Capnocytophaga canimorsus is a fastidious, slow-growing, Gram-negative rod of the genus Capnocytophaga. It is a commensal bacterium in the normal microbiota of the gums of canine and feline species, but can cause illness in humans. Transmission may occur through bites, licks, or even proximity to animals. C. canimorsus generally has low virulence in healthy individuals, but has been observed to cause severe, even grave, illness in persons with pre-existing conditions such as asplenia. The pathogenesis of C. canimorsus is still largely unknown, but increased clinical diagnoses have fostered an interest in the bacillus. Treatment with antibiotics is effective in most cases, but the most important yet basic diagnostic tool available to clinicians remains the knowledge of recent exposure to canines or felines.
History Capnocytophaga canimorsus was first observed in 1976 by Raymond Bobo and Eleanor Newton. The pair isolated a previously unknown Gram-negative bacterium from a patient presenting with meningitis in addition to sepsis. The patient had been previously exposed to two canine bites on two consecutive days from two different dogs. Noting the coincidence between the timing of the bites and the onset of symptoms, Butler et al. analyzed 17 similar cases of patients presenting with either sepsis or meningitis from 1961 to 1975. The cases had been sent to the CDC for examination due to the presence of an unknown Gram-negative bacillus isolated from infected individuals. Butler notified the CDC of the high incidence of dog bites in connection with the infections. The CDC could not identify the organism, so they applied the name CDC group DF-2. DF-2 stands for dysgonic fermenter, meaning that the bacterium is a slow-growing, fermentative bacillus. In 1989, while analyzing the properties of the unknown bacterium, Weaver et al. noted many similarities to bacteria of the genus Capnocytophaga. Later that same year, Brenner et al. proposed the name Capnocytophaga canimorsus after examining the morphology, G+C% content, and motility of the species.
Etymology The name Capnocytophaga is derived from the Greek word kapnos, meaning "smoke", and given here because of its dependence on carbon dioxide for growth. It was added to distinguish this genus from the Cytophaga genus, originating from the Greek words of kytos (meaning "cell"), and phagein (meaning "eat"). The species name of canimorsus comes from the Latin words canis and morsus, meaning "dog" and "bite" respectively.
Epidemiology Significant dog bites affect tens of millions of people globally each year, and cases of human infection following exposure to C. canimorsus have been observed worldwide. It is estimated that 2% of the U.S. population, 4.5–4.7 million people, are bitten by dogs each year. Cases have been reported in the United States, Canada, Europe, Australia and S. Africa. Symptoms may appear within 2–3 days after exposure, or up to 4 weeks later. Middle-aged and elderly persons are at greater risk for contraction of the disease; more than 60% of sufferers are 50 years of age or older. In addition, individuals who spend a greater portion of their time with canines and felines are also at higher risk. This includes veterinarians, breeders, pet owners, and keepers. Having certain pre-existing medical conditions exacerbates the risk. Chance of infection by any bacterial species after dog bites varies between 3 and 20%; for cats, it may be as high as 50%. A review of reported zoonotic Capnocytophaga bloodstream infections found that C. canimorsus was responsible for 93.1% of cases in the study. The patients had a median age of 60 years, and males were accounted for 61.8% of the cases. Other health conditions were common which affected 80.4% of patients, while about one-third were immunosuppressed (asplenia or alcohol use disorders)
Morphology, culture, and isolation
C. canimorsus is a fastidious, Gram-negative, fermentative, encapsulated, nonspore-forming rod. Bacilli are usually 1-3 μm in length. After growth on agar plates, longer rods tend to have a curved shape. The bacteria do not have flagella, but move with a gliding motion, although this can be difficult to see. C. canimorsus requires the right medium for growth. The bacterium grows well on blood agar plates (heart infusion agar with 5% sheep or rabbit blood) and chocolate agar plates. Colonies may not be visible for up to 48 hours due to slow growth. At 18 hours, colonies are usually less than 0.5 mm in diameter, and are spotty and convex. At 24 hours, colonies may be up to 1 mm in diameter. After 48 hours, colonies are narrow, flat, and smooth, with spreading edges. At this time, colonies may appear white-grey or grey, rather translucent, and once they are scraped from the agar plate, they may have a slightly yellow tint.
Genome The genome of C. canimorsus strain Cc5 consists of a single circular chromosome of 2,571,406 bp with a G+C content of 36.11%, and it encodes 2,405 open reading frames.
In animals Members of the genus Capnocytophaga are found in the oral cavities of humans and animals. Most of these species are not found in humans. C. canimorsus is a commensal bacterium found in dogs and cats; it is not a member of the normal microbiota of humans. About 26% of dogs carry these commensal bacteria in their mouths. C. canimorsus rarely causes disease symptoms in animals. One case of C. canimorsus isolated from a dog bite wound on a small dog's head has been reported; the bacteria were localized to the wound, and the dog did not present with bacteremia. A few cases of infection have been reported in rabbits after being bitten by dogs. Clinical manifestations of C. canimorsus in rabbits causes a range of symptoms, including disseminated intravascular coagulation, cellular necrosis (tissue death), low blood pressure, gangrene, and kidney failure.
High-risk categories
In addition to those at higher risk of developing complications from C. canimorsus due to greater contact with felines and canines, certain pre-existing conditions place individuals in a critically high-risk category. Among these are those who have undergone a splenectomy, alcoholics, and individuals with immunosuppression due to the use of steroids such as glucocorticoids. Individuals with β-thalassemia and smokers are also listed as high-risk. These individuals, such as people with asplenia and alcohol use disorder, have increased levels of alimentary iron in their bloodstream. C. canimorsus requires large amounts of iron to grow, so these conditions are optimal for the bacillus.
Asplenia Overwhelming post-splenectomy infection is associated with encapsulated organisms such as Capnocytophaga canimorsus.
Of the cases presented in literature, 33% occurred in asplenic individuals, who have decreased IgM and IgG production. They also have delayed macrophage assembly and produce less tuftsin. Tuftsin is responsible for the stimulation of phagocytosis, so its decrease in the presence of bacterial infection poses a problem. A functional spleen is important for the removal of pathogens. Because this particular pathogen seems to flourish in asplenic patients, both IgM antibodies and tuftsin may be critical in the process of marking this bacterium for destruction by phagocytosis. People with asplenia are 60 times more at risk of developing fatal clinical manifestations of the bacterium. Individuals with asplenia often experience symptom onset within a day of exposure. The infection rapidly progresses toward multiple organ system failures and finally death. The mortality rate in individuals with asplenia is much higher than in any other at-risk category for C. canimorsus infections.
Alcohol use disorder People who struggle with alcohol addiction represent around 24% of individuals presenting with C. canimorsus infections. Alcoholism has been shown to result in decreased superoxide production in neutrophils, as well as declines in neutrophil elastase activity. This results in an increase in predisposition to bacteremia (bacteria in the blood). As a result, people suffering from alcoholism are more likely to suffer from the more dangerous aspects of C. canimorsus invasions. Finally, people with alcohol addictions are associated with increased blood iron content.
Immunosuppression Immunosuppression resulting from an underlying illness or medical treatment is a risk factor for C. canimorsus infection. Immunosuppressants are often used to treat autoimmune diseases, such as systemic lupus erythematosus. These treatments, including glucocorticoids, reduce immune system activity and can impair the body's ability to fight infection. This reduces the body's ability to eliminate bacteria introduced through an animal bite, scratch, or contact with saliva. As a result, immunocompromised individuals may be more likely to develop severe infection after exposure to C. canimorsus than healthy individuals. In a review of reported cases, approximately 5% of patients presenting with C. canimorsus infection were immunosuppressed.
Symptom onset and clinical manifestations Symptoms generally develop within 1–8 days after exposure to C. canimorsus but onset of symptoms most commonly appears on the second day. Initial symptoms vary depending on whether the infection remains localized or spreads systemically. Local symptoms at the site of a bite or scratch may include redness, swelling, pain, blisters, cellulitis, or pus. When the infection spreads beyond the site of exposure, it may cause symptoms resembling an influenza-like illness. Reported symptoms include fever, chills, vomiting, fatigue, diarrhea, malaise, abdominal pain, myalgia, headaches, and skin rashes such as exanthema. Neurological symptoms, including confusion and altered mental status, may develop as the infection progresses. Respiratory symptoms such as dyspnea may also occur.
If C. canimorsus enters the bloodstream, it can cause bacteremia and fulminant sepsis, which can be fatal. Severe infections may also result in septic shock, multiorgan failurem endocarditis, disseminated intravascular coagulation, or meningitis. Prior treatment with methylprednisolone has been associated with prolonged bacteremia, which contributes to the development of endocarditis.
Differential diagnosis Diagnosing infections with C. canimorsus can be difficult. Common practice for culturing isolates is to keep agar plates for one week; sometimes, cultures of C. canimorsus are not visible at that point due to slow growth or inappropriate media. C. canimorsus requires very specific culture media and conditions; enriched media are necessary. C. canimorsus displays enhanced growth in high concentrations of carbon dioxide, so culturing the bacteria in candle extinction jars or carbon dioxide incubators is necessary. To diagnose this bacillus, certain reactions may be tested. The bacterium should test positive for catalase and oxidase, arginine dihydrolase, maltose, and lactose. It should test negative for nitrate reduction, urease, and H2S production. C. canimorsus can be distinguished from other Gram-negative bacteria by testing negative for inulin and sucrose.