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Goldfarb, Nosson S.1; Avery, Robin K.2; Goormastic, Marlene; Mehta, Atul C.; Schilz, Robert; Smedira, Nicholas; Pien, Lily; Haug, Marcus T.; Gordon, Steven M.; Hague, L. Kathleen; Dresing, Janna M.; Evans-Walker, Tracy; Maurer, Janet R.

Clinical Transplantation

Background. Infectious complications continue to represent a significant source of morbidity and mortality in lung transplant recipients.Identifying specific, remediable immune defects is of potential value. After one lung transplant patient with recurrent infections was noted to be severely hypogammaglobulinemic, a screening program for humoral immune defects was instituted. The objectives were to define the prevalence of hypogammaglobulinemia in lung transplant recipients, assess levels of antibody to specific pathogens, and correlate infectious disease outcomes and survival with immunoglobulin levels.

Methods. All lung transplant recipients followed at a single center between October 1996 and June 1999 underwent a posttransplant humoral immune status survey as part of routine posttransplant follow-up. This survey consists of total immunoglobulin levels (IgG, IgM, IgA), IgG subclasses (IgG1–4), and antibody titers to Pneumococcus, diphtheria, and tetanus. Since February 1997, this survey has been incorporated into the pretransplant evaluation as well. Humoral survey results for October 1996 through July 1999 were recorded, and clinical information on major infectious disease outcomes was obtained from chart reviews, discharge summaries, the Cleveland Clinic Unified Transplant Database, and review of all microbiological studies and pathology results for each patient.

Results. Of 67 patients with humoral immune surveys drawn posttransplant, 47 (70%) had IgG levels less than 600 mg/dl (normal 717-1410 mg/dl), of which 25 (37%) had IgG levels less than 400 mg/dl (“lowest IgG group”) and 22 (33%) had IgG levels between 400 and 600 mg/dl (“moderately low IgG group”). A total of 20 patients (30%) had IgG levels of more than 600 mg/dl (“normal IgG group”). Infections that were significantly more common in the lowest IgG group, and more common in the moderately low IgG group than the normal IgG group, included: number of pneumonias (P =0.0006), bacteremias (P =0.02), total bacterial infections (P =0.002), tissue-invasive cytomegalovirus (P =0.01), invasive aspergillosis (P =0.001), total fungal infections (P =0.001), and total infections (P =0.006). Median hospital days per posttransplant year was significantly different in the three groups (11.0 vs. 7.4 vs. 2.8 days, P =0.0003.) Invasive aspergillosis occurred in 44% of the lowest IgG group, 9% of the moderately low IgG group, and 0% of the normal IgG group (P <0.001). Survival was poorest in the lowest IgG group and intermediate in the moderately low IgG group. IgG subclass deficiencies occurred in a variety of patterns. Hypogammaglobulinemic patients lacked protective responses to Pneumococcus in 14/47 (30%), diphtheria in 15%, and tetanus in 19%. In a group of 48 patients screened pretransplant, 90% had normal immunoglobulin levels.

Conclusions. Hypogammaglobulinemia in lung transplant recipients is more common than has been previously recognized. An IgG level of less than 400 mg/dl identifies a group at extremely high risk of bacterial and fungal infections, tissue-invasive cytomegalovirus, and poorer survival. Immunoglobulin monitoring may offer an opportunity for intensive surveillance, tapering of immunosuppression, and preemptive therapy for infection.

Transplant Center and Departments of Pulmonary Medicine, Allergy-Immunology, Thoracic Surgery, Infectious Disease, and Pharmacy, Cleveland Clinic Foundation, Cleveland, OH 44195

1Current address: Kaiser Permanente, 10 Severance Circle, Cleveland Heights, OH 44118.

Received 20 March 2000.

Accepted 6 June 2000.

2 Address correspondence to: Robin K. Avery, Department of Infectious Diseases, Desk S-32, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

It has long been recognized that infectious disease complications represent a significant limitation to long-term survival in lung transplant recipients (1–3). In addition, frequent infections lead to repeated hospital admissions and poorer quality of life, and may also have impact on allograft function in the longer term. In addition to frequent episodes of bacterial pneumonia, bronchitis, and sinusitis, it has been suggested that lung transplant recipients have a disproportionate burden of certain infections, including cytomegalovirus (CMV) infections, in comparison with other solid organ recipients (4). Lung recipients appear to require more intensive and lengthy prophylaxis for CMV (5–8), and CMV in lung recipients is a risk factor for bronchiolitis obliterans (9–12), and for fungal infections including aspergillosis (13–17).

Reasons for this burden of infections in lung transplant recipients are likely multifactorial. First, lung recipients are the only solid organ recipients in which the allograft is in direct contact with the environment including airborne pathogens. Immunological events within the allograft are complex, and are a subject of intensive current research (18). Among the possible contributing factors to the “net state of immunosuppression” (15), it is of interest to identify any potentially reversible factors.

Hypogammaglobulinemia has been recently identified as a potential contributor to the net state of immunosuppression in heart transplant recipients at this center (19–20), and has been previously noted in a few reports in other solid organ recipients (21–25). Van Thiel et al. (24) found that 43/1684 (2.6%) liver recipients had immunoglobulin deficiencies at the time of transplantation, and found that patient and graft survival were reduced in the IgA-deficient group. In a study of long-term survivors after kidney transplantation, Braun et al. (25) found IgG levels of less than 600 mg/dl in 21% of patients with a functioning renal allograft for 20 years or more. One of these patients, who developed refractory gastrointestinal CMV at 25 years posttransplant, was found to be profoundly hypogammaglobulinemic (IgG=72 mg/dl), and was able to clear his CMV only after Ig replacement and azathioprine withdrawal (25, 26).

After one lung transplant recipient with repeated admissions for pneumonia and sinusitis was found to be profoundly hypogammaglobulinemic, this center began to screen patients for hypogammaglobulinemia in an attempt to identify patients at risk who might be candidates for decreased immunosuppression, augmented prophylaxis, and immunoglobulin replacement in selected cases.

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Between February 1990 and February 1998, the Cleveland Clinic Foundation Lung Transplant Team performed 130 lung and heart-lung transplants. A total of 59 of these transplant recipients are currently followed in the Lung Transplant Clinic; 69 have expired and 2 are followed elsewhere. Four patients transplanted at other centers are also followed at the Cleveland Clinic.

Beginning in October of 1996, all lung transplant recipients followed at the Cleveland Clinic had humoral immune status surveys obtained (Specialty Laboratories, Santa Monica, CA). This survey consists of immunoglobulin levels (IgG, IgM, IgA, IgE) and IgG subclasses (IgG1–4) and antibody titers to Pneumococcus (4 serotypes:3, 7F, 9N, 14), diphtheria, and tetanus. Because this group of patients tested were those currently being followed at the Lung Transplant Clinic, their transplant dates ranged from 1990 to 1998 and IgG levels were hence not obtained at a specific time posttransplant. In addition to the full humoral immune status surveys, IgG levels were also measured at different times according to the clinicians’ discretion.

We retrospectively reviewed all humoral immune surveys and IgG levels obtained between October 1996 and July 1999. Results were available for all patients except those who died before initiating the humoral immune evaluation, two patients followed elsewhere, and one other patient. We also initiated a prospective evaluation of humoral immune function as part of the pretransplant evaluation for all patients considered for lung transplantation beginning in February 1997. For purposes of this analysis, the lowest IgG level obtained was used to divide patients into three groups: IgG <400 mg/dl (lowest IgG group), IgG between 400 and 600 mg/dl (moderately low IgG group), and IgG >600 mg/dl (normal IgG group.)

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Immunosuppression was generally with a combination regimen of prednisone, cyclosporine, and azathioprine. Tacrolimus was substituted for cyclosporine, and mycophenolate for azathioprine, in a small number of patients due to rejection or adverse effects. Antilymphocyte therapies such as OKT3 (muromonab anti-CD3) and antithymocyte globulin are infrequently used in this lung transplant program (fewer than 10% of patients), and are never used as induction therapy.

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Since 1995, CMV prophylaxis has consisted of 2 weeks of i.v. ganciclovir, 5 mg/kg i.v. BID, followed by i.v. ganciclovir 5 mg/kg 3x/week to day 90. Before 1995, CMV prophylaxis consisted of 4 weeks of i.v. ganciclovir. For CMV donor seropositive, recipient seronegative (D+/R-) patients since 1994, in addition to ganciclovir, CMV hyperimmune globulin (CMVIG) is administered at a dose of 150 mg/kg at weeks 0, 2, 4, 6, 8, and 100 mg/kg at weeks 12 and 16 (27). Antifungal prophylaxis consists of inhaled amphotericin B 10 mg BID during the posttransplant admission, followed by itraconazole 200 mg p.o. QD indefinitely, with dose adjustment by itraconazole levels. Pneumocystis prophylaxis is with trimethoprim-sulfamethoxazole lifelong, or with dapsone or monthly aerosolized pentamidine in the case of significant sulfa allergy.

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“Pneumonia” was defined as pulmonary infection severe enough to require admission and bronchoscopy, with the exception of CMV, fungal, and other specific nonbacterial pathogens that were classified as outcomes in their respective categories. Milder pulmonary infections and bronchitis requiring outpatient treatment were not counted. “Bacteremia” was culture-proven bacterial bloodstream infection, with the exception of single culture coagulase-negative staphyloccal isolates that were considered to be contaminants. “Total bacterial infections” included pneumonia and bacteremia by the above definitions, and also sinusitis, cellulitis, abscesses, and other bacterial infections if they were severe enough to require hospital admission. Outpatient sinusitis episodes were not counted. “Invasive aspergillosis” was defined as the isolation of Aspergillus species from bronchoalveolar lavage or open lung biopsy or other tissue biopsy, in the presence of a radiographically and clinically compatible scenario. Isolation of Aspergillus species in the presence of a normal chest radiograph was not considered invasive aspergillosis. “Other fungal infection” was defined as significant invasive fungal infection such as cryptococcal meningitis, and excluded oral candidiasis and superficial dermatophyte infection. “Total fungal infections” included invasive aspergillosis and other significant fungal infections by the above definitions. “CMV viremia” was defined as any positive CMV-DNA by Digene hybrid capture assay. “Tissue-invasive CMV” was defined as CMV inclusions visualized in histopathological biopsies of the lung, gastrointestinal tract, or other organs. “Hospital days per posttransplant year since 1996” were calculated as hospital admission data were available in the computerized hospital record for the time period since 1/1/96. Because some patients were transplanted after 1/1/96, and some patients expired before the final data collection date of 7/31/99, hospital days were counted as all days admitted between the dates of 1/1/96 (or date of transplant if it occurred after 1/1/96) and 7/31/99 (or expiration date if before 7/31/99). The denominator was all days between the dates of 1/1/96 (or date of transplant if it occurred after 1/1/96) and 7/31/99 (or expiration date if before 7/31/99).

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Statistical analysis.

Frequencies and percents are presented for the categorical data. These data were analyzed using a χ2 test. Continuous data are presented as means with SDs and medians. Comparisons for the continuous variables were done using a Wilcoxon rank sum test. A Kaplan-Meier analysis was used to estimate survival. The log rank test was used to compare the survival curves. P= 0.05 or less was considered statistically significant.

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Pretransplant humoral immune surveys.

A total of 48 patients had humoral immune surveys drawn as a baseline as part of pretransplant evaluation. 43 of 48 (90%) had normal immunoglobulin levels. Four patients (8%) had a single globulinopathy (1 IgG, 1 IgM, 2 IgA). One other patient was known to have a preexisting panhypogammaglobulinemia pretransplant, with an IgG level of 488.

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Posttransplant humoral immune surveys.

Of 67 total patients on whom posttransplant humoral immune surveys were obtained, 47 of 67 (70%) had IgG levels <600 mg/dl, including 25 (37%) IgG less than 400 mg/dl (lowest IgG group) and 22 (33%) with IgG between 400 and 600 mg/dl (moderately low IgG group.) A total of 20/67 patients (30%) had IgG of more than 600 mg/dl (normal IgG group.) Gender, underlying diagnosis, and age at transplant of the patients in these three groups are summarized in Table 1. The mean age of the patients in the lowest IgG group was 45.3, that in the moderately low group was 47.5, and in the normal group was 37.2 (P =0.08).

Table 1

Table 1

Of the 47 hypogammaglobulinemic patients, 12 (25.5%) also had a deficiency of IgA (<70 mg/dl), with 4 (8.5%) having low IgM (<40 mg/dl). No patient had an isolated IgA- or IgM-deficient state.

Of the 44 patients with low IgG levels, subclass deficiencies occurred in a variety of patterns: IgG1 (5 patients), IgG2 (2), IgG3 (6), IgG4 (4), IgG1 and 2(1), IgG 2 and 3 (1), IgG 1 and 3 (5), IgG 2 and 4 (2), IgG 1 and 4 (2), IgG 1,2, and 3 (2), and IgG 1,3, and 4 (1).

Protective responses to Pneumococcus were absent in 14 (30%) of patients with IgG <600 mg/dl. Antibody levels to diphtheria were low in seven (15%) and to tetanus in nine (19%).

Patients were included in the IgG level categories based on their lowest recorded IgG level. The mean time to lowest IgG level was 899 days (29.6 months; range 2 weeks to 7 years), and the median time to lowest IgG level was 571 days (18.8 months). Because some patients had been transplanted at times long before our study, and therefore may have been hypogammaglobulinemic for some time before the study began, no meaningful conclusions can be drawn from our study regarding the most likely time posttransplant for hypogammaglobulinemia to develop. This awaits prospective data that are currently being collected. However, perhaps some idea of the time course posttransplant can be gleaned from a parallel prospective study of heart transplant recipients at the same institution, in whom the mean time to hypogammaglobulinemia was 6.5 months posttransplant (20).

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Immunoglobulin replacement.

As a result of this survey and clinical events, 12 patients received immunoglobulin replacement because of hypogammaglobulinemia and recurrent infections. Seven of these patients received CMV hyperimmune globulin (CMVIG); five patients received unselected i.v. immunoglobulin (IVIG) but two of these five were switched to CMVIG because of adverse reactions to IVIG. This immunoglobulin replacement was at clinician discretion and the number and timing of doses varied. Six patients received Ig replacement every 4 weeks; the other six received either single doses or as needed. For those patients with IgG levels drawn before and after replacement, the mean prereplacement IgG level was 378 (low 232) and the mean postreplacement level was 539. The only patients who received immunoglobulin preparations for reasons other than hypogammaglobulinemia were those who were CMV D+/R- and received CMVIG infusions as part of the CMV prophylaxis protocol at this center (detailed above.)

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Infectious disease outcomes, hospital days, and survival.

Table 2 summarizes major infectious outcomes, and hospital days per posttransplant year, for the three immunoglobulin groups according to the definitions above. Figure 1 is a Kaplan-Meier survival estimate for the three immunoglobulin groups.

Table 2

Table 2

Figure 1

Figure 1

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A majority of patients (70%) screened for hypogammaglobulinemia posttransplant were found to have hypogammaglobulinemia as defined by an IgG level of <600 mg/dl, with 25 (37%) having very low IgG levels (<400 mg/dl). This does not appear to be persistence of a pretransplant phenomenon, as evidenced by the 90% of patients with normal pretransplant IgG levels since pretransplant screening was begun. Patients in the lowest IgG group were at higher risk for almost every clinically significant infection (Table 2), including pneumonias, bacteremias, fungal infections, and tissue-invasive CMV (with the exception of CMV viremia and posttransplant lymphoproliferative disease). Patients in the moderately low IgG group were at higher risk for all of these infections than those in the normal IgG group, but were at lower risk than the lowest IgG group. Invasive aspergillosis occurred exclusively in the hypogammaglobulinemic groups and was most prominent in the lowest IgG group, in which 44% of patients had invasive aspergillosis. Mean and median hospital days per year posttransplant were significantly highest in the lowest IgG group, intermediate in the moderately low IgG group, and fewest in the normal IgG group.

This phenomenon was not explained by the higher global infection risk conferred by CMV donor seropositive, recipient seronegative (D+/R-) status, as low IgG level was not associated with D+/R- status. In fact, there was a trend toward a lower percentage of D+/R- patients in the lowest IgG group as opposed to the moderately low and normal IgG groups. It is possible that the administration of CMVIG as part of routine CMV prophylaxis up to week 16 for D+/R- patients at this center may be partly responsible for these patients being underrepresented in the lowest IgG group.

Although traditionally associated with increased risk for bacterial infections with encapsulated organisms such as Pneumococcus and Haemophilus influenzae, in this study hypogammaglobulinemia was associated with risk for fungal infections and tissue-invasive CMV as well. The incidence of CMV viremia was not different between the groups, but CMV tended to have more severe manifestations in the lowest IgG group. It is as yet unclear whether there is a causal relationship between hypogammaglobulinemia and these nonbacterial infections, or whether hypogammaglobulinemia is a marker for a globally immunosuppressed state which confers increased risk for these infectious outcomes. Aspergillosis is traditionally associated more with neutrophil number and function, and defective cellular immunity, than with humoral immune deficiencies. Cellular immune parameters, such as T helper and suppressor cell numbers and ratio, were not measured in this study, and it is possible that other aspects of the immunological profile are the key factors in the increased risk patterns observed. Prospective information on pneumococcal and tetanus vaccine responses in this population would be of interest, as a measure of the capacity for specific humoral responses. In any case, it is clear that very low IgG levels are at least a marker for a variety of adverse infectious outcomes, not limited to bacterial infections.

Further studies will be important, to clarify risk factors for hypogammaglobulinemia and to assess the impact of interventions based on early detection of a falling IgG level. Those interventions might include decreasing immunosuppression where possible, close monitoring for infections, intensified prophylaxis for infections, and immunoglobulin replacement in selected patients. As a result of this study, our clinical practice came to include immunoglobulin replacement for the patients in the lowest IgG group, and some patients in the moderately low group. Recognizing the need for a more rigorous definition of clinical outcomes and the effects of Ig replacement, a prospective randomized trial is currently underway to evaluate the impact of this intervention, and to define more precisely the optimal IgG level at which Ig replacement should be instituted. Regardless of what interventions are used, monitoring of IgG levels appears to have value in identifying a group of patients at increased risk.

Limitations of this study include the fact that immunoglobulin levels were not obtained at uniform times posttransplant, and thus the highest risk time period for hypogammaglobulinemia cannot be accurately defined. Because the time-dependence of development of hypogammaglobulinemia was not analyzed, it is more difficult to interpret the survival curve. Ascertainment bias may have occurred, in that patients with multiple infectious complications may have been more likely to have IgG levels drawn more frequently. In addition, this study did not attempt to correlate hypogammaglobulinemia with the administration of specific immunosuppressive medications, nor with the incidence of acute rejection, chronic allograft dysfunction, and bronchiolitis obliterans. An ongoing prospective study will attempt to address these questions. Further in vitro measures of immune function would be of interest, and more work remains to be done to define the nature of the immune defect in the subgroup of recipients who are hypogammaglobulinemic. Our report seeks primarily to highlight the existence of hypogammaglobulinemia in a significant percentage of patients after lung transplantation; further work will be needed to elucidate its causes, time course, consequences, and appropriate interventions.

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Hypogammaglobulinemia after solid organ transplantation has been infrequently described. Several case reports and small series have noted unexpectedly severe infectious complications in hypogammaglobulinemic patients after transplant. This report documents a high rate of hypogammaglobulinemia in lung transplant recipients that does not appear to be the persistence of a pretransplant phenomenon. The lowest IgG group appears to be a group at higher risk for severe bacterial, fungal, viral infections and for increased hospital admission days and poorer survival.

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