Anemia
Red cell production is driven by oxygen availability to tissues and oxygen requirements, thus varying greatly with age, activity, and environmental circumstances, such as altitude. The lower limits of normal hemoglobin levels range from 9.5 g/dL at three months of age to 11 g/dL in the teenager
Clinical Presentation
The signs and symptoms of anemia result from the decreased oxygen-carrying capacity of the blood and depend on the degree of anemia and acuteness of onset. Exercise intolerance, pallor, headache, fatigue, tachycardia, and systolic murmurs may occur with moderate anemia. Severe or rapidly developing anemia can cause nonexertional dyspnea, dizziness, orthostatic vital sign changes, cardiac gallop, syncope, hypotension, and heart failure.
Diagnosis
After determining that a patient is anemic for age with a CBC with red-cell indices, a reticulocyte count, and examination of the peripheral smear, the most expeditious way of narrowing the differential diagnosis is using an algorithm based on the red cell size (see Table 12.1). Microcytic anemias are due to delayed or abnormal hemoglobin formation, with disorders of the iron, globin chain, or porphyrin ring components. These disorders typically have decreased MCV, with a peripheral blood smear revealing hypochromic red cells. To further establish a diagnosis, consider additional testing such as iron and ferritin levels, hemoglobin electrophoresis, and a lead level. The Menser index (MCV in fL divided by the red blood cells [RBC] in millions: MCV/RBC) can help differentiate among the microcytic anemias. If the ratio is less than 11:1, thalassemia minor is likely, while a ratio greater than 14:1 suggests iron deficiency, lead intoxication, or anemia of chronic disease.
| Microcytic |
| Anemia of chronic disease |
| Chronic lead poisoning |
| Copper deficiency |
| Iron deficiency |
| Sideroblastic anemia |
| Thalassemia |
| Macrocytic |
| Diamond–Blackfan syndrome |
| Dyserythropoietic anemia |
| Fanconi’s anemia |
| Folic acid deficiency |
| Hypothyroidism |
| Liver disease |
| Myelodysplasia |
| Vitamin B12 deficiency |
| Normocytic: ↓reticulocytes |
| Acquired aplastic anemia |
| Chronic renal disease |
| Drug suppression |
| Leukemia |
| Neuroblastoma |
| Transient erythroblastopenia |
| Viral marrow suppression |
| Normocytic: ↑reticulocytes |
| Acute blood loss |
| G-6-PD deficiency |
| Hemoglobin C disease |
| Immune hemolytic anemia |
| Infectious agents (e.g., malaria) |
| Mechanical or thermal damage |
| Pyruvate kinase deficiency |
| Sickle cell disease |
| Spherocytosis, elliptocytosis |
| Splenic sequestration |
The uncommon macrocytic anemias with MCV >100 fL beyond the newborn period result from delayed nuclear maturation or elevated fetal hemoglobin content.
The normocytic anemias comprise the largest differential. The reticulocyte count and some additional features of the red cells can help establish the diagnosis.
Red Cell Shape
Variations in red cell shape include sickle cells (both crescent and “box car” shapes); target cells, often seen in hemoglobinopathies (especially Hgb C disease and the microcytic thalassemia syndromes) and liver disease; burr cells (renal disease, hemolysis); spherocytes (spherocytosis, ABO immune hemolysis); and schistocytes (hemolysis).
Color
Polychromasia occurs with increased RBC production in association with decreased life span or marrow recovery. This is usually indicative of an elevated reticulocyte count.
Inclusions
There may be Howell–Jolly bodies (decreased splenic function); basophilic stippling (thalassemia, lead poisoning, some enzyme deficiencies); or parasites (malaria, babesiosis).
History
A thorough history, including ethnicity, family background, and diet, is important in refining the etiology of anemia. Iron-deficiency anemia can be caused by excessive intake of cow’s milk in infants or by restricted diets containing no reliable source of iron in older children. A complete lack of fresh vegetables might lead to folate deficiency. Unusual cravings, such as pagophagia and pica, are occasionally seen in patients with iron deficiency, and may further complicate the picture (e.g., causing ingestion of lead-containing paint chips).
A history of recent infections may suggest EBV or Mycoplasma-induced hemolysis, or parvovirus suppression of the bone marrow (particularly in patients with chronic hemolytic disorders). Inquire about blood loss, such as epistaxis, irregular menstrual bleeding, hematuria, or gastrointestinal bleeding. A history of unexplained or prolonged bleeding may suggest a hemostatic disorder, such as mild von Willebrand disease, that is contributing to anemia. Ask about chronic medical problems and inflammatory disorders, such as juvenile rheumatoid arthritis, inflammatory bowel disease (IBD), or gastrointestinal (GI) complaints (abdominal pain or bloating, chronic diarrhea) that might suggest celiac disease. Recurrent episodes of jaundice suggest hemolytic disorders such as G-6-PD deficiency, hemoglobinopathies, and spherocytosis. A patient with a hemolytic disorder may have a positive family history for anemia, intermittent jaundice, cholecystectomy in a young person, or non-traumatic splenectomy (hereditary spherocytosis, sickle cell disease, and some enzyme deficiencies). Ask about medication use, since many medications can suppress erythropoiesis (e.g., sulfa drugs and anticonvulsants) or trigger hemolysis in patients with G-6-PD deficiency.
Physical Examination
On examination, a healthy, vigorous child is more likely to have mild iron-deficiency anemia, thalassemia trait, or a mild chronic hemolytic anemia. A patient with a malignancy, severe malnutrition, severe chronic disease, or bone marrow infiltration usually appears ill. Jaundice, often accompanied by abdominal pain, splenomegaly and dark urine, is frequently seen in hemolytic processes. Untreated or undiagnosed thalassemia major or intermedia is often associated with frontal bossing, malar prominence, hepatosplenomegaly, and dental malocclusion. Generalized lymphadenopathy and hepatosplenomegaly are frequent features of myeloproliferative disorders and malignancies, especially leukemia and lymphoma. Petechiae, purpura, and multiple ecchymoses can be expected in hemostatic disorders. Orthopedic anomalies may suggest Fanconi’s anemia (abnormal radii or thumbs) or Diamond–Blackfan syndrome (triphalangeal or bifid thumbs).
Iron Deficiency
Iron deficiency is the most likely diagnosis in an otherwise well child with mild-to-moderate microcytic, hypochromic anemia. While inadequate dietary intake of iron is the most common cause of iron deficiency in a young child, blood loss is more likely in an older child or adolescent.
ED Management
Iron Deficiency
Treat with oral ferrous sulfate, 6 mg/kg/day of elemental iron divided tid between meals. Give with juice (vitamin C enhances iron absorption), but not with milk, which impairs iron absorption. If there is difficulty with administration, give the iron as a single daily dose. Or, for young children, recommend iron gummies (15 mg ferrous fumarate = 5 mg elemental iron). A rise in hemoglobin and reticulocyte count after one week confirms both the diagnosis and adherence to the regimen. Lack of response suggests an incorrect diagnosis, ongoing blood loss, incorrect dose, malabsorption, or noncompliance with medication. Advise the patient or parents that GI complaints, particularly constipation and darkening of stools, may result from iron therapy. For occasional epigastric discomfort, divide the iron doses into smaller volumes at more frequent intervals or administer with food (not milk). Admit a patient with severe anemia and consult with a hematologist to consider a single dose of intravenous iron sucrose (0.5 mg/kg), which is a safe and well-tolerated preparation that facilitates a more rapid correction of anemia.
Blood Loss
Blood loss, particularly when acute, may require treatment with packed RBCs, especially if the patient is symptomatic (pronounced tachycardia, orthostatic hypotension, syncope). Do not rely solely on the level of the hematocrit to decide if a transfusion is necessary, since children often tolerate extremely low red cell counts without exhibiting any symptoms, if the anemia developed slowly. Consider associated clinical findings, such as resting heart rate and respiratory rate, as well as the likelihood of a further imminent decrease in the hematocrit in bleeding conditions. Other diseases that might warrant a transfusion include disorders associated with decreased erythrocyte production as seen in either bone marrow failure (aplastic anemia, transient erythroblastopenia of childhood, nutritional anemias, and drug-induced marrow suppression) or marrow replacement (leukemia, neuroblastoma, histiocytosis, storage disorders). Consult a pediatric hematologist before giving blood to these patients (see Transfusion Therapy, pp. 377–378).
Autoimmune Hemolytic Anemia
Initially treat with prednisone (2.5 mg/kg/day) after consultation with a pediatric hematologist. Packed red cell transfusions might be required, but this disorder can be associated with a high risk of transfusion reactions.
The treatment of most primary hematologic etiologies of anemia, other than iron deficiency, lead intoxication, and bleeding, usually requires consultation with a pediatric hematologist.
Indications for Admission
Significant cardiovascular or cerebral symptomatology (syncope, tachycardia, heart failure)
Acute blood loss requiring transfusion
Pancytopenia or suspicion of a malignancy
Acute Coombs positive or extrinsic hemolytic anemia with hemoglobin <8 g/dL
Chronic hemolytic disease with acute reticulocytopenia and significant fall in hematocrit (aplastic crisis seen in sickle cell disease and spherocytosis)
Severe glucose-6-phosphate dehydrogenase (G-6-PD) deficiency with exposure to oxidant stress (e.g., infections, mothballs, sulfonamides, antimalarials)
Hemoglobin <5 g/dL
Bibliography
Hemostatic Disorders
Thrombocytopenia involves a decrease in the number of circulating platelets secondary to underproduction, as in marrow failure (aplasia, infections, or drugs) or marrow replacement (leukemia, storage disorders, histiocytosis); increased peripheral destruction (immune thrombocytopenic purpura [ITP], hypersplenism, infections, hemangiomas); ineffective production (myelodysplasia); or microangiopathic processes (hemolytic-uremic syndrome, disseminated intravascular coagulation ([DIC]).
Platelet dysfunction can also cause bleeding manifestations. These disorders of platelet function can be acquired (uremia; ingestion of aspirin or nonsteroidal anti-inflammatory medications) or inherited (von Willebrand disease, storage pool disorder).
Coagulation factors are necessary for the formation of fibrin strands at bleeding sites. Hemorrhage can occur when any of these proteins are either decreased in amount or dysfunctional. Factor activity is decreased in inherited deficiencies (hemophilia [factor VIII or IX] and von Willebrand disease), vitamin K deficiency (normal newborns, sodium warfarin [Coumadin] therapy, prolonged oral antibiotic therapy), liver failure, and disseminated intravascular coagulation (DIC).
The endothelium is responsible for the production of factor VIII and prostacyclin (a platelet inhibitor) and the insulation of coagulation factors and platelets from exposure to underlying collagen. Dysfunction of the endothelial system is observed in vasculitis (lupus, Henoch–Schönlein purpura) and infections (meningococcemia, Rickettsia, dengue fever).
Clinical Presentation
The presenting complaint of hemostatic disorders may vary greatly, depending on the location, acuity, and severity of bleeding. Platelet abnormalities are commonly associated with petechial or mucosal bleeding that occurs immediately after the trauma and will often respond to local pressure. With ITP, skin and mucosal bleeding often follow a benign viral illness or measles vaccination. Patients with coagulation factor abnormalities, particularly the hemophilias, may have delayed, posttraumatic deep tissue hemorrhages into muscles and joints. In the first few weeks of life, a coagulopathy may present with delayed, persistent bleeding from the circumcision site or the umbilical stump. Abrasions and tooth extractions respond poorly to local pressure and can continue to ooze and bleed for days. Bleeding secondary to vasculitis (such as Henoch–Schönlein purpura) usually presents as palpable purpura.
Diagnosis
Suspect a bleeding disorder in a child who presents with a history of bruising or bleeding that is out of proportion to the level of trauma, bleeding in unusual locations, spontaneous hemorrhage, and prolonged or recurrent bleeding. Ask about a family history of inherited hemorrhagic disorders, such as hemophilia A and B (X-linked), factor XI deficiency (autosomal recessive), and von Willebrand disease (usually autosomal dominant), or unexplained significant bleeding, particularly if a blood transfusion was necessary. A seriously ill child may have leukemia (pallor, fever, fatigue, hepatomegaly, lymphadenopathy), hemolytic-uremic syndrome (lethargy, diarrhea, oliguria), liver disease (vomiting, jaundice, hepatomegaly, dark urine, acholic stools), or DIC.
The diagnosis can be facilitated by a few simple screening tests. Platelet count; prothrombin time (PT) or international normalized ratio (INR), which assess the extrinsic clotting system (factor VII, plus the factors in the common pathway [I, II, V, X]); and partial thromboplastin time (PTT) for the intrinsic system (factors VIII, IX, XI, XII, plus the factors in the common pathway [I, II, V, X]) (see Tables 12.2 and 12.3).
| Platelet count* | Prothrombin time* | Partial thromboplastin time* | Diagnoses |
|---|---|---|---|
| Normal | Prolonged | Normal | Circulating antibodies |
| Coumadin ingestion | |||
| Factor VII deficiency | |||
| Mild liver disease | |||
| Mild vitamin K deficiency | |||
| Normal | Normal | Prolonged | Circulating antibodies |
| Factor VIII, IX, XI, or XII deficiency | |||
| Heparin effect | |||
| von Willebrand disease | |||
| Decreased | Prolonged | Prolonged | Congenital heart disease |
| DIC | |||
| Severe liver disease | |||
| Decreased | Normal | Normal | Thrombocytopenia |
| Normal | Prolonged | Prolonged | Dysfibrinogenemia |
| Factor II, V, or X deficiency | |||
| High-dose heparin or warfarin therapy | |||
| Moderate liver disease | |||
| Vitamin K deficiency | |||
| Normal | Normal | Normal | Child abuse and trauma |
| Connective tissue disease | |||
| Factor XIII deficiency | |||
| Henoch–Schönlein purpura and other vasculitides | |||
| Platelet dysfunction (inherited and acquired) | |||
| Renal failure | |||
| Vitamin C deficiency | |||
| von Willebrand disease |
* Normal values: platelet count: 150,000–300,000/mm3; PT: <13 seconds or within 2 seconds of control or INR <1.2; PTT: <35–39 seconds or within 5 seconds of control.
| Diagnosis | Differentiating features |
|---|---|
| Drug induced | Taking antibiotics for 1–2 weeks |
| Epstein–Barr virus | Fever, fatigue, pharyngitis, splenomegaly |
| Fanconi’s anemia | Short stature, abnormal thumbs, café-au-lait spots, macrocytosis |
| Gaucher’s disease | Family history; bone pain, pathologic fractures, splenomegaly |
| Histiocytosis | Eczema, chronic otitis, bone lesions, hepatosplenomegaly |
| HIV | Adenopathy, recurrent infections, bruising, pallor, lymphopenia |
| HUS | Bloody diarrhea, lethargy, oliguria, pallor, jaundice |
| ITP | Extensive bruising and petechiae in a well-appearing child |
| ↑ MPV | |
| RBCs and WBCs are normal | |
| Kasabach–Merritt syndrome | Enlarged portions of extremities, bleeding |
| Leukemia | Fever, bruising, pallor, adenopathy, abnormal white cells |
| Malaria | High fever, jaundice, splenomegaly, foreign travel |
| May–Hegglin anomaly | Family history of bruising and petechiae |
| ↑↑ MPV | |
| WBC inclusions | |
| Meningococcemia | Fever and toxicity; palpable purpura, hypotension |
| Neuroblastoma | Fever, lower extremity weakness, abdominal mass |
| Osteopetrosis | Infant with severely impaired vision; bruising, splenomegaly, |
| Thrombocytopenia-absent radii | Bleeding from birth, abnormal forearms |
| Wiskott–Aldrich syndrome | Infant boy with eczema, frequent infections, ↓ MPV |
ED Management
Give a patient with vitamin K deficiency who is actively bleeding 5–10 mg of vitamin K by slow IV infusion. Correction of coagulation factor levels begins within hours, with marked improvement by 24 hours. Treat severe bleeding with an infusion of fresh frozen plasma to rapidly correct the deficiencies. If there is a history of warfarin ingestion, a repeat administration of vitamin K might be necessary.
Treat thrombocytopenic conditions with local pressure to superficial bleeding sites. If this is unsuccessful, or the platelet count is <50,000/mm3, obtain a type and cross-match and consult a pediatric hematologist. Treat a patient with documented ITP and serious, life-threatening bleeding with high-dose intravenous gamma globulin (0.5–1.0 g/kg over 4–5 hours) or high-dose corticosteroids (methylprednisolone 20–40 mg/kg over 1 hour), while awaiting consultation with a hematologist. A platelet transfusion will not raise the platelet count but can slow life-threatening bleeding. A patient who is Rh positive can also be treated with WinRho, 50 mcg/kg. For a patient with thrombocytopenia caused by decreased production (leukemia, other marrow failure syndromes), transfuse single-donor apheresis platelets (see Transfusion Therapy, pp. 377–378).
Replace deficient clotting factors as soon as possible. As a general rule, 1 unit/kg of factor VIII will raise a patient’s factor level by 2%. Always consult with a hematologist before treating a coagulopathy patient with factor replacement, as the selection and dose of the factor product varies greatly and several synthetic, long-acting products are now available. Factor VII concentrate will often treat a variety of coagulopathies. Avoid giving aspirin and other medications that can inhibit proper platelet function to any child with a bleeding diathesis.
Obtain a CT scan of the head for a patient with a hemostatic disorder who has a moderate or severe headache or any neurologic symptoms (irritability, lethargy, vomiting, ataxia, loss of consciousness) after head trauma.
Follow-up
Indications for Admission
Massive bleeding that causes hypovolemia or requires transfusion of packed RBCs
Suspected or proven intracranial, intrathoracic, or abdominal hemorrhage
Hemophiliacs or patients with other severe hemostatic disorders who sustain significant head trauma (e.g., lethargic, skull fracture, abnormal neurologic finding, or loss of consciousness)
Significant hematemesis, hematochezia, or hematuria
Severe inherited coagulopathy with gross hematuria, large laceration, or severe abdominal pain
Clinical features suspicious for marrow replacement, DIC, hemolytic-uremic syndrome, or hepatic failure
Generalized petechial or purpuric eruption in an acutely ill febrile child
Bibliography
Infection and the Immunocompromised Host
The hallmark of an immunocompromised patient is an increased susceptibility to infection, including increased frequency, duration, and severity, as well as infection caused by unusual pathogens.
Clinical Presentation
Although symptoms will vary with the organism and site of infection, immunocompromised patients often have recurrent respiratory infections and repeated severe bacterial illnesses (sepsis, pneumonia, meningitis). Persistent lymphadenopathy and hepatosplenomegaly are common findings in these disorders. Many patients have chronic diarrhea with some form of malabsorption and failure to thrive (IgA deficiency, exocrine pancreatic insufficiency). A variety of skin lesions can be seen, including eczema (Wiskott–Aldrich syndrome), pyoderma (cyclic neutropenia, Kostmann’s syndrome, Job syndrome), and diffuse dermatitis (chronic granulomatous disease).
HIV infection presents in a variety of ways: lymphadenopathy, hepatosplenomegaly, and failure to thrive in an infant with maternal risk factors; a multiply-transfused child with interstitial pneumonitis; or a child with poorly responsive immune thrombocytopenic purpura.
Although most children with sickle cell disease are identified early in life by newborn hemoglobinopathy screening, a Caucasian child of Mediterranean background with unsuspected sickle cell disease may present with frequent bouts of unexplained bone pain, leukocytosis, and a chronic hemolytic anemia.
Lymphoma in an adolescent can cause adenopathy, fever, weight loss, splenomegaly, and herpes zoster or prolonged varicella infection.
Diagnosis
Prior to proceeding with an extensive immunologic evaluation, try to differentiate the immunodeficient child from one with frequent colds and normal immunologic function. Children can have 8–10 respiratory infections in any given year, but these are usually mild, self-limited, occasionally accompanied by fever, but with complete recovery between bouts. Allergy is more likely in children with repeated or persistent infections limited to the upper respiratory tract. An incompletely treated sinusitis or enlarged tonsils/adenoids are frequent underlying causes of recurrent upper respiratory infections. Likewise, infections limited to a particular organ suggest specific disease entities: cystic fibrosis, foreign body, collagen vascular diseases, or bronchiectasis with recurrent pneumonia; cow’s milk sensitivity, celiac disease, and IBD with chronic diarrhea and failure to thrive. Many chronic diseases predispose patients to frequent infections (rheumatic disorders, chronic renal disease, sickle cell disease, diabetes, nutritional deficiencies, malignancies). Finally, a history of blood product administration to the patient or parent, intravenous drug abuse, or high-risk sexual activity raises the possibility of HIV infection.
ED Management
If the child has had either two or more serious infections (pneumonia, meningitis, sepsis, osteomyelitis) in a short period of time or an infection with an unusual pathogen, obtain a CBC with differential and platelet count, ESR, and quantitative immunoglobulins. In addition, evaluate cell-mediated immunity by measuring T-cell subsets and consider skin testing (Candida, streptokinase-streptodornase, mumps, and purified protein derivative [PPD]). Assume that any patient with a history of treatment with chemotherapeutic drugs for malignancy or autoimmune disorders, or with immunosuppressive medications (corticosteroids for asthma or IBD; infliximab or adalimumab for IBD) is at high risk for infections. Consult a pediatric hematologist or immunologist for further evaluation with specific definitive tests.
When a patient with a known immunodeficiency or neutrophil disorder presents with a fever (>38.6 °C, 101.5 °F), a conservative approach is necessary. Obtain a CBC and cultures of the blood, urine, and any wounds prior to initiating treatment. If there are central nervous system symptoms, perform a lumbar puncture with additional fluid to evaluate for unusual organisms (mycobacteria, India ink stain for Cryptococcus, viral encephalitis panel [including herpes]) in addition to the standard culture, cell count, glucose, and Gram stain.
Treat an ill-appearing neutropenic patient with a combination of an aminoglycoside such as tobramycin or gentamicin (6 mg/kg/day IV div q 8–12h) and either a semisynthetic penicillin (piperacillin/tazobactam 250 mg/kg/day IV div q 6h) or ceftazidime (100 mg/kg/day IV div q 8h) or meropenem (60 mg/kg/day IV div q 8h) for adequate Pseudomonas coverage. Cefepime (100 mg/kg/day IV div q 12h) can be used for monotherapy in a patient who does not appear seriously ill or unstable.
Treat a child with defective cell-mediated immunity who has fever and respiratory symptoms with trimethoprim-sulfamethoxazole (20 mg/kg/day of TMP div q 6h) along with broad-spectrum antibiotics, as listed above. Treat patients with splenic dysfunction with ceftriaxone or cefuroxime (100 mg/kg/day). If the patient has a very high fever or a toxic appearance, add vancomycin (60 mg/kg/day div q 6h) to cover resistant Pneumococcus and Staphylococcus. Consult a hematologist for patients with neutrophil disorders who have serious infections, as granulocyte transfusions or granulocyte colony stimulating factor (G-CSF), 5 mg/kg/day, may be indicated. With the advent of more resistant organisms such as vancomycin-resistant enterococcus and methicillin-resistant S. aureus, other antibiotic combinations often need to be explored with an infectious disease expert or hematologist.
Often a well-appearing child can be managed as an outpatient after receiving broad-spectrum antibiotics and a period of observation in the ED. Cefepime, with or without a 24-hour dose of aminoglycoside, is one option for the neutropenic patient, with follow-up the following day.
Follow-up
Indications for Admission
Fever (>38.5 °C, 101.5 °F) in a patient with a granulocyte count <500/mm3, a documented phagocytic defect, or other immunodeficiency, after consultation with a hematologist
Immunocompromised patient with pneumonia, an abscess, or localized infection (e.g., otitis, cellulitis) not responding to initial antibiotic therapy
Patient with sickle cell disease under two years old with fever >39 °C (102.2 °F); older patient with high fever (>39.5 °C, 103.1 °F)
Suspected malignancy
Immunocompromised patient with a toxic appearance, regardless of the temperature
Varicella or herpes zoster infection in a child with defective cell-mediated immunity
Bibliography
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