Vidal et al. BMC Infectious Diseases (2019) 19:302 https://doi.org/10.1186/s12879-019-3933-3

CASE REPORT Open Access Fulminant arterial vasculitis as an unusual complication of disseminated staphylococcal disease due to the emerging CC1 methicillin-susceptible clone: a case report Charles Vidal1, Florence Moulin2, Xavier Nassif1, Louise Galmiche3, Delphine Borgel4, Alain Charbit5, Capucine Picard6,7, Jean-Paul Mira8,9, Olivier Lortholary10, Anne Jamet1,5 and Julie Toubiana9,11*

Abstract Background: Staphylococcus aureus has emerged as a leading cause of invasive severe diseases with a high rate of morbidity and mortality worldwide. The wide spectrum of clinical manifestations and outcome observed in staphylococcal illness may be a consequence of both microbial factors and variability of the host immune response. Case presentation: A 14-years old child developed limb ischemia with gangrene following S. aureus bloodstream infection. Histopathology revealed medium-sized arterial vasculitis. The causing strain belonged to the emerging clone CC1-MSSA and numerous pathogenesis-related genes were identified. Patient’s genotyping revealed functional variants associated with severe infections. A combination of virulence and host factors might explain this unique severe form of staphylococcal disease. Conclusion: A combination of virulence and genetic host factors might explain this unique severe form of staphylococcal disease. Keywords: S. aureus, Sepsis, Vasculitis, Virulence, Genetic susceptibility, Polymorphism, Case report

Background inflammatory cytokines through TLR2 pathway activa- Staphylococcus aureus is a major human pathogen and a tion in innate immune cells [2]. S. aureus also contains global healthcare issue. Humans are a natural reservoir several toxins that are able to potentiate host- of S. aureus, which can occasionally cause diseases that inflammatory response, target and injure leukocytes and range in severity from minor skin infections to severe tissues, and inhibit bacterial clearance [3]. Finally, S. aureus cases of pneumonia, bacteremia and septic shock [1]. avidly adheres to endothelial cells and platelet-fibrin The severity and outcome of the infection relies on bac- thrombi involved in the physiopathology of endocarditis or terial virulence, as S. aureus is known to have a wide ar- thrombophlebitis [4]. Recently, the role of genetic factors senal of components that contribute to the pathogenesis of the host has been extensively studied, revealing their in- of infection. S. aureus is the cause of septic shock fluence on the susceptibility to or the severity of sepsis. through cell wall components eliciting production of Rare monogenic inborn errors of immunity were found to predispose to severe infectious diseases, such as mutations * Correspondence: [email protected] that impair NF-κB responses [5]. In parallel, common vari- 9Department of Infection, Immunity and Inflammation, Institut Cochin, ants of genes involved in innate immune response, inflam- INSERM U1016, Paris, EU, France 11Department of General Pediatrics and Pediatric Infectious Diseases, Necker mation and coagulation during sepsis were found to be Enfants-Malades Hospital, APHP, Paris Descartes University, 149 rue de Sèvres, associated with severity of bacterial infections [6, 7]. We 75015 Paris, EU, France report here a severe and atypical phenotype of infection Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Vidal et al. BMC Infectious Diseases (2019) 19:302 Page 2 of 5

due to S. aureus. The young patient developed medium- destroyed and the walls were invaded by Gram-positive sized arterial infectious vasculitis that led to ischemia and cocci with subsequent thrombosis (Fig. 1candd). gangrene. We intended to decipher pathogen and host fac- In order to decipher mechanisms underlying these tors that could explain this dramatic presentation. clinical and histopathological findings, pathogen viru- lence and host factors were analyzed. A whole- Case presentation genome shotgun library was prepared with Nextera Clinical case XT Kit (Illumina, San Diego, CA, USA) and se- The patient was a 14-year-old male child without notable quenced on the MiSeq Illumina sequencing platform past medical history and no recent travel. On admission, (2 × 150 bp paired-end reads). All reads were screened he had fever, lethargy and diarrhea, and physical examin- by mapping to known alleles of virulence genes using ation revealed fever (39 °C), tachycardia, blood pressure the Short Read Sequence Typing for Bacterial Patho- 65/35 mmHg and poor peripheral perfusion. Several boils gens program (SRST2) [8]. Virulence gene allele se- were observed on the right elbow. He had subnormal quences were retrieved from the virulence factor white blood cell count 2.8 × 109 / L with low lymphocyte database (VFDB, http://www.mgc.ac.cn/VFs/). SRST2 count (13%), a moderate thrombocytopenia and raised was also used to define the sequence type of the CRP (347 mg/L) and procalcitonin plasma levels (279 ng/ strain. Antibiotic-resistance predictions were per- mL). The diagnosis of septic shock with a possible associ- formed directly from raw reads using “Mykrobe pre- ated toxic mechanism was retained and intravenous (i.v.) dictor S. aureus” tool [9]. All generated sequences are cefotaxime and clindamycin were started with concomi- available at NCBI’s BioProject database under acces- tant volume expansion. In the Intensive Care Unit, the pa- sion number PRJNA315766 (http://www.ncbi.nlm.nih. tient was intubated as he became confused, needed gov/bioproject/PRJNA315766). The sequenced S. aur- norepinephrine, inotropic support by epinephrine, and re- eus isolate was a methicillin-susceptible strain harbor- quired hemofiltration. Blood cultures showed methicillin ing a staphylococcal cassette chromosome (SCC). The susceptible S. aureus (MSSA) and treatment was switched patient’s strain genome encoded numerous to i.v. cloxacillin, clindamycin, and gentamicin. Comple- pathogenesis-related genes. The virulence gene equip- mentary explorations revealed multiple septic pulmonary ment of the strain notably included several cytotoxin abscesses, an abscess of the left occipital lobe, and the ab- genes encoding the gamma-hemolysin and the sence of endocarditis. In view of septic emboli, clindamy- Panton-Valentine (LukSF-PV), LukED and LukGH cin was switched to fosfomycin in order to have a better leukotoxins. It also included genes involved in adhe- cerebral diffusion. The patient then developed ischemia of sion and biofilm formation, genes encoding various the four limbs without any purpuric lesion or signs of dis- enterotoxins (A, H, K, and Q) and superantigens, seminated intravascular coagulation, which unfortunately exoproteases and immune response evasion rapidly progressed to dry gangrene of the left toes and of (Table 1). The patient’s strain belonged to the clonal the right leg requiring amputation at day 11 after admis- complex CC1-MSSA-SCCfus [PVL+]. sion. The clinical status of the patient improved slowly. Then, thrombophilic factors and immunity of the pa- Catecholamines were stopped at day 6, the patient got tient were examined. Initial low circulating an- extubated at day 11, and he recovered an efficient renal tithrombin, C and S returned to normal after one func