The Great pretender: the first case of septic shock due to Capnocytophaga canimorsus in Sardinia. A Case report and review of the literature

Abstract

Capnocytophaga canimorsus (C. canimorsus) is an emerging pathogen in critical care. C. canimorsus is a Gram-negative bacillus, commonly isolated as a commensal microorganism of the oral flora of healthy dogs and cats. A 63-year-old woman came to the emergency department with fever, chills, and malaise 2 days after a minor dog bite. After admission to the medicine ward, she developed respiratory failure and livedo reticularis. In the intensive care unit (ICU), she presented full-blown septic shock with thrombocytopenia, coagulopathy, severe acute kidney injury, and liver injury. We describe the first case of septic shock with Multiple Organ Dysfunction Syndrome related to Capnocytophaga canimorsus infection in Sardinia and its treatment in a tertiary hospital ICU. We also review recent literature on the relevance of C. canimorsus in human disease and critical illness.

Introduction

In 1976 Bobo and Newton published a case report describing the isolation of a new Gram-negative bacillus in a cerebrospinal fluid sample from a man who developed meningitis and sepsis after bites of dogs.¹ A subsequent report of 17 cases confirmed the causative role of this Gram-negative rod in human disease.² Due to its slow growth, the United States Centers for Disease Control and Prevention (CDC) classified it in group DF-2 as a “dysgonic fermenter.” In 1989 Brenner et al. proposed to reclassify the DF-2 group as a new species called Capnocytophaga canimorsus.³ This suggestive name refers to the specific requirement of a carbon dioxide-enriched environment for growth and its main way of transmission in human disease, that is, dog bite.³

After these case reports, Capnocytophaga canimorsus has been recognized as an uncommon but increasingly significant pathogen associated with severe sepsis and septic shock.

We present the first case of septic shock related to Capnocytophaga canimorsus in Sardinia and its management in a tertiary hospital intensive care unit (ICU) and review the recent literature on the pathogenesis and critical illness caused by C. canimorsus.

Case report

A 63-year-old woman came to the emergency department with a chief complaint of acute onset fever (tympanic temperature 39.9°C) with chills and malaise. She was beclouded and tachypnoeic. Her history was notable for cigarette smoking and a previous breast cancer resection.

She suffered a recent dog hand bite 2 days before presentation. Laboratory values at arrival showed: creatinine 1.22 mg/dl, lactate dehydrogenase (LDH) 298, AST 115, ALT 54 U/l, hyponatremia 130 mmol/l, hyposmolality 265 mOsm/kg, PaO₂/FiO₂ ratio (P/F) 246 mmHg. Computerized tomography showed bilateral basal hyperdensities of the lungs. Two sets of peripheral blood were collected for microbiological diagnosis.

She was admitted to the medicine department with a diagnosis of pneumonia and began empirical antibiotic therapy with levofloxacin (Sequential Organ Failure Assessment Score, SOFA 5).

The following day, she developed thrombocytopenia, acute kidney injury (AKI), livedo reticularis, arterial hypotension, and acute hypoxemic respiratory failure with high serum procalcitonin (79.7 ng/ml). The Gram staining of the blood culture showed thin and slender Gram-negative rods, so she started an empirical course of meropenem (Figure 1). The patient was admitted to the ICU and intubated. Her condition rapidly worsened to full-blown septic shock (SOFA 21) with severe lactic acidosis (pH 6.7, lactate 17 mmol/l). She required high-dose inotropic support (norepinephrine 0.5–1 μg/kg/min) and continuous mandatory mechanical ventilation (P/F 90). She was also administered hydrocortisone 200 mg/die. Her AKI stage was 3 according to Kidney Disease: Improving Global Outcomes classification due to anuria and a serum creatinine of 3.91 mg/dl, so she underwent renal replacement therapy using continuous venovenous hemodialysis (CVVHD) with a high cutoff and high flux hemofilter (Ultraflux EMiC2, Fresenius, Germany) under citrate anticoagulation. After 72 h, this strategy improved hemodynamics, gas exchange, and level of consciousness.

Figure 1.

Direct Gram stain of blood culture. This picture shows the Gram-negative slender rods isolated from our patient culture bottle.

On the fourth day of ICU stay, she developed rhabdomyolysis and liver injury (Figure 2). Severe thrombocytopenia (Figure 2) and coagulopathy required fresh frozen plasma and platelet transfusion under thromboelastographic guidance. Livedo reticularis worsened to a frank purpura, with ischemia of the limbs (Figure 3).

Figure 2.

Main laboratory findings during ICU stay. This picture shows six plots that illustrate serum creatinine (panel A), serum alanine aminotransferase (panel B), blood urea nitrogen (panel C), platelets count (panel D), serum creatine phosphokinase (panel E), seru m procalcitonin (panel F) on the y axis and the day of ICU stay on the x-axis.

Abbreviations: ICU: Intensive Care Unit; mg: milligram; dl: deciliter; U: international units; L: liter; ng: nanograms.

Figure 3.

Physical findings. This picture shows the purpuric skin lesions in different anatomic locations: left hand (panel A), thighs (panel B), right hand (panel C).

The microbiological diagnosis of this case began with the analysis of blood cultures using the automated BacT / ALERT system (bioMérieux, Marcy l’Etoile, France).

A sample of blood was then plated on blood agar and chocolate agar. After 1 week, the culture became positive. A sample from a direct smear of bacterial colonies was then analyzed by the MALDI Biotyper (Bruker, Germany). The MALDI biotyper provided a specific proteomic spectrum fingerprint for C. canimorsus. On the seventh day, she started ampicillin-sulbactam and ceftriaxone. After the resolution of the critical illness, we received the antibiogram. The isolated strain was sensitive to amoxicillin with clavulanic acid, ticarcillin with clavulanic acid, piperacillin, imipenem, cefoxitin, moxifloxacin, rifampin, chloramphenicol, while it was resistant to penicillin G, amoxicillin, clindamycin, vancomycin, metronidazole.

After 2 weeks of stay in the ICU, she was transferred to a facility near her hometown, where she underwent surgical amputation of her finger in the hand, ie, the site of the dog bite, and both inferior limbs below the knees. Eight months after her critical illness, she still required intermittent hemodialysis for end-stage renal disease.

The microbiological diagnosis of this case began with the analysis of blood cultures using the automated BacT/ALERT system (bioMérieux, Marcy l’Etoile, France).

A sample of blood was then plated on blood agar and chocolate agar. After 1 week, the culture became positive. A sample from a direct smear of bacterial colonies was then analyzed by the MALDI Biotyper (Bruker, Germany). The MALDI Biotyper provided a specific proteomic spectrum fingerprint for C. canimorsus.

Review of the literature

We searched the MEDLINE^® database using the medical subject headings term Capnocytophaga to retrieve pertinent studies on the microbiology, pathogenesis, and clinical manifestation of C. canimorsus in human patients. We did not enforce any language restriction. The genus Capnocytophaga was originally isolated from the human oral cavity and is made of Gram-negative, nonflagellated, fermentative, and capnophilic bacteria (5%–10% of carbon dioxide in growth medium) that exhibit glide motility. C. canimorsus appear as long, thin, filamentous, spindle-shaped cells in blood Agar plates.³

It is a common commensal species of the oral flora of dogs and cats and can be isolated in 21%–73% of oropharyngeal swabs from dogs.^4,5

C. canimorsus feeds on N-acetyl glucosamine and N-acetyl galactosamine from host cell glycoproteins (epithelial and macrophage cells), and the presence of macrophages increases bacterial growth.^{6 –8} The same surface N-glycan glycoprotein deglycosylation complex can also deglycosilate human immunoglobulin G (IgG) and modify the affinity of IgG for its Fc receptor.^8,9

C. canimorsus can also prevent effective secretion of pro-inflammatory cytokines such as nitric oxide, IL-1 α, IL-6, or TNFα, maybe through active production of a factor capable of complete dephosphorylation of the p38 mitogen-activated protein kinase and a peculiar lipopolysaccharide structure.^8,10

Evidence of resistance to phagocytic killing and feeding on macrophage glycoproteins may represent an essential factor not only for commensalism, but also for pathogenesis.^6,8

Host factors can determine the vulnerability to C. canimorsus infection, such as asplenia, hyposplenism, alcohol abuse, and malignancy, supported by the disproportionately low incidence of C. canimorsus sepsis despite widespread exposure to dog or cat saliva in the general population.¹¹

Butler’s comprehensive review included all microbiologically confirmed cases of C. canimorsus infection and an estimated 484 clinical cases with a lethality rate of 26%.¹¹

The same review listed 30 cases of septic shock and 18 cases of digital or limb gangrene in the period.¹¹

In Supplemental Table and Figure 4 we summarized (1990–2022, up to April 25, 2022) case reports and case series describing C. canimorsus infection in human patients, with a focus on clinical course, outcome, organ failure, risk factors for C. canimorsus infection (i.e. bites, scratching, or close contacts with dogs or cats), immunosuppressed status (i.e. alcohol abuse, asplenia, corticosteroid therapy, methotrexate, immunosuppression malignancy).

Figure 4.

Bar chart of organ failures described in published case reports and series. This graph shows how many papers described each type of organ injury or failure.

In the period 1990–2022, 125 articles described 207 cases of C. canimorsus infection (Supplemental Table).^{12 –137}

Forty-seven studies described 73 cases of severe sepsis or septic shock, with 31% case fatality (see Supplemental Table). Despite the importance of risk factors for the development of severe C. canimorsus infection, 33 patients were not immunocompromised.

Treatment of organ failures was not always described in detail in case reports, probably for editorial reasons and also because some patients died briefly after the first clinical manifestations of infection.^{57,63,78,90,91}

Furthermore, septic shock from C. canimorsus does not appear to require other specific treatments than those reported in current septic shock guidelines.

The most severe cases showed a high prevalence of acute kidney injury (60 reports). Renal replacement therapy was the most described therapy.^{52,55,67,70,80,89}

Feige et al. reported the use of renal replacement therapy with regional anticoagulation, to manage the rapid development of severe AKI with significant metabolic derangement, hemodynamic instability, and coagulopathy.⁸⁹

Coagulopathy is common in the setting of severe sepsis or septic shock of C. canimorsus (67 reports).

Furthermore, two case reports described the atypical hemolytic uremic syndrome and the Shwartzman reaction related to septic shock of C. canimorsus with their specific treatments, eculizumab (humanized monoclonal IgG anti-C5), and nebacumab (antilipid A IgG), respectively.^55,80

Irreversible limb or digit ischemia was described in association with severe sepsis or septic shock (22 reports), suggesting significant microcirculation injury as one of the main pathophysiological mechanisms of systemic C. canimorsus infection.

We suppose that the published literature provided an underestimation of the relevance of this pathogen, due to its difficult microbiological diagnosis and fulminant course in the most severe cases, which can misleadingly suggest a more common etiologic agent, such as Neisseria meningitidis. The published literature offers some descriptions of purulent cases of meningitis caused by C. canimorsus, whose identification was possible by broad-range polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) or 16S ribosomal RNA amplification from blood and CSF samples^72,128,138

Capnocytophaga canimorsus is a rare cause of endocarditis and it is particularly rare in immunocompetent hosts.^85,92,122 These cases of endocarditis share a common factor: the difficult process of microorganism isolation that occurred after many blood cultures or after PCR analysis of valvular tissue.

C. canimorsus infection can cause direct macrovascular damage, including single or multiple mycotic aneurysms.^{69,109,124,139} These aneurysms may present with rupture and hemodynamic instability or have a quite indolent course, resolving after surgical, and antibiotic treatment.

C. canimorsus infection may also display nonspecific skin changes, such as multiple erythematous macules, erythema annulare centrifugum, or urticaria.^111,127

C. canimorsus has also been isolated in conjunction with Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.^110,126

These case studies are important reminders to consider co-infection or super-infection by less common pathogens in patients with coronavirus disease 2019 (Covid-19). Furthermore, in the pandemic era, the diagnosis of SARS-CoV-2 infection is straightforward and has important consequences, such as that it may prompt significant changes in allocation and management, such as isolation wards and immunomodulatory therapies.

In this setting, the diagnosis of Covid-19 may overshadow rarer infections, including C. canimorsus.

As a confirmation of this, a case of C- canimorsus fulminant septic shock in a SARS-CoV-2 positive patient was diagnosed postmortem.¹²⁶

Conclusions

The case we presented is the first description of a septic shock with multiple organ dysfunction syndrome in an immunocompetent patient caused by C. canimorsus in Sardinia.

According to the data presented, both healthy and immunosuppressed hosts can rapidly develop a severe septic syndrome characterized by a high incidence of AKI, coagulopathy, and cardiovascular instability. C. canimorsus infection should always be suspected in the differential diagnosis of Gram-negative sepsis, and risk factors, such as immunocompromised status and exposure to pets, should not be overlooked. Despite the absence of a specific therapy or the limited relevance of antibiotic resistance in C. canimorsus, the clinical suspect of this infection must induce to treat aggressively in the ICU due to its rapid course. According to our experience and the published literature, the most alarming signs, such as purpura, rapid worsening of respiratory and renal failure, should be interpreted as the clinical manifestation of systemic microvascular damage due to C. canimorsus.

No other case report described the use of a high cutoff filter in septic shock from C. canimorsus, but in our experience, it could be the best option to address AKI and the accumulation of myoglobin, cytokines, and interleukins.^140,141 Considering the frequent occurrence of severe coagulopathy, we suggest early placement of a large-bore hemodialysis catheter in a compressible site.

Furthermore, we believe that a more widespread adoption of antibiotic prophylaxis after high-risk bite injuries could contribute significantly to reducing the incidence of C. canimorsus infection.

Our case report and review of the literature confirm the role of Capnocytophaga canimorsus as an emerging cause of septic shock and multiorgan failure. Our article aims to add a little piece to the enormous amount of collective experience on this increasingly important pathogen and to raise awareness of this uncommon species among intensivists. Given the proteiform manifestations of Capnocytophaga canimorsus, as demonstrated by the published literature, this pathogen should be on the differential diagnosis list of every clinician, even during the SARS-CoV-2 pandemic. This experience was so important to our group that we correctly identified a second case the following year, which resulted in an early diagnosis (data are not presented because we did not obtain patient consent to add this case to our report). Our take-home messages for intensivists are always suspect C. canimorsus in rapidly evolving sepsis/septic shock, proactively investigate its presence, and consider early renal replacement therapy, especially in those patients who show clinical signs of microvascular damage.