Sometimes a single cause may be the culprit when a child presents with multiple symptoms. However, there are those times when multiple symptoms stem from multiple causes, creating a diagnostic dilemma. To derive the most probable diagnoses and appropriate treatment plans, methodical synthesis of data about each of the multiple possible causes is imperative. Developing a schema for analyzing complex situations is essential for practitioners.
1. Develop a schema for approaching/evaluating the child who presents with multiple symptoms.
2. Integrate environmental histories into the data gathering for pediatric clients and their families.
3. Assess the child who presents with hematologic symptoms.
4. Analyze basic hematologic laboratory studies.
5. Differentiate among the causes and presentations of various anemias.
6. Integrate cultural information that might affect any aspect of the child’s diagnosis, treatment, or compliance.
7. Integrate age-relevant information into the decision-making process.
Case Presentation and Discussion
Oswaldo Garcia, an 18-month-old, is here for his well-child visit. He is with his mother and the clinic’s interpreter. Mrs. Garcia tells you that her family and friends in the housing area have expressed concern lately because the child is so pale and skinny. He recently has had a few nosebleeds and seems fussier than usual without any identifiable cause. You now look at Oswaldo for the first time and note blatant pallor in a quiet toddler sitting complacently on his mother’s lap. He is wearing a diaper and tee shirt, with a holy medal around his neck and his thumb in his mouth.
What aspects of the history would be useful to help you refine the nature of Oswaldo’s problem?
The following information would be helpful:
• History of present illness
• Past medical history
• Family medical history
• Social history
• Environmental history
• Complete review of systems
Oswaldo was last seen in the clinic 3 months ago for an ear infection and fever, and at that time he was given amoxicillin. Although he did not come in for follow-up, Mrs. Garcia reports that he got better very fast and has been fine. She states that she had an uncomplicated pregnancy except for hyperemesis and poor weight gain in the first 4 months of pregnancy. Her labor and delivery were uneventful, and he was discharged home at 2 days with mom and had no problems as a neonate. He has had no hospitalizations, surgeries, major illnesses, or visits to the emergency department.
Family medical history: The family consists of Mr. and Mrs. Garcia, Miguel (age 12 years, has mild asthma); Anna (age 10 years, in good health); Ignatio (age 9 years, recently diagnosed with ADHD), and Maria (age 5 years, with a seizure disorder for the past year). The parents are in good health, do not smoke or take medication, and have had no health problems. There is no family medical history of bleeding problems, G6PD, Fanconi anemia, chronic blood problems, autoimmune diseases, gall stone surgery, splenectomy, or heart disease.
Social history: The family moved to Yakima Valley, Washington, 6 months ago from California to work in the orchards. They had worked in California for a few years in the citrus industry before coming to Washington to be closer to family and to work at the same place year-round. Mrs. Garcia reports that the necklace that Oswaldo wears is a holy medal to keep him safe, which was given to him by his grandmother at his christening. Oswaldo’s mom confides that since his change in activity and appetite, the ladies and parents have been praying to the Virgin for Oswaldo and light many candles. The curandera gave them tea to help Oswaldo, amulets of the Virgin for the Mal de Ojo, and oils to rub in for the “empacho” (Kemp, 2005). Box 19-1 discusses Mexican/Chicano health practices that may provide insight about their health belief system.
Environmental history: The family lives in a three-bedroom apartment in the company’s housing complex, which was built just after World War II. The apple orchard and fruit farm where Oswaldo’s father is employed utilizes pesticides, and the workers wear masks when they apply it. Dad does not change clothes before coming home and playing with the children. They recently have had problems with mice in the apartment so the parents put out some rat poison (super warfarin). There has not been any observed contact with the poison by any of the children, but Mrs. Garcia admits that she does not watch each of the children every second. The other children are all doing fine except as noted above.
Box 19–1 Mexican/Chicano Health Practices
• Mexican immigrants are typically Roman Catholic with a spiritualism that also harkens to their Aztec and Mayan predecessors.
• Healers, or curanderas, are usually females (mothers, grandmothers) who have learned their healing practices through an ages-old apprenticeship process.
• Prayer is commonly used to help with healing, especially prayer to important saints such as the Virgin of Guadalupe or Our Lady of San Juan.
• Families commonly have shrines in their homes where they lay amulets and light candles.
• When faced with illness, prayer, lighting of candles, wearing of holy medals and amulets, and even pilgrimages to shrines are common practices.
• Herbs, teas, and massage are also commonly employed as cures.
• Health is a matter of balance. The major balance is hot–cold. Belief in the fundamental nature of the hot–cold balance in health regulation may have an influence about what the sick person may eat, what medicine they will take, and when they do. An example of a “cold” illness is empacho, which literally translated means an impacted stomach. Anyone can have empacho, but it is commonly associated with gastrointestinal illnesses of children. This “cold” illness is said to be caused by soft or hard-to-digest foods adhering to the stomach wall.
• The curandera is an integral member of the immigrant’s community with personal ties to the families she treats. Children and their families are not likely to reveal their interactions with these traditional healers until they feel very comfortable with the clinic and the provider.
Sources: Based on Spector, R. (1996). Culture and diversity in health and illness (4th ed.). Stamford, CT: Appleton & Lange; Kemp, C. (2005). Mexicans and Mexican-Americans: health beliefs and practices. Retrieved April 10, 2009, from http://bearspace.baylor.edu/Charles_Kemp/www/hispanic_health.htm
Review of systems: Because her son sometimes has “crampy stomachaches,” Mrs. Garcia gives him Maltsupex 1 tsp, which she adds to his bottle once or twice per week to help him move his bowels when he seems to have a stomachache. Amoxicillin was completed 2 weeks ago; she denies using herbals or other complementary or alternative medicine (CAM) remedies. Mom has not noticed rashes or lesions except for increased bruising for about a month. When he fusses, which he does more and more lately, he shakes his head and closes his eyes. He seems to focus on objects; his eyes are clear with no redness or discharge. He has had several nosebleeds over the past couple of weeks, which seem to be more frequent the past few days. There is cracking at the corners of his mouth, and his tongue looks redder to his mother than usual but doesn’t seem to hurt him.
There is no history of diarrhea or vomiting; he is still in diapers. Stools are dark clay-like about twice per week. No blood noted in his stools. He is a picky eater, preferring to drink cow’s milk from the bottle, which he carries around with him. As he has gotten thinner and paler, mom has just been happy with whatever he eats. For breakfast he usually eats some oatmeal and fruit, lunch consists of some vegetables and rice, and dinner is rice and beans or casseroles. There is always fruit to eat at home, which mom washes as soon as she brings it home. Total cow’s milk ingestion is between 32 and 40 ounces per day.
A review of his development reveals that he sat up at 6 months, stood alone at 11 months, is now walking, but lately prefers to crawl again. He said his first word at 12 months, now has 8–10 words in Spanish, puts everything in his mouth, and eats dirt when he plays outside. He plays quietly, preferring more and more to watch others play.
What should you know about the use of Maltsupex?
Maltsupex is commonly used in Mexican American populations for the treatment of constipation. You will address the use of laxatives with Oswaldo as part of your management plan.
Considering the child’s age and developmental stage, what are the most common etiologies for pallor and anemia?
What possible causes for this presentation come immediately to mind?
Acquired pallor in a toddler is unusual and should cause one to think of problems of cutaneous blood flow, anemia, or some unknown mechanism. At 18 months of age, the likelihood of cutaneous blood flow issues is rare; anemia is much more likely. The recent onset of the pallor is more indicative of anemia. Anemia is diagnosed when the hemoglobin concentration (hematocrit) is more than two standard deviations below the mean. Pallor can also occur in association with bleeding, which expands diagnostic possibilities to include leukemia.
Based on the information at hand, what are your priorities for assessment during the physical examination?
There may have been exposure to several environmental toxins—rat poison (blood thinner), pesticides from the orchard transmitted on father’s clothes (neurotoxin), and soil toxins such as lead or pesticides consumed via his pica behavior. The diet is inadequate in iron due to large quantities of milk ingestion and low ingestions of foods high in iron, and the milk ingestion could contribute to his constipation. Oswaldo’s development has regressed slightly, as demonstrated by his now preferring crawling to walking. Oswaldo has become more sedentary and irritable over the past few weeks. Therefore, the neurological, skin and mucus membrane, abdominal, and cardiac examinations will be key areas to evaluate during the physical examination. A developmental assessment will also provide important information.
Likewise, the healthcare provider should review his growth chart (see Table 19-1), which reveals that his height to weight ratio has stayed around 10% from birth, but over the past 6 months a decline in his growth trajectory is evident by a flattened curve. Currently, height and weight are below the third percentile.
Table 19–1 Measurements from Oswaldo’s Healthcare Visits
Oswaldo presents as a quiet, attentive, subdued child sitting on mom’s lap without moving around or reaching for toys or other objects. His vital signs are heart rate 112, respiratory rate 24, and height and weight below the third percentile. There are multiple 1 × 1 cm to 2 × 3 cm bruises of varying ages notable on extremities and forehead. Nails are without lesions with a capillary refill of 2 seconds. His anterior fontanel measures 1 × 1 cm and is flat. His ears and nose are within normal limits. The sclera have a bluish tint, and conjunctiva are pale; attempts to visualize fundi were futile. Irritation and cracking are noted at corners of mouth, and his tongue looks red but does not seem to hurt him. The oral mucosa is pale but no dark lines are noted along the gums. His neck, lungs, heart, and musculoskeletal exam are unremarkable. Abdominal exam is positive for palpable stool (left abdomen—midline and lower abdomen) and a palpable spleen 1 cm below the costal margin. His deep tendon reflexes are 2+ bilaterally, and cranial nerves are grossly intact.
The abnormal findings in the physical examination include:
• Decreased activity
• Central pallor
• Anterior fontanel borderline large for age
• Blue sclera
• Angular stomatitis
• Stool palpable in abdomen
Utilizing information from both the history and physical, what are the differential diagnoses to consider for Oswaldo?
The following are the possible differential diagnoses:
• Iron deficiency anemia
• Lead poisoning
• Developmental delay, possibly secondary to neurotoxic effects of organophosphates
• Organophosphate toxicity
• Warfarin ingestion
Before refining the diagnosis by ordering any laboratory or radiologic tests, a review of each of the possible diagnoses will be useful.
Discussion of the Differential Diagnoses
What facts in the history indicate that Oswaldo is at high risk for environmental health hazards?
Oswaldo lives in a household where the parents are migrant workers in an agricultural environment known to use organophosphate pesticides; pesticides are used in his home to eradicate mice; crawling is his primary modality; and he spends much time on the floor playing.
Environmental Toxins and Children
Research conducted in the early 1990s revealed that approximately 75% of U.S. households used at least one pesticide product indoors (American Lung Association, n.d.). Such widespread use of pesticides makes the environmental history an integral aspect of data collection in pediatrics. Unique physical characteristics make children especially vulnerable to accumulating toxins in their bodies and exhibiting symptoms of both acute and chronic exposures. Children’s bodies are less capable of detoxifying the toxins that get into their bodies due to immature levels of enzymes capable of accomplishing this task. Children spend much of their time close to the ground crawling and playing in the zones where pesticides accumulate. In this pesticide-rich environment, children breathe in fumes and ingest residue through hand-to-mouth activities, further increasing their ingestion of household pesticides.
Considering that the life expectancy of children from the time of toxic exposure is greater than if the exposure occurs in adulthood, there is more time for the development of diseases with long latency periods (Cohen, 2007). A child’s respiratory rate is more than twice that of an adult’s. Children consume seven times the amount of water as an adult in the first 6 months of life, and between ages 1 and 5 years children consume proportionally three times as much food as adults (Shea, n.d.). There are periods during development when certain systems are especially vulnerable, making them more susceptible to harm if exposed to toxins during these times, generally when organs such as the brain are rapidly growing. The timing of the ingestion of neurotoxic elements, such as lead, arsenic, mercury, PCBs, and alcohol, can have a more robust effect than the amount of the toxin itself.
Children’s diets include large amounts of fresh fruits, vegetables, and juices. Breastmilk may also be contaminated. Other factors to consider are that children consume a greater volume of liquids and foods per kilogram than adults, therefore ingesting more toxins per body weight. Table 19-2 shows various fruits and vegetables and the relative amount of pesticide that is absorbed into the food and found by government testing. It is clear from viewing the list of fruits and vegetables that children are at greater risk for proportionally larger amounts of potential pesticides ingestion than adults.
Lower organophosphate metabolites are noted in the urine of children who ate organic foods, compared to children who did not. Children of agricultural workers repeatedly demonstrate higher organophosphate metabolites than children in other environments. Organophosphate metabolites are transmitted via aerial spraying or transmission from parents’ clothing (Cohen, 2007; Curl et al., 2002; Thompson et al., 2008).
In the realm of acute effects, symptoms reflect the affected organ system: local irritation (skin, eyes, throat), respiratory system (respiratory distress), and the central nervous system (headache, seizure, coma, death). Chronic symptoms can range from birth defects, cancers, and asthma, to neurodevelopmental/ neurobehavioral symptoms. Many pesticides have been demonstrated to have disruptive effects on the endocrine systems.
Organophosphates (OP) are the most widely used pesticides in the United States, and those employed in agriculture experience the greatest levels of exposure. Data exist describing the health effects of both acute and chronic exposures. Repeated low-grade home spraying more often triggers acute toxic reactions than does agricultural exposure. The mechanism for these reactions is related to inhibition of cholinesterase activity, which results in accumulation of acetylcholine. These toxins target the central nervous system, and among the effects reported are verbal and visual attention problems, motor dexterity, confusion, cognitive deficits, and memory lapses, as well as muscle twitching, seizures, and coma (Fenske, Chensheng, Curl, Shirai, & Kissel, 2005; Karr, Solomon, & Brock-Utne, 2007). Organophosphates demonstrate a predilection for triggering hematologic and solid tumor cancers (Cohen, 2007; Lambert et al., 2005). Toxic symptomatologies can vary greatly between adults and children, with children’s symptoms having a much broader presentation. This makes it imperative for healthcare providers to maintain a high index of suspicion. Other symptoms include anorexia, dyspnea, miosis, salivation, tearing, and sweating. Symptoms can persist long after exposure to organophosphates. The mnemonic I PREPARE can be employed to remember the aspects of an environmental history (see Table 19-3).
Table 19–2 PESTnFOOD: Shoppers’ Guide to Pesticide Residue in Produce
Sources: Based on information from Cohen, M. (2007). Environmental toxins and health: the health impact of pesticides. Australian Family Physician, 36(12), 1002–1004; Karr, C. J., Solomon, G. M., & Brock-Utne, A. C. (2007). Health effects of common home, lawn, and garden pesticides. Pediatric Clinical of North America, 54, 63–80.
Oswaldo’s environment is abundant in potential pesticide exposures: his father’s work clothing, the types of foods he ingests, playing on the floor, hand-to-mouth behaviors, and home rat poison. The family history suggests that pesticide exposure may have had an impact on the siblings as well: Maria has a seizure disorder, Ignatio has ADHD, and Miguel has asthma. Further investigation should involve evaluation of the entire family’s exposure level and urinary metabolites as well as other possible toxins. Although these conditions do not necessarily indicate toxicity, but are listed as possible complications, environmental toxins should be explored in Oswaldo’s siblings.
Table 19–3 I PREPARE Mnemonic for Environmental History
Investigate potential exposures
Present work of child or parent
Residence (age and characteristics)
Referrals and resources
(http://www.epa.gov; http://www.atsdr.cdc.gov; http://www.aoec.org; http://www.hazard.com/msds; http://www.osha.gov)
Source: From Paranzino, G. K., Butterfield, P., Nastoff, T., & Ranger, C. (2005). I PREPARE: developmental and clinical utility of an environmental exposures history mnemonic. American Association of Occupational Health Nursing, 53(1) 37–42.
Specific tests would be based on history and symptomatology. Most urinary metabolite tests are nonspecific for the individual organophosphate. Treatment would be based on the agent and whether the poisoning was acute or chronic.
Decontamination of skin, nails, hair, and clothing is paramount because organophosphate absorption increases through breaks in the skin’s integrity. Therefore, open areas should be cleansed first with the water flowing away from the wound.
Because only 2% of 1 year olds are found to have iron deficiency anemia (IDA) during routine screening between 9 and 18 months of age, the U.S. Preventive Services Task Force does not find sufficient data to definitely recommend selective screening in the 6- to 12-month age group (U.S. Preventive Services Taskforce, 2006). However, general risk factors for anemia and the populations that should be screened for anemia have been identified.
• Premature infants (most hemoglobin accumulates in fetus during the last month of pregnancy)
• Cow’s milk consumed before 1 year of age
• Low iron formula in infancy
• Children over 1 year who consume more than 24 ounces of cow’s milk per day
• Menstruating adolescent females
• All children from low socioeconomic status families
In most of these situations there are cofactors of rapid growth and deficient nutritional states. These commonly occur together, making the child more susceptible to the depletion of iron at a time when the body has greater need for it. Some information regarding ethnic backgrounds can help point toward specific explanations for aberrant blood findings. Oswaldo’s history reveals many of these risk factors.
Pathophysiology of Anemia
Anemia is defined as a low hemoglobin level in the blood. The physiologic impact of anemia on a growing child can be devastating. The human brain undergoes rapid and fundamental development during the first 2 years of life; therefore, lack of nutrition, as seen with decreased oxygen transportation in iron deficiency anemia (IDA), results in life-long cognitive sequelae when occurring during this critical period. Iron deficiency occurs gradually. Dietary requirements for iron are noted in Table 19-4.
In the prelatent phase the body’s iron stores are depleted. During the latent phase, the serum iron and iron-binding capacity decrease below normal levels. Latency is also associated with reduced erythropoiesis that is reflected in a decreased mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) and an increase in the red cell distribution width (RDW) as iron deficiency alters red cell size unevenly. It is during the frank phase that anemia is evident through direct hematologic studies, noted through decreases in hemoglobin (Hgb) and hematocrit (Hct) (Berman, 2004; Lesperance, Wu, & Bernstein, 2002). Early identification of anemias and intervention are essential for mitigating irreparable effects.
Table 19–4 Recommended Dietary Allowances for Irona
Anemia results from an imbalance between the destruction and production of red blood cells. In IDA, the iron stores are depleted to the extent that the hemoglobin essential to red cell production is no longer adequate for this to happen. Decreased red blood cell (RBC) production typically occurs gradually and causes chronic anemia. Any of several mechanisms may be responsible for this decreased production: bone marrow failure, impaired erythropoietin production, and defects in the maturation of red cells. Hemolysis, or increased RBC destruction, may be triggered by extracellular causes: mechanical injury (such as in hemolytic–uremic syndromes or cardiac valvular defects), antibodies (as from autoimmune disorders), infections, drugs, toxins, and thermal injury to RBCs (as in severe burns). Hereditary causes tend to decrease RBC production due to intracellular defects, including defects in cell membrane, enzyme defects, hemoglobinopathies, thalassemias, porphyrias, and paroxysmal nocturnal hemoglobinuria. Blood loss, either acute or chronic, represents the last category of decreased RBC production and can result from disease processes or trauma (Lesperance et al., 2002; Lee & Truman, 2007).
There are three kinetic categories of red blood cells used to describe anemias: microcytic, indicating undersized red blood cells; normocytic, indicating normal sized red blood cells; and macrocytic, referencing cells that are larger than normal. The second characteristic used to differentiate the types of anemia refers to the amount of hemoglobin contained in cells. When the hemoglobin is low, the anemia is referred to as hypochromic.
Oswaldo’s history of acquired pallor, bluish sclera, lack of activity, and a diet of mostly cow’s milk with no other significant iron source makes iron deficiency the most likely etiology of his anemia. His health history reveals many risk factors for iron deficiency anemia as well: low socioeconomic status, immigrant, age, diet, and appearance. This diagnosis is further suggested by the physical presence of glossitis and stomatitis.
Conditions with Anemia as a Symptom
IDA is classified as a microcytic and hypochromic anemia and is the most common of the anemias. Iron deficiency is the most common nutritional deficiency, and IDA is its most severe expression (Centers for Disease Control and Prevention [CDC], 2002). Children between 6 and 20 months, preterm infants, and menstruating adolescent females are at the greatest risk in general, but the incidence doubles in Mexican Americans and African Americans (Borgna-Pignatti & Marsella, 2008).
Thalassemia is another microcytic, hypochromic anemia, though it is most often encountered in its minor or trait variation. The thalassemias are genetically transmitted, with homozygous disease having the greatest health impact. Thalassemia minor is important to differentiate from iron deficiency anemia because thalassemia does not respond to iron therapy. It occurs with greater prevalence among certain racial and ethnic groups. Alpha-thalassemias are most prevalent in persons of Southeast Asian descent, whereas the beta-thalassemias are found among persons of Southeast Asian, Middle Eastern, or Mediterranean descent. Symptoms may appear between 3 and 6 months of age. Information gathered from the family medical history, such as anemia, miscarriage, jaundice, gallstones, or splenomegaly, should further raise the index of suspicion. Laboratory studies help to differentiate thalassemia minor from anemia. The Mentzer index is determined by dividing the MCV by the RBC count. A score greater than 13 suggests iron deficiency anemia, whereas less than 13 is indicative of thalassemia. The free erythrocyte protoporphyrin (FEP) test is another lab that is useful in differentiating the two anemias: a microcytic anemia with an elevated FEP rules out a diagnosis of thalassemia; however; it does not confirm the diagnosis of iron deficiency anemia. For a definitive diagnosis, hemoglobin electrophoresis is necessary, with a quantitative A2 and F hemoglobin. Beta-thalassemia trait will show elevations of either or both A2 and F hemoglobin (Garfunkel, Kaczorowski, & Christy, 2007).
Celiac disease is another common cause of iron deficiency (10–30% of cases) because it decreases the body’s ability to absorb up to 46% of ingested iron. The only other disorder to equal this significant level of malabsorption is small bowel resection. Disorders that lead to decreased acid secretion, such as H. pylori, also impede iron absorption. Situations leading to blood loss (polyps, ulcers, hemorrhagic telangiectasia, and diverticulitis) also deplete iron stores, as do parasitic infestations (Irwin & Kirchner, 2001). After all other causes for a microcytic anemia have been ruled out, there is the possible explanation of anemia of chronic disease, which is only a diagnosis of exclusion.
It is interesting to note that in children with breath-holding spells there is a high incidence of iron deficiency anemia and that the rate of occurrence of these spells decreases following a therapeutic trial of elemental iron supplementation (Borgna-Pignatti & Marsella, 2008). Anemia in combination with leukopenia, neutropenia, or thrombocytopenia is more suggestive of failure of RBC production caused by conditions such as aplastic anemia, Fanconi anemia, or leukemia (Lee & Truman, 2007). This information underscores the need to seek the cause of anemia in order to provide the definitive treatment. Anemia is a symptom of an underlying disorder. As the anemia diagnosis narrows, the diagnosis of the underlying disorder then needs further treatment.
What physical findings in Oswaldo are suggestive of iron deficiency anemia?
Relying solely on physical examination to make a diagnosis of iron deficiency anemia is not very reliable because the findings are nonspecific and often late manifestations, including pallor, fatigue, glossitis, edema (due to milk-induced protein-losing enteropathy with iron deficiency), spoon nails, angular stomatitis, bluish tint to sclera, irritability, frontal bossing, exercise intolerance, abnormal immune response, growth retardation, impaired collagen synthesis (blue sclera), epithelial abnormalities (gastrointestinal mucosal lesions, spoon-shaped nails), and chewing ice. Tachycardia is noted as a poor compensation for an acute process, such as blood loss. A normal heart rate is suggestive of a chronic process. Jaundice may be seen in the face of a hemolytic process as bilirubin accumulates. Splenomegaly occurs as a result of malignancies, acute infections, inherited hemolytic anemia, or the case of hypersplenism secondary to portal hypertension (Hermiston & Mentzer, 2002; Lesperance, Wu, & Bernstein, 2002).
What aspects of the history indicate risk factors for lead toxicity?
The following are aspects of Oswaldo’s history that are risk factors for lead toxicity:
• Pica (eating non-nutritive substances)
• Crawling (increases amount of time on floor where residue accumulates)
• Mouthing behavior (young children explore their worlds)
• Age (toddlers are at increased risk due to floor play and hand–mouth exploration)
• Lower socioeconomic status
• Residing in an old building (lead paint was used until 1978 and still is utilized in some nonresidences and military installations [CDC, 2002])
• Wearing a medal on a chain—composition unknown
What physical findings would one look for in cases of suspected lead toxicity?
Children with lead poisoning can be without symptoms until levels rise high enough to result in permanent neurologic damage. Lethargy may be noted in children with mild levels and perhaps a complaint of abdominal pain. As the severity of poisoning increases, diffuse abdominal, even colicky pain becomes evident. For serum lead levels > 300 mcg/dL, expected signs may include lethargy, nausea, vomiting, green or tarry stools, hypotension, rapid pulse, metabolic acidosis, shock, coma, hepatic necrosis, renal failure, and local gastrointestinal erosions. The nonspecific nature of these symptoms underscores the need for a high level of suspicion and an organized environmental history. Encephalopathies occur more commonly in children than in adults. These encephalopathies are characterized by seizures, mania, delirium, and even coma. A horizontal line across the nails or gumline may be evident, though such lines are in evidence so rarely as to have little clinical significance (Roberts & Reigart, 2002). As with other anemias, there may also be pallor. On radiograph, lead fragments may be visible in the gut, and uptake lines may appear on long bones, but these measures are indicated in a more severe presentation of toxicity.
Epidemiology of Lead Poisoning
Plumbism has long been recognized as having significant impact on the well-being of children, but lead is inescapably present throughout the environment. The results of the National Health and Nutrition Examination Survey (NHANES) in 1994 and again in 1999–2002 indicate the occurrence of lead toxicity in the United States is on the decline as a result of increased public awareness and legislation. Rates in non-Hispanic African American children remain higher than in non-Hispanic white or Mexican American children (CDC, 2005; Roberts & Riegart, 2002).
Despite this improvement, lead toxicity remains a major health concern. A high index of suspicion and careful monitoring of children from at-risk populations is vital in order to provide early detection and treatment. The risk factors are the same as for iron deficiency, which itself facilitates lead absorption in children. Both pica and lead poisoning have been found to be associated findings in the presence of iron deficiency anemia.
Pathophysiology of Lead Poisoning
As in the discussion of environmental toxins, children absorb more lead and are more sensitive to its effects than are adults (Cohen, 2007). Children’s bones store only 64% of the absorbed lead, whereas adults’ bones sequester approximately 95%. That leaves 36% of the lead burden in the child’s circulation and soft tissues where it results in acute toxic effects. Other deficiencies compound the rates at which iron is taken up into the body and the degree to which it is stored.
Lead competitively binds with many proteins: the sulfhydryl (SH) group of cysteine, the amino group of lysine, the carboxyl group of glutamic and aspartic acids, and the hydroxyl group of tyrosine (Piomelli, 2002). This widespread affinity for key proteins helps to explain the widespread effects within the body.
In blood, an elevated lead level interferes with heme synthesis by inhibiting essential mitochondrial membrane function and interfering with enzymatic functions. In lead toxicity, iron is blocked from being incorporated into protoporphyrin, despite the fact that it is available. However, in iron deficient states this lack of iron results in an accumulation of erythrocyte protoporphyrin in blood. Both situations result in elevated circulating levels of FEP (Piomelli, 2002). Therefore, an elevated FEP level with a microcytic RBC morphology could indicate either iron toxicity or iron deficiency.
The brain is very sensitive to exposure to heavy metals or other toxins, with children’s brains being even more susceptible. The effect of these toxins is primarily reflected in neurobehavioral and neurodevelopmental disorders such as cognitive deficits, developmental delays, inattention problems, and psychosocial disorders, and in central nervous system dysfunctions such as ataxia, seizures, paresthesias, paralysis, coma, or death. The extent of sequelae is influenced by the level of intoxication.
Which of Oswaldo’s physical findings would be suggestive of leukemia or another cancer?
The following findings could be suggestive of cancer:
Pathophysiology of Leukemia and Lymphoma
Although the specific cause of lymphoblastic leukemia is not known, in general cancers are known to stem from damage to DNA resulting in an uncontrolled overproduction of cells that overcrowd the bone marrow, crowding out normal cells. Because these abnormal cells are blood-borne, they can spread throughout the body and infiltrate organs and sites such as the liver, spleen, central nervous system, lymph nodes, and reproductive organs (Belson, Kingsley, & Holmes, 2007). These cells also develop abnormally long life spans. Leukemia may be the result of exposure to radiation or chemicals. Regarding chemical exposures, only benzene has been clearly demonstrated to cause cancer, but other agents, such as organophospates and other pesticides, have been noted as possible links (Belson et al., 2007).
Symptoms consistent with leukemias are typically present days to weeks before diagnosis. Disruption of hematopoiesis accounts for the most common presenting symptoms of anemia—infection, easy bruising, and bleeding. Other symptoms and signs of leukemia tend to be less specific (pallor, fatigue, fever, tachycardia, chest pain, malaise, and weight loss) and are attributable to anemia and a hypermetabolic state rather than to the direct effect of the cancer.
Multiple factors influence the outcomes for leukemia. Acute lymphoblastic leukemia (ALL) occurs most often in children and has a greater cure rate than acute myeloblastic leukemia (AML). Females tend to fare better than males. Whites tend to be diagnosed with ALL more often than African Americans, but Asian Americans and Hispanic Americans have survival rates higher than African Americans. Children between 1 and 10 years have greater survivability than older persons. Persons with Down syndrome have a greater likelihood of developing leukemia than do any other groups (Gamis et al., 2003; Robison et al., 1984). Overall survival rates drop off markedly if these cancerous cells are evident in the brain or central nervous system.
If suspicions of leukemia are strong, the initial evaluation would first include a complete blood count (CBC) and a peripheral blood smear (PBS). The red cell size may present as normocytic with decreased RBC production, and the MCV is occasionally increased. The presence of pancytopenia (thrombocytopenia/leucopenia/cytosis) and peripheral blasts suggest acute leukemia. The differential diagnosis of the finding of pancytopenia includes: aplastic anemia, viral infections such as infectious mononucleosis, and vitamin B12 and folate deficiency. The peripheral smear may also reveal tear-drop erythrocytes and leukocyte casts. Blast cells in the blood smear may approach 90%, unless the WBC count is markedly decreased. Although the preliminary diagnosis can usually be made from the blood smear, bone marrow examination is the diagnostic gold standard. Blast cells in the bone marrow range between 30% and 95%. Immediate referral to a hematologist/oncologist is required.
A diagnosis of leukemia is unlikely in Oswaldo’s case; however, you will do initial basic blood testing (CBC) that will assure you that leukemia is not the cause of his symptoms.
What physical findings are suggestive of warfarin (rat poison) ingestion?
The following symptoms are suggestive of warfarin ingestion:
• Bruising and purpura
• Anemia secondary to acute blood loss
Pathophysiology of Warfarin Toxicity
The majority of accidental warfarin ingestions occur in children younger than 6 years of age and consist of ingestions of small amounts of warfarin. There are several long-acting coumarin derivatives, so-called Super warfarin anticoagulants (brodifacoum, diphenadione, chlorophacinone, bromodialone) commonly used as rodenticides. They produce profound effects and prolong anticoagulation. The mechanism of action of these common coumarin derivatives is to inhibit vitamin K1-2,3 epoxide reductase, preventing vitamin K from being reduced to its active form (Olson, Trickey, Miller, & Yungmann-Hile, 2008). The degree of this effect is based on dose and duration of exposure to warfarin. The oral bioavailability is excellent. Once in the system, it is bound to plasma protein (albumin) and distributed to the kidneys, lungs, and spleen. Anticoagulant effects typically occur 5–7 days after a single dose; however, the Super warfarin effects may persist for weeks to months.
Minor bleeding complications are usually noted from mucosal surfaces, but also increase the ease of bruising, nosebleeds, and hematuria. As the ingested amount of Super warfarin increases, major complications become evident. Major bleeding commonly includes hemorrhages from gastrointestinal, intracranial, and retroperitoneal sites, but could progress to massive bleeding from any organ system.
What characteristics from the history and physical relate to the possible diagnosis of hypothyroidism?
The following could suggest hypothyroidism:
• Loss of developmental skills
Pathophysiology of Hypothyroidism
Fatigue, constipation, poor feeding, delayed development, and the slow growth reported in Oswaldo’s case are consistent with a diagnosis of hypothyroidism. In infants with congenital hypothyroidism, symptoms become evident within weeks to months of birth. Among the presenting symptoms are prolonged jaundice, poor feeding, constipation, cool mottled skin, excessive sleepiness, decreased crying, umbilical hernia, and large fontanel and tongue (Avery, 1994). A decrease in growth velocity in the presence of anemia suggests the possibility of hypothyroidism. This anemia tends to be normo- or macrocytic anemia. This finding should not be confused with the megaloblastic anemia associated with folate or cobalamin deficiency. Anemia associated with hypothyroidism responds when the primary hormone deficiency is treated (Irwin & Kirchner, 2001).
Of those neonates diagnosed with hypothyroidism, 10% will develop normal thyroid levels within days to months of birth. For the other 90% of affected neonates, if their hypothyroidism is left untreated, severe developmental delay and mental retardation as well as growth delays result (Kliegman, Greenbaum, & Lye, 2004).
Acquired hypothyroidism has an insidious onset, with slowing of growth being the most common initial symptom. Linear growth is very dependent on the amount of circulating thyroid hormone; in the absence of this hormone, growth will cease completely until it is replaced. A goiter often appears early and can be noted on routine examination even before growth slowing occurs. Hypothyroidism also impacts energy level and may produce a dull expression in children. Other findings include pale, thick, cool skin; constipation; delayed deep tendon reflexes; slow pulse and lowered blood pressure; and dulling of the child’s cognitive ability, although these symptoms are reversible with hormone replacement therapy (Burchett, Hanna, & Steiner, 2009).
There are a few possible reasons for a young child to manifest signs and symptoms of hypothyroidism after the neonatal period. Delayed onset of congenital hypothyroidism occurs when the newborn has a vestigial or defective thyroid gland, which is incapable of meeting the demands of a growing child. Inhibition of thyroid hormone production within the gland itself is a more common explanation for the development of hypothyroidism. Inadequate dietary iodine is a cause that is common in less developed countries, but it is not a health concern in the United States (Kliegman et al., 2004). Some drugs may also block thyroid hormone production, and when prescribing lithium or iodine-containing drugs such as amiodarone, hormone level monitoring is essential (Taketomo, Hodding, & Kraus, 2008). Hypothyroidism from these causes can be reversed. Occasionally the body will have an autoimmune reaction to its own thyroid gland. In Hashmoto’s thyroiditis, the antibodies attack and destroy thyroid cells.
Making the Diagnosis
Your diagnostic list now includes IDA, possible warfarin ingestion, and hypothyroidism as the most likely causes of Oswaldo’s signs and symptoms. The next phase in determining Oswaldo’s diagnosis and subsequent treatment is to perform laboratory diagnostic tests. For expediency and to minimize trauma to the toddler, several tests should be ordered simultaneously. Thus, you order the following tests:
• Complete blood count with white blood cell differential and peripheral blood smear (CBC with diff and PBS)
• Thyroid screen (T4, TSH, +/- T3)
• Lead level
• Urinary metabolites for organophosphates
• Stool guaiac
IDA: CBC with Differential
Specific tests to determine the type of anemia will be directed by the clinical presentation, history, and initial blood work. The causative factors of the anemia must be clarified. Information revealed in the complete blood count, peripheral blood smear, lead studies, thyroid studies, and hemoglobin electrophoresis would all help in refining the etiology of anemia. Findings in patient examination and history will further guide the diagnosis of anemia and the additional examinations needed to confirm the diagnosis. It is vital to remember that having the diagnosis of the type of anemia is not the end point. Bone marrow examination by itself is not a useful diagnostic tool in infants and toddlers because there is little or no iron stored in the marrow hemosiderin in these young children who do not have the marrow reserves that older children develop (Scott, 2006).
Warfarin Intoxication: Prothrombin Time
Serum measurements of warfarin are not readily available or useful in most ingestions because most labs are not able to provide timely reports of vitamin K–dependent clotting factors. Daily prothrombin time (PT) levels serve to quantify the anticoagulant effect of ingested rodenticide and to determine the necessary duration of vitamin K treatment. Some sources recommend repeating the PT test 24 and 48 hours post-ingestion (Olson et al., 2008). Mullins, Brands, and Daya’s (2000) study, however, suggests that in normal pediatric exposures to Super warfarin the PT test is not necessary and does not affect outcome. Normalization of the PT level within 48–72 hours indicates the quantity of warfarin ingested was insignificant.
Lead Intoxication: Lead Level
An elevated lead level is diagnostic of plumbism. The sample may be from either a capillary or venous source, but preparation of the site is vital to getting an accurate result. The skin must be well-cleaned to prevent contamination from surface lead dust. Capillary samples are much more sensitive to surface contamination due to the small size of the sample. If a capillary sample yields a lead level greater than 10 mcg/dL, a venous sample must be obtained to provide diagnostic confirmation. Levels less than 10 mcg/dL are considered normal. Table 19-5 indicates the increments within elevated levels and how they are addressed therapeutically.
Hypothyroidism: Thyroxine and Thyroid Stimulating Hormone
A diagnosis of hypothyroidism would explain some but not all of Oswaldo’s symptoms. The tests used to determine thyroid status are the thyroxine (T4) and thyroid stimulating hormone (TSH) levels. Eighty percent of circulating thyroid hormone is T4 and the remaining 20% is T3, so determining the T4 level is usually adequate, but one can also include the T3 level for a complete thyroid picture. TSH levels reveal the functioning and role of the pituitary gland in directing thyroid function. A normal TSH level with a low T4 level indicates that the pituitary gland is not sensing or responding to the low circulating level of thyroid hormone. An elevated TSH level indicates that the pituitary gland has detected the low serum thyroid levels and has attempted to spur the thyroid gland to greater activity to compensate. When the TSH is high and the T4 is low, the implication is that the thyroid gland is malfunctioning (Kliegman et al., 2004).
You review the results of your laboratory studies, which are found in Table 19-6. Based upon these findings you identify the following diagnoses:
Interpretation of CBC with differential and PBS:
• Microcytic, hypochromic anemia
• RDW is increased, consistent with iron deficiency anemia
• Normal white blood cell count
• Reticulocyte is increased, as is normally seen in IDA
Interpretation of iron studies:
• Serum iron and serum ferritin are very low, indicating inadequate iron stores.
• The FEP is elevated, consistent with IDA and/or elevated lead level.
These results rule out thalassemia trait (diagnostic for thalassemia traits is microcytic anemia and normal FEP).
• A lead level of 42 constitutes a moderately high level, CDC classification III.
Table 19–5 Treatment Recommendations Based on Blood Lead Level
Table 19–6 Oswaldo’s Laboratory Results with Norms for Children 6 Months to 3 Years
• T4 and TSH are both within normal range, indicating there is no hypothyroidism.
If hypothyroidism had been identified, primary treatment is by oral hormone replacement with levothyroxine. Because this medication can interact with many different drugs, it is important to review the child’s medication history at each visit. Families should be instructed to limit ingestion of goitrogenic foods (asparagus, cabbage, peas, turnip greens, broccoli, spinach, brussel sprouts, lettuce, and soybeans), plus soybean-based formulas, cottonseed meal, walnuts, and dietary fiber, because these may decrease absorption (Takemoto, Hodding, & Kraus, 2008). The dosage varies by age, decreasing as the child ages. Laboratory monitoring of serum levels consists of annual TSH levels. Treatment is best accomplished in consultation with or referral to a pediatric endocrinologist.
• The PT is elevated, which is consistent with ingestion of Super warfarin.
• The results of Oswaldo’s developmental testing reveal he is delayed in gross and fine motor areas. There is a recommendation for close follow-up testing.
From these results, you arrive at your final list of diagnoses and determine their ICD codes. Table 19-7 lists the ICD-9 codes based upon your final diagnoses. These diagnoses are:
• Moderate-severe iron deficiency anemia
• Lead poisoning, moderate
• Organophosphate exposure and warfarin ingestion
• Poor growth and delayed development
There are general guidelines to consider when managing the diagnostic problems that Oswaldo has.
Table 19–7 ICD-9 Codes for Oswaldo’s Final Diagnoses
Moderate-severe iron deficiency anemia
Lead poisoning, moderate
Warfarin ingestion (poison by agents affecting blood components)
Iron Deficiency Anemia
Iron supplementation is necessary with laboratory monitoring of the child’s response. Typically a trial of oral iron is started at 4 to 6 mg/kg/day of elemental iron in two to three divided doses per day. Reticulocytosis is typically seen after 4 days of therapy. Hemoglobin levels should be monitored. A return to normal Hgb level occurs within 4 to 6 weeks if iron supplementation is taken as prescribed. Because iron stores must be replenished, a course of iron supplementation is recommended for 2 to 3 months. Dietary counseling regarding iron-rich foods is an essential part of patient education. Blood monitoring of hemoglobin is typically done at 1 month. If there is an adequate response (an Hgb increase of at least 1 g/dL or a greater than 3% increase in hematocrit), the diagnosis of IDA is confirmed. A hemoglobin level is then drawn again approximately 6 months after iron supplementation is discontinued to confirm a full return to normal levels of Hgb (Schwartz, 2009). Because Oswaldo does not simply have IDA but also has elevated lead levels and a hemoglobin of 7 gm/dL, you want to want to discuss his case with the hematologist.
The CDC committee developed guidelines to direct treatment of plumbism in primary care practices (see Table 19-5). The primary step in treatment is to remove the lead source from the child’s environment. Proper nutrition and the passage of time will generally serve to lower the levels of lead in mild to moderate intoxications. For symptomatic and severe intoxications by lead, it may be necessary to use chelation. Chelating agents are not without risks of their own and should be used by experienced healthcare providers in controlled situations.
Dimercaptosuccinic acid (DMSA) [Chemet] is a water-based oral agent approved in the treatment of heavy metals such as lead, cadmium, arsenic, and mercury toxicity by the Food and Drug Administration (FDA). DMSA is the safest of the chelating agents with a wide margin between the doses needed to be effective and the dosages that would be toxic. British anti-lewit (BAL) is oil-based and unpleasant to patients. Significantly, BAL forms a toxic substance when combined with iron, so it must never be given during iron therapy. Edetate Calcium Disodium (Calcium EDTA) is water-soluble and best given intravenously. It is possible to give intramuscularly, but is quite painful and should be drawn up with 2% procaine to minimize site discomfort. The primary risk associated with this chelating agent is that due to its actions within the body there is an increased likelihood of seizures.
Vitamin K (phytonadione, AquaMEPHYTON) overcomes the coagulation, thereby blocking the effect of warfarin. It takes several hours for the liver to then produce clotting factors and release them into the circulation. Typical pediatric dosing is 1–5 mg orally; however, higher doses are necessary to reverse the Super warfarin coagulopathies, and these doses need to be titrated based on the results of daily prothrombin times (Taketomo, Hodding, & Kraus, 2008). Consultation with a hematologist is recommended.
Although Oswaldo’s PT level is only slightly above the normal range, you initiate a call to your hematologist consultant to determine whether vitamin K is needed at this point and to discuss the issue of his IDA, elevated lead levels, and positive urinary metabolite screen.
Plan of Care
You discuss your plan of care with Oswaldo’s mother, which is as follows:
Consult with hematologist regarding anemia, lead toxicity, and likely low level of warfarin ingestion.
Department of Public Health involvement: Site visit and lead abatement.
Visiting nurse to provide home monitoring, teaching, coaching, medication administration technique, and to promote success.
Referral to early intervention program: for infant stimulation.
Fer-in-sol (which comes in 75 mg/0.6 ml, in a 50 ml bottle) 6 mg/kg @ 9.2 kg = 0.2 ml orally bid, OR iron polysaccharide complex taken daily by mouth.
Take with orange juice or cranberry juice.
Wipe teeth clean after administering to minimize dark discoloration.
Put medicine toward back of mouth if possible.
Consider iron chelation therapy with BAL or Calcium EDTA (doses) if lead levels do not drop as the environment becomes less toxic. This will necessitate a follow-up discussion with the hematologist.
Nutritional consult: There will be much information for Mrs. Garcia to absorb, so an ongoing consult would be appropriate until Oswaldo’s condition improves. Referral to address:
Decrease cow’s milk to not greater than 16 ounces in a day.
Discontinue baby bottle.
Encourage iron-fortified foods and meats.
Discontinue the use of Maltsupex and encourage juices to help ease constipation, especially nectars, prune juice, and apple juice.
Increase caloric intake.
Provide telephone follow-up in several days, not longer than 1 week, to determine how the family is doing with all the changes.
Dental care: Iron may discolor teeth, but regular dental brushing and wiping teeth clean after administration of iron preparation will minimize this. This discoloration is temporary.
Developmental assessment today, repeat in month, continue to monitor.
Return to clinic in 2 weeks for repeat CBC and reticulocyte count.
Provide telephone follow-up in several days, not longer than 1 week, to determine how the family is doing with all the changes.
With your written instructions, Oswaldo’s mother seems to understand what will happen and how to manage his care at this point. She is happy to know that help is coming for his condition.
What long-term follow-up should be planned for Oswaldo?
Oswaldo should be followed closely for several months to ensure that his problems with anemia and lead poisoning are fully treated. Developmental assessments will be monitored regularly to determine if there has been a significant impact affecting Oswaldo’s development. The primary care provider needs to contact the agencies that investigate toxic environments (Department of Public Health, Environmental Protection Agency, local Visiting Nurse Association, or other agencies) in order to ensure the environment is once again conducive for the health of children such as Oswaldo.
The follow-up reports indicate that Oswaldo’s family now has been moved to one of the newer facilities at the orchard. There is no evidence of mice or lead. There is a functioning smoke detector. Mr. Garcia now showers at work and changes clothes before coming home, a change that the employer now encourages for all workers. The response from the employer has been very positive and several more safety measures have been instituted for these employees. The siblings have been screened but do not have toxic levels of organophosphates in their systems.
What information about the implications of IDA, even after treatment, could you give the concerned parents?
There can be cognitive developmental implications, especially regarding reading scores and behavioral manifestations. The brain is undergoing significant development during the first 2 years of life. Lack of proper nutrition (oxygenation) results in irreparable damage and lost developmental opportunities. Oswaldo will need to be followed to help him maximize his development with early intervention programs.
For a toddler with an uncomplicated CBC indicative of a microcytic, hypochromic anemia, what further appropriate diagnostic process should you consider?
Unlike the child with a complicated presentation, the average toddler with apparent IDA (microcytic, hypochromic) needs no further testing before initiating therapy. A therapeutic trial of oral iron is usually adequate in high-risk populations as a diagnostic measure for presumptive iron deficiency anemia (Hermiston & Mentzer, 2002). Fer-in-sol is prescribed at 6 mg elemental iron/kg, divided into two or three doses a day. It is important to follow up with a reticulocyte count in 2–4 weeks. An elevated reticulocyte count indicates that iron is adequate to promote RBC growth and reticulocytosis has begun. During the initial phase of therapy, the rate of RBC development is faster than normal and the reticulocytes are released early, with an extended lifespan of 2 days. Iron therapy needs to continue for 3–4 months to replenish the body’s iron stores. Poor response to iron therapy necessitates further laboratory work-up of the anemia.
What evaluation should be pursued for the child with severe anemia, atypical hematological findings, or a history suspicious for iron deficiency, or who does not respond to an initial trial of iron therapy?
Specific tests will be directed by the clinical presentation, history, and initial blood work. The causative factors of the anemia must be clarified. Information revealed in the complete blood count, peripheral blood smear, lead studies, thyroid studies, and hemoglobin electrophoresis would all help in refining the etiology of anemia. Findings in patient examination and history will further guide the diagnosis of anemia and the examinations needed to confirm the diagnosis. It is vital to remember that having the diagnosis of the type of anemia is not the end point. Anemia is a symptom of an underlying disorder. The anemia diagnosis narrows the diagnosis of the underlying disorder that needs further treatment.
Key Points from the Case
1. Assessing the child with anemia is a complex process that necessitates careful data gathering to determine the ultimate etiology. Providers need to walk a fine line between making too narrow and too wide a focus.
2. Integrate information from all available sources to help formulate the final diagnosis. All variables must be considered, with a focus on the incidence at the child’s stated age and health status. This necessitates a systematic and organized process of elimination.
3. A detailed history often reveals more useful data than the physical examination alone, so time is best spent obtaining as much relevant information as possible.
4. Keep in mind that the child is a product of his or her environment; explore environmental histories as a mainstay of healthcare visits.
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