Continuing Education Activity

Pseudoappendicitis can describe any condition mimicking acute appendicitis. Pseudoappendicitis classically presents with anorexia, acute right lower quadrant abdominal pain, and tenderness over McBurney point. Pseudoappendicitis is most commonly due to acute yersiniosis caused by Yersinia enterocolitica infecting the gastrointestinal tract. While most cases of acute yersiniosis are self-limited, the signs and symptoms of acute yersiniosis so closely resemble that of acute appendicitis that patients may undergo negative appendectomy. This activity reviews the evaluation, treatment, and complications of pseudoappendicitis and summarizes the importance of an interprofessional team approach to managing this increasingly common disease process.

Objectives:

• Correlate the pathogenicity of Y enterocolitica with the clinical spectrum of disease in symptomatic patients.
• Identify patients with suspected pseudoappendicitis based on their clinical history.
• Apply best practices when diagnosing and managing pseudoappendicitis.
• Develop and implement effective interprofessional team processes to improve outcomes in patients with pseudoappendicitis.

Introduction

Pseudoappendicitis describes any condition that mimics acute appendicitis. The characteristic signs and symptoms of acute appendicitis are acute right lower quadrant abdominal pain, anorexia, and point tenderness of the right lower abdominal quadrant.

Typically, pseudoappendicitis syndrome is due to acute yersiniosis, a zoonotic disease caused by Yersinia enterocolitica. Y enterocolitica is a gram-negative coccobacillus of the family Enterobacteriaceae. However, in rare cases, pseudoappendicitis may be due to Campylobacter infection.

Acute yersiniosis and Campylobacter infection can present with symptoms such as right lower quadrant abdominal pain, fever, vomiting, leukocytosis, and mild diarrhea, thus mimicking the typical signs of appendicitis.[1][2] More severe cases may present with mesenteric adenitis or terminal ileitis. However, most cases of acute yersiniosis are mild and self-limiting.[3]

Immunocompromised patients are more susceptible to infections from Y enterocolitica and prone to developing more severe sequelae of the disease, including sepsis and splenic or hepatic abscesses from bacterial dissemination. Individuals with hereditary hemochromatosis are also prone to Y enterocolitica infections. The higher-than-normal total body iron of patients with hereditary hemochromatosis proves a hospitable environment for the siderophilic Y enterocolitica.

Y enterocolitica is the most common bacterial contaminant in packed red blood cells. While most patients with acute yersiniosis will experience mild and self-limited disease, older persons and those with underlying comorbidities are at increased risk of infection and severe symptomatology. Patients who have recently received a blood transfusion and subsequently develop symptoms inconsistent with transfusion reactions, such as generalized malaise, gastrointestinal symptoms, and abdominal pain, should be evaluated for Y enterocolitica bacteremia.[4][5]

Etiology

The most common cause of the syndrome of pseudoappendicitis is acute yersiniosis or Campylobacter infection.

Epidemiology

Acute yersiniosis may mimic acute appendicitis. In one instance, an outbreak of acute yersiniosis was identified by an unusually high number of cases presenting symptoms resembling appendicitis. Approximately 42 percent of these identified cases underwent appendectomy. Comparatively, in other outbreaks, the rates of appendectomy have been reported from 0% to 14%, highlighting the significance of acute yersiniosis manifesting as pseudoappendicitis.[6]

In areas with high rates of yersiniosis, a significant number of appendectomies occur in the setting of acute yersiniosis. In a study where 2861 Belgian patients who underwent appendectomies for a preoperative diagnosis of acute appendicitis were cultured for Y enterocolitica, 3.6% of the samples tested positive for harmful Y enterocolitica during a nonoutbreak setting. Surprisingly, out of the 73 patients whose appendiceal cultures revealed Y enterocolitica, 75% exhibited mesenteric adenitis or terminal ileitis during the intraoperative examination instead of the anticipated diagnosis of acute appendicitis.

Pathophysiology

Y enterocolitica is carried and harbored by virtually all animals. The bacteria may also be found in contaminated water and soil. Y enterocolitica is transmitted via the fecal-oral route, and infection can occur from direct or indirect contact with infected animals or ingesting contaminated water or foods, most commonly pork or pork products. 

Y enterocolitica is an invasive organism. After ingestion, the bacterium infiltrates the epithelial cells of the small intestine and underlying Peyer patches via ingestion by M (microfold) cells. M cells are specialized cells of the gastrointestinal-associated lymphoid tissues designed to sample antigens in their role in mucosal immunity. High concentrations of M cells are found in Peyer patches. Y enterocolitica replicates in the reticuloendothelial system of the terminal ileum, invading mesenteric lymph nodes and causing mesenteric lymphadenitis. 

Y enterocolitica produces the three invasion and adherence proteins: ail, YadA, and inv. These proteins bind to the β1-chain integrins receptors abundant on the luminal surface of M cells. Yersinia outer proteins (YOPs) contribute to the resistance against opsonization and phagocytosis by neutrophils by interfering with the secretion of cytokines such as TNF-α and IL-8.[7]

Y enterocolitica also secretes urease, an enzyme that converts blood urea into ammonia, allowing the bacteria to survive the acidic gastric environment, similar to Helicobacter pylori. 

Y enterocolitica has approximately 60 serogroups typed by their O and H lipopolysaccharide surface antigens. Most subtypes are nonpathogenic to humans. Pathologic serogroups in humans include but are not limited to O:3, O:8, and O:9.

Animals and humans infected with this bacteria who never develop symptoms or convalesce from a symptomatic episode may become carriers.[8]

Histopathology

The underlying pathological causality dictates the histopathological findings of pseudoappendicitis. The histopathological finding is remarkable for histiocytic necrotizing lymphadenitis in some extremely rare causes of pseudoappendicitis, including Kikuchi-Fujimoto disease.[5] 

Y. enterocolitica causes varying degrees of enteritis with inflammation of the gastrointestinal mucosa. The mucosa and submucosa exhibit extensive vascular congestion, accompanied by hyperplasia of the lymphoid tissue. Lymphatic granulomas are characterized by multinucleated giant cells surrounded by infiltrating lymphocytes.The histologic findings of Y enterocolitica enteritis are similar to salmonellosis and shigellosis. Y enterocolitica bacteria can be cultured from these sources, as well as blood or stool.[9]

History and Physical

The clinical presentation of pseudoappendicitis syndrome may differ by underlying causality. However, several nonspecific historical and physical examination findings are common.

Patients with a history of negative appendectomy with unresolved or aggravated abdominal pain following the procedure may have pseudoappendicitis, particularly in the setting of nondiagnostic laboratory and imaging studies. The intractable abdominal pain in these patients might be mistakenly labeled as a psychosomatic disorder.[10]

Y enterocolitica infections are mostly asymptomatic. However, mild abdominal pain and diarrhea may occur. Severe yersiniosis presents with watery or bloody diarrhea, fever, chills, and increased abdominal pain. If mesenteric lymph nodes are involved, patients will have moderate-to-severe right lower quadrant abdominal pain, which could masquerade as acute appendicitis. These patients may exhibit abdominal guarding and rebound tenderness with a positive McBurney sign, predicting localized terminal ileitis. Patients with severe watery or bloody diarrhea may be misdiagnosed with salmonellosis, shigellosis, or Giardia enteritis.

Patients with advanced infections, mainly if left untreated, may present with signs of sepsis, dehydration, and shock.[11]

Evaluation

Stool Culture

Stool culture is a reliable diagnostic tool for identifying bacterial pathogens causing pseudoappendicitis, including Campylobacter, Salmonella, Shigella, and Yersinia. However, results may take several days, delaying the diagnosis and initiation of appropriate treatment. Additionally, not all cases of pseudoappendicitis are caused by bacterial infections, making stool culture ineffective. However, stool culture is the preferred diagnostic test for Y enterocolitica for patients with gastrointestinal symptoms. The microbiology department should be notified that acute yersiniosis is suspected; isolating this organism from stool requires a special Cefsulodin-Irgasan-Novobiocin (CIN) agar.[4][10]

Nucleic Acid Amplification Testing

Nucleic acid amplification testing (NAAT), including reverse transcription polymerase chain reaction (RT-PCR), is a molecular diagnostic technique that amplifies and detects the genetic material of specific pathogens. NAAT is highly sensitive and specific, allowing for detecting even small amounts of genetic material. NAAT, particularly RT-PCR, has revolutionized the diagnosis of various infectious diseases, including Campylobacter. NAAT offers rapid and accurate identification of pathogens, enabling early and targeted treatment. However, the availability and cost of NAAT may limit its routine use in some healthcare settings. Like stool culture, NAAT is only effective in identifying specific pathogens and may miss other causes of pseudoappendicitis.

Fecal Microscopy and Gram Staining

Fecal microscopy involves examining a stool sample under a microscope to identify the presence of specific microorganisms or white blood cells. While fecal microscopy and Gram staining can provide valuable insights into the presence of microorganisms, they are not the primary diagnostic methods for pseudoappendicitis. These techniques are more commonly used to identify specific infections rather than to diagnose pseudoappendicitis directly. They may provide supportive evidence in some instances of Campylobacter infection, but their effectiveness in diagnosing pseudoappendicitis is limited.

Calprotectin

Calprotectin may be of benefit in the diagnosis of pseudoappendicitis. Calprotectin is secreted into the intestinal lumen during the early stages of intestinal mucosal damage. Notably, calprotectin demonstrates resistance to bacterial degradation at room temperature, enhancing its stability as a biomarker. The collection of samples for calprotectin is noninvasive. Fecal calprotectin has already shown its value as a diagnostic marker for various bowel pathologies, including chronic inflammatory bowel diseases.

Imaging Studies

Acute and chronic appendiceal conditions that radiographically imitate acute appendicitis have been reported, and their manifestations on computed tomography (CT) have been described. These conditions, specifically in chronic settings, share a common characteristic of a relatively slow inflammation progression, contrasting with the shorter duration of inflammation observed in acute appendicitis. Differentiating many of these conditions, including pseudoappendicitis from acute appendicitis, based on primary or secondary CT signs is challenging.[12]

Treatment / Management

Most Y enterocolitica infections are self-limiting and require no treatment. Patients with more pronounced symptoms of diarrhea and dehydration should be treated symptomatically with intravenous fluid resuscitation and stabilization. Antibiotics are usually not required. However, antibiotics should be initiated in advanced cases that do not respond to symptomatic therapy and immunocompromised patients.

Most Y enterocolitica subtypes produce beta-lactamase rendering the penicillins and cephalosporins ineffective therapeutic agents. The recommended antibiotic therapy for Y enterocolitica combines doxycycline and an aminoglycoside. Other antibiotics that have proven effective in treating acute yersiniosis are trimethoprim-sulfamethoxazole, fluoroquinolones, chloramphenicol, and third-generation cephalosporins.

Immunocompromised patients with splenic or hepatic abscesses may respond to percutaneous abscess drainage combined with long-term intravenous antibiotics.[4][13]

Differential Diagnosis

Acute appendicitis is probably the most common misdiagnosis of patients with acute yersiniosis. However, pseudoappendicitis syndrome may share characteristics with inflammatory bowel disease, Meckel diverticulitis, mesenteric lymphadenitis, ischemic colitis, and sigmoid diverticulitis.

Additionally, acute infectious gastroenteritis such as giardiasis, salmonellosis, shigellosis, and Clostridioides difficile colitis should be considered.[14][15]

Prognosis

Pseudoappendicitis due to acute yersiniosis is most often self-limiting. Conservative management with intravenous fluid replacement and supportive measures are usually sufficient. Complete recovery is expected after 24 to 48 hours.

Immunocompromised patients or patients with comorbidities might experience a less favorable outcome.[16]

Complications

While there are no identifiable long-term sequelae of acute yersiniosis, erythema nodosum and reactive arthropathy may occur, usually resolving within six months. Some studies have speculated that patients with prolonged yersiniosis might develop autoimmune hyperthyroidism, but this has not been proven.[16]

Deterrence and Patient Education

Y enterocolitica is transmitted via the fecal-oral route. Prevention is based on the principles of safe food handling and personal hygiene.

Pearls and Other Issues

Often patients with pseudoappendicitis are misdiagnosed with acute appendicitis and undergo a negative appendectomy. In these cases, the diagnosis of Y enterocolitica might be missed as patients frequently recover spontaneously with minimal supportive treatment.[9]

Enhancing Healthcare Team Outcomes

Obtaining an accurate medical history usually leads to the correct diagnosis of pseudoappendicitis. Understanding the epidemiology and treatment best practices of this condition could spare the ill patient unnecessary surgery. The clinician must also exercise patience, as supportive care is the appropriate treatment for this condition. Awareness of the self-limiting nature of this disease is mandatory for the treating staff and patients.