Acute Bronchiolitis in Children PDF

Acute bronchiolitis in children Definition of a disease or condition (group of diseases or conditions) Acute bronchiolitis is inflammatory disease of the lower respiratory tract with a predominant lesion of small bronchi and bronchioles and develops in children under the age of 2 years (most ofte...

Acute bronchiolitis in children Definition of a disease or condition (group of diseases or conditions) Acute bronchiolitis is inflammatory disease of the lower respiratory tract with a predominant lesion of small bronchi and bronchioles and develops in children under the age of 2 years (most often in children under the age of 1 year). The symptom complex of acute bronchiolitis includes obstruction of the lower respiratory tract, which occurs against the background of acute respiratory viral infection (or when exposed to irritants) and is accompanied by cough and signs of respiratory failure: difficult grunting breathing, tachypnea, retraction of intercostal spaces and/or hypochondria, swelling of the wings of the nose and bilateral wheezing in the lungs. Classification There is no single classification of bronchiolitis. The clinical classification of bronchiolitis is based on etiology, and also includes systemic diseases in which bronchiolitis develops as one of the syndromes: Bronchiolitis developed as a result of inhalation of various substances: Bronchiolitis developed as a result of smoke inhalation Bronchiolitis developed as a result of exposure to irritating gases and mineral dust Bronchiolitis developed as a result of inhalation of organic dust Infectious bronchiolitis (viral) Postinfectious (obliterating) bronchiolitis Drug-induced bronchiolitis Bronchiolitis associated with collagenoses Bronchiolitis associated with inflammatory bowel diseases Posttransplant bronchiolitis Bronchiolitis associated with paraneoplastic pemphigus Neuroendocrine cell hyperplasia with bronchiolar fibrosis Diffuse panbronchiolitis Cryptogenic bronchiolitis Clear criteria for the severity of bronchiolitis have not yet been developed. To assess the severity of bronchiolitis, it is necessary to focus on signs of respiratory failure. Table 1 Symptoms of respiratory insufficiency in accordance with the degrees of severity. Etiology and pathogenesis 1.2 Etiology and pathogenesis of a disease or condition (group of diseases or conditions) Bronchiolitis develops more often in response to respiratory syncytia viral infection (60-70%). In premature infants, especially with bronchopulmonary dysplasia (BPD) and on artificial feeding, rhinovirus may be an etiologically significant agent in bronchiolitis (up to 40% of cases. Influenza A and B viruses, parainfluenza, adenovirus, coronavirus, metapneumovirus and human bocavirus are also considered as causal factors of the disease. RS-viral infection is carried by almost all children in the first 2 years of life (90%), but only in about 20% of cases they develop bronchiolitis, which may be due to the presence of predisposing factors. Risk factors for the development of bronchiolitis include: The presence of older children in the family. Age up to 6 months. Birth less than 6 months before the start of the RSV season. Large family (≥ 4 people). Breastfeeding < 2 months. Kindergarten attendance. Children from multiple pregnancies [6,7,8]. Risk factors for the development of severe bronchiolitis: Prematurity ( 380 for more than 3 days, symptoms of toxicosis, shortening of percussion sound, asymmetry of wheezing. Comments on: Chest X-ray in patients with bronchiolitis often reveals lung swelling, increased bronchovascular pattern, areas of decreased transparency of lung tissue, small atelectases, which are sometimes mistaken for pneumonia, which leads only to unjustified prescribing of antibiotics. To determine the severity of respiratory insufficiency in bronchiolitis and, accordingly, the patient's management tactics, it is recommended to monitor blood oxygen saturation (including after inhalation of Adrenergic agents for inhalation administration (bronchodilators). Comment: Pulse oximetry (Determination of oxygen partial pressure in soft tissues (oximetry)), determination of blood gases (Study of blood oxygen level, Study of carbon dioxide level in blood) and acid-base state (CBS) (Study of acid-base state and blood gases) is required only in severe respiratory disorders. During treatment, control pulse oximetry and / or monitoring of vital functions (blood pressure, pulse, respiration, oxygen saturation in the blood, diuresis) is performed. Treatment Treatment, including drug and non-drug therapy, diet therapy, anesthesia, medical indications and contraindications to the use of treatment methods Conservative treatment The main task of bronchiolitis therapy is the relief of respiratory failure. It is recommended to ensure the patency of the upper respiratory tract to improve the general condition of the child with short courses of decongestants and other nasal preparations for topical use (sympathomimetics), the use of nasal aspirators is possible. Comment: Cleaning the upper respiratory tract can somewhat ease the child's well-being. At the same time, there is no strong evidence of its effect on the course of bronchiolitis. There is evidence that deep catheter insertion should not be routinely used to aspirate mucus from the nasopharynx. Antibiotics for acute bronchiolitis are not recommended except in situations where there is a concomitant bacterial infection or serious suspicion of it. Comments on: The effectiveness and safety of managing children with acute bronchiolitis without antibacterial drugs has been proven. Routine use of systemic antiviral drugs is not recommended for children with acute bronchiolitis due to the lack of data on their effectiveness. Comment: currently, there is insufficient evidence of the effect of antiviral drugs on the course of bronchiolitis. It is recommended to provide adequate hydration to a child with bronchiolitis. The main route is oral. If oral hydration is not possible, fluid should be injected through a nasogastric tube or intravenously. Comments on: Parenteral rehydration is necessary if it is impossible to drink, as well as with exicosis of the II-III degree. For this purpose, you should use sodium chloride** (0.9% solution) or a complex sodium chloride solution [Potassium chloride+Calcium chloride+Sodium Chloride]. However, given the likelihood of developing the syndrome of inadequate secretion of antidiuretic hormone, as well as the risk of pulmonary edema, the volume of intravenous infusions should be limited and administered no more than 20 ml / kg / day. Humidified oxygen therapy is recommended for SPRO2 ≤ 92-94%. Comment: Currently there is no consensus on the exact value of SP2, from which oxygen therapy should be started for children with acute bronchiolitis, however, most specialists recognize the need for oxygen supply until the values of this indicator reach 95% steadily. Routine use of inhalations of drugs with bronchiolitis in children with bronchospasmolytic effect is not recommended, since in most cases inhaled bronchospasmolytic therapy does not affect the duration of bronchiolitis [2.25]. Comments on: Some children with acute bronchiolitis may develop bronchospasm against the background of the disease. In this regard, many foreign guidelines allow the use of drugs for the treatment of obstructive respiratory tract diseases in doses specified in the instructions for the drug as a trial therapy. Obtaining the effect of inhalation of drugs for the treatment of obstructive respiratory tract diseases after 20 minutes (SpO2 growth, a decrease in the frequency of respiratory movements (BDD) by 10-15 in 1 minute, a decrease in the intensity of wheezing, a decrease in intercostal retractions), breathing relief, justifies the continuation of inhalation therapy. In the absence of an effect, further inhalation with drugs for the treatment of obstructive respiratory diseases does not make sense. - salbutamol for 2.5 mg (for children from 18 months) Routine use of a hypertonic (3%) sodium chloride solution in the form of inhalations through a nebulizer is not recommended due to the likelihood of bronchospasm. Comment: The effectiveness of this intervention is not recognized by everyone. The positive effect of inhalation therapy with hypertonic sodium chloride solution in acute viral bronchiolitis is noted by a number of researchers [27,28] and is recommended by AAP (The American Academy of Pediatrics – American Academy of Pediatrics) for children hospitalized for bronchiolitis. A number of children with inhalation of hypertonic sodium chloride solution may develop bronchospasm. It is not recommended to use inhaled glucocorticoids (IGCS) in bronchiolitis due to the lack of evidence of their clinical effect. It is not recommended to use corticosteroids for systemic use in bronchiolitis due to their inefficiency. The use of vibration and/or percussion massage is not recommended, since in most cases it also does not have a pronounced effect in patients with bronchiolitis. Prognosis The prognosis after acute bronchiolitis is usually favorable. Moderate respiratory symptoms may persist for approximately 3 weeks. About half of the children who have had acute bronchiolitis may have episodes of bronchial obstruction in the future. Among them, patients with atopic heredity are more common, for whom bronchiolitis may be one of the risk factors for the development of bronchial asthma. It is rarely possible to develop postinfectious obliterating bronchiolitis, characterized by a chronic course with the development of fibrosis and obliteration of the bronchial lumen, disability. Bronchitis in children Bronchitis is an inflammatory disease of the bronchi, mainly of infectious etiology, manifested by a cough (dry or productive) lasting no more than 3 weeks. Classification: There is no generally accepted classification of bronchitis: By analogy with other acute respiratory diseases, etiological and functional classification signs can be distinguished. Epidemiological studies on bronchitis have not been conducted in Kazakhstan. The etiology of bronchitis is viral and bacterial, in young children and primary school age, the cause of bronchitis is rhinovirus, respiratory syntial virus, whooping cough virus, adenovirus, as well as pathogens mycoplasma and chlamydia. In older children, the predominant pathogens of bronchitis are parainfluenza viruses, adenovirus, rhinovirus, as well as Streptococcus pneumonia, Moraxella catarrahalis, Haemophilus influenza. Along the course of the disease:: · acute (lasting up to 4 weeks); · prolonged (lasting more than 4 weeks from the onset of the disease) occurring mainly with bacterial inflammation. According to clinical manifestations: · acute bronchitis (AB); · acute obstructive bronchitis (АOB); · bacterial bronchitis (BB); Diagnostics Diagnostic criteria: Complaints and anamnesis: · cough (dry or productive); · wheezing breath; · weakness. Physical examination: · rapid or difficult breathing (children under 2 months of BH ≥60 per minute; from 2 months- up to 1 year ≥50 per minute; 1-5 years ≥40 per minute; older than 5 years >28 per minute); · retraction of the lower chest; · auscultative signs (bronchial (hard) breathing, wheezing). Laboratory tests: · general blood test (leukocytosis with neutrophil shift to the left, leukopenia, acceleration of ESR). Instrumental studies: · spirometry of changes in indicators of external respiration function (in older children). TREATMENT TACTICS AT THE OUTPATIENT LEVEL Non-drug treatment: · for the period of temperature rise - bed rest; · adequate hydration (plenty of warm drink); · encouraging breastfeeding and adequate nutrition according to age; · compliance with the sanitary and hygienic regime (ventilation of premises, exclusion of contact with infectious patients). Medical treatment Treatment of АOB: Inhalation bronchodilator Salbutamol, a dosed aerosol of 100 mcg or an inhalation solution in an age dose Inside as a bronchodilator for adults and children over 12 years of age - 2-4 mg 3-4 times / day, if necessary, the dose can be increased to 8 mg 4 times / day. Children aged 6-12 years - 2 mg 3-4 times / day; children 2-6 years - 1-2 mg 3 times / day. Inhalation bronchodilator Ipratropium bromide /phenoterol 20 ml 4 times a day at an age dose; Treatment of BB: Drug group International nonproprietary name of the drug Method of application Level of evidence Protected penicillin Amoxicillin + clavulanic acid, suspension for oral administration 125 mg / 5 ml 45mg / kg 2 times a day. Macrolide Azithromycin, powder for suspension preparation 100 mg/5 ml (200 mg/5 ml) 5 mg/kg 1 time per day. Indicators of treatment effectiveness: · cough relief; ·relief of symptoms of Respiratory failure. normalization of Respiratory rate; · improvement of well-being and appetite. What is a Ventricular Septal Defect A ventricular septal defect happens during pregnancy if the wall that forms between the two ventricles does not fully develop, leaving a hole. A ventricular septal defect is one type of congenital heart defect. Congenital means present at birth. In a baby without a congenital heart defect, the right side of the heart pumps oxygen-poor blood from the heart to the lungs, and the left side of the heart pumps oxygen-rich blood to the rest of the body. In babies with a ventricular septal defect, blood often flows from the left ventricle through the ventricular septal defect to the right ventricle and into the lungs. This extra blood being pumped into the lungs forces the heart and lungs to work harder. Over time, if not repaired, this defect can increase the risk for other complications, including heart failure, high blood pressure in the lungs (called pulmonary hypertension), irregular heart rhythms (called arrhythmia), or stroke. Types of Ventricular Septal Defects Click here to view a larger image An infant with a ventricular septal defect can have one or more holes in different places of the septum. There are several names for these holes. Some common locations and names are (see figure): 1. Conoventricular Ventricular Septal Defect In general, this is a hole where portions of the ventricular septum should meet just below the pulmonary and aortic valves. 2. Perimembranous Ventricular Septal Defect This is a hole in the upper section of the ventricular septum. 3. Inlet Ventricular Septal Defect This is a hole in the septum near to where the blood enters the ventricles through the tricuspid and mitral valves. This type of ventricular septal defect also might be part of another heart defect called an atrioventricular septal defect (AVSD). 4. Muscular Ventricular Septal Defect This is a hole in the lower, muscular part of the ventricular septum and is the most common type of ventricular septal defect. Diagnosis A ventricular septal defect usually is diagnosed after a baby is born. The size of the ventricular septal defect will influence what symptoms, if any, are present, and whether a doctor hears a heart murmur during a physical examination. Signs of a ventricular septal defect might be present at birth or might not appear until well after birth. If the hole is small, it usually will close on its own and the baby might not show any signs of the defect. However, if the hole is large, the baby might have symptoms, including:  Shortness of breath,  Fast or heavy breathing,  Sweating,  Tiredness while feeding, or  Poor weight gain. During a physical examination the doctor might hear a distinct whooshing sound, called a heart murmur. If the doctor hears a heart murmur or other signs are present, the doctor can request one or more tests to confirm the diagnosis. The most common test is an echocardiogram, which is an ultrasound of the heart that can show problems with the structure of the heart, show how large the hole is, and show how much blood is flowing through the hole. Treatments Treatments for a ventricular septal defect depend on the size of the hole and the problems it might cause. Many ventricular septal defects are small and close on their own; if the hole is small and not causing any symptoms, the doctor will check the infant regularly to ensure there are no signs of heart failure and that the hole closes on its own. If the hole does not close on its own or if it is large, further actions might need to be taken. Depending on the size of the hole, symptoms, and general health of the child, the doctor might recommend either cardiac catheterization or open-heart surgery to close the hole and restore normal blood flow. After surgery, the doctor will set up regular follow-up visits to make sure that the ventricular septal defect remains closed. Most children who have a ventricular septal defect that closes (either on its own or with surgery) live healthy lives. Medicines Some children will need medicines to help strengthen the heart muscle, lower their blood pressure, and help the body get rid of extra fluid. Nutrition Some babies with a ventricular septal defect become tired while feeding and do not eat enough to gain weight. To make sure babies have a healthy weight gain, a special high-calorie formula might be prescribed. Some babies become extremely tired while feeding and might need to be fed through a feeding tube. Atrial Septal Defect? An atrial septal defect is a birth defect of the heart in which there is a hole in the wall (septum) that divides the upper chambers (atria) of the heart. A hole can vary in size and may close on its own or may require surgery. An atrial septal defect is one type of congenital heart defect. Congenital means present at birth. As a baby’s heart develops during pregnancy, there are normally several openings in the wall dividing the upper chambers of the heart (atria). These usually close during pregnancy or shortly after birth. If one of these openings does not close, a hole is left, and it is called an atrial septal defect. The hole increases the amount of blood that flows through the lungs and over time, it may cause damage to the blood vessels in the lungs. Damage to the blood vessels in the lungs may cause problems in adulthood, such as high blood pressure in the lungs and heart failure. Other problems may include abnormal heartbeat, and increased risk of stroke. Learn more about how the heart works » Occurrence In a 2019 study using data from birth defects tracking systems across the United States, researchers estimated that each year about 2,118 babies in the United States are born with Atrial Septal Defect. In other words, about 1 in every 1,859 babies born in the United States each year are born with Atrial Septal Defect1. Causes and Risk Factors The causes of heart defects such as atrial septal defect among most babies are unknown. Some babies have heart defects because of changes in their genes or chromosomes. These types of heart defects also are thought to be caused by a combination of genes and other risk factors, such as things the mother comes in contact with in the environment or what the mother eats or drinks or the medicines the mother uses. Read more about CDC’s work on causes and risk factors » Diagnosis An atrial septal defect may be diagnosed during pregnancy or after the baby is born. In many cases, it may not be diagnosed until adulthood. During Pregnancy During pregnancy, there are screening tests (prenatal tests) to check for birth defects and other conditions. An atrial septal defect might be seen during an ultrasound (which creates pictures of the body), but it depends on the size of the hole and its location. If an atrial septal defect is suspected, a specialist will need to confirm the diagnosis. After the Baby is Born An atrial septal defect is present at birth, but many babies do not have any signs or symptoms. Signs and symptoms of a large or untreated atrial septal defect may include the following:  Frequent respiratory or lung infections  Difficulty breathing  Tiring when feeding (infants)  Shortness of breath when being active or exercising  Skipped heartbeats or a sense of feeling the heartbeat  A heart murmur, or a whooshing sound that can be heard with a stethoscope  Swelling of legs, feet, or stomach area  Stroke It is possible that an atrial septal defect might not be diagnosed until adulthood. One of the most common ways an atrial septal defect is found is by detecting a murmur when listening to a person’s heart with a stethoscope. If a murmur is heard or other signs or symptoms are present, the health care provider might request one or more tests to confirm the diagnosis. The most common test is an echocardiogram which is an ultrasound of the heart. Treatments Treatment for an atrial septal defect depends on the age of diagnosis, the number of or seriousness of symptoms, size of the hole, and presence of other conditions. Sometimes surgery is needed to repair the hole. Sometimes medications are prescribed to help treat symptoms. There are no known medications that can repair the hole. If a child is diagnosed with an atrial septal defect, the health care provider may want to monitor it for a while to see if the hole closes on its own. During this period of time, the health care provider might treat symptoms with medicine. A health care provider may recommend the atrial septal defect be closed for a child with a large atrial septal defect, even if there are few symptoms, to prevent problems later in life. Closure may also be recommended for an adult who has many or severe symptoms. Closure of the hole may be done during cardiac catheterization or open-heart surgery. After these procedures, follow-up care will depend on the size of the defect, person’s age, and whether the person has other birth defects. References 1. Mai CT, Isenburg JL, Canfield MA, et al. for the National Birth Defects Prevention Network. National population- based estimates for major birth defects, 2010-2014. Birth Defects Res 2019; 1– 16. https://doi.org/10.1002/bdr2.1589. 1 Tetralogy of Fallot Epidemiology: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in all age groups, constituting approximately 8% of congenital heart disease overall. TOF occurs in approximately 0.19- 0.26/1,000 live births. In the United States, the prevalence of TOF is approximately 3.9 per 10,000 live births. Definition: Tetralogy of Fallot is characterized by the presence of four anatomical findings: 1. Ventricular septal defect 2. Pulmonary stenosis (right ventricular outflow obstruction) 3. Dextroposition of the aorta (overriding aorta) 4. Right ventricular hypertrophy Pathophysiology: The figure below compares the normal anatomy and blood flow of the heart to that found in Tetralogy of Fallot. The initial defect in TOF is a narrowing of the right ventricular outflow tract into the pulmonary artery. This prevents deoxygenated blood from entering the pulmonary circuit. In response to this outflow obstruction, the myocardium of the right ventricle hypertrophies in order to contract forcefully enough to push blood past the stenosis. Additionally, patients have a large ventricular septal defect which allows shunting of blood between the ventricles. In a patient with an isolated VSD, the blood flow is shunted initially from left-to-right. However, in TOF, the right ventricular outflow obstruction may impede the normal blood flow so significantly that the left side of the heart becomes the path of least resistance. Blood from the right ventricle is then forced into the left ventricle, creating a right-to-left shunt and subsequent cyanosis. Finally, the aorta overrides the ventricular septal defect, straddling the VSD. This allows deoxygenated blood shunted from the right ventricle to immediately exit the heart mixed with blood from the left ventricle. The most important determinant of the severity and clinical consequences of TOF is the degree of right ventricular outflow obstruction. With a lesser obstruction, blood is shunted from left-to-right and permitted to preferentially enter the pulmonary circulation, allowing for oxygenation. With a greater degree of obstruction, however, blood is forced in the opposite direction, away from the pulmonary circulation, leftward across the VSD and ultimately blood exits the heart before being oxygenated. Patients will present with differing degrees of outflow obstruction, and this may fluctuate throughout the course of the illness.2 Other Associated Abnormalities: Of note, approximately 40% of patients with TOF have additional congenital heart defects. This includes frank pulmonic stenosis, right aortic arch, abnormalities of the coronary arteries, collateral vessels supplying the pulmonary arteries, patent ductus arteriosus or other defects. It is important to evaluate the patient for all associated heart defects as this may affect surgical intervention or medical therapy. Additionally, clinicians should recall that TOF is associated with a number of genetic syndromes. This includes Trisomy 21 (Down Syndrome) as well as DiGeorge Syndrome and velocardiofacial syndromes. Presenting Signs and Symptoms: The timing and features of presentation depend on the degree of right ventricular outflow obstruction. Patients with more severe obstruction will present earlier due to cyanosis. This may be as early as the immediate newborn period. For patients with more moderate disease, the presenting sign may be a heart murmur (see below). Finally, for patients with mild disease, with so-called “pink tetralogy” due to the lack of cyanosis, their presentation may consist of signs and symptoms of congestive heart failure due to the left-to-right shunting across the VSD and subsequent pulmonary overcirculation. Ultimately, most patients with mild disease will become cyanotic as the degree of outflow obstruction increases over time. Clinical Features: Patients with TOF have a number of distinguishing signs and symptoms that can be found on physical exam and elucidated with a detailed history. Cardiac exam: Most importantly, the heart murmur heart in TOF is not due to the VSD! It is in fact due to the right ventricular outflow obstruction. The murmur is typically crescendo- decrescendo with a harsh systolic ejection quality; it is appreciated best along the left mid to upper sternal border with radiation posteriorly. (Remember, an isolated VSD murmur is a holosystolic murmur, best heard in the tricuspid area. It may radiate to the right lower sternal border.) Patients will have a normal S1 and possibly a single S2 due to diminished P2 component. Cyanosis: If patients are cyanotic, this is most commonly seen on the lips or nail beds. Tet spells: Tet spells are hypercyanotic episodes precipitated by a sudden increase in right-to- left shunting of blood. They can be elicited by activity (e.g. feeding, crying), or they may occur without warning. The classic description is of a patient who becomes cyanotic and then assumes a squatting position to relieve the cyanosis and hypoxia. Squatting serves to increase peripheral vascular resistance, thereby increasing the pressure in the left heart, and subsequently forcing blood back into the pulmonary circulation. Chest X-Ray: As seen on the chest x-ray below, patients with TOF have right ventricular hypertrophy, a “boot shaped” heart and decreased pulmonary vascular markings. Electrocardiogram: On EKG, patients with TOF will show increased right ventricular forces as evidenced by tall R waves in V1. Additionally, right atrial enlargement is manifested by prominent P waves in V1 (*). Right ventricular hypertrophy is demonstrated by a rightward deviated axis.3 Echocardiogram: Findings on echocardiogram are the mainstay of diagnosis in TOF. Echocardiogram will demonstrate a ventricular septal defect with an overriding of the aorta, pulmonic stenosis and right ventricular hypertrophy. This constellation of findings serves to clinch the diagnosis of TOF. In about 25% of cases, patients will also have a right aortic arch. As seen in the echocardiogram below, the blood (blue) from both the right ventricle and left ventricle enters the overriding aorta across the VSD. Treatment: Once TOF is diagnosed, almost all patients undergo corrective surgical repair within the first year of life. In the interim period, prostaglandin treatment may be necessary to maintain the patency of the ductus arteriosus. Additionally, some patients may require digoxin or diuretics if signs of heart failure are present. Treatment of hypercyanotic spells is directed towards improving pulmonary blood flow. These include oxygen, knee/chest position, morphine, intravenous fluids, sodium bicarbonate, beta- blockers or pharmacologically increasing systemic vascular resistance by administration of drugs, such as phenylephrine. Once an infant has developed progressive cyanosis or has evidence of hypercyanotic spells, surgical correction is indicated. There are two common surgical procedures:4 Blalock-Taussig shunt creates a shunt between the aorta and the pulmonary artery using the subclavian artery. This is used as a palliative procedure in infants who are not acceptable candidates for intracardiac repair due to prematurity, hypoplastic pulmonary arteries, or coronary artery anatomy. Patients will require additional surgery as this is not a curative surgery. Intracardiac repair is the definitive repair for patients with TOF and is the preferable procedure. This consists of patch closure of the ventricular septal defect, and enlargement of the RVOT with relief of all sources of obstruction. In some cases, the pulmonary valve may need to be removed to eliminate the obstruction. Outcome and Complications: Overall, patients undergoing surgical repair for TOF have an excellent prognosis with a 20-year survival rate of over 90%. Complications of surgical repair of TOF include arrhythmias particularly ventricular tachycardia (VT), and atrial arrhythmias. Furthermore, patients may experience right ventricular hypertrophy or enlargement due to residual pulmonary stenosis and backward blood flow into the right ventricle. Long-term complications include the need for additional surgeries, neurodevelopmental delay and myocardial fibrosis. Patients should be followed closely by a pediatric cardiologist to monitor for these short-term and long-term complications. Intracardiac repair for TOF. The ventricular septal defect is closed with a patch. The right ventricular outflow tract is enlarged by opening the RVOT and pulmonary valve, resecting the subinfundibular muscle bundles, and patching the area open. In some cases, a conduit may be inserted to further open the RVOT.5 References: 1. Up-to-date: “Pathophysiology, clinical features and diagnosis of Tetralogy of Fallot” 2. SC Greenway et al. “De Novo Copy Number Variants Identify New Genes and Loci in Isolated, Sporadic Tetralogy of Fallot.” Nature Genetics 41, 931 - 935 (2009). 3. M Silberbach, D Hannon.“Presentation of Congenital Heart Disease in the Neonate and Young Infant”. Pediatrics in Review. Vol 28, No. 4. (2007). 4. Up-to-date: “Overview of the Management of Tetralogy of Fallot” 5. “Tetralogy of Fallot Repair”, Children’s Hospital of Pennsylvannia, http://www.chop.edu/img/cardiac-center/tetralogy-of-fallot-repair. 6. DV Reddy. “Case-Based Pediatrics for Medical Students and Residents: Cyanotic Congenital Heart Disease”. http://www.hawaii.edu/medicine/pediatrics/pedtext/s07c03.html , Dec 2002. 7. “Tetralogy of Fallot”. Nationwide Children’s Hospita, Columbus, OH. http://www.nationwidechildrens.org/tetralogy-fallot. Page 1 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 Introduction Immune thrombocytopenia is the most common acquired bleeding disorder in the pediatric population with an approximate incidence of 5 per 105 children annually (1-3). Despite the overall high disease burden of ITP, many unanswered questions remain about its cause and how to best manage patients. This review will focus on the initial management of pediatric ITP patients including early laboratory assessments, and front-line therapies. Significant gaps in knowledge have impeded stratifying the best second and third-line treatment options for patients. Current experience with, mechanisms of action and clinical pearls for using individual drugs will be described. Finally, emerging therapeutics for novel genetic disorders associated with ITP as well as newer adult treatments which may eventually be applied to pediatrics are described. Initial workup Upon presentation with isolated thrombocytopenia, in addition to a complete history and exam, the following initial laboratory tests are obligatory: a complete blood count (CBC), reticulocyte count, review of peripheral blood smear. In addition, because they may help guide therapy Review Article Pediatric immune thrombocytopenia (ITP) treatment Taylor Olmsted Kim1,2, Jenny M. Despotovic1,2 1 Baylor College of Medicine, Department of Pediatrics, Section of Hematology/Oncology, Houston, TX, USA; 2 Texas Children’s Cancer and Hematology Centers, Houston, TX, USA Contributions: (I) Conception and design: TO Kim; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Taylor Olmsted Kim, MD, Feigin Research Tower, 1102 Bates Street, Suite 1025.03, Houston, TX, 77030, USA. Email: [email protected]. Abstract: Pediatric immune thrombocytopenia (ITP) is a heterogeneous autoimmune condition with variability in etiology, bleeding phenotype, need for treatment and response to therapy, as well as duration of disease. Fortunately, many children have mild bleeding and experience spontaneous disease resolution, however it is not possible to predict which patients will have this outcome. For most children, initial management involves attention to screening for underlying secondary causes of ITP, followed by careful observation. When treatment is required, first line therapies are relatively standardized and aim to rapidly diminish bleeding risk. When ITP becomes persistent, chronic or otherwise necessitates alternative therapies, there is much less existing data on the optimal sequence of treatment choices and hence more variability in clinical practice. Further complicating management, there is no reliable way to predict which treatments will be effective, leading patients to be exposed to adverse effects of therapy without confidence in the degree of response. ITP management continues to evolve: as research expands our understanding of the molecular underpinnings of ITP, providers are increasingly able to refine and individualize treatment regimens. Further, novel therapeutics are being tested and used to treat adult ITP patients and these drugs may ultimately be applied to the benefit of children with this condition. Keywords: Immune thrombocytopenia; pediatric immune thrombocytopenia; pediatric ITP; Evans syndrome; thrombopoietin agonists Received: 19 September 2020; Accepted: 06 January 2021; Published: 31 March 2021. doi: 10.21037/aob-20-96 View this article at: http://dx.doi.org/10.21037/aob-20-96 13Annals of Blood, 2021 Page 2 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 and uncover common underlying causes of ITP a direct antiglobulin test (DAT) and quantitative immunoglobulin levels are recommended (4). The peripheral smear should be normal with variable platelet size including large platelets and rare giant platelets (Figure 1). A DAT tests for the presence of autoantibodies against erythrocytes. The test is necessary if anti-D immune globulin (anti-D) therapy is being considered because active hemolysis is a contraindication to anti-D use, as will be discussed in detail below. In the absence of hemolysis, a positive DAT in a patient with ITP can provide evidence of more systemic immune dysregulation and warrants investigation of other underlying autoimmune conditions. An ITP patient with a positive DAT in association with hemolytic anemia has Evans syndrome, defined as two autoimmune cytopenias developing concurrently or in succession (5). Identification of Evans syndrome should prompt further evaluation for secondary causes of ITP and has implications for treatment. Some evidence suggests that a positive DAT, in the absence of hemolysis is associated with both evolution to chronic ITP and need for second line treatments (6). Immunoglobulin testing may uncover underlying immune defects which would significantly alter management such as common variable immune deficiency (CVID) or Selective IgA Deficiency. It is valuable to test quantitative immunoglobulins and a DAT prior to initiating therapy. IVIG may obscure low immunoglobulin levels and therefore delay detection of underlying immune deficiencies. Both IVIG and anti-D immune globulin will result in a positive DAT result because of passive antibody transfer. Importance of defining ITP A diagnosis of exclusion, primary ITP is characterized by isolated thrombocytopenia (platelet count 80% $2,492 Headache, nausea, aseptic meningitis 2nd dose may be given if needed Anti-D immune globulin 50–75 µg/kg ×1 Single dose 24–48 hours ~75% $2,035 Headache, chills, fever, hemolysis *estimated for 20 kg child.Annals of Blood, 2021 Page 5 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 Emergency care Regardless of disease status (new, persistent, or chronic), for severe uncontrolled bleeding, multiple treatment modalities may be applied together including platelet transfusion, IV steroids, IVIG and/or anti-D. If bleeding does not improve rapidly and the patient continues to have major bleeding, emergency splenectomy may be the only option. While platelet transfusion is usually avoided because transfused platelets are thought to be rapidly consumed in the setting of ITP, some patients may have a modest increase in platelets and have reduction in bleeding (28,29). Individuals who have a response to platelet transfusions may represent a distinct ITP phenotype that is T-cell mediated as opposed to antibody-driven (30). Front-line therapies given in concert with transfusions may prolong the life-span of transfused platelets (16,29). Increasingly, thrombopoietin receptor agonists (TPO RAs) are being used earlier in the management of pediatric ITP. TPO-RAs may have a role as adjunct in the setting of severe or life-threatening bleeding. While these agents do not generate a rapid platelet count increase, they may help sustain platelet counts after the effect of initial IV therapies wane. In the case of ICH, medical management is initiated immediately and emergency splenectomy and/or neurosurgical intervention considered. Secondary ITP diagnostic workup Children with chronic ITP warrant further evaluation for secondary ITP, or underlying conditions that lead to immune thrombocytopenia. Similar to those with long standing single cytopenias, children with multi-lineage autoimmune cytopenias require more extensive testing. Evans syndrome, defined as two or more cytopenias, either occurring concurrently or sequentially (31), is most often characterized by ITP and autoimmune hemolytic anemia (AIHA) (32). Evans syndrome was previously defined as idiopathic, but increasingly underlying causative lesions are being identified, including novel genetic syndromes (33). Conditions associated with secondary ITP include lymphoproliferative disorders [e.g., autoimmune lymphoproliferative syndrome (ALPS)], immunodeficiency syndromes (e.g., CVID, DiGeorge syndrome, SCID), rheumatologic conditions (e.g., Systemic lupus erythematosus (SLE), Antiphospholipid antibody syndrome, Sjögren syndrome, juvenile rheumatoid arthritis), malignancies (e.g., Hodgkin lymphoma, non Hodgkin lymphoma), or chronic infections (e.g., HIV, hepatitis, cytomegalovirus, H. Pylori). In the setting of chronic infections, priority should be given to treating the underlying condition, which in itself, may ameliorate thrombocytopenia (34). For example, HIV should be managed with antiretrovirals, and if ITP requires treatment, IVIG, steroids or anti-D can be used. In the setting of Hepatitis C virus infection, treatment involves antivirals and interferon. Interferon may drop platelet counts, and IVIG is preferentially used to treat thrombocytopenia in this setting, as steroids may increase viral loads (34). Work-up is tailored based on the child’s history, individual risk factors, physical exam findings, and family history. Minimum screening for disorders frequently implicated as causing secondary ITP or those for which diagnosis alters management substantially are outlined in Table 2. While a bone marrow evaluation is not recommended for new pediatric ITP patients and is not required prior to starting therapy, in the setting of chronic, refractory disease, it may be considered (3). Second line therapy options Second line agents are indicated for children who do not respond or relapse after first line agents. These first line therapies are utilized with the goal of rapidly increasing the platelet count, thereby mitigating severe bleeding risk, but are not intended for use as a maintenance therapy, or to elicit a durable response in those with persistent or chronic ITP. Second line therapies in children are similar to those used in adults, however splenectomy is avoided in children given the likelihood of spontaneous resolution in pediatric populations and potential for complications. Splenectomy is generally only considered after failure of medical management including combination therapy in a child over age 5 with ITP for at least 12 months, or in the setting of uncontrolled life-threatening bleeding. TPO-RAs: eltrombopag and romiplostim Increasingly TPO-RAs are being utilized as the initial second line agent for pediatric ITP patients who do not respond to upfront therapies (corticosteroids, IVIG or anti-D). The most recent American Society of Hematology guidelines, published in 2019, suggest the use of TPO-RAs over rituximab and splenectomy in children (3). In contrast, selection of TPO-RAs versus rituximab or splenectomy in adults depends more heavily on patient preferences Annals of Blood, 2021 Page 6 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 regarding use of daily medications and feelings about surgical interventions (3). Eltrombopag was approved for use in children with chronic ITP in 2015 following two multicenter, double blind, placebo controlled trials (PETIT and PETIT2) demonstrated its efficacy at raising the platelet count with a favorable side effect profile (35,36). Romiplostim was approved in December 2018 for use in children over 1 year of age who had refractory disease persisting beyond 6 months, however it had been used off-label for many years prior to this (37). The majority of children who received eltrombopag or romiplostim in clinical trials had a favorable response to the drugs (35,36,38-40). Selecting eltrombopag or romiplostim depends on the preferences of the patient, their family and comfort of the provider with prescribing one or the other. Differences in administration heavily impact choice of TPO-RAs. Eltrombopag is dosed once daily and is available as an oral tablet or as a powder for suspension (41). A more challenging issue with eltrombopag administration in the pediatric population is the need to space doses 2 hours before or 4 hours after dairy consumption, as divalent cations such as calcium decrease its absorption (42). Romiplostim is dosed as a weekly subcutaneous injection. Romiplostim is not FDA approved for home administration, so families may be required to make weekly clinic visits to receive treatment. If patients are transitioned between one TPO-RA to the other, the likelihood of a response with an alternate agent is approximately 75% (43). Mechanism Both eltrombopag and romiplostim act by binding the TPO receptor, c-mpl, thereby driving increased platelet production by megakaryocytes. Structurally homologous to endogenous TPO, first generation TPO-RAs, formulated as pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and recombinant human thrombopoietin (rhTPO), induced antibody development against endogenous TPO (44-46). However, second generation TPO-RAs lack sequence homology with endogenous TPO, bind different regions of the TPO receptor, and are less immunogenic (47). Aside from stimulating platelet production, there is also some evidence to suggest that TPO-RAs have immunomodulatory effects (48,49). This is being studies currently in pediatric ITP populations (NCT03939637). Romiplostim is comprised of two peptides conjugated to the IgG1 heavy chain and binds the extracellular binding domain of c-mpl. Eltrombopag, is a small, non-peptide molecule which interacts with the juxtamembrane domain of the TPO receptor (Figure 3). Both romiplostim and eltrombopag stimulate platelet production via multiple signaling pathways including the SHC-Ras-Raf pathway, JAK-STAT pathway and PI3k-Akt signaling (50). Risks and adverse effects Overall, the TPO-RAs are well tolerated by pediatric patients and shown to be safe in clinical trials. Thromboembolic events are a concern in ITP patients treated with TPO-RAs, but recent data show the risk does not appear to be elevated compared to children with ITP who were treated with other therapies (50). Concern for thrombosis also draws largely on experience in adults, who have other comorbidities contributing to thrombosis risk (50). Pediatric patients have not developed thrombi while on TPO-RAs in clinical trials, but theoretically, Table 2 Recommended testing for multilineage cytopenias or chronic ITP Test Disease evaluated DAT SLE, Evans syndrome, other autoimmune disorders ANA SLE, other rheumatologic disorders Antiphospholipid antibodies APS, SLE Quantitative immunoglobulin CVID, XLA, specific antibody deficiency, selective IgA deficiency, IgG subclass deficiency, SCID Flow cytometry for double negative T cells (ideally 4 color flow) TCRα/β+ CD3+ CD4-CD8- ALPS ALPS, autoimmune lymphoproliferative syndrome; ANA, antinuclear antibody; SLE, systemic lupus erythematosus; CVID, common variable immunodeficiency; XLA, X-linked agammaglobulinemia; APS, antiphospholipid antibody syndrome; SCID, severe combined immunodeficiency.Annals of Blood, 2021 Page 7 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 adolescents with additional risk factors such as obesity or estrogen contraceptive use may have a risk more similar to adult ITP patients (38,51). Based on lens changes in animal models, cataract development was an initial concern with TPO-RA use. In the PETIT2 trial, 1 patient had progression of an existing cataract and another developed a new cataract, however both patients were also treated with steroids (36). By stimulating megakaryocytes, which then release cytokines that promote collagen synthesis by marrow fibroblasts, both eltrombopag and romiplostim can lead to reticulin fiber deposition in the bone marrow (52,53). However, in studies of both agents, bone marrow fibrosis was extremely rare, and when it did develop, was mild and did not impact peripheral blood counts. Fibrosis also appears to be reversible on discontinuation (54,55). Eltrombopag has hepatic metabolism and drug levels may be up to 41% higher in the setting of even mild hepatic dysfunction (56). Eltrombopag can cause transaminitis, however this is typically mild (36,39). Finally, as a chelator, eltrombopag can also result in decreased iron absorption and lead to iron deficiency (35,57). Because divalent cations, such as calcium, decrease eltrombopag absorption, it must be taken on an empty stomach and doses should be timed at least 4 hours before or after dairy and other calcium rich food consumption (42). This factor significantly limits the use of eltrombopag in children. Rituximab Though not FDA approved for use in ITP, based on experience with other autoimmune conditions, rituximab has long been used for patients with ITP and inadequate response to upfront therapy. Dosing in ITP is typically 375 mg/m2 in 4 weekly infusions (58). While TPO-RAs have around 70–80% response rate (35,36,59), reported response rates to rituximab are approximately 60% (60). Response to rituximab is frequently not sustained, with reports showing only 26% of children maintain their platelet counts at 5 years from rituximab dosing (60). Ascertaining the underlying cause of secondary ITP is critical when planning to use rituximab for refractory disease. In those with SLE, rituximab may have better response rates than primary ITP patients (61). However, there are conditions where rituximab should be avoided. In ALPS, those who receive rituximab are at increased risk of having prolonged B cells depletion and hypogammaglobulinemia. Prolonged neutropenia is reported in ALPS patients and those with underling immunodeficiencies treated with rituximab (33,62). In general, we recommend all children receiving rituximab have immunoglobulin levels tested and be screened for normal B cell populations as a baseline prior to dosing. Some patients who receive rituximab experience symptomatic hypogammaglobulinemia and increased infection risk (63). Patients with underlying immune defects such as CVID are at particular risk for this outcome (63). Mechanism Rituximab is a chimeric monoclonal antibody directed against CD20, expressed on B cells (64). Once bound, rituximab triggers B cell destruction via complement or Fc receptor mediated clearance (65). With depleted B cells, the production of auto-antibodies directed against platelet glycoproteins is reduced. Risks and adverse effects The most common adverse events associated with rituximab are related to infusion reactions including fevers, myalgias, hives, chest tightness, headache and hypertension. Severe side effects are exceedingly rare in children with ITP and include serum sickness or progressive multifocal leukoencephalopathy (66). Finally, rituximab can reactivate Figure 3 Binding regions of romiplostim and eltrombopag. Both romiplostim and eltrombopag bind and stimulate the thrombopoetin receptor, c-mpl. Romiplostim binds at the distal cytokine homology 2 (CRH-2) domain while eltrombopag binds a transmembrane region. Image created with BioRender.com. Increased platelet production Eltrombopag Romiplostim c-MPLAnnals of Blood, 2021 Page 8 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 hepatitis B infection resulting in fulminant, even fatal disease (66). Splenectomy In the past, splenectomy was a commonly utilized second line treatment, but is now rarely performed (67,68). When used, it should be reserved for children with significant bleeding, over the age of 5, who have tried and failed available medical management, including combination therapies. Unless being used for emergency bleeding control, an invasive and permanent intervention such as splenectomy should also be limited to those with chronic ITP due to the high likelihood of spontaneous disease resolution (3). Prior to surgery, vaccinations should be up to date including Haemophilus influenza type B, meningococcal and pneumococcal 13-valent conjugate vaccines, followed by pneumococcal 23-valent vaccine (3). Pediatric response rates to splenectomy are around 60- 70% within a day of surgery, hence its application in the case of life-threatening bleeding. Over 4 years, 80% of splenectomized children maintain a response (16). Risks and adverse effects Splenectomy results in an increased risk for infection, both in the immediate post-operative period as well as an overall life-long increased risk for sepsis or invasive infection. There is increased risk for deep venous thrombus and pulmonary hypertension development as well, though most reports on these outcomes focus on adults. In addition, there is mortality and morbidity risk associated with the surgery itself (69). Alternative treatments After first- and second-line therapies have been tried, the next therapy option is selected in discussions between the medical team, caregivers and patient. In a study focused on treatment choices from the ITP Consortium of North America, the most common reason to select a particular agent was the possibility of long-term remission, followed by parental or patient preference, and side effect profile (68). Other factors which impact decision making include the provider’s experience and ease of administration for the individual drugs (33). There is a paucity of large, formal studies evaluating outcomes of third line agents in pediatric ITP and certainly, there are no randomized controlled trials comparing the many available therapies directly. Other agents used as third line management include purine analogues (azathioprine, mercaptopurine), mycophenolate mofetil, sirolimus, cyclophosphamide, cyclosporine A, dapsone, danazol and vincristine. Collectively, initial response rates for these drugs range from around 30–60% (3). For refractory patients, combination therapies may also be trialed. In our experience, using medications which target different disease mechanisms is more efficacious. Emerging therapies Targeted therapies The genetic and molecular understanding of ITP pathogenesis is expanding. Increasingly, patients thought to have primary ITP without a typical response to therapies or an unexpected disease course, are found to carry novel genetic alterations resulting in loss of immune tolerance. Armed with this knowledge and increasing availability of genetic testing, an individual patient’s treatment regimen can be refined to their specific condition, rather than trialing a series of broad immune suppressive agents. CTLA-4 haploinsufficiency and LRBA deficiency Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is constitutively expressed on regulatory T cells and inhibits T cell activation (70,71). LPS-responsive beige-like receptor anchor protein (LRBA) is thought to be a regulator of CTLA-4 function. Impacting the same molecular signaling pathway, both CTLA-4 haploinsufficiency and LRBA deficiency lead to abnormal activation and proliferation of T cells resulting in loss of immune tolerance (72-75). While patients have other features including recurrent infections, hypogammaglobulinemia, and lymphocytic infiltration of multiple organ systems, ITP is a feature of both conditions (70,76,77). Abatacept, a fusion protein comprised of the extracellular domain of CTLA-4 bound to IgG1, restores CTLA-4 and ameliorates symptoms of autoimmunity (76,78). Both these conditions present in the early adolescent population and are an important consideration for chronic ITP patients with additional features of immune dysregulation (74). PI3Kδ syndrome Gain-of-function mutations in PI3Kδ lead to activation of the mTOR pathway and, though Akt phosphorylation, Annals of Blood, 2021 Page 9 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 may promote effector T cell development (79). Presenting in children age 1 to 7 years of age, those with PI3Kδ syndrome have autoimmune cytopenias, lymphadenopathy, hepatosplenomegaly and immunodeficiency (80). Sirolimus is an mTOR inhibitor and has been used in treatment of PI3Kδ syndrome. A selective PI3Kδ inhibitor, Leniolisib is currently in clinical trials (81). STAT1 and 3 gain-of-function Excess STAT1 signaling results in skewed Th17 differentiation and hyperresponsiveness to IFN-γ (33). Clinically, patients experience autoimmunity and chronic mucocutaneous candidiasis (82). When stimulated, Janus kinase (JAK) recruit STATs, leading to signal transduction. Ruxolitinib, a JAK inhibitor, acts to correct the molecular defect in these patients, though STAT levels may not correlate directly to symptomatology (83). Excess STAT3 activation leads to suppressed apoptosis via cytokine signaling, including IL-6 (84). Tocilizumab, an IL-6 inhibitor and ABT-737, which targets anti-apoptotic protein Bcl2, are being used as treatments for this condition (85). Potential future pediatric therapies A number of newer agents are being employed for adult ITP management which may eventually have utility in pediatric populations. A transcytosis receptor, the neonatal Fc receptor (FcRn) regulates circulating IgG (86). Inhibition of the FcRn, results in increased lysosomal IgG degradation and subsequently decreases serum IgG levels. Efgardigomod and rozanolixizumab are both novel FcRn receptor antagonists. Phase 2 trials of efgardigomod, a weekly intravenous infusion, showed efficacy and favorable side effect profiles in adults with refractory ITP (87). Rozanolixizumab, a subcutaneous injection, raised platelet counts and decreased IgG levels with minimal side effects in phase 2 trials of adult ITP patients with multiply refractory disease (88). It is currently in phase 3 trials for adult ITP patients (NCT04200456). Neither FcRn antagonist has been studied in children. Avatrombopag is an oral TPO-RA first approved in adults with ITP and chronic liver disease. As of June 2019, its approval was expanded to use in adults with chronic ITP who failed prior therapies (89). Avatrombopag is attractive as a potential future option in children because it is oral and does not have the same dietary restrictions that accompany eltrombopag (90). At the time this article was being written, avatrombopag was going into pediatric clinical trials (NCT04516967). Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor which inhibits Fc receptor mediated platelet destruction. It was approved in 2018 for use in refractory adult ITP patients. A phase III study in multiply refractory adult chronic ITP patients demonstrated 43% of patients achieved a platelet count of ≥50,000/μL at 3 months (91). Due to concerns on effects on cartilage in growing children, it has yet to be studied in pediatrics. Conclusion For many children ITP symptoms are mild and self-resolve, and it would initially seem that treatment is straight forward. However, pediatric ITP is a heterogeneous disorder, with each patient’s case differing in bleeding phenotype, duration of disease and response to therapy. In particular, for those with chronic ITP, multi-lineage cytopenias or individuals with thrombocytopenia which is a component of another underlying systemic disorder, management is even more complex. The field of ITP study continues to identify more genetic risk factors. These can now be leveraged to both elucidate the cause of an individual child’s ITP, and be used to develop better targeted therapies in the future. Acknowledgments Funding: None. Footnote Provenance and Peer Review: This article was commissioned by the Guest Editors (John W. Semple and Rick Kapur) for the series “Treatment of Immune Thrombocytopenia (ITP)” published in Annals of Blood. The article was sent for external peer review organized by the Guest Editors and the editorial office. Peer Review File: Available at http://dx.doi.org/10.21037/ aob-20-96 Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http:// dx.doi.org/10.21037/aob-20-96). The series “Treatment of Immune Thrombocytopenia (ITP)” was commissioned by the editorial office without any funding or sponsorship. Dr. JMD reports grants and personal fees from Novartis, Annals of Blood, 2021 Page 10 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 personal fees from Dova, personal fees from Amgen, personal fees from Uptodate, outside the submitted work. The authors have no other conflicts of interest to declare. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/. References 1. Terrell DR, Beebe LA, Vesely SK, et al. The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. Am J Hematol 2010;85:174-80. 2. Neunert CE, Buchanan GR, Imbach P, et al. Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura. Blood 2008;112:4003-8. 3. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. 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Eltrombopag for use in children with immune thrombocytopenia. Blood Adv 2018;2:454-61. 43. González KJ, Zuluaga SO, DaRos CV, et al. Sequential treatment with thrombopoietin-receptor agonists (TPO RAs) in immune thrombocytopenia (ITP): experience in our center. Ann Hematol 2017;96:507-8. 44. Kuter DJ. Whatever happened to thrombopoietin? Transfusion 2002;42:279-83. 45. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 2001;98:3241-8. 46. Wang S, Yang R, Zou P, et al. A multicenter randomized controlled trial of recombinant human thrombopoietin treatment in patients with primary immune thrombocytopenia. Int J Hematol 2012;96:222-8. 47. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol 2013;98:10-23. 48. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med 2017;376:1540-50. 49. González-López TJ, Pascual C, Alvarez-Roman MT, et al. Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol 2015;90:E40-3. 50. Gilbert MM, Grimes AB, Kim TO, et al. Romiplostim for Annals of Blood, 2021 Page 12 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 the Treatment of Immune Thrombocytopenia: Spotlight on Patient Acceptability and Ease of Use. Patient Prefer Adherence 2020;14:1237-50. 51. Neunert C, Despotovic J, Haley K, et al. Thrombopoietin Receptor Agonist Use in Children: Data From the Pediatric ITP Consortium of North America ICON2 Study. Pediatr Blood Cancer 2016;63:1407-13. 52. Cuker A, Chiang EY, Cines DB. Safety of the thrombopoiesis-stimulating agents for the treatment of immune thrombocytopenia. Curr Drug Saf 2010;5:171-81. 53. Kuter DJ, Mufti GJ, Bain BJ, et al. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood 2009;114:3748-56. 54. Rodeghiero F, Stasi R, Giagounidis A, et al. Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials. Eur J Haematol 2013;91:423-36. 55. Wong RSM, Saleh MN, Khelif A, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood 2017;130:2527-36. 56. Burness CB, Keating GM, Garnock-Jones KP. Eltrombopag: A Review in Paediatric Chronic Immune Thrombocytopenia. Drugs 2016;76:869-78. 57. Vlachodimitropoulou E, Chen YL, Garbowski M, et al. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator. Blood 2017;130:1923-33. 58. Cuker A. Transitioning patients with immune thrombocytopenia to second-line therapy: Challenges and best practices. Am J Hematol 2018;93:816-23. 59. Cuker A, Neunert CE. How I treat refractory immune thrombocytopenia. Blood 2016;128:1547-54. 60. Patel VL, Mahevas M, Lee SY, et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 2012;119:5989-95. 61. Serris A, Amoura Z, Canoui-Poitrine F, et al. Efficacy and safety of rituximab for systemic lupus erythematosus associated immune cytopenias: A multicenter retrospective cohort study of 71 adults. Am J Hematol 2018;93:424-9. 62. Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood 2011;118:5741-51. 63. Levy R, Mahevas M, Galicier L, et al. Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature. Autoimmun Rev 2014;13:1055-63. 64. Einfeld DA, Brown JP, Valentine MA, et al. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J 1988;7:711-7. 65. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435-45. 66. Administration FaD. Rituxan (Rituximab) Package Insert. 2010. 67. Palandri F, Polverelli N, Sollazzo D, et al. Have splenectomy rate and main outcomes of ITP changed after the introduction of new treatments? A monocentric study in the outpatient setting during 35 years. Am J Hematol 2016;91:E267-72. 68. Grace RF, Despotovic JM, Bennett CM, et al. Physician decision making in selection of second-line treatments in immune thrombocytopenia in children. Am J Hematol 2018;93:882-8. 69. Cuker A, Cines DB, Neunert CE. Controversies in the treatment of immune thrombocytopenia. Curr Opin Hematol 2016;23:479-85. 70. Mitsuiki N, Schwab C, Grimbacher B. What did we learn from CTLA-4 insufficiency on the human immune system? Immunol Rev 2019;287:33-49. 71. Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014;345:1623-7. 72. Besnard C, Levy E, Aladjidi N, et al. Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations. Clin Immunol 2018;188:52-7. 73. Kostel Bal S, Haskologlu S, Serwas NK, et al. Multiple Presentations of LRBA Deficiency: a Single-Center Experience. J Clin Immunol 2017;37:790-800. 74. Gámez-Díaz L, August D, Stepensky P, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol 2016;137:223-30. 75. Lopez-Herrera G, Tampella G, Pan-Hammarstrom Q, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet 2012;90:986-1001. 76. Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 2014;20:1410-6. 77. Verma N, Burns SO, Walker LSK, et al. Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin Exp Immunol 2017;190:1-7.Annals of Blood, 2021 Page 13 of 13 © Annals of Blood. All rights reserved. Ann Blood 2021;6:4 | http://dx.doi.org/10.21037/aob-20-96 doi: 10.21037/aob-20-96 Cite this article as: Kim TO, Despotovic JM. Pediatric immune thrombocytopenia (ITP) treatment. Ann Blood 2021;6:4. 78. Lee S, Moon JS, Lee CR, et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allergy Clin Immunol 2016;137:327-30. 79. Grimes AB. Evans Syndrome: Background, Clinical Presentation, Pathophysiology, and Management. In: Despotovic JM, editor. Immune Hematology. Springer International Publishing AG; 2018. 80. Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: A large patient cohort study. J Allergy Clin Immunol 2017;139:597-606.e4. 81. Rao VK, Webster S, Dalm V, et al. Effective "activated PI3Kdelta syndrome"-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood 2017;130:2307-16. 82. Toubiana J, Okada S, Hiller J, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 2016;127:3154-64. 83. Bloomfield M, Kanderova V, Parackova Z, et al. Utility of Ruxolitinib in a Child with Chronic Mucocutaneous Candidiasis Caused by a Novel STAT1 Gain-of-Function Mutation. J Clin Immunol 2018;38:589-601. 84. Forbes LR, Milner J, Haddad E. Signal transducer and activator of transcription 3: a year in review. Curr Opin Hematol 2016;23:23-7. 85. Nabhani S, Schipp C, Miskin H, et al. STAT3 gain of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds. Clin Immunol 2017;181:32-42. 86. Pyzik M, Sand KMK, Hubbard JJ, et al. The Neonatal Fc Receptor (FcRn): A Misnomer? Front Immunol 2019;10:1540. 87. Newland AC, Sanchez-Gonzalez B, Rejto L, et al. Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia. Am J Hematol 2020;95:178-87. 88. Robak T, Kazmierczak M, Jarque I, et al. Phase 2 multiple dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia. Blood Adv 2020;4:4136-46. 89. Pharmaceuticals D. Dova Pharmaceuticals Announces FDA Approval of Supplemental New Drug Application for DOPTELET® (avatrombopag) for Treatment of Chronic Immune Thrombocytopenia (ITP). 2019. Available online: https://www.globenewswire.com/news release/2019/06/27/1875237/0/en/Dova-Pharmaceuticals Announces-FDA-Approval-of-Supplemental-New Drug-Application-for-DOPTELET-avatrombopag-for Treatment-of-Chronic-Immune-Thrombocytopenia-ITP. html. Accessed August 20 2020. 90. Administration FaD. Doptelet (avatrombopag) Package Insert. 2018. 91. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol 2018;93:921-30. ANALYSIS FOR ACCURATE DIAGNOSIS OF DIFFERENT TYPES OF ANEMIA: CURVE OF PRAYS-JONES ONE OF THE IMPORTANT DIAGNOSTIC TESTS TO ESTABLISH A CORRECT AND ACCURATE DIAGNOSIS IS THE MEASUREMENT OF THE DIAMETER OF ERYTHROCYTES – ERITROTSITOPENIA. These eritrotsitopenia represent in a graph. Graphic representation of the ratio of blood red blood cells with different diameters called erythrocytometric Price-Jones curve, where the abscissa axis is deposited the diameter of red blood cells (in microns), and the ordinate axis-the percentage of red blood cells of the corresponding value. In percentage terms, the diameters of red blood cells in healthy people are distributed as follows: 5 microns — 0.4% of all red blood cells; 6 microns — 4%; 7 microns — 39%; 8 microns — 54%; 9 microns — 2.5%. In healthy people eritrotsitopenija curve is correct, with a fairly narrow base, almost symmetrical form. Eritrotsitopenija curve of Prays-Jones in healthy people. The results of eritrotsitopenia are important to clarify the nature of the anemia. In hereditary anemia( microspherocytosis), thalassemia, iron deficiency anemia, lead poisoning-usually reveal a large number of small red blood cells-microcytosis, and accordingly, the shift of the Price-Jones curve to the left. An increase in the number of large red blood cells (macrocytes) is a sign of anemia with a deficiency of vitamin B12 and folic acid. In these forms of anemia, the Price-Jones curve has an irregular flat shape with a wide base and is shifted to the right, that is, towards large diameters. This analysis is especially important to clarify the diagnosis of anemia in children. Iron-deficiency anemia in children Kawsari Abdullah, MBBS, The Hospital for Sick Children, Toronto Stanley Zlotkin, MD, FRCPC, The Hospital for Sick Children, Toronto Patricia Parkin, MD, FRCPC, The Hospital for Sick Children, Toronto Danielle Grenier, MD, FRCPC, Canadian Paediatric Society, Ottawa What is iron-deficiency anemia? Iron deficiency (ID) is a state in which there is insufficient iron to maintain the normal physiological function of blood and tissues, such as the brain and muscles. The more severe stages of ID are associated with anemia. Iron-deficiency anemia (IDA) occurs when the hemoglobin concentration is below two standard deviations (–2SD) of the distribution mean for hemoglobin in an otherwise normal population of the same sex and age.1 IDA is generally characterized by a hemoglobin level of less than 110 g/L, plus a measure of poor iron status.2 Why are children at risk of IDA? Although the cause of IDA among young children can be multifactorial, the consumption of foods with low bioavailable iron is likely the primary contributing factor. Before 24 months of age, rapid growth coincident with frequently inadequate intake of dietary iron places children at the highest risk of any age group for ID.3 In full-term infants, the iron stores can meet the iron requirements until ages four to six months, and IDA generally does not occur until approximately nine months of age. Comparatively, preterm and low-birth-weight infants are born with lower iron stores and grow faster during infancy. Consequently, their iron stores are often depleted by two to three months of age and they are at greater risk for ID.4,5 After 24 months of age, the growth rate of children slows and the diet becomes more diversified, the risk for ID drops.6,7 After 36 months of age, dietary iron and iron status are usually adequate;7 however, risks for ID include limited access to food, a low-iron or other specialized diet, and medical conditions that affect iron status (e.g., malaria or parasitic infections).7 What is the epidemiology of IDA? Around the world, IDA affects approximately 750 million children.8 Using anemia as an indicator, it has been found that at least 30% to 40% of children and pregnant women in industrialized countries are iron deficient.9,10 Data from the third National Health and Nutrition Examination Survey (NHANES III) in the United States indicated that 3% of children aged 12–36 months and less than 1% in the 37–60 months age group had IDA.11 RESOURCES population is Although the prevalence of IDA in Canadian children among the general low (3.5% to 10.5%), there are certain Canadian Aboriginal populations in whom the prevalence is very high (14% to 50%).12-14 Factors associated with the increased prevalence of IDA in these populations include high consumption of evaporated milk and cow’s milk after six months of age, prolonged exclusive breastfeeding and significant burden of Helicobacter pylori infection.8 Other high-risk groups include children from families of low socioeconomic status, children of Chinese background, infants of low birth weight, and children who consume whole cow's milk before 12 months of age.4,5,8,15-17. How can IDA and ID be detected? The most reliable indicator of ID is the bone marrow histopathology; however, this is an invasive procedure that is not needed. The Committee on Nutrition of the American Academy of Pediatrics (AAP) recommends measurement of hemoglobin concentration (Hb) plus tests of iron status.18 For infants of 12 months of age, an Hb level less than 110 g/L is considered anemia. Several tests of iron status are available, but each has limitations. A serum ferritin of less than 10 µg/L has been suggested as a cut-off for children indicating depletion of iron stores; however, as it is an acute phase reactant, the Committee on Nutrition recommends simultaneous measurement of C-reactive protein (CRP). Other promising tests include reticulocyte hemoglobin content (CHr) and serum transferrin receptor 1 (TfR1). What are the clinical signs and symptoms of IDA? The clinical signs of IDA are those of anemia itself. Children with severe ID are often described as irritable, apathetic with a poor appetite. The physical signs of anemia include pallor of the conjunctivae, the tongue, the palms and the nailbeds.19 When anemia is severe, children can also have signs of congestive heart failure with fatigue, tachypnea, hepatomegaly, and edema. What are the risk factors of ID and IDA? The following have been identified as risk factors for ID and IDA: Race/ethnicity Low socioeconomic status Prematurity and low birth weight Excessive milk intake Early introduction of whole cow’s milk Prolonged bottle feeding Prolonged exclusive breastfeeding Overweight and obesity Non-attendance to daycare What long-term problems can IDA cause? ID is a systemic condition impairing physical endurance, work capacity, infant growth and development, and depressing immune function.20 Among these conditions, the association between ID and child development has evoked the most attention among researchers. Decreased brain iron stores may impair the activity of iron-dependent enzymes necessary for the synthesis, function and degradation of neurotransmitters, RESOURCES Iron-deficiency anemia in children (continued) such as dopamine, serotonin and noradrenaline, causing changes in behaviour and lowering of development test scores in children.21 Several extensive reviews have been published on the association between IDA and child development.2,22,23 These reviews have clearly shown that IDA does expose children to concurrent and future risk of poor development. Whether this condition is reversible by treatment of iron has been inconclusive. Of six randomized controlled trials in children less than two years old, only one showed a significant impact. Of eight double-blind, randomized controlled trials of iron therapy in children older than two years, four reported significant outcome.22 This indicates that either the impact of ID is irreversible or there are other factors associated with this condition. However, the authors have cautioned on the results of these studies, as many suffered from lack of statistical power and also very few trials have followed the children after the treatment stopped.22 ID can occur without the presence of anemia, and whether this state is also capable of causing developmental delay in children remains controversial. Only one study has demonstrated a significant effect of iron supplementation in these children.24 Further studies are needed to fully understand the effectiveness of oral iron treatment for children with only ID. How can IDA be prevented? The problem of IDA can be addressed through primary prevention efforts or through the secondary prevention efforts of early detection and subsequent therapy. Primary prevention has the potential of providing benefit to a whole population and preventing the onset of IDA. The Canadian Task Force on Periodic Health Examination (renamed The Canadian Task Force on Preventive Health Care), last updated in 1994, has recommended primary prevention of IDA in infants and preschool children to be achieved through various dietary interventions, including breastfeeding and fortification of formula (if not breast-fed) or infant cereal. These interventions are only effective when they are available and affordable for all children.25 The Nutrition and Gastroenterology Committee of the Canadian Paediatric Society recommends that assuming 10% of the iron in a mixed diet is absorbed, the required iron intake is approximately 7 mg/day for term infants aged five to 12 months, 6 mg/day for toddlers aged one to three years, and 8 mg/day for children aged four to 12 years.26 The AAP Committee on Nutrition recommends that healthy exclusively breast-fed infants be supplemented with 1 mg/kg/day of oral iron beginning at four months of age until iron-containing complementary foods are introduced. Whole milk should not be introduced before 12 months of age. Red meat and vegetables with higher iron content should be introduced early. Preterm infants fed human milk should receive an iron supplement of 2 mg/kg/day by one month of age until weaned to iron-fortified formula or beginning complementary foods.18 Secondary prevention includes efforts to identify children with IDA through screening programs. The success of this approach depends on being able to accurately identify individuals with IDA and on subsequent effectiveness of the therapy.25 Several studies have shown that routine screening for IDA, followed by a therapeutic trial of iron, to be problematic due to low follow-up rates, high spontaneous resolution rate and changing patterns of anemia.27, 28 The effectiveness of screening programs has not been RESOURCES considered investigated through controlled trials; hence, the results cannot be conclusive. The Canadian Task Force on Preventive Health Care concluded there was insufficient evidence to recommend screening for infants between six and 12 months of age. However, for all infants in high-risk groups, physicians may consider screening between six and 12 months of age, perhaps optimally at nine months.27 The AAP recommends screening with hemoglobin at 12 months. If the Hb level is less than 110 g/L at 12 months, additional screening tests should include measurement of serum ferritin plus CRP levels, or CHr concentration.18 What is the recommended treatment for IDA in children? When IDA is identified, the family should be counseled regarding the importance of limiting the total daily milk intake and increasing iron-rich foods, including those with vitamin C that improves iron absorption, and avoiding foods that impair iron absorption such as tea. Children with IDA should also receive iron supplementation. The recommended therapeutic dose of oral iron is 6 mg/kg/day of elemental iron, for three to four months. Adequate follow-up is also important. Conclusion In Canada, IDA in children remains a public health problem, and certain populations of children are at particularly high risk. IDA is associated with poor developmental outcomes in children; the impact of ID is less well understood. Laboratory investigations include hemoglobin and iron tests, such as serum ferritin. Primary prevention of IDA is recommended; the role of secondary prevention through screening programs remains inconclusive but recommended by some professional organizations. Treatment of children identified with IDA includes both dietary counseling and oral iron supplementation. References 1. WHO, UNICEF, UNU. Iron deficiency anaemia: assessment, prevention, and control. A guide for programme managers. Geneva, World Health Organization. 2001;WHO/NHD/01.3. 2. Martins S, Logan S, Gilbert RE. Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia. Cochrane Database of Systematic Reviews, 2001(Issue 2). 3. Yip R. The changing characteristics of childhood iron nutritional status in the United States. In: Filer LJ Jr, ed. Dietary iron: birth to two years. New York, NY: Raven Press 1989:37- 61. 4. Earl R, Woteki CE, éd. Iron deficiency anemia: recommended guidelines for the prevention, detection, and management among U.S. children and women of childbearing age. Washington, DC: National Academy Press, 1993. 5. Dallman PR, Siimes MA, Stekel A. Iron deficiency in infancy and childhood. Am J Clin Nutr 1980;33:86-118. 6. Dallman PR, Looker AC, Johnson CL, Carroll M. Influence of age on laboratory criteria for the diagnosis of iron deficiency anaemia in infants and children. In: Hallberg L, Asp N-G, eds. Iron nutrition in health and disease. London, UK: John Libby & Co., 1996:65-74. 7. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA 1997;277(12):973-6. 8. Christofides A, Schauer C, Zlotkin SH. Iron deficiency anemia among children: Addressing a global public health problem within a Canadian context. Paediatr Child Health 2005;10(10):597-601. RESOURCES Iron-deficiency anemia in children (continued) 9. Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia. Edited by Bruno de Benoist, Erin McLean, Ines Egli, Mary Cogswell. Geneva World Health Organization. 10. The prevalence of anaemia in women: a tabulation of available information. Geneva WHO, 1992 (WHO/MCH/MSM/92.2). 11. Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR 1998;47(No. RR-3). 12. Canadian Paediatric Society, Dietitians of Canada, Health Canada. Nutrition for healthy term infants. Ottawa: Minister of Public Works and Government Services, 1998. 13. Christofides A, Schauer C, Zlotkin SH. Iron deficiency and anemia prevalence and associated etiologic risk factors in First Nations and Inuit communities in northern Ontario and Nunavut. Can J Public Health 2005;96:304-7. 14. Harfield D. Iron deficiency is a public health problem in Canadian infants and children. Paediatr Child Health 2010;15:347-50. 15. Greene-Finestone L, Feldman W, Heick H, et al. Prevalence and risk factors of iron depletion and iron deficiency anemia among infants in Ottawa-Carlton. Can Diet Assoc J 1991;52:20-3. 16. Chan-Yip A, Gray-Donald K. Prevalence of iron deficiency among Chinese children aged 6 to 36 months in Montreal. Can Med Assoc J 1987;136:373-8. 17. Tunnessen WW Jr, Oski FA. Consequences of starting whole cow milk at 6 months of age. J Pediatr 1987;111:813-6. 18. Baker RD, Greer FR, and the Committee on Nutrition, American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron deficiency anemia in infants and young children. Pediatrics 2010;126:1040-50. 19. Kalantri A, Karambelkar M, Joshi R, Kalantri S, Jajoo U. Accuracy and reliability of pallor for detecting anaemia: a hospital-based diagnostic accuracy study. PLoS ONE 2010;5(1):e8545. 20. Dallman PR. Manifestations of iron deficiency. Semin Hematol 1982;19:19-30. 21. Dallman PR. Biochemical basis for the manifestation of iron deficiency. Annu Rev Nutr 1986;6:13-40. 22. Grantham-McGregor S. Ani C. A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr 2001;131:649S-68S. 23. Sachdev HPS, Gera T, Nestel P. Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials. Public Health Nutrition 2004;8(2):117–32. 24. Akman M, Cebeci D, Okur V, Angin H, Abali O, Akman AC. The effects of iron deficiency on infants’ developmental test performance. Acta Paediatrica 2004;93(10):1391-6. 25. Feightner JW. Prevention of iron deficiency anemia in infants. In: Canadian Task Force on the Periodic Health Examination. Canadian Guide to Clinical Preventive Health Care. Ottawa: Health Canada, 1994:244-55. 26. Nutrition Committee, Canadian Pediatric Society: Meeting the iron needs of infants and young children: an update. Can Med Assoc J 1991;144:1451-4. 27. Bogen DL, Krause JP, Serwint JR. Outcome of children identified as anemic by routine screening in an inner-city clinic. Arch Pediatr Adolesc Med 2001;155:366-71. 28. James J A, Laing GJ, Logan S. Changing patterns of iron deficiency anaemia in the second year of life. BMJ 1995;311:230. RESOURCES 1. Iron-deficiency anemia (IDA) is characterized by: Quiz a) hemoglobin level of