IgM‐enriched immunoglobulin as adjuvant therapy for heart transplant after infection of left ventricular assist devices

Abstract

Patients undergoing heart transplantation (HTx) with active infection of left ventricular assist devices (LVAD) are at high risk for postoperative infections. Between 2021 and 2022, five (P1–P5) of a total of n = 44 patients underwent HTx in our department while suffering from LVAD infection. Postoperatively, patients received adjuvant IgM‐enriched human intravenous immunoglobulin (IGM‐IVIG), consisting of 76% IgG, 12% IgM, and 12% IgA as a novel approach to prevent infective complications. While in P1, P2, and P4, LVAD driveline infection was known before HTx; in P3 and P5, abscess of device pocket was found incidentally during HTx. After a single dose of IGM‐IVIG, all patients showed adequate rise in serum immunoglobulins. In the postoperative course, no patient developed infective complications. All patients were successfully discharged and in good condition at the last follow‐up. Therefore, IGM‐IVIG seems to be an effective adjuvant treatment for patients undergoing HTx with LVAD infections.

Introduction

Implantation of left ventricular assist devices (LVAD) as a bridge‐to‐transplant therapy is a common approach in patients suffering from end‐stage heart failure. ¹ By now, infections are still frequent device‐related adverse events not only limiting the outcome of LVAD therapy itself but also affecting consecutive heart transplantation (HTx). ¹ , ² LVAD infections significantly increase the risk of postoperative infections following HTx. ³ As infections in general are one of the main causes for early mortality after HTx, patients with present LVAD infections while undergoing HTx are at additional risk. ⁴ Moreover, IgG hypogammaglobulinaemia was recently identified as another independent risk factor for infections in HTx. ⁵ As Sarmiento and colleagues reported, prophylactic application of immunoglobulin G may reduce infective complications after HTx. ⁶ Novel IgM‐enriched human immunoglobulin (IGM‐IVIG) consists not only of IgG (76%) but also of 12% IgM and 12% IgA. IGM‐IVIG has shown promising results in the therapy of sepsis as well as donor‐specific antibody‐mediated rejection after heart transplantation by directly addressing pathogens, neutralization of bacterial endotoxins and exotoxins, modulation of complement factors, and regulation of immune cells. ⁷ , ⁸ Therefore, adjuvant application of IGM‐IVIG may also facilitate protective anti‐infective effects in patients undergoing HTx with present LVAD infection.

In the current case series, we now report our early results of adjuvant IGM‐IVIG therapy in HTx patients with infected LVAD.

Case report

Ethical approval

This study followed the principles of the Declaration of Helsinki and the Declaration of Istanbul and was approved by our local University ethics committee. All patients gave their informed consent prior to inclusion.

Case series

Between January 2021 and 2022, a total of n = 44 patients underwent HTx in our department. Of those, n = 5 patients (P1–P5) suffered from a concomitant infection of a LVAD and were included in the present case series (Figure 1 ). The reported patients all suffered from either driveline infection (Figure 1 A ) or abscess of the device pocket (Figure 1 B ). Table 1 shows the detailed clinical data of the five reported patients.

Figure 1.

Schematic illustration of patients with infected left ventricular assist device. Patients 1, 2, and 4 suffered from driveline infection (A). In Patient 3 and 5, concomitant pericardial abscess of the device pocket was found intraoperatively (B).

Table 1.

Overview of the clinical parameters of the five study patients undergoing heart transplantation with infection of left ventricular assist devices

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
HTx date	01/2021	06/2021	06/2021	08/2021	01/2022
Age at HTx	68	60	65	49	67
Gender	male	male	male	male	male
LVAD support duration	14 months	12 months	65 months	21 months	4 months
LVAD infection	Driveline infection ( P. aeruginosa ))	Driveline infection ( S. aureus )	Pericardial abscess	Driveline infection ( S. aureus )	Pericardial abscess
Date of diagnosis of LVAD infection	10 months before HTx	7 days before HTx	Intraoperative	24 days before HTx	Intraoperative
Anti‐infective therapy	Piperacillin + Tazobactam Ciprofloxacin	Cefazolin Rifampicin Meropenem	Piperacillin + Tazobactam	Levofloxacin Rifampicin	Meropenem
Pre‐IGM‐IVIG IgG, mg/dL	793	619	827	921	777
Post‐IGM‐IVIG IgG, mg/dL (change in %)	not available	918 (48.3)	1060 (28.2)	1084 (17.7)	939 (20.8)
Pre‐IGM‐IVIG IgA, mg/dL	243	121	252	240	235
Post‐IGM‐IVIG IgA, mg/dL (change in %)	Not available	161 (33.1)	269 (6.7)	268 (11.7)	256 (8.9)
Pre‐IGM‐IVIG IgM, mg/dL	57	53	53	70	108
Post‐IGM‐IVIG IgM, mg/dL (change in %)	Not available	93 (75.5)	70 (32.1)	77 (10.0)	121 (12.0)
Quantity of IGM‐IVIG application	Single dose	Single dose	Single dose	Single dose	Single dose
Postoperative maximum Leukocytes, 1 × 1000/μL	15.1	21.7	28.4	18.6	28.4
Postoperative minimum Leukocytes, 1 × 1000/μL	5.8	5.1	5.9	4.8	5.7
Postoperative maximum CRP, mg/dL	8.3	11.8	3.1	16.3	4.9
Postoperative maximum PCT, ng/mL	5.95	20.10	1.53	4.05	23.00
IGM‐IVIG‐related adverse events	None	None	None	None	None
Postoperative infective complications	None	None	None	None	None
Postoperative adverse events	Acute kidney injury requiring haemodialysis on ICU	Limb ischaemia due to dissection of femoral artery Acute kidney injury requiring haemodialysis on ICU	None	Sinoatrial block requiring pacemaker implantation	Acute kidney injury requiring haemodialysis on ICU
In‐hospital outcome	Discharge to rehab centre	Discharge to rehab centre	Discharge to rehab centre	Discharge to rehab centre	Discharge to rehab centre
Date of last follow‐up	12 months after HTx	9 months after HTx	7 months after HTx	6 months after HTx	1 month after HTx
Status of last follow‐up	Good clinical condition	Good clinical condition	Good clinical condition	Good clinical condition	Good clinical condition, still in rehab centre

CRP, C‐reactive protein; HTx, heart transplantation; ICU, intensive care unit; LVAD, left ventricular assist device; PCT, procalcitonin.

Patients were postoperatively treated with adjuvant intravenous IgM‐enriched human immunoglobulin (IGM‐IVIG). Serum immunoglobulin reference range: IgG = 700–1600 mg/dL; IgA = 70–500 mg/dL; IgM = 40–230 mg/dL.

The first patient (P1), a 68‐year‐old male, underwent LVAD implantation (HeartWare HVAD™, Medtronic plc, Dublin, Ireland) in October 2019 due to ischaemic cardiomyopathy. Approximately 6 months later, the patient developed driveline infection. In the following, the driveline infection caused a peritoneal perforation and consecutive a perforation of the small intestine. Consequently, the patient underwent several abdominal operations including temporary stoma of the jejunum. After a successful revision of the abdominal infection and stoma reversal, the patient was planned for HTx due to residual driveline infection. Finally, 14 months after the initially LVAD implantation, the patient underwent orthotopic HTx. Piperacillin/tazobactam as well as ciprofloxacin were administered as directed antibiotic therapy. Postoperatively, immunoglobulin concentrations were examined and IGM‐IVIG administered. Unfortunately, no immunoglobulin concentrations after IGM‐IVIG application were available for this patient. In addition, the patients developed postoperative acute kidney injury with transient haemodialysis. Nevertheless, the patient fully recovered and did not experience infection‐related adverse events in the postoperative course of the HTx and was discharged to a rehabilitation centre. One year after HTx, the patient is in good clinical condition without any signs of heart failure (NYHA class I).

The second patient (P2) also suffered from driveline infection, approximately 1 year after LVAD implantation (HeartMate 3™, Abbott Laboratories, Chicago, IL, USA) for ischaemic cardiomyopathy. Besides directed therapy with cefazolin, rifampicin, and meropenem, the patient received adjuvant IGM‐IVIG directly after HTx. Afterwards, serum immunoglobulins increased by between 33.1% (IgA) and 75.5% (IgM). The patient developed limb ischaemia due to a local dissection of the right femoral artery correlated to the cannulation site of the heart‐lung machine. Therefore, the patient underwent patch reconstruction of femoral artery, thrombectomy, and bilateral fasciotomy. Furthermore, he also underwent temporary renal replacement therapy on the intensive care unit. Fortunately, the patient fully recovered and did not experience any infective complications, neither thoracic, nor driveline‐related or limb‐related. By now, approximately 9 months after HTx, the patient fully recovered (NYHA I).

Patient 3 (P3), another male patient suffering from end‐stage ischaemic cardiomyopathy, underwent HTx about 5 years after LVAD implantation (HeartMate 3™). Although no device‐related infection was previously known, intraoperatively abscess of the device pocket was found. Therefore, empiric antibiotic therapy by piperacillin/tazobactam was initiated and adjuvant IGM‐IVIG administered. Again, a sufficient rise in serum immunoglobulins was established after single dose application. In the following postoperative course, no adverse events, especially no infective complications, occurred. The patient was soon discharged and by now, 7 months after HTx, also without any clinical impairments.

The fourth patient (P4) suffered from repetitive driveline infections after LVAD implantation (HeartMate 3™) for hypertrophic cardiomyopathy caused by a genetic glycogen storage disease. He was treated with levofloxacin and rifampicin as a directed antibiotic therapy. After finally undergoing HTx, adjuvant IGM‐IVIG application was administered as a single dose with adequate increase in serum immunoglobulins. Once again, no infective complications were observed during the postoperative course. Due to a sinoatrial block, the patient underwent a pacemaker implantation before being discharged to a rehabilitation clinic. By now, at 6 months follow‐up, once again no clinical signs of infections occurred, and the patient is in stable and good clinical conditions.

Finally, the fifth patients of this case series, a 67‐year‐old male patient with ischaemic cardiomyopathy, was recently transplanted 4 months after LVAD implantation (HeartMate 3™). Similar to P3, a pericardial abscess of the device pocket was found intraoperatively as an incidental finding. Therefore, empiric antibiotic therapy with meropenem was initiated with meropenem and adjuvant IGM‐IVIG administered. Again, a sufficient boost in serum immunoglobulins was detected. The patient did not suffer from any infective complications, however again needed temporary haemodialysis. Nevertheless, he was successfully discharged to a rehabilitation clinic about 1 month after HTx in good clinical conditions.

IGM‐IVIG application

Appendix 1 shows the detailed study protocol. In brief, laboratory values including IgG, IgA, and IgM concentrations were examined directly after the HTx procedure. Afterwards, IGM‐IVIG (Pentaglobin®, Biotest AG, Dreieich, Germany) was applied with a dose of 3.0 mL/kg body weight (equal to 150 mg immunoglobulins/kg body weight) as a continuous venous infusion with a maximum infusion rate of 50 mL/h. Laboratory examinations were repeated the next day and in patients with IgG or IgM concentration below the reference range (IgG = 700–1600 mg/dL; IgM = 40–230 mg/dL) IGM‐IVIG application was repeated with a dose of 5.0 mL/kg body weight (equal to 250 mg/kg body weight). Laboratory values of the patients are displayed in Table 1 .

Immunosuppression and anti‐infective therapy

All patients followed the same immunosuppressive therapy consisting of prednisolone, tacrolimus, and mycophenolate mofetil. No additional induction therapy was applied. In guidance with the microbiologic examinations, besides adjuvant IGM‐IVIG, patients were treated with intravenous antibiotics (Table 1 ).

Discussion

In the current case series, we summarized our first results of the adjuvant treatment of patients undergoing HTx with present infection of a LVAD by IGM‐IVIG. By now, we have included five patients, none of them developed postoperative infective complications or therapy‐related adverse events.

While P1, P2, and P4 suffered from previously known driveline infection, in P3 and P5, infection of device pocket was found incidentally during the HTx procedure. Both driveline and pocket infection are the most common forms of LVAD infections reported in the literature. ⁹ Although no bloodstream infection, which is associated with a high risk of morbidity and mortality in LVAD patients, was diagnosed in our case series, all patients were at a high risk for severe postoperative infective complications due to the immunosuppression after HTx. ³ , ⁹ In a cohort study of Swiss VAD patients, one third of patients with LVAD infection developed infective complications after HTx. ¹⁰ Furthermore, the study reported 33.3% 1 year mortality for patients undergoing HTx with LVAD infection compared with 0% for patients with non‐infected LVAD. ¹⁰ Furthermore, in a previously reported study, we observed severe postoperative infective complications (sepsis, pneumonia, and infective wound healing disorders) in 12.3% of patients with pre‐transplant LVAD driveline infect who were treated with antibiotics but without IGM‐IVIG application. ² In contrast, after adjuvant IGM‐IVIG application, we did not observe any infective complications in our case series, and no death occurred so far. Moreover, despite active LVAD infection, postoperative serum values of C‐reactive protein and procalcitonin remained low and were comparable with reported data for HTx patients without infections. ¹¹

As IgG hypogammaglobulinaemia is a risk factor for infections in HTx patients, Sarmiento and colleagues reported beneficial effects of prophylactic IgG application. ⁵ , ⁶ However, in contrast to our case series, IgG was only administered in patients with proved postoperative hypogammaglobulinaemia, only one fourth of the reported patients underwent HTx after LVAD implantation and none of them suffered from present infections. ⁶ In addition, instead of stand‐alone intravenous IgG, we applied IGM‐IVIG which consists of additional IgM and IgA and has been reported to outclass standard IgG application due to its enhanced anti‐infective effects. ¹² , ¹³

As reported, IGM‐IVIG application was used as an adjuvant treatment in the current case series. Therefore, adequate antibiotic therapy was of course crucial in all patients. ¹⁴ As suggested by the literature, antibiotic regime was selected in guidance with the microbiology and pursued for 7 to 14 days after the HTx in every patient. ¹⁴

Three patients developed transient acute kidney injury with temporary haemodialysis on the intensive care unit. IGM‐IVIG application may be related to acute renal failure, especially in patients with already existing chronic renal insufficiency. ⁷ However, risk of acute renal dysfunction is relatively high in LAVD patients undergoing HTx, and therefore, this was most likely not related to the IGM‐IVIG application. ² , ¹⁵ Furthermore, observed limb ischaemia of P2 was caused by a local dissection of femoral vessel correlated to the cannulation of the heart‐lung machine and successfully treated by vascular surgery. No other potential therapy‐related adverse events were observed which was in line with our previous experiences with IGM‐IVIG therapy in HTx patients. ⁸

Conclusion

Infections are a life‐threatening complication after HTx. In particular, patients with LVAD infections or hypogammaglobulinaemia are at high risk for severe postoperative infective complications. After adjuvant application of IGM‐IVIG, we did not observe a single case of postoperative infections in this series. Furthermore, we did not experience any therapy‐related adverse side effects. Although larger studies are obviously needed to prove these early results, IGM‐IVIG application may act as an effective adjuvant therapy in patients undergoing HTx with LVAD infections.

Conflict of interest

M.B.I. and U.B. have received travel research grants from Biotest AG, Dreieich, Germany.

Funding

The authors did not receive any funding for this study.

Study protocol

Inclusion criteria

• Adult heart transplantation

• Active infection of ventricular assist device (left or biventricular assistance)

Laboratory examinations:

• Before IGM‐IVIG applications: routine blood count, CRP, PCT, Il‐6, IgA IgG, IgM

• First day after IGM‐IVIG applications: routine blood count, CRP, PCT, Il‐6, IgA IgG, IgM

Clinical examinations:

• Hemodynamics

• Thoracic X‐ray

Intervention:

• 3 mL/kg body weight (= 150 mg) intravenous IGM‐IVIG (Pentaglobin®, Biotest AG, Dreieich, Germany) directly after heart transplantation with a maximum infusion rate of 50 mL/h

• Repetition of IGM‐IVIG application 5 mL/kg body weight (= 250 mg) per day in patients with IgG or IgM concentration below the reference rage (IgG = 700–1600 mg/dL; IgM = 40–230 mg/dL)

Immohr, M. B. , Böttger, C. , Aubin, H. , Westenfeld, R. , Oehler, D. , Bruno, R. R. , Dalyanoglu, H. , Tudorache, I. , Akhyari, P. , Lichtenberg, A. , and Boeken, U. (2022) IgM‐enriched immunoglobulin as adjuvant therapy for heart transplant after infection of left ventricular assist devices. ESC Heart Failure, 9: 3630–3635. 10.1002/ehf2.14074.