Cases Of Pneumocystis Jirovecii Pneumonia Research Articles

Adjunctive corticosteroids may be associated with better outcome for non-HIV Pneumocystis pneumonia with respiratory failure: a systemic review and meta-analysis of observational studies

BackgroundEvidence supporting corticosteroids adjunctive treatment (CAT) for Pneumocystis jirovecii pneumonia (PCP) in non-HIV patients is highly controversial. We aimed to systematically review the literature and perform a meta-analysis of available data relating to the effect of CAT on mortality of PCP in non-HIV patients.MethodsWe searched Pubmed, Medline, Embase, and Cochrane database from 1989 through 2019. Data on clinical outcomes from non-HIV PCP were extracted with a standardized instrument. Heterogeneity was assessed with the I2 index. Pooled odds ratios and 95% confidence interval were calculated using a fixed effects model. We analyzed the impact of CAT on mortality of non-HIV PCP in the whole PCP population, those who had hypoxemia (PaO2 < 70 mmHg) and who had respiratory failure (PaO2 < 60 mmHg).ResultsIn total, 259 articles were identified, and 2518 cases from 16 retrospective observational studies were included. In all non-HIV PCP cases included, there was an association between CAT and increased mortality (odds ratio, 1.37; 95% confidence interval 1.07–1.75; P = 0.01). CAT showed a probable benefit of decreasing mortality in hypoxemic non-HIV PCP patients (odds ratio, 0.69; 95% confidence interval 0.47–1.01; P = 0.05). Furthermore, in a subgroup analysis, CAT showed a significantly lower mortality in non-HIV PCP patients with respiratory failure compared to no CAT (odds ratio, 0.63; 95% confidence interval 0.41–0.95; P = 0.03).ConclusionsOur meta-analysis suggests that among non-HIV PCP patients with respiratory failure, CAT use may be associated with better clinical outcomes, and it may be associated with increased mortality in unselected non-HIV PCP population. Clinical trials are needed to compare CAT vs no-CAT in non-HIV PCP patients with respiratory failure. Furthermore, CAT use should be withheld in non-HIV PCP patients without hypoxemia.

Variability of Pneumocystis jirovecii prophylaxis use among pediatric solid organ transplant providers.

Pneumocystis jirovecii pneumonia (PJP) prophylaxis after pediatric solid organ transplant (SOT) is routinely recommended, but practice varies. Online survey was sent in 2018 to 707 members of the International Pediatric Transplant Association. A total of 105 responded, representing 47 institutions in 18 countries consisting of transplant physicians (66%), transplant surgeons (19%), nurse practitioners (6%), infectious disease physicians (5%), or pharmacists (4%). PJP prophylaxis was reported by 88%, while 12% did not routinely give prophylaxis. The majority not using PJP prophylaxis performed renal transplants (67%) citing low incidence of PJP (62%). Trimethoprim/sulfamethoxazole was first-line agent (95%). PJP prophylaxis for 4-6months was the most frequent duration following kidney (48%, 27/56), liver (42%, 13/31), and heart (40%, 10/25) transplant. Abdominal multivisceral providers equally gave 10-12months (47%) or lifelong (47%); most lung transplant providers gave lifelong prophylaxis (85%). Across all organs, 21% provided lifetime prophylaxis. After completion of prophylaxis, 32% do not restart for any reason; majority of the rest would restart for treatment of acute graft rejection. 83% reported no PJP cases in the prior 12months; 14% reporting 1-5 infections. Only 3% reported a case of PJP infection on prophylaxis; none in SOT. PJP prophylaxis is routinely provided to pediatric SOT patients though practice and duration vary by center and organ type. Durations of 4-6months were most common for renal, liver, and heart transplant recipients, while 10-12months or lifelong prophylaxis were commonly reported for abdominal multivisceral recipients and most lung transplant recipients are given lifelong prophylaxis.

Severe hypercalcemia preceding a diagnosis of Pneumocystis jirovecii pneumonia in a liver transplant recipient

BackgroundIncidence of the opportunistic infection Pneumocystis jirovecii pneumonia (PJP) in solid organ transplant patients ranges from 5 to 15% with a mortality of up to 38%.Case presentationWe present a liver transplant recipient who developed hypoxemic respiratory failure related to PJP soon after treatment for allograft rejection. His presentation was preceded by severe hypercalcemia of 14.6 mg/dL and an ionized calcium of 1.7 mmol/L which remained elevated despite usual medical management and eventually required renal replacement therapy. As approximately 5% of PJP cases have granulomas, here we review the role of pulmonary macrophages and inflammatory cytokines in the pathophysiology of granuloma-mediated hypercalcemia. We also discuss the interpretation of our patient’s laboratory studies, response to medical therapy, and clinical risk factors which predisposed him to PJP.ConclusionsIt is important for clinicians to consider PJP as an etiology of granulomatous pneumonia and non-parathyroid hormone mediated hypercalcemia in chronically immunosuppressed organ transplant recipients for timely diagnosis and management.

Epidemiologic Trends and Clinical Features of Pneumocystis jirovecii Pneumonia in Non-HIV Patients in a Tertiary-Care Hospital in Korea over a 15-Year-Period.

Subsequent to the increasing use of immunosuppressant therapy, Pneumocystis jirovecii pneumonia (PcP) has emerged as a life-threatening condition in human immunodeficiency virus (HIV)-negative patients. We investigated changes in epidemiological and clinical characteristics among PcP cases with and without HIV infections. Data of 424 patients diagnosed with PcP in a 2,700-bed Korean tertiary care hospital between February 2003 and April 2017 were retrospectively analyzed. The study included patients with compatible clinical findings in whom PcP was confirmed via direct immunofluorescence assay. The annual average number of cases increased from 12.2 (initial 5-year period) to 42.2 (recent 5-year period). In HIV-negative patients, hematologic malignancy (34.8%) and solid organ transplantation (32.9%) were the most frequent major underlying conditions, and immunosuppressive therapies including corticosteroids (342/362, 94.5%) and chemotherapy (122/362, 33.7%) were significantly associated with PcP infection (p ＜ 0.001 for both). The incidence of PcP has continued to increase among non-HIV-infected immunocompromised patients in recent years.

1592. Safety of Oral Trimethoprim/Sulfamethoxazole Prophylaxis in Renal Transplant Recipients

BackgroundTrimethoprim/sulfamethoxazole (TMP/SMX) is the agent of choice for Pneumocystis jirovecii Pneumonia (PJP) prophylaxis in renal transplant (RT) recipients. All other prophylactic agents are considered second-line due to efficacy, drug intolerances, cost, administration requirements, and lack of coverage of Toxoplasma. Anecdotally, alternative agents are commonly used at our institution due to clinician hesitancy and perceived risk of adverse drug reactions (ADRs). Our objective was to assess the safety of TMP/SMX prophylaxis in RT recipients.MethodsRT recipients transplanted at a tertiary US medical center between May 9, 2015 and November 30, 2017 were retrospectively identified. Patient charts were reviewed for antimicrobial agents used for PJP prophylaxis and ADRs due to TMP/SMX. ADRs were classified using the National Institutes of Health, Division of Microbiology and Infectious Diseases (DMID) criteria and were scored for probability of association with TMP/SMX using the Naranjo ADR probability scale.ResultsDuring the study period, 64 of 95 adult RT recipients (67.4%) received TMP/SMX for PJP prophylaxis. Of the patients who received TMP/SMX, 26 (40.6%) had a clinician-documented ADR attributed to TMP/SMX and 24 (37.5%) had the drug discontinued. The most frequent provider-reported ADRs due to TMP/SMX were hyperkalemia (10 patients, 15.6%), neutropenia (nine patients, 14.1%), and elevated liver function tests (LFTs) (three patients, 4.7%). However, when classified using DMID criteria, nine of the 26 ADRs were less severe than Grade 1. Two ADRs were Grade 3 (severe), including 1 case each of neutropenia and elevated LFTs. No ADRs were Grade 4 (life-threatening). All ADRs received a score ≤4 on the Naranjo ADR probability scale, indicating a possible ADR related to TMP/SMX. Often, ADRs did not resolve or other additional medication adjustments were needed following TMP/SMX discontinuation (19 of 26 patients, 73.1%). No cases of PJP occurred.ConclusionTMP/SMX is underutilized in RT recipients at our institution, despite being well-tolerated and efficacious. Clinician hesitancy with TMP/SMX in this population may be unfounded. Internal efforts are underway to increase the use of TMP/SMX in RT recipients.Disclosures All authors: No reported disclosures.

402. Breakthrough Pneumocystis jirovecii Pneumonia Among Cancer Patients: Opportunity for Antimicrobial Stewardship?

BackgroundDespite available prophylaxis, Pneumocystis jirovecii pneumonia (PJP) still occurs in immunocompromised hosts. We set out to determine the overall burden of PJP among cancer patients in the modern era at our cancer center. Furthermore, we sought to describe reasons for failure to use prophylaxis among these patients.MethodsIn this retrospective cohort study, we identified PJP cases among patients admitted between January 2007 and December 2016 at our center. PJP was defined as any positive test (immunofluorescence or PCR) from sputum and/or bronchoalveolar lavage. Patient demographics, underlying malignancy, anti-pneumocystis antibiotics and mortality were assessed through electronic medical records. Current National Comprehensive Cancer Network (NCCN) guidelines were used to determine who should have received prophylaxis. Cases not on prophylaxis at the time of diagnosis were reviewed to determine reasons why prophylaxis was not administered. Incidence of PJP for the last 5 years of the study was estimated based on a Poisson distribution.ResultsA total of 37 patients had confirmed PJP over the 10-year study period. The majority were male (68%) with a median age of 60 years (IQR: 47, 67). The most common underlying malignancy was acute myeloid leukemia (24%); 24/37 (65%) were bone marrow transplant recipients. The 5-year incidence between 2012 and 2016 was 2.28 per 10,000 inpatient days (95% CI, 1.50–3.32). There was no evidence of clustering of PJP diagnoses. Overall, 26/37 (70%) of PJP patients were not on prophylaxis at the time of diagnosis, 12 of whom met NCCN criteria for use. Twenty-three were deceased by the end of the study with 11/23 (48%) deaths occurring within 30 days of diagnosis. The main reason prophylaxis was not administered was neutropenia (19%). A documented sulfa allergy was noted in seven PJP cases (19%); 2/7 (29%) were not administered alternate prophylaxis despite recommendations for use.ConclusionPJP incidence in this large cohort of cancer patients was low, but one-third of patients who developed PJP were not on recommended prophylaxis in accordance with NCCN guidelines. Infection Prevention and Antimicrobial Stewardship teams should enhance efforts to address missed opportunities for PJP prophylaxis in high-risk patients.Disclosures S. Pergam, Merck: Consultant, Consulting fee. Chimerix: Consultant, Consulting fee.

1487. Variability of Pneumocystis jirovecii Prophylaxis Use Among Pediatric Solid Organ Transplant Providers

Background Pneumocystis jirovecii pneumonia (PJP) prophylaxis after pediatric solid-organ transplant (SOT) is routinely recommended, but practice patterns vary.MethodsIn 2018, an online survey was sent to 707 members of the International Pediatric Transplant Association.Results105 responded, representing 47 institutions in 18 countries. Majority were transplant physicians (66%) or transplant surgeons (20%). Remainder were nurse practitioners (6%), infectious disease physicians (5%) or pharmacists (4%). Routine PJP prophylaxis was reported by 87%, while 13% do not routinely administer any prophylaxis. The majority not using PJP prophylaxis performed only renal transplants (67%) and listed low incidence of PJP infection as the primary reason (88%). Trimethoprim/sulfamethoxazole (TMP/SMX) was the preferred first-line agent (97%). Common second-line agents were dapsone (33%), inhaled pentamidine (33%), and atovaquone (12%). Of those that provide PJP prophylaxis following renal transplant (n = 51), the majority (51%) provide 4–6 months (Figure 1). Durations following liver transplant (n = 25) were similar; and heart transplant providers (n = 24) most commonly give 4–6 months (42%) as well. Majority of abdominal multivisceral (MVS) providers (55%) give 10–12 months and most lung transplant responders provide lifelong prophylaxis (81%). Across all organs, at least 20% provide lifetime prophylaxis. After completion of PJP prophylaxis, 36% do not restart for any reason and 54% would restart for treatment of acute graft rejection.Figure 1:Duration of PJP Prophylaxis.Reported PJP infections were uncommon with 80% reporting no PJP cases in the prior 12 months and 15% reporting 1–5 infections. Only 2% reported a case of PJP infection on prophylaxis.ConclusionPJP prophylaxis remains routine for the majority of pediatric SOT patients; albeit with notable practice variations. The most common duration of PJP prophylaxis following renal, liver and heart transplant was 4–6 months; while in abdominal multivisceral and lung transplant recipients, durations of either 10–12 months or lifelong prophylaxis were common. There remains a lack of evidence-based guidelines balancing the utility of PJP prevention against potential treatment side effects and unnecessary medication use.Disclosures All authors: No reported disclosures.

Pneumocystis jirovecii pneumonia prophylaxis in allogeneic hematopoietic cell transplant recipients: can we always follow the guidelines?

Pneumocystis jirovecii pneumonia (PCP) is a life-threatening disease in allogeneic hematopoietic cell transplantation (HCT) recipients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred prophylaxis but has significant toxicity. We assessed 139 consecutive HCT patients for PCP prophylaxis in our center. According to our procedures, TMP-SMX should be given as first-line prophylaxis from engraftment. In case of intolerance, atovaquone (ATO) or aerosolized pentamidine may be given. Thirteen (9.3%) patients did not receive prophylaxis because they early died. Of the 126 prophylaxed patients, 113 (90%) received TMP-SMX and 13 (10%) received ATO as first-line regimen. However, only 51/113 (45%) patients received TMP-SMX as the sole prophylaxis: 60 patients were switched to ATO because of side effect. There were 18 PCP cases: 3 occurred before engraftment, 7 occurred under ATO, 3 occurred while prophylaxis was pending the resolution of side effects, and 5 occurred after stopping prophylaxis. No cases occurred under TMP-SMX while 7 (9.6%) cases occurred under first-(n = 13) or second (n = 60)-line ATO. There are many concerns about PCP prophylaxis after HCT: patients may develop PCP before engraftment or several months after stopping immunosuppressors, and half of them do not receive TMP-SMX all along the at-risk periods. New prophylactic drugs and strategies should be evaluated.

2 cases of Pneumocystis Jirovecii Pneumonia occurring during treatment of Cushing's Syndrome. Is there a case for prophylaxis of PJP in the treatment of severe hypercortisolism?

2 cases of Pneumocystis Jirovecii Pneumonia occurring during treatment of Cushing's Syndrome. Is there a case for prophylaxis of PJP in the treatment of severe hypercortisolism?

Searching for a change: The need for increased support for public health and research on fungal diseases

Fungal diseases have been continually neglected over the years despite their alarming impact on human health. Recent estimates [1] suggest a global annual occurrence of approximately 3,000,000 cases of chronic pulmonary aspergillosis, more than 200,000 cases of cryptococcal meningitis, 700,000 cases of invasive candidiasis, 500,000 cases of Pneumocystis jirovecii pneumonia, 250,000 cases of invasive aspergillosis, 100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma, and 1,000,000 cases of fungal keratitis. It is estimated that fungal infections kill more than 1.5 million people every year [2]. Morbidity due to fungal infections is also significant. Chromoblastomycosis and eumycetoma, for instance, cause debilitating diseases affecting subcutaneous tissues, skin, and underlying bones [3,4]. Importantly, the epidemiology of fungal diseases is dynamic and hard to predict. Recently, the multidrug-resistant pathogen Candida auris has emerged as a serious threat to human health, with some infections resistant to all main classes of antifungal medications [5]. Known diseases also raise new concerns. The city of Rio de Janeiro, Brazil, currently faces the largest epidemic of sporotrichosis in history [6]. Paracoccidioidomycosis is still one of the most important systemic mycoses in Latin America and the leading fungal cause of mortality in non-immunosuppressed individuals in Brazil [3,7]. Mortality and morbidity due to fungal diseases mostly affect individuals living under socioeconomic restrictions [8,9]. Reliable and cost-effective diagnostic tools are available for a very limited number of mycoses, and therapeutic options are restricted to a few classes of poorly effective, toxic, and expensive pharmaceutical agents [10]. There are no licensed antifungal vaccines [12]. The last antifungals approved for clinical use were the echinocandins in 2002 [11]. According to the Global Fund for Fungal Infections (GAFFI), several key antifungals also are not available or not even registered in multiple regions where fungal diseases are most lethal [2]. These serious gaps in diagnostic, therapeutic, and preventive tools for fungal infections are a dangerous combination that results in high costs and low efficacy of clinical approaches [13]. To minimize the number of deaths caused by fungal diseases, novel therapeutic, diagnostic, and preventive tools must be developed, and the diagnostic tests and antifungal agents that are available must be rationally deployed.

Prophylactic effect of sulfasalazine against Pneumocystis pneumonia in patients with rheumatoid arthritis: A nested case-control study

ObjectivesTo evaluate the prophylactic effect of sulfasalazine against Pneumocystis jirovecii pneumonia (PJP) among rheumatoid arthritis (RA) patients. MethodsWe used a nationwide Japanese multicenter RA database to extract data from 2005 and 2014. To identify PJP cases, we selected patients hospitalized for PJP and verified their diagnosis. Two control groups, one unmatched and the other matched for age, sex, glucocorticoid, methotrexate, and tacrolimus dosage, and the use (and type, if used) of biological disease-modifying antirheumatic drug were selected by incidence-density sampling. The odds ratios for PJP associated with sulfasalazine use and other clinical factors were estimated by exact and standard conditional logistic regression. ResultsFrom 18,668 participants, 60 cases, 356 unmatched controls, and 337 matched controls were selected. None of the cases received sulfasalazine before PJP onset. A comparison of the cases with the unmatched controls showed that sulfasalazine use carried a decreased risk of PJP (adjusted odds ratio 0.18, 95% confidence interval 0.00–0.92). A comparison of the cases and matched controls also showed that sulfasalazine use had a decreased risk of PJP (0.08, 0.00–0.36). In an analysis of the cases and unmatched controls who did not receive sulfasalazine, an increased risk of PJP was associated with lung disease (3.88, 1.89–7.95) and the use of glucocorticoid (5.71, 2.68–12.19), methotrexate (5.25, 2.01–13.74), and tumor necrosis factor inhibitors (2.32, 1.10–4.93). ConclusionsThe results of this nested case-control study demonstrated the preventive effect of sulfasalazine against PJP. The results await confirmation by future prospective studies.

Late-onset Pneumocystis jirovecii pneumonia (PJP) in patients with ANCA-associated vasculitis.

Immunosuppression in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is complicated by increasing risk of infections including opportunistic infections like Pneumocystis jirovecii pneumonia (PJP). Available evidence on risk factors and indications for prophylaxis in AAV is derived from PJP occurring early in the course of AAV. In this retrospective study, we characterized the profile of PJP in patients with AAV. PJP cases were identified retrospectively based on positive polymerase chain reaction test from electronic record followed by confirmation from medical records over a 10-year period. AAV patients without PJP over the same period were used as control group. Sixteen PJP+AAV+ were identified; in 14 of them, we were able to confirm they received PJP prophylaxis during induction therapy, while in two cases, data were missing. The onset of the infection was after 6months from AAV diagnosis in 80% of cases. Escalations in immunosuppression prior to PJP were observed in six cases within 3months prior to PJP onset. Overall mortality was 12.5%. By univariate analysis, renal involvement at AAV diagnosis was associated with PJP. These results indicate that PJP is not limited to the first 6months following AAV diagnosis. Late-onset infection can occur in context of augmented immunotherapy, particularly with concurrent lymphopenia. Other risk factors that can independently predict late-onset PJP remain to be identified.

Single-center outbreak of Pneumocystis jirovecii pneumonia in heart transplant recipients.

Pneumocystis jirovecii pneumonia (PJP) outbreaks are described in solid organ transplant recipients. Few reports suggest interhuman transmission with important infection control implications. We described a large PJP outbreak in heart transplant (HTx) recipients. Six cases of PJP occurred in HTx recipients within 10months in our hospital. Demographics, clinical characteristics, treatment and outcomes were described. To identify contacts among individuals a review of all dates of out-patient visits and patient hospitalizations was performed. Cross exposure was also investigated using genotyping on PJ isolates. At the time of PJP-related hospitalization, patients' mean age was 49±standard deviation 4years, median time from HTx was 8 (25%-75% interquartile range [Q1-Q3] 5-12) months and none of the cases were on prophylaxis. At PJP-related admission, 5 patients had CMV reactivation, of whom 4 were on antiviral preemptive treatment. Median in-hospital stay was 30 (Q1-Q3, 28-48) days; and 2 cases required intensive care unit admission. All patients survived beyond 2years. Transmission map analysis suggested interhuman transmission in all cases (presumed incubation period, median 90 [Q1-Q3, 64-91] days). Genotyping was performed in 4 cases, demonstrating the same PJ strain in 3 cases. We described a large PJP cluster among HTx recipients, supporting the nosocomial acquisition of PJP through interhuman transmission. Based on this experience, extended prophylaxis for more than 6months after HTx could be considered in specific settings. Further work is required to understand its optimal duration and timing based on individual risk factor profiles and to define standardized countermeasures to prevent and limit PJP outbreaks.

Incidence and Type of Opportunistic Infections during Ibrutinib Treatment at a Single Academic Center

BACKGROUNDIbrutinib is an irreversible inhibitor of Burton's tyrosine kinase (BTK) in the B-cell receptor (BCR) signaling cascade and is a practice changing treatment for chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits Interleukin-2 Inducible Kinase (ITK) in T-cells and has demonstrated immunomodulatory effects. Recently, cases of opportunistic infections (OI) have been reported during ibrutinib treatment including pneumocystis jirovecii pneumonia (PJP), cryptococcus, and fusarium. To date there are no reports on OI in large unselected cohorts of patients taking ibrutinib. We conducted a single-institution retrospective study to determine the incidence and type of OI during ibrutinib treatment as well as outcomes and characteristics associated with risk. METHODSWe reviewed medical records of all patients treated with ibrutinib at the Ohio State University between June 1st 2010 and March 31st 2016. Patients who received ibrutinib for graft versus host disease were excluded. All charts were initially reviewed by one of the investigators and patients with OI were independently reviewed by a second investigator. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All OI occurring after the first dose of ibrutinib were recorded. Onset of OI was considered as the time of first presentation for a complaint related to OI. Time to OI was calculated from the date of starting ibrutinib until the onset of OI or censored at the last assessment date, discontinuation of ibrutinib, or death prior to OI as competing risks. The cumulative incidence of OI was estimated and the Fine and Gray regression models were used to examine the association between patient characteristics and risk of OI. Covariates with significance level of p<0.20 from univariable analyses were further evaluated in a multivariable analysis using a stepwise selection procedure, retaining those with p<0.05 in the final model. RESULTSThe cohort included 566 patients. Median age was 65 (range 23-89) and 70.1% (397/566) were men. The majority of patients had CLL (73.7%, 417/566). Other diagnoses included mantle cell lymphoma (9.9%, 56/566), indolent B-cell malignancies (8.1%, 46/566; 11 Waldenström's Macroglobulinemia, 13 Hairy Cell Leukemia, 15 Follicular Lymphoma, 6 Marginal Zone Lymphoma, and 1 Prolymphocytic Leukemia), and aggressive lymphoma (8.3%, 47/566; 35 diffuse large B-cell or transformed lymphoma and 12 Richter's syndrome). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/566) of patients were treatment naïve. Ibrutinib was prescribed on clinical trial for 80.9% (458/566) of patients with the rest receiving it as standard of care. A second agent was given with ibrutinib in 30.9% (175/566) of cases and was most often a monoclonal antibody (81.7%, 143/175). Use of antiviral prophylaxis was common (78.6%, 445/566) with fewer patients receiving PJP (44.9%, 254/566) or fungal (11.5%, 65/566) prophylaxis. The most utilized prophylactic antifungal agent was fluconazole (70.8%, 46/65). Total ibrutinib exposure for the cohort was 1,225 person-years with a median exposure of 1.98 (range 0.008-6.40) years. Median duration of follow-up was 2.69 (range 0.03-6.40) years. Twenty-three of 566 (4.1%) patients developed an OI at a median of 0.39 (range 0.03-4.33) years after starting ibrutinib. The cumulative incidence of OI was 2.3% (95% CI: 1.3-3.8%) at 0.5 years and increased to 4.7% (95% CI: 3.0-7.0-%) at 5 years. Types of OI and outcomes are detailed in Table 1. Median survival of the entire cohort was not reached. Among 23 OI patients, the median survival after infection was 1.39 years. Univariable analysis revealed ≥3 prior treatments (HR 2.61), diabetes (HR 3.03), pulmonary disease (HR 2.81), chronic kidney disease (HR 2.56), and liver disease (HR 6.42) were associated with an increased risk for OI (p<0.05). In a multivariable analysis ≥3 prior treatments (HR 2.87, 95% CI: 1.12-7.35; p=0.028), diabetes (HR 3.63, 95% CI: 1.50-8.77; p=0.004), and liver disease (HR 7.53, 95% CI: 2.14-26.49; p=0.002) retained independent association with OI development. CONCLUSIONSThe cumulative incidence of OI during ibrutinib treatment was low (4.7% at 5 years) and the most common type was invasive fungal (61%) with no PJP cases. Three or greater prior treatments, diabetes, and liver disease were independently associated with risk for OI. [Display omitted] DisclosuresByrd:Janssen: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision.

Fungal diseases kill more than 1.5 million and affect over a billion people. However, they are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable. Serious fungal infections occur as a consequence of other health problems including asthma, AIDS, cancer, organ transplantation and corticosteroid therapies. Early accurate diagnosis allows prompt antifungal therapy; however this is often delayed or unavailable leading to death, serious chronic illness or blindness. Recent global estimates have found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDS, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually. Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated the estimation of the burden of serious fungal infections country by country for over 5.7 billion people (>80% of the world’s population). These studies have shown differences in the global burden between countries, within regions of the same country and between at risk populations. Here we interrogate the accuracy of these fungal infection burden estimates in the 43 published papers within the LIFE initiative.

Hypercalcaemia preceding diagnosis of Pneumocystis jirovecii pneumonia in renal transplant recipients.

BackgroundThe overall incidence of Pneumocystis jirovecii pneumonia (PJP) in solid organ transplant recipients is 5–15%. A timely diagnosis of PJP is difficult and relies on imaging and detection of the organism.MethodsWe present a case series of four patients displaying hypercalcaemia with an eventual diagnosis of PJP and document the management of the outbreak with a multidisciplinary team approach. We discuss the underlying pathophysiology and previous reports of hypercalcaemia preceding a diagnosis of PJP. We also reviewed the evidence concerning PJP diagnosis and treatment.ResultsWithin our renal transplant cohort, four patients presented within 7 months with hypercalcaemia followed by an eventual diagnosis of PJP. We measured their corrected calcium, parathyroid hormone (PTH), 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] and 25-hydroxycholecalciferol [25(OH)D] levels at admission and following treatment of PJP. All four patients diagnosed with PJP were 4–20 years post-transplantation. Three of the four patients demonstrated PTH-independent hypercalcaemia (corrected calcium >3.0 mmol/L). The presence of high 1,25(OH)2D3 and low 25(OH)D levels suggest negation of the negative feedback mechanism possibly due to an extrarenal source; in this case, the alveolar macrophages. All four patients had resolution of their hypercalcaemia after treatment of PJP.ConclusionsGiven the outbreak of PJP in our renal transplant cohort, and based on previous experience from other units nationally, we implemented cohort-wide prophylaxis with trimethoprim–sulphamethoxazole for 12 months in consultation with our local infectious diseases unit. Within this period there have been no further local cases of PJP.

Outbreak of Pneumocystis jirovecii Infection Among Heart Transplant Recipients: Molecular Investigation and Management of an Interhuman Transmission.

An outbreak of Pneumocystis jirovecii pneumonia (PCP) occurred among heart transplant recipients (HTR) at the outpatient clinic of a university hospital, from March to September 2015. Clinical, therapeutic, biological, and molecular data were analyzed to determine its origin and control the outbreak. Clinical and biological data regarding all HTR followed in the outpatient clinic were collected. PCP diagnosis was based on microscopy and real-time polymerase chain reaction (PCR). Investigations were performed by building a transmission map, completed by genotyping Pneumocystis isolates and by a control of chemoprophylaxis observance. Asymptomatic exposed patients were screened for colonization using real-time PCR. Among 124 HTR, 7 PCP cases were confirmed. Screening identified 3 additional patients colonized by P. jirovecii. All patients were cured, and no further cases were identified after trimethoprim-sulfamethoxazole prophylaxis was introduced in the entire cohort. Genotyping demonstrated the same strain in all PCP cases and colonized patients. All cases were linked with possible transmission chains from 2 possible index patients. Interhuman transmission was significantly associated with more frequent visits in the outpatient clinic. Six cases were receiving atovaquone as a prophylaxis. The occurrence of PCP was significantly associated with atovaquone prophylaxis. This is the first outbreak with detailed molecular analysis in HTR so far. Genotyping and transmission chain confirmed interhuman transmission in all colonized/infected PCP cases. Outpatient clinic layout and high encounters probably caused this PCP cluster, which was controlled after systematic trimethoprim-sulfamethoxazole prophylaxis in exposed patients.

An Ongoing Open-Label Phase 1/2 Study of INCB050465, a Selective PI3Kδ Inhibitor, in Patients with Previously Treated B-Cell Malignancies

Background: Signaling of PI3Kd has been implicated in proliferation, migration, and function of B cells. PI3Kd inhibitors have demonstrated clinical activity in a number of lymphoid tumor types. INCB050465 is a novel, potent, and highly specific inhibitor of PI3Kd (≥19,000-fold more selective for the d vs other isoforms) with no hepatotoxicity in preclinical evaluation at clinically relevant exposures. Here we report the emerging safety, pharmacokinetics, and efficacy results of INCB050465 monotherapy in B-cell malignancies.Methods: This phase 1/2 study (NCT02018861) enrolled patients aged ≥18 years with relapsed/refractory B-cell malignancies. After an initial single-patient cohort of oral INCB050465 5 mg once daily, a 3+3 dose escalation was conducted with doses ranging from 10 to 45 mg once daily; the dose-limiting toxicity observation period was 21 days. The 20 mg and 30 mg once daily doses were selected for monotherapy expansion. Efficacy was assessed every 9 weeks by Lugano Classification or International Working Group on Chronic Lymphocytic Leukemia (CLL) criteria.Results: As of the data cutoff (May 20, 2016), 39 patients had been enrolled and treated with INCB050465 monotherapy. The median age was 63 and 62% were men. Subtypes included diffuse large B-cell lymphoma (n=13); Hodgkin lymphoma (HL; n=8); follicular lymphoma (FL; n=6); CLL (n=5); marginal zone lymphoma (MZL; n=4); and mantle cell lymphoma (n=3). At baseline, the median number of prior systemic regimens was 3, and the median time since diagnosis was 4.9 years. INCB050465 demonstrated low oral clearance and linear pharmacokinetics, with a terminal half-life that supports once-daily dosing. The steady-state Cavg was 15-fold greater than the whole blood IC90 at the 30-mg dose. Pharmacodynamic analysis indicated maximal inhibition of the target throughout the dosing interval at all doses tested. Patients received INCB050465 for a median duration of 82 days (range: 4+ to 382+ days); no DLTs were observed. Treatment was discontinued in 16 patients due to disease progression (n=12), adverse events (AEs; n=3), or loss to follow-up (n=1). Dose interruption occurred in 6 patients (15%) and dose reduction in 1 (3%). The most common nonhematologic AEs were nausea (33%), pyrexia (21%), and cough (18%), all of which were grade 1 or 2. All observed alanine aminotransferase (15%) and aspartate aminotransferase elevations (15%) were grade 1. Nine patients (23%) experienced 16 grade ≥3 nonhematologic AEs, 3 of which were considered treatment-related by the investigator. New or worsening grade ≥3 anemia, thrombocytopenia, and neutropenia occurred in 8%, 10%, and 15% of patients, respectively. There was 1 instance (3%) each of colitis (grade 3) and pneumonitis (grade 2). Thirteen patients (33%) experienced a serious AE (SAE); SAEs occurring in more than 1 patient included diarrhea, exfoliative dermatitis, and hypotension (n=2 each). Among efficacy-evaluable patients (n=35), the objective response rate (ORR) was 57% and varied by disease subtype (Table 1). The ORRs for non-Hodgkin lymphoma (NHL) and HL were 66% (19/29) and 17% (1/6), respectively. Objective responses were observed in both transformed and non-transformed DLBCL, and both germinal center B-cell (GCB) and non-GCB subtypes. Objective responses were observed for all 10 patients with FL or MZL. Ninety percent of objective responses were observed at the first response assessment, and responses occurred at all but the 5-mg dose.Conclusion: The linear pharmacokinetics and absence of DLTs allow INCB050465 to achieve higher levels of target inhibition at the recommended phase 2 dose (30 mg once daily) than have been reported for other PI3Kd inhibitors. INCB050465 monotherapy was well tolerated at all doses tested with no significant transaminase elevations or early-onset diarrhea, and no cases of Pneumocystis jirovecii pneumonia. Objective responses, including complete responses, were observed in both aggressive and indolent NHL. Enrollment is ongoing at the 30 mg once daily dose level. [Display omitted] DisclosuresGutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage; Incyte Corporation: Consultancy; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging. Edenfield:Astellas/Medivation: Speakers Bureau; Novartis: Speakers Bureau; Greenville Health System Cancer Institute: Employment. Dawkins:Incyte Corporation: Employment, Other: Stocks. DeMarini:Incyte Corporation: Employment, Other: Stocks. Zhou:Incyte Corporation: Employment, Other: Stocks. Yeleswaram:Incyte Corporation: Employment, Other: Stocks. Newton:Incyte Corporation: Employment, Other: Stocks. Chen:Incyte Corporation: Employment, Other: Stocks. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding.

Temporal Profiles of Lymphocyte Subsets and the Correlation with Infectious Events in Idelalisib-Treated Patients

Introduction: Idelalisib (IDELA) is a targeted PI3Kd inhibitor approved as monotherapy in relapsed follicular lymphoma and in combination with rituximab in relapsed chronic lymphocytic leukemia (CLL). Increased rates of adverse events (AEs) were recently observed in the IDELA vs placebo arms of randomized controlled trials (RCT) evaluating IDELA added to standard therapies in front-line CLL and early-line indolent non-Hodgkin lymphoma (iNHL). AEs leading to death were mainly infectious and included pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV). This analysis across trials in the relapsed population evaluated whether quantitative changes in lymphocyte subsets may have contributed to these AEs.Methods: Peripheral blood immunophenotypic data available for analysis from patients (pts) (n = 1,480) treated in 5 IDELA RCTs were analyzed. Three studies (n = 787) included pts with relapsed CLL (NCT01569295: IDELA + bendamustine-rituximab [BR] vs placebo + BR; NCT01539512: IDELA + R vs placebo + R and NCT0165902: IDELA + ofatumumab [O] vs placebo + O) and 2 studies (n = 693) included R/R iNHL pts (NCT01732913: IDELA + R vs placebo + R and NCT01732926: IDELA +BR vs placebo + BR). Absolute numbers of T (CD4+ and CD8+), B (CD19+) and NK (CD16+/CD56+) cells were analyzed longitudinally in both IDELA and placebo pts across the 5 studies. Lymphocyte subsets were analyzed separately in those who died and then correlated with specific grade ≥3 AEs including infections, febrile neutropenia, and respiratory (acute respiratory failure, pneumonitis) events. Analysis was conducted within individual study and for all studies combined. Of note, samples were collected more frequently during the first 6 months (during combination therapy) and collection times varied among the 5 studies.Results: There was no specific trend noted with the CD8+ T-cells between treatment groups across the studies. Generally, NK-cells were decreased to a similar degree in both IDELA and placebo pts at weeks 10 to 12 with recovery starting around week 24. There were no differences in median NK- and CD8+ T-cell counts between pts with grade ≥3 AEs and no AEs within either group. In both BR trials, CD4+ T-cells nadir to <200 cells/µl occurred at week 22 in both groups. Recovery of CD4 to ≥200 cells/µL occurred at week 30 in CLL pts and at week 72 in iNHL pts. Median CD4+ T-cells in pts on the BR trials were lower in groups both with and without AEs, compared with non-BR trials (Table 1). There were a total of 31 cases of PJP (13 in the BR trials) and 32 cases of CMV infection (28 in the BR trials). Analysis of PJP and CMV pts with available immunophenotypic data (n = 46) revealed that 33 pts had CD4 <200 cells/µL; 31 of these were treated with IDELA plus combination therapy (Figure 1). Finally, while there were more grade ≥3 AEs within IDELA arms, these did not occur at any specific CD4 level and, in fact, grade ≥3 AEs were noted even in pts with CD4 >900 cells/µL.Conclusion: Within 5 RCTs evaluating IDELA vs placebo in combination with an anti-CD20 mAb or BR in R/R CLL or iNHL, there was no correlation between grade ≥3 AEs and NK- or CD8+ T-cell counts. Median CD4+ T-cells in pts on the BR trials were lower in both groups in those with and without AEs, compared with non-BR trials. In addition, pts with PJP and CMV infections were noted to have CD4+ T-cells <200 cells/ µL, and this was more common in IDELA-treated patients, especially when combined with BR, suggesting that the lymphosuppressive effect of IDELA may augment the myelosuppressive effect of bendamustine. While this current study involves the quantitative analysis of various immune cell subsets, it may be the qualitative function of these cells that contributed to infections. Assays evaluating the qualitative function of these cells are being investigated. All IDELA trials have been amended to include PJP prophylaxis and CMV monitoring. [Display omitted] [Display omitted] DisclosuresSharman:Gilead Sciences, Inc.: Honoraria, Research Funding. Salles:Mundipharma: Honoraria; Amgen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Jurczak:Celltrion, Inc: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Bayer: Research Funding. Jones:AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Research Funding; PCYC: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Owen:Janssen: Honoraria; Gilead: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Lundbeck: Honoraria, Research Funding; Novartis: Honoraria; Roche: Honoraria, Research Funding. Munugalavadla:Gilead Sciences: Employment, Equity Ownership. Dreiling:Gilead Sciences: Employment, Equity Ownership. Xiao:Gilead Sciences: Employment, Equity Ownership. Rao:Gilead Sciences: Employment, Equity Ownership. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria.

A Prospective Study of IV Pentamidine for Pneumocystis Jirovecii Pneumonia Prophylaxis in Adult Patients with Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplant or Chemotherapy

Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) is routinely administered to patients undergoing hematopoietic stem cell transplantation (SCT) or intensive chemotherapy. There is continued risk of PJP particularly in SCT recipients when they require prolonged immunosuppression or high dose corticosteroids. Trimethoprim-sulfamethoxazole is the drug of choice but its use is limited by hematologic toxicities. Inhaled pentamidine is an alternative, but frequently causes bronchospasm, needs to be given by a respiratory therapist, and requires use of a private room during administration due to its teratogenicity. Intravenous (IV) pentamidine is FDA approved for PJP treatment, and overcomes these challenges. We conducted the first ever prospective study of IV pentamidine for PJP prophylaxis in adult patients undergoing SCT or intensive chemotherapy.Fifty patients were enrolled in a single-arm trial. Patients requiring PJP prophylaxis according to institutional guidelines received pentamidine 4 mg/kg (maximum 300 mg) intravenously with ondansetron pre-medication. Patients were followed for the occurrence of PJP pneumonia. Adverse events were recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4. Patient satisfaction was assessed by conducting the Treatment Satisfaction Questionnaire for Medication (TSQM Version 1.4) survey. Thirty-two (64%) patients were male, and the median age was 55 years (range: 19-72). Twenty-four patients (48%) were undergoing intensive chemotherapy while 26 (52%) were undergoing SCT. Of the latter group, 62% received autologous SCT and 38% allogeneic SCT. At the time of IV pentamidine administration, 58% of patients were neutropenic (absolute neutrophil count < 0.5 thous/µL) and 86% of patients were lymphopenic (absolute lymphocyte count < 1 thous/µL). All patients received at least one dose of IV pentamidine (range: 1-9). There were no cases of PJP documented during the 12 month study period. There were no NCI-CTCAE grade 3/4 events. Seventeen (34%) patients experienced a grade 1 or 2 adverse event. The most common adverse events were nausea (n=4) and hypotension (n=6). Hypotension typically occurred at the end of the infusion, was transient, and asymptomatic. Grade 1/2 acute kidney injury developing within one week of pentamidine occurred in 2 patients (4%). In both patients, serum creatinine increased within 3 days, peaked within 7 days, and normalized within 10 days. Two treatment-related interruptions of drug infusion occurred; one due to infusion-related perioral and facial numbness which resolved as soon as the drug was stopped and one due to nausea which resolved after intravenous ondansetron. IV infusion was resumed successfully in both cases. Engraftment was not adversely affected in patients undergoing SCT. The median time to neutrophil and platelet engraftment was 12 (range: 11-15) and 14 (range: 10-16) days in autologous SCT recipients and 13 (range: 13-31) and 14 (range: 14-31) days in allogeneic SCT recipients.Results from the TSQM questionnaire indicate that the majority of patients found that IV pentamidine was "not at all bothersome" (n=33, 69%), "did not interfere with physical health and ability to function" (n=37, 77%), and was "extremely easy to receive" (n=29, 60%). The most common adverse events reported in the TSQM questionnaire were nausea (n=6), nasal congestion (n=2), and mouth numbness (n=2). However, they had "minimal" or "no effect at all" on patient satisfaction with the drug. Overall patients were satisfied with the administration of IV pentamidine (n=43, 86%, p<0.01).Our study illustrates the safety and feasibility of using IV pentamidine for PJP prophylaxis in patients undergoing SCT or intensive chemotherapy. In SCT patients, IV pentamidine did not delay engraftment. The incorporation of patient centered outcomes showed a high degree of satisfaction with this method of prophylaxis. Thus, although comparative studies are required, IV pentamidine overcomes many of the respiratory and logistic challenges faced when administering inhaled pentamidine and appears to be better tolerated. In particular, patients undergoing SCT who require PJP prophylaxis over a prolonged period may derive benefit from the improved safety and patient satisfaction profile of IV pentamidine. DisclosuresNo relevant conflicts of interest to declare.