Daniel F. Dilling

ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients

BACKGROUND Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo. METHODS We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days. RESULTS Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6% vs 30.3%, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores. CONCLUSIONS These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients.

Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans.

Disseminated infection with Ureaplasma species causes fatal hyperammonemia syndrome in lung transplant recipients, likely by disrupting ammonia metabolism. The killer within Hyperammonemia, or abnormal buildup of ammonia, is an uncommon but generally fatal condition that affects immunosuppressed patients, particularly those who receive a lung transplant. Although there are treatments that can lower the blood concentration of ammonia, their effects are short-lived, and they are typically ineffective for this condition. Now, Bharat et al. identified Ureaplasma bacteria as the cause of this condition and demonstrated that it can be successfully treated with antibiotics. These findings suggest that patients with hyperammonemia should be screened for Ureaplasma species and treated with the appropriate antibiotics for this infection. Moreover, the authors found evidence of Ureaplasma species in one donor’s lung fluid sample, indicating that donors may need to be screened for it as well. Hyperammonemia syndrome is a fatal complication affecting immunosuppressed patients. Frequently refractory to treatment, it is characterized by progressive elevations in serum ammonia of unknown etiology, ultimately leading to cerebral edema and death. In mammals, ammonia produced during amino acid metabolism is primarily cleared through the hepatic production of urea, which is eliminated in the kidney. Ureaplasma species, commensals of the urogenital tract, are Mollicutes dependent on urea hydrolysis to ammonia and carbon dioxide for energy production. We hypothesized that systemic infection with Ureaplasma species might pose a unique challenge to human ammonia metabolism by liberating free ammonia resulting in the hyperammonemia syndrome. We used polymerase chain reaction, specialized culture, and molecular resistance profiling to identify systemic Ureaplasma infection in lung transplant recipients with hyperammonemia syndrome, but did not detect it in any lung transplant recipients with normal ammonia concentrations. Administration of Ureaplasma-directed antimicrobials to patients with hyperammonemia syndrome resulted in biochemical and clinical resolution of the disorder. Relapse in one patient was accompanied by recurrent Ureaplasma bacteremia with antimicrobial resistance. Our results provide evidence supporting a causal relationship between Ureaplasma infection and hyperammonemia, suggesting a need to test for this organism and provide empiric antimicrobial treatment while awaiting microbiological confirmation.

Gastroesophageal reflux disease after lung transplantation: pathophysiology and implications for treatment.

BACKGROUND Gastroesophageal reflux disease (GERD) is thought to be a risk factor for the development or progression of chronic rejection after lung transplantation. However, the prevalence of GERD and its risk factors, including esophageal dysmotility, hiatal hernia and delayed gastric emptying after lung transplantation, are still unknown. In addition, the prevalence of Barretts esophagus, a known complication of GERD, has not been determined in these patients. The purpose of this study was to determine the prevalence and extent of GERD, as well as the frequency of these risk factors and complications of GERD in lung transplant patients. METHODS Thirty-five consecutive patients underwent a combination of esophageal function testing, upper endoscopy, barium swallow, and gastric emptying scan after lung transplantation. RESULTS In this patient population, the prevalence of GERD was 51% and 22% in those who had been retransplanted. Of patients with GERD,36% had ineffective esophageal motility (IEM), compared with 6% of patients without GERD (P = .037). No patient demonstrated hiatal hernia on barium swallow. The prevalence of delayed gastric emptying was 36%. The prevalence of biopsy-confirmed Barretts esophagus was 12%. CONCLUSION Our study shows that, after lung transplantation, more than half of patients had GERD, and that GERD was more common after retransplantation. IEM and delayed gastric emptying are frequent in patients with GERD. Hiatal hernia is rare. The prevalence of Barretts esophagus is not negligible. We conclude that GERD is highly prevalent after lung transplantation, and that delayed gastric emptying and Barretts esophagus should always be suspected after lung transplantation because they are common risks factors and complications of GERD.

Laparoscopic Antireflux Surgery for Gastroesophageal Reflux Disease After Lung Transplantation

BACKGROUND Although gastroesophageal reflux disease (GERD) is highly prevalent in lung transplantation, the pathophysiology of GERD in these patients is unknown. We hypothesize that the pathophysiology of GERD after lung transplantation differs from that of a control population, and that the 30-d morbidity and mortality of laparoscopic antireflux surgery (LARS) are equivalent in both populations. METHODS We retrospectively compared the pathophysiology of GERD and the 30-d morbidity and mortality of 29 consecutive lung transplant patients with 23 consecutive patients without lung transplantation (control group), all of whom had LARS for GERD between November 2008 and May 2010. RESULTS Both groups had a similar prevalence of endoscopic esophagitis and Barretts esophagus , comparable manometric profiles, and similar prevalence of abnormal peristalsis. However, hiatal hernia was more common in controls than in lung transplant patients (57% versus 24%; P = 0.04). Lung transplant patients had a higher prevalence and severity of proximal GERD (65% versus 33%; P = 0.04). The 30-d morbidity and mortality following LARS were similar in both groups regardless of the higher surgical risk of lung transplants (median ASA class: 3 versus 2 for controls, P < 0.001). CONCLUSIONS These results show that despite similar manometric profiles, lung transplant patients are more prone to proximal reflux than the general population with GERD; the prevalence of endoscopic esophagitis and Barretts esophagus is the same in both groups of patients; a hiatal hernia is uncommon after lung transplantation; and the morbidity and mortality of LARS are the same for lung transplant patients as the general population with GERD.

Melanoma-associated antigen expression in lymphangioleiomyomatosis renders tumor cells susceptible to cytotoxic T cells.

The antibody HMB45 is used to diagnose lymphangioleiomyomatosis, a hyperproliferative disorder of lung smooth muscle cells with mutations in both alleles of either TSC1 or TSC2. A subset of these tumor cells expresses the melanoma-associated antigens gp100 and melanoma antigen recognized by T cells (MART-1). To explore the feasibility of targeting tumors in lymphangioleiomyomatosis by melanoma immunotherapy, we therefore assessed melanoma target antigen expression and existing immune infiltration of affected tissue compared with normal lung and melanoma as well as the susceptibility of cultured lymphangioleiomyomatosis cells to melanoma reactive cytotoxic T lymphocytes in vitro. Tumors expressed tyrosinase-related proteins 1 and 2 but not tyrosinase, in addition to gp100 and MART-1, and were densely infiltrated by macrophages, but not dendritic cells or T cell subsets. Although CD8(+) lymphocytes were sparse compared with melanoma, cells cultured from lymphangioleiomyomatosis tissue were susceptible to cytotoxic, gp100 reactive, and major histocompatibility complex class I restricted CD8(+) T cells in functional assays. Responder T cells selectively clustered and secreted interferon-gamma in response to HLA-matched melanocytes and cultured lymphangioleiomyomatosis cells. This reactivity exceeded that based on detectable gp100 expression; thus, tumor cells in lymphangioleiomyomatosis may process melanosomal antigens different from melanocytic cells. Therefore, boosting immune responses to gp100 in lymphangioleiomyomatosis may offer a highly desirable treatment option for this condition.

A review of the potential applications and controversies of non‐invasive testing for biomarkers of aspiration in the lung transplant population

Davis CS, Gagermeier J, Dilling D, Alex C, Lowery E, Kovacs EJ, Love RB, Fisichella PM. A review of the potential applications and controversies of non‐invasive testing for biomarkers of aspiration in the lung transplant population.
Clin Transplant 2010: 24: E54–E61.

A current viewpoint of lymphangioleiomyomatosis supporting immunotherapeutic treatment options.

Lymphangioleiomyomatosis (LAM) leads to hyperproliferation of abnormal smooth muscle cells in the lungs, associated with diffuse pulmonary parenchymal cyst formation and progressive dyspnea on exertion. The disease targets women of child-bearing age. Complications include pneumothoraces and chylous pleural effusions. Ten-year survival is estimated at 70%, and lung transplantation remains the only validated treatment. It has been observed that LAM cells express markers associated with melanocytic differentiation, including gp100 and MART-1. Other melanocytic markers have also been observed. The same proteins are targeted by T cells infiltrating melanoma tumors as well as by T cells infiltrating autoimmune vitiligo skin, and these antigens are regarded as relatively immunogenic. Consequently, vaccines have been developed for melanoma targeting these and other immunogenic melanocyte differentiation proteins. Preliminary data showing susceptibility of LAM cells to melanoma derived T cells suggest that vaccines targeting melanosomal antigens can be successful in treating LAM.

Accuracy of chest high-resolution computed tomography in diagnosing diffuse cystic lung diseases

The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogeneous processes characterised by the presence of multiple, thin-walled, air-filled spaces within the pulmonary parenchyma [1]. The differential diagnosis of DCLDs includes lymphangioleiomyomatosis (LAM), follicular bronchiolitis (FB), lymphocytic interstitial pneumonia (LIP), Birt–Hogg–Dubé syndrome (BHD), pulmonary Langerhans cell histiocytosis (PLCH), amyloidosis, light chain deposition disease, cystic metastases, infectious entities such as Pneumocystis, and other aetiologies [2]. Bronchiectasis and bullous changes seen in chronic obstructive pulmonary disease can also produce high-resolution computed tomography (HRCT) patterns that mimic the DCLDs. Correct diagnosis of diffuse cystic lung diseases is established in most cases by critical review of HRCT features http://ow.ly/NvrCc

The Prevalence and Extent of Gastroesophageal Reflux Disease Correlates to the Type of Lung Transplantation

Background: Evidence is increasingly convincing that lung transplantation is a risk factor of gastroesophageal reflux disease (GERD). However, it is still not known if the type of lung transplant (unilateral, bilateral, or retransplant) plays a role in the pathogenesis of GERD. Study Design: The records of 61 lung transplant patients who underwent esophageal function tests between September 2008 and May 2010, were retrospectively reviewed. These patients were divided into 3 groups based on the type of lung transplant they received: unilateral (n=25); bilateral (n=30), and retransplant (n=6). Among these groups we compared: (1) the demographic characteristics (eg, sex, age, race, and body mass index); (2) the presence of Barrett esophagus, delayed gastric emptying, and hiatal hernia; and (3) the esophageal manometric and pH-metric profile. Results: Distal and proximal reflux were more prevalent in patients with bilateral transplant or retransplant and less prevalent in patients after unilateral transplant, regardless of the cause of their lung disease. The prevalence of hiatal hernia, Barrett esophagus, and the manometric profile were similar in all groups of patients. Conclusions: Although our data show a discrepancy in prevalence of GERD in patients with different types of lung transplantation, we cannot determine the exact cause for these findings from this study. We speculate that the extent of dissection during the transplant places the patients at risk for GERD. On the basis of the results of this study, a higher level of suspicion of GERD should be held in patients after bilateral or retransplantation.

Subtherapeutic ganciclovir (GCV) levels and GCV‐resistant cytomegalovirus in lung transplant recipients

Cytomegalovirus (CMV) infection results in significant morbidity and mortality in lung transplant recipients. Ganciclovir (GCV) has dramatically reduced complications caused by CMV infections. Unfortunately, GCV resistance is identified in 5–10% of CMV‐infected patients. Mismatched CMV status and ongoing replication due to immunosuppression are risk factors for drug resistance. Whether subtherapeutic GCV levels contribute to resistance remains unknown.