Fever, Jaundice, and Pancytopenia in a 16-Year-Old Boy

A 16-year-old previously healthy boy presents to the emergency department (ED) with acute onset of fever, chills, malaise, and jaundice in the setting of a recent 4-month travel on foot to the United States from Venezuela. He reports a 2-day history of intermittent tactile fevers with associated chills as well as progressive yellowing of his eyes and skin. He reportedly lost weight during travel but is unable to quantify the amount. He denies any associated headaches, changes in vision, abdominal pain, vomiting, diarrhea, rashes, joint pain, or preceding illnesses. His social history is significant for recent emigration from Venezuela, passing through tropical forests and sewage-contaminated bodies of water in several South and Central American countries, with arrival in the current city 4 days before presenting to the ED. He is up to date on all childhood vaccinations except for hepatitis A. He is currently living in a local shelter with known COVID-19 exposures.On arrival at the ED, he is febrile to 104.4 °F (40.2 °C), normotensive (blood pressure, 103/61 mm Hg), and tachycardic (heart rate, 118 beats/min). On examination he is alert and oriented. He has no signs of meningismus or focal neurologic deficits. He has unlabored breathing without focal lung findings, a III/VI systolic ejection murmur, and a soft, nontender, and nondistended abdomen. His liver edge is palpated 1 cm below the costal margin, and his spleen is not palpated. He has notable scleral icterus and jaundice to his face and trunk. There are no rashes, petechiae, purpura, or adenopathy. He has full range of motion of his joints, without edema or overlying erythema. He is given antipyretics and an isotonic fluid bolus, with subsequent improvement in vital signs.Initial testing in the ED included a complete blood cell count, a complete metabolic panel, and a respiratory viral panel that is significant for pancytopenia, hyponatremia, elevated transaminase levels, and hyperbilirubinemia (Table 1). A complete respiratory viral panel is positive for rhinovirus/enterovirus.Hematology is consulted in the ED owing to pancytopenia, and additional laboratory tests (Table 2) are performed, including peripheral blood smear, flow cytometry, ferritin level, lactate dehydrogenase, plasma haptoglobin, uric acid, coagulation panel, and blood culture.Given his travel history and acuity of symptoms, additional infectious laboratory tests are performed assessing for tuberculosis, viral hepatitis (A, B, C), human immunodeficiency virus (HIV), cytomegalovirus (CMV), Ebstein-Barr virus (EBV), rickettsial diseases (such as Rickettsia, Ehrlichia, and Anaplasma species), and thick and thin blood smears. Given his hyponatremia, elevated transaminase levels, and fever in an area where Ehrlichia and Rickettsia are endemic, he is started on empirical doxycycline to treat tickborne illnesses and is admitted to the pediatric hospital medicine service with infectious studies pending.This patient presented with acute onset of fever, chills, and malaise associated with pancytopenia, elevated transaminase levels, and indirect hyperbilirubinemia. The differential diagnosis of pancytopenia in pediatric patients includes infectious, oncologic, hematologic, and rheumatologic processes, with viral suppression being the most common cause of pancytopenia in a child.1 Because viral suppression is the most common cause of pancytopenia in children, it is important to consider common community-acquired illnesses such as EBV, CMV, influenza, and COVID-19. Given his recent emigration from South America, an infectious evaluation for fever in a newly returning traveler should include testing for viral hepatitis, tuberculosis, acute HIV, rickettsial illnesses, malaria, typhoid fever, leptospirosis, leishmaniasis, yellow fever, brucellosis, and dengue fever. Evaluation should be directed in a stepwise fashion for a stable patient, with testing for the most common infections sent first. Infectious diseases consultation can be helpful in identifying infections considered endemic to regions of travel.2 Peripheral smear and flow cytometry demonstrated no evidence of abnormal populations of cells (although the smear did give a clue to the final diagnosis), and tumor lysis laboratory values were reassuring, making oncologic and hematologic processes such as leukemia and aplastic anemia unlikely.3 The patient's elevated lactate dehydrogenase and low haptoglobin levels in the presence of normocytic anemia were consistent with hemolytic anemia. The patient did have elevated inflammatory markers, including ferritin as well as elevated transaminase levels, raising suspicion for a rheumatologic process; however, the acute timeline and physical examination findings made this less likely.The patient's thick and thin peripheral smear revealed malaria parasites consistent with Plasmodium vivax vs Plasmodium ovale infection. Polymerase chain reaction testing confirmed infection with P vivax with less than 1% parasitemia. Interestingly, the initial peripheral blood smear was read as normal without abnormal cells or malarial parasites, likely due to the low level of parasitemia. Other laboratory tests obtained at the time of admission evaluating for tuberculosis, viral hepatitis, HIV, CMV, EBV, Rickettsia rickettsii, Ehrlichia, and Anaplasma were all negative.Based on the most recent World Health Organization annual report, there were approximately 249 million malaria cases worldwide in 2022. Globally, the African region represents 93.6% of cases. In Central and South America, the countries of Venezuela, Brazil, and Colombia account for 73% of cases. P vivax is the primary species responsible for infections in endemic areas of Central and South America.4 Approximately 2000 cases of acute malaria infection are diagnosed every year in the United States, with most cases acquired from international travel. Although locally acquired infections are rare, the Centers for Disease Control and Prevention (CDC) is investigating recent reports of locally acquired malaria cases in Florida, Maryland, and Texas as of September 2023. As such, it is important for clinicians to consider acute malaria infections in patients with febrile illness with or without an identified travel history.5The presentation of acute malaria infection in the pediatric population is variable and can range from mild disease to severe disease. The most common symptoms are paroxysmal episodes of fever with rigor, nausea, vomiting, and headaches. There are several species of Plasmodium, including Plasmodium falciparum, P vivax, and P ovale. P falciparum can cause severe malaria infections, and P vivax and P ovale generally result in milder disease. Criteria for severe infection include hyperparasitemia (>5% red blood cells infected with the parasites), severe anemia (hemoglobin level, <7 g/dL <70 g/L), and evidence of end-organ dysfunction, such as cerebral malaria (altered mental status or other neurologic signs or symptoms), acute respiratory distress syndrome, coagulation abnormalities, hypotension, acute kidney injury, and metabolic acidosis. The time to onset of symptoms is variable and can range from 7 to 30 days after being bitten by an infected mosquito. Infection with P vivax and P ovale can result in relapse infections weeks to years after primary infection due to the dormant stage of infection. Initial testing with thick and thin peripheral blood smears allows clinicians to evaluate for the presence of parasites and the degree of parasitemia, an important marker of severity. Although not widely available, polymerase chain reaction testing is the most sensitive test and is recommended to confirm the speciation of Plasmodium. There are no consensus guidelines to suggest other screening laboratory tests that should be performed when malaria is suspected; however, it is important to assess for evidence of end-organ dysfunction as a marker of severe infection.6,7 Although anemia and thrombocytopenia are frequently cited in the literature as complications of P vivax infections, pancytopenia is a rare manifestation of P vivax infection and thought to be secondary to splenic sequestration. Various other mechanisms for pancytopenia have been described, including macroangiopathic hemolytic anemia, hemophagocytic syndrome, and direct bone marrow suppression.8Considerations when planning the treatment of acute malaria infection include the species of Plasmodium, the pattern of drug resistance based on the location of travel, the severity of disease, and the presence of glucose-6-phosphate dehydrogenase deficiency. It is important to determine the speciation of Plasmodium to guide treatment and stratify patients at risk for serious disease. The treatment of choice for patients with P falciparum depends on the geographic region where the infection was acquired. If the infection was acquired in a location with known chloroquine resistance, combination therapies are available. If the infection was acquired outside of these regions, oral chloroquine or hydroxychloroquine is recommended. The treatment of choice for acute infection with P vivax and P ovale infections is chloroquine or hydroxychloroquine. Mefloquine can be used for resistant species of P vivax and P ovale. Due to the risk of relapse, treatment of P vivax and P ovale also requires a 14-day course of primaquine phosphate in addition to treatment with chloroquine or hydroxychloroquine. However, these patients should be screened for glucose-6-phosphate dehydrogenase deficiency due to the risk of hemolytic anemia with this medication. Whereas uncomplicated infections can be treated with oral antimalarial therapies, severe infections require intravenous antimalarial therapy. Blood smears are routinely repeated every 12 to 24 hours to assess for reduction of parasitic density in response to therapy. Confirming a negative malaria smear after treatment is also recommended. Consultation with the CDC Malaria Hotline is recommended when questions arise regarding the diagnosis and treatment of acute malaria infection.9–11After the diagnosis of malaria was made, infectious diseases was consulted for additional guidance in management. The patient was admitted to the acute care floor on the pediatric hospital medicine service. Based on Red Book guidelines, our patient was treated with a complete course of oral hydroxychloroquine (initial dose of 1 g, then 500 mg at 6, 24, and 48 hours total dose at end of therapy, 2500 mg). After completing hydroxychloroquine therapy, he received a 14-day course of primaquine due to infection with P vivax. He also received 48 hours of intravenous ceftriaxone for empirical coverage of a possible co-infection with Salmonella Typhi due to recurrent fevers. He did not require vasoactive support and maintained reassuring hemodynamics and oral hydration throughout his hospitalization. Ceftriaxone and doxycycline were discontinued once blood cultures and tickborne illness studies returned negative. His fever, pancytopenia, elevated transaminase levels, and mild coagulopathy resolved with treatment, and he was discharged on day 5 of hospitalization. Repeated thick and thin peripheral smears revealed no parasitemia before discharge. The patient was scheduled for routine follow-up with infectious diseases after completion of his 14-day course of primaquine for repeated peripheral smears; however, the patient was lost to follow-up, and confirmation testing after completion of therapy was not obtained.The differential diagnosis of fever and pancytopenia includes oncologic, hematologic, rheumatologic, and infectious etiologies, with viral infection resulting in bone marrow suppression being the most common in pediatrics. Malaria should be considered on the differential diagnosis for patients presenting from international travel, including a history of travel to malaria-endemic countries.Evaluation for malaria includes thick and thin peripheral smear to assess the percentage of parasitemia; however, the gold standard for diagnosis is polymerase chain reaction testing.Severe malaria infection is characterized by hyperparasitemia, severe anemia, or evidence of end-organ dysfunction, such as cerebral malaria, acute respiratory distress syndrome, coagulation abnormalities, hypotension, acute kidney injury, and metabolic acidosis.