Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 15-3

Eight-Year-Old Girl

STACEY R. ROSE

HISTORY OF PRESENT ILLNESS

An 8-year-old girl presents with history of 2 days of headache, abdominal pain, vomiting, diarrhea, and 1 day of fever. Two days prior to admission, the patient developed a frontal headache that was relieved with acetaminophen. Shortly after, she started to complain of bilateral lower abdominal pain that soon spread to her left upper quadrant. The abdominal pain became more severe throughout the day and woke her from sleep. Overnight, she started having episodes of nonbloody, nonbilious emesis and non-bloody watery diarrhea. On the day of admission, she developed fever to 104°F and her parents noted that her eyes looked yellow so they brought her to the emergency room for evaluation.

The patient also reports recent fatigue and occasional chills but denies cough, rhinorrhea, congestion, sore throat, neck stiffness, joint pain, myalgias, or rash.

MEDICAL HISTORY

The patient was a full-term baby born in Malaysia with no complications. She moved to the U.S. at the age of 5 months. She has always been well and has had no prior hospitalizations or surgical procedures. She is up-to-date on all immunizations. She does not have any known allergies and was not taking any medications recently, other than acetaminophen for the headache. There is no family history of sickle cell disease, bleeding disorders, or liver disease. She lives at home with her parents and younger brother and is in second grade. The patient and her family report that they recently traveled to Pakistan to visit grandparents. They spent about 6 months there and returned about 2 weeks prior. They did not receive any specific vaccinations or medications prior to or during their travel.

PHYSICAL EXAMINATION

T 38.9°C; HR 96 bpm; RR 18/min; BP 97/65 mmHg; Weight 27.2 kg (50th-75th percentile)

On physical examination, the patient was awake, alert, smiling, and in no significant distress. HEENT examination was significant for mild scleral icterus and conjunctival pallor. Her oropharynx was clear, her neck was supple, and she had no cervical lymphadenopathy. Her lungs were clear to auscultation bilaterally. Cardiac examination revealed a regular rate and rhythm with a II/VI systolic ejection murmur at the right upper sternal border. On abdominal examination she was found to have a soft abdomen with normoactive bowel sounds. She was diffusely tender to palpation without guarding or rebound. Her liver was palpable about 2 cm below the costal margin and she had splenomegaly with the tip palpable about 3 cm below the left costal margin. The remainder of her examination was within normal limits.

DIAGNOSTIC STUDIES

Complete blood count: WBCs, 5800/mm3 (neutrophils: 43%, lymphocytes: 45%, eosinophils: 5%); hemoglobin, 7.8 g/dL; mean corpuscular volume, 81.3 fL; platelets, 192 000/mm3. Serum electrolytes: sodium, 140 mEq/L; potassium, 3.2 mEq/L; chloride, 103 mEq/L; bicarbonate, 19 mEq/L; blood urea nitrogen, 14 mg/dL; creatinine, 0.6 mg/dL; glucose, 112 mg/dL. Liver function tests: total bilirubin, 3.5 mg/dL; unconjugated bilirubin, 3.4 mg/dL; conjugated, 0.1 mg/dL; albumin, 4.4 mg/dL; ALT, 71 U/L; AST, 80 U/L; alkaline phosphatase, 240 U/L; GGT, 75 U/L. LDH, 410 U/L (elevated). Reticulocyte count, 3.1%. Urinalysis, small bilirubin, negative for RBCs or WBCs. CRP, 3.8 mg/dL; ESR, 98 mm/h; PT, 14.3 sec; PTT, 29.3 sec; INR, 1.22.

COURSE OF ILLNESS

The patient was admitted to the hospital where a blood smear revealed the diagnosis (Figure 15-5).

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FIGURE 15-5. Blood smear.

DISCUSSION CASE 15-3

DIFFERENTIAL DIAGNOSIS

The patient has an unconjugated hyperbilirubinemia associated with splenomegaly, anemia, an elevated lactate dehydrogenase (LDH), and a reticulocytosis. These findings are consistent with hemolysis, which is the likely cause of jaundice in this patient. The presence of an underlying hemoglobinopathy, such as sickle cell disease, thalassemia, hereditary spherocytosis, or G6PD deficiency in the face of a viral or other infectious stressor, may precipitate an episode of hemolysis. Most of these conditions are detected by newborn screening but some may go undetected until late childhood or adulthood, particularly in this patient since she was born outside the United States and may not have had newborn screening. Other causes of hemolysis include autoimmune processes, drug reactions, transfusion reactions, hemolytic-uremic syndrome, sepsis with disseminated intravascular coagulation (DIC), and other infections.

In addition to hemolysis, the patient had hepatomegaly and mild elevations in transaminases, suggesting that hepatocellular injury may also be contributing to the patient’s jaundice. While there are various causes of hepatitis in this age group, the acute onset of symptoms and the presence of fever point to an infectious etiology. Viruses are seen very frequently and the most common of the extensive list of possible pathogens are listed below. Acute viral hepatitis is often accompanied by flu-like systemic symptoms such as headache, vomiting, and diarrhea seen in the patient (Table 15-6).

TABLE 15-6. Viral causes of hepatitis.

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The differential diagnosis in this case must be expanded even further since the patient recently returned from international travel. Table 15-7 lists the most common illnesses seen in patients presenting with fever after international travel and their associated symptoms. Of these, malaria is the most common and should be considered in all travelers returning from malaria-infested regions with fever. Because the patient spent 6 months in an area with a high prevalence of malaria, she is at significant risk for having contracted the disease. Her presenting symptoms of fever, headache, abdominal pain, vomiting, and diarrhea are all consistent with a diagnosis of malaria. Furthermore, malaria is associated with red blood cell destruction, resulting in hepatosplenomegaly and jaundice, as seen in the patient (Table 15-7).

TABLE 15-7. Common causes of fever in the returned traveler.

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DIAGNOSIS

The patient had PCR testing for serum EBV, CMV, and adenovirus that were negative. She had titers for hepatitis A and B that were consistent with prior immunization and for hepatitis C that were negative. She had a G6PD assay that was normal. Thick and thin blood smears were sent to pathology for review. They revealed malaria with a parasitemia of 2.8 %. The blood smear below demonstrates a red blood cell with a central ring form that was later identified as Plasmodium vivax (Figure 15-5, arrow).

INCIDENCE AND EPIDEMIOLOGY

Malaria is caused by the parasite Plasmodium, a protozoan transmitted to humans through the bite of the Anopheles mosquito. Four species of Plasmodium cause human disease: P. falciparum, P. vivax, P. ovale, and P. malariae, but most infections are due to P. falciparum or P. vivax. Only P. falciparum causes cerebral malaria and it is the species responsible for most malaria-related deaths.

Worldwide, it is estimated that there are 200-500 million cases of malaria per year and approximately 1 million deaths, most of which occur in young children. The vast majority of cases are in developing nations with the highest prevalence found in tropical and subtropical regions, such as sub-Saharan Africa and South Asia. Though malaria is not endemic in the United States, there are roughly 1100-1500 reported annual cases. Most US cases are imported either by immigrants or travelers returning from malaria-endemic regions (Figure 15-6).

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FIGURE 15-6. Global distribution of malaria. (Reproduced, with permission, from World: Malaria risk areas, 2010. World Health Organization. Published 2011. http://gamapserver.who.int/mapLibrary/Files/Maps/Global_Malaria_2010.png Accessed April 15, 2013.) This map is intended as a visual aid only and not as a definitive source of information about malaria endemicity. Source: © WHO 2011. All rights reserved.

Disease occurs after the female Anopheles mosquito injects sporozoites into the human bloodstream during a blood meal. These travel to the liver where they mature into schizonts which rupture and release merozoites. Merozoites enter the bloodstream, invade red blood cells (RBCs), and mature into ring-forms known as trophozoites and later into schizonts. During the next 48-72 hours the schizonts rupture, releasing merozoites into the bloodstream and destroying the RBC. Anemia results as more merozoites are released and more RBCs are destroyed. Additionally, the release of merozoites triggers a proinflammatory response with cytokines, such as TNF-alpha, causing fever and systemic symptoms. The diagram below illustrates the various phases of the Plasmodium life cycle (Figure 15-7).

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FIGURE 15-7. Plasmodium life cycle. (Reproduced, with permission, from Shah SS, Pediatric Practice: Infectious Disease, New York: McGraw-Hill, 2009.)

CLINICAL PRESENTATION

Symptoms only occur during the erythrocyte phase of the life cycle, when merozoites are released and RBCs are destroyed. Until then, there is an asymptomatic incubation period which may last from several days to months. On average, the incubation period for P. falciparum infections is 9-14 days and 12-17 days for P. vivax. Symptoms often begin as a flu-like prodrome consisting of headache, myalgias, fatigue, diarrhea, and abdominal pain, similar to those seen in the patient. Patients then develop high fevers which classically occur every 48 hours (P. falciparum, P. vivax, and P. ovale) or every 72 hours (P. malariae) in conjunction with the release of the merozoites from the RBCs. However, in practice, these paroxysms of fever may be irregular. Other symptoms include nausea, vomiting, chills, sweats, and cough. As hemolysis progresses, patients develop jaundice and anemia. Hepatosplenomegaly and thrombocytopenia (due to splenic sequestration) may also occur and splenic rupture is possible.

Most cases of malaria are uncomplicated. However some patients develop severe disease, defined as parasitemia greater than 5%, severe anemia, cerebral involvement, or end-organ dysfunction. Almost all cases of severe disease are due to infection with P. falciparum which has several unique characteristics. Unlike the other species of malaria which only invade red blood cells at a particular stage (immature for P. vivax and P. ovale and mature for P. malariae), P. falciparum infects RBCs at every stage, resulting in higher levels of parasitemia and more severe anemia. P. falciparum is also the only species associated with cerebral malaria which may lead to seizures, coma, or death. Additionally, P. falciparum can cause microvascular changes that may lead to acute renal failure and other end organ damage. Other severe complications of malaria include respiratory distress, hypoglycemia, acidosis, splenic rupture, congenital malaria infection, and death.

DIAGNOSTIC APPROACH

Thick and thin blood smears. Diagnosis of malaria is made through light microscopy of Giemsa-stained thick and thin blood smears. Thick smears are useful in establishing the presence and degree of parasitemia and the thin smears aid in species identification. A negative smear does not exclude a diagnosis of malaria. Due to the cyclic nature of disease, smears should be repeated at 6-, 12-, or 24-hour intervals for the first 48 hours to establish the diagnosis and to follow the density of parasitemia.

Rapid diagnostic testing. A number of rapid diagnostic tests are available. Sensitivities for these tests are highest in detecting P. falciparum and are less reliable in diagnosing other species of malaria and detecting lower rates of parasitemia. Additionally, these tests are not quantitative and cannot be used to follow response to therapy.

PCR testing. Polymerase chain reaction (PCR) testing is also available. This test is more expensive and time-consuming than light microscopy but have a sensitivity and specificity of almost 100%. It is particularly useful in detecting very low levels of parasitemia and aiding in species identification, especially when infection by multiple species is suspected.

TREATMENT

Infants, young children, pregnant women, all patients returning from P. falciparum-endemic regions and any patients that are ill-appearing should be hospitalized and started on either an oral or parenteral treatment regimen. Any patient with symptoms of severe disease should be admitted to an intensive care unit and started on immediate parenteral therapy. In most cases, consultation with an infectious disease expert or referral to a specialty care center is warranted.

Recommendations for treatment are constantly evolving and vary by species and resistance patterns in the area of disease acquisition. The CDC offers a 24-hour Malaria Hotline (770-488-7788 or 770-488-7100) to assist providers with malaria management. In general, cases of uncomplicated nonfalciparum malaria may be treated with chloroquine. However, there is increasing chloroquine-resistant P. vivax, particularly in Indonesia and Papua New Guinea, requiring alternate treatment regimens. Primaquine is often used to prevent relapses in patients with P. vivax or P. ovale. Chloroquine resistance among P. falciparum is so widespread, that almost all cases should be considered resistant. Patients returning from P. falciparum-endemic regions should start on an alternate regimen. Several options exist, each with similar efficacy. These include atovaquone-proguanil, quinidine plus doxycycline or clindamycin, arte-mether-lumefantrine, or mefloquine.

Although the patient was ultimately found to have P. vivax, she was started on a 3-day course of atovaquone-proguanil, given the growing chloroquine-resistance in Papua New Guinea. Additionally, she received a 14-day course of primaquine phosphate to prevent disease recurrence. At the time of discharge, her parasitemia was undetectable and her hemoglobin was stable. She followed closely with her pediatrician and an infectious disease specialist and made a complete recovery.

Prevention is the best treatment. Travelers should be educated about the importance of avoiding mosquitoes through the use of insect repellents and insecticide-treated bed nets. Furthermore, all nonimmune patients traveling to malaria-endemic regions should be administered malaria chemopro-phylaxis according to the CDC guidelines.

SUGGESTED READINGS

1. Centers for Disease Control and Prevention: Malaria. Centers for Disease Control and Prevention. www.cdc.gov/malaria. Updated August 19, 2011. Accessed September 29, 2011.

2. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. New Engl J Med. 2006;354: 119-130.

3. Laurens MB, Hutter J, Laufer MK. Fever in the returned traveler. In: Shah SS, ed. Pediatric Practice Infectious Diseases. New York, NY: McGraw-Hill; 2009:675-686.

4. Miller LH, Baruch DI, March K, Doumbo OK. The pathogenic basis of malaria. Nature. 2002;415 (6872):673-679.

5. Murray CK, Gasser RA, Magill AJ, Miller RS. Update on rapid diagnostic testing for malaria. Clin Microbiol Rev. 2008;21:97-110.

6. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:438-444, 797-802.

7. Ryan ET, Wilson ME, Kain KC. Illness after international travel. New Eng J Med. 2002;347:505-516.

8. Sam-Agudu NA, John CD. Malaria. In: Shah SS, ed. Pediatric Practice Infectious Diseases. New York, NY: McGraw-Hill; 2009:687-700.

9. World Health Organization. Malaria. World Health Organization. www.who.int/malaria.en. Accessed September 29, 2011.