Correspondence on: A rare complication of bone marrow aspiration and trephine biopsy: Staphylococcus aureus osteomyelitis and septicaemia

We read with great interest the article of Khakwani et al (2019), in which an association between bone marrow (BM) examination and Staphylococcus aureus osteomyelitis was described in a patient receiving ibrutinib therapy for chronic lymphocytic leukaemia (CLL). The authors were quite correct to highlight this case as a matter of interest, as severe infections complicating this procedure are a very rare phenomenon. Indeed, in UK-based surveys involving 107 978 BM examinations performed in two phases during 1995– 2001 (retrospective) and 2002–2004 (prospective), only ten cases of infection were reported (incidence-rate = 9 26/ 100 000 procedures; 95% confidence interval = 9 08–9 45) (Bain, 2003, 2004, 2005, 2006). Moreover, none of these cases was reported as severe, or was associated with overt bacteraemia. Reflecting the case-mix of UK haematology services, it may be assumed that many of the patients in these surveys would have been immunosuppressed at the time of procedure – either by virtue of underlying haematological disease – including CLL-related hypogammaglobinaemia or prior treatment with immunosuppressive therapy. Thus, the florid presentation, as described in the aforementioned case, is particularly striking. We note, however, that the authors do not describe whether the blood culture isolate was sent for testing for Panton-Valentine Leukocidin (PVL) toxin, which may have been illuminating given the history of recurrent cutaneous abscesses. PVL is a well-described virulence factor in S. aureus, associated with a spectrum of disease ranging from recurrent skin/soft tissue infections (e.g. abscesses), necrotising pneumonia and overwhelming bacteraemic sepsis (Fogo et al, 2011). There is an emerging association between the use of ibrutinib (Imbruvica®, Janssen-Cilag LTD, UK) and opportunistic infections – a treatment first approved for clinical use in the European Union in 2014. Whilst fatal invasive mycoses (including central nervous system aspergillosis and Pneumocystis jirovecii pneumonia) have been highlighted as an issue of particular concern (Chamilos et al, 2017), serious bacterial infections have also been reported in patients receiving ibrutinib therapy for haematological disease (Tillman et al, 2018). Retrospective data from a US-based haemato-oncology cohort demonstrated severe bacterial infections, including pneumonia and bacteraemia, in 23/387 (5 9%) patients receiving ibrutinib. In this study, S. aureus was the commonest causative pathogen overall, in 7/23 patients (30 4%), and was responsible for 2/7 (28 6%) cases of bacteraemia (Varughese et al, 2018). Similarly, fatal meningitis secondary to S. aureus bacteraemia – a rare phenomenon observed in <1% of patients without a prior history of neurosurgical intervention – has been reported recently in a patient receiving ibrutinib (Diamantopoulos et al, 2017). This may suggest that ibrutinib engenders a state of increased vulnerability to aggressive staphylococcal infection. Taken together with the observed low rates of iatrogenic infection secondary to BM examination prior to the widespread use of small molecular kinase inhibitors, ibrutinib use may be an independent risk factor for invasive staphylococcal infections following percutaneous procedures, including BM examination. Prospective surveys of morbidity and mortality in the era of mechanistic therapy may be useful to determine whether patients receiving ibrutinib (and related kinase inhibitors) are at an increased risk of iatrogenic infection. We suggest that infection control practices (including aseptic, non-touch technique) are followed scrupulously in patients receiving ibrutinib, and that a low threshold for postponing percutaneous procedures should be exercised in patients with confirmed or suspected cutaneous infection at the examination site.