Lung transplantation in HIV seropositive recipients: An analysis of the UNOS registry.

BACKGROUND: Experience with lung transplantation (LT) in patients with human immunodeficiency virus (HIV) is limited. Many studies have demonstrated the success of kidney and liver transplantation in HIV-seropositive (HIV+) patients. Our objective was to conduct a national registry analysis comparing LT outcomes in HIV+ to HIV-seronegative (HIV-) recipients. METHODS: The United Network for Organ Sharing database was queried to identify LTs performed in adult HIV+ patients between 2016 and 2023. Patients with unknown HIV status, multiorgan transplants, and redo transplants were excluded. The primary endpoints were mortality and graft rejection. Survival time was analyzed using Kaplan-Meier analysis. RESULTS: The study included 17 487 patients, 67 of whom were HIV+. HIV+ recipients were younger (59 vs. 62 years, p = .02), had higher pulmonary arterial pressure (28 vs. 25 mm Hg, p = .04), and higher lung allocation scores (47 vs. 41, p = .01) relative to HIV- recipients. There were no differences in graft/recipient survival time between groups. HIV+ recipients had higher rates of post-transplant dialysis (18% vs. 8.4%, p = .01), but otherwise had similar post-transplant outcomes to HIV-recipients. CONCLUSIONS: This national registry analysis suggests LT outcomes in HIV+ patients are not inferior to outcomes in HIV- patients and that well-selected HIV+ recipients can achieve comparable patient and graft survival rates relative to HIV- recipients.

Performance status at the time of lung retransplant predicts long-term function.

BACKGROUND: Lung retransplantation is offered to select patients with chronic allograft dysfunction. Given the increased risk of morbidity and mortality conferred by retransplantation, post-transplant function should be considered in the decision of who and when to list. The aim of this study is to identify predictors of post-operative disability in patients undergoing lung retransplantation. METHODS: Data were collected from the UNOS national dataset and included all patients who underwent lung retransplant from May 2005-March 2023. Pre- and post-operative function was reported by the Karnofsky Performance Status (KPS) and patients were stratified based on their needs. Cumulative link mixed effects models identified associations between pre-transplant variables and post-transplant function. RESULTS: A total of 1275 lung retransplant patients were included. After adjusting for between-group differences, pre-operative functional status was predictive of post-transplant function; patients requiring Total Assistance ( n = 740) were 74% more likely than No/Some Assistance patients (n = 535) to require more assistance in follow-up (OR 1.74, 95% CI 1.13-2.68, p = .012). Estimated one year survival of Total Assistance patients is lower than No/Some Assistance Recipients (72% vs. 82%, CI 69%-75%; 79%-86%) but similar to overall re-transplant survival (76%, CI 74%-79%). CONCLUSION: Both survival and regain of function in patients requiring Total Assistance prior to retransplant may be higher than previously reported. Pre-operative functional status is predictive of post-operative function and should weigh in the selection, timing and post-operative care of patients considered for lung retransplantation.

Associations between the stanford integrated psychosocial assessment for transplant and one-year lung transplant medical and psychosocial outcomes.

The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) is a standardized measure of the psychosocial risk profile of solid organ transplant candidates. While studies have found associations between this measure and transplant outcomes, to date this has not been examined in lung transplant recipients. We examined relations between pre-transplant SIPAT scores and 1-year lung transplant medical and psychosocial outcomes in a sample of 45 lung transplant recipients. The SIPAT was significantly associated with 6-minute walk test (χ2(1) = 6.47, p = .010), number of readmissions (χ2(1) = 6.47, p = .011), and mental health services utilization (χ2(1) = 18.15, p < .001). It was not a significantly associated with the presence of organ rejection or mortality (ps > 0.10). Results suggest that the SIPAT can help identify patients who are at an elevated risk for transplant complications and thus would benefit from services to mitigate risk factors and improve outcomes.

Lung transplant recipients with telomere-mediated pulmonary fibrosis have increased risk for hematologic complications.

Idiopathic pulmonary fibrosis lung transplant recipients (IPF-LTRs) are enriched for short telomere length (TL) and telomere gene rare variants. A subset of patients with nontransplant short-TL are at increased risk for bone marrow (BM) dysfunction. We hypothesized that IPF-LTRs with short-TL and/or rare variants would be at increased risk for posttransplant hematologic complications. Data were extracted from a retrospective cohort of 72 IPF-LTRs and 72 age-matched non-IPF-LTR controls. Genetic assessment was done using whole genome sequencing or targeted sequence panel. TL was measured using flow cytometry and fluorescence in-situ hybridization (FlowFISH) and TelSeq software. The majority of the IPF-LTR cohort had short-TL, and 26% of IPF-LTRs had rare variants. Compared to non-IPF controls, short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued due to cytopenias (P = .0375), and BM dysfunction requiring BM biopsy was more prevalent (29% vs 4%, P = .0003). IPF-LTRs with short-TL and rare variants had increased requirements for transfusion and growth factor support. Multivariable logistic regression demonstrated that short-TL, rare variants, and lower pretransplant platelet counts were associated with BM dysfunction. Pretransplant TL measurement and genetic testing for rare telomere gene variants identified IPF-LTRs at increased risk for hematologic complications. Our findings support stratification for telomere-mediated pulmonary fibrosis in lung transplant candidates.

The kidney protects against sepsis by producing systemic uromodulin.

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. Although electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We have previously demonstrated that systemic Tamm-Horsfall protein (THP; uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we showed that the kidney increases circulating THP by enhancing the basolateral release of THP from medullary thick ascending limb cells. In patients with sepsis, changes in circulating THP were positively associated with a critical illness. THP was also found de novo in injured lungs. Genetic ablation of THP in mice led to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo led macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis, and chemotaxis, and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improved survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function, and systemic THP has therapeutic potential in sepsis.NEW & NOTEWORTHY Specific therapies to improve outcomes in sepsis with kidney injury have been limited by an unclear understanding of how kidney injury increases sepsis mortality. Here, we identified Tamm-Horsfall protein, known to protect in ischemic acute kidney injury, as protective in preclinical sepsis models. Tamm-Horsfall protein also increased in clinical sepsis without severe kidney injury and concentrated in injured organs. Further study could lead to novel sepsis therapeutics.

Characterization of the Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) in Lung Transplant Candidates.

The SIPAT is a standardized measure for pre-transplant psychosocial evaluation. Previous SIPAT studies utilized a relatively small lung transplant sample and only included listed patients. This study characterized the SIPAT in 147 lung transplant candidates to better elucidate its utility. The average score corresponded to a minimally acceptable rating and nearly half of the patients had relative or absolute contraindications. Interstitial Lung Disease (ILD) patients scored more favorably than non-ILD patients (U = 7.69, p < .05). The Total (ß = - .05, SE = .018, p < .01), Social Support Subscale (ß = - .133, SE = .058, p < .05), and Psychosocial Stability and Psychopathology Subscale (ß = - .103, SE = .040, p < .05) significantly predicted listing status. The SIPAT has a unique profile in lung transplant candidates and demonstrated utility for guiding transplant decisions. Future research should examine which lung transplant outcomes are significantly associated with SIPAT scores.

Extracorporeal photopheresis to attenuate decline in lung function due to refractory obstructive allograft dysfunction.

BACKGROUND: This study was designed to prospectively evaluate the efficacy of extracorporeal photopheresis (ECP) to attenuate the rate of decline of FEV1 in lung transplant recipients with refractory bronchiolitis obliterans. Due to an observed higher than expected early mortality, a preliminary analysis was performed. STUDY DESIGN AND METHODS: Subjects from 10 lung transplant centres were assigned to ECP treatment or to observation based on spirometric criteria, with potential crossover for those under observation. The primary endpoint of this study was to assess response to ECP (i.e., greater than a 50% decrease in the rate of FEV1 decline) before and 6 months after initiation of ECP. Mortality was also evaluated 6 and 12 months after enrolment as a secondary endpoint. RESULTS: Of 44 enrolled subjects, 31 were assigned to ECP treatment while 13 were initially assigned to observation on a non-random basis using specific spirometric inclusion criteria (seven of the observation patients subsequently crossed over to receive ECP). Of evaluable patients, 95% of patients initially assigned to treatment responded to ECP with rates of FEV1 decline that were reduced by 93% in evaluable ECP-treated patients. Mortality rates (percentages) at 6 and 12 months after enrolment was 32% and 41%, respectively. The most common (92%) primary cause of death was respiratory or graft failure. Significantly (p = 0.002) higher rates of FEV1 decline were observed in the non-survivors (-212 ± 177 ml/month) when compared to the survivors (-95 ± 117 ml/month) 12 months after enrolment. In addition, 18 patients with bronchiolitis obliterans syndrome (BOS) diagnosis within 6 months of enrolment had lost 38% of their baseline lung function at BOS diagnosis and 50% of their lung function at enrolment. CONCLUSIONS: These analyses suggest that earlier detection and treatment of BOS should be considered to appreciate improved outcomes with ECP.

Toxoplasmosis in non-cardiac solid organ transplant recipients: A case series and review of literature.

The risk of toxoplasmosis in high-risk cardiac transplant recipients is well recognized prompting universal donor and candidate screening with administration of targeted post-transplant chemoprophylaxis in high-risk (D+/R-) cardiac transplant patients. In contrast, until recently, there have been neither well-defined recommendations nor consensus regarding toxoplasmosis preventive strategies among non-cardiac solid organ transplant recipients. We report 3 cases of post-transplant toxoplasmosis in non-cardiac transplant recipients (one lung and two liver); all 3 infections presumed to be donor-derived. Not surprisingly, pre-transplant Toxoplasma serology was negative in all the patients. None of the patients were on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at the time of diagnosis of toxoplasmosis. The median time from transplant to onset of infection was 90 days (range: 30-120 days). Clinical presentations included cerebral (n = 1) and disseminated infections (n = 2). Two of the 3 patients, both with disseminated infection died (mortality ~ 67%).

Endemic Fungi Presenting as Community-Acquired Pneumonia: A Review.

In endemic areas, dimorphic fungal infections due to Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides posadasii/immitis account for up to 30% of cases of community-acquired pneumonia. Because respiratory manifestations are often indistinguishable from common bacterial causes of pneumonia, the diagnosis of pulmonary histoplasmosis, blastomycosis, and coccidioidomycosis is often delayed and associated with antibiotics overuse. In addition to being highly endemic to certain regions of North America, dimorphic fungi have global significance due to established areas of endemicity in all six inhabited continents, an increasingly interconnected world of travelers and transported goods, and a changing epidemiology as a result of global heating and anthropomorphic land utilization. In this review, we discuss the epidemiology, pathogenesis, clinical presentation, diagnostic modalities, and treatment strategies for histoplasmosis, blastomycosis, and coccidioidomycosis.

Current Concepts in the Epidemiology, Diagnosis, and Management of Histoplasmosis Syndromes.

Histoplasmosis is a global disease endemic to regions of all six inhabited continents. The areas of highest endemicity lie within the Mississippi and Ohio River Valleys of North America and parts of Central and South America. As a result of climate change and anthropogenic land utilization, the conditions suitable for Histoplasma capsulatum are changing, leading to a corresponding change in epidemiology. The clinical manifestations of histoplasmosis are protean, variably resembling other common conditions such as community-acquired pneumonia, tuberculosis, sarcoidosis, Crohn's disease, or malignancy. Making a successful diagnosis is contingent on a thorough understanding of epidemiology, common clinical presentations, and best testing practices for histoplasmosis. While most subclinical or self-limited diseases do not require treatment in immunocompetent patients, all immunocompromised patients and those with progressive disseminated disease or chronic pulmonary disease should be treated. Liposomal amphotericin B is the preferred agent for severe or disseminated disease, while itraconazole is adequate for milder cases and "step-down" therapy following response to amphotericin B. In this review, we discuss the current evidence-based approaches to the epidemiology, diagnosis, and management of histoplasmosis.

Microbiological Laboratory Testing in the Diagnosis of Fungal Infections in Pulmonary and Critical Care Practice. An Official American Thoracic Society Clinical Practice Guideline.

Background: Fungal infections are of increasing incidence and importance in immunocompromised and immunocompetent patients. Timely diagnosis relies on appropriate use of laboratory testing in susceptible patients.Methods: The relevant literature related to diagnosis of invasive pulmonary aspergillosis, invasive candidiasis, and the common endemic mycoses was systematically reviewed. Meta-analysis was performed when appropriate. Recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation approach.Results: This guideline includes specific recommendations on the use of galactomannan testing in serum and BAL and for the diagnosis of invasive pulmonary aspergillosis, the role of PCR in the diagnosis of invasive pulmonary aspergillosis, the role of ß-d-glucan assays in the diagnosis of invasive candidiasis, and the application of serology and antigen testing in the diagnosis of the endemic mycoses.Conclusions: Rapid, accurate diagnosis of fungal infections relies on appropriate application of laboratory testing, including antigen testing, serological testing, and PCR-based assays.

Improvement in Diagnosis of Histoplasma Meningitis by Combined Testing for Histoplasma Antigen and Immunoglobulin G and Immunoglobulin M Anti-Histoplasma Antibody in Cerebrospinal Fluid.

Background: Central nervous system (CNS) histoplasmosis is a life-threatening condition and represents a diagnostic and therapeutic challenge. Isolation of Histoplasma capsulatum from cerebrospinal fluid (CSF) or brain tissue is diagnostic; however, culture is insensitive and slow growth may result in significant treatment delay. We performed a retrospective multicenter study to evaluate the sensitivity and specificity of a new anti-Histoplasma antibody enzyme immunoassay (EIA) for the detection of IgG and IgM antibody in the CSF for diagnosis of CNS histoplasmosis, the primary objective of the study. The secondary objective was to determine the effect of improvements in the Histoplasma galactomannan antigen detection EIA on the diagnosis of Histoplasma meningitis. Methods: Residual CSF specimens from patients with Histoplasma meningitis and controls were tested for Histoplasma antigen and anti-Histoplasma immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody using assays developed at MiraVista Diagnostics. Results: A total of 50 cases and 157 controls were evaluated. Fifty percent of patients with CNS histoplasmosis were immunocompromised, 14% had other medical conditions, and 36% were healthy. Histoplasma antigen was detected in CSF in 78% of cases and the specificity was 97%. Anti-Histoplasma IgG or IgM antibody was detected in 82% of cases and the specificity was 93%. The sensitivity of detection of antibody by currently available serologic testing including immunodiffusion and complement fixation was 51% and the specificity was 96%. Testing for both CSF antigen and antibody by EIA was the most sensitive approach, detecting 98% of cases. Conclusions: Testing CSF for anti-Histoplasma IgG and IgM antibody complements antigen detection and improves the sensitivity for diagnosis of Histoplasma meningitis.

Detection of (1,3)-ß-d-Glucan in Cerebrospinal Fluid in Histoplasma Meningitis.

The diagnosis of central nervous system (CNS) histoplasmosis is often difficult. Although cerebrospinal fluid (CSF) (1,3)-ß-d-glucan (BDG) is available as a biological marker for the diagnosis of fungal meningitis, there are limited data on its use for the diagnosis of Histoplasma meningitis. We evaluated CSF BDG detection, using the Fungitell assay, in patients with CNS histoplasmosis and controls. A total of 47 cases and 153 controls were identified. The control group included 13 patients with a CNS fungal infection other than histoplasmosis. Forty-nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. The median CSF BDG level was 85 pg/ml for cases, compared to <31 pg/ml for all controls (P < 0.05) and 82 pg/ml for controls with other causes of fungal meningitis (P = 0.27). The sensitivity for detection of BDG in CSF was 53.2%, whereas the specificity was 86.9% versus all controls and 46% versus other CNS fungal infections. CSF BDG levels of ≥80 pg/ml are neither sensitive nor specific to support a diagnosis of Histoplasma meningitis.

Laboratory Diagnostics for Histoplasmosis.

The diagnosis of histoplasmosis is based on a multifaceted approach that includes clinical, radiographic, and laboratory evidence of disease. The gold standards for laboratory diagnosis include demonstration of yeast on pathological examination of tissue and isolation of the mold in the culture of clinical specimens; however, antigen detection has provided a rapid, noninvasive, and highly sensitive method for diagnosis and is a useful marker of treatment response. Molecular methods with improved sensitivity on clinical specimens are being developed but are not yet ready for widespread clinical use. This review synthesizes currently available laboratory diagnostics for histoplasmosis, with an emphasis on complexities of testing and performance in various clinical contexts.

Improved Diagnosis of Acute Pulmonary Histoplasmosis by Combining Antigen and Antibody Detection.

BACKGROUND: Acute pulmonary histoplasmosis can be severe, especially following heavy inoculum exposure. Rapid diagnosis is critical and often possible by detection of antigen, but this test may be falsely negative in 17% of such cases. Antibody detection by enzyme immunoassay (EIA) may increase sensitivity and permit the measurement of immunoglobulin M (IgM) and immunoglobulin G (IgG) classes of antibodies separately. METHODS: Microplates coated with Histoplasma antigen were used for testing of serum from patients with acute pulmonary histoplasmosis and controls in the MVista Histoplasma antibody EIA. Results for IgG and IgM were reported independently. RESULTS: IgG antibodies were detected in 87.5%, IgM antibodies in 67.5%, and IgG and/or IgM antibodies in 88.8% of patients with acute pulmonary histoplasmosis in this assay, while immunodiffusion, complement fixation, and antigen testing showed sensitivities of 55.0%, 73.1%, and 67.5%, respectively (n = 80). Combining antigen and antibody detection increased the sensitivity to 96.3%. CONCLUSIONS: The MVista Histoplasma antibody EIA offers increased sensitivity over current antibody tests while also allowing separate detection of IgG and IgM antibodies and complementing antigen detection. Combining antigen and EIA antibody testing provides an optimal method for diagnosis of acute pulmonary histoplasmosis.

Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases.

BACKGROUND: Histoplasmosis may complicate tumor necrosis factor (TNF)-α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. METHODS: We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. RESULTS: The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06-14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03-1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1-69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. CONCLUSIONS: In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months.

Evaluation of two new enzyme immunoassay reagents for diagnosis of histoplasmosis in a cohort of clinically characterized patients.

The performance characteristics of the recently available analyte-specific reagent based enzyme immunoassay (ASR-EIA) and in vitro diagnostic (IVD) kit for urine Histoplasma antigen detection were evaluated in a cohort of 50 clinically characterized patients with histoplasmosis and 50 control patients. Overall sensitivity and specificity of the ASR-EIA were significantly improved compared with those of the IVD kit (sensitivity 72% vs. 22%, P<.001, specificity 98% vs. 84%, P = .014). Fourteen specimens from patients with clinically characterized histoplasmosis (five with pulmonary histoplasmosis and nine with progressive disseminated histoplasmosis) were falsely negative by ASR-EIA. All 10 specimens from patients with severe symptoms of progressive disseminated histoplasmosis were positive by ASR-EIA, although the average reading value of these 10 specimens was not significantly different from that of others with positive results. Compared to the MiraVista antigen assay, both the IVD kit and the ASR-EIA were significantly less sensitive in detecting Histoplasma antigen in the urine of patients with histoplasmosis. The ASR-EIA and MiraVista assay had comparable specificity. In conclusion, the ASR-EIA has improved performance compared with the IVD kit in the detection of Histoplasma antigen in the urine. However, users should be aware of the potential for false negative results using the currently recommended cutoff value.

Positive (1-3) B-d-glucan and cross reactivity of fungal assays in coccidioidomycosis.

Fungal antigen testing in immunosuppressed patients has emerged as a powerful diagnostic tool. Some assays are relatively nonspecific, and misinterpretation can have severe clinical consequences. Additionally, when new assays become commercially available it is important to evaluate the potential for cross reactivity. We recently observed several immunosuppressed patients with positive (1→3)-ß-D-glucan (BG) who were eventually diagnosed with coccidioidomycosis in the endemic area of Tucson, Arizona. Although the BG assay is known to detect glucans of many fungal pathogens, reports of cross-reactivity with Coccidioides remain sparsely reported. To test the cross-reactivity of fungal antigens in detection assays, serum samples from patients with coccidioidomycosis testing positive for Coccidioides antigen were evaluated for BG. Of 12 samples positive for Coccidioides antigen (≥0.07 ng/ml), 11 (92%) were positive by BG (>80 pg/ml), and of 11 positive for Aspergillus galactomannan, 10 (91%) were positive by BG (>80 pg/ml). We conclude that the BG assay is nonspecific, detecting glucans from many fungal pathogens, including Coccidioides. In the endemic area, a positive BG warrants further specific testing.

Histoplasmosis: Up-to-Date Evidence-Based Approach to Diagnosis and Management.

Histoplasmosis is the most common endemic mycosis in the North America, Central America, and many countries of South America and also occurs in China, India, Southeast Asia, Africa, Australia, and Europe. Clinical syndromes are not specific and histoplasmosis often is overlooked in the evaluation of patients with community-acquired pneumonia, chronic cavitary pneumonia resembling tuberculosis or anaerobic infection, granulomatous inflammatory diseases such as sarcoidosis or Crohn disease, and malignancy. The diagnosis depends on understanding the geographic distribution, common clinical presentations, and tests used for diagnosis of histoplasmosis. While histoplasmosis resolves without treatment in most patients, treatment is indicated in all immunocompromised patients and those with progressive disseminated disease or chronic pulmonary disease. Treatment is appropriate in most patients with acute pulmonary disease but rarely in those with other pulmonary or mediastinal manifestations. The preferred agents include liposomal amphotericin B for more severe cases and itraconazole for milder cases and "step-down" therapy following response to amphotericin B.

Cutaneous blastomycosis masquerading as pyoderma gangrenosum.

Cutaneous blastomycosis (CB) is associated with a variety of skin manifestations. Among other entities, CB may be mistaken for pyoderma gangrenosum due to overlap of findings on histopathologic examination. We report a case of CB, initially diagnosed as pyoderma gangrenosum and treated with steroids, leading to disseminated blastomycosis and acute respiratory distress syndrome (ARDS).