Case report

A 21-month-old female with a past medical history of dilated cardiomyopathy and subsequent orthotopic heart transplantation complicated by Epstein-Barr virus viremia presented to the emergency department one year post-transplant with recurrent acute otitis media, swelling of the left posterior auricle, and mildly decreased oral intake. Ultrasound of the neck showed prominent cervical lymph nodes, chest radiograph revealed increasing right and left hilar rounded opacities, and Epstein-Barr virus titres were significantly elevated from baseline. Due to recurrent otitis media, broad-spectrum antibiotics including cefepime and linezolid were initiated and she underwent bilateral myringotomy and tube placement as well as adenotonsillectomy on hospital day 3. Pathology revealed findings consistent with Epstein-Barr virus positive polymorphic post-transplant lymphoproliferative disorder. The patient received treatment with rituximab on hospital day 4 and underwent monitoring for tumour lysis syndrome. Venous blood gas obtained after completion of the 5-hour rituximab infusion incidentally revealed a metabolic acidosis with a pH of 7.31, PCO₂ 21 mm Hg, bicarbonate 10.6 mmol/L, base deficit of 14, glucose 71 mg/dL, and lactate of 9.7 mmol/L. She was mildly tachycardic and tachypnoeic but otherwise well-appearing with normal perfusion on exam and receiving no respiratory support or inotropic or vasoactive medications. The acidosis was corrected with bicarbonate but due to subsequent increasing lactate to 11.3 mmol/L, she was intubated, sedated and paralysed to decrease metabolic demand. Milrinone was initiated to enhance systemic perfusion. She received volume resuscitation to optimise preload and bicarbonate boluses and then infusion to correct the metabolic acidosis. Her liver function was normal. An echocardiogram revealed normal biventricular systolic function and no pericardial effusion. CT scans revealed extensive lymphadenopathy in the cervical, mediastinal, hilar, axillary, retroperitoneal, mesenteric, and pelvic regions consistent with post-transplant lymphoproliferative disorder. Methylprednisolone and then cyclophosphamide were initiated for further cytoreduction. At this time, the treatment team considered Warburg effect as an aetiology of lactate production. Hyperlactatemia worsened to > 17.8 mmol/L on hospital day 5 and persisted until thiamine was administered on hospital day 7 which resulted in rapid resolution (Figure 1). The patient received 100 mg of intravenous thiamine daily for 5 days. Of note, she had previously been eating a varied, regular diet and her weight was > 97th percentile for age. She was extubated on hospital day 9, underwent lumbar puncture, bone marrow biopsy, and port placement on hospital day 15 as part of her post-transplant lymphoproliferative disorder treatment and was discharged home on hospital day 16.

Figure 1.

Trajectory of lactate level in relationship to PTLD treatement and thiamine administration.

Discussion

Warburg effect occurs when the metabolic rate of rapidly growing cancer cells is elevated and relies on glycolysis to generate energy. ^{Reference Permtawee, Tengsujaritkul and Choed-Amphai1,Reference Lerner, Pessach, Rubinstein and Paret2} These highly metabolically active malignant cells also preferentially utilise thiamine leading to thiamine deficiency which prevents pyruvate from entering the tricarboxylic acid cycle and subsequently inhibits aerobic metabolism. These factors lead to an increase in lactate production via glycolysis. Epstein-Barr virus infection itself also alters glucose metabolism and can cause Warburg effect. ^{Reference Cao, Xie and Shi3} Epstein-Barr virus upregulates all glycolytic enzymes, induces substantial relocalisation of glucose transporter-1, and enhances glycolytic flux. ^{Reference Cao, Xie and Shi3}

Warburg effect has been described in case reports of adult and paediatric patients, often with haematologic malignancies. ^{Reference Permtawee, Tengsujaritkul and Choed-Amphai1,Reference Lerner, Pessach, Rubinstein and Paret2} Treatment with chemotherapy, thiamine, bicarbonate, and dialysis have been utilised with varying success. Cases of Warburg effect have rarely been reported in adult patients with post-transplant lymphoproliferative disorder, with one patient improving with chemotherapy and the other succumbing to multi-organ failure; neither were treated with thiamine. ^{Reference Short and Sen4,Reference Golhar, Green and Guy5} As far as we know, no cases of children with post-transplant lymphoproliferative disorder and Warburg effect and successful management with thiamine have been described.

Other scenarios that can lead to thiamine deficiency and hyperlactatemia include malnutrition and septic shock. Cases of inadequate supplementation in parenteral nutrition as well as malabsorption have led to metabolic acidosis and severe hyperlactatemia which improved with thiamine administration. ^{Reference Didisheim, Ballhausen and Choucair6–Reference Teagarden, Leland, Rowan and Lutfi8} Cases of persistent hyperlactatemia in paediatric patients with septic shock have also improved after thiamine administration. ^{Reference Weiss, Blowey and Keele9} Contributing factors in those patients may be that many critically ill children have thiamine deficiency on presentation, limited body storage, high utilisation of thiamine, hypermetabolism, and limited nutrition during the initial phase of critical illness. ^{Reference Teagarden, Leland, Rowan and Lutfi8} Our patient had excellent nutrition prior to presentation and workup for sepsis during admission was negative. Thiamine levels are not routinely measured due to lack of standard references in paediatric and critically ill patient and testing turnaround time. Response to administration of thiamine has been used in prior reports to determine deficiency. ^{Reference Didisheim, Ballhausen and Choucair6,Reference Hasan and Shajira7} We did not obtain a thiamine level on our patient. Other cases of Warburg effect report that anywhere from low-normal to deficient levels have resulted in hyperlactatemia: 55 nmol/L (normal range 70–180 nmol/L), 56.6 nmol (normal range 66.5–200 nmol/L), and 70.7 nmol/L (normal range 60–200 nmol/L). ^{Reference Lerner, Pessach, Rubinstein and Paret2,Reference Didisheim, Ballhausen and Choucair6,Reference Teagarden, Leland, Rowan and Lutfi8}

Hypoglycaemia may be associated with Warburg effect. Paediatric oncology patients with Warburg effect present with hypoglycaemia approximately 43.8% of the time. ^{Reference Permtawee, Tengsujaritkul and Choed-Amphai1} Thiamine, in the form of thiamine pyrophosphate, becomes an essential cofactor in glycolysis and mitochondrial oxidative decarboxylation of carbohydrates for energy formation. Thiamine deficiency can lead to failure of glucose metabolism and ultimately compromise aerobic metabolism, resulting in a profound increase in the formation of pyruvate and lactic acid. ^{Reference Teagarden, Leland, Rowan and Lutfi8} Our patient’s glucose was 84 mg/dL on admission and 77 mg/dL when she developed hyperlactatemia. Blood glucose prior to thiamine was mostly 80–110 mg/dL, for the 60 hours after initiation of thiamine it was mostly 110–170 mg/dL, and then it decreased back to 80–100 mg/dL. Hyperglycaemia did not contribute to this case of severe hyperlactatemia.

There are rare cases of linezolid induced hyperlactatemia, usually occurring after prolonged administration. ^{Reference Ramesh, Gattu, Maqsood and Rao10} Our patient received linezolid from hospital day 1 to hospital day 6. Our patient’s lactate remained higher than the limit of detection for 2 days following discontinuation of linezolid and then suddenly and precipitously decreased immediately following thiamine administration, so we do not believe that exposure to linezolid contributed to this case of hyperlactatemia.

In conclusion, Warburg effect should be considered in the differential diagnosis for transplant patients with hyperlactatemia in the setting of post-transplant lymphoproliferative disorder. Treatment with thiamine should be considered early as it may lead to rapid resolution.

Consent was obtained from the patient’s family to write this case report.