今日の臨床サポート

貧血(新生児を含む)(小児科)

著者: 加藤格 京都大学医学部付属病院 小児科

監修: 五十嵐隆 国立成育医療研究センター

著者校正/監修レビュー済:2022/09/28
参考ガイドライン:
  1. 小児期ヘリコバクターピロリ感染症の診療と管理ガイドライン2018(改訂2版)
  1. 再生不良性貧血診療の参照ガイド 令和1年改訂版
  1. 自己免疫性溶血性貧血診療の参照ガイド 令和1年改訂版
  1. 輸血後鉄過剰症診療の参照ガイド 令和1年改訂版
  1. 2015 年版 日本透析医学会慢性腎臓病患者における腎性貧血治療のガイドライン
  1. 科学的根拠に基づいた小児輸血のガイドライン(平成30年 日本輸血・細胞治療学会)
  1. UpToDate:Approach to the child with anemia
患者向け説明資料

概要・推奨   

  1. 貧血とは血液中の赤血球成分、もしくはヘモグロビン濃度(Hb)が減少した病態を示し、年齢に応じたヘマトクリット(Hct)やHb基準値未満を貧血とする。日常診療で多く遭遇する小児の鉄欠乏性貧血は急激な発育による鉄需要が増大する離乳期と思春期が好発年齢であるが、小児における貧血の原因は多岐にわたるため発症年齢や性別、家族歴を含めて慎重に評価する必要がある(推奨度1)
  1. 小児においてもHelicobacter pylori菌感染は潰瘍性病変の有無にかかわらず鉄欠乏性貧血(IDA)の原因となり得る。臨床的に原因不明の難治性IDAに対しては、H. pylori菌感染の有無を確認し、保菌者に対して除菌治療を行うことがIDAの治療に有効である可能性が示唆された(推奨度2)
  1. 再生不良性貧血において移植ソースとして末梢血幹細胞を用いた場合、慢性移植片対宿主病(GVHD)のため、骨髄移植より生存率が低下する。若年者再生不良性貧血に対する移植ソースとしては、HLA一致同胞の骨髄が推奨される(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
加藤格 : 未申告[2022年]
監修:五十嵐隆 : 特に申告事項無し[2022年]

改訂のポイント:
  1. ガイドラインや参照ガイドの引用を追加しさらなる情報検索を容易にした
  1. 血液製剤の使用指針-新生児・小児に対する輸血療法の改訂に伴って「新生児・小児に対する赤血球液の適正使用」を改訂した

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 貧血のなかで最も頻度が高い鉄欠乏性貧血は思春期の男子の2~3%、女子の10~20%にみられる。
  1. 原因は多岐にわたるが、主な成因としては①赤血球の産生障害、②赤血球の分化障害、③赤血球喪失の亢進の3つに分類される。
  1. 各組織の需要に応じた酸素の供給を赤血球の基本的な生理機能とするならば、チアノーゼ型先天性心疾患や慢性呼吸不全などにおいても組織への酸素供給が低下しており、機能的には貧血と考えることができる。
  1. 再生不良性貧血、骨髄異形成症候群、白血病、悪性リンパ腫、固形腫瘍など骨髄造血障害を来す重症疾患を除外することが重要である。
  1. 小児は年齢によってヘモグロビンの正常値が異なるので、診断時の年齢を考慮する必要がある。
問診・診察のポイント  
  1. 一般的に、顔面蒼白、眼瞼結膜蒼白、爪床の蒼白化はヘモグロビン(Hb)8g/dl以下で認められるようになり、倦怠感、頻脈、動悸亢進、めまい、食欲不振などの症状はHb 5g/dl以下の高度な貧血で認められる。

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文献 

日本小児栄養消化器肝臓学会編:小児期ヘリコバクター・ピロリ感染症の診療と管理ガイドライン2018(改訂2版). CQ6.H,pylori感染が証明された小児の鉄欠乏性貧血に除菌療法は推奨されるか?.
Suja DuBois, David J Kearney
Iron-deficiency anemia and Helicobacter pylori infection: a review of the evidence.
Am J Gastroenterol. 2005 Feb;100(2):453-9. doi: 10.1111/j.1572-0241.2005.30252.x.
Abstract/Text
PMID 15667507
Huseyin Gulen, Erhun Kasirga, Sule Aslan Yildirim, Sebnem Kader, Gulseren Sahin, Semin Ayhan
Diagnostic yield of upper gastrointestinal endoscopy in the evaluation of iron deficiency anemia in older children and adolescents.
Pediatr Hematol Oncol. 2011 Nov;28(8):694-701. doi: 10.3109/08880018.2011.572145. Epub 2011 Jul 5.
Abstract/Text Iron deficiency anemia (IDA) is frequent in childhood. Inadequate nutrition and gastrointestinal malabsorption are the frequent causes of IDA in children. But reduced iron absorption and insidious blood loss from the gastrointestinal tract has been identified as the most frequent causes of IDA in older children and adolescents. Therefore the authors evaluated the frequency and etiologies of the upper gastrointestinal system pathologies causing IDA in older pediatric population. Patients with known hematological or chronic diseases, heavy menstrual flow, and obvious blood loss were excluded from the study. Forty-four children between the ages of 9.5 and 17.5 years and diagnosed with IDA were enrolled. They underwent upper gastrointestinal endoscopy and biopsy from esophagus, stomach, and duodenum. Mean age and hemoglobin (Hb) levels of study group (32 boys, and 12 girls) were 14.6 ± 2.0 years and 7.9 ± 1.8 g/dL, respectively. Only 1 patient had a positive serology testing with anti-tissue transglutaminase and small bowel biopsy correlating with celiac disease. Endoscopy revealed abnormal findings in 25 (56.8%) patients (21 endoscopic antral gastritis, 2 active duodenal ulcers, and 2 duodenal polyps). Helicobacter pylori (HP) infection was identified by using antral histopathological evaluation in 19 of 44 children (43.2%). In 2 of duodenal samples, one patient had celiac disease, and the other one was diagnosed as giardiasis. In conclusion, there are different etiologies resulting in IDA in older children and adolescents. When older children and adolescents are found to have iron deficiency, HP infection and other gastrointestinal pathologies should be ruled out before iron deficiency treatment.

PMID 21728721
Nicola L Jones, Sibylle Koletzko, Karen Goodman, Patrick Bontems, Samy Cadranel, Thomas Casswall, Steve Czinn, Benjamin D Gold, Jeannette Guarner, Yoram Elitsur, Matjaž Homan, Nicolas Kalach, Michal Kori, Armando Madrazo, Francis Megraud, Alexandra Papadopoulou, Marion Rowland, ESPGHAN, NASPGHAN
Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016).
J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):991-1003. doi: 10.1097/MPG.0000000000001594.
Abstract/Text BACKGROUND: Because of the changing epidemiology of Helicobacter pylori infection and low efficacy of currently recommended therapies, an update of the European Society for Paediatric Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations for the diagnosis and management of H pylori infection in children and adolescents is required.
METHODS: A systematic review of the literature (time period: 2009-2014) was performed. Representatives of both societies evaluated the quality of evidence using GRADE (Grading of Recommendation Assessment, Development, and Evaluation) to formulate recommendations, which were voted upon and finalized using a Delphi process and face-to-face meeting.
RESULTS: The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasizing strict adherence. Clarithromycin-containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high-dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth-based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests.
CONCLUSIONS: The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first-line therapies and broader availability of culture or molecular-based testing to tailor treatment to the individual child.

PMID 28541262
Wilma Barcellini, Francesco Zaja, Anna Zaninoni, Francesca Guia Imperiali, Marta Lisa Battista, Eros Di Bona, Bruno Fattizzo, Dario Consonni, Agostino Cortelezzi, Renato Fanin, Alberto Zanella
Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies.
Blood. 2012 Apr 19;119(16):3691-7. doi: 10.1182/blood-2011-06-363556. Epub 2012 Jan 20.
Abstract/Text This prospective study investigated the efficacy, safety, and response duration of low-dose rituximab (100 mg fixed dose for 4 weekly infusions) together with a short course of steroids as first- or second-line therapy in 23 patients with primary autoimmune hemolytic anemia (AIHA). The overall response was 82.6% at month +2, and subsequently stabilized to ∼ 90% at months +6 and +12; the response was better in warm autoimmune hemolytic anemia (WAIHA; overall response, 100% at all time points) than in cold hemagglutinin disease (CHD; average, 60%); the relapse-free survival was 100% for WAIHA at +6 and +12 months versus 89% and 59% in CHD, respectively, and the estimated relapse-free survival at 2 years was 81% and 40% for the warm and cold forms, respectively. The risk of relapse was higher in CHD and in patients with a longer interval between diagnosis and enrollment. Steroid administration was reduced both as cumulative dose (∼ 50%) and duration compared with the patient's past history. Treatment was well tolerated and no adverse events or infections were recorded; retreatment was also effective. The clinical response was correlated with amelioration biologic markers such as cytokine production (IFN-γ, IL-12, TNF-α, and IL-17), suggesting that low-dose rituximab exerts an immunomodulating activity. This study is registered at www.clinicaltrials.gov as NCT01345708.

PMID 22267606
P H B Bolton-Maggs, R F Stevens, N J Dodd, G Lamont, P Tittensor, M-J King, General Haematology Task Force of the British Committee for Standards in Haematology
Guidelines for the diagnosis and management of hereditary spherocytosis.
Br J Haematol. 2004 Aug;126(4):455-74. doi: 10.1111/j.1365-2141.2004.05052.x.
Abstract/Text Hereditary spherocytosis (HS) is a heterogeneous group of disorders with regard to clinical severity, protein defects and mode of inheritance. It is relatively common in Caucasian populations; most affected individuals have mild or only moderate haemolysis. There is usually a family history, and a typical clinical and laboratory picture so that the diagnosis is often easily made without additional laboratory tests. Atypical cases may require measurement of erythrocyte membrane proteins to clarify the nature of the membrane disorder and in the absence of a family history, occasionally molecular genetic analysis will help to determine whether inheritance is recessive or non-dominant. It is particularly important to rule out stomatocytosis where splenectomy is contraindicated because of the thrombotic risk. Mild HS can be managed without folate supplements and does not require splenectomy. Moderately and severely affected individuals are likely to benefit from splenectomy, which should be performed after the age of 6 years and with appropriate counselling about the infection risk. In all cases careful dialogue between doctor, patient and the family is essential. Laparoscopic surgery, when performed by experienced surgeons, can result in a shorter hospital stay and less pain.

PMID 15287938
Hubert Schrezenmeier, Jakob R Passweg, Judith C W Marsh, Andrea Bacigalupo, Christopher N Bredeson, Eduardo Bullorsky, Bruce M Camitta, Richard E Champlin, Robert Peter Gale, Monika Fuhrer, John P Klein, Anna Locasciulli, Rosi Oneto, Antonius V M B Schattenberg, Gerard Socie, Mary Eapen
Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia.
Blood. 2007 Aug 15;110(4):1397-400. doi: 10.1182/blood-2007-03-081596. Epub 2007 May 2.
Abstract/Text We analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic graft-versus-host disease (GVHD) were similar after PBPC and BM transplantations regardless of age at transplantation. In patients older than 20 years, chronic GVHD and overall mortality rates were similar after PBPC and BM transplantations. In patients younger than 20 years, rates of chronic GVHD (relative risk [RR] 2.82; P = .002) and overall mortality (RR 2.04; P = .024) were higher after transplantation of PBPCs than after transplantation of BM. In younger patients, the 5-year probabilities of overall survival were 73% and 85% after PBPC and BM transplantations, respectively. Corresponding probabilities for older patients were 52% and 64%. These data indicate that BM grafts are preferred to PBPC grafts in young patients undergoing HLA-matched sibling donor transplantation for SAA.

PMID 17475907
Antonio Piga, Renzo Galanello, Gian Luca Forni, Maria Domenica Cappellini, Raffaella Origa, Antonietta Zappu, Guido Donato, Elena Bordone, Antonella Lavagetto, Laura Zanaboni, Romain Sechaud, Nicola Hewson, John M Ford, Herbert Opitz, Daniele Alberti
Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload.
Haematologica. 2006 Jul;91(7):873-80.
Abstract/Text BACKGROUND AND OBJECTIVES: Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferoxamine (Desferal, DFO) reduces morbidity and mortality although the administration schedule of slow, parenteral infusions several days each week limits compliance and negatively affects long-term outcome. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. In a phase II study, the tolerability and efficacy of deferasirox were compared with those of DFO in 71 adults with transfusional hemosiderosis.
DESIGN AND METHODS: Patients were randomized to receive once-daily deferasirox (10 or 20 mg/kg; n=24 in both groups) or DFO (40 mg/kg, 5 days/week; n=23) for 48 weeks. Results. Both treatments were well tolerated and no patient discontinued deferasirox due to drug-related adverse events. The reported frequency of transient, mild to moderate gastrointestinal disturbances was higher in the deferasirox group than in the DFO group, but these disturbances settled spontaneously without dose interruption in all patients. Decreases in liver iron concentration (LIC) were comparable in the deferasirox 20 mg/kg/day and DFO groups; baseline values of 8.5 and 7.9 mg Fe/g dw fell to 6.6 and 5.9 mg Fe/g dw, respectively, by week 48. Deferasirox showed a plasma elimination half-life of 8-16 hours, supporting its once-daily administration.
INTERPRETATION AND CONCLUSIONS: Deferasirox at daily doses of 10 or 20 mg/kg was well tolerated and, at 20 mg/kg, showed similar efficacy to DFO 40 mg/kg in terms of decreases in LIC.

PMID 16818273
G Lucarelli, M Galimberti, P Polchi, E Angelucci, D Baronciani, C Giardini, P Politi, S M Durazzi, P Muretto, F Albertini
Bone marrow transplantation in patients with thalassemia.
N Engl J Med. 1990 Feb 15;322(7):417-21. doi: 10.1056/NEJM199002153220701.
Abstract/Text We reviewed the results of transplantation of allogeneic marrow from HLA-identical donors in patients with beta-thalassemia who were less than 16 years old. Among the 222 consecutive patients who had received transplants since 1983, survival and event-free-survival curves leveled off about one year after transplantation, at 82 and 75 percent, respectively. Pretransplantation clinical characteristics were examined for their impact on survival, event-free survival, and the recurrence of thalassemia in the 116 consecutive patients who were treated with our current regimen, in use since June 1985. In a multivariate analysis, portal fibrosis and either the presence of hepatomegaly or a history of inadequate chelation therapy were significantly associated with reduced probabilities of survival and event-free survival. The patients were divided into three classes on the basis of the presence of hepatomegaly or portal fibrosis (class 1 had neither factor, class 2 had one, and class 3 had both). For class 1 patients the three-year probabilities of survival, event-free survival, and recurrence were 94, 94, and 0 percent, respectively. For class 2 patients the probabilities were 80, 77, and 9 percent, and for class 3 patients 61, 53, and 16 percent. We conclude that for patients under 16 years of age, transplantation of bone marrow from an HLA-identical donor offers a high probability of complication-free survival, particularly if they do not have hepatomegaly or portal fibrosis.

PMID 2300104
日本透析医学会編:2015年版 慢性腎臓病患者における腎性貧血治療のガイドライン. CQ8:小児患者における腎性貧血治療の維持すべき目標 Hb 値と開始基準は何か?.
厚生労働省医薬・生活衛生局編:血液製剤の使用指針 Ⅶ 新生児・小児に対する輸血療法.

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