Onc and transplant ID: November 2018

Leukopenia and failure to receive ribavirin predict disease progression in hematologic cancer patients with RSV infection. (Note: this paper was published by my colleagues over at the MD Anderson Cancer Center). The authors reviewed the records of patients with hematologic malignancies who developed RSV infection at a single medical center between 2000 and 2013. One hundred and eighty-one patients were identified (52% male, median age 59); 88% were actively receiving chemotherapy at the time of infection. The cohort had a median 6 days of hospitalization, and the 90-day mortality rate was 15%.

Forty-four percent of patients either initially presented with or went on to develop a lower respiratory tract infection. In univariate analysis, leukemia, steroid use in the past month, and the combination of neutropenia and lymphopenia all predicted progression of upper respiratory tract RSV infection to lower tract infection; receipt of ribavirin, on the other hand was protective. In multivariate analysis, the two factors independently associated with progression of RSV upper respiratory tract disease to lower respiratory tract disease were combined neutropenia and lymphopenia (OR 7.2; p<0.001) and having received ribavirin (OR 0.03; p<0.001). Only the combination of neutropenia and lymphopenia was associated with 90-day mortality (OR 4.3, p=0.02). The authors conclude that ribavirin treatment of RSV upper respiratory tract infection is important to prevent progression to RSV pneumonia. 30113677


Colonization with ESBL Enterobacteriaceae is a risk factor bacteremia in hematopoetic stem cell transplant (HSCT) recipients. For two years, the authors collected perianal swabs from patients undergoing HSCT at their medical center, both on admission and then weekly during hospitalization. Patients received levofloxacin prophylaxis while neutropenic, and the swabs were all referred for culture and susceptibilities. The patients were stratified and compared based on whether they were colonized with ESBL-producing organisms before transplantation; the primary outcomes of interest were rates of febrile neutropenia and bacteremia.

A total 312 patients were included in the analysis; the median age was 58 years, and most patients were transplanted to treat AML (36%), multiple myeloma (19%), or non-Hodgkin’s lymphoma (19%). Prior to transplantation, 10% of HSCT recipients were colonized with ESBL Enterobacteriaceae (ESBL-E), most of which were E.coli carrying the CTX-M gene and only a quarter of which were quinolone-susceptible.  Of the 31 patients with ESBL-E colonization, 32% developed ESBL-E bacteremia while neutropenic, compared to <1% of the patients without pretransplant ESBL-E colonization. All of the EBSL-E bacteremias in the colonized group were due to quinolone-resistant isolates, and the risk of bacteremia in this subgroup was 42%; most were bacteremias with isolates identical to those detected during pretransplant screening. The pretransplant ESBL-E colonized patients had a higher incidence of febrile neutropenia than the noncolonized patients (71% vs 53%; p=0.06), and were more likely to have bacteremia when febrile neutropenia occurred (55% vs 28%; p=0.01). Among the patients who were not colonized with ESBL-E before transplantation, only 3% acquired ESBL-E, and all but one isolate was quinolone-resistant.

What’s the take-home? Giving antibiotic prophylaxis for neutropenia doesn’t work nearly as well when the patient is already colonized with pathogens resistant to that antibiotic. Don’t get me wrong – I’m not advocating that we need to move to routine carbapenem prophylaxis – but maybe HSCT patients would benefit from pretransplant screening and susceptibility-based individualized antimicrobial prophylaxis, or even pretransplant FMT to flush out those quinolone-resistant ESBLs. What do you think? 29701766


Even in the era of routine prophylaxis and preemptive treatment, CMV mismatch still portends a bad outcome in renal transplantation. The authors reviewed renal transplant outcomes from the Organ Procurement and Transplant Network / United Network for Organ Sharing database, including several thousand patients transplanted between 2010 and 2015. They stratified the cohort based on donor and recipient CM serostatus (i.e. into four groups: D-/R-, D+/R-, D-/R+, D+/R+) and compared rates of rejection at one year, patient mortality, and graft survival in surviving patients. The authors also conducted this analysis within a “paired kidney cohort” of donors with 2 recipients who had different CMV serostatuses.

A total 52,394 patients were included in the cohort; the mean duration of follow-up was 2.9 years. The breakdown of serostatuses was 13% D-/R-, 18% D+/R-, 44% D+/R+, and 25% D-/R+. The paired kidney cohort included 14,932 patients (2899 pairs with a seronegative donor and 4567 pairs with a seropositive donor). Compared to CMV-seropositive recipients, seronegative recipients were more likely to be white, male, not have diabetes, and to have received preemptive transplants; similarly, seronegative donors were more likely to be young, white, and male.

All patients received similar induction therapy for their transplants. The cumulative incidence of acute rejection at one year was 9-10% and similar across groups in both the main and paired kidney cohorts. CMV serostatus was not associated with acute rejection in either univariate or multivariate analyses. CMV serostatus was, however, associated with graft survival in the main cohort; relative to the D-/R- transplant recipients, both D+/R+ and D+/R- statuses were associated with graft loss (HR 1.1; p=0.04 and HR 1.2; p=0.01). In the paired kidney cohort, graft loss did not vary by recipient serostatus for either seropositive or seronegative donors. Finally, in multivariate analysis, all-cause mortality risk was higher for D+/R- recipients when compared to either D-/R- or D+/R+ transplant recipients (HR 1.2; p<0.001 for both) in the main cohort; similar findings were observed in the paired kidney cohort.

Bottom line? Despite our best efforts to prevent and promptly treat CMV infections in solid organ transplantation, CMV serostatus mismatch remains associated with graft loss and death. 30431703


At what point can we hold the leaders of the anti-vaccination movement legally liable for killing our immunocompromised patients? Title 18, Chapter 102, section 2102 of the US code defines a riot as “a public disturbance involving an act or acts of violence by one or more persons…[which] constitute a clear and present danger of, or shall result in, damage or injury to the property of any other person or to the person of any other individual.” and further defines inciting a riot as ”urging or instigating other persons to riot.” Seems to me that urging large groups of people to let themselves and their children go unvaccinated is disturbing the public in a manner that constitutes a clear and present danger to… well, everybody, but especially our immunocompromised patients. Anybody know a particularly sharky lawyer?

I mention this because this month’s OFID reports the case of an appropriately vaccinated young man in Switzerland who nonetheless died of measles pneumonitis after receiving fludarabine and rituximab-based chemotherapy for CLL. The case occurred in the backdrop of a strong anti-vacinnation movement that’s spread through Europe over the past few years and has been predictably followed by a resurgence of vaccine-preventable diseases, including over 14,000 cases of measles in 2017. The patient had no known contact with an unvaccinated person, which you wouldn’t necessarily expect given how contagious measles is and how long it persists in aerosol.

So what’s the clinical course of fatal measles infection in patients undergoing chemotherapy for hematologic malignancy? This young man presented to the hospital with a day of sore throat, fever and dry cough; pharyngitis was the only new finding on physical exam, and the admission chest film showed no infiltrates. On day four, the patient developed a diffuse maculopapular rash initially attributed to drug eruption from the empiric cefepime he’d been given and/or his TMP/SMX prophylaxis; however, on day seven the patient additionally developed bilateral conjunctivitis and Koplik spots, which provoked testing for measles. Intravenous immunoglobulin, ribavirin, and vitamin A were started at this point. Nonetheless, on day 8 the patient developed progressive dyspnea and hypoxia, which evolved into acute respiratory distress syndrome requiring mechanical ventilation and then ECMO, which was complicated by hemorrhage and ultimately death due to severe pneumonitis and shock. Lung histology at autopsy was consistent with measles pnuemonitis.

Aside from a sense of outrage, I did take a few points away from this case. First, measles in immunocompromised patients results in serious complications in up to 80% of cases; pneumonitis is both the most common complication and the most likely to result in death. Second, measles in immunocompromised patients often presents atypically, and up to 40% of patients won’t develop a rash. Third, protection from measles infection is primarily mediated by antibodies, so rituximab (which, in trashing B cells, induces transient hypogammaglobinemia) placed this patient at high risk of measles infection even though he’d been vaccinated appropriately during childhood. Last, once measles infection has been established, T-cell mediated cellular immunity is responsible for clearing the disease – so for example, while kids with hypogammaglobulinemia are more likely that their healthy peers to develop measles infection, their course of disease is no more severe, whereas a kiddo with cellular immune defects would not be at elevated risk for developing measle, but would be more likely to have a poor outcome if they did get infected. In this case, the patient’s receipt of fludarabine (and cyclophosphamide) probably knocked out his cellular immunity and produced the fulminant infection. 30397623