Capnocytophaga canimorsus infection was recently recognized as a zoonosis. We report the first case of fulminant septic shock in Italy caused by this pathogen. The patient, with a history of splenectomy, died at the main hospital in Brescia with a presumptive diagnosis of sepsis. PCR and sequencing on post mortem samples confirmed C. canimorsus as a causative organism. Our purpose is to alert medical professionals to the virulence of C. canimorsus in asplenic and immunocompromised patients. Keywords: Capnocytophaga canimorsus, septic shock, PCR, sequencin

Andrea Tironi

Arnaldo Caruso

Elena De Peri

Fabio Facchetti

Francesca Caccuri

Francesco Castelli

Franco Gargiulo

Giorgio Piccinelli

Lucia Dora Notarangelo

Nicola Latronico

Silvia Odolini

International Journal of Infectious Diseases

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Fulminant septic shock caused by  Capnocytophaga canimorsus  in Italy: Case report

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International Journal of Infectious Diseases 72 (2018) 3–5Case ReportFulminant septic shock caused by Capnocytophaga canimorsus in Italy:Case reportGiorgio Piccinellia, Francesca Caccuria, Elena De Perib, Andrea Tironic, Silvia Odolinid,Lucia Dora Notarangeloe, Franco Gargiuloa, Francesco Castellid, Nicola Latronicob,Fabio Facchettic, Arnaldo Carusoa,*a Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, and ASST-Spedali Civili, Brescia, Italyb Section of Anesthesia and Critical Care Medicine, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, and ASST-SpedaliCivili, Brescia, Italyc Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, and ASST-Spedali Civili, Brescia, Italyd Section of Infectious and Tropical Diseases, Department of Clinical and Experimental Sciences, University of Brescia, and ASST-Spedali Civili, Brescia, ItalyeUnit of Pediatric Onco-Hematology, ASST-Spedali Civili, Brescia, ItalyA R T I C L E I N F OArticle history:Received 20 March 2018Received in revised form 24 April 2018Accepted 26 April 2018Corresponding Editor:Eskild Petersen, Aarhus, DenmarkKeywords:Capnocytophaga canimorsusseptic shockPCRsequencingA B S T R A C TCapnocytophaga canimorsus infection was recently recognized as a zoonosis. We report the first case offulminant septic shock in Italy caused by this pathogen. The patient, with a history of splenectomy, died atthe main hospital in Brescia with a presumptive diagnosis of sepsis. PCR and sequencing on post mortemsamples confirmed C. canimorsus as a causative organism. Our purpose is to alert medical professionals tothe virulence of C. canimorsus in asplenic and immunocompromised patients.© 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Contents lists available at ScienceDirectInternational Journal of Infectious Diseasesjournal home page: www.elsevier .com/ locat e/ i j idIntroductionCapnocytophaga canimorsus is a commensal microorganismpresent in the oral cavity of different animals, including dogs andcats. It can be transmitted to humans by pets’ bites, scratches andlicks. In immune competent individuals infections are usuallyasymptomatic, whereas patients with immune suppression and/orasplenia are at high risk of severe infections such as sepsis,meningitis, endocarditis and pneumonia (Butler, 2015). Fatal septicshock caused by C. canimorsus infection has only been rarelyreported (Zazula et al., 2015). Here we describe, for the first time inItaly, a case of C. canimorsus-related fulminant septic shock.Case reportIn November 2017, at 2 p.m., a 22-year-old man with a history ofspherocytosis and splenectomy (at the age of 11) was admitted at* Corresponding author at: Section of Microbiology, Department of Molecularand Translational Medicine, University of Brescia, Piazza Spedali Civili, 1 – 25123Brescia, Italy.E-mail address: arnaldo.caruso@unibs.it (A. Caruso).https://doi.org/10.1016/j.ijid.2018.04.43191201-9712/© 2018 The Author(s). Published by Elsevier Ltd on behalf of International Solicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).the Emergency Department of the main hospital in Brescia. Onadmission, he declared that the first symptoms occurred earlierthan 20–24 h. He was awake and oriented, and presented withheadache, vomiting, muscle pain, fever (39 C) and facial petechiaeappeared 3–4 h before admission and rapidly spreading to thetrunk and limbs. A septic shock was suspected. His conditionrapidly worsened, requiring urgent hospital admission. At 2:40 p.m., upon arrival to the Intensive Care Unit (ICU), he had severearterial hypotension with absent peripheral pulse, heart rate of150/min, and marked tachypnea (respiratory rate of 30–35breaths/min). Arterial blood gas analysis revealed severe metabolicacidosis with hyperlactatemia (pH 7.1; lactates 10.5 mmol/L). Afterinvasive monitoring position, the first blood pressure was 60/40.Laboratory tests on blood showed the following results: acute-phase protein C: 127 mg/L, creatinine: 3.58 mg/dl, total bilirubin:3.33 mg/dl, alanine aminotransferase: 97 U/L, leukocytosis:(15.620/ml). Moreover, blood analysis showed hemoconcentration,with hemoglobin concentration of 20.1 g/dl, and coagulopathywith unmeasurable PT and PTT due to undetectable fibrinogen andsevere thrombocytopenia (18.000/ml). In the ICU, the provisionaldiagnosis was septic shock of unknown cause. The patient wasanuric and severely hypoxic with undetectable oxygen saturationat pulse oximetry despite aggressive intravenous fluidciety for Infectious Diseases. This is an open access article under the CC BY-NC-ND4 G. Piccinelli et al. / International Journal of Infectious Diseases 72 (2018) 3–5resuscitation and oxygen therapy. At clinical examination, therewas intense peripheral vasoconstriction, marked cyanosis of theextremities and confluent petechiae all over the body.According to clinical presentation meningococcal sepsis diag-nosis was supposed, blood was drawn for blood culture and PCRdiagnosis of the potential pathogens, and treatment withceftriaxone (3 g) was initiated. Severe hypotension persisteddespite high-dose, continuous i.v. infusion of noradrenaline andbicarbonate followed by adrenaline, terlipressin, and hydrocorti-sone. Despite emergent tracheal intubation and mechanicalventilation with 100% oxygen, the patient developed plasmaextravasation with massive pulmonary edema and edema of thetrunk and extremities. Bradycardia ensued rapidly followed bycardiac arrest refractory to cardiopulmonary resuscitation. At 5 p.m. the patient was declared dead.A Gram stain of blood was negative, as well as serum-solubleantigens for Neisseria meningitides (group A,B,C,Y and W135),Haemophilus influenza, Streptococcus pneumoniae, Streptococcusagalactiae, Listeria monocytogenes, and Escherichia coli K1. PCRanalysis excluded the presence of Neisseria meningitidis, Haemo-philus influenzae or Streptococcus pneumoniae in the blood sample.Blood cultures under aerobic and anaerobic condition showed nogrowth of bacteria.Post-mortem examination revealed cutaneous purpura withdiffuse petechiae, bilateral pleural and pericardial effusion,massive lung edema, gastrointestinal hemorrhage involving thestomach and duodenum and massive bilateral adrenal hemor-rhagic necrosis. On histology, skin lesions showed intraluminalfibrin deposits corresponding to intravascular coagulation (Figure1A); similar findings were observed in several other tissues. Thebone marrow showed numerous macrophages containing redblood and nucleated cells in their cytoplasm, indicating hemo-phagocytosis (Figure 1B). Similar, albeit less pronounced, featuresoccurred in Kupffer cells and lung macrophages. Numerousgranulocytes were found in the liver sinusoids and lunginterstitium, suggestive for a septic status; overt abscesses wereundetectable. No pathogens were identified on Gram stain.Meninges were normal. Anatomical diagnosis revealed hemopha-gocytosis, disseminated intravascular coagulation, bilateral adre-nal hemorrhagic necrosis and gastrointestinal hemorrhage.Conventional blood culture broth of post-mortem intracardiacblood, pleural liquid and cerebral ventricular fluid samples werenegative. The suspected infectious etiology of the shock wasconfirmed by the detection of the pathogen in all post-mortem-collected fluids by sequencing of the 16S ribosomal RNA genes andidentifying C. canimorsus (628-bp amplification product with 100%identity with strain CcD131 on Basic Local Alignment Search Tool)(Bémer et al., 2014). The same samples were subjected to PCR andsequencing by using C. canimorsus specific primers (Suzuki et al.,Figure 1. (A) Skin biopsy showing intravascular fibrin deposits (arrows), with partial ocwith intracytoplasmic red cells and nucleated cells (arrows), (Haematoxylin/Eosin).2010). Data obtained confirmed the presence of C. canimorsus in alltested samples (100% identity with the strain CcD131).The patient did not show any sign of animal scratches or bites.However, since the patient owned a dog as pet, pharyngeal swabsand saliva samples were collected from the animal and subjectedto molecular analysis. PCR and sequencing confirmed the presenceof C. canimorsus in all tested dog samples.DiscussionC. canimorsus is a commensal rod shaped Gram negativebacterium hosted in the oral cavity of different domestic pets. Themicroorganism is transmitted to humans by animal bites, scratchesand licks. In case of occurrence of risk factors, such as asplenia, longhistory of alcohol abuse, cirrhosis, immunosuppressive therapy,the infection may have serious consequences. The most commonpresentation in risky patients is sepsis, meningitis, osteomyelitis,peritonitis, endocarditis, pneumonia or septic arthritis (Gaastraand Lipman, 2010; Griego et al., 1995). All over the world, 81 casesof fatal C. canimorsus infection over 484 total documented caseshave been reported from 1961 to 2014, with a higher incidence inUSA, The Netherlands, Denmark and France (Butler, 2015). C.canimorsus is one of the most lethal of sepsis pathogens everdescribed, with its estimated-fatality rate of about 26% (Butler,2015). Patients with asplenia are more prone to overwhelminginfection due to encapsulated organisms which can progressrapidly and can be fatal (Dudley et al., 2006). This implicates thatspleen is a key organ for protection against C. canimorsus infection.Splenic macrophages in the red pulp are important cells of theinnate immune system for removing bacteria from the blood. In C.canimorsus sepsis, which can develop as fast as one day after a dogbite, it is clearly the early phagocytosis of the innate immunesystem that has failed because specific antibody requires a longertime to develop. For patients with spleen, splenic function may bedepressed by immunosuppressive therapies, irradiation, alcohol-ism or other diseases (Oehler et al., 2009). The recognition of C.canimorsus as the cause of severe infections after pet exposuredepends on improved laboratory methods for the identification ofthis fastidious bacterium in clinical samples. Our case is the firstItalian clinical report of a fulminant fatal sepsis caused by C.canimorsus. Only a few invasive C. canimorsus infections have beenreported in Italy up to date. It is worth noting that these occurred inapparently immunocompetent patients who recovered fromendocarditis (Frigiola et al., 2003), brain abscess (Ulivieri et al.,2008), septic shock and meningitis (Bertin et al., 2018).Capnocytophaga species are regarded as difficult to culturebecause of their specific requirements for nutrients and long-termincubation to observe growth and colony formation. Often, themicroorganism cannot be detected by standard laboratoryclusion of the lumen (Haematoxylin/Eosin). (B) Bone marrow shows macrophagesG. Piccinelli et al. / International Journal of Infectious Diseases 72 (2018) 3–5 5methods. Our diagnosis has been based on an accurate molecularmethod of bacteria identification. We first obtained a pure PCRproduct using universal 16S rRNA primers that was sequenced andaligned against bacterial DNA database. Then we confirmed thepresence of C. canimorsus in clinical samples by using a species-specific set of primers. C. canimorsus is an unexpected bacteriumand to a certain extent, unknown in ICU and in the diagnosticlaboratory practice. PCR diagnostics provided clear and robustevidence of the causative organism, which would not be identifiedby using standard laboratory methods. Therefore, we believe itrepresents a useful and rapid tool for pathogen detection inselected cases of sepsis of unknown etiology.Incidence of C. canimorsus infection is expected to increase overtime because of a rising incidence of splenectomy due to injuriesand accidents, or to impaired immune responses due to a highprevalence of alcoholism, immunosuppressive therapies, aging ofhuman population, together with popularity of pet ownership dueto a public perception of their safety. In particular, preventivestrategies in reducing post-splenectomy infections include educa-tion, immunoprophylaxis and chemoprophylaxis. The potentialseriousness of post-splenectomy sepsis and rapid time course ofprogression should be explained to patients who also have to beinstructed to seek immediate medical attention in the event of anyacute febrile illness. Further, patients should be educated about therisk of C. canimorsus through animal contact.Research has recently demonstrated that animal-assistedtherapy can yield many positive outcomes for hospitalizedpatients’ well-being (Lundqvist et al., 2017). Animal therapy isbecoming more and more popular, with hospitals letting petsvisiting their sick owners. C. canimorsus infection is an extremelyrare event. However, this possibility should be considered withcaution whenever severely compromised immunity is suspected.Funding sourcesThe authors declare that they have no funding sources toacknowledge.Conflict of interestThe authors declare that they have no competing interests.Ethical approvalThe authors declare that the ethical approval was not requiredfor this studyReferencesBémer P, Plouzeau C, Tande D, Léger J, Giraudeau B, Valentin AS, et al. Evaluation of16S rRNA gene PCR sensitivity and specificity for diagnosis of prosthetic jointinfection: a prospective multicenter cross-sectional study. J Clin Microbiol2014;52(10):3583–9.Bertin N, Brosolo G, Pistola F, Pelizzo F, Marini C, Pertoldi F, et al. Capnocytophagacanimorsus: an emerging pathogen in immunocompetent patients-experiencefrom an emergency department. J Emerg Med 2018;, doi:http://dx.doi.org/10.1016/j.jemermed.2018.01.042 [Epub ahead of print].Butler T. Capnocytophaga canimorsus: an emerging cause of sepsis, meningitis, andpost-splenectomy infection after dog bites. Eur J Clin Microbiol Infect Dis2015;34(7):1271–80.Dudley MH, Czarnecki LA, Wells MA. Fatal capnocytophaga infection associatedwith splenectomy. J Forensic Sci 2006;51(3):664–6.Frigiola A, Badia T, Lovato R, Cogo A, Fugazzaro MP, Lovisetto R, et al. Infectiveendocarditis due to Capnocytophaga canimorsus. Ital Heart J 2003;4(10):725–7.Gaastra W, Lipman LJ. Capnocytophaga canimorsus. Vet Microbiol 2010;140(3–4):339–46.Griego RD, Rosen T, Orengo IF, Wolf JE. Dog, cat, and human bites: a review. J AmAcad Dermatol 1995;33(6):1019–29.Lundqvist M, Carlsson P, Sjödahl R, Theodorsson E, Levin LÅ. Patient benefit of dog-assisted interventions in health care: a systematic review. BMC ComplementAltern Med 2017;17(1):358.Oehler RL, Velez AP, Mizrachi M, Lamarche J, Gompf S. Bite-related and septicsyndromes caused by cats and dogs. Lancet Infect Dis 2009;9(7):439–47.Suzuki M, Kimura M, Imaoka K, Yamada A. Prevalence of Capnocytophaga canimorsusand Capnocytophaga cynodegmi in dogs and cats determined by using a newlyestablished species-specific PCR. Vet Microbiol 2010;144(1-2):172–6.Ulivieri S, Oliveri G, Filosomi G. A case of Capnocytophaga canimorsus brain abscesssecondary to dog’s bite. G Chir 2008;29(3):79–80.Zazula R, Prucha M, Moravec M, Valeska F. Capnocytophaga canimorsus: rare cause offatal septic shock. Case report. Clin Microbiol 2015;4:4, doi:http://dx.doi.org/10.4172/2327-5073.1000217.

Fulminant septic shock caused by Capnocytophaga canimorsus in Italy: Case report

Capnocytophaga canimorsus infection was recently recognized as a zoonosis. We report the first case of fulminant septic shock in Italy caused by this pathogen. The patient, with a history of splenectomy, died at the main hospital in Brescia with a presumptive diagnosis of sepsis. PCR and sequencing on post mortem samples confirmed C. canimorsus as a causative organism. Our purpose is to alert medical professionals to the virulence of C. canimorsus in asplenic and immunocompromised patients

Fulminant septic shock caused by Capnocytophaga canimorsus in Italy: Case report

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