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Home , Fanconi anemia

. Classification and diagnosis

B. Rosich del Cacho*, Y. Mozo del Castillo** *Consultant physician, Pediatrics Service, Hospital Universitario Joan XXIII, Tarragona. **Consultant physician, Pediatric Hemato-Oncology and Hematopoietic Transplantation Service, Hospital Universitario La Paz, Madrid

Abstract Resumen Anemia is defined as a reduction in hemoglobin La anemia se define como una reducción de la concentration below normal levels for age, gender concentración de la hemoglobina por debajo de los and ethnicity. It is the result of an imbalance niveles considerados normales para la edad, sexo y raza. between the production and destruction of red Es el resultado de un desequilibrio entre la producción y blood cells, which characterizes or accompanies la destrucción de hematíes, que caracteriza o acompaña a various conditions. It is the most common diferentes patologías. Se trata del problema hematológico hematological abnormality in childhood, the más frecuente en la infancia, cuya causa principal es la main cause of which is iron deficiency. Clinical ferropenia. Con frecuencia, las manifestaciones clínicas manifestations are often nonspecific. Diagnosis son inespecíficas. El diagnóstico comienza con: un begins with a full blood count, peripheral blood hemograma, el frotis de sangre periférica y los parámetros smear and biochemical parameters of hemolysis bioquímicos de hemólisis y del metabolismo del hierro. and iron metabolism. The overall diagnostic Se revisa la aproximación diagnóstica general del niño approach of the child with anemia is here con anemia, proponiendo un enfoque basado en un reviewed, and an algorithm is proposed based on algoritmo a partir de los datos hematológicos básicos. basic hematological data. Finally, a brief list of Finalmente, se aporta un breve listado de referencias references is provided. bibliográficas básicas.

Key words: Anemia; Child; Infant; Classification; Diagnosis. Palabras clave: Anemia; Niño; Lactante; Clasificación; Diagnóstico.

Introduction or hematocrit in peripheral blood below the following Hb thresholds according Anemia is defined as a reduction in the 2 standard deviations (-2 SD) for the to age group: concentration of hemoglobin or hematocrit, age, sex and ethnicity of the patient • 11 g/dl in children 0.5-4.99 years-old the normal levels of which depend on age, (Table I). (preschool age). sex, and ethnicity. Iron deficiency anemia • Hemoglobin (Hb): complex protein • 11.5 g/dl between 5-11.99 years of age. is the most prevalent hematologic disorder made up of heme groups containing • 12 g/dl between ages 12-14.99 years. of childhood. iron and a protein portion, globin. The concentration of this erythro- The global prevalence of anemia n this article, the general concepts cyte pigment is presented in grams was 47.4% ([95% CI] 45.7-49.1) in of anemia in childhood and its diag- (g) per 100 ml (dl) of whole blood. preschool-age children and 25.4% ([95% I nostic approach are reviewed. Iron • Hematocrit (Hct): fraction of the CI] 19.9-30.9) in school-age children. deficiency anemia (the most common volume of erythrocyte mass with The prevalence in preschool children cause of anemia in the pediatric age) respect to total blood volume. It is varied widely by country, led by coun- and are specifically expressed as a percentage (%). tries in South America and Africa. This discussed in other articles. Epidemiology(2-4,7) is because iron deficiency accounts for Definition(1,2) 50% of this prevalence and it is closely Anemia is the most common hema- linked to nutritional deficiencies, the- The word anemia is of Greek origin, tological disorder in childhood. In refore, to the social and development meaning “without blood.” It is defined 2008, the World Health Organization conditions in these countries. as the reduction in the concentration (WHO) published the results of a sur- In addition to acknowledging iron of hemoglobin (Hb), erythrocyte mass vey of 192 member states, establishing deficiency as the most common cause of

214 en - PEDIATRÍA INTEGRAL Pediatr Integral 2021; XXV (5): 214 – 221 Anemia. Classification and diagnosis

Table I. Normal values of the red series according to age and gender casians or Asians. HbS and HbC are (various sources) more common in black and Hispanic populations. Furthermore, within Age Hb (g/dl) Hct (%) MCV (fl) the same country there are areas with 1-3 days 19,5 58 98-118 a higher prevalence of hemoglobino- (14.5-235) (45-72) pathies, endocellular parasites, such 7 days 17,5 55 88-126 as malaria and infestation with intes- (14-22) (43-67) tinal parasites that impact on the 14 days 16,5 50 86-119 prevalence of anemia. Thus, thalas- (13-20) (42-66) semic syndromes are more prevalent 1 month 14 43 85-123 on the Mediterranean coast, a large (10-18) (31-51) part of Africa, the Middle East, the 2 months 11,5 35 77-118 Indian subcontinent, and Southeast (9-14) (28-42) Asia; conversely, G6PDH deficiency 3-12 months 11,5 35 74-108 is observed, predominantly, in mala- (9.5-13-5) (29-41) ria endemic areas, since it seems to 12-24 months 12,5 37 71-89 be a protective factor against this (11-14) (32-42) (a higher prevalence is 2-3 years 12,6 37 74-89 found among: Kurdish Jews, Sardi- (11-14.2) (33-41) nian, Nigerian, African-American, 4-6 years 12,9 38 77-91 Filipino and Greeks). (11.7-14,1) (34-42) • Height above sea level: the higher above the sea level, the higher the 7-10 years 13,5 40 78-91 (12-15) (35-45) Hb count, since lower oxygen con- tent in the air results in a stimulus 11-14 years Female 13,7 40 80-94 (12.3-15,1) (36-44) for hematopoiesis. 14,3 46 80-94 Pathophysiology(2,5) Male (12.6-16) (40-52)

15-18 years Female 13,7 40 81-96 Anemia is the result of the imbalance (11.5-15,9) (34-46) between production and loss of red blood 15,4 46 81-96 cells. The redistribution of blood, the sti- Male (13.7-17.1) (40-52) mulation of erythropoiesis and the decrease in the affinity of Hb for O2 are compensa- tory mechanisms. anemia in pediatric age worldwide, we - 3-6 months: iron deficiency is must take into account the factors and rare during this period, and he- Erythropoiesis mainly takes place causes of this disorder that influence its moglobinopathies must be ruled in the during postnatal prevalence: out. and adult life (in the fetal period and • Age: Hb and Hct counts vary - 6 months-adolescence: there are up to 6 months of extrauterine life, the throughout childhood (Table I), differences in Hb counts accor- endodermal sinus also participates, as well as the causes of anemia ding to age and sex (Table I). where it begins at 3-4 weeks of gesta- differ according to the age of the During this entire stage, the main tion, and later on in the liver). Various patients: cause of anemia is iron deficiency. regulatory factors (being blood oxygen - Birth-3 months: Hb achieves • Sex: starting at puberty, testoste- saturation the main one) act on the peri- maximum concentrations (16.5- rone secretion induces an increase tubular cells of the kidneys involved in 18.5 g/dl) in the newborn and in erythrocyte mass, which is why the synthesis of erythropoietin (EPO), drops to 9-10 g/dl between 6-9 the normal level of Hb is higher in a hormone that acts on the hemato- weeks of life, as a consequence of men than in women. On the other poietic precursors of the bone marrow, increased oxygenation of tissues hand, some hereditary which finally give rise to mature red and a drastic decrease in erythro- are X-linked, and hence, being blood cells. During this complex pro- poiesis; in what is referred to as more frequent in men (eg, glu- cess of differentiation and maturation “physiological anemia of infancy”. cose-6-phosphate dehydrogenase leading to the production of the mature Any anemia in this age group that (G6PDH) deficiency and sidero- erythrocyte, the participation of diffe- differs from the characteristics of blastic anemia). rent molecules, growth factors (G and physiological anemia (Hb <9 g/dl, • Race and ethnicity: normal Hb GM-CSF), trace elements (such as iron, anemia prior to 1 month of age, levels are observed with approxima- essential for the elaboration of the heme or signs of hemolysis) will require tely 0.5 g/dl less in black children group of Hb, copper and zinc) and cyto- further study. compared to those observed in Cau- kines (IL 1, 3, 4, 6, 9 and 11).

PEDIATRÍA INTEGRAL - en 215 Anemia. Classification and diagnosis

Medical history Mature erythrocytes are shaped determined by: adaptation mechanisms, like a biconcave disc, they are filled age of onset, underlying disease and An adequate medical history is the with Hb in the inside and are devoid type of onset (acute or chronic): starting point for the etiological diag- of mitochondria or other organelles. Hb • Pale skin and mucous membranes: nosis of anemia. In addition to noti- is composed of 4 globin subunits and direct consequence of the decrease cing the age, gender, ethnicity and heme groups, and it is involved in the in Hb and the accompanying peri- geographical origin of the patient, the exchange of oxygen and carbon dioxide pheral vasoconstriction. Sometimes following should be investigated: throughout the body. may not be evident until the • Symptoms (see previous section): After erythrocytes have been in cir- Hb level falls below 8 g/dl and can beginning and speed of onset, tole- culation for a long period (half-life 120 be difficult to identify depending on rance, history of (digestive, days), they are taken up and destroyed the pigmentation of the skin. menstrual, etc.), symptoms sugges- by the reticuloendothelial system of the • Cardiocirculatory symptoms and tive of hemolysis, etc. spleen. To maintain normal Hb levels, signs (palpitations, tachycardia, sys- • Neonatal history: gestational age, there must be a balance between the tolic murmur, exertional dyspnea and blood group, history of hospital continued loss of senescent red cells tachypnea): in general, they are due admission for jaundice/anemia, neo- and erythropoiesis in the bone marrow. to the onset of compensatory mecha- natal screening results for endocrine- Therefore, anemia is the result of the nisms due to the decrease in blood metabolic diseases (sickle cell anemia imbalance between production (decrea- volume, and become more evident is included in Spain). sed) and destruction or loss of red blood the greater the degree of anemia and • Underlying pathology: previous cells (increased). the speed of its establishment. episodes of anemia and treatment There are different compensation • General symptoms (headache, irri- received, presence of coagulopathy, mechanisms as an adaptive response to tability, mood swings, asthenia, concomitant diseases (infectious and/ the situation of anemia: anorexia): due to tissue hypoxia. In or inflammatory), malabsorptive • Redistribution of blood flow: this chronic anemia, there may also be an problems (eg, celiac disease). guarantees the oxygenation of vital impact on diverse organs, leading to: • Family history: the former existence organs (brain and myocardium), with neurological dysfunction (impaired of: anemia, jaundice, gallstones, the consequent vasoconstriction of psychomotor development, learning splenomegaly or the need for chole- less needy areas, such as skin and difficulty), delayed puberty, osteope- cystectomy in family members, can kidney. nia, cardiological abnormalities (left guide the diagnosis of hereditary • Stimulation of erythropoiesis: this ventricular hypertrophy that can lead hemolytic anemia. is mediated by an increase in EPO to heart failure), etc. • Diet: to be queried in order to con- synthesis, the main trigger of which • Accompanying symptoms: derived sider possible nutritional deficiencies is tissue hypoxia. This mechanism is from the causes and pathogenic (iron, vitamin B12 and folic acid). It only effective if the bone marrow is mechanisms involved, such as: is important to document the type able to respond with increased pro- - Hemolytic anemia: jaundice, cho- of lactation (breastfeeding/artifi- duction of red blood cells and the luria, abdominal pain, splenome- cial formula), the amount and the consequent increase in reticulocytes galy (due to the role of the spleen possibility of supplementation/for- in peripheral blood. in the destruction of erythrocytes) tification. The presence of pica can • Increased ability of Hb to deli- or hepatosplenomegaly (because guide towards a deficit of nutrients. ver oxygen to tissues: through an of extramedullary erythropoiesis), To consider that the intake of cer- increase in the concentration of gallstones and bone abnormalities tain foods (eg: fava beans) can tri- 2,3-diphosphoglycerate, which (due to extramedullary erythro- gger hemolytic crises in G6PDH decreases the affinity of Hb for O2 poiesis). deficiency. and favors oxygenation of the tissues. - Deficiency anemia: trophic di- • Exposure to drugs/toxins: medica- sorders of the skin and mucous tions (antibiotics, anti-inflamma- Understanding all of the above will membranes. tory drugs, anticonvulsants), herbs, help to understand the clinical mani- - Anemia of central origin (medu- homeopathic products, drinking festations and the pathophysiological llary): bleeding and if water containing nitrates, oxidants classification of anemia, which are associated with thrombopenia and or products with lead. explained in the following sections. leukopenia. Physical examination Clinical manifestations(4,6) Diagnosis(2,7-9) Special attention should be paid to: skin, eyes, mouth, face, chest, hands Anemia can have both nonspecific clinical Adequate history-taking, physical examina- and abdomen. Skin paleness is a spe- manifestations as well as guiding signs and tion, full blood count with red cell indices, cific but poorly sensitive finding; and symptoms for the etiological diagnosis. reticulocytes, peripheral blood smear and so is tachycardia, as a manifestation of biochemistry, are cost-effective tools for the severity. Jaundice and hepatospleno- The clinical picture of the anemic diagnostic approach of anemia. megaly, characteristic of hemolysis, are syndrome has common manifestations

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Table II. Diagnostic guidance based on signs observed on physical examination

Organ/system Sign Diagnostic orientation

Skin - Hyperpigmentation - Fanconi anemia - Petechiae, purpura - Autoimmune hemolytic anemia with: thrombopenia, hemolytic-uremic syndrome, bone marrow aplasia, and bone marrow infiltration - Jaundice - Hemolytic anemia, hepatitis, and

Face - Malar and maxillary bony prominences - Congenital hemolytic anemia, major

Eyes - Microcornea - Fanconi anemia - Retinal and conjunctival vessel - abnormalities - Cataracts - G6PDH deficiency, galactosemia, and hemolytic anemia - Periorbital edema - Malnutrition, iron deficiency, and

Mouth - Glossitis - Iron and/or vitamin B12 deficiency

Chest - Pectoral muscle abnormalities - Poland syndrome

Hand - Triphalangeal thumb - Red series aplasia - Thenar eminence hypoplasia - Fanconi anemia - Nail abnormalities - Iron deficiency

Spleen - Splenomegaly - Hemolytic anemia, /lymphoma, and acute infection

G6PDH: glucose-6-phosphate-dehydrogenase (Hernández Merino, 2016).

also specific data, but with relatively low lability at each moment; whilst in etc. Additionally, the presence of sensitivity. thalassemia, RDW is usually normal other cytopenias or leukocytosis with Table II shows certain physical signs (although it may be elevated), because immature forms can point toward which can guide towards a specific the Hb distribution is uniform. certain etiologies (infections, medu- cause of anemia. • Reticulocyte Production Index llary aplasia/hypoplasia, infiltration Laboratory evaluations (RPI): reticulocytes report on the of the bone marrow due to leukemia/ regenerative capacity of the bone lymphoma, etc.). Work-up tests should begin with a marrow, so this parameter will • Iron metabolism: ferritin is the most full blood count with red cell indices allow a pathophysiological classifi- useful parameter to measure iron sto- and a thorough examination of the cation of anemia (see next section). res; values ​​below 15mcg/l are indi- peripheral blood smear. In addition, Normal values of​​ RPI range between cative of iron deficiency. However, first-level studies require: reticulocyte 2 and 3. The correct interpretation its usefulness is limited by its role as count, basic biochemistry and study of of the reticulocyte number requires an acute phase reactant, increasing iron metabolism. the adjustment of the crude number with inflammation/infection and In any study of anemia, we must take (%) according to the real number of tissue destruction. into account the following parameters of red cells of each patient, using the According to the previous findings, the full blood count, which will aid in formula shown in figure 1. we will have to expand the inves- the classification of anemia and conse- • Peripheral blood smear examina- tigations with second level studies quently in its etiological diagnosis: tion: this must be performed by an (Diagnostic algorithms, algorithms • (MCV): experienced hematologist. The size 1 and 2): this is the average size (fl) of the red and morphology of the red blood - If reticulocytosis and data sugges- blood cells. Depending on this value, cells can be essential to identify tive of hemolysis are present, the the morphological classification of disorders such as: existence of hemolytic anemia anemia will be carried out (see next (sickle cells), spherocytosis (sphero- section). cytes), hemoglobinopathies[real reticulocytes (target (%)] x [real Hct] Reticulocyte • Red cell distribution width (RDW): RPIcells), = hemolysis (Heinz bodies), half-life (according to Hct): this informs of the coexistence of red [normal Hct for age/gender] x [reticulocyte half-life (days)] cell populations of different sizes. Hct Days This parameter helps to distinguish [real reticulocytes (%)] x [real Hct] Reticulocyte45 1 RPI = half-life 35 1.5 between iron deficiency and thalas- (according to Hct): [normal Hct for age/gender] x [reticulocyte half-life (days)] 25 2 semia, since in the former it is usually Hct Days high, due to the different distribution 15 2.5 Figure 1. Formula for adjusting the reticulocyte count. 45 1 of Hb depending on the iron avai- 35 1.5 25 2 PEDIATRÍA15 INTEGRAL2.5 - en 217 Anemia. Classification and diagnosis

should be ruled out and the fo- Table III. Anemia classification according to MCV and reticulocytosis* llowing should be requested: hap- toglobin, Coombs test to determi- Regenerative (RPI ≥ 3) Arregenerative (RPI <2) ne autoimmunity, and if negative, Microcytic* - Iron deficiency anemia - Iron deficiency anemia hemoglobin electrophoresis to under treatment - Chronic infection / rule out (con- - Congenital or corpuscular inflammation sidering that HbF is predominant hemolytic anemias - Lead poisoning (spherocytosis, thalassemia, within the first months of life, and sickle cell disease) its decrease is slower in sickle cell disease, where it persists in va- Normocytic* - Extracorpuscular hemolytic - Medullary aplasia riable amounts) and/or quanti- anemia (hypersplenism, - Spinal infiltration microangiopathy, drugs, - Aplastic crisis or transient fication of enzymes (G6PDH, infections) erythroblastopenia in pyruvate-kinase) to study enzy- - Corpuscular hemolytic corpuscular hemolytic anemia mopathies, and/or membrane stu- anemia - Infectious anemia dies (osmotic fragility, cytometry) - Acute bleeding - Chronic kidney disease for membranopathies. Macrocytic* - Hemolytic crisis in AIHA - Folic acid or vitamin B12 - If (elevated MCV) with marked reticulocytosis deficiency is found: there may be a defi- - Fanconi anemia ciency cause (vitamin B12, folic - Blackfan-Diamond anemia acid) or hypothyroidism (request - Liver disease TSH and FT4), but it could also - - be a central maturational disor- - Hypothyroidism der (bone marrow aspirate/biopsy must be performed). *Always adjust MCV according to age and sex for each patient (Table I). AIHA: - If there is and autoimmune hemolytic anemia. RPI: reticulocyte production index. Adapted from: San Román S, Mozo Y, 2017. parvovirus B19 infection has been ruled out, a bone marrow aspira- te/biopsy must be carried out to assess anemia of central origin. - Macrocytic: MCV ≥ 97.5 percen- tions, deposit diseases (Nieman- tile for age, sex, and ethnicity. In Pick, Gaucher...) or congenital or Classification of anemia(2,7-9) childhood the most common acquired aplasia. ones are due to vitamin B12 and/ Morphological and pathophysiological clas- or folic deficiency or exposure Role of the Primary Care sifications of anemia are complementary to certain drugs (eg, anticonvul- pediatrician and required for the etiological diagnosis sants and immunosuppressants). approach. Macrocytosis can also be found • From the Primary Care setting, in acute regenerative anemia, due full blood count with erythrocyte Following the results obtained in the to the presence of reticulocytosis, indices, reticulocytes, biochemistry first-level investigations, the morpho- and in maturation disorders of the with hemolysis parameters and iron logical and pathophysiological classifi- bone marrow (myelodysplasia and profile, can be requested, which pro- cations of anemia will be carried out, aplasia). vide the diagnostic approach of most which will lead to the determination of • Pathophysiological classification: anemia cases in the pediatric age. the etiology after conducting specific based on the medullary regenerative • In our environment, the anemia cases additional work-up (Table III and Algo- capacity, determined by the RPI. that the Primary Care pediatrician rithms 1 and 2). - Regenerative: there is an eleva- can most frequently find are: iron • Morphological classification: based ted reticulocyte response (reticu- deficiency anemia, physiological on the MCV (Table I). locytes >3% or RPI ≥3). Examples anemia of infancy, β-heterozygous - Microcytic: MCV ≤ 2.5 percentile of this include: hemolytic anemia thalassemia or thalassemic trait, ane- for age, sex, and ethnicity. In chil- and anemia secondary to hemorr- mia of chronic disorders, anemia due dhood, these are iron deficiency hage. to hemorrhage and, currently also, anemia and thalassemia par ex- - A/hyporegenerative: normal or sickle cell anemia. cellence. low reticulocyte response for the • In general terms, any anemia of the - Normocytic: Normal MCV (bet- degree of anemia (reticulocytes following characteristics: combined ween 2.5 and 97.5 percentiles) for <1-1.5% or RPI <2). It translates with another cytopenia, hemoglo- age, sex and ethnicity. This can the existence of a hypo/inactive binopathies, hemolytic anemia, are- be due to: blood loss, chronic di- bone marrow as a result of various generative anemia, those that do not sorders, infections or it can be the reasons: deficiency of substrates respond to treatment, and whenever initial stage of micro or macro- (iron, folic acid, vitamin B12), tu- there is any other warning sign, is sus- cytic anemia. mor medullary infiltration, infec- ceptible to referral to specialized care.

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Bibliography 8.** San Román Pacheco S, Mozo del Castillo General chapter, suitable for the stu- Y. Síndrome anémico. In: Guerrero-Fdez. dy of hematopoiesis and the pathophysiology of The asterisks show the interest of the article in J, Cartón Sánchez A, Barreda Bonis A, anemia. the opinion of the authors. Menéndez Suso J, Ruiz Domínguez J, ed. 1. Glader B. Anemia. In: Kliegman RM, Behr- Manual de Diagnóstico y Terapéutica en - Prudencio García-Paje M. Aproximación man RE, Jenson HB, Stanton BF, ed. Nelson. Pediatría. 6ª edición, Madrid. Editorial diagnóstica al paciente con anemia. In: Textbook of Pediatrics. 18th ed., Barcelona. Panamericana; 2017. p. 1117-30. Madero L, Lassaletta A, Sevilla J, ed. Elsevier España; 2009. p. 2003-6. Hematología y Oncología Pediátricas. 3ª 9. Buttarello M. Laboratory diagnosis of ane- edición, Madrid. Ergon; 2015. p. 81-6. 2. Hernández Merino A. Anemias en la infan- mia: are the old and new red cell parameters Chapter where a general presentation is made cia y adolescencia; clasificación y diagnósti- useful in classification and treatment, how? on anemia in Pediatrics, useful to make a global co. Pediatr Integral. 2016; XX(5): 287-96. Int J Lab Hematol. 2016; 38: 123-32. 3. Word Health Organization. Worldwide approach to the subject. In the same book, there 10. Sevilla Navarro J. Abordaje de la anemia prevalence of anemia 1993-2005: WHO are other specific chapters describing the different microcítica; nuevas herramientas diagnós- global database on anemia. Geneva: World types of anemia in greater depth. ticas. In: AEPap, ed. 7º Curso de Actuali- Health Organization; 2008. zación en Pediatría 2010. Madrid: Exlibris - Sandoval C. Approach to the child with 4.** Allali S, Brousse V, Sacri AS, Chalumeau Ediciones; 2010. p. 239-9. anemia (Literature review: September M, de Montalembert M. Anemia in chil- 2020. Last update: June 20, 2019). Avai- dren: prevalence, causes, diagnostic work- Recommended bibliography lable at: www.uptodate.com. up, and long-term consequences. Expert This frequently updated source of evidence-based Rev Hematol. 2017; 10: 1023-8. - Allali S, Brousse V, Sacri AS, Chalumeau M, de Montalembert M. Anemia in chil- medicine offers a comprehensive review of chil- 5.** Arrizabalaga B, González FA, Remacha. dren: prevalence, causes, diagnostic work- dhood anemia, presented in a clear educational Eritropatología. Edición Ambos Marketing up, and long-term consequences. Expert structure. Services. Barcelona. 2017. Rev Hematol. 2017; 10: 1023-8. 6.** Prudencio García-Paje M. Aproximación - San Román Pacheco S, Mozo del Castillo This article summarizes in a practical way, the diagnóstica al paciente con anemia. In: Y. Síndrome anémico. In: Guerrero-Fdez. causes of anemia in Pediatrics and the investi- Madero L, Lassaletta A, Sevilla J, ed. J, Cartón Sánchez A, Barreda Bonis A, gations necessary for its diagnosis, highlighting Hematología y Oncología Pediátricas. 3ª Menéndez Suso J, Ruiz Domínguez J, ed. the comorbidity that this pathology implies in the edición, Madrid. Ergon; 2015. p. 81-6. Manual de Diagnóstico y Terapéutica en long term. 7.*** Sandoval C. Approach to the child with Pediatría. 6ª edición, Madrid. Editorial anemia (Literature review: September - Arrizabalaga B, González FA, Remacha. Panamericana; 2017. p. 1117-30. 2020. Last update: June 20, 2019). Avai- Eritropatología. Edición Ambos Marketing Presentation of the topic of anemia in childhood, lable at: www.uptodate.com. Services. Barcelona. 2017. with practical tables and algorithms.

Clinical case

Presentation • Maternal grandmother: deficiency anemia. A 7-year-old girl is seen in clinic because of progressive • No other background of interest. paleness and a one-month clinical picture of asthenia, initia- lly attributed by the family to various infectious processes of Physical examination probable viral etiology (gastroenteritis, upper respiratory tract Weight: 20 kg. Temperature: 36.5°C. Respiratory rate: 22 catarrh and otitis), without any of them requiring admission rpm. Heart rate: 105 bpm. Systolic/diastolic blood pressure: or antibiotic therapy. Her physical activity remains intact. 115/65 mmHg. She has not had: fever, sweating, anorexia, weight loss or Good general condition. Marked skin and mucosal paleness. musculoskeletal pain. She had taken mebendazole in the No rashes or petechiae. No respiratory distress. Good peripheral month prior to the consultation as treatment for oxyuriasis, perfusion, capillary filling time <2 seconds, peripheral pulses and ibuprofen occasionally. Her pediatrician had reques- are present and symmetrical. Cardiac auscultation: rhythmic ted a test where Hb of 8 g/dl stands out. Deficiency and/or sounds, systolic murmur II/VI. Lung auscultation: normal. parainfectious etiology was suspected, and iron therapy was Normal oropharynx. Normal bilateral otoscopy. No pathologic prescribed. She attends the clinic today after two weeks of lymphadenopathies. Soft, non-tender abdomen, without mas- starting treatment for clinical and analytical control. ses or organ enlargement. Preserved peristalsis. No signs of peritoneal irritation. Glasgow coma scale 15/15, collaborating, Personal history negative meningeal signs, no neurological focus. • Up-to-date vaccination, according to her region´s (auto- nomous community) immunization schedule. Work-up tests No known allergies. • • Full blood count: Hb: 6.5 g/dl; MCV: 89 fl; leukocytes: 9 9 • No medical-surgical history of interest. 4.76x10 /l; neutrophils: 0.98x10 /l; lymphocytes: 9 9 9 • Pets: a dog who has lived at home for 10 years, correctly 3.61x10 /l; monocytes: 0.16x10 /l; : 120x10 /l; vaccinated. MPV: 10 fl. Reticulocytes: 21x109/l (0.7%). She lives in an urban area. No recent trips. • • Biochemistry: glucose: 80 mg/dl; urea: 25 mg/dl; crea- • Exercise: swimming. tinine: 0.4 mg/dl; sodium: 140 mEq/l; potassium: 4.1 mEq/l; chloride: 105 mEq/l; GOT: 29 IU/l; GPT: 21 IU/l; Family background total bilirubin: 0.4 mg/dl; LDH: 206 IU/l; phosphorus: 5.5 mg/dl; total calcium: 10 mg/dl. • Parents and a 10-year-old brother, all healthy.

PEDIATRÍA INTEGRAL - en 219 Anemia. Classification and diagnosis

Algorithm 1. Diagnosis of anemia without abnormalities of other cell lines

ANEMIA

Yes *Signs of hemolysis: Abnormalities in other cell lines Go to: Algorithm 2 - Splenomegaly, jaundice, abdominal pain, choluria, No cholelithiasis Yes Go to: Coombs - Normo/ Hemolysis* Hemolytic Test - Elevation of reticulocytes anemia chapter - Increased LDH No - Indirect bilirubin increase No - Decrease in haptoglobin Elevated Hidden Reticulocytes / RPI Hemorrhage bleeding

Normal or low

MCV

Decreased Normal Raised

LIKELY DIAGNOSES: LIKELY DIAGNOSES: - Vitamin B12/folic acid deficiency LIKELY DIAGNOSES: - Infection - Medications - Iron deficiency - Anemia of chronic disorders - Transient erythroblastopenia - Thalassemia - Drugs / intoxication - Hypothyroidism - Sideroblastic anemia - Acute bleeding - Myelodysplastic syndrome - Anemia of chronic disorders - Chronic kidney disease - Chronic liver disease - Lead poisoning - Transient erythroblastopenia - Blackfan-Diamond anemia - Bone marrow aplasia - Fanconi anemia

INVESTIGATIONS TO CONSIDER: INVESTIGATIONS TO CONSIDER: INVESTIGATIONS TO - PB smear - PB smear CONSIDER: - Vitamin B12 / folic acid - Iron profile, vitamin B12 and - PB smear - Viral serologies folic acid - Iron profile (parvovirus B19) - Viral serologies (parvovirus - Hb electrophoresis - Thyroid hormones B19) - Determination of lead - Bone marrow aspirate/biopsy - Determination of lead - Bone marrow aspirate/biopsy +/– directed genetic studies - Bone marrow aspirate/biopsy

RPI: reticulocyte production index; LDH: lactate dehydrogenase; PB: peripheral blood; MCV: mean corpuscular volume. Adapted from: San Román S, Mozo Y, 2017 and Sandoval C, 2019.

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Algorithm 2. Diagnosis of anemia with alteration of other cell lines

ANEMIA

No Other abnormal cell lines Go to: Algorithm 1

Yes

Which cell lines?

Pancytopenia/bicytopenia Anemia and Anemia and Anemia and without signs of hemolysis thrombopenia with thrombocytosis leukocytosis signs of hemolysis

LIKELY DIAGNOSES: - Leukemia / neoplastic infiltration LIKELY - Medullary aplasia LIKELY DIAGNOSES: LIKELY - Myelosuppression caused by DIAGNOSES: - Iron deficiency DIAGNOSES: medications/toxins - HUS / TTP - Infection - Infection - Vitamin B12/folic acid - Evans syndrome - Post- - Leukemia deficiency - DIC splenectomy - Hypersplenism anemia - Infection (HIV, parvovirus, etc.)

INVESTIGATIONS FOR DIAGNOSTIC CONFIRMATION: - PB smear - Review the history for drugs, toxins and diet - Iron profile, vitamin B12 and folic acid - Biochemistry with hemolysis parameters (LDH, haptoglobin, total and fractionated bilirubin) - Coombs test - Viral serologies (HIV, parvovirus B19, CMV, EBV) and bacterial cultures - Bone marrow aspirate/biopsy

DIC: disseminated intravascular ; CMV: cytomegalovirus; LDH: lactate dehydrogenase; TTP: thrombocytopenic thrombotic purpura; HUS: hemolytic uremic syndrome; PB: peripheral blood; EBV: Epstein Barr virus; HIV: human immunodeficiency virus. Adapted from: San Román S, Mozo Y, 2017 and Sandoval C, 2019.

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Anemia. Classification e. The RDW (Red Cell Distribu- e. In all of the above, hepatosple- tion Width) helps to differen- nomegaly can be found. and diagnosis tiate between iron deficiency and thalassemia, as it is usually Clinical case 1. Regarding the factors that influen- ce the Hb count, indicate the CO- elevated in the latter. RRECT statement: 6. Which parameter/s in the blood 3. Regarding reticulocytes, select the tests carried out in the clinical case a. At sea level, Hb count is higher, CORRECT answer: given that the lower oxygen con- patient results DISCORDING tent in the air results in a stimu- a. They allow to make a morpho- with the diagnosis of iron deficien- lus for hematopoiesis. logical classification of anemia. cy anemia? b. Testosterone turns out to be a b. They require the interpretation a. The hemoglobin value. stimulus for erythropoiesis. of an expert hematologist. b. Normocytosis. c. Hb levels are characteristically c. The reticulocyte production c. . index is normal above 3. lower in children of Asian ori- d. Answers A and B are correct. gin. d. The gross number should be e. Answers B and C are correct. d. Physiological anemia occurs bet- adjusted to the actual count. ween 3-6 months of life. 7. What diagnostic possibility are we e. In iron deficiency anemia they e. HbC is more common in chil- able to DISCARD given the results are always diminished. dren of Asian origin. of this patient’s biochemistry? a. Myelodysplastic syndrome. 2. Regarding the work-up tests in the 4. One of the following is NOT a cli- evaluation of anemia, indicate the nical feature of Fanconi anemia: b. Hemolytic anemia. INCORRECT statement: a. Ocular abnormality. c. Acute leukemia. a. Ferritin can be altered by b. Hypoplasia of the thenar emi- d. Bone marrow aplasia. inflammatory processes; howe- nence. e. Infective process. ver, a value <15 mcg/l is indica- c. Malar bone prominence. tive of iron deficiency. d. Skin hyperpigmentation. 8. Based on the results of the analy- b. Anemia of chronic disorders e. . sis, which additional test would usually presents with a normal be MOST USEFUL to make the MCV. 5. In which anemia disease(s) is hepa- diagnosis of the patient? c. A decrease in the haptoglobin tosplenomegaly NOT expected to a. Coombs test. level is consistent with hemolytic be found in physical examination? b. Urine test strip. anemia. a. Acquired bone marrow aplasia. c. Iron metabolism. d. Examination of the peripheral blood smear should be perfor- b. Acute lymphoblastic leukemia. d. Determination of vitamin B12 med by an experienced hema- c. Viral infection. and folic acid. tologist. d. Sickle cell anemia. e. Peripheral blood smear.

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