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Background Preliminary data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients indicate that a cytokine storm may increase morbidity and mortality. Tocilizumab (anti-IL-6R) is approved by the Food and Drug Administration for treatment of cytokine storm associated with chimeric antigen receptor T-cell therapy. Here we examined compassionate use of tocilizumab in patients with SARS-CoV-2 pneumonia. Methods We report on a single-center study of tocilizumab in hospitalized patients with SARS-CoV-2 pneumonia. All patients had confirmed SARS-CoV-2 pneumonia and oxygen saturations Results Twenty-seven SARS-CoV-2 pneumonia patients received one 400 mg dose of tocilizumab. Interleukin (IL)-6 was the predominant cytokine detected at tocilizumab treatment. Significant reductions in temperature and CRP were seen post-tocilizumab. However, 4 patients did not show rapid CRP declines, of whom 3 had poorer outcomes. Oxygen and vasopressor requirements diminished over the first week post-tocilizumab. Twenty-two patients required mechanical ventilation; at last follow-up, 16 were extubated. Adverse events and serious adverse events were minimal, but 2 deaths (7.4%) occurred that were felt unrelated to tocilizumab. Conclusions Compared to published reports on the morbidity and mortality associated with SARS-CoV-2, tocilizumab appears to offer benefits in reducing inflammation, oxygen requirements, vasopressor support, and mortality. The rationale for tocilizumab treatment is supported by detection of IL-6 in pathogenic levels in all patients. Additional doses of tocilizumab may be needed for those showing slow declines in CRP. Proof of efficacy awaits randomized, placebo-controlled clinical trials.

Background Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted. Methods and Results A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed LVEF 58% (with EF 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously x1 dose. Within 24 hours, he noted significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers. There was a transient leukopenia which improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms. Conclusion Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide., Highlights • Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. • A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein, interleukin-6 (IL-6), and other inflammatory markers. Echocardiogram showed normal LV function. • The patient received clazakizumab (anti-IL-6 monoclonal antibody) 25 mg as a single dose, with significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers within 24 hours, and discharge to home on day 11. He had a negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, developed a positive serum COVID-19 IgG antibody, and was continuing to do well clinically on day 60. • Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19.

Purpose In the past, Hepatitis B donors have been declined in patients who have not been vaccinated by the Hepatitis B vaccine. There is concern that these donors would transmit Hepatitis B to the recipient if they are not vaccinated. There is treatment available for these Hepatitis B infections, however, it has not been established as to its efficacy in patients on immunosuppression. In addition, hepatitis viruses have been reported to affect the endothelium of vital organs. Hepatitis B may injure the endothelium of the coronary vascular tree and could potentially result in a greater development of cardiac allograft vasculopathy (CAV) after heart transplantation. Therefore, we sought to assess this possibility by examining our patients who received Hepatitis B donors. Methods Between 2010 and 2016 we assessed 24 heart transplant patients who received a Hepatitis B donor. All of the recipients had received a Hepatitis B vaccine prior to transplantation. Endpoints include 3-year survival, 3-year freedom from CAV, 3-year freedom from non-fatal major adverse cardiac events (NF-MACE), and freedom from first year rejection, including any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). These study patients were compared with 600 patients without Hepatitis B donors in a contemporaneous era. Results 3-year survival, freedom from NF-MACE, and freedom from first year rejection were similar between the Hepatitis B and control groups. There is numerically a lower incidence of freedom from CAV in the Hepatitis B group compared to the control, but this was not statistically significant. Conclusion Hepatitis B donors appear to have acceptable outcome compared to non-Hepatitis B donors after heart transplantation. Larger numbers of Hepatitis B donors will be needed to assess risk for increased CAV development.

Purpose To date, there are no studies evaluating the effects of prophylactic antibiotic regimens in patients receiving temporary Impella® mechanical circulatory support (MCS). The purpose of this study was to compare the incidence of surgical-related infections within 30 days of temporary MCS implantation in patients receiving narrow versus broad spectrum peri-operative antibiotics. Methods 89 Patients receiving Impella® 5, 5.5, and CP devices in a surgical setting at Cedars-Sinai Medical Center from January 2017 to August 2020 were included for analysis which was IRB approved. This study period includes devices implanted before and after the implementation of MCS Antibiotic Selection for Surgical Prophylaxis Guideline. This protocol recommends cefazolin or ceftriaxone for pre-op surgical prophylaxis, with gentamicin for additional gram-negative coverage and vancomycin for beta-lactam allergy. 34/89 (38.2%) patients were identified as Stewardship (protocol adherence), while 27/89 (30.3%) were identified as Conventional (protocol non-adherence) another 28/89 (31.5%) patients were identified as Pre-existing (admitted with prior antimicrobial). The primary endpoint was the incidence of surgical site infections (SSI) and surgical-related bacteremia (SRB) within 30-day post-implant period. The secondary endpoint was protocol adherence. Results 72%, 26% and 2% of patients were bridged to heart transplant, durable MCS or no device, at 30 days respectively. There were no cases of SSI within 30 days post-operatively in any group, except for one case of SRB with Streptococcus mitis bacteremia in the Conventional group. Patients were screened for Methicillin-resistant Staphylococcus aureus (MRSA) colonization before incision in 72.2% of cases (mean, 2.6 days prior to device implantation). Reasons for non-adherence included incorrect duration of post-operative antibiotic(s) (44.4%), no pre-operative antibiotic given prior to incision (25.9%), and incorrect pre-operative antibiotic(s) given (22.2%). Conclusion The absence of SSI and SRB among Stewardship group supports narrow spectrum pre-op antibiotic prophylaxis over broad-spectrum agents for Impella® non-durable MCS.

Purpose Chagas disease (CD) is caused by the parasite T cruzi and may reactivate in immunosuppressed transplant recipients. The incidence of CD has increased in Southern California as patients with Chagas cardiomyopathy may progress to require heart transplantation. While there are prophylactic medications for CD, is it not clear whether this prophylaxis prevents CD reactivation. Methods We reviewed 13 recipients transplanted between 1999 and 2019 who had CD prior to transplant. These patients had CD serologies checked at 1, 3, 6, 12 months post-transplant. 7 had T cruzi IgG antibodies and were given nifurtimox (n=2) or benznidazole (n=5). The other 6 did not develop antibodies and were not given antimicrobial therapy. Outcomes were compared: symptomatic CD, 1-year survival, freedom from rejection [any-treated (ATR), acute cellular (ACR) and antibody-mediated rejections (AMR)]. Results The patients who received antimicrobial therapy had numerically better 1-year survival. There was no difference in 1-year rejection (Table). Of the 7 patients who received antimicrobial therapy, none had CD reactivation while 3 patients in the no-prophylaxis group had CD reactivation. Conclusion Heart transplant patients with a history of CD appear to have acceptable outcome when closely monitored and administered antimicrobial therapy when indicated. Administration of prophylactic antimicrobial therapy to all CD, even without IgG antibodies, may be considered.

Oral mucormycosis is a rare and high risk of infection in patients following hematopoietic cell transplantation few cases in the literature. We review the literature and present an additional case to emphasize the subtle changes that resulted in positive outcome when diagnosed and managed in a comprehensive transplant team.A patient was diagnosed with gingival mucormycosis on day +25 following a hematopoietic stem cell transplant for lymphoblastic transformation of chronic myeloid leukemia. The patient was diagnosed with minor and nonspecific symptoms and was successfully treated with local dental extraction, a short course of liposomal amphotericin B and 4 months of oral posaconazole.The good outcome of this case highlights the subtle clinical changes that present early in mucormycosis and the importance of early detection and treatment of post-transplant oral infections by an experienced multidisciplinary team.

Purpose Cholecystitis after mechanical circulatory support (MCS) implantation is possibly related to hemodynamic changes related to continuous peripheral blood flow. Visceral hypoperfusion is also a reported risk factor. We aimed to evaluate the incidence of cholecystitis in non-pulsatile LVAD vs pulsatile TAH devices. Methods We reviewed data from all durable MCS patients at a single large center from 2011 through 2019. The primary endpoint was cholecystitis requiring surgery. We reviewed explanted gallbladder pathology, the length of time between implantation and cholecystectomy, as well as INTERMACS profile at time of MCS. Results 11 out of 151 (7.3%) LVAD patients required cholecystectomy versus 18 out of 93 (19.4%) TAH patients, p-value 0.004. While cholecystectomies occurred earlier in patients with TAH vs LVAD, it was not statistically significant p 0.251. Wilcoxon Ranked Sum Test showed that surgical interventions occurred earlier in acute acalculous cholecystitis (ACC) than in calculous cholecystitis (CC) Z=151, p Conclusion There was a significantly higher incidence of cholecystitis requiring surgery in the pulsatile (TAH) vs non-pulsatile (LVAD) MCS devices. Surgical intervention occurred earlier in patients with ACC versus CC. This may be related to both biventricular failure and higher acuity at time of implant in TAH patients.

First described in the United States in the late 1990s, West Nile virus (WNV) infection following solid organ transplantation is a rare but life-threatening complication. The many ways in which WNV may be acquired, patient specific risk factors, and variability in clinical severity present challenges to health care providers caring for these patients.

Purpose Thymoglobulin (ATG) is commonly used as induction therapy immediately after heart transplantation (HTx). ATG has been associated with an increase in CMV infection when used with maintenance cyclosporine. In the current era, tacrolimus has replaced cyclosporine as the main maintenance immunosuppressive agent. It is not clear whether ATG induction does indeed lead to more CMV infection in the tacrolimus era. Methods Between 2010 and 2016, we assessed 342 patients who received ATG induction therapy and compared them with HTx patients who did not receive ATG (n=312). ATG is routinely administered to patients with renal insufficiency to delay tacrolimus initiation and to sensitized patients (PRA ≥ 10%). Patients treated with ATG were then divided into their donor/recipient CMV serology matching (D+R-, D+R+, D-R+ and D-R-) and analyzed for the development of CMV infection defined as patients presenting with clinical symptoms and detected CMV virus via PCR. Incidence of rejection was also evaluated. Valcyte is routinely administered for CMV prophylaxis. Results There was a trend towards an increase in CMV infection in patients who received ATG induction therapy after HTx (see table). When the ATG population was analyzed by CMV serology, CMV mismatch (D+R-) had a numerical increase in CMV infection but this result was not statistically significant. When compared to the D-R- group on pairwise analysis, there was a trend towards increase in CMV infection and any-treated rejection in the CMV mismatch group (D+R-). (see table). Of note, valcyte induction was similar between groups per the transplant protocol. Conclusion ATG therapy trends towards increased CMV infection post-transplant in the tacrolimus era. Patients who have been treated with ATG and have CMV mismatch (D+R-) may have increased CMV infection risk as well as rejection risk by 2-years after HTx. Larger numbers are needed to confirm these findings.

Purpose Cytomegalovirus (CMV) has been documented as a risk factor for the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). It has not been firmly established whether CMV would cause an increase in first-year intimal thickening via intravascular ultrasound (IVUS) in the current tacrolimus era. First-year maximal intimal thickening (MIT) ≥0.5mm has been found to be predictive of poor outcome (worse survival, CAV) at 5-years post-transplant. In addition, there has not been a differentiation between CMV infection, CMV syndrome, and CMV disease as it applies to IVUS intimal thickening. CMV infection is noted by positive IgG CMV serology only; CMV syndrome refers to patients with documented CMV virus along with a clinical presentation; CMV disease is defined as organ-specific CMV infection i.e. CMV pneumonitis, CMV colitis etc. Therefore, we sought to use first-year IVUS to determine whether CMV infection, syndrome, or disease would lead to more first-year MIT ≥0.5mm. Methods Between 2010 and 2017, 294 heart transplant patients underwent baseline and 1-year IVUS. These patients were then divided into 4 groups: (Group A - no CMV infection (n=108); Group B - CMV infection (n=173); Group C - CMV syndrome (n=9); and Group D - CMV disease (n=3)). Diagnosis of CAV was based on a ≥ 0.5 mm increase in maximal intimal thickness (MIT) from baseline. Results Baseline MIT was similar among all study groups. The percent of patients with first-year MIT ≥0.5mm was also similar among all patient groups. Conclusion The development of CMV infection, syndrome and disease, does not appear to increase CAV risk by first-year MIT obtained by IVUS in the current tacrolimus era. Larger number of patients with longer follow-up studies are warranted to confirm these findings.

Purpose The lack of standardization in MCS surgical infection prophylaxis (ppx) has led to highly varied antimicrobial regimens with broad-spectrum activity. The purpose of this study is to compare the incidence of SSI with narrow vs broad-spectrum antibiotics (abx) in MCS patients within 30 days post-op, and to assess adherence to abx ppx standards. Methods A single-center, IRB-approved retrospective analysis was performed on 52 patients implanted with a durable MCS device from 4/2017-6/2018, after implementation of the MCS Antibiotic Selection for Surgical Prophylaxis Guideline at Cedars-Sinai Medical Center. The protocol recommends cefazolin or ceftriaxone for pre-op surgical ppx, with optional gentamicin for additional gram-negative coverage and vancomycin for severe β-lactam allergy. 26 patients were identified as On-Protocol (Cohort 1; protocol adherence), while another 26 patients were identified as Off-Protocol (Cohort 2; protocol non-adherence). The primary endpoint was SSI incidence among Cohort 1 (C1) and Cohort 2 (C2) within 30 days post-op. The secondary endpoints assessed protocol adherence. Results No patients in either cohort developed an SSI within 30 days post-op. C1 received a median of 1 pre-op abx, while C2 received a median of 2 pre-op abx (p=0.009). 12 patients in C1 received non-protocol abx post-op for open chest ppx or empiric treatment of a non-cardiac infection. Non-protocol antimicrobials used in C2 included vancomycin in patients with no β-lactam allergy (73%), piperacillin-tazobactam (31%), fluconazole (4%), and cefepime (4%). The average time between pre-op abx administration and first incision time was 18 min for C1 and 27 min for C2 (p=0.04). 83% of C1 and 53% of C2 received peri-op abx ppx for surgeries longer than 4 h (p=0.04). 46% of C1 and 54% of C2 had post-op abx extended beyond 48 h. Of these patients, 81% in C1 and 77% in C2 were empirically treated for non-cardiac infections, with only 27% of C1 and 4% of C2 having positive cultures (p=0.05). Conclusion The absence of SSI among Cohorts 1 and 2 supports narrow-spectrum pre-op abx ppx over broad-spectrum agents for durable MCS. The results of this preliminary, ongoing study promote abx stewardship and protocol adherence, which will help minimize the risk of antimicrobial resistance.

Purpose Proliferation signal inhibitors (PSIs) have been shown to decrease the incidence of cardiac allograft vasculopathy (CAV) and rejection in clinical trials when given at the time of heart transplantation. These trials have also demonstrated that patients on PSIs have a reduced risk of CMV infection post-transplant. However, the effect of PSIs on overall infection rates when given later post-transplant has not been clearly delineated. We sought to evaluate the incidence of infection post-PSI initiation at our single center. Methods Between 2010 and 2015 we assessed 550 heart transplant patients, 187 of which were initiated on a PSI (sirolimus or everolimus) over a five-year period after heart transplant. Endpoints included subsequent 2-year survival and subsequent 2-year freedom from infection (including CMV). A control population with patients not initiated on a PSI (n=363) was also included. Results 187/550 (34.0%) of heart transplant patients were initiated on a PSI over a five-year period after heart transplant. Patients were initiated on a PSI due to rejection, malignancy, CMV viremia, CAV, circulating antibodies, renal insufficiency and infection. The average time to PSI initiation was 1.3 years. Patients on a PSI compared to patients on no PSI had significantly reduced subsequent 2-year survival and reduced subsequent 2-year freedom from infection (see table). There was no difference in subsequent 2-year freedom from CMV infection. Conclusion PSI initiation later after heart transplant is associated with less than optimal outcomes. However, as PSI is used in high-risk patients, the outcomes are not unexpected but PSI use may have increased infection risk. PSI should be used with caution in these patients.

Since an initial case in 2006, we noted multiple patients undergoing heart transplantation (HTx) for Chagas cardiomyopathy (CC) at our transplant program. The clinical characteristics, laboratory results and outcomes of patients with CC undergoing HTx in the United States have not been reported previously. In 2010, we implemented a systematic screening and management program for patients undergoing HTx for CC. Before HTx, all patients with idiopathic dilated cardiomyopathy who were born in a Chagas disease endemic country were screened for Trypanosoma cruzi (TC) infection with serology. After HTx, monitoring for TC reactivation was performed using clinical visits, echocardiography, endomyocardial biopsy and serial whole blood polymerase chain reaction (PCR) testing. Between June 2006 and January 2012, 11 patients underwent HTx for CC. One patient was empirically treated due to the presence of TC amastigotes in explanted cardiac tissue. Two patients experienced allograft dysfunction due to TC reactivation and three patients experienced subclinical reactivation (positive PCR results), which were treated. Chagas disease is a common cause of dilated cardiomyopathy in patients from endemic countries undergoing HTx at a transplant program in the United States. Reactivation is common after transplantation and can cause adverse outcomes.

Herpes simplex virus (HSV) infection commonly occurs during the immunosuppression associated with hematopoietic stem cell transplantation (HSCT). Prophylaxis of recurrent infection and management of clinical infection have relied upon acyclovir and congeners. More recently, resistant HSV infection is seen in HSCT and presents new challenges in management. We present a case of HSV following HSCT that provided effective symptomatic management. Oral symptoms and lesions were repeatedly reduced when topical cidofovir was used, strongly supporting the effect of cidofovir used in a host who could not tolerate systemic antiviral medications. Topical cidofovir can provide effective management of symptomatic oropharyngeal HSV while reducing risk of systemic toxicity and drug interaction and represents an additional approach to management for management in medically compromised patients.

We reviewed the current literature on the role of antibiotic therapy in cystic fibrosis, concentrating on studies directing therapy at Pseudomonas aeruginosa. To highlight controversial areas, we examined studies comparing monotherapy with combination therapy, home intravenous treatment versus hospital treatment, intravenous versus oral therapy, and the role of aerosolized antibiotics. We found that all systemic therapies with antipseudomonal activity were of comparable efficacy. Data on the efficacy of aerosolized treatment were equivocal. There is a substantial body of anecdotal literature addressing the issue of antibiotic resistance complicating treatment of cystic fibrosis. This will be briefly reviewed and the responsible mechanisms will be outlined. There is a secular trend for selection of more resistant pathogens in the lungs of CF patients. In the individual patient, however, emergence of antibiotic resistance may occur without deleterious clinical effects.