A Rare Culture-Negative Ascites Induced by Clostridium Difficile in a Patient with End-Stage Renal Disease: A Case Report and Literature Review

Case Report

Austin J Nephrol Hypertens. 2021; 8(2): 1097.

A Rare Culture-Negative Ascites Induced by Clostridium Difficile in a Patient with End-Stage Renal Disease: A Case Report and Literature Review

Alsultan MH¹* and Hassan Q²

1Department of Nephrology, Al Assad and Al Mouwasat University Hospitals, Damascus, Syria

2Department of Nephrology, Al Assad University Hospitals, Damascus, Syria

*Corresponding author: Alsultan MH, Department of Nephrology, Al Assad and Al Mouwasat University Hospitals, Damascus, Syria

Received: August 10, 2021; Accepted: October 07, 2021; Published: October 14, 2021

Abstract

Clostridium difficile infection was identified as the major cause of antibioticassociated diarrhea and cause wide manifestations include asymptomatic, fulminant disease and unusual manifestations such as protein-losing enteropathy. The incidence and severity of healthcare-associated clostridium difficile have been dramatically increased.

A 25-years old male with end-stage renal disease who on hemodialysis complained of nonbloody watery diarrhea and abdominal pain for a month. Also, he had a hospital admission due to secondary peritonitis with negative investigations and was treated with antibiotics with no improvement. Abdominal CT scan revealed a moderate amount of ascites with wall thickening of transverse colon and culture of ascites was negative. A stool examination was positive for clostridium difficile toxins (A+B) and cured by 21 days of oral vancomycin.

A literature review for ascites- induced by clostridium difficile yielded only one patient with end-stage renal disease on hemodialysis. First-line clinicians may not be familiar with such a rare manifestation and may not initially consider it when making differential diagnosis related to secondary peritonitis.

Clostridium difficile should be suspected in all cases of diarrhea in patients with chronic kidney disease and should be considered in the presence of ascites in the context of diarrhea with no obvious source.

Keywords: Clostridium Difficile; Culture-Negative Ascites; End-Stage Renal Disease

Introduction

Clostridium Difficile Infection (CDI) was identified as the major cause of antibiotic-associated diarrhea and colitis after widespread use of antibiotics. There are well-established risk factors for CDI include advanced age, hospitalization, severe illness, chemotherapy and gastric acid suppression. Any antibiotic can predispose to CDI even the perioperative antibiotic prophylaxis, most implicated antibiotics include clindamycin, fluoroquinolones, and broadspectrum penicillins and cephalosporins [1].

The incidence and severity of healthcare-associated CDI have been dramatically increased since 2000. The rate of nosocomial CDI in USA increased from 31 to 61 per 100,000 between 1996 and 2003, and a 20-50% rate of carriage occurs in hospitals and long-term care facilities. The incidence of recurrent and community-associated CDI is also increasing, 36% of patients with community-associated CDI in one multistate study did not receive antibiotics in the 12 weeks prior to diagnosis and up to 25% experience recurrent infection within 30 days of treatment [1].

CDI can cause a wide spectrum of manifestations ranging from an asymptomatic to fulminant disease. Also, unusual manifestations have been reported such as extracolonic involvement and Protein- Losing Enteropathy (PLE), which associates with acute CDI in the absence of fulminant colitis [2].

In this confusing case, a patient with End-Stage Renal Disease (ESRD) developed secondary peritonitis with culture-negative ascites and nearly normal albumin levels. Oral vancomycin induced improvement with no recurrence of diarrhea or abdominal pain and ultrasound showed a significant decrease of ascites.

Case Presentation

A 25-years old male was admitted to the Nephrology Department of Al Assad University Hospital due to non-bloody watery diarrhea (3-5 per day), nausea and vomiting, malaise and abdominal pain for the past month. His past medical history included kidney transplantation 12 years ago. Currently, he had End-Stage Renal Disease (ESRD) with two sessions per week of Hemodialysis (HD) for the past 2 years due to chronic allograft rejection.

Also, two weeks ago, he had hospital admission due to secondary peritonitis with antibiotics treatment (levofloxacin, ceftazidime, metronidazole), but abdominal Computed Tomography (CT) scan and ascites culture were negative.

Physical exam showed diffuse abdominal pain with shifting dullness, diminished breathing sounds in lung bases, diminish heart sounds, blood pressure (BP) 100/70 mmHg, temperature 38oC, and oxygen saturation 96%.

Chest CT scan showed bilateral pleural effusion with massive pericardial effusion (Figure 1A). Echocardiography showed congestive Heart Failure (CHF), Ejection Fraction (EF) 20-25%, large pericardial effusion measured 3.5cm on apical four chambers window, Inferior Vena Cava (IVC) diameter 1.4cm with collapsibility >50% in inspiration and no signs of cardiac tamponade. Abdominal CT scan revealed ascites, which surrounding the liver and in pelvis, with wall thickening of the transverse colon (Figure 2A).

Figure 1: Chest and Abdominal CT. A) Chest; bilateral pleural effusion with massive pericardial effusion. B) Abdomen; ascites around the liver with wall thickening of the transverse colon.

    

    
    

    

    Figure 1: Chest and Abdominal CT. A) Chest; bilateral pleural effusion with massive pericardial effusion. B) Abdomen; ascites around the liver with wall thickening of the transverse colon.

Abdominal and pleural paracentesis was performed. Laboratory findings in Table 1, revealed secondary peritonitis and transudate pleural effusion with negative culture for both. The patient received ceftriaxone and metronidazole for secondary peritonitis and due to a history of inadequate HD, pericardial and pleural effusion were treated with increased HD sessions.

Table 1: Laboratory tests.





  

    
Blood

    
Pleural fluid

    
Ascites

  

  

    
HB

    
7.4

    
WBC

    
50

    
WBC

    
2400

  

  

    
Ur

    
65

    
RBC

    
10

    
N%

    
80%

  

  

    
Cr

    
11

    
Glu

    
86

    
L%

    
20%

  

  

    
TP

    
5.5

    
TP

    
1.9

    
RBC

    
1000

  

  

    
ALB

    
3

    
ALB

    
1.1

    
Glu

    
75

  

  

    
LDH

    
326

    
LDH

    
230

    
TP

    
3.4

  

  

    
ALT

    
5

    
Chol

    
23

    
ALB

    
2.1

  

  

    
AST

    
17

    
LDH ratio

    
0.7

    
LDH

    
352

  

  

    
CRP

    
12.4

    
TP ratio

    
0.3

    
SAAG

    
0.9

  

  

    
HBS Ag

    
neg

    
ALB gradient

    
1.9

    
Culture

    
Neg

  

  

    
Anti HCV

    
neg

    
Culture

    
Neg

    
    
  

  

    
HB: Hemoglobin; Ur: Urea; Cr: Creatinine; AST:    Aspartate Transaminase; ALT: Alanine Aminotransferase; LDH: Lactate    Dehydrogenase; GLU: Glucose; TP: Total Protein; ALB: Albumin; CRP: C-Reactive    Protein; HBS Ag: Hepatitis B Surface Antigen; Anti HCV: Hepatitis C Virus    Antibody; WBC: White Blood Count; N%: Neutrophils Proportion; L%: Lymphocytes    Proportion; RBC: Red Blood Cell Count; Chol: Cholesterol; SAAG: Serum Ascites    Albumin Gradient. 

  










Table 1: Laboratory tests.

This case was confusing due to secondary peritonitis with negative abdominal CT and ascites culture on two occasions. We started the approach from chronic diarrhea. A stool examination was positive for fecal white blood cells and toxins (A+B) for clostridium difficile (C. difficile). By reviewing the literature, we found that severe and rare cases of C. difficile infection may induce culture-negative neutrocytic ascites (CNNA).

Antibiotics were discontinued and started with oral vancomycin (125mg/4 times daily). However, the patient status improved, diarrhea recurred after 10 days. This obligated an increasing dose of vancomycin (250mg/4 times daily) and combined with oral metronidazole (500mg/3 times daily) for total 21 days.

The patient was cured with no recurrence of diarrhea or abdominal pain and ultrasound showed a significant decrease of pericardial, pleural and ascites accumulations.

Discussion

A literature review for ascites induced by Clostridium Difficile Infection (CDI) yielded 16 patients in 12 case reports, Table 2 [3-14]. Previous history of antibiotic was mentioned in 12 patients [3-5,9,11- 14]. Culture-Negative Neutrocytic Ascites (CNNA) was reported in all patients except 3 cases, two of them had culture-positive ascites after abdominal interventions and ascites culture was not performed in the third case [7,8,12]. Only one patient had ESRD with HD [10], but the other 4 patients developed Acute Kidney Injury (AKI) [7-9].

Table 2: Summary of case studies with CDI presenting with ascites.





  

    
Author

    
Age and Primary disease

    
Antibiotics induced CDI

    
Ascit/culture

    
Other symptoms

    
Diagnosis of CDI

    
treatment/duration

  

  

    
Guido Poggi et al. [3]

    
    
      
  • 54–y
    • 
      
  • necrotizing    fasciitis
    • 
    

    
    
      
  • Ciprofloxacin/clindamycin    (IV).
    • 
      
  • Ciprofloxacin/    rifampicin (PO).
    • 
    

    
+/Neg

    
    
      
  • Non–bloody,    watery diarrhea, fever, abdominal pain.
    • 
      
  • Abdominal    swelling peripheral edema.
    • 
    

    
    
      
  • Pos    stool for toxins.
    • 
    

    
    
      
  • PO    vancomycin (500mg daily/for 5 days)
    • 
    

  

  

    
Christie Masters et al. [5]

    
    
      
  • 36-y
    • 
      
  • cesarean    section
    • 
    

    
    
      
  • IV    cefazolin
    • 
    

    
+/Neg

    
    
      
  • Abdominal    pain, watery diarrhea, fever, nausea, vomiting.
    • 
      
  • small    pleural effusions
    • 
    

    
    
      
  • Pos    stool for toxins
    • 
    

    
    
      
  • Long    taper of po vancomycin and metronidazole
    • 
    

  

  

    
Ali Bukhari et al. [6]

    
    
      
  • 46-y
    • 
      
  • ND
    • 
    

    
ND

    
+/Neg

    
    
      
  • Watery    diarrhea and abdominal pain.
    • 
    

    
    
      
  • C.    difficile- pos
    • 
    

    
ND

  

  

    
George I. Tsourous et al. [13]

    
    
      
  • 60-y
    • 
      
  • soft    tissue infection/possible osteomyelitis
    • 
    

    
    
      
  • Po    amoxicillin/clindamycin.
    • 
    

    
+/Neg

    
    
      
  • Watery    diarrheas, fever, vomiting, abdominal pain.
    • 
    

    
    
      
  • Pos    stool for toxin A.
    • 
    

    
    
      
  • Oral    vancomycin (500mg daily/ for 15d)
    • 
    

  

  

    
Yujian Liang et al. [14]

    
    
      
  • 6-y
    • 
      
  • Severe pneumonia.
    • 
    

    
    
      
  • Cephalosporin
    • 
    

    
+/Neg

    
    
      
  • Diarrhea,    abdominal distension, nausea, vomiting, shortness of breath.
    • 
      
  • Massive    hydrothorax.
    • 
    

    
    
      
  • Pos PCR    stool for toxin B.
    • 
      
  • Pos    stool culture.
    • 
    

    
    
      
  • PO    vancomycin for 10 d.
    • 
    

  

  

    
ELI ZUCKERMAN et al. [9]

    
    
      
  • 54-y
    • 
      
  • AIDS
    • 
    

    
    
      
  • Trimethoprim/    sulfamethoxazole
    • 
    

    
+/Neg

    
    
      
  • Abdominal    distention pain, pedal edema, weight gain fever, nonbloody watery stools
    • 
      
  • AKI
    • 
    

    
    
      
  • Autopsy    showed PMC.
    • 
    

    
ND

  

  

    
    
      
  • 48-y
    • 
      
  • Heroin    IV usage/URI
    • 
    

    
    
      
  • Erythromycin
    • 
    

    
+/Neg

    
    
      
  • Watery    stools, abdominal distention
    • 
      
  • AKI
    • 
    

    
    
      
  • Sigmoidoscopy
    • 
    

    
    
      
  • Metronidazole
    • 
    

  

  

    
    
      
  • 30y
    • 
      
  • AIDS
    • 
      
  • P. aeruginosa pneumonia
    • 
    

    
    
      
  • IV    ceftazidim/gentamicin.
    • 
    

    
+/Neg

    
    
      
  • Two    episodes of diarrhea: 1st nonbloody watery diarrhea. 2nd    cachexia, mild lower extremity edema, ascites.
    • 
    

    
    
      
  • Sigmoidoscopy.
    • 
      
  • Pos    stool culture, toxins.
    • 
    

    
    
      
  • 1st    metronidazole/ po.
    • 
      
  • 2nd    vancomycin/ po/15d
    • 
    

  

  

    
    
      
  • 33-y
    • 
      
  • AIDS
    • 
    

    
    
      
  • Trimethoprim/sulfamethoxazole
    • 
    

    
+/Neg

    
    
      
  • Diarrhea,    increasing abdominal girth, peripheral edema.
    • 
    

    
    
      
  • Pos    stool culture, toxins.
    • 
      
  • Colonoscopy.
    • 
    

    
    
      
  • Metronidazole/14d.
    • 
    

  

  

    
    
      
  • 58-y
    • 
      
  • CAP
    • 
    

    
    
      
  • Erythromycin
    • 
    

    
+/Neg

    
    
      
  • Nonbloody    watery diarrhea, abdominal distention
    • 
    

    
    
      
  • Pos    stool culture, toxins.
    • 
      
  • Sigmoidoscopy
    • 
    

    
    
      
  • Metronidazole/21d.
    • 
    

  

  

    
Aman boaz et al. [11]

    
    
      
  • 25y
    • 
      
  • Dental    infection
    • 
    

    
    
      
  • Clindamycin.
    • 
    

    
+/ND

    
    
      
  • Green-colored    mucoid diarrheas, abdominal pain.
    • 
      
  • Pleural    effusion.
    • 
    

    
    
      
  • Sigmoidoscopy
    • 
    

    
    
      
  • PO    vancomycin
    • 
    

  

  

    
p.de leeuw et al. [7]

    
    
      
  • 50y
    • 
      
  • Chronic    alcohol abuse/surgical duodenal ulcer
    • 
    

    
ND

    
+/Pos*

    
    
      
  • No    diarrhea
    • 
      
  • Abdominal    distention
    • 
      
  • AKI
    • 
    

    
    
      
  • Pos    culture of ascites.
    • 
      
  • Neg    toxins and sigmoidoscopy
    • 
    

    
    
      
  • IV    metronidazole.
    • 
    

  

  

    
MOHAMMAD ABU HISHMEH et al. [8]

    
    
      
  • 39-y
    • 
      
  • Liver    cirrhosis/splenic embolization
    • 
    

    
ND

    
+/Pos*

    
    
      
  • Diarrhea,    abdominal pain.
    • 
      
  • MOF
    • 
    

    
    
      
  • Pos    blood culture and PCR stool for toxins.
    • 
    

    
    
      
  • Po    vancomycin / IV metronidazole.
    • 
    

  

  

    
Shweta Garg et al. [10]

    
    
      
  • 50-y
    • 
      
  • ESRD on    HD
    • 
      
  • AIDS
    • 
    

    
ND

    
+/Neg

    
    
      
  • Abdominal    distension, abdominal pain, diarrhea
    • 
    

    
    
      
  • Pos    stool toxins.
    • 
    

    
    
      
  • Po    vancomycin/IV metronidazole.
    • 
      
  • Colonoscopy    for vancomycin infusion.
    • 
    

  

  

    
F. Berhane et al. [12]

    
    
      
  • 23 y
    • 
      
  • Anoxic    brain injury
    • 
    

    
    
      
  • Linezolid
    • 
    

    
+/ND

    
    
      
  • Fever,    productive cough, vomiting, diarrhea, lethargy
    • 
    

    
    
      
  • Pos    antigen.
    • 
      
  • Neg    stool toxins A/B.
    • 
      
  • Pos    stool PCR.
    • 
    

    
ND

  

  

    
Elie Chouillard et al. [4]

    
    
      
  • 47-y
    • 
      
  • Adenocarcinoma/ileostomy.
    • 
    

    
    
      
  • Cefuroxime
    • 
    

    
+/Neg

    
    
      
  • Abdominal    pain, diarrhea, fever.
    • 
    

    
    
      
  • Toxin    neg
    • 
      
  • Stool    culture pos
    • 
    

    
    
      
  • 48h/IV,    10d/po metronidazole
    • 
    

  

  

    
*Positive ascites    culture for CDI and both cases after surgery, 1st case showed no    intestinal infection, 2nd case with intestinal infection. IV: Intravenous;    Po: per os; AIDS: Acquired Immunodeficiency Syndrome; P. aeruginosa:    Pseudomonas aeruginosa; CAP: Community-Acquired Pneumonia; ESRD: End- Stage Renal    Disease; HD: Hemodialysis; ND: Non-Defined; Neg: Negative; Pos: Positive;    AKI: Acute Kidney Injury; MOF: Multiorgan Failure; C. difficile: Clostridium    difficile; PCR: Polymerase Chain Reaction; PMC: Pseudomembranous colitis; d: day;    y: year. 

  










Table 2: Summary of case studies with CDI presenting with ascites.

Several studies demonstrated ESRD as a risk factor of CDI [15- 17], this might be multifactorial due to impaired defenses from uremia, repeated hospitalizations and frequent antibiotic use [15].

A Meta-Analysis showed risk ratio of CDI in patients with Chronic Kidney Disease (CKD) and ESRD were 1.95 and 2.63, respectively [17]. Another study demonstrated that more advanced CKD correlated with a higher risk of CDI and patients with dialysis were at the highest risk [16].

The incidence of CDI in ESRD patients was 4.25%, recurrent CDI occurred in 23.6% and associated with increased mortality. Most patients with CDI (over 78%) had a hospital admission in the prior 3 months of CDI diagnosis [16].

Although the patient, in this case, did not receive antibiotics prior to CDI, he had a severe and recurrent infection. This might due to frequent hospital exposer of weekly HD sessions or impaired immunity from uremia. Reviewing records in our department, in the past 3 months, showed CDI-induced diarrhea in another 3 patients with ESRD, who demand hospital admission.

Ascites is a rare manifestation and is not considered a well-known characteristic of severe CDI. Several mechanisms were described to explain ascites induced by CDI, which include Protein-Losing Enteropathy (PLE) secondary to bowel wall inflammation, which allows leakage of albumin into the lumen [2]. Also, transmural colonic inflammation with microperforation and toxin-mediated inflammatory cytokines causing vascular permeability have been described [6].

Herein, the patient had nearly normal albumin and colonic wall thickening, therefore, it is likely that the ascites was a result of transmural colonic inflammation with cytokines-induce vascular permeability.

In the end, first-line clinicians may not be familiar with such a rare manifestation of CDI and may not initially consider it when making differential diagnosis related to secondary peritonitis, which delays the diagnosis as in our case.

Conclusion

In conclusion, CDI should be suspected in all cases of diarrhea in patients with CKD even with no prior antibiotics use. Also, high suspicion of CDI should be considered in the presence of ascites in the context of diarrhea with no obvious source.

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Citation: Alsultan MH and Hassan Q. A Rare Culture-Negative Ascites Induced by Clostridium Difficile in a Patient with End-Stage Renal Disease: A Case Report and Literature Review. Austin J Nephrol Hypertens. 2021; 8(2): 1097.