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Home , Pancytopenia, Splenomegaly

An 8-Year-Old Boy With , , and Rachel Offenbacher, MD,a,b Brad Rybinski, BS,b Tuhina Joseph, DO, MS,a,b Nora Rahmani, MD,a,b Thomas Boucher, BS,b Daniel A. Weiser, MDa,b

An 8-year-old boy with no significant past medical history presented to his abstract pediatrician with 5 days of fever, diffuse , and pallor. The pediatrician referred the patient to the emergency department (ED), out of concern for possible malignancy. Initial vital signs indicated fever, tachypnea, and tachycardia. was significant for marked , , and abdominal tenderness in the right upper and lower quadrants. Initial laboratory studies were notable for pancytopenia as well as an elevated erythrocyte sedimentation rate and C-reactive protein. aThe Children’s Hospital at Montefiore, Bronx, New York; and bAlbert Einstein College of Medicine, Bronx, New York Computed tomography (CT) of the and pelvis showed massive splenomegaly. The only significant history of travel was immigration from Dr Offenbacher led the writing of the manuscript, recruited various specialists for writing the Albania 10 months before admission. The patient was admitted to a tertiary manuscript, revised all versions of the manuscript, care children’s hospital and was evaluated by –oncology, and was involved in the care of the patient; infectious , genetics, and rheumatology subspecialty teams. Our Mr Rybinski contributed to the writing of the multidisciplinary panel of experts will discuss the evaluation of pancytopenia manuscript and critically revised the manuscript; Dr Joseph contributed to the writing of the manuscript, with apparent multiorgan involvement and the diagnosis and appropriate cared for the patient, and was critically revised all management of a rare disease. versions of the manuscript; Dr Rahmani contributed to the writing of the manuscript, revised the manuscript, and was involved in the care of the patient; Mr Boucher contributed to the writing and DR OFFENBACHER (PEDIATRIC RESIDENT) revision of the manuscript; Dr Weiser led the writing minute, blood pressure of 113/81 of the final manuscript, revised the manuscript, and An 8-year-old previously healthy boy mm Hg, and oxygen saturation of 97% was involved in the care of the patient; and all fi presented to his pediatrician with on room air. Eye examination was authors approved the nal manuscript as submitted. fi 5 days of fever and diffuse abdominal signi cant for conjunctival pallor with DOI: https://doi.org/10.1542/peds.2019-2372 pain, worse in the lower right quadrant anicteric sclerae. Cardiovascular and Accepted for publication Jan 28, 2020 and associated with decreased oral pulmonary examinations revealed no Address correspondence to Rachel Offenbacher, MD, intake, , and nonbloody, murmurs, rhonchi, rales, or wheezing. Department of Pediatrics, Children’s Hospital at fi nonbilious emesis. There was no was signi cant Montefiore, 3415 Bainbridge Ave, Bronx, NY 10467. , , or weight loss for marked distention, hypoactive E-mail: [email protected] and no history of respiratory symptoms bowel sounds, and tenderness to PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, or activity change. He reported feeling palpation along the right side without 1098-4275). slightly fatigued in the recent week. He rebound tenderness. His was Copyright © 2020 by the American Academy of had significant abdominal distention enlarged and palpable 2 cm below the Pediatrics and pallor on brief assessment. His right costal margin. His was FINANCIAL DISCLOSURE: The authors have indicated fi mother reported no sick contacts. His grossly enlarged and palpable to the they have no nancial relationships relevant to this article to disclose. only history of travel was emigrating level of his pelvis, crossing the midline. FUNDING: from Albania 10 months before His skin was intact without lesions, No external funding. admission. His pediatrician sent him to rashes, or . There were no POTENTIAL CONFLICT OF INTEREST: The authors have fl the ED for further evaluation. musculoskeletal deformities noted, indicated they have no potential con icts of interest with full range of motion in all major to disclose. In the ED, initial vital signs revealed joints. There was no . a temperature of 102.7°F (39.3°C), A thorough family history taken from To cite: OffenbacherR,RybinskiB,JosephT,etal. respiratory rate of 47 breaths per the mother, a nurse, revealed no An 8-Year-Old Boy With Fever, Splenomegaly, and Pancytopenia. Pediatrics. 2020;146(1):e20192372 minute, heart rate of 137 beats per incidence of ,

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 146, number 1, July 2020:e20192372 DIAGNOSTIC DILEMMAS immunodeficiency, autoimmune effusions and 3-mm calcified , , or metabolic granuloma within the left upper lobe disorders. of the lung (Fig 1) without any lymphadenopathy. Initial laboratory studies revealed pancytopenia ( count In the setting of fever and 1.4 3 103 per µL [absolute neutrophil , a blood culture was count 900], hemoglobin 7.2 g/dL, drawn, and cefepime was initiated count 64 3 103 per mL, mean to provide empirical coverage for corpuscular volume 78.9 fL) (Table 1) potential bacteremia. as well as elevated inflammatory Hematology–oncology was consulted markers (erythrocyte sedimentation because of the patient’s pancytopenia rate: 74 mm per hour, C-reactive and massive splenomegaly. Dr protein: 6.84 mg/dL). Point-of-care Rahmani, given the physical finger-stick hemoglobin done by our examination and laboratory findings, patient’s pediatrician 2 months are you concerned about a primary before presentation was normal, hematologic or oncologic process at suggesting acute onset of . this point? Reticulocyte count was 89.9, with a slightly elevated percentage of DR RAHMANI (PEDIATRIC 3.6%. The metabolic profile, bilirubin, HEMATOLOGIST–ONCOLOGIST) lactate dehydrogenase, and uric acid ’ levels were normal. Given our patient s fever, splenomegaly, and pancytopenia, I am A CT scan of his abdomen and pelvis concerned about acute lymphoblastic revealed a liver size within normal (ALL), the most common limits and marked splenomegaly hematologic malignancy in children (24 3 16 3 5 cm). Although the CT and adolescents.1 Fever can be showed displacement of the bowel by caused by ALL itself or in the setting the enlarged spleen, the bowel and of an opportunistic infection, both appendix were normal, with no signs of which can result in elevated of neutropenic colitis or appendicitis inflammatory markers. Leukemic and no lymphadenopathy. Chest CT infiltration of the liver and spleen revealed mild to moderate pleural results in hepatosplenomegaly, and FIGURE 1 A and B, CT scan of the abdomen without TABLE 1 Initial Laboratory Evaluation: Admission, 24 Hours After Beginning Treatment and After contrast. There is marked splenomegaly (24 3 Completion of Treatment 16 3 5 cm). Spleen is heterogeneous in ap- Admission Data 24 h After 1 mo After Initial pearance with ill-defined areas of low density Initiation of Presentation scattered throughout the spleen. This is a non- fi fi Amphotericin speci c nding. The liver is not enlarged. There is no peritoneal or pelvic fluid. The gallbladder WBC count (4.5–13.5), k/mL 1.4 5 5.9 is not enlarged. The bowel is displaced medi- Hemoglobin (12.0–14.4), g/dL 7.2 8.1 13.5 ally and inferiorly by the spleen, but the Hematocrit (35–40), % 23.6 26.3 42.8 intestines and mesentery are normal. The ap- Platelet count (150–400), k/mL 42 144 162 pendix is normal. There is no abdominal or Mean corpuscular value (77–95), fL 77 79.1 77 pelvic lymphadenopathy. There are small to Red cell distrbibution width (11.5–13.4), % 16.9 17.4 18.8 moderate pleural effusions with subsegmental Mean corpuscular hemoglobin 30.7 30.1 31.5 atelectasis at the lung bases and posteriorly in concentration (31–37), g/dL the lungs. RBC count (4.00–5.20), MIL/mL 3.07 3.4 5.55 Neutrophil count (1.5–8.0), k/mL 1.3 3 2.2 Lymphocyte count (1.5–6.0), k/mL 0.8 1.5 3 replacement of with – Monocyte count (0.3 0.5), k/mL 0.1 0.4 0.5 leukemic lymphoblasts results in Eosinophil count (0.1–0.3), k/mL 0 0 0.2 2 Spleen size Spleen palpated Spleen palpated Spleen palpated pancytopenia. In our patient, the at the umbilicus at the level of the 2 cm below absence of lymphadenopathy, as and in the LLQ umbilicus costovertebral noted in half of patients with ALL, margin does not narrow the differential.3 LLQ, left lower quadrant; MIL, millions. Given the high suspicion for leukemia,

Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 OFFENBACHER et al a bone marrow aspirate and biopsy autoimmune disorders, and certain EBV, CMV, or parvovirus), or by bone should be obtained because they are genetic disorders, such as lysosomal marrow or spleen infiltration. the most sensitive and definitive tests storage diseases (LSDs).2 The latter 3 Although the most recent travel to diagnose leukemia and allow for diagnoses are not likely given the history was 10 months ago, we histologic review. One may also negative family history of should also consider typical consider other diagnoses that occur autoimmune and genetic disorders. pathogens that cause fever in a recent in this age group, such as Langerhans immigrant or returned traveler and of cell histiocytosis or and, DR OFFENBACHER course be aware of those exposures although rare, primary hepatic specific to Albania. Of the infections malignancies, including Because the patient’s presentation endemic to this region, those that hepatoblastoma and hepatocellular was highly concerning for acute cause fever, splenomegaly, and carcinoma.4 leukemia, we initiated precautions for pancytopenia include , tumor lysis syndrome, including , visceral (VL), Pancytopenia can also be caused by hyperhydration (1.5 cc per hour and . inherited or acquired bone marrow maintenance fluids) and allopurinol. failure syndromes, although these are However, the patient’s bone marrow Disseminated tuberculosis can cause fi not typically associated with evaluation did not reveal a malignant in ltration of the bone marrow, liver, splenomegaly. Inherited or congenital infiltrative process and, in fact, and spleen. Although only 0.5% to causes typically present in the first demonstrated normal trilineage 3% of children develop symptomatic few years of life, and our patient has hematopoiesis. Consistently, flow lymphohematogenous spread of 5 been previously healthy. Our patient cytometry and peripheral smear were tuberculosis, given our international ’ fi lacks classic features of bone marrow unable to identify any leukemic patient s signi cant presentation, it failure syndromes, including lymphoblasts. Thus, a leukemic must be worked up. This progression (skin process was ruled out, and can present months after the initial pigmentation, nail dystrophy, and allopurinol and hyperhydration infection, but it can also remain occult 3 mucosal leukoplakia), Fanconi were discontinued. and present even later during acute anemia (musculoskeletal stress. Tuberculous bacilli can 2 Given the absence of leukemic malformations), and Shwachman- infiltrate the liver, spleen, and bone infiltration in the bone marrow and Diamond syndrome (neutropenia and marrow, as well as skin, lungs, 2 the presence of normal trilineage exocrine pancreatic dysfunction). kidneys, heart, and brain. Despite the hematopoiesis, our differential shifted severity and the widespread Acquired bone marrow failure in to focus on other etiologies of dissemination of the infection, timely children is most commonly caused by pancytopenia. We considered treatment is usually successful in an medications, chemicals, or infections. infectious etiologies, hepatic sources, immunocompetent host.5 The most frequently implicated rheumatologic causes, and metabolic fi medications include disorders. Dr Joseph, what infectious Malaria can present with nonspeci c chemotherapeutics and antiepileptic etiologies would you consider in symptoms in children and should be drugs, although and a patient who is persistently febrile considered in any child with a febrile fl with pancytopenia and illness in the context of appropriate nonsteroidal anti-in ammatory drugs 5 can also trigger marrow suppression splenomegaly? exposure. For our patient in and secondary pancytopenia. particular, I would be concerned for hyperreactive malarial splenomegaly, Infectious causes include , DR JOSEPH (PEDIATRIC INFECTIOUS a chronic stimulation of the immune Epstein-Barr virus (EBV), DISEASE) system thought to be related to cytomegalovirus (CMV), and HIV, 6 which may be associated with When concerned for an infection in chronic malaria exposure. The hepatosplenomegaly. Drug exposure the setting of neutropenia, we should syndrome results in massive was not reported with our patient determine if underlying neutropenia hepatosplenomegaly, anemia, and and was not a concern, although an is the risk factor for infection or if the often and infectious etiology explaining infection is causing the neutropenia. neutropenia; therefore the risk of pancytopenia is quite possible. Because we have already determined secondary bacterial infections can be that a malignancy or primary significant.6 Although malaria is Finally, pancytopenia can also be immunodeficiency is unlikely in this uncommon in Albania, there have caused by peripheral destruction or patient, we can focus on infectious been several cases reported of splenic sequestration of blood cells; causes of neutropenia. The , ovale, and these may occur in the setting of neutropenia could be caused by viral vivax7; the latter 2 can remain malignancy, infection, hepatic disease, suppression of the bone marrow (like asymptomatic in the liver for months,

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 146, number 1, July 2020 3 making his travel 10 months before opportunistic infections in HIV the portal vein should be examined presentation pertinent. patients, with a fulminant course. via Doppler .

Leishmaniasis is a protozoal, vector- When considering splenomegaly in transmitted infection that is currently DR OFFENBACHER the setting of a febrile patient with endemic to India, Africa, the Middle pancytopenia, it is important to East, South America, and the Appropriate testing for malaria, consider hemophagocytic Mediterranean,8 therefore making the brucellosis, leishmaniasis, HIV, and lymphohistiocytosis (HLH), an diagnosis of VL a possibility in our tuberculosis was sent. Microscopic uncommon but life-threatening patient. Patients typically present examination of the bone marrow did disorder of severe uncontrolled with fever, notable not reveal fungi or Leishmania activation of the immune system.14 hepatosplenomegaly, and bone parasites. In addition, the result from Patients are generally considered to marrow suppression due to a peripheral smear was negative for have HLH if they fulfill 5 of the proliferation of parasites and infected malaria parasites and plasmodium following 8 criteria: (1) fever $38.5° throughout the spleen, antigens. HIV testing for HIV p24 C, (2) splenomegaly, (3) cytopenias liver, and bone marrow.8 Leishmania antigen and antibodies to HIV type 1 affecting 2 lineages in the peripheral parasites may be visible on bone and/or type 2 were nonreactive. blood (hemoglobin ,9 g/dL, marrow examination, but the Blood cultures did not show growth ,100 g/dL, neutrophils ,1 3 sensitivity is 60% to 85% and it of Brucella. The screening and 103/mL), (4) hypertriglyceridemia cannot morphologically distinguish diagnosis of tuberculosis were (fasting, .265 mg/dL) and/or between species.8 Therefore, when evaluated by using an interferon-g hypofibrinogenemia (,150 mg/dL), there is high suspicion for VL, testing release assay as well as an acid-fast (5) hemaphagocytosis in the bone should be performed by the Centers bacterial (AFB) blood culture. The marrow, (6) low or absent NK cell for Disease Control and Prevention by interferon-g release assay results activity; (7) hyperferritinemia using serology and molecular testing were indeterminate because of failure .500 ng/mL, and (8) high levels of on serum and bone marrow.8,9 The of the positive control, and the AFB sCD25 (soluble interleukin-2 incubation period of Leishmania blood culture showed no organisms receptor).15 parasites can be as long as several on initial smear and was incubated years,8 so although our patient for 6 weeks with no growth. EBV and immigrated from Albania 10 months CMV serum polymerase chain DR OFFENBACHER ago, he is still at risk. reactions (PCRs) returned and were nonreactive. To further evaluate his Ultrasound with Doppler noted fl In the setting of any patient with prolonged fever of unknown origin, normal ow through the portal vein, prolonged , occult brucellosis an echocardiogram was performed, effectively ruling out portal vein should be considered in the absence which showed no intracardiac dysfunction. Markers for HLH, fi of an alternative source. Brucellosis is vegetation suggestive of . including ferritin, brinogen, NK cell a bacterial zoonotic infection and is Dr Rahmani, how else can you explain activity, and sCD25 levels, were all particularly endemic to the pancytopenia in a patient with within normal limits. Triglyceride Mediterranean basin, including normal trilineage hematopoiesis in levels were mildly elevated, but not to 10 14 Albania. Foodborne sources (eg, the marrow? levels consistent with HLH. In unpasteurized milk and cheese) and addition, the previous bone marrow direct contact with infected animals aspirate demonstrated no are the primary modes of DR RAHMANI hemophagocytosis. Although several transmission10,11; our patient did not markers and genetic testing for HLH endorse these specific exposures. The With a normal bone marrow were not immediately available, most common presentation of evaluation and no obvious infection, a normal ferritin level is reassuring. localized brucellosis is osteoarticular the etiology of pancytopenia is likely The patient only met 3 out of the 8 involvement, but it can present with secondary to splenomegaly, or splenic criteria and therefore was not splenomegaly and cytopenias. sequestration of peripheral blood thought to have HLH. Significant complications can include cells. Congestive splenomegaly can neurobrucellosis and endocarditis.12 result from splenic vein thrombosis There are also several causes of or any entity that increases hepatic splenomegaly that have a genetic Finally, HIV can alter your immune venous pressure, such as liver origin. Although the patient’s system and cause myelosuppression, disease, , and presentation was acute, this does not and testing would be useful as many congestive .13 Therefore, necessarily rule out a genetic organisms could manifest as an evaluation of blood flow through condition. Dr Levy, would you

Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 OFFENBACHER et al consider a genetic cause for our present in the most common ophthalmology examination to patient’s symptoms? LSDs. I would obtain a formal evaluate for uveitis, which is ophthalmologic examination to assess a common finding in .23 for cherry red spots, which can occur An angiotensin converting enzyme DR LEVY (PEDIATRIC GENETICIST) in Niemann Pick disease. level, which is often elevated in Glycogen storage disease type IV sarcoidosis,23 should be checked often presents with hypoglycemia and as well. DR OFFENBACHER . Splenomegaly usually arises secondary to and A quantitative immunoglobulin panel portal hypertension. However, as was significant for elevated DR OFFENBACHER previously described, there was no immunoglobulin G of 2750 mg/dL A formal ophthalmologic examination evidence of cirrhosis or portal – (normal 700 1600 mg/dL), which was performed. There were no hypertension on imaging, so can be seen in infectious or findings suggestive of LSDs, such as a glycogen storage disease is unlikely. rheumatologic conditions. Dr fatty deposits in the sclera or a cherry Rubinstein, would you consider Splenomegaly is a consistent finding red macular spot. To be conclusive, an a rheumatologic origin for our in many LSDs, such as Gaucher LSD panel was sent, with the patient’s presentation, particularly disease, mucopolysaccharidoses, and understanding that results would given the prolonged fevers and Niemann Pick type A, B, or C. Gaucher take several weeks. There was also no cytopenias? disease, in which lipid-laden evidence of uveitis, which would have macrophages accumulate in the been suggestive of rheumatologic liver, spleen, bone marrow, and DR RUBINSTEIN (PEDIATRIC etiology. Although his angiotensin other affected organs, can RHEUMATOLOGIST) converting enzyme level was mildly present at variable ages with elevated to 72 U/L (normal 8–52 In the setting of unexplained fevers hepatosplenomegaly, bone U/L), this is a nonspecific finding, and and pancytopenia, an important crises, and pancytopenia.16 there is some evidence that the value rheumatologic etiology to rule out is 24 Mucopolysaccharidoses are LSDs that may be normal for a male child. systemic erythematosus, which result from deficiency of various is possible but rare in young boys. enzymes required to break down While we continued our workup, our The patient’s antinuclear antibody glycosaminoglycans.17 These patient continued to have persistent testing was negative, making this accumulate in lysosomes resulting in fevers with pancytopenia. Ten days highly unlikely. Other rheumatologic fi diverse diseases that may include after admission, we were noti ed by etiologies can be complicated by and hepatosplenomegaly.17 Although the Centers for Disease Control and can present with some of the mucopolysaccharidoses Prevention of positive antibody activation syndrome, an entity highly present at birth, other more- serology and serum PCR testing for similar to HLH, but as discussed attenuated forms can present in late complex, previously, his ferritin, bone marrow fi childhood or early adulthood with con rming a diagnosis of VL. The LSD findings, and other testing were not musculoskeletal or joint complaints.17 panel and AFB blood culture later consistent. The additional finding of Niemann Pick types B and C can both resulted as negative. a small 3-mm calcified granuloma in present at any age with hepatic, the left upper lobe seen on chest CT splenic, and respiratory disease.18,19 could be evidence of a granulomatous FINAL DIAGNOSIS AND SUMMARY: Gaucher disease, disease such as sarcoidosis. mucopolysaccharidoses, and Sarcoidosis is a systemic Drs Offenbacher and Joseph Niemann Pick types B and C are quite inflammatory disease that typically rare (1:25 000–1:250 000 live affects the eyes, lungs, and liver but Our patient’s presentation with fever, births)19–22 and are associated with can affect any organ.23 Rarely, splenomegaly, and pancytopenia symptoms absent in our patient. sarcoidosis can include splenic made us especially concerned for Although it is rarer to have these involvement that presents with leukemia. When evaluation for diseases present at 8 years old pancytopenia secondary to a malignancy did not reveal the without other significant signs and hypersplenism.23 This patient also source, an infectious workup ensued, symptoms, it is important to screen developed respiratory distress with with VL high on our differential given for them because early intervention pleural effusions, which may be his massive splenomegaly and can reduce morbidity and mortality. I compatible with pulmonary previous travel history from an area would send an LSD panel, which tests manifestations of sarcoidosis.23 It is known to have high rates of for the enzymatic deficiencies that are reasonable to proceed with formal leishmaniasis.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 146, number 1, July 2020 5 Leishmaniasis is rarely seen in New infection was acquired, and host Our patient had a rapid response to York City and the United States, factors such as age and immune treatment with amphotericin B; his although the global health burden is status.8 Liposomal amphotericin B is blood counts started to improve significant. There are concentrated the only US Food and Drug (Table 1), and his fevers resolved regions in Somalia, Brazil, Ethiopia, Administration–approved drug for within 24 hours. The patient then Kenya, India, South Sudan, and Sudan, treatment of VL in the United States completed his amphotericin B which encompass over 90% of the and results in close to a 100% cure treatment as an outpatient and was worldwide cases of VL.25 VL is also rate when administered at a high managed by infectious disease and endemic in Albania; between 1998 cumulative dose.28 Liposomal hematology with no relapses or skin and 2016, ∼1631 zoonotic VL cases amphotericin is preferred in several lesions for 18 months. He had were reported, with domestic and other countries; however, worldwide resolution of his abdominal distention wild canines serving as a reservoir treatment varies by country, and splenomegaly and normalization and the bite of the Phlebotomus and depending on the availability and cost of his blood counts within 2 weeks Lutzomyia species of sandflyas of each drug. Other drugs used to (Table 1). He and his family were vectors.26,27 treat VL include miltefosine and later screened for L donovani with pentavalent antimonial drugs (eg, serum PCR testing, which was VL generally presents as a subacute sodium stiboglutinate or negative. illness with insidious onset of fever, meglumine).29,30 The US Food and malaise, splenomegaly, and With our case, we illustrate the Drug Administration currently multidisciplinary approach necessary pancytopenia. Patients generally recommends a series of 3 mg/kg complain of abdominal pain to create a broad differential doses on days 1 to 5, 14, and 21 for diagnosis in the face of a less common secondary to massive splenomegaly. a total dose of 21 mg/kg.28 Fever Progression of the disease is typical in disease entity and the importance of should resolve within 1 to 2 weeks, a detailed travel and exposure history, the months after infection from and hepatosplenomegaly should fl and we highlight how our a sand y bite but can range from resolve in ∼1 month.29 weeks to years. Our patient’s travel understanding of pathophysiology history was significant for migration Treatment success is determined can guide effective clinical decision- from Albania, although it was by resolution of clinical and making. 10 months before what appeared to laboratory findings, as antibody be an acute illness. This long testing may remain positive for 29 ACKNOWLEDGMENTS incubation period combined up to several years. Patients with the rarity of US cases of who respond clinically to We thank David Goldman, MD, VL originally made it seem unlikely amphotericin B should be Christina Coyle, MD, Tamar to be the patient’s diagnosis. managed for at least 1 year, as Rubinstein, MD, Paul Levy, MD, Aileen Although the sensitivity of a bone relapses can occur despite adequate Raizer, MD, Jonathan Sterman, MD, 29 marrow evaluation for Leishmania treatment. Most relapses occur Nunzia Fatica, MD, and Peter parasites is 60% to 85%, reaching between 6 and 12 months after Belamarich, MD for their 8 a diagnosis was prolonged by its treatment, but relapses have been contributions to the clinical care and negative result. observed up to 18 months discussion of the differential 31 posttreatment. For patients who diagnosis of this patient. Diagnosis can be made by PCR or by relapse, a dose increase to 30 to serological testing for the antibody to 40 mg/kg total may be warranted. the K39 antigen of the L donovani There are no trial data to determine ABBREVIATIONS complex; however this does not the optimal regimen.32 distinguish between the species L AFB: acid-fast bacterial donovani, L infantum,orL chagasi.9 A small subset of patients ALL: acute lymphoblastic leukemia Our patient’s serum was PCR successfully treated for VL can later CMV: cytomegalovirus positive and antibody positive for L develop diffuse maculopapular or CT: computed tomography nodular skin lesions called post-kala- EBV: Epstein-Barr Virus donovani complex. L donovani was 8 detected in his bone marrow by azar dermal leishmaniasis. It is ED: emergency department immunohistochemistry but not poorly understood and generally HLH: hemophagocytic by PCR. occurs in patients infected with L lymphohistiocytosis donovani, like our patient, but most LSD: lysosomal storage disease Treatment of VL is dependent on the cases have been reported in patients PCR: polymerase chain reaction species and strain of Leishmania, the who became infected in Sudan or VL: visceral leishmaniasis geographic region in which the India.8

Downloaded from www.aappublications.org/news by guest on September 28, 2021 6 OFFENBACHER et al REFERENCES 13. Chapman J, Azevedo AM. Splenomegaly. 25. Burza S, Croft SL, Boelaert M. StatPearls. Treasure Island, FL: Leishmaniasis. Lancet. 2018;392(10151): 1. Hunger SP, Mullighan CG. Acute StatPearls Publishing StatPearls 951–970 lymphoblastic leukemia in children. Publishing LLC; 2018 N Engl J Med. 2015;373(16):1541–1552 26. World Health Organization. Albania: 2. Weinzierl EP, Arber DA. The differential 14. Jordan MB, Allen CE, Weitzman S, leishmaniasis country profiles. 2019. diagnosis and bone marrow evaluation Filipovich AH, McClain KL. How I treat Available at: https://www.who.int/ of new-onset pancytopenia. Am J Clin hemophagocytic lymphohistiocytosis. leishmaniasis/burden/Leishmaniasis_ Pathol. 2013;139(1):9–29 Blood. 2011;118(15):4041–4052 Albania/en/. Accessed July 10, 2019 3. Clarke RT, Van den Bruel A, Bankhead C, 15. Henter JI, Horne A, Aricó M, et al. HLH- 27. Galati EAB, Galvis-Ovallos F, Lawyer P, Mitchell CD, Phillips B, Thompson MJ. 2004: diagnostic and therapeutic Léger N, Depaquit J. An illustrated guide Clinical presentation of childhood guidelines for hemophagocytic for characters and terminology used in leukaemia: a systematic review and lymphohistiocytosis. Pediatr Blood descriptions of Phlebotominae (Diptera, meta-analysis. Arch Dis Child.2016; . 2007;48(2):124–131 Psychodidae). Parasite. 2017;24:26 101(10):894–901 16. Stirnemann J, Belmatoug N, Camou F, 28. Centers for Disease Control and 4. Kane JM, Schmidt K, Conway JH. Fever, et al. A review of Gaucher disease Prevention. Resources for health hepatosplenomegaly, and pancytopenia pathophysiology, clinical presentation professionals: parasites - leishmaniasis. in a 5-month-old infant. Arch Pediatr and treatments. Int J Mol Sci. 2017;18(2): 2018. Available at: https://www.cdc.gov/ – Adolesc Med. 2003;157(2):201 205 E441 parasites/leishmaniasis/health_ 5. Cherry J, Demmler-Harrison G, Kaplan professionals/index.html#tx-vl. Accessed 17. Cimaz R, La Torre F. SL, Steinbach WJ, Hotez PJ. Feigin and November 9, 2018 Mucopolysaccharidoses. Curr Cherry’s Textbook of Pediatric Infectious Rheumatol Rep. 2014;16(1):389 29. Aronson N, Herwaldt BL, Libman M, et al. Diseases. Philadelphia, PA: Elsevier/ Diagnosis and treatment of Saunders; 2014 18. Schuchman EH, Desnick RJ. Types A and leishmaniasis: clinical practice B Niemann-Pick disease. Mol Genet 6. McGregor A, Doherty T, Lowe P, Chiodini guidelines by the Infectious Diseases Metab. 2017;120(1–2):27–33 P, Newsholme W. Hyperreactive malarial Society of America (IDSA) and the splenomegaly syndrome–can the 19. Vanier MT. Niemann-Pick disease type C. American Society of Tropical Medicine diagnostic criteria Be improved? Am Orphanet J Rare Dis. 2010;5:16 and Hygiene (ASTMH). Am J Trop Med J Trop Med Hyg. 2015;93(3):573–576 Hyg. 2017;96(1):24–45 20. Nalysnyk L, Rotella P, Simeone JC, 7. Shkurti K, Vyshka G, Velo E, Boçari A, Hamed A, Weinreb N. Gaucher disease 30. WHO Expert Committee. Control of the Kokici M, Kraja D. Imported malaria in epidemiology and natural history: Leishmaniases. Report of a Meeting of Albania and the risk factors that could a comprehensive review of the the WHO Expert Committee on the allow its reappearance. Malar J.2013; literature. Hematology. 2017;22(2):65–73 Control of Leishmaniases, Geneva, 22–26 12:197 March, 2010. Geneva, Switzerland: WHO 21. Tomatsu S, Fujii T, Fukushi M, et al. 8. Pace D. Leishmaniasis. J Infect. 2014; Press; 2010 69(suppl 1):S10–S18 Newborn screening and diagnosis of mucopolysaccharidoses. Mol Genet 31. Burza S, Sinha PK, Mahajan R, et al. Five- 9. Boelaert M, Verdonck K, Menten J, et al. Metab. 2013;110(1–2):42–53 year field results and long-term Rapid tests for the diagnosis of visceral effectiveness of 20 mg/kg liposomal 22. Meikle PJ, Hopwood JJ, Clague AE, Carey leishmaniasis in patients with suspected amphotericin B (Ambisome) for visceral WF. Prevalence of lysosomal storage disease. Cochrane Database Syst Rev. leishmaniasis in Bihar, India [published 2014;(6):CD009135 disorders. JAMA. 1999;281(3):249–254 correction appears in PLoS Negl Trop 10. Pappas G, Papadimitriou P, Akritidis N, 23. Heinle R, Chang C. Diagnostic criteria for Dis. 2014;8(4):e2813]. PLoS Negl Trop Dis. Christou L, Tsianos EV. The new global sarcoidosis. Autoimmun Rev. 2014; 2014;8(1):e2603 map of human brucellosis. Lancet Infect 13(4–5):383–387 Dis. 2006;6(2):91–99 32. Aronson N, Herwaldt BL, Libman M, et al. 24. Bénéteau-Burnat B, Baudin B, Morgant Diagnosis and treatment of 11. Seleem MN, Boyle SM, Sriranganathan N. G, Baumann FC, Giboudeau J. Serum leishmaniasis: clinical practice Brucellosis: a re-emerging zoonosis. Vet angiotensin-converting enzyme in guidelines by the Infectious Diseases – – Microbiol. 2010;140(3 4):392 398 healthy and sarcoidotic children: Society of America (IDSA) and the 12. Franco MP, Mulder M, Gilman RH, Smits comparison with the reference interval American Society of Tropical Medicine HL. Human brucellosis. Lancet Infect Dis. for adults. Clin Chem. 1990;36(2): and Hygiene (ASTMH). Clin Infect Dis. 2007;7(12):775–786 344–346 2016;63(12):e202–e264

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 146, number 1, July 2020 7 An 8-Year-Old Boy With Fever, Splenomegaly, and Pancytopenia Rachel Offenbacher, Brad Rybinski, Tuhina Joseph, Nora Rahmani, Thomas Boucher and Daniel A. Weiser Pediatrics originally published online June 12, 2020;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2020/06/10/peds.2 019-2372 References This article cites 26 articles, 5 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2020/06/10/peds.2 019-2372#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Hematology/Oncology http://www.aappublications.org/cgi/collection/hematology:oncology _sub Blood Disorders http://www.aappublications.org/cgi/collection/blood_disorders_sub Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Epidemiology http://www.aappublications.org/cgi/collection/epidemiology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 An 8-Year-Old Boy With Fever, Splenomegaly, and Pancytopenia Rachel Offenbacher, Brad Rybinski, Tuhina Joseph, Nora Rahmani, Thomas Boucher and Daniel A. Weiser Pediatrics originally published online June 12, 2020;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2020/06/10/peds.2019-2372

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