Extracorporeal Membrane Oxygenation Support in a Situation of Diagnostic Dilemma

Abstract

Severe acute respiratory distress syndrome (ARDS) in children carries a high morbidity and mortality. High frequency ventilation and extracorporeal membrane oxygenation (ECMO) are used as rescue modes of support in difficult situations. Malignancy may be considered to be a relative contraindication to ECMO support. We report a case where the decision was made to support the patient with ECMO for fulminant Epstein–Barr (EBV) infection while investigations were being done to exclude an underlying malignancy.

Case Report

A three year-old previously healthy boy, of non consanguinous Iranian immigrant parents, was transferred from a local hospital for respiratory distress with X-ray changes consistent with extensive right sided bronchopneumonia (Fig. 1 ). Upon arrival, the patient was tachycardic, tachypneic saturating 92% in 8 litres of oxygen and was febrile to 38.8 °C. Bilateral coarse crackles in the lungs and hepato-splenomegaly was noted. His routine blood tests showed a Hb of 10 gm/dl, WCC of 7.7 × 10⁹/l, platelets of 591 × 10⁹/l, INR 1.2, total bilirubin 43, alkaline phosphatase (ALP) 280 U/l, alanine transaminase (ALT) 64 U/l, aspartate aminotransferase (AST) 294 U/l, C-reactive protein (CRP) 317 mg/l, and a reticulocyte count of 0.5%. A direct coombs test was negative.

Figure 1.

CXR: there is an extensive opacity in the right hemithorax with only a small area of aerated lung in the right lower zone medially. There is an air bronchogram in the right upper zone, consistent with consolidation.

He was commenced on broad spectrum intravenous antibiotics. He continued to deteriorate, with increased work of breathing and increasing oxygen requirements requiring intubation. Azithromycin and oseltamivir were added to cover for the possibility of mycoplamsa or H1N1 infections respectively. Computed tomography (CT) of the chest demonstrated right upper lobe consolidation with cavitating pneumonia extending into the middle and lower lobe, with bilateral pleural effusion more significant on the right side (Fig. 2 ). He proceeded to have a broncheolaveolar lavage and a right sided video assisted thorascopic (VATS) drainage and decortication on the following day, which demonstrated soft, significantly adherent fibrinous exudate within the pleural space. The right lung was partially collapsed but otherwise normal. The pleural exudates were removed, saline washed and the right lung mobilised. A 20 Fr chest drain was inserted into the right thoracic cavity.

Figure 2.

CT: there are cavitating spaces in the apical extending to the entire right lung. There is also patchy consolidation in the middle lobe with aerated lung interspersed between the consolidated areas. There are moderate bilateral pleural effusions with evidence of empyema.

The microbiology demonstrated gram positive cocci but no growth was demonstrated from the purulent fluid. Broncho-alveolar lavage (BAL) fluid was sent for extended viral screen, fungal and mycobacterial testing.

Over the next 48 h he became increasingly difficult to ventilate secondary to poor lung compliance. He was commenced on high frequency oscillatory ventilation (HFOV) on day-3. His liver functions continued to deteriorate (ALT 430 U/l, AST 4148 U/l) for which he was commenced on n-acetylcysteine. An initial extended viral hepatitis screen was negative and an ultrasound of the liver was unremarkable. He had evidence of multisystem involvement with acute renal failure requiring renal replacement therapy, evolving pancytopaenia (Hb 93 g/l, reticulocyte count 12.4 × 10⁹/l (n = 20–80), platelets 146 × 10⁹/l (n = 200–450)), coagulaopathy (prothrombin time 16.7 s (n = 12–14.5 s), INR 1.3 (n = 0.92–1.14), d-dimers 18.94 μg/ml (n = 0.09–0.53)) and profound inflammation (ferritin 3705 U/l (normal < 45), CRP 72 mg/l (n < 3)). Atypical mycoplasma serology was negative. The patient developed a clinical picture of severe sepsis, worsening hepatic function, evolving marrow failure with features of hypochromic microcytic anaemia, thrombocytopaenia and coagulopathy, which raised the possibility of a primary or secondary haemophagocytic syndrome. However the initial bone marrow examination, performed on day 4 predominantly showed toxic reactive changes with only small amount of haemophagocytosis.

By day 5 his respiratory status declined with difficulty in oxygenating the child despite optimising HFOV settings (MAP 20, ΔP  = 47% Hz), trialling nitric oxide (NO) or prone positioning. As all infectious screens were negative a decision was made to start the child on methylprednisolone at 1 mg/kg day for his ARDS (Meduri protocol).

Repeat Epstein–Barr virus (EBV) serology and nucleic acid testing on day 6 was consistent with acute EBV infection, with a positive EBV VCA IgG, a low VCA IgG avidity index, a positive EBV VCA IgM, a negative EBV nuclear antigen IgG and a positive plasma EBV PCR. A presumptive diagnosis of fulminant infectious mononucleosis (FIM) complicating X-lymphoproliferative disorder (X-LPD) was strongly considered. Bloods for SAP protein expression by flow cytometry were sent urgently to clarify a possible diagnosis of X-LP.

Due to the severity and the rapid progression of the patient's illness, presumptive treatment with rituximab (375 mg/m²/dose weekly) to control acute EBV infection was commenced on day 8 whilst awaiting the results of the intracellular adaptor molecule SAP [SLAM (signalling lymphocytic activation molecule)-associated protein] expression studies. The patient was also treated with high dose acyclovir, intravenous immunoglobulin and offered maximal supportive care in the intensive care unit.

As his respiratory status worsened (OI > 40 for more than 4 h) he was supported by percutaneous veno-venous extra-corporeal membrane oxygenation (ECMO). In preparing for ECMO, a drainer cannula was inserted into the right internal jugular vein and an infuser cannula was inserted into the inferior vena cava via the right femoral vein. Despite systemic heparinization, bleeding was slight. While on ECMO inotropic support was weaned off and ventilation support weaned to MAP of 15 cm H₂O, ΔP of 40 and FiO₂ of 40%. He was weaned off from support after 10-days of ECMO.

Following the introduction of ECMO and treatment with rituximab there was a steady improvement in the patient's status with improvement in bone marrow, renal and hepatic function with normalisation of liver function tests and serum creatinine over the next two weeks and the patient became transfusion independent 12 days after the first dose of rituximab. EBV was not detected on PCR of follow up plasma samples and rituximab therapy was ceased after two weekly doses due to the improvement in the patient's condition. A SAP protein expression was examined by flow cytometry and found to be normal in the patient's activated peripheral blood mononuclear cells. This result suggested that an underlying diagnosis of X-LP due to a SH2D1A mutation was unlikely.

Once off the ventilation and sedation, the child was noted to have peripheral weakness and hypotonia. Nerve conduction studies demonstrated peripheral axonal neuropathy consistent with critical illness polyneuropathy that has significantly improved over the course of follow-up.

Discussion

Reported survival rate for the use of ECMO as a rescue therapy in ARDS in children is >50% (CCM 2009 Aug 37.8). Extensive testing for an infective cause of the patient's initial rapid respiratory deterioration failed to identify a definitive cause although gram positive cocci were seen on the gram stain of pleural fluid. An initial screen for viral hepatitis was negative. However the patient's fulminant multiorgan deterioration and repeat positive EBV and the detection of EBV in the plasma by PCR prompted consideration of fulminant infectious mononucleosis (FIM) complicating X-linked lymphoproliferative disease (X-LP). As his clinical condition was deteriorating a decision was made to provide maximal support with ECMO and commence treatment with rituximab whilst awaiting results of the SAP flow cytometry. Fulminant infectious mononucleosis results from a dysregulated, excessive immune response to EBV infection with the potential for widespread tissue infiltration and end organ damage [1], [2], [3]. In the setting of X-LP, FIM has an estimated mortality rate of over 90% [3]. Mutations in the SH2D1A gene are commonly identified in typical X-LP patients but are much less common in atypical X-LP patients [4], [5], [6].

The indication to commence rituximab treatment was to rapidly control EBV infection by ablating EBV infected B-cells. This approach has been used in a small number of X-LP patients with documented severe EBV infection and results in dramatic reductions in both EBV copy number and liver function abnormalities [7]. Published data on the use of ECMO in children with malignancy is very limited. The latest data published on interrogating the ELSO data base on use of ECMO in paediatric respiratory failure shows a survival rate of only 5% for children with a primary diagnosis of haemopoetic stem cell transplant and 34% with an underlying immunodeficiency disorder [8], [9]. We commenced the child on rituximab while awaiting the confirmatory test results. We have not been able to find any published data on use of rituximab while on ECMO.