Treatment of rheumatoid arthritis with total lymphoid irradiation: long-term survival

OBJECTIVE: Total lymphoid irradiation (TLI) has been used to treat rheumatoid arthritis (RA) since the 1970s. This study reviews long-term (15-20-year) mortality outcomes of patients treated with TLI for RA at Stanford University Medical Center and compares these outcomes with those in patients treated with disease-modifying antirheumatic drugs (DMARDs). METHODS: Fifty-three patients with RA were treated with full-dose TLI at Stanford University Medical Center. All had failed previous therapy with gold salts and penicillamine. One hundred six control patients were selected from the Arthritis, Rheumatism, and Aging Medical Information Systems database and were matched with the patients for age, sex, disease duration, and mean Health Assessment Questionnaire (HAQ) score. Survival was analyzed using Kaplan-Meier methods and Cox proportional hazards regression. RESULTS: No significant difference in age and sex was found between TLI-treated patients and controls. TLI-treated patients had more education (mean 13.4 years versus 11.8 years; P = 0.016) and received more DMARDs prior to TLI (mean 2.1 versus 1.3; P = 0.0001). TLI-treated patients had lower mean HAQ scores at the time of TLI (2.0 versus 2.4; P = 0.0002). TLI had no significant overall effect on survival in treated patients compared with controls (P = 0.62). The survival curves appeared to cross over at approximately 11 years of followup, with better early survival in the TLI group and better late survival in the control group. There was a total of 25 deaths in the TLI group. There were 45 deaths in the control group, with causes of death available for 20 patients. There were 3 patients with lymphoma and 2 with myelodysplastic syndrome in the TLI group, and none in the control group. The most common cause of death in both groups was infection. CONCLUSION: TLI had no significant effect on overall survival, with trends toward higher early mortality in controls and trends toward higher late mortality in TLI-treated patients. Overall, there was no difference in mortality, but it appears that there may have been more lymphoproliferative malignancies in the TLI cohort. We would recommend that TLI be used cautiously for patients with refractory RA in whom the benefits outweigh the risks.     

Prophylactic granulocyte transfusions during human bone marrow transplantation

Thirty-eight uninfected patients undergoing bone marrow transplantation were assigned at random to receive prophylactic granulocyte transfusions and oral nonabsorbable antibiotics (group 1) or oral nonabsorbable antibiotics alone (group 2) when their neutrophil count fell below 0.5 x 10(9)/liter. The two groups were comparable in terms of age, sex, underlying disease, immunosuppressive therapy and days of neutropenia. There were three cases of septicemia (all due to gram-positive organisms) in group 2 and none in group 1 (p = 0.23). There was no difference in the incidence of other documented infections, and survival between the two groups was comparable. Recipients of prophylactic granulocyte transfusions had a significantly higher incidence of cytomegalovirus (CMV) infections (13 of 18 versus six of 17, p = 0.043). These data suggest that prophylactic granulocyte transfusions may prevent septicemia, have no effect on other infections or survival in patients undergoing bone marrow transplantation, and are associated with a higher incidence of CMV infection. Oral nonabsorbable antibiotics alone are equally effective in preventing serious infections in bone marrow transplant recipients.     

Long-term followup of patients treated with total lymphoid irradiation for lupus nephritis

OBJECTIVE: To describe the long-term survival, renal condition, and morbidity outcomes in patients who received total lymphoid irradiation (TLI) for the treatment of lupus nephritis. METHODS: Twenty-one patients with biopsy-proven, diffuse membranoproliferative glomerulonephritis and significant proteinuria of >2.5 grams/day received TLI from 1980 to 1987 at Stanford University Medical Center. All patients had previously failed to respond to treatment with high-dose corticosteroids or therapy with corticosteroids plus immunosuppressive agents (azathioprine, cyclophosphamide, or chlorambucil). RESULTS: The mean duration of followup since TLI was 10.7 years. Fifteen of 21 patients (71%) remained alive at the time of this assessment. Nine of the 21 patients (43%) survived without developing end-stage renal disease (ESRD). The probability of long-term survival without ESRD and without need for additional immunosuppressive agents after TLI was 19% (4 of 21). Factors predicting renal failure at the time of TLI included elevated creatinine levels, increased interstitial fibrosis on renal biopsy, and increased fractional excretion of immunoglobulin and albumin. Malignancies were found in 4 patients, and opportunistic infections occurred in 7 patients. CONCLUSION: Overall, patients with lupus nephritis treated with TLI do not appear to have better 10-year survival with lower incidence of ESRD compared with patients in published series treated with conventional immunosuppressive therapies. However, in this series of patients, treatment with conventional immunosuppressive therapies had been unsuccessful and given the limited number of adverse events and the efficacy seen in some patients, TLI appears to be a reasonable therapeutic option for the treatment of severe lupus nephritis among patients who fail to respond under standard cytotoxic regimens.     

Treatment of rheumatoid arthritis with total lymphoid irradiation: Long‐term survival

Objective

Total lymphoid irradiation (TLI) has been used to treat rheumatoid arthritis (RA) since the 1970s. This study reviews long‐term (15–20‐year) mortality outcomes of patients treated with TLI for RA at Stanford University Medical Center and compares these outcomes with those in patients treated with disease‐modifying antirheumatic drugs (DMARDs).

Methods

Fifty‐three patients with RA were treated with full‐dose TLI at Stanford University Medical Center. All had failed previous therapy with gold salts and penicillamine. One hundred six control patients were selected from the Arthritis, Rheumatism, and Aging Medical Information Systems database and were matched with the patients for age, sex, disease duration, and mean Health Assessment Questionnaire (HAQ) score. Survival was analyzed using Kaplan‐Meier methods and Cox proportional hazards regression.

Results

No significant difference in age and sex was found between TLI‐treated patients and controls. TLI‐treated patients had more education (mean 13.4 years versus 11.8 years; P = 0.016) and received more DMARDs prior to TLI (mean 2.1 versus 1.3; P = 0.0001). TLI‐treated patients had lower mean HAQ scores at the time of TLI (2.0 versus 2.4; P = 0.0002). TLI had no significant overall effect on survival in treated patients compared with controls (P = 0.62). The survival curves appeared to cross over at ∼11 years of followup, with better early survival in the TLI group and better late survival in the control group. There was a total of 25 deaths in the TLI group. There were 45 deaths in the control group, with causes of death available for 20 patients. There were 3 patients with lymphoma and 2 with myelodysplastic syndrome in the TLI group, and none in the control group. The most common cause of death in both groups was infection.

Conclusion

TLI had no significant effect on overall survival, with trends toward higher early mortality in controls and trends toward higher late mortality in TLI‐treated patients. Overall, there was no difference in mortality, but it appears that there may have been more lymphoproliferative malignancies in the TLI cohort. We would recommend that TLI be used cautiously for patients with refractory RA in whom the benefits outweigh the risks.

     

Effect of thymoglobulin induction on HIV-infected renal transplant recipients: differences between HIV-positive and HIV-negative patients

The best immunosuppressive regimen in HIV-infected renal transplant recipients has not been established. Thymoglobulin has been associated with an increased risk of serious bacterial infections in HIV-negative patients and, for this reason, there is some concern over its use in the HIV-infected population. We describe three consecutive HIV-infected renal transplant recipients who received thymoglobulin as induction therapy, and we compared their progress with a cohort of 23 HIV-negative recipients. Median follow-up was 24 and 11 months, respectively. Nadir lymphocytopenia was observed at 1 week in both groups, and their absolute lymphocyte count recovery was similar. An early and deep (<30 cells/mm(3)) CD4(+) T cell lymphocytopenia was seen in two of the three HIV-infected patients. No opportunistic infections were diagnosed in HIV-positive patients. One HIV-positive patient had a bacterial infection and five HIV-negative patients had one or more bacterial infections. Thymoglobulin was safe in our three HIV-infected renal transplant recipients. Until those data are confirmed in larger studies, close monitoring is recommended during the thymoglobulin-induced CD4(+) T cell lymphocytopenia period.     

Long‐term followup of patients treated with total lymphoid irradiation for lupus nephritis

Objective

To describe the long‐term survival, renal condition, and morbidity outcomes in patients who received total lymphoid irradiation (TLI) for the treatment of lupus nephritis.

Methods

Twenty‐one patients with biopsy‐proven, diffuse membranoproliferative glomerulonephritis and significant proteinuria of >2.5 grams/day received TLI from 1980 to 1987 at Stanford University Medical Center. All patients had previously failed to respond to treatment with high‐dose corticosteroids or therapy with corticosteroids plus immunosuppressive agents (azathioprine, cyclophosphamide, or chlorambucil).

Results

The mean duration of followup since TLI was 10.7 years. Fifteen of 21 patients (71%) remained alive at the time of this assessment. Nine of the 21 patients (43%) survived without developing end‐stage renal disease (ESRD). The probability of long‐term survival without ESRD and without need for additional immunosuppressive agents after TLI was 19% (4 of 21). Factors predicting renal failure at the time of TLI included elevated creatinine levels, increased interstitial fibrosis on renal biopsy, and increased fractional excretion of immunoglobulin and albumin. Malignancies were found in 4 patients, and opportunistic infections occurred in 7 patients.

Conclusion

Overall, patients with lupus nephritis treated with TLI do not appear to have better 10‐year survival with lower incidence of ESRD compared with patients in published series treated with conventional immunosuppressive therapies. However, in this series of patients, treatment with conventional immunosuppressive therapies had been unsuccessful and given the limited number of adverse events and the efficacy seen in some patients, TLI appears to be a reasonable therapeutic option for the treatment of severe lupus nephritis among patients who fail to respond under standard cytotoxic regimens.

     

Infectious risk factors in the immunosuppressed host

A survey of 194 renal transplant recipients was undertaken to clarify factors of importance in the genesis of infections in the immunosuppressed host. The need for high dose prednisone therapy and the occurrence of hyperglycemia were significantly greater in patients with fatal and nonfatal post-transplant infections than in patients without such infection. Being over 40 years of age at the time of transplantation and the presence of leukopenia were occasionally significantly associated with infectious death after transplantation. Renal failure was associated with infectious death in some transplant recipients; this association likely reflected the use of high dose immunosuppressive agents to treat refractory rejection. Hypogammaglobulinemia, azathioprine therapy (at the dosage level studied) and the sex and race of the recipient, the type of underlying renal disease, nephrectomy, splenectomy and thymectomy were not associated with post-transplant infectious death.There was a marked diminution in infection and infectious death after 1965. We postulate that this decline was due to two factors: (1) the accumulation of extensive experience with post-transplant infections leading to a more aggressive diagnostic and therapeutic approach in recent transplant recipients with infection, and (2) a decrease in the use of high dose prednisone therapy and of the occurrence of hyperglycemia in recent transplant recipients. The more frequent use of related donor kidneys and the introduction of antilymphocyte globulin permitted less use of high dose prednisone therapy in transplant recipients after 1965.     

Opportunistic infections with Strongyloides stercoralis in renal transplantation

Opportunistic infections with the nematode Strongyloides stercoralis occur most often in patients with impaired T lymphocyte function, including recipients of renal allografts. Occult intestinal infection can remain quiescent for more than 30 years, becoming apparent only after the initiation of immunosuppression. Pulmonary and gastrointestinal symptoms predominant as initial clinical manifestations in patients with strongyloides hyperinfection or dissemination. Although thiabendazole remains the treatment of choice for all forms of strongyloidiasis, the duration of therapy must be individualized on the basis of frequent examinations of both stool and sputum. Transplantation centers drawing patients from areas with endemic Strongyloides should evaluate potential recipients closely for occult strongyloides infection prior to initiating immunosuppressive therapy. Empiric therapy with thiabendazole should be considered for renal allograft recipients with unexplained eosinophilia and a history of travel or residence in an area with endemic Strongyloides. Prophylactic monthly administration of thiabendazole in immunocompromised patients who have survived strongyloides hyperinfection or dissemination can prevent reinfection.     

Adenovirus infections in adult recipients of blood and marrow transplants.

Adenoviruses are increasingly recognized pathogens that affect blood and marrow transplant (BMT) recipients. Experiences with 2889 adult BMT recipients were reviewed to study the incidence, clinical spectrum, risk factors for dissemination, response to therapy, and outcome of adenovirus infections. Eight-five patients (3%) were diagnosed by means of culture (n=85) or culture and histopathological examination (n=6). Nine patients had asymptomatic viruria, and 76 had symptomatic infections, which included upper respiratory tract infection (n=20), enteritis (n=18), hemorrhagic cystitis (n=10), pneumonia (n=15), and disseminated disease (n=13). The overall mortality rate was 26%. A higher mortality rate was observed among patients with pneumonia (73%) and disseminated disease (61%). Risk factors for dissemination included receipt of an allogeneic transplant, presence of graft-versus-host disease (GVHD), and receipt of concurrent immunosuppressive therapy. Intravenous ribavirin was not associated with an appreciable benefit among 12 patients who received this treatment. In conclusion, adenovirus infections are an important cause of morbidity and mortality in adult BMT recipients, particularly allogeneic transplant recipients with GVHD who are receiving immunosuppressive therapy. The need for an effective, nontoxic antiviral therapy is apparent.     

Efficacy and Safety of ICD Therapy in a Population of Elderly Patients Treated with Optimal Background Medication

Introduction: Implantable cardioverter-defibrillator (ICD) therapy has been shown to improve survival in patients with structural heart disease and at high risk for life threatening ventricular arrhythmias. Whether elderly patients benefit from device therapy in a similar way as younger patients is largely unknown. Methods: We retrospectively analyzed data from 375 consecutive ICD recipients with structural heart disease. Patients were divided into two groups, younger than 70 years at time of ICD implantation (group 1) or 70 years or older (group 2). Main outcome measures were time to death from any cause and time from first appropriate ICD therapy to death. Results: Group 1 and 2 patients were comparable with respect to clinical presentation and average follow-up duration. In the elderly patient group, 78% received an ICD for secondary prevention versus 63% in group 1 (p = 0.007). During a mean follow-up period of 26.5 ± 18.1 months, there was no significant difference in overall mortality among the two groups: 47 patients died, 34 (12.5%) of group 1 versus 13 (12.7%) of group 2. The average time to death was 28.4 ± 16.7 vs 30.4 ± 22.1 months after device implantation, respectively (p = ns). There was no difference in time from device implantation to first adequate ICD therapy and time from first appropriate ICD therapy to death among the two groups (p = ns). Device associated complications were comparable in both groups. Conclusions: Elderly ICD recipients had comparable survival rates and appropriate use of the ICD compared to younger individuals. There was no external financial support of this study.     

Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan

We report the results of a randomized study to elucidate whether addition of granulocyte colony-stimulating factor (G-CSF) to immunosuppressive therapy is valuable for the treatment of severe aplastic anemia (SAA) in adults. A total of 101 previously untreated patients (median age, 54 years; range, 19 to 75 years) were randomized to receive antithymocyte globulin (ATG) and cyclosporin A (CyA) (G-CSF- group) or ATG, CyA, and G-CSF (G-CSF+ group). In the G-CSF+ group, the hematologic response rate at 6 months was higher (77% vs 57%; P = .03) than in the G-CSF- group. No differences were observed between the groups in terms of the incidence of infections and febrile episodes. There were no differences between the G-CSF- group and the G-CSF+ group in terms of survival (88% vs 94% at 4 years), and the development of myelodysplastic syndrome (MDS)/acute leukemia (AL) (1 patient vs 2 patients). However, the relapse rate was lower in the G-CSF+ group compared with the G-CSF- group (42% vs 15% at 4 years; P = .01). Further follow-up is required to elucidate the role of G-CSF in immunosuppressive therapy for adult SAA.     

Primary cutaneous fungal infection after solid-organ transplantation: report of five cases and review.

Solid-organ transplant recipients who are receiving immunosuppressive therapy are at increased risk of acquiring opportunistic infections, particularly fungal infections. We present the cases of five liver transplant recipients who developed primary cutaneous opportunistic fungal infections that remained localized to the skin. These cases are compared with 27 previously reported cases of primary cutaneous fungal infections. In these previously reported cases, administration of systemic antifungal medications, including amphotericin B, ketoconazole, griseofulvin, and miconazole, resulted in a 71% survival rate. Medical and surgical therapy together resulted in an 86% survival rate, and surgical excision resulted in a 100% survival rate. Thus, regardless of the age of the patient, type of immunosuppressive therapy, clinical presentation, or organisms involved, surgical excision yielded the highest cure rate. When possible, surgical excision should be performed on solid-organ transplant recipients who acquire opportunistic fungal infections.     

Phaeohyphomycosis due to Alternaria species in transplant recipients

R.D. Boyce, P.J. Deziel, C.C. Otley, M.P. Wilhelm, A.J. Eid, N.L. Wengenack, R.R. Razonable. Phaeohyphomycosis due to Alternaria species in transplant recipients.
Transpl Infect Dis 2010: 12: 242–250. All rights reserved Abstract: Alternaria species are members of a heterogenous group of dematiaceous fungi that rarely cause opportunistic infections in transplant recipients. During a 20‐year period from 1989 to 2008, 8 solid organ transplant recipients (63% males; median age, 48 years) developed Alternaria species infections at the Mayo Clinic. All patients were highly immunocompromised as evidenced by their receipt of multiple transplants, treatment of acute and chronic allograft rejection, and occurrence of other opportunistic infections. All patients presented with non‐tender erythematous or violaceous skin papules, nodules, or pustules in exposed areas of the extremities. No case of visceral dissemination was observed. Itraconazole was the most common drug used for treatment, although voriconazole, posaconazole, and caspofungin could potentially be useful based on our limited clinical data and in vitro antifungal susceptibility testing. One patient was treated with voriconazole, while another patient who was refractory to itraconazole had rapid resolution of lesions after the addition of caspofungin. Attempts at antifungal therapy alone were unsuccessful; all patients eventually required surgical excision of lesions. In conclusion, Alternaria species are rare but increasingly recognized opportunistic infections among highly immunocompromised transplant recipients. Wide excisional surgery combined with prolonged systemic antifungal therapy and reduction in immunosuppressive regimens provided the best chance of cure. Although itraconazole remains the most common drug for treatment, this case series highlights the potential clinical utility of caspofungin, voriconazole, and posaconazole as alternative regimens.     

Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency.

Epstein-Barr virus (EBV) lymphoproliferative disease is seen in patients with both congenital and acquired immunodeficiencies. Lymphoproliferative disease has been reported in 1 to 3% of renal transplant recipients. Most patients presented with solid tumor masses, rather than an infectious mononucleosis-like syndrome. About one third of cases had involvement of the renal allograft with tumor; the small intestine or central nervous system was also frequently affected. About half of the patients survived. The most frequent therapy used for survivors was decreasing the dose of immunosuppressive therapy and surgical resection of lymphoproliferative lesions. Compared with fatal cases, survivors more often had evidence of active EBV infection (primary or reactivated), received cyclosporine as the major immunosuppressive agent, had polyclonal lesions, and had B-cell hyperplasia rather than lymphoma. Lymphoproliferative disease has been described in 5 to 13% of heart transplant recipients. In our review, the cardiac allograft was not involved by disease in any patient; however, the lungs were involved in more than half of the cases. The soft tissues were frequent sites of lymphoproliferative disease. All patients had lymphoma or immunoblastic sarcoma on pathology and all had monoclonal lesions. While only 8% of patients survived, about half died from causes unrelated to lymphoproliferative disease. EBV lymphoproliferative disease has been reported in 9% of heart-lung transplant recipients. Most of the patients presented with pulmonary symptoms and the pulmonary allograft was involved in 80% of cases. The large and small intestine were frequently affected. About 60% of patients survived; survivors were treated with acyclovir and decreases in the dose of immunosuppressive drugs. Lymphoproliferative disease has been described in 2% of liver transplant recipients. In our review, the hepatic allograft was involved in one third of cases; the tonsils, kidneys, and small intestine were frequently affected. Half of the patients survived; survivors were most often treated with reduction in immunosuppressive therapy and surgical resection of lesions. Compared with fatal cases, survivors had fewer organs involved and fewer monoclonal lesions. Lymphoproliferative disease has been reported in 1 to 2% of bone marrow transplant recipients. Use of T-cell depleted bone marrow and infusion of anti-T-cell antibodies to prevent graft-versus-host disease increased the risk of EBV lymphoproliferative disease. In our review, the bone marrow was involved by lymphoproliferative disease in one third of cases; the liver, spleen, kidney, and lungs were frequently affected. About 16% of patients survived; 2 survivors were treated with infusions of monoclonal anti-B-cell antibodies and 1 received interferon alpha.(ABSTRACT TRUNCATED AT 400 WORDS)     

Hypogammaglobulinemia after heart transplantation: impact of pre-emptive use of immunoglobulin replacement (CytoGam®) on infection and rejection outcomes

Hypogammaglobulinemia (HGG) in solid organ transplant (SOT) patients confers an increased risk of opportunistic infections and poorer outcomes. Severe HGG (IgG < 350 mg/dL) after heart transplantation may follow intensification of immunosuppressive therapy and the resultant increased risk of opportunistic infections, particularly cytomegalovirus (CMV) disease. Evaluation of the effects of replacement therapy using intravenous immunoglobulin (CMV-IGIV, CytoGam®) was conducted in cardiac transplant recipients and the data matched with a historical control group. Patients with severe HGG who received pre-emptive replacement therapy had significantly fewer opportunistic infections ( P < 0.001) and episodes of rejection (grade 3; P  = 0.03 and grade 2; P  = 0.04) compared with the control group.     

Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag

Pretreatment blood counts, particularly an absolute reticulocyte count ≥25×10⁹/L, correlate with response to immunosuppressive therapy in severe aplastic anemia. In recent trials, eltrombopag combined with standard immunosuppressive therapy yielded superior responses than those to immunosuppressive therapy alone. Our single institution retrospective study aimed to elucidate whether historical predictors of response to immunosuppressive therapy alone were also associated with response to immunosuppressive therapy plus eltrombopag. We sought correlations of blood counts, thrombopoietin levels and the presence of paroxysmal nocturnal hemoglobinuria clones with both overall and complete responses in 416 patients with severe aplastic anemia, aged 2-82 years (median, 30 years), initially treated with immunosuppressive therapy plus eltrombopag between 2012 and 2019 (n=176) or with immunosuppressive therapy alone between 1999 and 2010 (n=240). Compared to non-responders, patients in the group of overall responders to immunosuppressive therapy plus eltrombopag had significantly higher pretreatment absolute reticulocyte counts, higher neutrophil counts and reduced thrombopoietin levels, as also observed for the group treated with immunosuppressive therapy alone. Addition of eltrombopag markedly improved the overall response in subjects with an absolute reticulocyte count between 10-30×10⁹/L from 60% (54 of 90) to 91% (62 of 68). Absolute lymphocyte count correlated with complete response in the groups treated with immunosuppressive therapy with or without eltrombopag, especially in adolescents aged ≥10 years and adults, but the correlation was reversed in younger children. Platelet count and the presence of a paroxysmal nocturnal hemoglobinuria clone did not correlate with responses to immunosuppressive therapy. Blood counts remain the best predictors of response to nontransplant therapies in severe aplastic anemia. Addition of eltrombopag to immunosuppressive therapy shifted patients with a lower absolute reticulocyte count into a better prognostic category.     

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

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 steroid‐resistant 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.     

Pneumococcal infections after human bone-marrow transplantation.

Seven of 26 long-term survivors (greater than 7 months post-transplant) of bone-marrow transplantation developed penicillin-sensitive pneumococcal infections more than 7 months after transplantation. One patient had two infections. Six of eight infections were associated with pneumococcal bacteremia, and Streptococcus pneumoniae type 6A was isolated in three cases. Two infections were fatal. All patients had normal nematopoietic function, and none was receiving immunosuppressive therapy. The development of pneumococcal infection was significantly associated with males and with abnormally low or high serum IGG and IgM levels but not with graft-versus-host disease. Serum opsonic activity for S. pneumoniae type 6A was decreased in six of the seven patients when compared to normal pooled serum in an in-vitro bactericidal assay. Four of the six patients with impaired opsonic activity had low serum antibody levels for S. pneumoniae type 6A capsular polysaccharide, while the other two patients had low serum CH100 complement activity. Bone-marrow transplant recipients have an increased susceptibility to pneumococcal infections and should be evaluated for prophylactic penicillin or pneumococcal vaccination.     

Pneumococcal infections in children after transplantation.

Bacterial infections in recipients of bone marrow and solid-organ transplants remain a major cause of morbidity and death. The cases of 42 children who had undergone transplantation and developed an infection with Streptococcus pneumoniae were retrospectively reviewed. Thirty-four patients had 1 episode of infection, whereas 7 had 2 episodes and 1 had 3 episodes of infection. Solid-organ recipients were more likely to have recurrent invasive disease (P<.02). A total of 31 (74%) of 42 patients were on immunosuppressive therapy, and 74% had been on antimicrobial therapy within 30 days before diagnosis of S. pneumoniae infection. Only 33% of eligible patients had received a pneumococcal vaccine. Twenty-six percent of isolates recovered were not susceptible to penicillin, and 18% were not susceptible to ceftriaxone. Two patients experienced infection-related deaths; one of these had a penicillin-nonsusceptible isolate. The antimicrobial susceptibilities and outcome of infections with S. pneumoniae in patients who have undergone transplantation are similar to those in the general pediatric population.     

Asymptomatic pulmonary cryptococcosis in solid organ transplantation: report of four cases and review of the literature

Abstract: Cryptococcus neoformans is the third most common cause of invasive fungal infections in solid organ transplantation. The infection generally presents as disseminated disease, involving multiple sites including the central nervous system, lungs, and skin. An increase in the incidence of primary pulmonary cryptococcal infections has been reported recently in solid organ recipients; these infections were generally symptomatic with an accelerated clinical course. We report four cases of asymptomatic pulmonary cryptococcosis in solid organ recipients (kidney, n=2, heart, n=2). In each case, an incidental finding on a routine chest radiograph led to the microbiological or histopathological diagnosis of invasive pulmonary C. neoformans infection. In these patients, cryptococcosis occurred a median of 25 months (range 7–36 months) after organ transplantation. All patients had a calcineurin inhibitor, prednisone, and azathioprine or mycophenolate mofetil as part of their immunosuppressive therapy at the time of diagnosis. Serum cryptococcal antigen was available and positive in the three patients studied; assessment of cerebrospinal fluid (CSF) of all four patients revealed no organisms by smear or culture. Therapy consisted of oral fluconazole in all cases, with flucytosine in one case, combined with resection of lung tissue in two individuals. All patients have remained free of cryptococcal disease (follow‐up median 42 months, from 18 to 88 months). Cryptococcal disease in solid organ recipients may present as asymptomatic, localized pulmonary disease. The natural history of such infections is unknown. New pulmonary radiographic findings should prompt an aggressive diagnostic evaluation including serum and CSF cryptococcal antigen assays, and a biopsy of pulmonary lesions. Prolonged therapy may be used to reduce the risk of progression and dissemination during periods of intensified immune suppression.