Pneumocystis Carinii Pneumonia Prophylaxis Research Articles

Nebulised pentamidine prophylaxis of pneumocystis pneumonia in adults accessing HIV services at royal free hospital, London.

Receipt of nebulised pentamidine in people with HIV was audited to identify if individuals were appropriately receiving nebulised pentamidine, and whether national guidelines were being followed when prophylaxis was commenced and discontinued. Of 76 people with who received nebulised pentamidine, the main indication for starting nebulised pentamidine was a co-trimoxazole adverse drug reaction. Co-trimoxazole desensitization was not attempted before starting nebulised pentamidine. The main indication for stopping nebulised pentamidine prophylaxis was when immune reconstitution occurred. This single centre audit revealed that national guidelines were being followed in most cases. The lack of information regarding the reason for starting or stopping nebulised pentamidine prophylaxis, or detail of the clinician's concerns about potential poor adherence with oral regimens of prophylaxis as a reason for choosing nebulised pentamidine prophylaxis, identifies a need for improved documentation of clinicians' decision-making. Introduction of pharmacist-led interventions/alerts using patients' electronic records, similar to those used in primary care, would enable the specialist pharmacy team to identify when and if co-trimoxazole desensitization has been offered and discussed/declined before a clinician prescribes nebulised pentamidine as well as enabling identification of those in who pentamidine prophylaxis has been continued, despite "immune reconstitution".

Incidence and Outcomes of Pneumocystis Pneumonia Following Chimeric Antigen Receptor T-Cell Therapy: A Real-World Analysis

Background: Pneumocystis Pneumonia (PCP) is a known opportunistic infection after chimeric antigen receptor (CAR) T-cell therapy. However, the incidence and outcomes of PCP are poorly understood, and there has been no clear consensus on the optimal duration for PCP prophylaxis post-CAR T-cell treatment. Methods: From a large real-world database, TriNetX Research Network, we identified patients who underwent commercial anti-CD19 and anti-BCMA CAR T-cell therapy between January 2019 and January 2023. The diagnosis of PCP was established using the ICD-10-CM code B59 (pneumocystosis) or through Logical Observation Identifiers Names and Codes (LOINC) documentation of positive microbiologic tests from respiratory samples. Results: Among the 1,107 and 280 patients who received anti-CD19 and anti-BCMA CAR T-cell therapies, 19 (1.7%) and 4 (1.4%) patients developed PCP, respectively. Altogether, a total of 23 (1.7%) patients developed PCP within a median of 139 days (range 19 to 732 days) post-infusion. (Figure) Demographics, the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and the initial choice for PCP prophylaxis, were similar for patients with and without PCP. Patients who developed PCP were more likely to have used dexamethasone (65 vs 43%, p=0.02) and have a shorter duration of trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis (median 9 [range 1 to 45] vs 19 [range 1 to 106] weeks, p=0.002). In the univariate analysis, patients who received TMP/SMX prophylaxis for less than 3 months showed a trend of a higher incidence of PCP compared to those who received it for more than 3 months (hazard ratio [HR] 3.54, 95% confidence interval [CI] 0.87 to 14.3, p=0.06). (Table) Regarding survival outcomes, patients with and without PCP had similar time-to-next-treatment or death (median 84 vs 68 days, HR 0.96, 95%CI 0.61 to 1.51) and overall survival (median 518 days vs not-reached, HR 1.61, 95%CI 0.91 to 2.88). Conclusions: In real-world conditions with routine prophylaxis, PCP is an infrequent opportunistic infection following anti-CD19 or anti-BCMA CAR T-cell therapy. Patients with and without PCP were associated with similar survival outcomes.

FRI232 Importance Of Rapid Treatment Initiation In Ectopic Cushing Syndrome: Abstract

Abstract Disclosure: D. Mendez: None. M.G. Fernandez: None. D.J. Selen: None. Background: Endogenous Cushing syndrome may result from an ectopic non-pituitary tumor. Severe hypercortisolism has high mortality, so prompt medical management to acutely decrease cortisol levels is necessary when no surgical options are available. Clinical Case: A 67-year-old male presented to the hospital with four weeks of fatigue and was found to have a right hilar mass with unsuppressed cortisol levels for which an ectopic tumor was suspected. On initial evaluation, the patient presented with hypokalemia, acute kidney injury, and metabolic alkalosis. In addition, a CT of the chest and abdomen with contrast revealed a right hilar mass with multiple liver lesions concerning for metastasis. These findings prompted workup for hypercortisolism, including 1mg and 8 mg dexamethasone suppression tests. Both tests demonstrated unsuppressed cortisol levels above 150 (reference range [RR] 5.5-20 ug/dl and assay maximum>150) and elevated 24-hour urinary cortisol of 8125 (RR <60 ug/dl), suspicious for an ACTH-secreting tumor. Subsequently, he underwent a liver biopsy to characterize the tumor further and was started on Bactrim for Pneumocystis pneumonia prophylaxis. Metyrapone and osilodrostat were considered for treatment but not available at our facility such that treatment was initiated with ketoconazole 200 mg orally twice daily with subsequent dose titration. He had a mild elevation of AST 52 (RR 7-42 IU/L) and ALT 52 (RR 10-45); therefore, his liver profile was monitored daily due to his elevated risk for hepatotoxicity. With the initiation of ketoconazole, cortisol serum levels decreased to 145 ug/dl after two days of treatment. The pathology report revealed small lung cell carcinoma as the etiology for ectopic Cushing’s syndrome, for which the oncology team-initiated etoposide and carboplatin. Unfortunately, on day 6 of the initiation of treatment, the patient rapidly deteriorated and passed away from pneumonia and septic shock. Conclusion: Severe hypercortisolism leads to an immunosuppressed state resulting in high mortality. Therapeutic options depend significantly on the accessibility of first-line treatment options and prompt initiation of medical treatment. When no other agents are available, ketoconazole should be started at high doses despite the mild elevation of liver enzymes with close monitoring of LFTs. While it is unclear if the patient’s deterioration was due to his cancer burden, chemotherapy, severe hypercortisolism, or a combination, given that osilodrostat and metyrapone are first-line treatment options, standardized systems should be reviewed in hospitals for faster acquisition of these medications to avoid delays in treatment initiation. In addition, the decision to transfer patients to the intensive care unit for etomidate infusion while awaiting the acquisition of the above medications should be considered promptly. Presentation: Friday, June 16, 2023

SAT316 Severe Cushing’s Syndrome Due To Ectopic ACTH In Newly Diagnosed Small Cell Lung Cancer: The Pivotal Role Of Etomidate In Acute Treatment

Abstract Disclosure: H. Belal: None. G.Y. Gandhi: None. Introduction: Ectopic ACTH syndrome can present as an endocrine emergency. Etomidate, the only parenteral steroidogenesis inhibitor, can rapidly treat critically ill patients with Cushing’s syndrome (CS) and concurrent significant metabolic derangements, severe hypertension, or psychosis. Case Description: A 66-year-old female presented with abdominal pain, vomiting, proximal muscle weakness, and confusion for 6 months. Physical exam revealed hypertension, bilateral supraclavicular fat pads, and abdominal distention, while laboratory evaluation uncovered severe hypokalemia <1.5 mmol/L, metabolic alkalosis, and elevated proBNP. A hilar soft tissue mass with mediastinal lymphadenopathy and bilaterally enlarged adrenal glands were seen on CT imaging. Serum cortisol was high at 114 mcg/dL. ACTH was inappropriately elevated at 111 pg/mL. MRI revealed a normal pituitary gland. She developed hypertensive emergency and status epilepticus, requiring intubation. Due to her life-threatening presentation, a guideline-based hypercortisolism workup was forgone for emergent treatment with continuous etomidate infusion. Serum cortisol normalized after 4 days of etomidate therapy. Due to concerns of reduced seizure threshold with etomidate therapy, it was weaned off after 14 days and replaced by ketoconazole. She subsequently developed recurrent hypercortisolism (serum cortisol 92 mcg/dL). After 14 days of etomidate, 9 days of ketoconazole, and 3 days of chemotherapy for biopsy-proven small-cell lung carcinoma, serum cortisol reached a trough of 22 mcg/dL. At this point, hydrocortisone therapy was initiated (block-and-replace). Recurrent clinical hypercortisolism then developed, and hydrocortisone was discontinued. Hypercortisolism comorbidities were treated appropriately: trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis, anticoagulation for DVT prophylaxis, antibiotics for acute diverticulitis, and insulin for hyperglycemia. Despite treatment, her condition worsened; she was transitioned to comfort care one month after admission and died 4 days later. Discussion: Etomidate inhibits steroidogenesis through 11 beta-hydroxylate blockade and works rapidly (within 12-24 hours) to decrease cortisol levels versus ketoconazole (several days) and has a reduced risk of hepatic injury. Side effects of etomidate include respiratory depression, myoclonus, and reduced seizure threshold. Several experts have suggested a block-and-replace strategy in severe CS treatment. While effective, this strategy poses risks of etomidate toxicity and makes serum cortisol interpretation unreliable. Etomidate analogs are on the horizon that retain the potent adrenostatic action of etomidate without its sedative-hypnotic activity, offering an alternative treatment option for treating patients with severe CS in non-ICU hospital settings. Presentation: Saturday, June 17, 2023

Sulfamethoxazole-trimethoprim for pneumocystis pneumonia prophylaxis, causes of discontinuation and thrombocytopenia observed during administration: A single-center retrospective study

IntroductionThe development of pneumocystis pneumonia (PCP) has recently become a growing concern; thus, its prevention has become increasingly important. Sulfamethoxazole-trimethoprim (ST) is a cost-effective first-line and prophylactic treatment for PCP. However, ST administration criteria for PCP prophylaxis remain unclear and are often discontinued because of adverse events (AEs). In this study, we aimed to investigate the causes of ST discontinuation and the associated AEs using objective data. MethodsWe retrospectively analyzed the data of 162 patients admitted to Kansai Medical University Hospital between January 2018 and December 2020, who received ST for PCP prophylaxis. We compared clinical characteristics, laboratory data, and incidence of AEs between ST non-discontinuation and ST discontinuation groups. Additionally, we divided the patients into non-developing and developing thrombocytopenia (≥ Grade 1) groups based on the investigation results. ResultsNo patients developed PCP while receiving ST. The most common causes of ST discontinuation were thrombocytopenia (37%), liver dysfunction (20%), and rash (18%). Multivariate analysis revealed thrombocytopenia (≥ Grade 1) as a factor significantly associated with ST discontinuation. Furthermore, we identified three factors correlated with thrombocytopenia (≥ Grade 1): age ≥50 years, lymphocyte count <1000/μL, and platelet count <180,000/μL. ConclusionsPatients with the aforementioned factors are at higher risk of developing thrombocytopenia (≥ Grade 1) during ST administration for PCP prophylaxis. Therefore, platelet count monitoring is essential to enhance safety and efficacy of ST treatment. Nonetheless, further research is warranted to explore additional implications and interventions.

Incidence of Pneumocystis Pneumonia in Immunocompromised Patients without Human Immunodeficiency Virus on Intravenous Pentamidine Prophylaxis: A Systematic Review and Meta-Analysis.

Trimethoprim-sulfamethoxazole (TMP-SMX) is a first-line Pneumocystis pneumonia (PCP) prophylaxis agent, but monthly intravenous pentamidine (IVP) is used in immunocompromised hosts without human immunodeficiency virus (HIV) infection because IVP is not associated with cytopenia and delayed engraftment. We performed a systematic review and meta-analysis to estimate breakthrough PCP incidence and adverse reactions in HIV-uninfected immunocompromised patients receiving IVP. MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched from their inception until 15 December 2022. The pooled incidence of breakthrough PCP with IVP was 0.7% (95% CI, 0.3-1.4%, 16 studies, 3025 patients) and was similar when used as first-line prophylaxis (0.5%; 95% CI, 0.2-1.4%, 7 studies, 752 patients). The pooled incidence of adverse reactions was 11.3% (95% CI, 6.7-18.6%, 14 studies, 2068 patients). The pooled adverse event-related discontinuation was 3.7% (95% CI, 1.8-7.3%, 11 studies, 1802 patients), but was lower in patients receiving IVP monthly (2.0%; 95% CI 0.7-5.7%, 7 studies, 1182 patients). Monthly IVP is an appropriate second-line agent for PCP prophylaxis in certain non-HIV immunocompromised hosts, especially in patients with hematologic malignancies and hematopoietic stem cell transplant recipients. Using IVP for PCP prophylaxis as an alternative to oral TMP-SMX while patients are unable to tolerate enteral medication administration is feasible.

Prophylaxis for Pneumocystis carinii pneumonia in non-Hodgkin’s lymphoma undergoing R-CHOP21 in China: a meta-analysis and cost-effectiveness analysis

ObjectiveRituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone, once every 3 weeks (R-CHOP21) is commonly used in non-Hodgkin’s lymphoma (NHL), but accompanied by Pneumocystis carinii pneumonia (PCP) as a fatal treatment...

Pneumocystis pneumonia in COVID-19 patients: A comprehensive review

The admitted patients of intensive care units with coronavirus disease 2019 (COVID-19) meet the challenges of subsequent infections. Opportunistic fungal infections such as Pneumocystis pneumonia (PCP) are among the important factors in the context of COVID-19 patients affecting illness severity and mortality. We reviewed the literature on COVID-19 patients with PCP to identify features of this infection. Although studies confirmed at least the presence of one immunosuppressive condition in half of PCP patients, this disease can also occur in immunocompetent patients who developed the immunosuppressive condition during Covid-19 treatment. The major risk factors associated with COVID-19 patients with PCP can be considered low lymphocyte counts and corticosteroid therapy. Diagnostic and treatment options are complicated by the overlapping clinical and radiologic characteristics of PCP and COVID-19 pneumonia. Therefore, physicians should comprehensively evaluate high-risk patients for PCP prophylaxis.

32015 Practice patterns on the management of pemphigus – An international survey study

Autoimmune blistering diseases (AIBD) such as pemphigus are characterized by circulating autoantibodies to desmosomal proteins which manifest as blisters and erosions of the skin and/or mucosa. Despite emerging diagnostic and therapeutic armamentarium, there remains considerable variability in the management of pemphigus. An anonymous survey was distributed to a group of bullous disease experts through the International Pemphigus and Pemphigoid Foundation. The χ2 and t tests were used for comparisons. P 75% of newly diagnosed and treatment naive pemphigus patients. Use of RTX first line was not associated with AIBD practice volume. Most (72.3%) prefer rheumatoid arthritis dosing regimen. 68.1% of respondents use desmoglein levels in assessing treatment response and need for retreatment. 63.8% of respondents provided concomitant systemic steroids, while 19.1% provided concomitant steroid-sparing agents to ≥90% of their patients on RTX. Few dermatologists (4.3%) routinely prescribe pneumocystis pneumonia (PCP) prophylaxis to all patients and only 34% prescribe PCP prophylaxis to some of their patients. Most (74.5%) do not routinely prescribe varicella zoster prophylaxis. 78.7% do not routinely administer prophylactic RTX for patients in clinical remission. Clinical relapse is the most common reason (76.1%) for RTX retreatment. This study highlights the variability in pemphigus management and the importance of further evidence-based guidelines for this condition.

Clinical features of glioma patients who develop pneumocystis pneumonia with temozolomide chemoradiotherapy.

The treatment of glioma with temozolomide chemoradiotherapy predisposes patients to pneumocystis pneumonia (PCP). Because PCP is a rare outcome, very little is known about specific clinical risk factors for its development in patients with glioma. We performed a population-based retrospective cohort study of glioma patients undergoing temozolomide chemoradiotherapy 2005 to 2019 in Ontario, Canada. We compared clinical features of patients who did not versus did develop PCP within one year of chemoradiotherapy. We examined the overall survival of patients by PCP status. There were 5130 patients with glioma treated with temozolomide chemoradiotherapy. Ultimately, 38 patients (0.74%) were diagnosed with PCP within 1year of chemoradiotherapy. Most (71%) infections occurred between 0-90days and 29% occurred between 91-365days. Median survival was 12.3months in patients who did not develop PCP and 8.6months in those who did develop PCP (P < 0.001). Trough 90-day lymphocyte counts were lower in the PCP group. When the lymphocytes fell below 0.19 × 109/L (or 0.25 × 109/L among patients without PCP prophylaxis), the risk of PCP was > 3.5%. Pneumocystis pneumonia is rare in glioma patients who receive temozolomide chemoradiotherapy. Infection is associated with shorter survival and the development of lymphopenia. Reserving PCP prophylaxis for patients whose lymphocyte counts drop below 0.25 × 109/L may be a reasonable strategy.

64-Year-Old Woman With Aphasia and Troponin Elevation

64-Year-Old Woman With Aphasia and Troponin Elevation

AB0697 Dramatic reduction of mortality rate by tofacitinib in anti-MDA-5 antibody-positive patients with rapidly progressive interstitial lung disease

BackgroundRapidly progressive interstitial lung disease (RP-ILD) is often seen in dermatomyositis patients with anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody. They often have a poor prognosis with rapid decline in pulmonary function, leading to respiratory failure (1). Aggressive immunosuppressive therapy has been reported with improved prognosis, however; it may lead to opportunistic infections, including cytomegalovirus (CMV) or Pneumocystis pneumonia (PCP) infection (2, 3).ObjectivesThis study aimed to evaluate the effectiveness of tofacitinib (TOF) in combination with CMV and PCP prophylaxis in anti-MDA-5-positive patients.MethodsMedical records of 17 anti-MDA-5-positive RP-ILD patients enrolled during Mar 2017 to May 2021 were reviewed. RP-ILD was defined by the presence of deteriorated dyspnea, with a decrease in PaO2 levels and emerging radiographic anomalies within 4 weeks without evidence of infection (4). Chest CT was scored using Ichikado score (5). Clinical parameters including ferritin levels, white counts (WBC), Lactate dehydrogenase (LDH) levels, GAP scores (Gender, Age, and Physiology score for idiopathic pulmonary fibrosis) were recorded. Medications included cyclophosphamide (CyP), intravenous immunoglobulin (IVIG), mycophenolic acid derivatives (MPA), rituximab (RTX), and calcineurin inhibitor (CNI). Kaplan-Meier survival analysis and Log-rank test were used to evaluate one-year mortality differences (MedCalc version 19.6). The Ethics Committee approved our study (CE17038B).ResultsSix anti-MDA-5-positive RP-ILD patients were treated with tofacitinib; five had concomitant CMV prophylaxis with valganciclovir (VGCV); 4 had PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP-SMX). Patients’ demographic data are shown in Table 1. The median age, clinical manifestations, laboratory data, and chest CT scores were comparable between tofacitinib and non-tofacitinib groups. Prevalence of MPA use was higher in the non-TOF group. Kaplan-Meier survival analysis (Figure 1) indicated that patients with tofacitinib treatment (p=0.001), valganciclovir (p=0.003), and TMP-SMX (p=0.028) prophylaxis exhibited better 1-year survival rates compared with those without TOF therapy, VGCV, and TMP-SMX prophylaxis.Table 1.Clinical characteristics of anti-MDA-5 antibody-positive patients with RP-ILD receiving tofacitinib vs non-tofacitinib treatment.Tofacitinib (n=6)Non-tofacitinib (n=11)p valueAge (years)58 (42.3-77)57 (50.0-62.0)0.884Female sex, n (%)2 (33.3)6 (54.5)0.620Diabetes mellitus, n (%)0 (0)5 (45.5)0.102Fever, n (%)5 (83.3)10 (90.9)1.000Mechanic’s hands, n (%)4 (66.7)5 (45.5)0.620Ferritin (n=16, ng/ml))2670.9 (719.7-4209.7)1563.5 (967.8-3169.0)0.635WBC (x1000μl)8.7 (6.5-9.9)8.7 (6.0-12.9)0.884LDH (n=16, U/l)367.0 (218.0-557.5)433.0 (331.0-625.3)0.313GAP score5 (2.5-8)5 (2-6)0.808CT score200.0 (124.2-214.2)196.7 (153.3-273.3)0.733TMP-SMX, n (%)4 (66.7)0 (0)0.006**VGCV, n (%)5 (83.3)0 (0)0.001**CyP, n (%)1 (16.7)4 (36.4)0.600IVIG, n (%)1 (16.7)6 (54.5)0.304MPA, n (%)0 (0)7 (63.6)0.035*RTX, n (%)3 (50.0)5 (45.5)1.000CNI, n (%)2 (33.3)6 (54.5)0.620Continuous variables were expressed as median (inter-quartile range).*p&lt;0.05, **p&lt;0.01 by Mann–Whitney U test or Fisher’s Exact test.Figure 1.ConclusionThe study demonstrated the efficacy of tofacitinib treatment in anti-MDA-5-positive RP-ILD. In addition, CMV and PCP prophylaxis appeared to improve in 1-year survival. Rheumatologists might consider TOF with prophylaxis as an option for anti-MDA-5-positive patients in daily practice.

Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy

The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain. To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline. An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021. Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group). The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure. Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P < .001; absolute annual event rate difference, -4.8% per year [95% CI, -8.0% to -1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P = .008; annual event rate difference, -2.9% per year [95% CI, -5.4% to -0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]). Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy. ClinicalTrials.gov Identifier: NCT01560052.

Evolving epidemiology of pneumocystis pneumonia: Findings from a longitudinal population-based study and a retrospective multi-center study in Germany.

SummaryBackgroundPneumocystis pneumonia (PCP) is a life-threatening opportunistic infectious disease of immunocompromised patients. Its incidence has decreased worldwide in the past, but data concerning its recent epidemiology are lacking.MethodsWe retrospectively analyzed all German inpatient cases from January 1, 2014 to December 31, 2019, to describe the recent epidemiology, incidence, clinical course, mortality and underlying diseases of PCP. Simultaneously, we conducted a retrospective multi-center study at two German university hospitals, and analyzed PCP cases treated there to gain deeper insights on the basis of primary patient data.FindingsThe incidence of PCP significantly increased from 2·3 to 2·6 per 100,000 population from 2014 to 2019 (1,857 to 2,172 cases, +17·0%, p < 0·0001), as well as PCP-related deaths (516 to 615 cases, +19·2%, p = 0·011). The spectrum of underlying diseases changed: Risk groups with established chemoprophylaxis for PCP based on international guidelines (HIV, hematologic malignancies, and transplantation) showed a significant decrease in PCP cases and deaths. Others, especially those with solid malignancies, and autoimmune and pulmonary diseases showed a significant increase in case numbers and deaths. Data from the retrospective multi-center study added information regarding prophylaxis and diagnostics of PCP.InterpretationThe incidence of PCP has reversed its trend, showing a significant increase in mortality on population level. Patients who were not previously considered in prophylactic measures are increasingly affected by PCP. This development deserves further investigation, and additional comprehensive guidelines for the use of chemoprophylaxis in new risk groups are needed.FundingDepartment of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Kiel.

Neonate with Respiratory Distress, Bilateral Microtia, Hypocalcemia, and Lymphopenia.

Neonate with Respiratory Distress, Bilateral Microtia, Hypocalcemia, and Lymphopenia.

Neutrophil-erythrocyte rosettes suggestive of Coombs-negative autoimmune haemolysis

A 62-year-old man with well-controlled HIV infection presented to Columbia University Medical Center (New York, NY, USA) in December, 2016, with progressive fatigue. He was found to have a haemoglobin concentration of 5·0 g/dL, with laboratory evidence of haemolytic anaemia. Polyspecific direct antibody testing (DAT; also known as direct Coombs testing) was negative. Evaluation of a peripheral blood film revealed the findings presented in the figure. His home medications included his HIV anti-retroviral therapy, along with trimethoprim-sulfamethoxazole (160 mg and 800 mg orally three times a week) for Pneumocystis pneumonia prophylaxis.

Effectiveness and safety of pneumocystis pneumonia prophylaxis for patients receiving temozolomide chemoradiotherapy.

Malignant gliomas are treated with temozolomide chemoradiotherapy. Because pneumocystis pneumonia (PCP) can occur in patients receiving temozolomide, the product monograph recommends PCP prophylaxis during temozolomide chemoradiotherapy. Not all neuro-oncologists follow these recommendations, though. We performed a population-based retrospective cohort study of glioma patients undergoing temozolomide chemoradiotherapy 2005 to 2019 in Ontario, Canada. A propensity score model was used to predict the use of PCP prophylaxis. We compared the risk of PCP within 90 days of starting radiotherapy with versus without PCP prophylaxis using inverse probability of treatment weighting (IPTW). We also examined overall survival, hospitalizations, and myelosuppression. There were 3,225 patients included in the cohort (648 received antibiotics and 2,434 did not). Only 18 patients developed PCP within 90 days of therapy. The IPTW-adjusted absolute risk reduction in PCP with antibiotics was 0.0035 (95% CI, -0.0013 to 0.0083), number needed to treat: 288. Neither overall survival nor hospitalization count differed between the groups. The number needed to harm by causing grade 3/4 neutropenia was 39. In regions (like Ontario) where PCP is rare, routine PCP prophylaxis with trimethoprim-sulfamethoxazole should not be offered, since the harms may outweigh the benefits.

Update on Dihydropteroate Synthase (DHPS) Mutations in Pneumocystis jirovecii.

A Pneumocystis jirovecii is one of the most important microorganisms that cause pneumonia in immunosupressed individuals. The guideline for treatment and prophylaxis of Pneumocystis pneumonia (PcP) is the use of a combination of sulfa drug-containing trimethroprim and sulfamethoxazole. In the absence of a reliable method to culture Pneumocystis, molecular techniques have been developed to detect mutations in the dihydropteroate synthase gene, the target of sulfa drugs, where mutations are related to sulfa resistance in other microorganisms. The presence of dihydropteroate synthase (DHPS) mutations has been described at codon 55 and 57 and found almost around the world. In the current work, we analyzed the most common methods to identify these mutations, their geographical distribution around the world, and their clinical implications. In addition, we describe new emerging DHPS mutations. Other aspects, such as the possibility of transmitting Pneumocystis mutated organisms between susceptible patients is also described, as well as a brief summary of approaches to study these mutations in a heterologous expression system.

Comparative effectiveness of trimethoprim-sulfamethoxazole versus atovaquone for the prophylaxis of pneumocystis pneumonia in patients with connective tissue diseases receiving prolonged high-dose glucocorticoids

We compared the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) with atovaquone for pneumocystis pneumonia (PCP) in patients with connective tissue diseases (CTDs) receiving high-dose glucocorticoids. Patients with CTDs aged ≥ 18years who were treated with a prolonged course (≥ 4weeks) of glucocorticoids (≥ 20mg/day prednisone) in a Japanese tertiary center between 2013 and 2017 were included. The patients were categorized into two groups: TMP-SMX and atovaquone group. Adjusted cumulative incidence of PCP was compared between the two groups after propensity score weighting for differences in confounding factors. A total of 480 patients with a prolonged high-dose glucocorticoid treatment were identified. Out of 383 patients with TMP-SMX prophylaxis, 102 (26.8%) patients experienced adverse events leading to discontinuation within 4weeks of initiation, while no patient in the atovaquone discontinued the therapy. Two hundred eighty-one patients received TMP-SMX, while 107 received atovaquone for PCP prophylaxis. During a total of 397.0 person-years, 7 PCP cases (2 in the TMP-SMX, 5 in the atovaquone) occurred with a mortality rate of 54.5%. After adjusting for differences in baseline characteristics, the adjusted cumulative incidence of PCP was similar between the two group (HR 0.97, 95% CI 0.19-5.09, p = 0.97). Prophylactic effects for PCP in CTDs patients receiving prolonged high-dose glucocorticoids were similar between TMP-SMX and atovaquone. Atovaquone was well-tolerated with no side effects.

Safety and efficacy evaluation of low-dose trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis pneumonia in HIV uninfected patients undergoing hemodialysis: a retrospective observational study

BackgroundPneumocystis pneumonia (PCP) is a potentially life-threatening infection. Trimethoprim-sulfamethoxazole (TMP-SMX) is considered as the first regimen for PCP prophylaxis according to several guidelines. The recommended prophylactic dose of TMP-SMX has been determined based on patients with normal renal function, but the appropriate dosage for patients undergoing hemodialysis is unknown. The aim of this study was to investigate the efficacy and safety of low-dose TMP-SMX in patients undergoing hemodialysis.MethodsHIV-uninfected adult patients who were undergoing hemodialysis and administered TMP-SMX for PCP prophylaxis, were included, and divided into standard-dose (≥6 single strength (SS, TMP-SMX 80 mg/400 mg tablets/week) and low-dose groups (< 6 SS tablets/week). The endpoints were cumulative incidence of PCP and cumulative discontinuation rate of TMP-SMX due to adverse events. For comparison of the groups, we employed the chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. Risk factors for the endpoints were evaluated using the Cox Fine and Gray method.ResultsThe median age of the 81 patients included in the study was 67 years (IQR: 60–76 years), and 52 patients (64.2%) were men. No patients in either group developed PCP during the observation period. The yearly cumulative incidence of discontinuation was 12.1% (95% confidence interval [CI]: 0.027–0.29) in the low-dose group and 35.6% (95% CI: 0.20–0.52) in the standard-dose group (P = 0.019). The adjusted hazard ratio of the low-dose group compared to standard-dose group was 0.18 (95% CI: 0.04–0.86, P = 0.032).ConclusionsNone of the study patients developed PCP, and the cumulative discontinuation rate of TMP-SMX due to adverse events was significantly lower in the low-dose group compared to that in the standard-dose group (P = 0.032). These results indicate that low-dose TMP-SMX is an appropriate regimen to maintain a balance between PCP prophylaxis and prevention of adverse events due to TMP-SMX administration. These findings can guide health care professionals to determine TMP-SMX dosage when considering PCP prophylaxis for patients undergoing hemodialysis.