Pediatric Pulmonology 44:616–618 (2009)

Case Report

Fungal Pleural Effusion Secondary to a Rare Cause ofPancreatic Pseudocyst

Atul Gupta, MD, MRCPCH,1* Tom Marrs, MRCPCH,1 Donald Urquhart, MSc, MRCPCH,1

Simon Clarke, FRCS, FRCS (Paed Surg),2 Mark Rosenthal, FRCP, FRCPCH,1

and Andrew Bush, MD, FRCP, FRCPCH1

Summary. We report a case of fungal pleural effusion secondary to presumed valproate

induced pancreatitis with pseudocyst and stricture formation. A child with dyskinetic cerebral

palsy who had been on sodium valproate for several years was transferred for drainage of a left

sided pleural effusion. Pleural fluid culture consistently grew Candida glabrata although the

patient was treated with broad-spectrum antibiotic and antifungal therapy. Clinical deterioration

ensued with abdominal discomfort, feed intolerance, and re-accumulation of the effusion.

Investigations revealed a large pancreatic pseudocyst compressing the stomach and impairing

pancreatic function. Subsequent therapeutic evacuation of pancreatic fluid demonstrated

C. glabrata. This case underscores that pleural disease may be secondary to abdominal

pathology, and always to consider rare side-effects of medication in the face of a puzzling clinical

picture. Pediatr Pulmonol. 2009; 44:616–618. � 2009 Wiley-Liss, Inc.

Key words: fungal effusion; Candida glabrata; pancreatitis; pancreatic pseudocyst.

INTRODUCTION

Parapneumonic effusion complicating pneumonia hasincreased dramatically in children in the UK over the lastdecade.1 The reason for this remains unclear. Pleuraleffusions are usually secondary to acute bacterial pneumo-nia. Less commonly, pleural effusion may have associatedatypical clinical features and may be the presenting sign ofan underlying malignancy, or be secondary to congenitalheart disease including post-cardiothoracic surgery, renaldisease, connective tissue disorders, and trauma. Wedescribe an unusual cause of pleural effusion in a child,which highlights two important lessons.

CASE

We report a 4-year-old with dyskinetic cerebral palsydue to perinatal hypoxia, who presented with a 4-dayhistory of fever and cough. Significant co-morbiditiesincluded epilepsy, which had been well controlledon sodium valproate (35 mg kg�1 twice daily) for theprevious 3 years. She had an unsafe swallow and wasprincipally fed via a gastrostomy tube, but had enduredworsening vomiting and reduced feed tolerance over theprevious year. She had suffered recurrent respiratorytract infections, suggestive of aspiration. Additional

regular medications included oral Azithromycin as wellas Ranitidine and Domperidone to prevent gastro-oesophageal reflux.

On admission, chest radiograph showed left sidedconsolidation with pleural effusion which was treatedwith intravenous Cefuroxime. However, subsequentchest radiograph (Fig. 1) showed further accumulationof pleural fluid and mediastinal shift that was accom-panied by rising inflammatory markers. At this point, shewas transferred to the Royal Brompton Hospital. A chest

1Department of Respiratory Paediatrics, Royal Brompton Hospital,

London, United Kingdom.

2Department of Paediatric Surgery, Chelsea and Westminster Hospital,

London, United Kingdom.

*Correspondence to: Atul Gupta, MD, MRCPCH, 4th Floor Chelsea Wing,

Royal Brompton Hospital, Sydney Street, London SW3 6NP, United

Kingdom. E-mail: atulgupta@doctors.org.uk

Received 13 July 2008; Revised 16 September 2008; Accepted

16 September 2008.

DOI 10.1002/ppul.20982

Published online 11 May 2009 in Wiley InterScience

(www.interscience.wiley.com).

� 2009 Wiley-Liss, Inc.

drain was inserted in the left pleural space, whichresulted in marked clinical improvement. The drain wasremoved after 2 days and broad-spectrum antibiotics werecontinued. Biochemical analysis of pleural fluid revealedpleural/serum protein ratio of 0.5, glucose concentra-tion of 0.5 mmol L�1 and LDH of 2,122 IU L�1. Thepleural fluid culture grew only Candida glabrata, andintravenous liposomal Amphotericin B was accordinglycommenced.

Throughout the first 2 weeks of admission, fluctuatingsigns of malabsorption and feed intolerance were noted,associated with loose stools and intermittent abdominaldiscomfort. The only abnormal clinical finding onabdominal examination was mild distension.

On day 14 of admission, temperature spikes recurredand re-accumulated left sided pleural effusion was notedon chest radiograph and ultrasound. Antibiotic treatmentwas converted to Augmentin with Gentamicin, anda second chest drain was inserted with 210 ml of blood-stained serous fluid aspirated. Pleural fluid again onlygrew C. glabrata with the same sensitivities as before.

Clinical improvement was poor and 2 days after theprocedure further temperature spikes continued with anincrease in CRP to 243 mg L�1, prompting a thoroughseptic review. Intravenous Caspofungin was added to theliposomal Amphotericin. This stabilized the temperatureand inflammatory markers started to normalize. Animmunology screen revealed normal immunoglobulinlevels, negative HIV serology, and a normal coeliacscreen. However, she became increasingly intolerant tofeeds and developed bilious vomiting. On examination,abdomen remained mildly distended and uncomfortable,but soft in all areas. Further investigations revealedlarge numbers of stool fat globules as well as a faecalelastase of 75 mg g�1. These results are compatible with

severe pancreatic exocrine failure. Serum amylase levelwas 102 U L� (normal range 35–130 U L�).

Exogenous pancreatic enzyme (CreonTM, SolvayHealthcare Ltd, Southampton, UK) supplementationsuccessfully reduced the load of faecal fat globules.Cystic Fibrosis was excluded (no mutations detected ongenetic analysis and sweat chloride of 8 and 9 mmol L�1

on two separate samples). Abdominal ultrasound andsubsequent contrast study showed a 7 cm� 7 cm� 4 cmfluid filled cystic structure lying centrally in the epigas-trium (Fig. 2). A CT scan with intravenous contrastshowed a fluid filled cystic space lying immediatelyposterior to a near total compressed stomach and abuttingthe antero-inferior surface of the pancreas suggestive of apancreatic pseudocyst (Fig. 3).

Sodium valproate therapy can rarely be associated withpancreatitis, hence this was discontinued and phenytoincommenced. The chronic pseudocyst was treated initiallywith open surgical drainage via a cystgastrostomy. Fluidculture revealed a florid growth of C. glabrata. A secondcyst in the tail continued to grow and ERCP confirmed a

Pediatric Pulmonology

Fig. 1. Chest radiograph showed a large left pleural effusion

causing mediastinal shift to the right.Fig. 2. Contrast study showed a large fluid filled cystic structure

lying centrally.

Fig. 3. CT scan with intravenous contrast.

Fungal Effusion due to Pancreatic Pseudocyst 617

mid-duct stenosis. She eventually underwent a successfulcystojejunostomy and was discharged after 5 months.

DISCUSSION

In summary, a 4-year-old girl with cerebral palsypresented with a pleural effusion from which C. glabratawas grown repeatedly. The final diagnosis was pleuralspace infection secondary to infection of an iatrogenicpancreatic pseudocyst. The most likely primary etiologywas sub-acute pancreatitis secondary to valproate therapyresulting in pancreatic pseudocyst formation and asubsequent secondary pleural effusion.

Although uncommon, there has been a steady rise in theincidence of pancreatic fungal infections,2 the mostfrequent being with Candida species organisms.2 Infec-tion can arise by hematogenous spread, reflux ofcontaminated bile, or translocation from the intestinallumen, although the exact mechanism by which they reachthe pancreas still remains unclear.2–6 We can onlyspeculate in our case extraluminal pressure from thepancreatic pseudocyst may have caused a partial smallbowel obstruction and relative gut dysmotility withtranslocation of C. glabrata from the intestinal lumen tothe pancreas and via diaphragmatic lymphatics to thepleural space, explaining the growth of C. glabrata fromboth pleural and pancreatic pseudocyst fluid samples.Hematogenous spread seems unlikely as the child was notas severely unwell as would be expected in a C. glabratasepticemia, and repeated blood cultures were negative.

In children with neurological problems and unsafeswallow, aspiration is a well-recognized cause of pleuro-pulmonary infection. Species of the Streptococcus millerigroup may act in synergy with anaerobic pathogens incausing tissue damage and spread of infection. AlthoughS. milleri or anaerobes were not detected in our case,aspiration being etiological could not be excluded.

Pancreatitis complicated by pancreatic pseudocysts inchildhood is reported predominantly after abdominaltrauma. In general, a pseudocyst is a rare complicationof pancreatitis.7 Drug-induced pancreatitis constitutesapproximately 13% of all cases of acute pancreatitis inchildhood.8 The development of pancreatitis has beenrelated to more than 55 different drugs.9–12 Since the firstcase report of valproate induced pancreatitis,13 a literaturereview suggests that it remains a rare and idiosyncraticdrug-induced reaction. Pellock et al.14 found that 2 out of3,007 valproate treated patients across 34 clinical trialswere reported to have had episodes of pancreatitis relatedto valproate use, while Werlin and Fish analyzed data from22 children with valproate related pancreatitis. Theyconcluded that valproate-associated pancreatitis is inde-

pendent of serum valproate level and may occur any timeafter the onset of therapy.15 Routine measurements ofserum amylase and lipase during valproate use are notrecommended.7,14 Valproate induced pancreatitis shouldalso be a diagnosis of exclusion following all other morecommon causes have been excluded.

CONCLUSION

We report this case because it illustrates two importantlessons. The first is that pleural disease may in factbe secondary to intra-abdominal and not pleuropulmonarydisease; and secondly, when confronted with a difficultclinical problem in a child with co-morbidities, the side-effects of concomitantly administered medications shouldbe considered as a possible cause of the problem when allothers have been excluded.

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