Infect Dis Research Articles

Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH)

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by undesirable drug-like properties of lead compounds. Prodrug approaches temporarily mask undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin (Fsm), exhibit significantly higher antimalarial potency than their parent compounds [R.L. Edwards et al., Sci. Rep. 7, 8400 (2017)]. However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a fluorogenic ester library, we characterize the structure-activity relationship of APEH and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug-activating enzymes are a common mechanism for antimicrobial drug resistance [E. S. Istvan et al., Nat. Commun. 8, 14240 (2017); K. M. V. Sindhe et al., mBio 11, e02640-19 (2020); J. H. Butler et al., Acs Infect Dis. 6, 2994-3003 (2020)]. Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.

P-1256. Pharmacokinetic/Pharmacodynamic (PK/PD) Target Attainment Analyses for Aztreonam-Avibactam Dosing Regimens

Abstract Background Aztreonam-avibactam (ATM-AVI) is a fixed-ratio β-lactam/β-lactamase inhibitor recently approved in Europe for adults with serious Gram-negative infections. Prior to commercial availability of ATM-AVI, doses for ceftazidime-avibactam (CAZ-AVI) + ATM have been proposed.1 We evaluated probability of joint PK/PD target attainment (PTA) for ATM-AVI and CAZ-AVI + ATM in adults with complicated intra-abdominal infection (cIAI). Methods A simultaneous population PK model for ATM and AVI was developed using data from the CAZ-AVI and ATM-AVI adult clinical programs, including two ATM-AVI phase 3 trials. The final model was used to simulate exposures and calculate PTA (5000 patients/simulation) for ATM-AVI dose regimens adjusted for renal function, and two proposed CAZ-AVI + ATM dose regimens in cIAI patients with CrCL 80 to ≤150 mL/min. PTA was calculated for the joint PK/PD target of ATM 60% fT > 8 mg/L and AVI 50% fT > 2.5 mg/L. Results The analysis included 4,914 ATM plasma samples (431 subjects) and 18,222 AVI samples (2,635 subjects). The final model was a two-compartment model for ATM and AVI with zero-order infusion and first-order elimination. Standard allometric exponent functions of body weight on clearances (0.75) and volumes (1) were applied; body surface area-normalized CrCL was used to describe clearance changes during treatment. Infection type was a key covariate on clearance and volume for both drugs. Steady-state exposures for ATM-AVI dose regimens were associated with joint PTA 89 to > 99% across renal function groups (Table 1). CAZ-AVI + ATM dose regimens resulted in similar (or higher) geometric mean ATM Cmax,ss and AUC24,ss compared with ATM-AVI, but AVI AUC24,ss was approximately 25% lower, and joint PTA was < 85% (Table 2). Conclusion ATM-AVI dose regimens achieved high joint PTA across renal function groups. In contrast, joint PTA with proposed CAZ-AVI + ATM dose regimens for normal renal function were < 85% because of insufficient AVI exposures, regardless of the ATM dose (2g q6h or q8h). Joint PTA with both combinations is driven by the AVI plasma PK/PD target and is independent of pathogen MIC up to 8 mg/L. 1. Tamma PD et al. Clin Infect Dis 2023: ciad428. Trial registration: NCT03329092; NCT03580044. Study sponsored by Pfizer. Disclosures Susan R. Raber, PharmD, MPH, Pfizer: Employee|Pfizer: Stocks/Bonds (Public Company) Rujia Xie, PhD, Pfizer: Former employee|Pfizer: Stocks/Bonds (Public Company) Elena Soto, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds (Public Company) Heidi Leister-Tebbe, BSN, Pfizer: Employee|Pfizer: Stocks/Bonds (Public Company)

P-2162. Utility of Metagenomic Sequencing of Microbial Plasma Cell-Free DNA with Different Testing Strategies

Abstract Background While promising, optimal use criteria for metagenomic next-generation sequencing of microbial cell-free DNA (mcfDNA) to diagnose infectious diseases (ID) are not yet established. We examined this question by comparing the real-world clinical impact of mcfDNA testing on ID management in two academic medical systems with similar patient case mix but differing test ordering practices. Both institutions used the Karius assay (Redwood City, CA). Intermountain Health (IH) used an expedited pathway for specimen shipping and restricted test ordering to ID physicians with suggested use criteria. By contrast, at University of Utah Health (UU), testing occurred without systemic education and lab processing was slower. Demographics Methods We conducted a retrospective study of all mcfDNA testing at IH and UU from April 2022 – June 2023. We compared indications, incidence (per ID consult), and turn-around-time (TAT) for testing at each institution. Clinical impact of mcfDNA testing was evaluated for each institution using published criteria (Table 2). Clinical Impact Criteria UU, University of Utah; IH, Intermountain Health; mcfDNA, metagenomic next generation sequencing of plasma microbial cell-free DNA. Criteria adapted from Hogan CA, Yang S, Garner OB, et al. Clinical Impact of Metagenomic Next-Generation Sequencing of Plasma Cell-Free DNA for the Diagnosis of Infectious Diseases: A Multicenter Retrospective Cohort Study. Clin Infect Dis. 2021;72(2):239-245. doi:10.1093/cid/ciaa035 Results During the study period 123 tests were ordered (106 at IH and 17 at UU) (Table 1). Most were obtained via ID consult (118/122). Testing incidence at IH was 3.24/100 ID consults and at UU was 0.3/100 ID consults. At least one organism was identified in 44% (47/106) of tests at IH and 70% (12/17) at UU (p=0.06). Median TAT was 2 days at IH vs 8 days at UU (p < 0.05, Figure 1). Clinical impact varied by criterion between institutions (Table 2). Overall, mcfDNA testing had no discernible clinical impact in 64% (68/106) of IH cases and 76% (13/17) UU cases, (p= 0.41). A positive change in management resulted after 14% (15/106) of tests at IH and 23% (4/17) of tests at UU, p=0.46. Ordering and clinical impact varied by clinical indication (Table 3). Tests by clinical indication UU, University of Utah; IH, Intermountain Health Conclusion At UU, test ordering was more selective but yielded higher test positivity. At IH, where ordering practices were slightly more liberal, a clinical diagnosis was more often confirmed by mcfDNA results. Despite differences in testing availability and strategy, positive impact percentages were similar between institutions. At IH, mcfDNA results positively changed management for more patients, at the cost of more tests sent overall. Further research is needed to further clarify best mcfDNA testing strategies. Turnaround time UU, University of Utah; IH, Intermountain Health Disclosures Bert K. Lopansri, MD, D(ABMM), FIDSA, Cepheid: Grant/Research Support|Seegene: Advisor/Consultant

P-1925. Incidence of long COVID symptoms during the year post admission among patients hospitalized for COVID-19

Abstract Background The CDC defines long COVID as new, returning or ongoing health problems occurring at least 4 weeks after infection. However, it is uncertain how long different conditions may last after the infection. Our objective was to characterize incidence of common conditions that may be associated with long COVID across the first year after admission among patients hospitalized for COVID-19.Table 1.Patient DemographicsIQR, interquartile rangea Immunocompromised condition during the past 12 months (symptomatic HIV infection, haematologic and solid malignancy, organ transplant, rheumatologic/inflammatory, or other immune conditions).1. Patel M, et al. Emerg Infect Dis. 2020;26(8):1720-1730b Measured 365 to 15 days prior to admission Methods We identified patients hospitalized with COVID-19 from May 1, 2020-January 21, 2024 and with at least 31 days of followup in the HealthVerity claims and hospital chargemaster database. Patients with a diagnosis of long COVID (ICD-10-CM U09.9) were excluded. We assessed the incidence of long COVID outcomes, based on diagnosis codes, during two periods – 31-197 days and 198-365 days after hospital admission – to determine if incidence of these outcomes changed over the year. Rates per 1000 person-years and 95% confidence intervals were calculated for all hospitalized patients, patients who had no record of those conditions in the year prior to admission, and immunocompromised patients. The percentage change in the rates for each symptom between the time periods was also calculated.Table 2.Rate of long COVID conditions per 1000 person-years in 31- to-197-day and 198- to- 365-day time periods post hospital admission, all hospitalized patients (N=92,913) Results We identified 92,913 patients who met the study criteria. Cohort characteristics are described in Table 1; some outcomes were already present at baseline. In the overall hospitalized population (Table 2), incidence of all outcomes decreased between the first and second time periods. The decrease varied by symptom from 4% for muscle pain to 69% for hair loss. The trend was similar for the 12,100 patients who had none of the conditions at baseline (Table 3) and for the 39,185 immunocompromised patients (Table 4); some of the rare outcomes showed a nominal increase from the first to the second time periods, but this may be due to small sample sizes.Table 3.Rate of long COVID conditions per 1000 person-years in 31- to-197-day and 198-to- 365-day time periods post hospital admission, among hospitalized patients who had none of the conditions at baseline (N=12,100) Conclusion The observed consistent tendency towards a decline in incidence over time indicates that many of these outcomes may have resulted from COVID-19 infection. Of note, incidence tended to decline more steeply for some conditions than others. This could be a result of an improvement in inflammatory response or decline in viral reservoir over the year. Additional research on drivers of long COVID over time is necessary.Table 4.Rate of long COVID conditions per 1000 person-years in 31- to- 197-day and 198-to- 365-day time periods post hospital admission, among immunocompromised hospitalized patients (N=39,185) Disclosures Mark Berry, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Valentina Shvachko, MS, Gilead Sciences: employee|Gilead Sciences: Stocks/Bonds (Public Company)|Gilead Sciences, Inc.: Employee of Gilead Sciences, Inc.|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Amanda Kong, DrPH, Aetion Inc: Employee|Aetion Inc: Stocks/Bonds (Public Company) Rohan Shah, BS, Aetion Inc: employee|Aetion Inc: Stocks/Bonds (Public Company) Gina Brown, MD, Gilead Sciences, Inc.: Employee of Gilead Sciences, Inc.|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anand Chokkalingam, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

P-1191. Maternal Antibodies Against Parechovirus-A3 Before and During the Coronavirus Disease 2019 Pandemic

Abstract Background Parechovirus-A3 (PeV-A3) is an important emerging virus that causes severe disease in neonates and young infants. The coronavirus disease 2019 (COVID-19) pandemic greatly affected the incidence of infectious diseases, including PeV-A3 infection. Before the pandemic, we reported that maternal neutralizing antibody response against PeV-A3 was important in protecting neonates and young infants from PeV-A3 and that neutralizing antibody titers (NATs) were higher in younger mothers (Emerg Infect Dis. 2015;21:1966-1972). Because the impact of the COVID-19 pandemic on maternal NATs against PeV-A3 is unclear, we investigated NATs against PeV-A3 during the COVID-19 pandemic and compared our findings with previous data. Methods Cord blood (CB) samples for healthy newborns born at full-term were collected from June through December 2023 at Niigata University Hospital in Niigata, Japan. Maternal clinical data were collected, and NATs measured using LLC-MK2 cells were compared with the pre-pandemic data, classified by age group, ie, 16–24 years, 25–34 years, and 35–44 years. Results In total, 102 CB samples were collected. Median maternal age was 34.5 years (range: 30–37 years), and the geometric mean titer (GMT) of antibodies against PeV-A3 was 98.4 (95% CI: 61.7–156.8). The GMT values for age 25–34 years during the pandemic (184.6, n = 45) and age 16–24 years before the pandemic (336.5, n = 11) did not significantly differ (P = 0.84). Similarly, the GMT for age 35–44 years during the pandemic (56.3, n = 51) did not significantly differ from that for the matching age group, 25–34 years, before the pandemic (31.9, n = 107) (P = 0.14). Notably, the GMT was significantly higher for age 25–34 years during the pandemic than for age 25–34 years and age 35–44 years before the pandemic (P < 0.001), which is consistent with our finding that the pre-pandemic age group 16–24 years had the highest GMT. Conclusion Maternal NATs against PeV-A3 in CB before and during the COVID-19 pandemic were similar, which suggests that humoral immunity to PeV-A3 was not substantially altered even after 3 years of limited PeV-A3 infections during the COVID-19 pandemic. Disclosures All Authors: No reported disclosures

Nomenclature for human and animal fungal pathogens and diseases: a proposal for standardized terminology.

Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host's immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428-e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, "rhinocerebral mucormycosis." A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds.

Human metapneumovirus SH protein promotes JAK1 degradation to impair host IL-6 signaling.

Human metapneumovirus (HMPV) is a leading cause of respiratory infections in children, older adults, and those with underlying conditions (K. M. Edwards et al., N Engl J Med 368:633-643, 2013, https://doi.org/10.1056/NEJMoa1204630; A. R. Falsey et al., J Infect Dis 187:785-790, 2003, https://doi.org/10.1086/367901; J. S. Kahn, Clin Microbiol Rev 19:546-557, 2006, https://doi.org/10.1128/CMR.00014-06; N. Shafagati and J. Williams, F1000Res 7:135, 2018, https://doi.org/10.12688/f1000research.12625.1). HMPV must evade immune defenses to replicate successfully; however, the viral proteins used to accomplish this are poorly characterized. The HMPV small hydrophobic (SH) protein has been reported to inhibit signaling through type I and type II interferon (IFN) receptors in vitro in part by preventing STAT1 phosphorylation (A. K. Hastings et al., Virology (Auckl) 494:248-256, 2016, https://doi.org/10.1016/j.virol.2016.04.022). HMPV infection also inhibits IL-6 signaling. However, the mechanisms by which SH inhibits signaling and its involvement in IL-6 signaling inhibition are unknown. Here, we used transfection of SH expression plasmids and SH-deleted virus (ΔSH) to show that SH is the viral factor responsible for the inhibition of IL-6 signaling during HMPV infection. Transfection of SH-expression vectors or infection with wild-type, but not ΔSH virus, blocked IL-6-mediated STAT3 activation. Furthermore, JAK1 protein (but not RNA) was significantly reduced in cells infected with wild-type, but not ΔSH virus. The SH-mediated reduction of JAK1 was partially restored by the addition of proteasome inhibitors, suggesting proteasomal degradation of JAK1. Confocal microscopy indicated that infection relocalized JAK1 to viral replication factories. Co-immunoprecipitation showed that SH interacts with JAK1 and ubiquitin, further linking SH to proteasomal degradation machinery. These data indicate that SH inhibits IL-6 and IFN signaling in infected cells in part by promoting proteasomal degradation of JAK1 and that SH is necessary for IL-6 and IFN signaling inhibition in infection. These findings enhance our understanding of the immune evasion mechanisms of an important respiratory pathogen.IMPORTANCEHuman metapneumovirus (HMPV) is a common cause of severe respiratory illness, especially in children and older adults, in whom it is a leading cause of hospitalization. Prior research suggests that severe HMPV infection is driven by a strong immune response to the virus, especially by inflammatory immune signals like interferons (IFN). HMPV produces a small hydrophobic (SH) protein that is known to block IFN signaling, but the mechanism by which it functions and its ability to inhibit other important immune signals remains unexplored. This paper demonstrates that SH can inhibit another related immune signal, IL-6, and that SH depletes JAKs, which are critical proteins involved in both IL-6 and IFN signaling. A robust understanding of how HMPV and related viruses interfere with immune signals important for disease could pave the way for future treatments aimed at mitigating severe infections.

7982 Is there a Connection between Alpha Thalassemia and Thyroid Disorders

Abstract Disclosure: W. Akhter: None. V. Taqi: None. J.L. Gilden: None. IntroductionA number of case reports suggest an association between thalassemia and autoimmune diseases through specific mutations and molecular pathways. An example is thyroid disease in thalassemia patients. Due to factors such as age, ethnicity and treatment protocol differences, the frequency of hypothyroidism in thalassemia patients is a wide range of 4 to 29% based on free T4 and TSH levels. Subclinical hypothyroidism is more common in thalassemia patients as compared to overt hypothyroidism. 90% of morbidity and mortality in B-Thalassemia patients is attributed to iron overload, anemia and hypoxia. Understanding this possible mechanism helps guide treatment and monitoring. Case PresentationWe present the case of a 26-year-old African American with Haitian ethnicity female, who upon routine testing was found to have a very high TSH level of 79.084 uIU/ml (nl=0.550-4.780 uIU/ml) for which 125 mcg of Levothyroxine was started, and then she was referred to the endocrine clinic. Past history was notable for sickle cell trait and alpha thalassemia trait. Patient stated that at age 12, she developed fatigue and low energy and was found to have hyperthyroidism which was treated with RAI ablation. After that, no follow up or lab tests were done until recently. The patient denied symptoms of hypo or hyperthyroidism or enlargement of the thyroid gland. She denied any family history of thyroid disorders. After presenting to the endocrine clinic a few days later, she was diagnosed with postprocedural hypothyroidism and the same dose of levothyroxine was continued. Physical exam was unremarkable and no thyromegaly was appreciated on exam. Labs were notable for decreased Hemoglobin of 11.4 g/dL (nl=12-16 g/dL) and CMP was unremarkable except low glucose of 65 mg/dL (nl=70-99 mg/dL). The patient’s most recent labs after 8 weeks of taking Levothyroxine were notable for TSH of 14.65 uIU/ml (nl=0.550-4.780 uIU/ml) and free T4 of 1 ng/dL (nl= 0.89-1.76 ng/dL) and the patient admitted to having still no thyroid symptoms and a little more energy. ConclusionEndocrinopathies are common complications of thalassemia with hypothyroidism being the second most common endocrine disorder in thalassemia patients after hypogonadism, reported in 5.6-17% of patients. In thalassemia patients, endocrine disorders have to be managed as early as possible. Therefore, it is recommended that an endocrine evaluation be carried out in thalassemia patients at a young age.Monitoring for glucose homeostasis, hypothyroidism and hypoparathyroidism is also warranted. Physicians caring for thalassemia patients should perform routine screening for and treat thyroid dysfunction appropriately. Reference: De Sanctis V, Soliman AT, Canatan, et al.. Thyroid Disorders in Homozygous β-Thalassemia: Mediterr J Hematol Infect Dis. 2019 May 1;11(1):e2019029. doi: 10.4084/MJHID.2019.029. PMID: 31205633; PMCID: PMC6548211. Presentation: 6/2/2024

12553 Severe Hyperglycemia After Initiation Of Bictegravir Antiretroviral Therapy With Resolution Upon Discontinuation

Abstract Disclosure: S. Hudson: None. J. Aurora: None. K. Grossman: None. L. Kogelman: None. A.G. Pittas: None. Background: Antiretroviral therapy (ART) containing bictegravir (BIC), a second-generation integrase strand transfer inhibitor (INSTI), is a first-line treatment for HIV. There are mixed reports of INSTIs causing adverse metabolic effects, such as weight gain and hyperglycemia. There are cases of BIC causing hyperglycemia and diabetic ketoacidosis (DKA) within weeks to months following initiation; however, this has not been reported in clinical trials (1). It is unclear whether discontinuing BIC resolves hyperglycemia. We report a case of a patient with prediabetes who developed severe hyperglycemia after switching to a BIC-containing ART. The discontinuation of BIC resulted in significant improvement in glycemia, leading to the de-escalation of diabetes pharmacotherapy. Clinical Case: A 36-year-old woman with obesity was diagnosed with HIV during pregnancy, which was complicated by gestational diabetes mellitus. After pregnancy, she had prediabetes. Her initial ART was darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Due to intolerable GI side effects, six years later, she was switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Laboratory tests four months before starting BIC/FTC/TAF were consistent with prediabetes (HbA1c 6.4%, non-fasting blood glucose of 118 mg/dL). After one month, she was started on metformin when her HbA1c increased to 9.1% with a non-fasting blood glucose of 332 mg/dL. Another month later, HbA1c increased to 12.8% with a non-fasting blood glucose of 685 mg/dL without DKA. She was hospitalized for diabetes management. There were no significant changes in weight, viral load, or CD4 count. A search for secondary causes of hyperglycemia (diabetogenic medications, hypercortisolism, and autoimmune diabetes) was not revealing. She was discharged on metformin and insulin glargine. Her HIV regimen was switched to FTC/TAF and doravirine due to suspicion of BIC-induced hyperglycemia. After five months, she developed symptoms of hypoglycemia, and her estimated HbA1c by continuous glucose monitoring was 6.3%. Insulin glargine was discontinued. While on metformin, HbA1c three months later was 6.3%. Two years later on metformin and linagliptin: HbA1c was 6.1% and beta-cell function did not reveal insulin deficiency or resistance (non-fasting blood glucose 96 mg/dL, insulin 13.5 uIU/mL [RR 2.6-24.9 mIU/mL], C-peptide 3.7 ng/mL [RR 1.1-4.4 ng/mL]). Conclusion: Patients with HIV and a history of obesity and/or dysglycemia who are switched to a BIC-containing ART regimen should be educated and monitored for acute hyperglycemia. This may be due to impaired beta-cell function and/or insulin resistance; however, further research is needed to understand the mechanism. An alternative ART regimen should be considered if hyperglycemia develops. Reference: 1. Nolan NS, et al. Open Forum Infect Dis. 2021;16;8(5): ofab077. Presentation: 6/3/2024

Rothia mucilaginosa Pneumonia in an Immunocompromised Patient

Abstract Rothia mucilaginosa is a gram-positive coccus recognized as an opportunistic pathogen capable of causing pneumonia in immunocompromised patients (Antimicrob Agents Chemother. 1995;39:268–270). The organism is often resistant to fluoroquinolones and trimethoprim/sulfamethoxazole, agents routinely used as anti-infective prophylaxis in immunocompromised individuals (Inf Dis Clin Pract. 2020;28:361–365; Infect Dis Now. 2021;51:228–235). Plasma next-generation sequencing (NGS) is increasing in clinical use to aid in diagnosis of infections in immunocompromised patients (Infect Dis (Lond). 2015;47:125–1299). A patient with advanced multiple myeloma was admitted with pneumonia. Plasma NGS initially suggested R. mucilaginosa, which was confirmed by cultures of bronchoalveolar lavage (BAL) fluid. Treatment with eravacycline led to clinical and radiographic resolution of pneumonia.

Clinicopathological CasesCPC01 An unexpected infection in dermatology outpatients: cutaneous diphtheria

Abstract A 29-year-old asylum seeker presented to the emergency department with abdominal pain and a 1-month history of bilateral crusted plaques on his shins, associated with night sweats and lethargy. On examination he had multiple crusty erythematous plaques on the lower limbs, with some scattered pustules. Full-body examination was otherwise normal, except for multiple palpable inguinal lymph nodes bilaterally. Investigations revealed normal bloods and also included chest X-ray, urinalysis and computed tomography of the urinary tract. A dermatology referral was made, and differentials included ecthyma, atypical mycobacterial infection, fungal infection, or an iatrogenic cause with secondary infection. The patient was planned for multiple punch biopsies to be sent for haematoxylin and eosin staining, and tissue and mycobacterial culture. Unfortunately, a skin swab was rejected. A punch biopsy sent for culture surprisingly demonstrated the growth of a Gram-positive rod, identified as Corynebacterium ­diphtheriae, which was toxin gene positive. Histology showed a vesicopustule within the stratum corneum and upper epidermis containing neutrophils. The patient was diagnosed with cutaneous diphtheria. Cutaneous diphtheria is the most common nonrespiratory manifestation of the disease and can occur as a primary infection or in a pre-existing wound (Rahim NRA, Koehler AP, Shaw DD, Graham CR. Toxigenic cutaneous diphtheria in a returned traveller. Commun Dis Intell Q Rep 2014; 38: E298–300). It presents with shallow rolled-edged ulcers with a grey membrane at any skin site, including the genitals. It is reported that diphtheria is most contagious in its cutaneous form, where ulcers act as a reservoir for infection, which can be spread via wound manipulation (de Benoist A, White JM, Efstratiou A et al. Imported cutaneous diphtheria, United Kingdom. Emerg Infect Dis 2004; 10: 511–13). Prior vaccination does not prevent infection but stops systemic symptoms. Although rare, cases of cutaneous diphtheria are increasing in the UK, especially in asylum seekers. This case was identified by the dermatology department, which can be the location of first presentation. Lesions are clinically indistinguishable from other cutaneous infections, and so diphtheria must be considered as a differential in high-risk individuals. Vaccination does not prevent infection, but merely reduces the severity of the disease course. This can have important implications for staff safety if not recognized early, as in our case multiple exposed members of staff were required to isolate, take prophylactic antibiotics and receive a booster vaccination following exposure.

Flat dose intravenous immunoglobulin (IVIG) for primary infection prophylaxis after CAR-T for B-cell non-Hodgkin lymphoma (B-NHL).

e19004 Background: Prolonged hypogammaglobulinemia is a common side effect of CD19 chimeric antigen receptor (CAR) T-cell therapy for B-NHL. Average infection rates 1 year (yr) post CAR-T are 44-53% (Kampouri, Tran Infect Dis 2023). Prophylactic IVIG is typically dosed by weight; however, optimal dosing strategy remains unknown. We explored the efficacy of reduced flat IVIG dose on infection rates and non-relapse mortality (NRM) post CAR-T. Methods: B-NHL pts who received commercial CD19 CAR-T therapy from Nov 2017 to Mar 2023 at Vanderbilt Medical Center were included. All pts were on trimethoprim-sulfamethoxazole and valacyclovir for prophylaxis. IVIG at a flat dose of 10 grams was given for IgG < 400 mg/dL. Relevant clinical variables were collected from day 30 to 1 yr. Infections were defined as mild (treated outpatient), moderate (required admission), or severe (required intensive care unit) and by CTCAE v5 criteria. Severe neutropenia was defined as ANC<500 and severe lymphopenia was ALC<500. NRM was defined by death without progression or relapse. Estimated cost of therapy was $140/gram of IVIG based on previously published data. Results: A total of 43 pts (35 large cell lymphoma, 7 mantle cell lymphoma, and 1 follicular lymphoma) with median follow up of 445 days (range 134-2141) were included. Axicabtagene ciloleucel was given to 34 pts (79%), tisagenlecleucel to 2 pts (5%), and brexucabtagene autoleucel to 7 pts (16%). Median age was 58 (range 22-81). Median number of pre CAR-T therapies was 3 (range 1-7). There were 52 total infections with median time to first infection of 165 days (range 31-365). Of all infections, 21 (40%) were viral, 29 (56%) bacterial, and 2 (4%) fungal. There were 31 (60%) mild infections, 19 (36%) moderate, and 2 (4%) severe. Multiple G≥3 infections occurred in 14 pts (33%). At first infection, 4 pts (10%) had severeneutropenia and 13 pts (31%) had severelymphopenia. IVIG was given to 27 pts (63%). Median IgG at D30 was 438 mg/dL (range 143–1099) and 414 mg/dL (range 133–842) at D60. Prolonged IgG≤400 at 6 months occurred in 15 pts (35%). Median IVIG cost using flat dosing was $2800 (range $0-12,600) compared to a median cost of $8,075 (range $0-76,642) if weight-based dosing was utilized. NRM was 9% (4 pts). Of those pts, only 1 had a G≥3 infection during the first-year post CAR-T. Conclusions: We demonstrate comparable infection rates 1 yr post CD19 CAR-T and low NRM with the use of 10g flat IVIG dosing for consecutively treated pts. In addition, only 1 of 4 pts with NRM had severe infection within 1 yr. Notably, 35% of pts had persistent hypogammaglobulinemia at 6 mo and use of a flat dosing schedule provided substantial cost reduction. These findings should be validated in a prospective randomized trial.

A Misdiagnosis of MIS-C: Acute Pneumococcal Meningitis Due to Serotype 19F in A Child with Acute SARS-CoV-2 Infection with a Severe Disease Course.

According to the 2020 CDC criteria, multisystem inflammatory syndrome in children (MIS-C) due to Coronavirus disease-19 (COVID-19) is diagnosed when all of the following criteria are met: fever for+≥+24 hours, laboratory evidence of inflammation, multisystem (+≥+2) organ involvement, evidence of SARS-CoV-2 infection or exposure, and no alternative plausible diagnoses (CDC, 2020). Alternative diagnosis need to be excluded before coming upon an MIS-C diagnosis since there are plenty of infectious diseases that may mimic MIS-C (Dworsky et al., Pediatr Infect Dis J 2021; 40; e159-e161; Yalçinkaya et al., Pediatr Infect Dis J 2021; 40; e524-e525; Kaneta et al., Pediatr Infect Dis J 2023; 42; 590-593; Stanzelova et al., Pediatr Infect Dis J 2023; 42; e201-e203; Kolsi et al., Arch Pediatr 2023; 30; 521-523). Herein, we present a 6-year-old girl who was preliminarily diagnosed with MIS-C and received intravenous immunoglobulin (IVIG) treatment before referral to our center. She was diagnosed with acute pneumococcal meningitis due to serotype 19 F and ultimately suffered from sensorineural hearing loss (SNHL) as a sequela. We present this case to remind physicians that MIS-C should not be diagnosed unless other infectious causes are excluded.

What COVID-19 Vaccine Distribution Disparity Reveals About Solidarity

Current conceptions of solidarity impose a morality and sacrifice that did not prevail in the case of COVID-19 vaccine distribution. Notably, the vaccine distribution disparity revealed that when push came to shove, in the case of global distribution, self-interested persons reached inward rather than reaching out, prioritized their needs, and acted to realize their self-interest. Self-interest and loyalty to one's own group are natural moral tendencies. For solidarity to be normatively relevant in difficult and emergency circumstances, solidarity scholars ought to leverage the knowledge of the human natural tendency to prioritize one's own group. This paper recommends a nonexclusive approach to solidarity that reflects an understanding of rational self-interest but highlights commonalities among all people. A recommended task for future studies is to articulate what the account of solidarity informed by loyalty to the group would look like.

Adult Onset Acute Disseminated Encephalomyelitis (ADEM): A Comprehensive Case Repot

INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is a rare immune-mediated condition affecting the central nervous system, characterized by acute encephalopathy and multifocal neurological deficits. This disorder predominantly impacts children but here, we document a rare adult case, emphasizing the necessity for considering organic causes in psychiatric symptomatology. AIMS / OBJECTIVES: A detailed review of literature was conducted through PubMed focusing on the atypical presentations of ADEM and the incidence of organic diseases manifesting psychiatric complaints. This approach informed our diagnostic strategy and management of an unusual adult case of ADEM, underscoring the importance of maintaining a wide differential diagnosis in emergency medicine. CASE DESCRIPTION: A 22-year-old female presented with generalized weakness, confusion, apathy, and reduced appetite, following an upper respiratory tract infection and a distressing dental visit. Her neurological examination revealed dysarthria, dysmetria, and ataxia, with a significant reduction in motor strength and generalized hyperreflexia. Laboratory tests were largely unremarkable except for elevated ESR and CRP. MRI findings were consistent with a demyelinating process, See Figure 1A and 1B, fulfilling the criteria for ADEM diagnosis. RESULTS: Results: Initiation of a steroid regimen led to significant clinical improvement, and by day 11 of hospitalization, there was a marked improvement in the patient\'s condition, enabling discharge with outpatient neurology and ophthalmology follow-ups. A six-week steroid taper was prescribed. Follow-up MRI confirmed resolution of the demyelinating lesions, confirming the effectiveness of the treatment protocol. DISCUSSION: This case underscores the complexity of diagnosing ADEM in adults, particularly when presenting with psychiatric symptoms. It highlights the critical importance of comprehensive evaluation in emergency settings to identify rare organic causes of psychiatric presentations. This report reinforces the need for awareness among clinicians to consider ADEM in differential diagnoses, ensuring timely and appropriate management for affected patients.

Family System and Gender as Predictors of Religious Coping in Pakistani Patients with Hepatitis C.

Pakistan has the second-largest number of HCV infections in the world with homogeneity across provinces and no evidence of decline over the past 30years (Mahmud et al. in BMC Infect Dis 19(1):1-11, 2019). Currently, one in every 20 Pakistanis is suffering from HCV (Haqqi et al. in Viral Immunol 32(9):402-413, 2019). The disease significantly interferes with the everyday life of the patient (Silberbogen et al. in Psychosomatics 50(2):114-122, 2009;Foster in Viral Hepat 16(9):605-611, 2009).The present research aimed to find the role of gender, family system, and social support in predicting coping in patients with hepatitis C (HCV). A sample of 100 HCV patients was taken using purposive sampling from different public and private hospitals in Lahore, Pakistan. For assessment, the Multidimensional Scale of Perceived Social Support and Brief Cope Inventory were used. Results showed that male hepatitis C patients used a higher level of religious coping. Hepatitis C patients living in a joint family system used a higher level of religious coping. It also showed that there was no significant relationship between social support and coping. Patients suffering from hepatitis C for 2years or more adopted avoidant coping strategies as compared to the patients diagnosed for 1year or more. This research has important implications for psychologists, paramedical staff, doctors, social workers, caregivers, peers, and families of patients suffering from HCV. It would help in formulating effective therapeutic interventions. It would also add to the literature in the field of health psychology.

A case of fatal monkeypox infection: necropsy and molecular findings, with some considerations related to clinical management

A case of fatal monkeypox infection: necropsy and molecular findings, with some considerations related to clinical management

Evaluation of Platelet and Clotting Parameters in Hematologic Malignancies and Hematopoietic Stem Cell Transplantation Patients with Candidemia

Evaluation of Platelet and Clotting Parameters in Hematologic Malignancies and Hematopoietic Stem Cell Transplantation Patients with Candidemia

Fluoroquinolone-Resistant Enterobacteriaceae Prevalence for Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation (aHSCT) in the Treatment of Multiple Myeloma (MM)

Fluoroquinolone-Resistant Enterobacteriaceae Prevalence for Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation (aHSCT) in the Treatment of Multiple Myeloma (MM)

Invasive Fungal Infections after CAR T-Cell Therapy for B-Cell Lymphoma: A Study from the French Descart Registry

Invasive Fungal Infections after CAR T-Cell Therapy for B-Cell Lymphoma: A Study from the French Descart Registry