Article Text
PDF
Abstract
Prosthetic pulmonary valve endocarditis is a rare but serious infective complication following correction of tetralogy of Fallot (ToF). We describe a probable zoonotic case of Streptococcus equi subspecies zooepidemicus prosthetic pulmonary valve infective endocarditis in a young woman with corrected ToF with regular exposure to horses. The case was further complicated by acalculous cholecystitis, which was the initial presenting syndrome, requiring laparoscopic cholecystectomy. Microbiological analysis of blood cultures yielded growth of S. equi with whole genome sequencing confirming the subspecies identification of zooepidemicus. The patient underwent successful combined medical and surgical management incorporating a 6-week course of intravenous antibiotics and a re-do homograft pulmonary valve replacement followed by prolonged oral antibiotic therapy. Clinicians should be mindful of the increased risk of endocarditis in adult congenital heart disease and relevant bacteraemia detection should prompt thorough valvular assessment.
- Infectious diseases
- Blood Culture
- Valvar diseases
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
Background
Right-sided valvular intervention of the tricuspid and/or pulmonary valve occurs most commonly for repair of valve degeneration due to injecting drug use or central venous access device-associated right-sided infective endocarditis.1 The evidence base for understanding the epidemiology, aetiology, diagnosis, management and outcomes of right-sided endocarditis is heavily based on the study of these populations. However, pulmonary valve replacement is also observed in correction of congenital heart diseases such as tetralogy of Fallot (ToF).2 Postcorrection, these patients remain at lifelong increased risk of prosthetic valve infective endocarditis (PVE), a severe and life-threatening infection with significant morbidity and mortality.2–4 Furthermore, episodes of PVE require prolonged intravenous antimicrobial therapy, hospitalisation and may require additional surgical intervention to achieve adequate source control and/or valvular function. Pulmonary PVE has an estimated incidence rate of 22.4 per 10 000 person years in patients with ToF.2 Streptococcus equi subspecies zooepidemicus (SEZ) is a commensal organism of the upper respiratory and urogenital tract of horses. SEZ has been described as a zoonotic pathogen in humans implicated in reported cases of respiratory, skin and soft tissue, osteoarticular and endovascular infections.5 Here, we describe a case of probable zoonotic pulmonary PVE and its sequelae in a patient with surgically corrected ToF caused by SEZ.
Case presentation
A woman in her 30s presented to a regional hospital with a 2-day history of fever, nausea, vomiting, diarrhoea and dizziness. She reported anorexia but denied any chills, sweats, significant abdominal pain, bloody stools or weight loss. In relation to exposure history, she had no history of any relevant travel although lived on a large rural property with regular exposure to livestock including daily interaction with horses. In terms of sick contacts, she recalled her husband having a febrile illness 1 week before the onset of her own symptoms which fully resolved without intervention. Her medical history was significant for ToF which was surgically corrected over three operations, the most recent being a bioprosthetic pulmonary valve replacement 20 years before this presentation.
At presentation, she was noted to be febrile to 38.2°C, borderline tachycardic with a regular heart rate of 100 beats per minute and hypotensive with a systolic blood pressure of 75 mm Hg. On cardiovascular examination, there were neither peripheral stigmata of infective endocarditis nor any palpable heaves or thrills. Auscultation of the chest revealed a grade 3 systolic murmur loudest over the left parasternal area with no radiation, breath sounds in all lung fields were vesicular with no adventitious sounds. A 12-lead ECG showed normal sinus rhythm, an established incomplete right bundle branch block and low voltage amplitudes. Abdominal examination was significant for right upper quadrant tenderness with positive Murphy’s sign.
In the setting of septic shock with localising abdominal signs suggestive of a biliary source, the patient was commenced on empiric broad-spectrum antimicrobial therapy with intravenous piperacillin/tazobactam. A CT of the abdomen and pelvis was undertaken demonstrating gallbladder wall thickening. Targeted ultrasonography the next day confirmed the diagnosis of acalculous cholecystitis. The patient was admitted under the general surgical team with a collaborative referral to general medicine in view of her complex cardiac history. On day 2 of admission, blood cultures flagged positive for an organism identified as S. equi, specialist infectious diseases advice was sought and antimicrobial therapy was narrowed to intravenous amoxicillin/clavulanate. The patient proceeded to an uncomplicated laparoscopic cholecystectomy on day 4 of admission under the general surgical team to manage the acalculous cholecystitis.
Postoperatively, the patient’s care was transferred to the general medical team. Repeat blood cultures after initial presentation were negative and the patient remained afebrile and clinically well. The growth of Streptococcal species in blood culture in a patient with a prosthetic pulmonary valve raised suspicion for PVE. After an inconclusive transthoracic echocardiogram (TTE), the general medical team advocated strongly for transfer of the patient to a tertiary centre for further valvular assessment with transoesophageal echocardiogram (TOE). On day 11 of admission, the patient was transferred to the state referral cardiothoracic surgical centre where TOE confirmed the presence of a large, mobile vegetation on the prosthetic pulmonary valve.
Investigations
Medical imaging
Abdomen
CT abdomen and pelvis (day 1): transmural thickening of the gallbladder.
USS abdomen (day 2): hepatomegaly with associated steatosis and a thick-walled gallbladder with increased vascularity and with pericholecystic fluid, but no calculi. A small pocket of fluid adjacent to the gallbladder measured 21 × 13 × 10 mm and was overall suggestive of acalculous cholecystitis (figure 1).
Ultrasound image of long axis of gallbladder demonstrating mural wall thickening with no visualised cholelithiasis.
Cardiac
TTE (day 3): pulmonary valve replacement was not well visualised but appeared well seated without regurgitation.
TOE (day 14): a large vegetation attached to the 24 mm pulmonary homograft (possible left pulmonary leaflet). The mass consisted of a thickened and irregular segment attached to the leaflet measuring 19 mm and a more thin, highly mobile segment measuring 23 mm extending distally. Leaflet motion appeared normal; no significant pulmonary regurgitation was noted (online supplemental video 1).
Supplementary video
Blood tests
Full blood count (day 1)—(reference range)
Haemoglobin: 117g/L (115–160)
White cell count: 7.0×109/L (4.0–11.0)
Neutrophils: 6.73×109/L (2.00–8.00)
Lymphocytes: 0.22 109/L (1.00–4.00)
Platelets: 186×109/L (140–400)
Biochemistry (day 1)—(reference range)
Sodium: 136 mmol/L (135–145)
Potassium: 3.4 mmol/L (3.5–5.2)
Creatinine: 75 µmol/L (45–90)
eGFR>90 mL/min/1.73m2 (>90)
Total bilirubin: 19 µmol/L (<20)
Conjuated bilirubin: 11 µmol/L (<4)
Alkaline phosphatase: 32 U/L (30–110)
Gamma-GT: 42 U/L (<38)
Alanine tranasminase: 32 U/L (<34)
Aspartate transaminase: 22 U/L (<31)
Lactate dehydrogenase: 228 U/L (120–250)
C-reactive protein: 334 mg/L (<5.0)
Biochemistry (day 48)—(reference range)
C-reactive protein: 11 mg/L (<5)
Microbiology
Blood cultures
Blood cultures (BC; day 1): flagged positive at 1.6 hours of incubation from arrival in the microbiology laboratory with S. equi grown in four of four bottles (table 1).
Blood culture results
Antimicrobial susceptibility testing interpreted with EUCAST breakpoints demonstrated that the isolate was susceptible to penicillin, erythromycin, clindamycin and vancomycin.6 The penicillin minimum inhibitory concentration was verified by E-test and was measured at 0.064 mg/L. Initial organism species identification was achieved using matrix-assisted laser desorption ionisation time of flight. Further identification of the blood culture isolates to the subspecies level was achieved by whole genome sequence analysis using the 16S ribosomal RNA and whole genome sequences analysed through the curated type (strain) genome server taxonomic tool, which demonstrated the highest fidelity matches to the published genome of reference strain SEZ NCTC 4676 (figure 2). This result was consistent with an identification of the clinical isolate as SEZ.
Phylogenomic tree based on whole genome sequences demonstrating closest match of clinical isolate to sequence of Streptococcus equi subspecies zooepidemicus NCTC 4676. Phylogenomics-based tree constructed by author TK using the type (strain) genome server (https://tygs.dsmz.de/). GBDP distances were calculated from genome sequences. Branch lengths are scaled in terms of GBDP distance formula d5. The numbers above branches are GBDP pseudo-bootstrap support values >60% from 100 replications, with an average branch support of 64.0%. GBDP, genome BLAST distance phylogeny.
BC (days 5, 13, 15, 20): negative.
Operative samples
Pulmonary valve homograft tissue (day 19): no growth after 5 days of incubation.
Pulmonary valve homograft fluid (day 19): no growth after 5 days of incubation.
Histology
Gallbladder (day 4): mild muscular hyperplasia, no inflammation and no calculi, consistent with the diagnosis of acalculous cholecystitis.
Differential diagnosis
The patient’s initial presentation with gastrointestinal symptoms including fever, nausea, vomiting and diarrhoea combined with abdominal signs including right upper quadrant tenderness and positive Murphy’s sign raised the clinical suspicion of biliary sepsis and cholecystitis. Abdominal imaging with CT followed by USS confirmed the diagnosis of acalculous cholecystitis with subsequent operative management. The patient’s history of corrected congenital heart disease with prosthetic pulmonary valve, S. equi bacteraemia, combined with her diagnosis of acalculous cholecystitis which is observed in settings of high inflammatory burden such as systemic infection raised suspicion of underlying PVE.
Treatment
Surgical management
Acalculous cholecystitis
The patient underwent an uncomplicated laparoscopic cholecystectomy on day 4 of admission. Surgical findings demonstrated a thick-walled gallbladder with surrounding free fluid.
Prosthetic valve infective endocarditis
The patient proceeded to definitive surgical management for PVE with a re-do homograft pulmonary valve replacement on day 20 of admission. Surgical findings demonstrated significant adhesions around the infected pulmonary valve prosthesis and pulmonary arterial trunk, leading to a difficult explantation and the achievement of complete debridement was uncertain.
Antimicrobial therapy
Acalculous cholecystitis
The initial presentation with septic shock from a biliary source led to the initiation of broad-spectrum antimicrobial therapy with intravenous piperacillin/tazobactam 4.5 g 6 hourly in line with local treatment guidelines and antimicrobial resistance surveillance data.7 Subsequent identification of SEZ in blood culture prompted consultation with an infectious diseases specialist with therapy narrowed to intravenous amoxicillin/clavulanate 1.2 g 6 hourly on day 3 of admission. This was to provide adequate cover for the isolated SEZ while providing additional enteric Gram-negative and anaerobic cover, acknowledging the polymicrobial nature of cholecystitis.8 Amoxicillin/clavulanate was continued for 7 days after cholecystectomy, through to day 11 of admission.
Prosthetic valve infective endocarditis
The patient was subsequently transitioned to directed therapy for SEZ PVE with 6 weeks of intravenous benzylpenicillin 2.4 g 4 hourly in combination with 2 weeks of synergistic intravenous gentamicin 60 mg 8 hourly. Data are limited on the treatment of zoonotic Streptococci infections associated with intravascular prosthesis. Treatment course was adopted as per oral streptococci with PVE according to the European Society of Cardiology guidelines for the management of endoarditis; ‘in patients with PVE due to oral Streptococci and S. gallolyticus, oral penicillin G, amoxicillin or ceftriaxone for 6 weeks combined with gentamicin for 2 weeks is recommended’.9 Given the risk of long-term mortality when surgical clearance cannot be achieved, a recommendation was made for long-term suppressive antibiotic therapy with oral amoxicillin 500 mg three times per day for review at 2 years, although the optimum approach is yet to be defined.9
Outcome and follow-up
Postoperative pulmonary valve replacement assessment demonstrated a well-seated prosthesis with satisfactory haemodynamics. The patient was discharged home on day 35 of admission, linking in with hospital in the home facilitated by her local regional hospital, allowing her to complete her intravenous antimicrobial therapy at home. At 4 weeks postsurgical intervention, the patient remained well with no recurrence of fevers or sweats, and she reported good appetite with weight gain; her C-reactive protein had reduced to near normal levels. At 3 months postsurgery, the patient felt her health status had returned to baseline. She was suffering no adverse medication effects and achieved good adherence with the three times per day oral pill burden.
Discussion
Pulmonary PVE is a serious infective complication that can occur in adults with corrected congenital heart disease and remains a significant source of morbidity and mortality in this population.3 The most commonly reported bacterial cause of PVE is Staphylococcus aureus, though many other aetiologies have been described.1 10 11 Routes of infection acquisition are often through translocation of commensal organisms from the gastrointestinal tract, dissemination of local infection, for example, skin and soft tissue infections, or iatrogenically (eg, in the setting of vascular access devices).11 This case demonstrates a probable zoonotic source of SEZ leading to destructive pulmonary PVE requiring surgical revision and prolonged antimicrobial therapy. Our experience in managing this case highlighted four key elements; SEZ as a zoonotic pathogen and cause of PVE, the utility of whole genome sequencing (WGS) to confirm the microbiological diagnosis, acalculous cholecystitis as a rare association with infective endocarditis and the importance of multidisciplinary management of complex cases of PVE.
The microbiological basis of PVE is varied and in order of frequency includes Staphylococcus spp., Streptococcus spp., Enterococcus spp. and other less commonly reported organisms like Gram-negative bacilli and fungi.1 However, data on the specific epidemiology of pulmonary PVE are limited, as they are often reported as part of larger case series and cohort studies where the majority of included cases of PVE involve the aortic or mitral valves. This case of pulmonary PVE was caused by SEZ, a beta-haemolytic Lancefield group C Streptococcus that is often isolated as a coloniser of the upper respiratory tract of horses.12 SEZ can cause a wide array of infections in animals and has been recognised as an emerging zoonotic pathogen, implicated in human case reports of severe meningitis, endocarditis, osteoarticular infection and complex skin and soft tissue infections.5 12–18 To date, there have been eight reported cases of SEZ endocarditis (table 2) with the aortic valve most frequently involved.
Reported cases of Streptococcus equi subspecies zooepidemicus endocarditis
Each of these cases had epidemiological exposure to horse products or horses as was seen in our case.5 12–18 Only one case of native mitral valve endocarditis required surgical replacement; all other cases were treated successfully with antibiotics alone.13 Our case is the first reported case of right-sided endocarditis caused by SEZ. Although it is important to acknowledge that microbiological identification of SEZ to the subspecies level is difficult with standard approaches and may have led to an under-reporting of cases.
Advanced molecular techniques like WGS are increasingly used in diagnostic microbiology to definitively identify isolates, determine genotypic antimicrobial resistance and infer the relatedness of isolates. These techniques can be particularly useful when traditional phenotypic, biochemical and/or proteomic methods are insufficient or inconsistent in the determination of a subspecies-level identification of an isolate as was seen in this case. S. equi is comprised of three recognised subspecies, of which two, SEZ and S. equi ssp. ruminatorum, are very closely related and difficult to discriminate via biochemical and proteomic methods. 16S ribosomal RNA sequencing and WGS allow for higher-level discrimination between closely related organisms offering high-confidence identification. Daubie et al19 illustrated their experience of 16S ribosomal RNA sequencing in reaching a high-confidence identification of S. equi subspecies ruminatorum where there was discordance between phenotypic methods. Furthermore, WGS offers the opportunity to infer the relatedness of isolates, which can strengthen the clinician’s ability to determine the source of infection and can prove invaluable in outbreak investigation. Although in this case we were unable to obtain clinical samples from the horses to which the patient was exposed, sequencing of SEZ isolates from patient and horse samples by Sleutjens et al18 was able to prove this concept in practice.
Our case of SEZ pulmonary PVE presented with acalculous cholecystitis, a rare but recognised association. Prior reports of the association between infective endocarditis and acalculous cholecystitis have been predominantly in the setting of Staphylococcus aureus infection; however, other bacterial aetiologies have been described.20 21 The diagnosis of acalculous cholecystitis should lead the clinician to judiciously investigate for an underlying cause and infective endocarditis should be considered.22 Our case demonstrates the importance of multidisciplinary and collaborative care for these patients to obtain the correct underlying diagnosis and to achieve the best possible outcome. This was of particular importance in this case given the additional complexity of corrected congenital heart disease and the presence of a pulmonary valve prosthesis.
Patient’s perspective
It started with a rash 10 days before my hospital admission. The rash was followed by body aches and fevers that lasted 2 days, recovered for 4 days and then the fevers, body aches returned. They were then followed by dizziness and vomiting, and I was admitted to hospital. Before the gallbladder surgery, I was very weak (could hardly talk or move and could not get out of the hospital bed without assistance) and had swollen abdomen. I remember hearing my heartbeat ringing in my ears the entire time and my headache was extremely painful. I was given half a dose of gentamicin before my gallbladder surgery, and I remember feeling better after this dose.
After the gallbladder surgery, I started to regain my strength and was relatively independent, but was still experiencing dizziness, mind fog and headaches. I also had lost about 5 kg, and my appetite was very low. I did not have a temperature during this time. 13 days after my hospital admission, I started to experience septic showers where my temperature spiked and my body would be rigorous. I lost control of my temperature and started experiencing hot sweats. My headache was still extremely painful.
It was discovered that the infection had spread to my donor pulmonary valve and surgery was needed to replace the valve. My antibiotics were changed, and the septic showers ceased 2 days before surgery.
After surgery, the hot sweats continued, and I still had a lack of temperature control over my body. However, the headache disappeared after surgery.
I experienced the night sweats for around 2 weeks after surgery. I also experienced sweating under my eyes when I would eat food. This continued to around 8 weeks post-surgery. At times, I still mildly experience this if I am eating food quickly. Presently, 17 weeks post-surgery and 21 weeks post the first signs of the infection, I have regained 90% of my fitness, gained weight and am presently not experiencing any infection symptoms.
Learning points
Clinicians should be aware of the association between acalculous cholecystitis and infective endocarditis, prompting the rapid collection of blood cultures.
Streptococcus equi species zooepidemicus is an emerging zoonotic pathogen transmitted from horses to humans and can cause a wide spectrum of infections including infective endocarditis.
Microbial whole genome sequencing is a valuable diagnostic tool that can improve taxonomic classification, assist with inferring relatedness of isolates and identify genotypic antimicrobial resistance mutations.
Complex cases of endocarditis like prosthetic valve endocarditis in corrected congenital heart disease should be managed by a multidisciplinary team.
Ethics statements
Patient consent for publication
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
ME and GS are joint first authors.
Contributors ME, GS, TJK and JFM were responsible for drafting the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content. All authors also gave final approval of the article.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.