Journal Logo

Original Clinical Science—General

Recent Trends of Infectious Complications Following Heart Transplantation

Multani, Ashrit MD1,2; Moayedi, Yasbanoo MD3,4; Puing, Alfredo MD1; Henricksen, Erik PharmD3; Garvert, Donn W. MS1; Gomez, Carlos A. MD5; Tremblay-Gravel, Maxime MD3; Bunce, Paul E. MD6; Luikart, Helen RN3; Ross, Heather J. MD4; Khush, Kiran K. MD3; Montoya, Jose G. MD1,2; Teuteberg, Jeffrey J. MD3

Author Information
doi: 10.1097/TP.0000000000003307
  • Free

Abstract

INTRODUCTION

The success of solid organ transplantation has been enhanced by advances in immunosuppression. Unfortunately, while rejection rates have declined, there has been an increase in posttransplant infections.1-3 According to a recent International Society of Heart and Lung Transplantation registry report, noncytomegalovirus (CMV) infection is the leading cause of death between 31 days and the first year after heart transplantation and is responsible for 30% of deaths overall.4 In 1971, the pioneers of heart transplantation in the United States reported the infectious complications related to the first 20 heart transplants performed at Stanford University Medical Center.5 Twelve of 20 patients developed infectious complications, likely due to overimmunosuppression in the absence of rejection surveillance. Thirty years later, Montoya et al found that 80%–90% of infectious episodes (IEps) following heart transplantation were caused by bacterial and viral infections.2 There was a significant decrease in the rate of IEp overtime attributed to antimicrobial prophylaxis and targeted immunosuppression.2

The aim of our study was to systematically evaluate IEp in a contemporary cohort of patients at Stanford from 2008 to 2017. Compared with our previous reports, this new cohort comprises a growing number using mechanical circulatory support, tailored immunosuppression, and improved antimicrobial use.

MATERIALS AND METHODS

Population

A total of 279 consecutive adult (aged ≥18 y) patients underwent 282 orthotopic heart transplant procedures and were followed at Stanford from January 2008 to September 2017. Baseline clinical and demographic information on recipients and donors, pretransplant infectious diseases screening, presence of left ventricular assist device (LVAD) pretransplantation, duration of antiviral and antifungal prophylaxis, incidence and type of IEp (in both inpatient and outpatient settings), rate of hemodynamically significant rejection, antibody-mediated rejection, and survival were retrospectively collected and recorded in a secure electronic database. Patients who underwent heart-lung transplantation and those who were not followed at Stanford in the outpatient setting were excluded.

Immunosuppression

All patients who were included in this database underwent induction therapy with antithymocyte globulin or daclizumab from 2008 to 2010 and then only antithymocyte globulin after March 2010 as per Stanford heart transplant protocol. Maintenance immunosuppression included corticosteroids, mycophenolate mofetil/mycophenolic acid, and tacrolimus. Based on the Stanford protocol, corticosteroids were tapered within 1 year posttransplantation. Patients who developed cardiac allograft vasculopathy, refractory neutropenia, progressive renal dysfunction, or otherwise required a calcineurin-free regimen were transitioned to everolimus or sirolimus after 3 months posttransplantation. No patients were maintained on calcineurin inhibitor monotherapy. Assays to monitor immune status such as Cylex Immune Cell Function Assay (ImmuKnow; Cylex, Inc., Columbia, MD) were used on occasion but were not included in the standard protocol or recorded in the database.

Perioperative Antibacterial Prophylaxis

According to the protocol between December 2007 and October 2017, perioperative antibacterial prophylaxis consisted of cefazolin (2 g IV in the operating room [OR] followed by 1 g IV every 8 h) for 48 hours. Patients allergic to penicillin received vancomycin (at least 1 g IV in the OR, repeated after 4 h in the OR, then 1 g or weight-based IV every 12 h) for 48 hours.

After a protocol update in October 2017, perioperative antibacterial prophylaxis consisted of cefazolin (2 g IV in the OR followed by 2 g IV every 8 h) for 48 hours. Patients with known penicillin allergies or colonized with methicillin-resistant Staphylococcus aureus were given vancomycin (at least 1 g IV in the OR, repeated after 4 h in the OR, then 1 g or weight-based IV every 12 h) for 48 hours. Patients who were hospitalized before the heart transplant surgery and those with LVAD were given piperacillin-tazobactam (3.375 g IV in the OR, then every 8 h) plus vancomycin for 48 hours. Patients with LVAD-associated infections had posttransplant antibacterial regimens and durations guided by immunocompromised host infectious diseases services consultation based upon microbiologic data and extent of infection (if any) seen at the time of LVAD explantation and orthotopic heart transplantation.

Antiviral Prophylaxis

Antiviral prophylaxis was dictated by the donor and recipient CMV IgG serostatus. Between December 2007 and October 2017, CMV serological mismatch (donor positive, recipient negative, D+/R−) patients received valganciclovir 900 mg twice daily for 2 weeks posttransplantation, then 900 mg daily until 6 months posttransplantation, and then 450 mg daily until 12 months posttransplantation. CMV hyperimmune globulin (CMV-IVIG) was given at a dose of 150 mg/kg within 72 hours posttransplantation, 100 mg/kg at weeks 2, 4, 6, and 8 posttransplantation, and then 50 mg/kg at weeks 12 and 16 posttransplantation. CMV R+ patients received valganciclovir 900 mg daily for 2 weeks posttransplantation, then 450 mg daily until 12 months posttransplantation. CMV D−/R− patients received acyclovir 400 mg twice daily for herpes simplex virus (HSV) and Varicella-zoster virus (VZV) prophylaxis until 12 months posttransplantation.

After a protocol update in October 2017, CMV D+/R− patients received valganciclovir 900 mg daily until 6 months posttransplantation, followed by acyclovir 400 mg twice daily for HSV/VZV prophylaxis until 12 months posttransplantation. After valganciclovir discontinuation, patients underwent regular surveillance for CMV viremia until 12 months posttransplantation. CMV-IVIG was no longer administered. CMV R+ patients received valganciclovir 900 mg daily for 2 weeks posttransplantation, then 450 mg daily until 6 months posttransplantation, followed by acyclovir 400 mg twice daily for HSV/VZV prophylaxis until 12 months posttransplantation. CMV D−/R− patients received acyclovir 400 mg twice daily for HSV/VZV prophylaxis until 12 months posttransplantation.

Patients who were unable to take oral drugs were given ganciclovir intravenously at a dose comparable to the recommended valganciclovir dose (eg, ganciclovir 5 mg/kg IV every 24 h if they were supposed to be taking valganciclovir 900 mg daily) until they were able to take valganciclovir orally. Patients who developed myelotoxicity underwent a CMV preemptive approach, which comprises acyclovir 800 mg thrice daily instead of valganciclovir for CMV/HSV/VZV prophylaxis and also had weekly plasma quantitative CMV DNA polymerase chain reaction (PCR) monitoring. Dose adjustments were made for patients with reduced creatinine clearance.

Antifungal Prophylaxis

Since December 2007, patients received either nystatin (5 mL swish and swallow) or clotrimazole (10 mg troche) for the prevention of oropharyngeal candidiasis while on corticosteroids. Mold prophylaxis consisted of amphotericin B deoxycholate (20 mg via inhalation twice daily, started posttransplantation, and continued until discharge from the hospital) and itraconazole solution (200 mg in the morning and 100 mg in the evening, started as soon as the patient was able to tolerate oral medications, and continued until 3 mo posttransplantation). Patients were also instructed to wear a high-efficiency particulate air (HEPA) filter respiratory mask anytime they were outside of their home until 3 months posttransplantation and then to wear either a HEPA filter respiratory mask or an N95 respirator mask when going to and from clinic appointments or during activities that involved close contact with soil or dust (eg, yard work) from 3 to 12 months posttransplantation.

Pneumocystis jirovecii Prophylaxis

Since December 2007, patients received prophylaxis against Pneumocystis jirovecii for 12 months posttransplantation. Trimethoprim-sulfamethoxazole (TMP-SMX) 80–400 mg daily was the preferred agent. Patients with a history of sulfa allergy or myelotoxicity received atovaquone 1500 mg daily or dapsone 100 mg daily (if not G6PD-deficient). Pentamidine (300 mg via inhalation monthly) was only used in the setting of TMP-SMX, atovaquone, and dapsone intolerance.

Toxoplasma gondii Prophylaxis

Routine screening of deceased solid organ donors for Toxoplasma gondii IgG was implemented by United Network for Organ Sharing in April 2017. Heart donor Toxoplasma gondii IgG serology was performed, but results were not systematically recorded by United Network for Organ Sharing before this (personal communication). Since December 2007, patients who were known to have Toxoplasma gondii D+/R− serostatus mismatch received prophylaxis for at least 12 months posttransplantation. TMP-SMX 80–400 mg daily was the preferred agent. Alternative regimens included atovaquone 1500 mg daily or pyrimethamine 25 mg daily (plus folinic acid 10 mg daily).

Definition of Infection

Infections were defined according to Centers for Disease Control and Prevention/National Healthcare Safety Network (CDC/NHSN) surveillance definitions. Bloodstream infection (BSI) was defined as any IEp that met CDC/NHSN surveillance definition for primary BSI, secondary BSI, central line-associated BSI, or noncentral line-associated BSI. For ease of comparison between organisms, viremia was also classified as BSI. Lower respiratory tract infection (LRTI) was defined as any IEp that met CDC/NHSN surveillance definition for nonventilator associated pneumonia, ventilator-associated pneumonia, or lower respiratory infection other than pneumonia. Urinary tract infection (UTI) was defined as any IEp that met CDC/NHSN surveillance definition for symptomatic UTI, asymptomatic bacteremic UTI, urinary system infection, or catheter-associated UTI. If patient symptomatology was not recorded, a positive urine culture with no >2 species of organisms (at least 1 of which was a bacterium of at least 100 000 CFU/mL) for which targeted antimicrobial therapy was administered was classified as UTI. Disseminated infection was defined as 1 that involved >1 anatomic location.

Infections were coded for positive microbiological (eg, culture and PCR) and histopathological data (eg, immunohistochemical stains) that were deemed to be clinically significant warranting targeted antimicrobial therapy. Clinical syndromes that were strongly suggestive of an infectious process but did not yield positive microbiological or histopathological data were coded as IEp without an identified organism. All consecutive IEps in each transplant recipient in both inpatient and outpatient settings were included.

Statistical Analysis

Baseline characteristics were described using absolute and relative frequencies for categorical variables, mean ± SD or median, and interquartile range (IQR) for continuous variables. Baseline characteristics were compared using Student t test (Mann-Whitney U test when appropriate) for continuous variables and chi-squared test (Fisher’s exact test when appropriate) for categorical variables. Survival data were estimated and summarized using the Kaplan-Meier method. The log-rank test was used to test differences in survival across subgroups if the Kaplan-Meier curves did not cross. In the instances of crossing, univariate Cox-proportional hazard modeling was used to test for differences across subgroups. STATA (version 15.1) was used for all statistical analyses. A 2-sided P value of 0.05 was defined as the threshold for statistical significance.

This study was approved by the Stanford University Institutional Review Board.

RESULTS

Baseline characteristics of heart transplant recipients and donors are presented in Table 1. The cohort consisted of predominantly men (69.2%), with a median age of 53 (IQR, 43–61 y) years and a median body mass index of 25.6 (IQR, 22.7–29.0) kg/m2. Patients were primarily Caucasian (59.5%), followed by Hispanic (18.3%), Asian (11.5%), African American (8.2%), and Native Hawaiian/Pacific Islander (2.5%). Recipient comorbidities included hypertension (60.0%), diabetes mellitus (47.0%), and chronic obstructive pulmonary disease (10.0%). The cause of the recipient’s heart failure was mainly nonischemic cardiomyopathy (44.8%), followed by ischemic cardiomyopathy (22.6%), other (19.4%), and congenital cardiomyopathy (6.5%). Multiorgan transplants consisted of heart-kidney (10.3%) and heart-liver (2.1%). Durable LVAD as bridge-to-transplantation was placed in 72 (25.8%) recipients. In this cohort, 21 (7.4%) patients underwent retransplantation, including 3 who underwent 2 heart transplants each within the study period.

TABLE 1. - Baseline characteristics of heart transplantation recipients and donors at Stanford University Medical Center between January 2008 and September 2017
Baseline characteristic N Result
Recipient
 Age (y)—mean (IQR) 279 53 (43, 61)
 Male sex—No. (%) 279 193 (69.2)
 Race/ethnicity—No. (%) 279
  Caucasian 166 (59.5)
  Hispanic 51 (18.3)
  Asian 32 (11.5)
  African American 23 (8.2)
  Native Hawaiian/Pacific Islander 7 (2.5)
Comorbidities—No. (%) 279
 Hypertension 167 (60.0)
 Diabetes mellitus 132 (47.0)
 Chronic obstructive pulmonary disease 28 (10.0)
Body mass index (kg/m2)—median (IQR) 279 25.6 (22.7, 29.0)
Heart failure cause—No. (%) 279
 Dilated cardiomyopathy 125 (44.8)
 Ischemic cardiomyopathy 63 (22.6)
 Other 54 (19.4)
 Congenital 18 (6.5)
Multiorgan transplantation—No. (%) 282
 Heart-kidney 29 (10.3)
 Heart-liver 6 (2.1)
Left ventricular assist device bridge—No. (%) 279 72 (25.8)
Retransplantation—No. (%) 282 21 (7.4)
Ischemic time (min)—median (IQR) 282 230 (196.3,260.8)
Donor
Age (y)—median (IQR) 32 (24,43)
Male sex—No. (%) 275 188 (68.4)
Cause of death—No. (%) 281
 Intracranial hemorrhage 203 (72.2)
 Anoxia 65 (23.1)
 Gunshot wound/hemorrhage 11 (3.9)
 Domino heart—No. (%) 2 (0.7)
CMV D+/R– serostatus—No. (%) 282 54 (19.1)
Public health service increased risk—No. (%) 282 43 (15.2)
CMV, cytomegalovirus; D, donor; IQR, interquartile range; R, recipient.

Median follow-up period was 3.0 (1.3, 6.0) years. Allograft dysfunction, as defined by a left ventricular ejection fraction <45% occurred in 45 (16.1%) patients. Hemodynamically significant rejection occurred in 37 (13.3%) patients. Treated antibody–mediated rejection occurred in 36 (12.9%) patients. Survival at 1 year posttransplantation was as follows: overall, 87.9% (95% CI, 83.5-95.2); those with any IEp within the first year posttransplantation, 83.3% (95% CI, 76.2-88.4); and those without any IEp within the first year posttransplantation, 93.0% (95% CI, 87.2-96.4; P = 0.07) (Figure 1). There were 58 (20.8%) deaths, of which 17 (29.3%) were attributed to IEp and 5 (8.6%) were attributed to allograft rejection. However, there was no difference in mortality conditional on 1-year survival (P = 0.86), suggesting that the effect of infection is associated with early short-term survival.

FIGURE 1.
FIGURE 1.:
Kaplan-Meier survival estimates stratified by development of infection within the first posttransplant y in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017.

Pretransplantation Infectious Diseases Screening

Pretransplant infectious disease screening of donors and recipients is presented in Table 2. CMV serostatus was positive among 179 (68.1%) donors and 179 (63.5%) recipients. CMV mismatch (D+/R–) occurred in 54 (19.1%) transplants.

TABLE 2. - Pretransplant infectious diseases screening of heart transplantation donors and recipients at Stanford University Medical Center between January 2008 and September 2017
HIV Syphilis TB Toxo CMV EBV VCA EBNA HAV HBsAg HBsAb HBcAb HBV NAT HCV HCV NAT HSV VZV
Donor (N = 282)
(+) 0 1 0 4 179 247 19 0 0 0 12 0 2 2 0 0
(−) 262 261 0 39 84 11 5 0 262 0 250 172 260 256 0 0
Unk. 20 20 282 239 19 24 258 282 20 282 20 70 20 24 282 282
Recipient (N = 282)
(+) 0 2 21 38 179 264 244 133 0 59 20 0 8 0 135 212
(−) 273 254 197 219 101 11 24 139 275 163 246 0 269 0 70 7
Unk. 9 26 64 35 2 7 12 10 2 60 16 282 5 282 77 63
(−), negative; (+), positive; CMV, cytomegalovirus IgG; EBNA, Epstein-Barr virus nuclear antigen IgG; EBV VCA, Epstein-Barr virus viral capsid antigen IgG; HAV, hepatitis A virus IgG; HBcAb, hepatitis B core antibody IgG; HBsAb, hepatitis B surface antibody IgG; HBsAg, hepatitis B surface antigen; HBV NAT, hepatitis B virus nucleic acid test; HCV NAT, hepatitis C virus nucleic acid test; HCV, hepatitis C virus antibody IgG; HSV, herpes simplex virus-1/2 IgG; IgG, immunoglobulin G; TB, positive or indeterminate quantiferon for Mycobacterium tuberculosis; Toxo, Toxoplasma gondii IgG; Unk., unknown; VZV, Varicella-zoster virus IgG.

Two recipients received organs from hepatitis C PCR-positive donors and had evidence of donor-derived transmission. One recipient received sofosbuvir/velpatasvir for 12 weeks and achieved sustained virologic response. The other received ledipasvir/sofosbuvir without response and subsequently achieved sustained virologic response after being switched to sofosbuvir/velpatasvir/voxilaprevir for 12 weeks.

Twelve donors were hepatitis B core antibody positive, hepatitis B surface antigen negative, hepatitis B surface antibody negative, and hepatitis B PCR negative. This pattern of test results was interpreted as false-positive hepatitis B core antibody testing. Recipients of organs from these donors underwent periodic surveillance with hepatitis B PCR testing during the first 12 months posttransplant without antiviral therapy, and none demonstrated donor-derived transmission.

Infectious Episodes, by Organism Category and Location of Infection

There were 600 IEp in 279 patients (2.15 IEp per patient), which are summarized by organism category and location in Table 3. By organism category, bacterial IEp were the most common (n = 375; 62.5%), followed by viral (n = 180; 30.0%), fungal (n = 40; 6.7%), and parasitic (n = 5; 0.8%). By location of infection, BSI was the most common (n = 130; 21.7%), followed by LRTI (n = 129; 21.5%) and UTI (n = 104; 17.3%). By organism category and location of infection, bacterial UTIs (n = 101; 16.8%) were the most common, followed by bacterial LRTIs (n = 84; 14.0%) and bacterial BSIs (n = 66; 11.0%).

TABLE 3. - Causes and locations of infectious episodes in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017
Organism category Location of infection Total
BSI Bone/joint CNS Diss. GI HRT HB LRTI MDST None Ocular Oral SSTI URTI UTI
Bacteria 66 14 0 0 55 3 5 84 7 0 1 0 37 2 101 375
Fungi 6 1 1 1 2 1 0 19 0 0 0 1 4 3 1 40
Viruses 57 0 0 2 22 0 2 26 0 0 1 7 7 54 2 180
Parasites 1 0 0 0 1 1 0 0 0 2 0 0 0 0 0 5
Total 130 15 1 3 80 5 7 129 7 2 2 8 48 59 104 600
BSI, bloodstream infection; CNS, central nervous system; Diss., disseminated; GI, gastrointestinal/intraabdominal; HB, hepatobiliary; HRT, heart/pericardium; LRTI, lower respiratory tract infection; MDST, mediastinum; none, no location; SSTI, skin and soft tissue infection; URTI, upper respiratory tract infection; UTI, urinary tract infection.

Bacterial Infections

There were 375 bacterial infections (1.34 bacterial IEp per patient) as summarized in Table 4. Infections by Gram-negative bacteria (n = 210) outnumbered those by Gram-positive bacteria (n = 142) (Figure 2). The most common bacterial infection was Escherichia coli UTI (n = 43). By organism, Escherichia coli was the most common (n = 76), followed by Klebsiella species (n = 55) and Staphylococcus aureus (n = 41). Twelve of the 41 (29.3%) Staphylococcus aureus isolates were methicillin resistant. There were 36 Clostridioides difficile (formerly Clostridium difficile) infections (including 1 skin and soft tissue infection), 21 infections caused by vancomycin-resistant enterococci, 5 infections caused by Mycobacterium avium-intracellulare complex, 3 infections caused by Nocardia species, and 1 infection caused by Listeria monocytogenes. There were no bacterial central nervous system (CNS) infections nor any infections caused by carbapenem-resistant Gram-negative bacteria, Legionella species, Mycobacterium tuberculosis, or Mycobacterium chimaera.

TABLE 4. - Causes and locations of bacterial infectious episodes in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017
Organism Location of infection Total
BSI Bone/joint GI HRT HB LRTI MDST Ocular SSTI URTI UTI
Gram-positive (N = 142)
MSSA 4 1 0 1 0 7 1 1 14 0 0 29
MRSA 2 1 0 1 0 2 1 0 5 0 0 12
CoNS 5 2 1 0 0 1 0 0 1 0 3 13
Streptococcus pneumoniae 1 0 0 0 0 2 0 0 0 0 0 3
Other Streptococcus sp 6 1 0 0 1 0 0 0 1 1 0 10
Enterococcus sp 2 0 1 0 0 0 1 0 0 0 8 12
VRE sp 10 0 1 0 0 3 1 0 1 0 5 21
Clostridioides difficile 0 0 35 0 0 0 0 0 1 0 0 36
Corynebacterium sp 0 0 0 0 0 1 0 0 1 0 0 2
Listeria monocytogenes 1 0 0 0 0 0 0 0 0 0 0 1
Other GPB 0 0 2 0 0 1 0 0 0 0 0 2
Gram-negative (N = 210)
Escherichia coli 16 1 3 0 1 10 0 0 2 0 43 76
Klebsiella sp 10 1 3 0 1 11 0 0 3 0 26 55
Enterobacter sp 4 3 0 1 0 4 1 0 1 0 3 17
Serratia sp 0 0 0 0 0 1 0 0 2 0 2 5
Citrobacter sp 0 0 0 0 0 1 0 0 0 0 5 6
Proteus sp 1 0 0 0 0 0 0 0 0 0 3 4
Other Enterobacteriaceae 0 0 1 0 0 0 0 0 0 0 0 1
Pseudomonas sp 2 1 1 0 0 9 1 0 2 0 2 18
Acinetobacter sp 0 0 0 0 0 4 0 0 0 0 0 4
Salmonella sp 0 0 2 0 0 0 0 0 0 0 0 2
Helicobacter sp 0 0 1 0 0 0 0 0 0 0 0 1
Other GNB 2 1 3 0 0 13 0 0 0 1 1 21
Other (N = 23)
Mycoplasma sp 0 0 0 0 0 1 0 0 0 0 0 1
Anaerobe 0 0 0 0 1 0 0 0 0 0 0 1
Mixed 0 0 0 0 0 2 0 0 1 0 0 3
Nocardia sp 0 0 0 0 0 0 1 0 0 0 0 1
Nocardia veterana 0 0 0 0 0 1 0 0 0 0 0 1
Nocardia cyriacigeorgica 0 0 0 0 0 1 0 0 0 0 0 1
Mycobacterium avium–intracellulare complex 0 0 0 0 0 5 0 0 0 0 0 5
None 0 2 1 0 1 4 0 0 2 0 0 10
Total 66 14 55 3 5 84 7 1 37 2 101 375
BSI, bloodstream infection; CoNS, coagulase-negative Staphylococcus species; GI, gastrointestinal/intraabdominal; GNB, Gram-negative bacteria; GPB, Gram-positive bacteria; HB, hepatobiliary; HRT, heart/pericardium; LRTI, lower respiratory tract infection; MDST, mediastinum; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; SSTI, skin and soft tissue infection; URTI, upper respiratory tract infection; UTI, urinary tract infection; VRE, vancomycin-resistant Enterococcus species.

FIGURE 2.
FIGURE 2.:
Frequency of bacterial infectious episodes in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017. CoNS, coagulase-negative staphylococci; GNR, Gram-negative rods; GPC, Gram-positive cocci; GPR, Gram-positive rods; MAC, Mycobacterium avium–intracellular complex; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; VRE, vancomycin-resistant Enterococcus.

Viral Infections

There were 182 viral infections (0.65 viral IEp per patient) as summarized in Table 5. Of these, 76 (42%) were caused by respiratory viruses (Figure 3). The most common viral IEp was CMV BSI (n = 42; 23%). By organism, CMV was the most common (n = 50; 28%), followed by rhinovirus (n = 29; 16%), and influenza virus (n = 16; 9%). Of the 50 CMV IEp, there were 42 cases of BSI and 8 cases of end-organ disease including 5 cases of gastroenteritis/colitis, 2 cases of LRTI, and 1 case of hepatitis. There were no viral CNS infections nor any infections caused by West Nile virus.

TABLE 5. - Causes and locations of viral infectious episodes in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017
Organism Location of infection Total
BSI Diss. GI HB LRTI Ocular Oral SSTI URTI UTI
CMV 42 0 5 1 2 0 0 0 0 0 50
EBV 4 0 0 0 0 0 0 0 0 0 4
HSV 2 0 1 0 0 1 7 3 0 0 14
VZV 0 2 0 0 0 1 0 4 0 0 7
Hepatitis 0 2 0 0 0 0 0 4 0 0 6
Norovirus 0 0 13 0 0 0 0 0 0 0 13
Adenovirus 0 0 0 0 1 0 0 0 0 0 1
Influenza A 0 0 0 0 0 0 0 0 8 0 8
Influenza A H1N1 0 0 0 0 0 0 0 0 1 0 1
Influenza B 0 0 0 0 3 0 0 0 4 0 7
Parainfluenza 0 0 0 0 4 0 0 0 5 0 9
Metapneumovirus 0 0 0 0 4 0 0 0 5 0 9
Rhinovirus 0 0 0 0 4 0 0 0 25 0 29
Coronavirus 0 0 0 0 4 0 0 0 6 0 10
RSV 0 0 0 0 3 0 0 0 0 0 3
Other virus (GI) 0 0 3 0 0 0 0 0 0 0 3
Other virus 6 0 0 0 0 0 0 0 0 2 8
Total 54 4 22 1 25 2 7 11 54 2 182
BSI, bloodstream infection; CMV, cytomegalovirus; Diss., disseminated; EBV, Epstein-Barr virus; GI, gastrointestinal/intraabdominal; HB, hepatobiliary; Hepatitis, hepatitis A/B/C viruses; HP, hepatobiliary; HSV, herpes simplex virus; LRTI, lower respiratory tract infection; other viruses (GI), virus other than norovirus detected on BioFire FilmArray Gastrointestinal multiplex PCR panel; RSV, respiratory syncytial virus; SSTI, skin and soft tissue infection; URTI, upper respiratory tract infection; UTI, urinary tract infection; VZV, Varicella-zoster virus.

FIGURE 3.
FIGURE 3.:
Frequency of viral infectious episodes in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017. CMV, Cytomegalovirus; EBV, Epstein-Barr virus; Hepatitis, Hepatitis A/B/C viruses; HSV, herpes simplex virus; Other virus (GI), virus other than norovirus detected on BioFire FilmArray Gastrointestinal multiplex PCR panel; RSV, respiratory syncytial virus; VZV, Varicella-zoster virus.

Fungal Infections

There were 40 fungal IEp (0.14 fungal IEp per patient) as summarized in Table 6. Of these, 26 were mold infections, 12 were yeast infections, and 2 were caused by Coccidioides species (Figure 4). The most common fungal infection was Aspergillus species LRTI (13). Of the 26 mold infections, 18 were caused by Aspergillus species, 2 were caused by Mucorales, 2 were caused by Scedosporium/Pseudallescheria species (including 1 brain abscess), and 4 were caused by other molds. Of the 12 yeast infections, 10 were caused by Candida species and 2 were caused by Cryptococcus species. There were 2 Coccidioides species IEp, 1 of which was donor-derived and has been previously described.6 There were no infections caused by Pneumocystis jirovecii.

TABLE 6. - Causes and locations of fungal infectious episodes in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017
Organism Location of infection Total
BSI Bone/Joint CNS Diss. GI HRT LRTI Oral SSTI URTI UTI
Candida sp 5 1 0 0 1 0 1 1 0 0 1 10
Cryptococcus sp 0 0 0 0 0 0 1 0 1 0 0 2
Aspergillus sp 0 0 0 1 1 0 13 0 1 2 0 18
Mucorales 0 0 0 0 0 0 1 0 1 0 0 2
Scedosporium/Lomentospora sp 0 0 1 0 0 0 1 0 0 0 0 2
Other mold 1 0 0 0 0 1 1 0 0 1 0 4
Coccidioides sp 0 0 0 0 0 0 1 0 1 0 0 2
Total 6 1 1 1 2 1 19 1 4 3 1 40
BSI, bloodstream infection; CNS, central nervous system; Diss., disseminated; GI, gastrointestinal/intraabdominal; HRT, heart/pericardium; LRTI, lower respiratory tract infection; SSTI, Skin snd soft tissue infection; URTI, upper respiratory tract infection; UTI, urinary tract infection.

FIGURE 4.
FIGURE 4.:
Frequency of fungal infectious episodes in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017.

Parasitic Infections

There were 5 parasitic infections (0.02 IEp per patient). Of these, 1 patient with chronic Chagas cardiomyopathy as the indication for transplantation had Trypanosoma cruzi reactivation 1 month posttransplant manifesting as cardiac pseudocyst and parasitemia. Four years posttransplant, the same patient developed eosinophilia and was subsequently found to be seropositive for both Strongyloides species and Toxocara species. Another patient developed gastrointestinal cryptosporidiosis. There were no infections caused by Toxoplasma gondii.

Timing of Infections

The number of IEp stratified by month posttransplantation is shown in Figure 5. There is a bimodal relationship with peaks within 1 month and from 7 to 12 months for bacterial LRTI (n = 17 from 0 to 1 mo; n = 12 from 7 to 12 mo), UTI (n = 17 from 0 to 1 mo; n = 12 from 7 to 12 mo), and Clostridioides difficile infections (n = 9 from 0 to 1 mo; n = 5 from 7 to 12 mo). CMV IEp increased after 6 months posttransplant (n = 14 from 7 to 12 mo). Aspergillus species IEp were highest within the first 3 months posttransplant with 9 (50.0%) of the 18 IEp occurring during this time period.

FIGURE 5.
FIGURE 5.:
Number of selected infectious episodes stratified by mo posttransplantation in heart transplantation patients at Stanford University Medical Center between January 2008 and September 2017. CMV, cytomegalovirus; LRTI, lower respiratory tract infection; UTI, urinary tract infection.

DISCUSSION

Since the first heart transplant was performed >50 years ago, significant improvements have been made in decreasing the risk of infection and improving infectious disease-related outcomes in heart transplant recipients.7 This is largely a result of increased globally shared knowledge of infectious diseases in the immunocompromised host, the introduction and modification of antimicrobial prophylaxis regimens, advancements in diagnostics, continued development of antimicrobial agents, and tailored immunosuppressive regimens.1,8 There have been changes in the epidemiology of infectious complications in heart transplant patients over time.2,5,3 The standard immunosuppression and antimicrobial prophylaxis protocols used overtime at Stanford are summarized in Table 7.

TABLE 7. - Standard immunosuppression and antimicrobial prophylaxis protocols used in heart transplantation patients at Stanford University Medical Center overtime
Time period Immunosuppression Antimicrobial prophylaxis
Induction Maintenance Antiviral Antifungal Pneumocystis jirovecii Toxoplasma gondii D+/R−
CMV D+/R− CMV R+ CMV D−/R−
1978–1980 ATG (1 mg/kg daily × 3 doses) Azathioprine (200 mg initially, then 1–2 mg/kg daily), prednisone (initial dose 1.5 mg/kg daily) None None None Nystatin topical None None
1982–1984 ATG (1 mg/kg daily × 3 doses) Cyclosporine (initial dose 18 mg/kg, then goal trough 150–300 ng/mL), prednisone (initial dose 1.5 mg/kg daily) None None None Nystatin topical None Pyrimethamine × 4–6 wk
1988–1993 OKT3 (5 mg daily × 14 d) Azathioprine (1 mg/kg), cyclosporine (initial dose 15 mg/kg, then goal trough 100–300 ng/mL), prednisone (initial dose 1 mg/kg) Ganciclovir × 4 wk Ganciclovir × 4 wk None Nystatin topical TMP-SMX × 3-12 mo Pyrimethamine × 4–6 wk
1993–1995 OKT3 (5 mg daily × 14 d) Azathioprine (1 mg/kg), cyclosporine (initial dose 15 mg/kg, then goal trough 100–300 ng/mL), prednisone (initial dose 1 mg/kg) Ganciclovir × 4 wk Ganciclovir × 4 wk None Nystatin topical, amphotericin B inhaled until discharge TMP-SMX × 3-12 mo Pyrimethamine × 4–6 wk
1996–2001 OKT3 (5 mg daily × 7 d) Azathioprine (1 mg/kg), cyclosporine (initial dose 15 mg/kg, then goal trough 100–300 ng/mL), prednisone (initial dose 1 mg/kg) Ganciclovir × 6 wk, CMV-IVIG × 16 wk Ganciclovir × 4 wk None Nystatin topical, amphotericin B inhaled until discharge TMP-SMX lifelong Pyrimethamine × 4–6 wk
2002–2005 Daclizumab (1 mg/kg daily × 4 doses) Cyclosporine (initial dose 15 mg/kg, then goal trough 100–300 ng/mL), MMF (average total dose 2 g daily), prednisone (initial dose 1 mg/kg, then tapered over 12 mo) (Val)ganciclovir × 6 mo, CMV-IVIG × 16 wk Ganciclovir × 4 wk None Nystatin topical, amphotericin B inhaled until discharge TMP-SMX lifelong Pyrimethamine × 4–6 wk
2008–2010 ATG (1 mg/kg daily × 3 doses) or Daclizumab (1 mg/kg daily × 4 doses) Tacrolimus (goal trough 10–15 ng/mL), MMF (average total dose 2 g daily), prednisone (initial dose 1 mg/kg, then tapered over 12 mo) (Val)ganciclovir × 12 mo, CMV-IVIG × 16 wk (Val)ganciclovir × 12 mo Acyclovir × 12 mo Nystatin topical or clotrimazole troche, amphotericin B inhaled until discharge, itraconazole suspension × 3 mo TMP-SMX × 12 mo TMP-SMX × 12 mo
2010–2017 ATG (1 mg/kg daily × 3 doses) Tacrolimus (goal trough 10–15 ng/mL), MMF (average total dose 2 g daily), prednisone (initial dose 1 mg/kg, then tapered over 12 mo) (Val)ganciclovir × 12 mo, CMV-IVIG × 16 wk (Val)ganciclovir × 12 mo Acyclovir × 12 mo Nystatin topical or clotrimazole troche, amphotericin B inhaled until discharge, itraconazole suspension × 3 mo TMP-SMX × 12 mo TMP-SMX × 12 mo
2017–2019 None or ATG (1 mg/kg daily × 3 doses, only in recipients who have renal dysfunction or are highly sensitized) Tacrolimus (goal trough 10–15 ng/mL), MMF (average total dose 2 g daily), prednisone (initial dose 1 mg/kg, then tapered over 6 mo) (Val)ganciclovir × 6 mo (Val)ganciclovir × 6 mo Acyclovir × 12 mo Nystatin topical or clotrimazole troche, amphotericin B inhaled until discharge, itraconazole suspension × 3 mo TMP-SMX × 12 mo TMP-SMX × 12 mo
ATG, antithymocyte globulin; CMV, cytomegalovirus; CMV-IVIG, CMV hyperimmune globulin; D-, donor IgG seronegative; D+, donor IgG seropositive; MMF, mycophenolate mofetil; OKT3, muromonab-CD3; R-, recipient IgG seronegative; R+, recipient IgG seropositive; TMP-SMX, trimethoprim-sulfamethoxazole.

In our cohort, the rate of IEp was 2.15 per patient, predominantly caused by bacteria (1.34 IEp per patient), followed by viruses (0.65 IEp per patient) and fungi (0.02 IEp per patient). In comparison, Stinson et al (1968–1971) demonstrated an overall rate of infection of 2.83 per patient while Montoya et al (1980–1996) demonstrated an overall rate of infection of 1.73 per patient.2,5 Another study comparing transplant infections across 4 eras (1978–1980; 1982–1984; 1988–1997; 2002–2005) demonstrated overall rates of infection ranging from 0.60 to 3.35 IEp per patient depending on the particular immunosuppression era.3

The differences in overall infection rates per patient transplanted at our institution between previous studies and ours are likely multifactorial. First, our study included all IEp occurring in both inpatient and outpatient settings, whereas Montoya et al excluded infections treated in the outpatient setting. The clinical setting was not reported by Stinson et al or Haddad et al.3,5 Second, advancements in culture techniques and the implementation of newer molecular diagnostic assays (eg, multiplex syndromic PCR panels) have enabled the detection of multiple organisms that would previously have been undiagnosed. Third, some definitions for infection (eg, CMV) differed between eras depending on the diagnostic assays available during that time period. Fourth, evolution in immunosuppressive and antimicrobial prophylaxis regimens have had a substantial impact on the incidence of IEps (Table 7).

Compared with the study by Montoya et al, our study cohort had an overall increased proportion of bacterial IEp, decreased proportion of viral and fungal IEp, and a similar proportion of parasitic IEp. There was a notable shift in the epidemiology of bacterial infections with Gram-negative bacterial infections (n = 210) outnumbering Gram-positive bacterial infections (n = 142), a trend which has been previously reported.9,10 We speculate that over the last decade, there have been fewer indwelling vascular catheter-related IEp accounting for this shift.9,10 The 3 most common bacterial IEp in our cohort were Escherichia coli UTI (n = 43), Clostridioides difficile gastroenteritis/colitis (n = 35), and Klebsiella species UTI (n = 26). It should be noted that simply detecting an organism does not automatically connote a clinically significant infection warranting targeted antimicrobial therapy. This is especially true for Clostridioides difficile, where PCR-based detection cannot discriminate between the asymptomatic carrier state and active infection.11 Some of the patients deemed to have UTI may have had asymptomatic bacteriuria, treatment of which is no longer recommended in heart transplant recipients.12,13

In the study by Montoya et al, there were 12 infections caused by Listeria monocytogenes, of which 9 involved the CNS (6 episodes of meningitis and 3 episodes of brain abscess) in addition to 23 Nocardia species infections when TMP-SMX 160–800 mg thrice weekly was the preferred regimen for Pneumocystis jirovecii prophylaxis.2 Our study had only 1 episode of Listeria monocytogenes bacteremia without CNS involvement and 3 Nocardia species infections. These reductions may partly be due to a more consistent use of TMP-SMX 80–400 mg daily prophylaxis.

There was a decrease in the proportion of viral IEp in our study compared with the study by Montoya et al. Of particular importance is the significant decrease in rates of CMV, HSV, and VZV IEp. This is particularly notable for CMV because of the more sensitive diagnostic assays used in our study (eg, PCR) compared with the study by Montoya (eg, rise in IgG serological test titer, seroconversion, and virus isolation). In the study by Montoya et al, ganciclovir was given for, at most, 8 weeks posttransplant and acyclovir was not utilized. In our study, patients received CMV prophylaxis for at least 6–12 months posttransplant and received HSV/VZV prophylaxis until 12 months posttransplant when CMV prophylaxis was not being administered. These changes decreased the incidence of CMV, HSV, and VZV IEps and delayed the median time of onset posttransplant. We also note that routine CMV-IVIG administration was discontinued with our 2017 protocol update, but it is unlikely that this had any significant effect on outcomes.14 CMV IEp occurred most frequently after 6 months posttransplantation, typically in a CMV D+/R− patient after prophylaxis discontinuation. The implementation of PCR-based monitoring and a preemptive approach after discontinuation of prophylaxis was instrumental in detecting CMV viremia and intervening before the development of CMV syndrome or tissue-invasive disease. Detection of CMV pp65 antigen by immunofluorescence or CMV DNA by PCR was not used in the study by Montoya et al. CMV-specific immune monitoring assays have not been performed systematically at our center, but may have an increased role in the future as they have shown promise in being able to identify patients in whom it may be safe to discontinue antiviral therapy.14

There was also a decrease in the proportion of fungal infections in our study compared with the study by Montoya et al. Importantly, there were no cases of Pneumocystis jirovecii infection in our cohort. Historically, Stanford has appeared to have had a significant number of invasive fungal infections. While there was already a previously noted decrease in fungal infections after the introduction of inhaled amphotericin B prophylaxis, our study noted a further decrease after the introduction of systemic antifungal (eg, itraconazole) prophylaxis in addition to the routine use of HEPA filter and N95 respiratory masks. It is unclear to what extent climate and ongoing construction had on our incidence of invasive fungal infections, but these interventions seem to have made a positive impact. We presume that our fungal infection rates would have been higher had these preventive measures not been instituted. We believe that each transplant center should examine their incidence of fungal infections and decide whether such intervention(s) should be instituted. Based on the timing and nature of fungal infections throughout the study period, suspicion for a nosocomial outbreak was not raised.

The proportion of parasitic infections was similar in our study compared with prior studies, but Figure 5 is skewed because 4 of the 5 parasitic infections were diagnosed in a single patient, likely reflecting his individual epidemiological exposure history rather than incidence in the entire cohort. There were no cases of posttransplant toxoplasmosis.

This study has several limitations inherent to any retrospective study. Some data elements such as donor and recipient pretransplant infectious diseases screening were missing, exact dates related to discontinuation of prophylactic regimens were not consistently documented, and rationale for antimicrobial treatment was not always readily apparent in provider documentation. When patients were seen at other institutions, IEp was not recorded and could result in an underestimation of infection rate. Because of our study definitions, the clinical significance of organism detection and appropriateness of antimicrobial utilization was not assessed, but it is likely that the true incidence of clinically significant bacterial infections warranting targeted antimicrobial therapy was overestimated.

CONCLUSIONS

This contemporary descriptive analysis highlights recent trends of infectious complications after heart transplantation at a single center in the setting of multiple advancements in the field including tailored immunosuppression and antimicrobial prophylaxis. There was a significant decrease in the frequency of multiple infectious complications, including decreased rates of CMV, Aspergillus, and Nocardia infections and the complete prevention of Pneumocystis jirovecii, Toxoplasma gondii, and Mycobacterium tuberculosis posttransplant.

REFERENCES

1. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007; 357:2601–2614
2. Montoya JG, Giraldo LF, Efron B, et al. Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis. 2001; 33:629–640
3. Haddad F, Deuse T, Pham M, et al. Changing trends in infectious disease in heart transplantation. J Heart Lung Transplant. 2010; 29:306–315
4. Khush KK, Cherikh WS, Chambers DC, et al.; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation. J Heart Lung Transplant. 2018; 37:1155–1168
5. Stinson EB, Bieber CP, Griepp RB, et al. Infectious complications after cardiac transplantation in man. Ann Intern Med. 1971; 74:22–36
6. Nelson JK, Giraldeau G, Montoya JG, et al. Donor-derived coccidioides immitis endocarditis and disseminated infection in the setting of solid organ transplantation. Open Forum Infect Dis. 2016; 3:ofw086
7. Stehlik J, Kobashigawa J, Hunt SA, et al. Honoring 50 years of clinical heart transplantation in circulation: in-depth state-of-the-art review. Circulation. 2018; 137:71–87
8. Potena L, Zuckermann A, Barberini F, et al. Complications of cardiac transplantation. Curr Cardiol Rep. 2018; 20:73
9. Kritikos A, Manuel O. Bloodstream infections after solid-organ transplantation. Virulence. 2016; 7:329–340
10. Oriol I, Sabé N, Simonetti AF, et al. Changing trends in the aetiology, treatment and outcomes of bloodstream infection occurring in the first year after solid organ transplantation: a single-centre prospective cohort study. Transpl Int. 2017; 30:903–913
11. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018; 66:e1–e48
12. Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clin Infect Dis. 2019; 68:1611–1615
13. Goldman JD, Julian K. Urinary tract infections in solid organ transplant recipients: guidelines from the American Society of transplantation infectious diseases community of practice. Clin Transplant. 2019; 33:e13507
14. Kotton CN. Migrating from universal to personalized prevention: predicting the risk of cytomegalovirus infection after organ transplantation. Transplantation. 2018; 102:1787–1788
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.