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Acalculous Cholecystitis in a Pediatric Patient With Plasmodium Falciparum Infection: A Case Report and Literature Review

Aguilera-Alonso, David, MD; López Medina, Eva, María, MD; Del Rosal, Teresa, MD, PhD; Villota Arrieta, Julián, MD; Escosa-García, Luis, MD; García-Hortelano, Milagros, MD

The Pediatric Infectious Disease Journal: February 2018 - Volume 37 - Issue 2 - p e43–e45
doi: 10.1097/INF.0000000000001734
Brief Reports

Malaria has been associated with acute acalculous cholecystitis, a very uncommon complication in children. We present a 5-year-old girl, originally from Equatorial-Guinea, diagnosed with severe malaria with acute kidney injury, thrombocytopenia and acute acalculous cholecystitis. She was treated with intravenous quinine and clindamycin, plus cefotaxime and metronidazole with a full resolution without surgery.

From the Department of Infectious Diseases and Tropical Pediatrics, Hospital La Paz, Madrid, Spain.

Accepted for publication July 29, 2017.

The authors have no funding or conflicts of interest to disclose.

Address for correspondence: Milagros García-Hortelano, MD, Department of Infectious Diseases and Tropical Pediatrics, Hospital La Paz, Paseo de la Castellana, 261, 28046, Madrid, Spain. E-mail: mghortelano@salud.madrid.org.

Malaria is still a leading cause of death and disease in many developing countries. Each year 5200 cases of malaria are imported to EU countries, with a progression to severe malaria in 10% of them.1 Severe malaria can be associated with different complications. Acute acalculous cholecystitis (AAC) is an uncommon condition in children that can be associated with some infections. Among these, the association with malaria is very rare. We report an AAC in a girl diagnosed with malaria and review published pediatric cases.

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CASE

A 5-year-old girl, originally from Equatorial Guinea, presented to the Pediatric Emergency Department immediately after landing in Madrid from her hometown. Seven days before, she had started with spiking fever. On the second day, she was diagnosed with acute otitis media and oral cefaclor was prescribed. The next day she experienced abdominal pain and asthenia. A second evaluation diagnosed malaria infection using a rapid diagnostic test based on detection of malaria-specific antigens in a blood sample. The complete blood count was normal. She was treated with intramuscular artemether (unknown dose), but she only received two doses of the three prescribed. Two days before travelling to Madrid she developed jaundice.

On arrival in Madrid, she was evaluated and presented icteric sclera, tenderness in the right and left hypochondrium and hepatomegaly 2 cm below the costal margin, without signs of peritoneal irritation or splenomegaly. Vital signs were within normal limits. Her medical history and family history were unremarkable. She was born in Spain but alternated long stays in Equatorial Guinea with shorter stays in Spain and had never had malaria. Laboratory examinations showed a white blood cell count of 14300/mm3 (neutrophils, 72%), hemoglobin level 11.9 g/L, thrombocytopenia (27000/mm3), C-reactive protein 128 mg/L, procalcitonin 32.8 ng/mL, total bilirubin 22.9 mg/dL, (direct, 18.3 mg/dL), aspartate transaminase 201 IU/L, alanine transaminase 187 IU/L and renal failure (creatinine, 2.19 mg/dL), with normal coagulation. Urinalysis was positive for urobilinogen and bilirubin. Chest radiograph was normal. Abdominal ultrasound was consistent with AAC (thickened gallbladder wall of 4.5 mm with sludge inside), with increased liver size (longitudinal diameter of the right lobe was 14 cm) without other complications. Peripheral smear showed Plasmodium falciparum (2% parasitemia).

She was diagnosed with severe malaria with acute renal failure, thrombocytopenia and AAC and admitted to the Pediatric Intensive Care Unit. She was treated with intravenous quinine and clindamycin, plus cefotaxime and metronidazole because of a possible septicemia associated with severe malaria. Acute renal failure was managed with intravenous fluids without oral feeding because of acute cholecystitis. During the first 12 hours of admission, she developed hypotension that required the administration of dopamine in continuous perfusion. Renal function and echographic gallbladder abnormalities were fully recovered on the third day of admission. The fever ceased and peripheral smear did not show parasitemia after the third dose, with significant clinical improvement.

IgG antibody to Epstein-Barr virus nuclear antigen and anti-viral capsid antigen IgM were positive, with a blood viral load undetectable (detection limit, 3.5 E3 copies/ml). The remaining microbiologic tests were negative: blood and stool cultures, viral serology (cytomegalovirus HIV, Hepatitis viruses A, B and C), parasite serology (Strongyloides, Toxoplasma, Schistosoma, Toxocara, Leishmania, Echinococcus, Taenia solium and Entamoeba histolytica) and stool ova and parasite examination. She was discharged after completing 7 days of antimalarial treatment. The physical examination, complete blood count and clinical biochemistry profile were all normal in the follow-up visit, 2 weeks after discharge.

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DISCUSSION

AAC is a very uncommon complication in children. It has been defined with echographic criteria (gallbladder wall thickening ≥ 3 mm, wall edema, intramural gas, gallbladder distension > 5 cm, biliary sludge or pericholecystic fluid).2 AAC has been associated with abdominal trauma, malignant diseases, congestive heart failure, diabetes and different infectious agents like tuberculosis, Salmonella typhi, Mycoplasma pneumoniae, Coxiella burnetii, Escherichia coli, Brucella, Rickettsia, Leptospira, Candida, microsporidia, Cryptosporidium, Aspergillus, dengue hemorrhagic fever and Staphylococcus aureus and group A Streptococcus sepsis.3 , 4

The first reported case associated with malaria was in 1999. To our knowledge, only isolated pediatric cases of AAC related to malaria have been published3–6; one with P. vivax and the remaining with P. falciparum (Table 1). Including our case, four were females and two males, all from Plasmodium endemic areas, with an age range from 3 to 9 years. These patients presented the usual malaria symptoms (fever, chills, drowsiness, headache) associated with specific digestive symptoms (abdominal pain, diarrhea, vomiting) and more characteristic symptoms or signs related to cholestatic syndrome (tenderness in the right hypochondrium, Murphy's sign—painful palpation of the subcostal region during inspiration—jaundice and dark urine). Hepatomegaly was described in all cases. As for analytic findings, three cases had mild elevation of liver enzymes with bilirubin elevation in only two. AAC diagnosis was based on echographic findings (the most common gallbladder was wall thickening 4.5–6 mm). All patients were treated with antimalarials, associated in four cases with broad spectrum antibiotics, showing improvement in 3–5 days without surgery.

TABLE 1

TABLE 1

Different hypotheses have been proposed to explain the physiopathology of AAC due to malaria.6 , 7 In cases of severe malaria, both rosetting (aggregation of parasitized red blood cells to nonparasitized cells) and cytoadherence (adherence of parasitized red blood cells to vascular endothelium) that cause microvascular obstruction and ischemia in multiple organs have been documented. These phenomena have been related to different complications, such as ischemic injury of brain parenchyma in cerebral malaria and acute tubular necrosis causing acute kidney injury. AAC could also be secondary to microcirculatory obstruction in the gallbladder vessels. Severe malaria is often associated with hypovolemia due to increased fluid losses and distributive shock caused by septicemia that could aggravate the hypoperfusion of the gallbladder. A third proposed mechanism is the release of proinflammatory cytokines (TNF, IL-6, IL-8, IL-12 or IL-18) during malaria infection that can contribute to gallbladder inflammation. Septicemia by enteric bacteria (mainly Salmonella) in children with severe malaria could also be associated with AAC, although all blood cultures from the reviewed cases were sterile.

Epstein-Barr virus has also been involved in AAC, almost all of them primary infections. A recent review showed 18 pediatric cases with AAC during Epstein-Barr virus primary infection published to date.8 Unlike AAC reported cases related to a plasmodium infection, these patients present a higher elevation of liver enzymes (usually alanine transaminase > 250 UI/L and aspartate transaminase. > 200 UI/L) and higher gallbladder wall thickening (usually > 7 mm) with a similar resolution without surgery. Also, the presentation is typical infectious mononucleosis with clinical signs such as fever, pharyngitis, cervical lymphadenopathy, hepatosplenomegaly and asthenia with characteristic laboratory abnormalities (lymphocytosis with atypical lymphocytes), which differentiate it from malaria. In our case, the full recovery after malaria treatment, the lack of clinical signs and laboratory abnormalities suggestive of infectious mononucleosis and Epstein-Barr virus markers compatible with a past infection lead us to think that the malaria infection has been the cause of AAC.

Abdominal pain is a common finding in acute malaria. Minor stress ulceration of the stomach and duodenum is common in severe malaria due to gut sequestration and visceral vasoconstriction. Other cholestatic signs such as hyperbilirubinemia can be secondary to hemolysis, which is very frequent in malaria. The high frequency of these symptoms, together with the lack of resources in malaria endemic areas, can lead to the underdiagnosis of AAC, as abdominal ultrasound is not routinely performed. A recent study9 conducted in an adult Intensive Care Unit found AAC ultrasound criteria in 7 of 42 abdominal ultrasounds performed in those patients with severe malaria and one or more of the following signs or symptoms: unexplained fever, vomiting, tenderness in the right upper quadrant, intolerance to enteral nutrition, jaundice, liver dysfunction or sepsis.

Changes in malaria epidemiology, with an increase in tourist or business travelers to tropical regions and migrants visiting friends and relatives in their previous home, are associated with a higher risk of complications because of their nonimmune situation.1 Visiting friends and relatives are also less likely to take anti-malarial prophylaxis. Another concern is the emergence of artemisinin-resistant P. falciparum in Southeast Asia and more recently in Africa.10

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ACKNOWLEDGMENTS

The authors thank Mr. Martin J. Smyth, BA, for his help in revising the language.

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REFERENCES

1. Kurth F, Develoux M, Mechain M, et alSevere malaria in Europe: an 8-year multi-centre observational study. Malar J. 2017;16:57.
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6. Kumar A, Taksande AM, Vilhekar KYAcalculous cholecystitis by P. falciparum in a 3-year-old child. J Vector Borne Dis. 2008;45:76–77.
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8. Branco L, Vieira M, Couto C, et alAcute Acalculous cholecystitis by Epstein-Barr virus infection: a rare association. Infect Dis Rep. 2015;7:6184.
9. Abreu C, Santos L, Poínhos R, et alAcute acalculous cholecystitis in malaria: a review of seven cases from an adult cohort. Infection. 2013;41:821–826.
10. Lu F, Culleton R, Zhang M, et alEmergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa. N Engl J Med; 2017. 2017;376:991–993.
Keywords:

malaria; acute acalculous cholecystitis; cholestatic syndrome; tropical infection

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