SUBMITTED:
February 2022
Accepted:
June 2022
M. de Wit-van Dongen (1), E.F.F. Jonker (1), C.E.A. Dronkers (2), M. Lambregts (2), J. van Paassen (1)
1 Departments of Intensive Care and 2 Internal Medicine and Infectious Diseases, Leiden University Medical Centre, Leiden, the Netherlands
Correspondence:
M. de Wit-van Dongen - marjoleindewitvandongen@gmail.com
When man’s best friend becomes a dangerous breed
Keywords:
Abstract
In this article we present two cases of Capnocytophaga canimorsus (C. canimorsus)-related sepsis presenting with different clinical symptoms. C. canimorsus is a commensal bacterium in the gingival flora of dogs and cats but can cause severe illness in humans after transmission through bites or licks. Risk factors include a reported dog or cat bite, alcoholism, immune deficiency, advanced age, splenectomy or hyposplenism. We discuss the role of hyposplenism in this disease. Treatment of C. canimorsus sepsis is with antibiotics and in the case of multi-organ failure supportive.
Introduction
In this article we present two recent cases of Capnocytophaga canimorsus (C. canimorsus) related severe sepsis in Leiden University Medical Center. Although the disease is not rare, the almost simultaneous occurrence of two cases presenting in a very different manner was surprising. Furthermore, as Case 2 will show, the disease may not present with classic symptoms and may in fact be missed without an adequate level of suspicion. C. canimorsus is a fastidious, slow-growing, Gram-negative rod of the genus Capnocytophaga. It is a commensal bacterium in the normal gingival flora of canine and feline species, but can cause illness in humans. Transmission may occur through bites, licks, or even close proximity with animals as our cases will demonstrate.
Furthermore, we discuss the role of the spleen and hyposplenism in patients with C. canimorsus sepsis.
Case 1
History and physical examination
A 71-year old female with no past medical history presented to the emergency department with malaise and a fever of 39 °C. The patient reported diarrhoea and vague abdominal symptoms. No close contacts had similar symptoms, there was no travel history or any remarkable events in the last few days. In the emergency department, we observed a patient in shock with hypotension (60/20 mmHg), tachycardia and a compromised circulation with mottled and blue-purple discoloured skin as well as purpura on the extremities (figure 1). No clinical signs of meningitis were present. The abdomen was diffusely painful without muscular defence. The laboratory results on admission are shown in table 1.
Resuscitation with fluids and noradrenaline was initiated. After drawing blood cultures cefuroxime and gentamicin were administered for the clinical suspicion of septic shock without a clinically identifiable source of infection.
CT scan
Thickening of the jejunal wall was seen; the radiologist suggested possible ischaemia associated with low-flow state since the vasculature of the intestines and abdominal organs showed no abnormalities. The spleen was described by the radiologist as present but small and measured 6.3 cm in maximum diameter (normal spleen size depends on gender, age and length but is approximately 12 cm long, 7 cm wide and has a thickness of 5 cm).
Course of the disease
The patient was admitted to the intensive care unit (ICU) with the diagnosis of septic shock. She suffered from severe central cyanosis and livedo reticularis of the skin initially localised on her legs but shortly after also prevalent on her abdomen, chest and arms. On admission she mentioned that her dog had bitten her in her right hand two days earlier. There was a small wound (approximately 0.5 cm) on her right hand, which was attended to by a surgeon. Within 24 hours after ICU admission she developed multi-organ failure with acute kidney injury, elevated liver enzymes, respiratory failure and diffuse intravascular coagulation (DIC). Renal replacement therapy and mechanical ventilation were initiated. She received high-dose vasopressors.
During the first days she developed purpura fulminans of the majority of the skin with necrosis of her fingers, toes and feet. Blood cultures drawn in the emergency department were positive for C. canimorsus one day after admission and the antibiotic treatment was changed to ceftriaxone and clindamycin. Since the micro-organism was beta-lactamase negative, the antibiotics were later switched to penicillin monotherapy. She had no known past medical history (e.g. no excessive alcohol intake, no past infections with capsulated micro-organisms) that could direct towards hyposplenism. She was admitted to the ICU for several weeks and after a long stay in the ICU, ward and rehabilitation centre she fully recovered, including her kidney function, and was discharged home.
Case 2
History and physical examination:
A 61-year-old male with no past medical history presented to the emergency department complaining of fatigue, fever and ‘a cold feeling’. The patient was a professional gardener and he was able to work until shortly before presentation to the emergency room (noticeable from the dirt under his finger nails and chapped hands). He complained about pain in his fingers, toes and face. His nose felt remarkably cold to him. The day before admission he experienced mild diarrhoea but no other abdominal symptoms. He has two dogs at home but reported no recent dog bites. He reported drinking about three to four units of beer a day.
On physical examination an acutely ill, shivering patient was seen with a remarkable blue discoloration of his nose, fingers and toes (figure 2). Palpation of his feet was extremely painful and his legs were mottled. His blood pressure was 160/90 mmHg, heart rate was 90/min and respiratory rate was 18/min. ECG showed sinus tachycardia and subtle ST-segment elevation of the inferior leads without reciprocal depression. Transthoracic cardiac echo showed a non-dilated left ventricle with overall diminished function, a normal right ventricular function, no pericardial effusion and no signs of endocarditis. The laboratory results on admission are shown in table 1.
CT scan
No dissection or pulmonary embolism was seen and the radiologist described a remarkably small spleen measuring 6 cm as maximum diameter.
Course of the disease
The patient was primarily admitted to the coronary care unit with the diagnosis of myocarditis and multi-organ failure with acute kidney injury, DIC and purpura fulminans. He was treated with the inotrope dobutamine and broad-spectrum antibiotics were administered after taking blood cultures. One day after admission to the coronary care unit the patient was transferred to the ICU because of onward multi-organ failure and the need for treatment with renal replacement therapy. ADAMTS-13 activity was normal so thrombotic thrombocytopenic purpura as primary diagnosis was unlikely. Because of a suspected infection with C. canimorsus, due to the clinical symptomatology combined with increased awareness caused by the first case, a smear of peripheral blood was done. This showed intracellular rods (figure 3). Blood cultures grew C. canimorsus at day 4 after incubation. In the first days of ICU admission the clinical picture quickly improved and the patient recovered but remained dependent on haemodialysis.
Discussion
An infection in humans with C. canimorsus can cause a broad range of clinical symptoms. In the first case the patient had been bitten by her dog whereas in the second case no history of a dog bite was apparent. Possibly in this case a minor abrasion of the patient’s chapped skin of his hands, secondary to his work as a gardener, was the port of entry of C. canimorsus when one of his dogs had licked this area.
Microbiology
C. canimorsus is part of the normal oral flora of cats and dogs. The majority of cases are transmitted by dog bites, but transmission by licking or scratching is also described.[1] Sheep, cows, horses, guinea pigs and rabbits also carry the microorganism in their mouth although there are no case reports of human clinical infections caused by those animals.
C. canimorsus was first described by Bobo and Newton in 1976.[2] It is a slow-growing Gram-negative rod which needs several days of incubation (2-7 days). Capnocytophaga literally means CO2-consuming and therefore incubation in a CO2 environment is necessary. Microscopic examination of a blood smear can show thin and long intracellular rods which could direct to the diagnosis earlier than blood cultures will.[1] This procedure is not a routine diagnostic tool and therefore dependent on clinical suspicion. Also, polymerase chain reactions (PCR) can be used to identify the causative micro-organism earlier.[3] The genus Capnocytophaga consists of nine species which are all encountered in the oral cavity of humans and domestic animals. The species C. canimorsus, C. canis and C. cynodegmi are part of the flora in the mouth of dogs and cats, whereas C. gingivalis, C. granulosa, C. haemolytica, C. leadbetteri, C. ochracea, and C. sputigena are part of human oral microflora.[4] Patients with human-oral associated Capnocytophaga infections are often immunocompromised because of treatment for hematological malignancies (chemotherapy and stem cell transplantation). Furthermore human-oral associated Capnocytophaga infections can cause head and neck infections as part of a polymicrobial flora.[4]
Clinical symptoms
C. canimorsus is a bacterium notorious for its capacity to cause serious infections and bacteraemia in (immunocompetent) humans.[4,5] More than 70% of C. canimorsus infections present with bacteraemia.[1] C. canimorsus is protected by a lipo-oligosaccharide and a polysaccharide capsule, making it relatively resistant to phagocytosis by macrophages.[1,6] Literature shows that there is a different immune response to C. canimorsus leading to a diminished release of pro-inflammatory cytokines (lower levels of IL-1b and IL-6 in response to C. canimorsus than other gram-negative bacteria), chemokines and nitric oxide. Therefore, it is suggested that C. canimorsus can make a relatively silent entry into the patient where it replicates and gets the opportunity to cause severe disease (e.g. septic shock) as primary presenting symptom.[5]
The clinical presentation is thus seldom only that of a local infection and in almost half of the patients that of severe sepsis.[7] Remarkably, around half of the patients report no history of dog or cat biting nor scratching them.[8] In patients with septic shock, C. canimorsus bacteraemia is often accompanied by purpura or petechiae, gangrene and sometimes by haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and/or DIC. Shock can go along with cardiovascular collapse, acute kidney injury and respiratory failure.[7] Also, a common presentation of infection with C. canimorsus is meningitis. Meningitis caused by C. canimorsus is characterised by a longer incubation period than for sepsis (median of seven days instead of three days) and has a lower mortality rate.[1] Furthermore, presenting symptoms can be nausea or diarrhoea, endocarditis, aortitis, or myocardial infarction which is sometimes due to septic emboli caused by an endocarditis or the result of type II myocardial ischaemia during severe sepsis. Older literature suggests that C. canimorsus may induce localised endothelial damage (similar to DIC) in the coronary arteries leading to thrombosis and subsequent myocardial infarction.[9] This diverse onset of symptoms is illustrated by the second case where the patient was primarily suspected of myocarditis before overt sepsis became apparent.
When there is suspicion of endocarditis (by means of the Duke’s criteria) there are often no blood or intra-operative cultures positive for C. canimorsus and 16S DNA PCR sequencing is necessary to make a definitive diagnosis.[3,10] Therefore, in a patient with dog or cat exposure combined with culture-negative endocarditis C. canimorsus should be considered as a possible cause.
Risk factors
A retrospective nationwide study performed in the Netherlands in 2011 showed a yearly incidence of 0.67 per million for infection and 0.63 per million for sepsis.[8] About two-thirds of the patients are male with a median age of 50 years.[1,7] Risk factors are a reported dog or cat bite, alcoholism, immune deficiency, advanced age, splenectomy or hyposplenism.[1,7] In our two patients the radiologist described a remarkably small spleen, without any past events that could point in the direction of hyposplenism except that in the second case there was excessive alcohol intake as a risk factor. Literature shows a relationship between spleen volume and infections with encapsulated bacteria. A Japanese retrospective study showed that spleen volumes in patients with bacteraemia caused by encapsulated organisms were smaller in the non-survive group than in the group who survived.[11] There is an indication that in an atrophied spleen there is a reduction of macrophages in the marginal zone of the spleen, leading to immune dysfunction.[5,6] The spleen has an important role in the humoral immune response, especially in the formation of antibodies against bacteria with a polysaccharide capsule (e.g. C. canimorsus).[12,13] In patients with asplenia or functional hyposplenism as a result of various systemic conditions there is an increased risk for severe infections, often described as ‘overwhelming post splenectomy infection’ (OPSI).
In both of our cases the spleen was considered small on CT scan. We were not informed about the possibility of functional hyposplenism in our patients and a smear of peripheral blood was not performed on admission. When Howell-Jolly bodies are present in the red blood cells in a smear, this is pathognomonic for splenic dysfunction although it has a low sensitivity.[12,14] Based on the severity of the fulminant presentation combined with the small splenic size both patients were referred for vaccination and prophylactic/on demand antibiotic therapy according to the hyposplenism guideline.[12]
Mortality
In immunocompetent hosts C. canimorsus can cause high-grade bacteraemia and fatal disease. In the literature sepsis is a strong independent risk factor of fatality and in immune competent hosts mortality is up to 30%.[7] In patients with sepsis mortality is up to 55.7%.[7] Mortality in the immunocompromised group is even higher but also dependent on comorbidities, poorer baseline clinical status, polymicrobial infections and overall decreased survival regarding the underlying (often haematological) disease.[4]
Treatment
Early (surgical) wound cleaning and prophylactic antibiotic use after an animal bite reduces the number of pathogens and the evolution to sepsis and thereby reduces mortality. Therefore, it is recommended to prescribe a beta-lactam antibiotic in combination with a beta-lactamase inhibitor in patients with bite or scratch wounds from a dog or cat, especially in patients with risk factors. The beta-lactamase inhibitor is necessary to cover for other anaerobic flora that often accompany these wounds.[7,15] Furthermore, patients with asplenia or hyposplenism should be instructed to use their on-demand antibiotics immediately and it is strongly advised to treat them with antibiotics for one week after a dog or cat bite.[12] Further therapy in case of septic shock and multi-organ failure caused by C. canimorsus is mostly supportive.
An interesting finding is that amid the global COVID-19 pandemic, there have been several case reports about patients admitted to hospital with COVID-19 who had a concurrent bacteraemia with C. canimorsus (sometimes diagnosed post-mortem). Possibly, as a result of social isolation during the pandemic, there is more human-pet contact (more people have got themselves a pet to have a reason to go outside in times of curfews) and thus an increased predisposition for infection with C. canimorsus or other zoonoses.[16,17]
Conclusion
An infection with C. canimorsus can cause a diverse range of clinical symptoms and one should be aware of it in patients presenting with signs of septic shock. When there is no other possible cause or source rapidly identified, one should look for close contact with cats or dogs, also in an immunocompetent host and in absence of a distinct dog or cat bite. C. canimorsus is a slow-growing micro-organism in blood cultures and therefore microscopic examination of a blood smear can be of diagnostic value in suspected patients. If there is indeed a C. canimorsus sepsis in a patient with possible hyposplenism, this can be a reason for further diagnostics and treatment (vaccinations and/or on-demand antibiotics).
Disclosures
All authors declare no conflict of interest. No funding or financial support was received.
Informed consent was obtained from the patients for the publication of this case report and the accompanying images.
References:
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- Bobo RA, Newton EJ. A previously undescribed gram-negative bacillus causing septicemia and meningitis. Am J Clin Pathol. 1976;65:564-9.
- Hansen M, Crum-Cianflone NF. Capnocytophaga canimorsus Meningitis: Diagnosis Using Polymerase Chain Reaction Testing and Systematic Review of the Literature. Infect Dis Ther. 2019;8:119-36.
- Chesdachai S, Tai DBG, Yetmar ZA, Misra A, Ough N, Abu Saleh O. The Characteristics of Capnocytophaga Infection: 10 Years of Experience. Open Forum Infect Dis. 2021;8:ofab175
- Shin H, Mally M, Kuhn M, Paroz C, Cornelis GR. Escape from immune surveillance by Capnocytophaga canimorsus. J Infect Dis. 2007;195:375-86.
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- Ehrbar HU, Gubler J, Harbarth S, Hirschel B. Capnocytophaga canimorsus sepsis complicated by myocardial infarction in two patients with normal coronary arteries. Clin Infect Dis. 1996;23:335-6.
- Harris KA, Hartley JC. Development of broad-range 16S rDNA PCR for use in the routine diagnostic clinical microbiology service. J Med Microbiol. 2003;52:685-91.
- Shimoyama K, Azuma K, Nakamura I, Oda J. Prediction of the prognosis of patients with bacteremia caused by encapsulated organisms using spleen volume: A retrospective study. Acute Med Surg. 2021;8:e698.
- Richtlijn Asplenie Rijksinstituut voor Volksgezondheid en Milieu, versie 2018, (Accessed Februari 2022, https://lci.rivm.nl/richtlijnen/asplenie)
- Renzi F, Ittig SJ, Sadovskaya I, et al. Evidence for a LOS and a capsular polysaccharide in Capnocytophaga canimorsus. Sci Rep. 2016;6:38914
- Mathew H, Dittus C, Malek A, Negroiu A. Howell-Jolly bodies on peripheral smear leading to the diagnosis of congenital hyposplenism in a patient with septic shock. Clin Case Rep. 2015;3:714-7.
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