Unusual accumulation of a wide array of antimicrobial resistance mechanisms in a patient with cytomegalovirus-associated hemophagocytic lymphohistiocytosis: a case report

Abstract

Background: Infections with multidrug-resistant organisms (MDRO) pose a serious threat to patients with dysregulated immunity such as in hemophagocytic lymphohistiocytosis (HLH), but such infections have rarely been comprehensively characterized. Here, we present a fatal case of HLH secondary to cytomegalovirus (CMV) infection complicated by both anti-viral drug resistance and sepsis from multiple MDROs including pandrug-resistant superbug bacteria.

Case presentation: A previously healthy, six-year-old boy presented with a 45-day history of fever prior to a diagnosis of hemophagocytic lymphohistiocytosis and hemorrhagic colitis, both associated with CMV. On hospital admission, the patient was found to be colonized with multiple, multidrug-resistant (MDR) bacteria including vancomycin-resistant enterococci (VRE) and carbapenamase-producing organisms (CPO). He eventually developed respiratory, urine and bloodstream infections with highly drug-resistant, including pandrug-resistant bacteria, which could not be controlled by antibiotic treatment. Antiviral therapy also failed to contain his CMV infection and the patient succumbed to overwhelming bacterial and viral infection. Whole genome sequencing (WGS) of the MDR bacteria and metagenomic analysis of his blood sample revealed an unusual accumulation of a wide range of antimicrobial resistance mechanisms in a single patient, including antiviral resistance to ganciclovir, and resistance mechanisms to all currently available antibiotics.

Conclusions: The case highlights both the risk of acquiring MDR superbugs and the severity of these infections in HLH patients.

Keywords: Antiviral resistance; Cytomegalovirus; Hemophagocytic lymphohistiocytosis; Multidrug-resistant organism.

Fig. 1

Hospital course, microbiology and antimicrobial treatment history. ID, infectious disease clinic; ED, emergency department, GP, general pediatrics clinic; Gen. Ped., general pediatrics unit; Ped. Surg., pediatric surgery unit; PICU, pediatric intensive care unit. Orange bars, orange arrows and red bar show inpatient days, outpatient visits and PICU days, respectively. Grey bars show approximate timing of hospitalization in India

Fig. 2

Genotype and antiviral resistance profiles of the cytomegalovirus strain. Nucleic acid extract from patient serum was subjected to NGS library preparation using Nextera XT kit (Illumina, USA) and sequencing was performed on a MiSeq (Illumina). Paired sequence reads were mapped to UL97 and UL54 sequences (Gene ID 3077517 and GenBank accession ABV71585.1, respectively) to obtain corresponding gene sequences from the patient’s CMV strain. The sequences were then analyzed by using an online mutational resistance analyzer (MRA) available from the University of Ulm, https://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/mra/app/index.php?plugin=form [5]. Ganciclovir resistance was confirmed by the presence of the A594V mutation in UL97 [6]