A CASE OF PNEUMOCYSTIS JIROVECI PNEUMONIA MIMICKING METHOTREXATE-INDUCED PNEUMONITIS

SESSION TITLE: Procedures in Chest Infections Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is known to cause potentially life-threatening pneumonia in patients on immunosuppressive therapy. Here we describe a case of an elderly man on low dose methotrexate with PJP pneumonia initially mistaken for drug induced pneumonitis. CASE PRESENTATION: A 79 year old man with T-cell large granular lymphocytic leukemia on methotrexate, indeterminate colitis on azathioprine and sulfasalazine and interstitial lung disease was admitted for 3 week history of worsening dyspnea, lethargy and cough. On arrival his oxygen saturation was 87% on room air, requiring 5 liters oxygen via nasal canula. Lung examination was notable for bilateral crackles. Laboratory studies showed white blood cell count 12.4k/μL, lactate 2.7mmol/L, procalcitonin 0.137ng/mL, lactate dehydrogenase(LDH) 925 IU/L, 1,3 β-D glucan elevated at 154pg/mL. Infectious work up including COVID-19 testing was unremarkable. Chest radiograph showed bilateral diffuse interstitial infiltrates (figure 1) and computed tomography (CT) scan showed peripheral reticular changes and patchy ground glass opacities bilaterally (figures 2;3). He was initially treated for possible bacterial pneumonia;then with 125mg of methylprednisolone for presumed methotrexate induced pneumonitis without improvement. He underwent bronchoscopy with bronchoalveolar lavage(BAL) gram stain showing numerous histiocytes and scattered lymphocytes;no infectious organisms were isolated. PJP PCR from BAL came back positive and trimethoprim-sulfamethoxazole (TMP-SMX) was started. Despite maximum therapy he deteriorated clinically, transitioned to comfort care and expired. DISCUSSION: Diagnosis of PJP is made by visualization of cystic or trophic forms in respiratory tissue obtained via biopsy, BAL or sputum. Fungal burden is typically lower in non-HIV patients with PJP, and may result in negative BAL or sputum stain. Thus PCR testing is a useful diagnostic tool. Positive PCR alone cannot distinguish between colonization and active disease, and should be performed when clinical suspicion is high. 1,3 β-D glucan and LDH are nonspecific markers that help in presumptive diagnosis. First line therapy for PJP is TMP-SMX, with atovaquone, dapsone and pentamidine available as alternative therapies. Duration of therapy should be at least 21 days. Adjunctive corticosteroids show survival benefit in HIV-infected individuals. In severely hypoxic patients, corticosteroids are beneficial if started within 72 hours of antibiotic initiation. Their use in non-HIV PJP cases remains controversial. CONCLUSIONS: This case highlights the risk of PJP with long term methotrexate therapy. Cough, hypoxemia and bilateral interstitial infiltrates should prompt work-up for PJP. Timely recognition and early treatment are crucial to prevent mortality. Further studies are needed to assess the efficacy and provide guidelines for primary prophylaxis in this population. Reference #1: Wilson JW, Limper AH, Grys TE, Karre T, Wengenack NL, Binnicker MJ. Pneumocystis jirovecii testing by real-time polymerase chain reaction and direct examination among immunocompetent and immunosuppressed patient groups and correlation to disease specificity. Diagn Microbiol Infect Dis. 2011 Feb;69(2):145-52. doi: 10.1016/j.diagmicrobio.2010.10.021. PMID: 21251557;PMCID: PMC6855182. Reference #2: Salzer HJF, Schäfer G, Hoenigl M, Günther G, Hoffmann C, Kalsdorf B, Alanio A, Lange C. Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and Non-HIV-Infected Immunocompromised Patients with Pneumocystis jirovecii Pneumonia. Respiration. 2018;96(1):52-65. doi: 10.1159/000487713. Epub 2018 Apr 10. PMID: 29635251 DISCLOSURES: No relevant relationships by Rutendo Jokomo-Nyakabau No relevant relationships by Richard Swaney No relevant relationships by Manasa Velagapudi

SYSTEMATIC LITERATURE REVIEW on the SCREENING and PROPHYLAXIS of CHRONIC and OPPORTUNISTIC INFECTIONS

Background: Opportunistic and chronic infections can arise in the context of treatment used for Autoimmune Rheumatic Diseases (ARDs). Although it is recognized that screening procedures and prophylactic measures must be followed, clinical practice is largely heterogeneous, with relevant recommendations not currently developed or disparately located across the literature. Objectives: To conduct a systematic literature review (SLR) focusing on the screening and prophylaxis of opportunistic and chronic infections in ARDs. This is preparatory work done by members of the respective EULAR task force (TF). Methods: Following the EULAR standardised operating procedures, we conducted an SLR with the following 5 search domains;1) Infection: infectious agents identifed by a scoping review and expert opinion (TF members), 2) Rheumatic Diseases: all ARDs, 3) Immunosuppression: all immunosuppressives/immunomodulators used in rheumatology, 4) Screening: general and specifc (e.g mantoux test) terms, 5) Prophylaxis: general and specifc (e.g trimethop-rim) terms. Articles were retrieved having the terms from domains 1 AND 2 AND 3, plus terms from domains 4 OR 5. Databases searched: Pubmed, Embase, Cochrane. Exclusion criteria: post-operative infections, pediatric ARDs, not ARDs (e.g septic arthritis), not concerning screening or prophylaxis, Covid-19 studies, articles concerning vaccinations and non-Εnglish literature. Quality of studies included was assessed as follows: Newcastle Ottawa scale for non-randomized controlled trials (RCTs), RoB-Cochrane tool for RCTs, AMSTAR2 for SLRs. Results: 5641 studies were initially retrieved (Figure 1). After title and screening and removal of duplicates, 568 full-text articles were assessed for eligibility. Finally, 293 articles were included in the SLR. Most studies were of medium quality. Reasons for exclusion are shown in Figure 1. Results categorized as per type of microbe, are as follows: For Tuberculosis;evidence suggests that tuberculin skin test (TST) is affected by treatment with glucocorticoids and conventional synthetic DMARDs (csDMARDs) and its performance is inferior to interferon gamma release assay (IGRA). Agreement between TST and IGRA is moderate to low. Conversion of TST/IGRA occurs in about 10-15% of patients treated with biologic DMARDs (bDMARDs). Various prophylactic schemes have been used for latent TB, including isoniazide for 9 months, rifampicin for 4 months, isoniazide/rifampicin for 3-4 months. For hepatitis B (HBV): there is evidence that risk of reactivation is increased in patients positive for hepatitis B surface antigen. These patients should be referred for HBV treatment. Patients who are positive for anti-HBcore antibodies, are at low risk for reactivation when treated with glucocorticoids, cDMARDs and bDMARDs but should be monitored periodically with liver function tests and HBV-viral load. Patients treated with rituximab display higher risk for HBV reactivation especially when anti-HBs titers are low. Risk for reactivation in hepatitis C RNA positive patients, treated with bDMARDs is low. However, all patients should be referred for antiviral treatment and monitored periodically. For pneumocystis jirovecii: prophylaxis with trimeth-oprim/sulfamethoxazole (alternatively with atovaquone or pentamidine) should be considered in patients treated with prednisolone: 15-30mg/day for more than 4 weeks. Few data exist for screening and prophylaxis from viruses like E B V, CMV and Varicella Zoster Virus. Expert opinion supports the screening of rare bugs like histoplasma and trypanosoma in patients considered to be at high risk (e.g living in endemic areas). Conclusion: The risk of chronic and opportunistic infections should be considered in all patients prior to treatment with immunosuppressives/immunomod-ulators. Different screening and prophylaxis approaches are described in the literature, partly determined by individual patient and disease characteristics. Collaboration between different disciplines is important.

Drug Repurposing: A Potentially Emerging Discipline

Drug repurposing is the remodeling of already existing drugs to reduce the time frame, costs, and efforts in developing a new novel drug. This strategy has secured significant momentum in the previous decade. It overcomes the snags and pitfalls in the traditional means of drug discovery. This core research strategy has now become the sole approach to containing many deadly diseases that have no cure in the present. In astound, for pandemics like COVID-19 that is spreading like a wildfire worldwide, large-scale research programs and trials have been carried out to identify and modify existing drugs to counter the novel virus. Thus, this technology of drug repurposing offers a new lease of life, and greatly promotes the progress of the medicine, health, and pharma sectors. The purpose of this study is to understand the current status of drug repurposing in the field of virology, bacteriology, mycology, and oncology for clinical translatability.

Nocardiosis in Renal Transplant Recipients Linked to Decreased Utilization of Trimethoprim/Sulfamethoxazole during COVID-19

Background. The renal transplant population is at increased risk of Nocardiosis due to impaired T-cell mediated immunity with immunosuppression. Pneumocystis jirovecii (PJP) prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX) provides coverage against Nocardia spp. unlike alternative agents such as atovaquone (ATQ), aerosolized pentamidine (AP), and dapsone. During the COVID-19 pandemic, patients receiving AP were transitioned to ATQ to avoid the use of nebulized medication. This, in turn, led to decreased use of TMP/SMX as patients on oral ATQ were not reassessed for the use of TMP/SMX as would have occurred while on AP. Additionally, an increased incidence of Nocardia infections was observed during this time. The objective of this study was to determine the association between the incidence of Nocardia infections and number of TMP/SMX prophylaxis-days in preversus COVID-19 cohorts. Methods. This was a single center retrospective chart review of all renal transplant recipients between September 2018 - August 2019 (pre-COVID-19 cohort) and April 2020 - March 2021 (COVID-19 cohort). Patients were included if they were at least 18 years of age and a recipient of a cadaveric or living donor kidney transplant. Exclusion criteria included multi-organ transplant, pediatric patients, and repeat transplants. The primary outcome was incidence of Nocardiosis within the first 6 months post-transplant in the pre- and COVID-19 cohorts. Results. A total of 218 patients were included (Table 1). Induction therapy and initial immunosuppression did not differ significantly between groups, nor did rates of rejection within 180 days of transplant (Table 2). Although the pre-COVID-19 cohort had a higher rate of neutropenia, there was no difference in median absolute lymphocyte count between the two groups. The COVID-19 cohort had a decreased percentage of TMP/SMX prophylaxis-days (59.2% vs. 72.5%, p < 0.0001) and an increased incidence of Nocardia infections in the first 6 months post-transplant (4% vs. 0%, p=0.0292). All 4 cases of Nocardia infections occurred in patients receiving ATQ. Conclusion. The increased incidence of Nocardiosis was associated with a decreased use of TMP/SMX for PJP prophylaxis which may have been an unintended consequence of increased use of ATQ in lieu of AP during COVID-19.

Ninety Years of Pentamidine: The Development and Applications of Pentamidine and its Analogs.

Pentamidine, an FDA-approved human drug for many protozoal infections, was initially synthesized in the late 1930s and first reported to be curative for parasitosis in the 1940s. After ninety years of sometimes quiet growth, pentamidine and its derivatives have gone far beyond antibacterial agents, including but not limited to the ligands of DNA minor groove, modulators of PPIs (protein-protein interactions) of the transmembrane domain 5 of lateral membrane protein 1, and the blockers of the SARS-CoV-2 3a channel. This mini-review highlights the development and applications of pentamidine and its analogs, aiming to provide insights for further developing pentamidine derivatives in the following decades.