Continuing Education Activity

Clostridium perfringens is an anaerobic Gram-positive spore-forming bacillus that is associated with acute gastrointestinal infection ranging in severity from diarrhea to necrotizing enterocolitis and myonecrosis in humans. This activity will highlight the epidemiology, pathophysiology, and other key factors pertinent for members of the interprofessional healthcare team in the management of patients with Clostridium perfringens infections.

Objectives:

• Summarize the epidemiology of Clostridium perfringens.
• Review the major toxins released by Clostridium perfringens.
• Describe the pathophysiology of Clostridium perfringens.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with Clostridium perfringens infection.

Introduction

Clostridium perfringens is an anaerobic gram-positive spore-forming bacillus that is associated with acute gastrointestinal infection ranging in severity from diarrhea to necrotizing enterocolitis and myonecrosis in humans. This pathogen possesses an arsenal of toxins that are responsible for disease pathogenesis and can form spores that are resistant to environmental stress.

Etiology

Clostridium perfringens was first discovered by William H. Welch, MD, in 1891 at The Johns Hopkins Hospital after an autopsy on a 38-year-old man and was initially named Bacillus aerogenes capsulatus.[1] Later, it was known as Bacillus welchii before finally renamed to Clostridium perfringens, which is derived from Latin for “burst through.”

Classification is based on the production of the six major toxins: alpha-toxin (CPA), beta-toxin (CPB), epsilon-toxin (ETX), iota-toxin (ITX), enterotoxin (CPE), and necrotic enteritis B-like toxin (NetB).[2]

• A: CPA only
• B: CPA, CPB, ETX
• C: CPA, CPB, CPE (+/-)
• D: CPA, ETX, CPE (+/-)
• E: CPA, ITX, CPE (+/-)
• F: CPA, CPE
• G: CPA, NetB

Epidemiology

Type A and Type C toxins are known to cause human disease. Type A is responsible for most of the C. perfringens-associated food poisoning and non-foodborne diarrheal disease. According to CDC epidemiology surveillance data for foodborne disease outbreaks, C. perfringens accounts for 5% of outbreaks, 10% of illnesses, and 4% of hospitalizations.[3] The annual median outbreak size was 24, with a median outbreak-associated disease of close to 1,200. Data shows a slightly higher prevalence in males (65%), with the majority of cases presenting between 20-49 years of age. The most common vehicle for transmission is undercooked beef, followed by poultry. Outbreaks occurred throughout the year, with the highest prevalence in November and December.[4]. The pathogen ranks within the top five most common etiologies for foodborne disease outbreaks in the US and even higher prevalence worldwide.[5]

Type C has been associated with endemic enteritis necroticans in post-World War II Germany from 1944 to 1949 and in the Highlands of Papua New Guinea, named Darmbrand and Pigbel, respectively.[6] It is hypothesized that severe malnutrition increases susceptibility to type C infection. In the 1960s to 1970s, Pigbel was identified as the most common cause of death in children over 1-year-old.[7] A vaccination campaign in the 1980s helped to reduce the incidence, but the disease continues to cause significant morbidity and mortality.[8]

Pathophysiology

Pathophysiology from C. perfringens is through toxin-mediated tissue necrosis. Most toxins are pore-forming, causing an influx of solute and water, leading to cellular swelling and cell death. A hallmark of C. perfringens infection is the production of histotoxic gas through glucose fermentation.[9]

Toxins produced by C. perfringens

• CPA is an enzyme that can breakdown phosphatidylcholine and sphingomyelin on the cell membrane, inhibit both migration and maturation of neutrophils, and activate arachidonic acid metabolism leading to vasoconstriction and platelet aggregation.[10]. Consequently, this toxin creates a micro-environment with poor tissue circulation and impairment of the innate immune response.[11]
• CPB is a pore-forming toxin known to bind endothelial cells and have neurotoxic properties through the release of substance P. Furthermore. The toxin has been shown to play a critical role in the pathogenesis of necrotizing enterocolitis.[12]
• CPE is a pore-forming toxin that binds to claudin receptors on the cell surface, forming a hexamer complex that allows an influx of calcium. This toxin is the major culprit causing food-poisoning and non-foodborne diarrhea. Calcium influx is dose-dependent and leads to activation of calpain and, ultimately, cell death.[2]
• ETX is associated with hemorrhagic enteritis and enterotoxaemia in sheep. The toxin is activated by enteric proteases and increases intestinal permeability through the disruption of tight junctions and the lamina propria. It causes perivascular edema with rapid cellular swelling and is found to accumulate in the kidney and brain, but the mechanism has remained elusive.[13]
• ITX is a binary toxin that is produced as two distinct proteins Ia and Ib. Ib binds to a cell surface receptor and associates with Ia. The complex is then endocytosed. Ia will pass to the cytosol through a membrane channel created by Ib and then go on to depolymerize the actin cytoskeleton via ADP-ribosylation.[14]
• NetB is a pore-forming toxin identified in avian necrotic enteritis that has been shown to have a 38% sequence similarity with CPB. Its discovery created the type G classification but so far has not been linked to pathogenicity in humans.[15]
• Perfringolysin O (PFO) is a pore-forming toxin shown to have synergistic effects with CPA and has been implicated in the pathogenesis of gas gangrene.[16] It is known to target red blood cells and cause coagulative necrosis. Furthermore, this toxin shares homology with other pore-forming toxins found in Streptococcus, Bacillus, and Listeria.[17]

Histopathology

Microscopy and gram staining will reveal gram-positive bacillus.

History and Physical

In food poisoning and non-foodborne diarrheal disease, a history and physical can help to identify the causative agent and help to create a differential. The onset of symptoms is typically 8-16 hours after consuming raw or undercooked meat or poultry. The patient will often have a combination of diffuse abdominal pain, profuse watery non-bloody diarrhea, and vomiting.

Rarely, these patients can present with abdominal sepsis that may manifest with hypotension, tachycardia, and abnormal thermal homeostasis. In addition to hemodynamic instability, there will likely be signs of abdominal distention with tenderness, a rigid hypertympanic abdomen, and altered mental status. These signs are indicative of a medical and surgical emergency.

Clostridial myonecrosis (gas gangrene) typically occurs after an injury (traumatic) but can develop spontaneously in patients with ischemic vascular disease or diabetes(non-traumatic). The patients present with cellulitis at the site of infection, fever, and chills. The wound has edema, tenderness, and bullae that can have a discharge with a musty odor. Symptoms are disproportionately dominant compared to signs. Infection of the deeper tissues results in necrosis of subcutaneous fat, muscle, or nerves. Symptoms can rapidly progress to septic shock, disseminated intravascular coagulation, and acute respiratory distress syndrome, which is associated with very high mortality.[18][19]

Evaluation

In suspected C. perfringens infections, stool studies should be performed, which include stool culture and ELISA testing for CPA toxin. Often stools studies will also include WBCs, ova, and parasites to help rule out other etiologies. In more severe clostridial infections, imaging will be warranted to help identify the affected tissue.

An outbreak of foodborne disease is defined as the “occurrence of two or more cases of a similar illness from ingestion of a common food.”[4] Outbreak data, including the number of illnesses, hospitalizations, and mortality, should be reported to the local public health department and the Centers for Disease Control and Prevention.

In cases of clostridial myonecrosis, imaging such as an x-ray or CT scan of the affected area should be obtained in addition to blood tests, which include a CBC, CMP, blood culture, CK level, ABG, and lactic acid.

Treatment / Management

Since most C. perfringens-associated acute diarrheal disease is self-limiting, only supportive care is needed to maintain a euvolemic state. Antibiotics are generally not indicated.

The exception is clostridial sepsis, which is a medical emergency. Clostridial sepsis often presents in septic shock with possible intravascular hemolysis due to CPA-mediated destruction of red blood cells. In this situation, early antibiotic treatment with penicillin G and clindamycin, tetracycline, or metronidazole in combination with surgical debridement of necrotic tissue may help to prevent death.[20][21] These patients will likely be refractory to medical therapy unless source control is achieved.

A suspicion of clostridial myonecrosis warrants a surgical consultation. Consultation should not be delayed waiting for laboratory or imaging results. Broad-spectrum antibiotics should be promptly administered. In addition, hyperbaric oxygen is shown to improve outcomes in cases of severe infection.

Differential Diagnosis

Acute infectious diarrhea

• Norovirus
• Salmonella
• Campylobacter
• Staphylococcus aureus
• Escherichia coli producing Shiga toxin

Abdominal sepsis

• Appendicitis
• Infectious colitis
• Ischemic colitis
• Perforated peptic ulcer
• Pancreatitis

Clostridial cellulitis/myonecrosis

• Escherichia coli
• Klebsiella
• Streptococcus pyogenes
• Staphylococcus aureus
• Anaerobic bacteria: Bacteroides and Peptostreptococcus

Prognosis

The majority of cases of food poisoning and non-foodborne diarrheal disease are self-limiting. Those who are hospitalized need fluid resuscitation and advancing diet when tolerated. Generally, the prognosis is good. On the other hand, clostridial myonecrosis and sepsis are medical emergencies with a guarded prognosis. Early recognition and treatment, including surgical debridement, are vital. Even with appropriate treatment, the mortality rate is 20-30%, while without treatment, the mortality rate is 100%.[18]

Complications

The majority of cases from food poisoning and non-foodborne diarrheal disease have minimal to no complications if volume status is adequately managed. However, the bloodstream infection can result in toxin-mediated intravascular hemolysis and septic shock. Clostridial myonecrosis may require extensive debridement, amputation, and complications of severe sepsis, including shock, encephalopathy, acute respiratory distress syndrome, and death.

Consultations

A consultation from general surgery and infectious disease specialists should be considered in the evaluation of C. perfringens associated infections.

Deterrence and Patient Education

Most of the food poisoning and non-foodborne diarrheal diseases from C. perfringens is due to undercooked meat or poultry. Therefore, patient education regarding food safety protocols is essential for preventing and limiting the spread of disease. Patients with risk factors such as diabetes or vascular disease must not delay seeking medical attention in the event of cellulitis or trauma due to an increased risk of severe infection and rapid progression.

Enhancing Healthcare Team Outcomes

Infection with C. perfringens is often a benign self-limiting disease that is treated with fluid resuscitation. However, patients can present with or develop septic shock with myonecrosis, which will require antibiotics, blood pressure support, and surgical intervention. It is essential to educate the healthcare team to be vigilant so that rapid diagnosis and treatment can be initiated. An interprofessional team of physicians, surgeons, radiologists, nurses, pharmacists, and physical therapists is needed to care for the patient. Also, the healthcare team can model effective communication to provide early detection of possible C. perfringens-mediated outbreaks and ensure that the necessary public health departments are aware to minimize spread. [Level 4]