = 0.23–13.5 mg/dL,八名患者升高)。所有患者的甲型、乙型和丙型肝炎病毒检测结果均为阴性,并排除了儿童肝炎和感染的其他几种原因,包括自身免疫性肝炎、威尔逊病、菌血症、尿路感染和 SARS-CoV-2 感染。这些孩子都没有记录以前的 SARS-CoV-2 感染史。

通过实时 PCR 检测(初始病毒载量范围 = 991–70 680 拷贝/mL)在所有患者的全血标本中检测到腺病毒。对5例患者标本进行Hexon基因高变区测序,5例标本均检测出41型腺病毒。低病毒载量阻碍了三名患者的测序,一名患者的残留标本无法用于测序。七名患者同时感染了其他病毒病原体(表 1)。六名患者通过 PCR 检测获得 EB 病毒 (EBV) 阳性检测结果,但 EBV 免疫球蛋白 M (IgM) 抗体检测结果呈阴性(一名患者未进行 IgM 检测),表明这些可能不是急性感染,而是低-以前感染的水平重新激活。其他检测到的病毒包括肠道病毒/鼻病毒、

六名患者的肝活检显示不同程度的肝炎,未观察到病毒包涵体,未发现腺病毒的免疫组织化学证据,或未通过电子显微镜识别病毒颗粒。三名患者出现急性肝功能衰竭,其中两人接受了西多福韦(标签外使用)和类固醇治疗,并被转移到不同的医疗机构,在那里他们接受了肝移植。这两名患者的血浆标本在到达接收医疗机构时通过实时 PCR 检测呈腺病毒阴性,但在使用全血标本通过相同的实时 PCR 检测重新检测时,两名患者均获得阳性检测结果。所有患者都已经康复或正在康复,包括两名移植受者。

41 型腺病毒主要通过粪口途径传播,主要影响肠道。它是小儿急性胃肠炎的常见原因,通常伴有腹泻、呕吐和发烧,通常伴有呼吸道症状 ( 1 )。腺病毒被认为是免疫功能低下儿童中肝炎的病因 ( 2 )。它可能是健康儿童肝损伤的一个未被充分认识的因素 ( 3 );然而,这种关系的严重程度仍在调查中。

该集群以及最近在欧洲发现的可能病例 ( 4-6),建议在小儿不明原因急性肝炎的鉴别诊断中应考虑腺病毒。临床医生和实验室人员应了解不同标本类型的腺病毒检测敏感性可能存在差异;使用全血的测试可能比使用血浆的测试更敏感。CDC 正在密切监测情况,以了解疾病的可能原因,并确定预防或减轻疾病的潜在努力。正在与辖区公共卫生合作伙伴协调加强监测。鼓励临床医生向公共卫生当局报告 2021 年 10 月 1 日或之后可能发生的病因不明的小儿肝炎病例,以供进一步调查。4个

更新日期:2022-07-05
down
wechat
bug