J A C C : C A S E R E P O R T S VO L . 1 , N O . 3 , 2 0 1 9

ª 2 0 1 9 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E AM E R I C A N

C O L L E G E O F C A R D I O L O G Y F O U N DA T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

CASE REPORT

CLINICAL CASE

Spontaneous Fungal PeritonitisA Rare Complication of Heart Failure

Ariel F. Gonzalez-Cordero, MD, Melanie Malavé-Sánchez, MD, Mark Vergara-Gómez, MD, Hilton Franqui-Rivera, MD

ABSTRACT

L

�

�

ISS

Fro

Th

Ma

This report presents a case of spontaneous fungal peritonitis (SFP) in a patient with cardiogenic ascites. Physicians

need to be aware of this life-threatening condition because early suspicion of SFP can improve survival.

(Level of Difficulty: Intermediate.) (J Am Coll Cardiol Case Rep 2019;1:372–5) © 2019 The Authors. Published by

Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the

CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

HISTORY OF PRESENTATION

This is the case of a 36-year-old man who presentedwith abdominal pain of 1-day evolution. He describedthe pain as 8/10 intensity, crampy, nonradiating,diffuse, exacerbated by movement, but withoutrelieving factors. Associated symptoms includedabdominal distension, unquantified fever, shortnessof breath, and lower extremity edema. Physicalexamination was significant for hypotension of80/43 mm Hg, fever of 38.9�C, and tachycardia of110 beats/min. There was a positive ascitic fluid wavewith shifting dullness and diffuse tenderness topalpation of the abdomen. Lung auscultationrevealed bibasilar crackles and grade 3/4 pittingedema of the lower extremities.

MEDICAL HISTORY

He had a history of Class III morbid obesity andnonischemic dilated cardiomyopathy with an ejection

EARNING OBJECTIVES

To suspect SFP in patients with cardiogenicascites.To become familiar with the gut hypothesisof heart failure.

N 2666-0849

m the Department of Medicine, Cardiovascular Division, University of Pu

e authors have reported that they have no relationships relevant to the c

nuscript received April 10, 2019; revised manuscript received July 29, 20

fraction of 35%. Medications included carvedilol,lisinopril, spironolactone, and furosemide for thetreatment of heart failure. He denied toxic habits,family history was noncontributory, and review ofsystems was unremarkable.

DIFFERENTIAL DIAGNOSIS

The differential diagnoses included spontaneousbacterial peritonitis (SBP), spontaneous fungal peri-tonitis (SFP), or gastrointestinal perforation.

INVESTIGATIONS

Laboratory values were significant for white bloodcells of 6,780 cells/mm3 with 51% neutrophils and 31%bands; hemoglobin 11 g/dl, platelet count of 221,000cells/mm3, blood urea nitrogen 46 mg/dl, serumcreatinine 2.6 mg/dl, bicarbonate 27.9 mEq/l, and to-tal bilirubin of 8.6 mg/dl with direct bilirubin of7.5 mg/dl. Liver enzymes were normal with alanineaminotransferase of 5 IU/l and aspartate aminotrans-ferase of 13 IU/l, lipase 17 IU/l, pro-B-type natriureticpeptide 9,318 pg/ml, serum lactate 18 IU/l, anderythrocyte sedimentation rate of 77 mm/h. Anabdominal ultrasound demonstrated ascites andhepatomegaly; there was no evidence of cirrhosis orobstruction of the hepatic vein.

https://doi.org/10.1016/j.jaccas.2019.07.036

erto Rico School of Medicine, San Juan, Puerto Rico.

ontents of this paper to disclose.

19, accepted July 30, 2019.

FIGURE 1 Ascitic Fluid Diagnostic Algorithm

This algorithm shows the differential diagnosis of ascites using serum ascites albumin

gradient and total proteins.

AB BR E V I A T I O N S

AND ACRONYM S

SBP = spontaneous bacterial

peritonitis

SFP = spontaneous fungal

peritonitis

PCR = polymerase chain

ion

J A C C : C A S E R E P O R T S , V O L . 1 , N O . 3 , 2 0 1 9 Gonzalez-Cordero et al.O C T O B E R 2 0 1 9 : 3 7 2 – 5 Spontaneous Fungal Peritonitis

373

MANAGEMENT

Initial paracentesis revealed >2,000 poly-morphonuclear cells, serum-ascites albumin gradientof 1.3 mg/dl (Figure 1), and total ascitic fluid protein of4.4 g/dl. The ascitic fluid culture was positive forEscherichia coli and Streptococcus sanguinis. Thesefindings were consistent with SBP in the presence ofcardiogenic ascites. Because of the presence of >1organism in ascitic fluid, elevated lactate dehydro-genase, and low glucose levels, an abdominalcomputed tomography scan with oral contrast wasobtained. This study showed no evidence of contrastleakage into the peritoneal cavity, which suggested apreserved intestinal mucosal lining.

The patient was admitted with a diagnosis ofseptic shock secondary to SBP and acute decom-pensation of chronic systolic heart failure. He wasstarted on intravenous ceftriaxone, furosemidedrip, and norepinephrine to maintain a mean arte-rial pressure >65 mm Hg. A transthoracic echocar-diogram revealed a severe biventricular dilation,global hypokinesis, and an ejection fraction of 10%.There was severe tricuspid regurgitation withelevated right ventricular pressure of 72 mm Hg.Right ventricular systolic function was severelydecreased.

The patient showed no clinical improvementand continued to deteriorate 48 h later. Anti-biotic therapy was changed to ertapenemand daptomycin to cover community-acquiredinfections.

After changing antibiotic therapy, the patientdemonstrated an initial improvement. However,2 weeks after admission and despite uninterruptedantibiotic therapy, the patient developed increasedabdominal distension, pain, recurrence fever, andhypotension that required vasopressor therapy. Anew paracentesis was done. Ascitic fluid was stillconsistent with cardiogenic ascites, but the fluidappearance was turbid, dark yellow; and poly-morphonuclear cells were markedly elevated at118,624 cells/mm3. The ascitic fluid culture waspositive for fluconazole-susceptible Candida albi-cans, consistent with a diagnosis of SFP. He wasstarted on fluconazole with a loading dose of800 mg, and 400 mg for maintenance, but due to alack of clinical response, antibiotic therapy waschanged to ceftazidime-avibactam and caspofungin.Resolution of SFP was achieved after 30 days ofcaspofungin. The authors performed a follow-upparacentesis that demonstrated culture negative re-sults for 5 days.

DISCUSSION

SFP is defined as a fungal infection of perito-neal fluid with no apparent intra-abdominalsource, anatomical malformation, or malig-nancy. Although SBP is relatively common inpatients with end-stage liver disease, occur-ring in approximately 30% of patients as per

initial fluid culture, SFP remains rare, with an inci-dence of 3.5% (1). The organisms most frequentlyassociated with this condition, in descending order,are Candida albicans, Candida glabrata, Candidakrusei, Cryptococcus spp., and Aspergillus spp. (2).

SFP in patients with cirrhosis is attributed toopsonin deficiency, as well as inadequate neutrophiland T-cell response. However, SFP can also happen inpatients with cardiogenic ascites (although rarely), inwhom impaired host defense seen in patients withend-stage liver disease is usually absent. Somestudies have proposed the “gut hypothesis of heartfailure” as the predisposing mechanism in thispopulation. This hypothesis states that the gutexperiences chronic ischemia�reperfusion damage,compromising the gut barrier morphology and func-tionality (Figure 2). In animal models, the intestinalmucosal permeability increased in the presence oflow blood flow and hypoxemia. Underperfused tissuedevelops localized intestinal hypoxia and acidic pH,along with a cascade effect of decreased nitric oxiderelease, increased release of reactive oxygen species,and interleukins. Ischemia leads to tissue malfunc-tion, which then leads to a constant state of inflam-mation that promotes intestinal flora proliferation.

react

FIGURE 2 Gut Hypothesis of Heart Failure

Reactive Oxygen SpeciesNeutrophils Red Blood Cells

Acute-Over-ChronicDecompensation of

Heart Failure

Chronic Ischemiaand Reperfusion Injury

Low Cardiac Output Normal Asc

itic

Flui

dIn

test

inal

Lin

ing

Inte

stin

al L

umen

Antibiotic ExposureNormal Microbiota

OPerfusion

pHCO

NeutrophilsMyeloperoxidaserelease

DysfunctionalNeutrophils and T-cellsCytokines

Intestinal Barrier Function

Chronic Inflammation

Interleukin-17Dysfunctional Immune System

OPerfusion

pHCO

Organism TranslocationIntestinal Barrier Function

A B C D

Progressive effects of hypoperfusion on the mucosal barrier. (A) Normal mucosa is affected by (B) low cardiac output, which results in

ischemia. (C) Chronic ischemia and reperfusion�injury cause a release in reactive oxygen species, erosion, and distortion of the mucosal

barrier. (D) Acute decompensation of chronic heart failure increases the risk of microperforations that facilitates organism translocation into

the ascitic fluid. With a weakened immune response and low interleukin-17, the host becomes predisposed to multiple infections, including

fungi. Antibiotics change intestinal flora, which facilitates the growth of fungal species, which then may translocate into the ascitic fluid.

CO2 ¼ carbon dioxide; O2 ¼ oxygen.

Gonzalez-Cordero et al. J A C C : C A S E R E P O R T S , V O L . 1 , N O . 3 , 2 0 1 9

Spontaneous Fungal Peritonitis O C T O B E R 2 0 1 9 : 3 7 2 – 5

374

Furthermore, acute decompensation of systolicheart failure worsens tissue edema, and splanchnichypoperfusion because the hepatosplanchnic circu-lation receives approximately 30% of the total car-diac output. In a decreased cardiac output state, suchas in this patient, it is understood that perfusion toorgans is proportionately decreased. Our patient hadseptic shock that required vasopressors, on top ofsystolic heart failure, which worsened splanchniccirculation.

Fungi are much larger than bacteria, which makesit more difficult for this infection to occur. Some havetheorized that antibiotic exposure leads to fungalovergrowth within the alimentary tract, increasingtheir virulence and making translocation conceivable.Our patient received antibacterial therapy for the

management of the initial SBP. This might explain theprogression to SFP.

Other investigators classify SFP as a nosocomialinfection, arguing that peritoneal fungal infectionscan be explained by direct percutaneous inoculationin patients with refractory ascites, which leads torepeated paracentesis. However, this patient hadundergone only 1 paracentesis 2 weeks before thediagnosis of SFP.

SFP is a life-threatening complication, with anestimated mortality of 56% to 90%. Tardy suspicion,current diagnostic (culture) methods, the difficulty ofearly differentiation from SBP, and delay in therapymay account for its high mortality (3). Some studiessupport the use of polymerase chain reaction (PCR)for (1/3)-b-D-glucan and galactomannan testing

J A C C : C A S E R E P O R T S , V O L . 1 , N O . 3 , 2 0 1 9 Gonzalez-Cordero et al.O C T O B E R 2 0 1 9 : 3 7 2 – 5 Spontaneous Fungal Peritonitis

375

for early diagnosis of fungal peritonitis. Whereveravailable, PCR is encouraged because it is a cost-effective alternative that delivers rapid and reliableresults, leading to early antifungal therapy (4).

The authors found only 1 other reported case of SFPin a patient with cardiogenic ascites. Unlike this pa-tient, this one was infected by C. glabrata and wassuccessfully treated with intravenous caspofungin (5).Similar to this case, this patient was treated with an-tibiotics for >2 weeks before presenting with SFP. Ourpatient had an unsatisfactory response to azole ther-apy but responded well to caspofungin. Although thiscondition is uncommon, azole therapy is generallyconsidered first-line therapy when SFP is suspected,until the organism and sensitivity are identified.

FOLLOW-UP

After 5 months of hospitalization and multiple com-plications, the patient lost 178 lbs of weight, and there

was a complete resolution of ascites; left ventricularejection fraction improved to 35%. Subsequently,serum creatinine decreased to 1.6 mg/dl.

CONCLUSIONS

SFP of cardiogenic ascites is extremely rare and canbe easily underdiagnosed. Nonculture-based fungaldiagnostic tests, such as PCR, should be considered inpatients with a history of repeated paracentesis orwho fail to respond to antibacterial therapy for SBP.Fluconazole is an acceptable first-line therapywhenever invasive candidiasis is suspected because itcan improve overall prognosis.

ADDRESS FOR CORRESPONDENCE: Dr. ArielGonzalez-Cordero, Internal Medicine Program,University of Puerto Rico School of Medicine, SanJuan, Puerto Rico. E-mail: ariel.gonzalez1@upr.eduOR arielgonzalezcordero@gmail.com.

RE F E RENCE S

1. Hwang SY, Yu SJ, Lee JH, et al. Sponta-neous fungal peritonitis: a severe complica-tion in patients with advanced liver cirrhosis.Eur J Clin Microbiol Infect Dis 2014;33:259–64.

2. Shi L, Wu D, Wei L, et al. Nosocomial andcommunity-acquired spontaneous bacterialperitonitis in patients with liver cirrhosisin China: comparative microbiology and

therapeutic implications. Sci Rep 2017;7:46025.

3. Shizuma T. Spontaneous bacterial and fungalperitonitis in patients with liver cirrhosis: a litera-ture review. World J Hepatol 2018;10:254–66.

4. Pagès A, Iriart X, Molinier L, et al. Cost effec-tiveness of candida polymerase chain reactiondetection and empirical antifungal treatmentamong patients with suspected fungal peritonitis

in the intensive care unit. Value Heal 2017;20:1319–28.

5. Wang Y, Gandhi S, Attar BM. Spontaneousfungal peritonitis in ascites of cardiac origin. ACGCase Rep J 2017;4:e42.

KEY WORDS chronic heart failure, obesity,systolic heart failure