Significant post-transplant hypogammaglobulinemia in six heart transplant recipients: an emerging clinical phenomenon?

Case report R. Corales, J. Chua, S. Mawhorter, J.B. Young, R. Starling, J.W. Tomford, P. McCarthy, W.E. Braun, N. Smedira, R. Hobbs, G. Haas, D. Pelegrin, M. Majercik, K. Hoercher, D. Cook, R.K. Avery

Key words: heart transplant; infections; hypogammaglobulinemia

Received 12 October 1999, revised 4 January, accepted for publication 5 January 2000 Copyright c Munksgaard 2000 Transplant Infectious Disease . ISSN 1398-2273 Transpl Infect Dis 2000: 2: 133–139 Printed in Denmark . All rights reserved

Significant post-transplant hypogammaglobulinemia in six heart transplant recipients: an emerging clinical phenomenon?

Abstract: Background: The recent development of powerful agents such as mycophenolate mofetil and tacrolimus has altered current regimens for the prevention and treatment of allograft rejection. Questions have been raised about these newer regimens in terms of susceptibility to opportunistic infections and effects on host defenses. Severe hypogammaglobulinemia has been infrequently described in solid organ transplant recipients, but has been recently noted in six heart transplant recipients at one center, of whom five were receiving a combination of tacrolimus, mycophenolate mofetil, and prednisone. Methods: Case summaries of six recent heart transplant recipients with total immunoglobulin G (IgG) levels of less than 310 mg/dl, five of whom had cytomegalovirus (CMV) infection and three of whom had multiple infections including Nocardia, invasive Trichophyton, and Acinetobacter bacteremia. Previous literature was reviewed with the aid of a Medline search using the search terms hypogammaglobulinemia; kidney, liver, heart, lung, and organ transplantation; mycophenolate mofetil; tacrolimus; cyclosporine; azathioprine; and nocardiosis. Results: We here report six cardiac transplant recipients seen over a period of one year who were found to have immunoglobulin G levels of 310 mg/dl or below (normal: 717–1400 mg/dl). The first five patients were diagnosed because of evaluation for infections; the sixth, who was asymptomatic with an IgG level of 175, was found during screening for hypogammaglobulinemia instituted as a result of these first five patients. All six patients had received steroid pulses for rejection; all received mycophenolate mofetil; and 5/6 had been switched from cyclosporine to tacrolimus because of steroidresistant rejection. Transient neutropenia (absolute neutrophil count less than 1000) was observed in 2/6; 3/6 had received OKT3 therapy for refractory rejection. These six patients were treated with a combination of antimicrobials, immunoglobulin replacement, and decrease in immunosuppressive therapy. Conclusions: The finding of unexpected hypogammaglobulinemia and concomitant infectious complications in six heart transplant recipients highlights a possible complication in a subset of patients receiving newer immunosuppressive agents. A larger prospective study is underway to determine risk factors for development of post-transplant hypogammaglobulinemia and to assess pre-transplant immune status of these recipients. Monitoring of immunoglobulin levels in high-risk patients receiving intensified immunosuppressive therapy for rejection may help to prevent infectious complications.

Authors’ affiliations: R. Corales2, J. Chua2, S. Mawhorter2, J.B. Young1,3, R. Starling1,3, J.W. Tomford2, P. McCarthy1,4, W.E. Braun1,5, N. Smedira1,4, R. Hobbs1,3, G. Haas1,3, D. Pelegrin3, M. Majercik3, K. Hoercher4, D. Cook1, R.K. Avery1,2 1

Transplant Center,

2

Department of Infectious Disease,

3

Department of Cardiology,

4

Department of Cardiothoracic Surgery,

5

Department of Nephrology, Cleveland Clinic Foundation, Cleveland, Ohio, USA Correspondence to: Robin K. Avery, MD Department of Infectious Disease, Desk S-32 Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Tel: π216 444 8977 Fax: π216 445 9446 e-mail: averyr/ccf.org

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Corales et al : Post-transplant hypogammaglobulinemia in heart transplant recipients

The introduction of powerful newer agents including mycophenolate mofetil (MMF, 1–11) and tacrolimus (12–17) or their combi-

Case 1

nation (11, 18–22) for the prevention and treatment of allograft rejection in solid organ transplant recipients has greatly altered clinical

A 55-year-old white male received a CMV Dπ/Rπ (cytomegalovirus

practice. With this new era in immunosuppressive therapy, it is

donor seropositive, recipient seropositive) heart transplant on 13 Oc-

important to re-examine the incidence and nature of opportunistic

tober 1997 for idiopathic cardiomyopathy. The initial immunosup-

infections in transplant recipients, with particular attention to poss-

pressive regimen was cyclosporine, mycophenolate mofetil 1000 mg

ible alterations of immune function which may differ from the ef-

po BID, and prednisone. He received 4 weeks of intravenous (IV) gan-

fects of traditional regimens. Although a recent large multicenter

ciclovir for CMV prophylaxis, and continuous thrice weekly prophy-

study (5) showed no significant increase in cytomegalovirus (CMV)

laxis with double-strength trimethoprim-sulfamethoxazole (TMP-

incidence in MMF-treated heart transplant recipients, our center has

SMX). Two episodes of stage 3B rejection at 1 and 2 months post-

noted a group of patients over the past two years with a constel-

transplant were treated with methylprednisolone, 1 g daily for 3 days,

lation of profound hypogammaglobulinemia, CMV, and other oppor-

and he also received a subsequent oral steroid pulse. At 6 weeks post-

tunistic infections, such as Nocardia which has traditionally been

transplant, tacrolimus was substituted for cyclosporine. No OKT3 or

uncommon at this center. Six of these patients are reported here;

antithymocyte globulin (ATG) was administered. At 6 months post-

five were receiving the combination of MMF, tacrolimus, and pred-

transplant, while still receiving TMP-SMX prophylaxis, the patient

nisone at the time they were found to be hypogammaglobulinemic.

developed low-grade fevers and a 4 kg weight loss, and was noted to

The sixth was receiving MMF, cyclosporine, and prednisone, but

have a right upper lung nodule on chest x-ray which had enlarged to

had also previously undergone total lymphoid irradiation and

2.7¿1.7 cm. Bronchoscopy and subsequent open lung biopsy re-

plasmapheresis for severe early vascular rejection. Whether or not

vealed pathology consistent with Nocardia species and CMV in-

the combination of tacrolimus and MMF represents a greater risk

clusions; cultures of the lung biopsy specimen grew only CMV. The

for hypogammaglobulinemia and for infection than other regimens,

blood CMV-DNA (by hybrid capture assay) was negative. Quantitat-

such as MMF in combination with cyclosporine, is the subject of

ive immunoglobulin (Ig) analysis showed an IgG of 225 mg/dl, IgA 93,

an ongoing prospective study in heart transplant recipients (23).

and IgM 33. Lymphocyte subset analysis showed a CD4 lymphocyte

We here report the clinical characteristics of the first six patients

count of 253 cells/ml and CD8 lymphocyte count of 66 cells/ml with

whom we have noted to have significant hypogammaglobulinemia

a CD4/CD8 ratio of 3.84. The patient responded to a combination of

post-transplant. Two cases are reported in detail below; the charac-

intravenous trimethoprim-sulfamethoxazole, ganciclovir, IVIG, and

teristics of all six are summarized in Table 1.

tapering of immunosuppression. After administration of CMV hyper-

Six heart transplant recipients with IgG levels below 310 mg/dla

Age

Transplant date

Regimenb

IgG (mg/ dl)

1.

55 M

Infections

10/97

Pred/MMF/FK

225

2.

55 M

Nocardia, CMV in lung

5/97

Pred/MMF/FK

300

Nocardia, CMV, invasive Trichophyton

3. 4.

45 M

3/98

Pred/MMF/FK

225

GI-CMV, aspergillosis, Acinetobacter in BCs

45 F

12/97

Pred/MMF/FK

309

GI-CMV

5.

45 M

5/98

Pred/MMF/Cyclo

205

CMV viremia

6.

45 M

9/98

Pred/MMF/FK

175

None

a

b

Patient 3 also had had a prior splenectomy due to remote Hodgkin’s disease. Patients 3, 4, and 5 had received OKT3; Patients 1, 2, and 6 received no antilymphocyte therapy. Patient 5 had also undergone treatment with cyclophosphamide, plasmapheresis, and total lymphoid irradiation due to early severe vascular rejection. Patients 3 and 5 had neutropenia (ANC less than 1000) at the time of diagnosis of hypogammaglobulinemia. None of the six patients was CMV Dπ/Rª. Regimen at time of lowest IgG level.

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Transplant Infectious Disease 2000: 2: 133–139

Table 1

Corales et al : Post-transplant hypogammaglobulinemia in heart transplant recipients

Quantitative immunoglobulins (mg/dl) before and after administration of CMV hyperimmune globulin, tapering of immunosuppression, and therapy for infections in Patients 1 and 2

performed and the cultures grew Nocardia asteroides. He received intravenous imipenem-cilastatin for 6 weeks followed by oral TMPSMX continuous prophylaxis thereafter, with a clinical and radio-

Patient 1

Patient 2

Before

After

Before

After

Normal values

IgG

225

403

300

590

717–1411

IgA

93

111

70

93

78–391

IgM

33

51

66

97

53–334

IgG1

ND

273

ND

ND

400–950

IgG2

ND

150

ND

136

70–450

IgG3

ND

19

ND

9

IgG4

ND

5

ND

29

graphic response. However, at 9 months post-transplant, he developed low-grade fevers and was found to have multiple lobulated soft tissue masses in the lingula and left upper lung on CT scan. He had also developed a 3 cm by 3 cm fungating, exophytic skin lesion on the right heel. The blood CMV-DNA was positive. Skin biopsy of the heel lesion grew Trichophyton rubrum, and transbronchial biopsy again showed organisms consistent with Nocardia

20–90

species. Quantitative immunoglobulin analysis showed IgG of 300

3–180

mg/dl, IgA of 70, and IgM of 66. Adequate titers were detected to

Table 2

12 of 12 pneumococcal serotypes tested, while tetanus titer was in the indeterminate range. Vaccines against these agents had been administered in 1997 and 1992, respectively. The patient responded

immune globulin (CMVIG) (150 mg/kg) and tapering of mycophenol-

to a combination of ganciclovir, liposomal amphotericin B, ceftri-

ate mofetil to 500 mg BID, the IgG rose to 403 mg/dl, with IgA of 111

axone, and CMVIG, but later developed adenocarcinoma of the lung

and IgM of 51. The CD4 count rose to 593, in the low normal range, as

and subsequently expired.

did B cell numbers (113, or 11%). IgG subclass analysis showed mild

After administration of 150 mg/kg of CMV hyperimmune globu-

decreases of IgG1 and IgG3 (Table 2). This patient also was found

lin, the immunoglobulin levels rose to IgG of 590, IgA of 93, and

subsequently to have developed asymptomatic hepatitis C (HCV) vi-

IgM of 97; IgG1 and IgG3 at that time were mildly decreased (Table

remia, having received a heart from an HCV positive donor.

2). B cells (CD19π) were severely reduced at 14 cells/ml (1% of lymphocytes). T cells showed normal numbers and activation (Table 3). When tested after treatment, T cell function was generally pre-

Case 2

served to mitogenic stimulation, though the stimulation index for the B cell mitogen Staphylococcus A Cowan strain (SAC) was severely reduced (Table 4).

A 62-year-old man received a CMV Dπ/Rπ heart transplant for ischemic cardiomyopathy on 24 May 1997. The initial immunosuppressive regimen consisted of cyclosporine, azathioprine, and prednisone. He received 4 weeks of IV ganciclovir and thrice weekly TMP-SMX prophylaxis. Because of persistent Grade 3A rejection,

Discussion

azathioprine was changed to mycophenolate mofetil 1500 mg po BID at 6 weeks post-transplant, and he received methylprednisolone

Patterns of infection following heart transplantation have been well

1 g daily for 3 days. Two weeks later, cyclosporine was changed to

described (24–26). In general, infections following solid organ trans-

tacrolimus. At 5 months post-transplant he was noted to have a left

plantation can be divided into a schema of three main time periods,

lower lung nodule. Bronchoscopy with transbronchial biopsy was

as elucidated by Rubin (24). The second of these time periods, from

Flow cytometric analysis of T cell subsets and B cells in Patient 1 before and after, and in Patient 2 after treatment with CMVIG, antimicrobials, and diminished immunosuppression (cells/ml) Patient

1 Before

1 After

2 After

Normal ranges

CD3

ND

789 (73%)

816 (82%)

958–2388

(60–89%)

CD4

253

593 (55%)

552 (55%)

533–1674

(34–61%)

CD8

66

186 (17%)

410 (41%)

284–958

(16–41%)

CD19 (B cells)

ND

113 (11%)

14 (1%)

75–660

(5–22%)

CD8 CD38

ND

115 (11%)

374 (37%)

292–945

(16–38%)

π

Table 3

Transplant Infectious Disease 2000: 2: 133–139

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Corales et al : Post-transplant hypogammaglobulinemia in heart transplant recipients

Stimulation index to T cell and B cell mitogens, after treatment Mitogen

Patient 1

Patient 2

Phytohemagglutinin

78.3

21.8

Concanavalin A

41.9

9.1

Pokeweed mitogen

2.2

14.1

Staphylococcus A Cowan strain

0.001

0.1

hypogammaglobulinemic. Although this association is infrequent (32), nocardiosis has been seen in a variety of immunocompromised hosts, in whom it may cause pulmonary nodules, brain abscesses, septic arthritis, and other infections (33–37). Although many infections can be seen in the second period post-transplant, the infections in the two patients described above were noteworthy. First of all, nocardiosis is uncommon at this center. Of more than 500 patients

Table 4

receiving heart transplants at this center in the years preceding the cases above, only two other cases of nocardiosis occurred. Also, none of the six patients reported herein was in the highest risk

months 1–6 post-transplant, is the time when opportunistic infec-

group for CMV (donor seropositive, recipient seronegative), so high-

tions most frequently occur. There is a strong association between

risk CMV status is not the explanation for multiple infections in

the type, dose, timing, and duration of immunosuppressive medi-

this group. At this center, the 4-week IV ganciclovir prophylaxis

cations utilized, on the one hand, and the transplant recipient’s risk

regimen (38, 39) has been highly successful in the donor seroposi-

of infection on the other (24, 25, 27).

tive, recipient seropositive (Dπ/Rπ) subgroup, to which both of the

The newer antirejection drugs MMF and tacrolimus are powerful

above patients belonged. Neither of these patients received anti-

agents for the prevention and treatment of allograft rejection (1–22).

lymphocyte therapy. The fact that TMP-SMX prophylaxis in both

Concerns have been raised about the possibility that the incidence

patients failed to prevent Nocardia infection may also reflect their

of CMV and other opportunistic infections (2–4, 28, 29) might in-

degree of immunosuppression. Finally, the invasive Trichophyton

crease with MMF-containing regimens, although a protective effect

infection in the second patient is highly unusual. Table 1 summar-

against Pneumocystis carinii has also been suggested (30), and some

izes the characteristics of these two cases and four other heart

larger studies of newer immunosuppressive agents have not sug-

transplant recipients found to have very low post-transplant im-

gested an excess of major opportunistic infections (5, 16). Recent

munoglobulin levels. Infections in the other four patients also in-

work on the pharmacokinetics of the combination of mycophenolate

cluded gastrointestinal CMV in two, pulmonary aspergillosis, and

mofetil and tacrolimus suggests that there is an augmentation of

Acinetobacter bacteremia. Although these are not infections tra-

immunosuppression beyond their additive effects (20–22). The

ditionally associated with hypogammaglobulinemia, the occurrence

mechanism of action of MMF has been well described to include

of these unusually severe constellations of opportunistic infection in

inhibition of both T- and B-lymphocyte proliferation through inter-

patients with extremely low IgG levels is notable.

ference with the de novo pathway of purine synthesis (6, 31). The

Hypogammaglobulinemia in solid organ transplant recipients

anti-B cell effect of MMF has even led to its proposed use for de-

has occasionally been described (40–45). Pollock et al. noted recur-

creasing pre-transplant anti-human leukocyte antigen (HLA) anti-

rent infections in 5 renal transplant recipients with low immuno-

body titers (Smedira N, personal communication). However, the oc-

globulin levels (42). Van Thiel et al. found that 43/1684 liver trans-

currence of clinically significant post-transplant hypogammaglobul-

plant recipients had immunoglobulin deficiencies at the time of

inemia in patients treated with mycophenolate, tacrolimus, or their

transplantation, and found that patient and graft survival were sig-

combination has not previously been described.

nificantly reduced in the IgA-deficient group (43). A recent study of

Mycophenolate mofetil in heart transplantation has been re-

humoral immune status in lung transplant recipients at our center

cently reviewed (6, 11) and has been studied in a large multicenter

described severe hypogammaglobulinemia in approximately one-

trial (5), in which 650 patients were randomized to MMF versus

third of patients post-transplant, with significantly higher risk of

azathioprine in addition to cyclosporine and corticosteroids. This

infectious complications (45).

study showed a significant reduction in one-year mortality (6.2%

A study of long-term survivors of renal transplantation by

vs. 11.4%) as well as a reduction in rejection treatment in MMF-

Braun et al. (44) revealed IgG levels of less than 600 mg/dl in 21%

treated patients. Opportunistic infections were more common in the

of patients with a functioning renal allograft 20 or more years post-

MMF group (53.3% vs. 43.6%), but herpes simplex and herpes zos-

transplant. One of these patients developed refractory CMV colitis

ter accounted for most of these. There were no significant differ-

at 25 years after kidney transplantation, with an IgG level of 72

ences in CMV infection, tissue-invasive CMV, aspergillosis, or can-

mg/dl. He responded to discontinuation of azathioprine and short-

didiasis (5).

term immunoglobulin replacement (44). This patient was not re-

The patients reported above both developed nocardiosis while

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Transplant Infectious Disease 2000: 2: 133–139

ceiving mycophenolate, but there is evidence that azathioprine may

Corales et al : Post-transplant hypogammaglobulinemia in heart transplant recipients

also decrease immunoglobulin synthesis (46) and that this may be a property of purine antagonists in general.

Five of these six patients had CMV infection, which may have been both a result of, and a contributing factor to, their net state of

Could the low IgG levels reported here have been present pre-

immunosuppression (24, 25). The possibility that other immuno-

transplant? A recent report describes a 15-year-old renal transplant

modulatory viruses could have been playing a role cannot be ruled

recipient discovered retrospectively to have common variable im-

out. In particular, one patient was the recipient of a heart from an

munodeficiency (47). Though pre-transplant immunoglobulin levels

HCV-positive donor; also it would have been of interest to perform

are not available on the six patients reported here, total globulins

Epstein-Barr virus polymerase chain reaction (EBV-PCR) determi-

at that time were within the normal range. In subsequent pre-trans-

nations in these patients at the time of the lowest IgG level. How-

plant IgG screening in 20 patients at this center, the mean IgG level

ever, the absence of post-transplant lymphoproliferative disease

was 1226 mg/dl. Only one patient had moderately low IgG (400 mg/

(PTLD) in these patients, and the low rate of PTLD in this center’s

dl) which actually rose after transplant. Thus, it appears likely that

heart transplant program, speaks against widespread active EBV

hypogammaglobulinemia in the patients reported here was ac-

infection as the cause of hypogammaglobulinemia in these patients.

quired post-transplant.

In summary, this report highlights a recently noted clinical phe-

The mechanism of hypogammaglobulinemia in these patients is

nomenon of unexpectedly low IgG levels in certain heart transplant

unclear. Lymphocyte subset analysis on the first patient suggests a

recipients. Of the six patients with the lowest IgG levels, five of the

π

six were receiving tacrolimus, mycophenolate mofetil, and pred-

T cells, which are required to stimulate B cell responses. Total B cell

nisone. Although no conclusions can be drawn from this current

numbers in the second patient were significantly reduced. When mito-

report regarding causal relationships, it will be of interest to moni-

genic responses were tested, the isolated lack of reactivity to Staphy-

tor various specific parameters of immune function in patients on

lococcus A Cowan strain (SAC) is consistent with significant B cell

newer immunosuppressive regimens. A prospective study is on-

dysfunction (Table 4). In all six patients, IgG levels improved over

going to study hypogammaglobulinemia in a larger group of heart

time, generally into the 500 mg/dl range. It would have been of inter-

transplant patients, and to attempt to correlate this with immuno-

est to measure these stimulation parameters in these patients before

suppressive regimens and clinical outcomes (23).

multifactorial process, including a decrease in the number of CD4

tapering of immunosuppression and administration of CMVIG.

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