Peritonitis upon fasting-refeeding in APECED patients: a case series

Autoimmune polyendocrinopathy-Candidiasis-Ectodermal dystrophy (APECED) is a monogenic autoimmune disorder -caused by AIRE mutations- featuring chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency and several non-endocrine autoimmune manifestations including intestinal dysfunction^1,2. We present three APECED patients with pre-existing APECED-associated intestinal dysfunction who developed peritonitis upon refeeding following varying periods of fasting.

A 57-year-old female with several APECED-associated complications including gastrectomy and hemicolectomy for stomach and colon cancer presented with a 14-kg weight loss (Table 1). She underwent jejunostomy, which was complicated by subcutaneous soft-tissue infection and enterocutaneous fistula that resolved with antibiotics and bowel rest with total parenteral nutrition (TPN). After a 12-day bowel rest, upon refeeding via the jejunostomy tube (Peptamen; 50mL/hr) she developed acute abdominal pain with peritoneal signs. She remained hemodynamically stable. Imaging showed pneumatosis intestinalis, bowel wall thickening and pneumobilia concerning for bowel ischemia (Figure 1A). CRP was elevated while WBC (Figure 1B) and lactic acid (1mmol/L) were not. Exploratory laparotomy revealed dilated bowel loops without other abnormalities. Corticosteroids and broad-spectrum antibiotics led to resolution of clinical, CRP and radiographic abnormalities within 14 days (Figure 1A,B). Enteral feeding was re-initiated 11 days after the initial episode without peritonitis relapse.

Table 1.

Demographic, clinical, genetic, laboratory radiographic and treatment data of refeeding-associated peritonitis in APECED patients

	Patient 1	Patient 2	Patient 3
Demographics (age at onset)
Age at peritonitis	57 years-old	20 years-old	29 years-old
Ethnicity	Caucasian/Not Hispanic	Hispanic/Latino	Hispanic/Latino
Gender	Female	Male	Male
AIRE mutations
Allele 1	c.967_979del13 (p.L323SfsX51)	c.1235delC (p.S412fsX68)	c.957delC (p.L320Wfs*58)
Allele 2	c.769C>T (p.R257X)	c.1235delC (p.S412fsX68)	No identified mutation
Classic triad clinical manifestations (age at onset)
CMC	Yes (3 months-old)	Yes (11 months-old)	Yes (12 years-old)
Hypoparathyroidism	Yes (2 years-old)	No	Yes (9 years-old)
Adrenal Insufficiency	Yes (10 years-old)	Yes (20 years-old)	Yes (9 years-old)
Non-triad clinical manifestations (age at onset)
Alopecia	No	No	Yes (12 years-old)
Gastritis	Yes (54 years-old)	No	Yes (29 years-old)
Hepatitis	No	Yes (20 years-old)	No
Hypogonadism	Yes (18 years-old)	No	Yes (10 years-old)
Hypothyroidism	Yes (35 years-old)	Yes (13 years-old)	Yes (3 years-old)
Intestinal dysfunction	Yes (1.5 years-old)	Yes (12 years-old)	Yes (12 years-old)
Pernicious anemia	Yes (16 years-old)	No	Yes (13 years-old)
Pneumonitis	Yes (50 years-old)	No	Yes (29 years-old)
Sjogren’s-like syndrome	Yes (54 years-old)	No	No
Tubulointerstitial nephritis	No	No	No
APECED-associated autoantibodies
Interferon omega	Positive	Positive	Positive
Tryptophan hydroxylase	Positive	Positive	Positive
History of APECED-associated intestinal dysfunction symptoms (prior to developing refeeding-associated peritonitis)
Abdominal pain	No	Yes	Yes
Abdominal bloating	No	Yes	Yes
Foul-smelling flatulence	Yes	No	Yes
Nausea	No	Yes	No
Diarrhea	No	No	Yes
Constipation	No	No	No
Alternating pattern of diarrhea with constipation	Yes	Yes	No
GI-related medications (at the onset of refeeding-associated peritonitis)
Proton pump inhibitor	Yes (omeprazole)	No	No
H2-blocker	No	No	No
Anti-diarrheal	No	No	No
Laxatives	No	No	No
Prior GI procedures (age at procedure; time interval between procedure and onset of refeeding-associated peritonitis)
	Hemicolectomy (55 year-old; 2 years)	Gastrostomy tube (20 years-old; 86 days)	Gastrostomy tube (29-years-old; 3 days)
	Total gastrectomy (56 years-old; 1 year)	Exploratory laparotomy (20 years-old; 4 days)
	Roux-en-Y esophagojejunostomy (56 years-old; 1 year)	Surgical resection of abdominal cocoon (20 years-old; 4 days)
Clinical symptoms and signs at onset of refeeding-associated peritonitis
Abdominal pain	Yes	Yes	Yes
Abdominal bloating	Yes	Yes	Yes
Diarrhea	No	Yes	No
Fever	No	Yes	No
Nausea	No	Yes	No
Tachycardia	No	Yes	Yes
Radiographic findings of refeeding-associated peritonitis
Peritoneum	Trace ascites	Trace ascites	Pneumoperitoneum
Intestines	Interval development of pneumatosis within the ileum and colon. Moderate wall thickening of the jejunum.	Diffuse small bowel wall thickening and areas of distended small bowel	Markedly distended large bowel
Liver/biliary tree	Pneumobilia	Unremarkable	Unremarkable
Therapeutic Intervention during refeeding-associated peritonitis
Exploratory laparotomy	Yes	No	No
Antibiotics	Meropenem, metronidazole, daptomycin	Vancomycin, meropenem	Meropenem, daptomycin
Antifungal agent	Micafungin	Anidulafungin	Micafungin
Immunosuppressive	Azathioprine (25 mg/day)*, rituximab (1000 mg/dose)*	Everolimus (0.5 mg twice daily)†	Azathioprine (75 mg/day)*, rituximab (1000mg/dose)*
Steroids (mg/kg; days)	Methylprednisolone (1 mg/kg/day, 13 days) transitioned to prednisone (1 mg/kg/day, 5 days) transitioned to a 28-day prednisone taper transitioned to physiologic hydrocortisone replacement (30 mg/day)	Methylprednisolone (1 mg/kg/day, 15 days) transitioned to prednisone (1 mg/kg/day, 14 days) transitioned to a 28-day prednisone taper transitioned to physiologic hydrocortisone replacement (15 mg/day) and everolimus (as above)	Methylprednisolone (0.5 mg/kg/day, 13 days) transitioned to methylprednisolone (0.25 mg/kg/day, 2 days) transitioned to physiologic hydrocortisone replacement (20mg/day)
Laboratory values at the onset of refeeding-associated peritonitis
Calcium (mmol/L)	1.82	2.01	2.29
Potassium (mmol/L)	3.7	3.3	4.4
Phosphorus (mg/dL)	3.6	4.8	3.9

AIRE, autoimmune regulator; CMC, chronic mucocutaneous candidiasis; GI, gastrointestinal

^*, Initiated prior to peritonitis for other autoimmune manifestation management and continued during and after resolution of refeeding-associated peritonitis

^†, Initiated after the resolution of peritonitis

Figure 1. Radiographic and inflammatory marker abnormalities in APECED patients with refeeding-associated peritonitis.

(a) Abdominal CT images during and after refeeding-associated peritonitis at the resolution of symptoms. (b) CRP and WBC before, during and after refeeding-associated peritonitis. Dashed lines with grey rectangles indicate the normal range of CRP and WBC values. CT, computed tomography; CRP, C-reactive protein; WBC, White blood cell count.

A 20-year-old TPN-dependent male with abdominal cocoon-associated small bowel obstruction (SBO) developed a 9-kg weight loss (Table 1)³. Four days post-surgical correction of SBO, after a 31-day bowel rest, enteral feeding was initiated with clear liquids leading to acute abdominal pain with peritoneal signs and culture-proven peritonitis (Enterobacter, Enterococcus, Bifidobacterium). He remained hemodynamically stable. Imaging revealed distended and thickened bowel (Figure 1A). CRP was elevated but WBC was not; lactic acid was not measured (Figure 1B). Corticosteroids and broad-spectrum antibiotics led to clinical, CRP and radiographic remission within 17 days (Figure 1A,B). Enteral feeding was re-introduced 12 days after the initial event without peritonitis relapse.

A 29-year-old male with pneumonitis-associated respiratory failure necessitating tracheostomy underwent percutaneous gastrostomy placement (Table 1). After a 3-day bowel rest, refeeding via the gastrostomy tube (Peptamen; 55mL/hr) led to acute abdominal pain with peritoneal signs. He remained hemodynamically stable. Imaging showed pneumatosis intestinalis, distended bowel and pneumoperitoneum (Figure 1A). CRP and WBC were elevated (Figure 1B) while lactic acid was not (0.7mmol/L). Corticosteroids and broad-spectrum antibiotics led to resolution of clinical, CRP and radiographic abnormalities within 10 days (Figure 1A,B). Enteral feeding was re-started 4 days after the initial event without peritonitis relapse.

We report the first cases of peritonitis with associated intestinal inflammation, which may develop in APECED upon refeeding following varying periods of fasting, even in patients already-receiving immunomodulatory treatment for other autoimmune manifestations. Predisposing factors may include pre-existing APECED-associated intestinal dysfunction and presence of gastrostomy/jejunostomy tubes. Corticosteroids and antibiotics remit peritonitis enabling re-introduction of enteral feeding without peritonitis relapse; hence, selective conservatism is important in the management of these patients who may not require surgical intervention. CRP is a useful biomarker for supporting the diagnosis and monitoring remission. The mechanism of refeeding-associated peritonitis requires investigation but may relate to rapid intestinal re-distribution of AIRE-deficient autoreactive lymphocytes upon fasting-refeeding, as shown in mice⁴.