Perils of medical tourism Dr Theo Gouliouris Microbiology and Infectious Diseases StR Addenbrooke’s Hospital, Cambridge

Case history 55 year old man, Pakistani origin ESRD secondary to hypertensive nephrosclerosis 2007 Haemodialysis via AV fistula 2009 Transplant waiting list

Case history Summer 2010 Travelled to Pakistan August 2010 HCV antibody and PCR positive Removed from transplant waiting list pending antiviral therapy September 2010 commenced on ribavirin 200 mg daily October 2010 travelled to Pakistan against medical advice

Acute presentation May 2011 Presented to Addenbrooke’s unwell Living-related kidney transplant in Pakistan Nov 2010 Donor and HLA match unclear Recipient CMV positive Complications ARDS, ventilated in ICU for 4 days Wound dehiscence and infected perinephric haematoma, treated with imipenem and colistin Poor graft function: creatinine 477 mol/L Medications: Prednisolone 10mg od, Tacrolimus 3mg/4mg, Mycophenolic acid 720mg bd Letter said wound healed. Patient believes kidney working well.

Examination Vomiting Febrile T 38.9°C Tachycardia Widespread vesicular rash consistent with shingles Open wound in right iliac fossa, packed, discharging pus Commenced on empirical piperacillin-tazobactam and aciclovir Barrier nursed

Baseline investigations Blood test Result Normal range Urea 19.9 0.0-7.5 mmol/l Creatinine 398 35-125 mol/l Albumin 29 30-51 g/l ALP 145 30-135 U/l ALT 6 0-50 U/l Bilirubin 0-17 mol/l CRP 59 0-6 mg/l WCC 6.8 4.0-11.0x109/l Neutrophils 6.3 2.0-8.0x109/l Lymphocytes 0.26 1.0-4.5x109/l Haemoglobin 8.8 g/dl Platelets 258 150-400x109/l PT 13.4 9.8-12.6 s

CT abdomen and pelvis CT abdomen showed an intraparenchymal abscess lower pole of kidney communicating with perinephric abscess. Multiple intramuscular abscesses R flank and R abdominal muscle.

Management and progress Ultrasound-guided drainage of 3 largest collections Clinical deterioration Ongoing fever Productive cough CXR pulmonary infiltrates Metabolic acidosis Diarrhoea Mycophenolate and tacrolimus stopped Transplant nephrectomy 12 days post-admission

Microbiology / virology results Skin vesicles: VZV DNA detected Blood: Low-grade CMV viraemia Stool: Norovirus detected Wound swabs: Multidrug-resistant ESBL-producing Klebsiella pneumoniae and E. coli vancomycin-resistant Enterococcus faecium Peri-nephric abscess aspirates Filamentous mould - Aspergillus terreus (amphotericin B resistant) Meropenem-resistant Klebsiella pneumoniae

Klebsiella pneumoniae antibiogram Antimicrobial MIC (mg/l) S/I/R Breakpoint Ampicillin >64 R 8 Amoxillin/Clavulanate 64 Cefotaxime >256 1-2 Ceftazidime 1-8 Ertapenem >16 0.5-1 Imipenem 16 2-8 Meropenem Aztreonam Not done 2-4 Piperacillin/Tazobactam Colistin 32 2 Ciprofloxacin >8 Gentamicin 1 S 8-16 Amikacin Tobramycin 4 I Tigecycline 0.5 Fosfomycin (32)

Real-time PCR detection of New Delhi metallo- beta-lactamase Purple - control NDM positive extract DNA Green - clinical isolate extract DNA Black/blue - PCR negative control isolates Courtesy of R. Swayne and M.Ellington, Cambridge HPA

Histopathology results Numerous branching septal hyphae invading vessel walls and in necrotic parenchyma. Balls of fungal hyphae.

GII.4 – Most prevalent norovirus in humans GIV Cluster GII.4 – Most prevalent norovirus in humans GI Cluster Partial sequencing of capsid encoding region - genogroup 1 genotype 4 GII Cluster Adapted from Glass et al. Norovirus Gastroenteritis. N Engl J Med 2009;361:1776 Courtesy of M. Curran, Cambridge HPA

Further management Recurrent collections requiring drainage procedures Antimicrobial therapy complex – renal impairment, drug interactions and toxicity, multiple MDR organisms, need for prolonged treatment Long courses of tigecycline (63d), amikacin (45d) and voriconazole

Transplant tourism Common 5 to 10% of kidney transplants performed worldwide Pakistan 2006: 2/3 of 2000 transplants for foreign recipients1 Ethical issues Organ trafficking Transplant commercialism Declaration of Istanbul on Organ Trafficking and Transplant Tourism, 2008 Ethical issues: equity, justice, respect for human dignity Summit meeting of 150 representatives of scientific and medical bodies from around the world, govt officials, social scientists and ethicists 1. Naqvi et al, Transpl Int 2007; 20: 934

Literature review of outcomes 21 case series between 1990 and 2012 Total no. of patients 1331 (range 5 – 515) Countries: India (62%), Pakistan (13%), China (12%), Philippines (3%), Egypt (3%), Iran Graft 1-yr survival rate 86.9% (range 60-100%) Patient 1-yr survival rate 91.9% (range 68-100%) Acute rejection common 23.4% (range 10-50%)

Infective complications Infections common, esp. CMV, wound infections Significant risk of BBV acquisition HIV 0.8% HBV 4% HCV 16% Risk of TB 3% Malaria reported (1.8%) Little emphasis on resistant organisms (mainly ESBL producing Enterobacteriaceae, one panresistant Acinetobacter baumannii)

Aspergillus infections in renal transplants 1.3% one-year cumulative incidence of invasive fungal infections in renal transplants1 14% of IFI caused by Aspergillus spp. (<5% A. terreus) Usually pulmonary or disseminated infection Recognised association with transplant tourism2 17 cases identified Infection in transplanted graft 35% Graft loss or death 76% TRANSNET 1500 patient American cohort Pappas et al, CID 2010; 50: 1101 Shoham et al, Transplant ID 2010; 12: 371

Outcome Discharged from hospital on day 82 Last clinical review: wound completely healed, incisional hernia HCV RNA negative

Conclusions Transplant tourism is associated with significant morbidity and mortality, particularly related to infection NDM-1 producers, pose a significant risk to patients who travel to the Indian subcontinent for medical treatment Patients returning following hospitalisation in endemic countries should be screened for the presence of resistant bacteria and isolated Rapid molecular detection methods for antimicrobial resistance facilitate prompt diagnosis

Acknowledgments Dr S.H. Aliyu, Dr S. Ojha, Prof S. J. Peacock, Dr M.E. Török Renal Transplant team Microbiology and Infectious Diseases colleagues Dr Matthew Ellington, Dr Rosie Swayne (Cambridge HPA) Dr Martin Curran (Cambridge HPA) Dr Verena Broecker (Histopathology Department) Dr Winterbottom (Radiology Department)