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Ehrlichiosis and anaplasmosis are rising tickborne infections posing significant risks to solid-organ transplant (SOT) patients. We present three cases highlighting clinical presentations, diagnostic challenges, and the benefits of microbial cell-free DNA (mcfDNA) sequencing. Emphasizing early diagnosis and preventive measures, we advocate for advanced diagnostic modalities to improve outcomes in this vulnerable population.
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BACKGROUND: Cytomegalovirus retinitis (CMVR) is a well-described complication of CMV disease in immunocompromised hosts. While robust data exists for CMVR in patients with acquired immunodeficiency syndrome (AIDS), the incidence and risk factors for CMVR in solid organ transplant recipients (SOTR) with CMV viremia are less defined. METHODS: We performed a retrospective cohort study of SOTR who had CMV viremia and underwent routine ophthalmologic examination between 1/1/2018 and 3/16/2022. Univariate statistics were performed to evaluate risk factors for development of CMVR. RESULTS: Overall, 38 patients were included, primarily kidney (78.9%), heart (7.9%), and liver (7.9%) transplant recipients. Five patients (13.2%) developed CMVR during the study period. CMVR was diagnosed an average 281 days after index transplantation, 84 days from the most recent rejection episode, and 69 days from onset of viremia. Only 1 patient (20%) had symptoms at the time of CMVR diagnosis. CMVR was associated with preceding allograft rejection as well as transplanted organ type. CONCLUSION: While CMV tissue disease more commonly manifests in other organs, CMVR occurred relatively frequently in this group of high-risk SOTR with CMV viremia. As most of the patients in our study did not have ocular symptoms at the time of diagnosis, routine ophthalmologic screening should be considered in SOTR with CMV viremia.
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A 48-year-old man with history of recent travel to central Mexico and immunosuppression sought treatment with a 1-month-long history of progressive headache, fatigue, word-finding difficulties, and night sweats. The patient had a history of end-stage renal disease; he had undergone a kidney transplantation 7 years prior with good graft function with immunosuppression with tacrolimus, everolimus, and low-dose prednisone. At an outside hospital, he recently had been treated with empiric antibiotics for meningitis, but these were discontinued given the low suspicion for a bacterial cause. After discharge, he continued to have headaches, limited oral intake, persistent nausea, urinary frequency, and falls, prompting him to seek treatment at the ED. Physical examination findings were benign aside from disorientation. Laboratory workup was significant for hyponatremia of 122 mM, creatinine of 1.4 mg/dL (baseline, 1.4-1.5 mg/dL), WBC count of 7.2 109/L, hemoglobin of 13 g/dL, and platelet count of 349 109/L. Neither tacrolimus nor everolimus levels were supratherapeutic.
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PURPOSE OF REVIEW: Sepsis remains a leading global cause of morbidity and mortality, and despite decades of research, no effective therapies have emerged. The lack of progress in sepsis outcomes is related in part to the significant heterogeneity of sepsis populations. This review seeks to highlight recent literature regarding sepsis phenotypes and the potential for further research and therapeutic intervention. RECENT FINDINGS: Numerous recent studies have elucidated various phenotypes, subphenotypes, and endotypes in sepsis. Clinical parameters including vital sign trajectories and microbial factors, biomarker investigation, and genomic, transcriptomic, proteomic, and metabolomic studies have illustrated numerous differences in sepsis populations with implications for prediction, diagnosis, treatment, and prognosis of sepsis. SUMMARY: Sepsis therapies including care bundles, fluid resuscitation, and source control procedures may be better guided by validated phenotypes than universal application. Novel biomarkers may improve upon the sensitivity and specificity of existing markers and identify complications and sequelae of sepsis. Multiomics have demonstrated significant differences in sepsis populations, most notably expanding our understanding of immunosuppressed sepsis phenotypes. Despite progress, these findings may be limited by modest reproducibility and logistical barriers to clinical implementation. Further studies may translate recent findings into bedside care.
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Background: Severe gram-positive infections are frequent in people who inject drugs, and successful completion of treatment presents unique challenges in this population. Objectives: We aimed to evaluate the feasibility of a long-acting antibiotic, dalbavancin, as an alternative to standard-of-care antibiotics for severe infections due to vancomycin-susceptible pathogens requiring ⩾2 weeks of therapy. Design: We designed an investigator-initiated single-arm unblinded prospective cohort study to evaluate the safety and efficacy of an early switch to dalbavancin in two doses administered 1 week apart. Methods: We screened patients admitted with bloodstream infection, osteomyelitis, septic arthritis, infective endocarditis or deep abscesses, and comorbid substance use disorder (SUD) for eligibility. Consenting patients were switched to dalbavancin within 7 days from their index culture. They were monitored in the hospital for efficacy and safety of the treatment until the second dose of dalbavancin 7 days later and then discharged if stable. Study participants were evaluated with a decision support engine for a hypothetical appropriate level of care regarding their SUD after discharge. Their follow-up was planned for 12 months from the index culture, either in-person or via telehealth/telephone. Results: The enrollment was terminated early due to significant loss-to-follow-up. In all, 11 patients were enrolled, 4 completed 12 months of follow-up, 2 completed 8 months of follow-up, and 1 was seen once after discharge. The remaining five patients were lost to follow-up immediately after discharge. All 11 patients continued to improve after switching to dalbavancin between the first and second doses. There were two per-protocol failures of treatment. Dalbavancin was well tolerated, though some adverse events were reported. Conclusion: Dalbavancin may be a safe and effective alternative for an early switch in treating severe gram-positive infections. Trial registration: The trial was registered as NCT04847921 with clinicaltrials.gov.
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Introduction: The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) announced conditions for using recombinant human interleukin-1 receptor antagonist (rhIL-1ra) to treat hospitalized patients with Coronavirus disease 2019 (COVID-19) and risk for progression. These decisions followed publication of the suPAR-guided Anakinra treatment for Validation of the risk and early Management OF seveRE respiratory failure by COVID-19 (SAVE- MORE) phase 3 clinical trial that yielded positive results. Methods: We conducted a literature review and theoretical analysis of IL-1 blockade as a therapy to treat COVID-19. Using a stepwise analysis, we assessed clinical applicability of the SAVE-MORE results and evaluated conceptual support for interleukin-1 suppression as a suitable approach to COVID-19 treatment. This therapeutic approach was then examined as an example of inflammation-suppressing measures used to treat sepsis. Results: Anakinra use as a COVID-19 therapy seems to rely on a view of pathogenesis that incorrectly reflects human disease. Since COVID-19 is an example of sepsis, COVID-19 benefit due to anti-inflammatory therapy contradicts an extensive history of unsuccessful clinical study. Repurposing rhIL-1ra to treat COVID-19 appears to exemplify a cycle followed by inflammation-suppressing sepsis treatments. A landscape of treatment failures is interrupted by a successful clinical trial. However, subsequent confirmatory study fails to replicate the positive data. Discussion: We suggest further experimentation is not a promising pathway to discover game-changing sepsis therapies. A different kind of approach may be necessary.
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Background: HIV-negative patients have substantial mortality from Pneumocystis jirovecii pneumonia (PJP). We lack predictors of HIV-negative PJP-associated mortality. Objective: We aim to characterize the role of prior corticosteroid exposure in PJP-related mortality. Methods: We queried a global research network to identify adult HIV-negative patients with PJP with or without corticosteroid exposure in the preceding year before diagnosis (n = 8,021). We performed a propensity score-matched analysis to adjust baseline patient characteristics and analyzed outcomes. We follow-up the results with a multicenter ten years retrospective case-control cohort of HIV-negative patients tested for PJP by PCP Direct Fluorescent Antigen. We used a Cox proportional hazards model for survival analysis. Results: 1822 HIV-negative propensity-scored matched patients with prior corticosteroid exposure had significantly increased 10 weeks (16% versus 9%, p < 0.0001) and one-year mortality after PJP diagnosis (23% versus 14%, p < 0.0001). (1â3)-ß-D-glucan (197.6 ± 155.8 versus 63 ± 0 pg/ml, p = 0.014), ferritin levels (1227 ± 2486 versus 768 ± 1060 mcg/l, p = 0.047), lymphopenia (1.5 ± 1.5 versus 2.0 ± 1.6 103 cells/µl, p < 0.0001) and hypoxia (SatO2: 86.7% versus 91.6%, p < 0.0001) were higher or worse in those with prior steroid use. Patients who died were more likely to have previously received dexamethasone (35% versus 16%, p < 0.001) or prednisone (49% versus 29%, p < 0.001). Adjusted Cox proportional-hazard model validation showed an independently increased mortality at 10 weeks (HR: 3.7, CI: 1.5-9.2, p = 0.004) and 1 year (HR: 4.5, CI: 2.0-10.4, p < 0.0001) among HIV-negative patients with previous corticosteroid exposure. Conclusion: Preceding corticosteroids in HIV-negative patients with PJP are associated with higher mortality. A higher fungal burden may influence corticosteroid-mediated mortality. Assessment of PJP prophylaxis must become a standard clinical best practice when instituting corticosteroid therapy courses.
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Tuberculosis is of particular concern in lung transplant recipients. We present the case of a patient who received a double lung transplant from a deceased donor from Mexico and developed disseminated tuberculosis 60 days post-transplant manifested as tenosynovitis, liver abscesses, and subcutaneous nodules with no definitive lung allograft involvement. The recipient did not have evidence of tuberculosis on explanted lungs, had a negative interferon gamma release assay pre-transplant, and did not have risk factors for this infection. Mycobacterium tuberculosis should remain in the differential diagnosis of early post-transplant infections with atypical presentations, evidence of dissemination, or lack of improvement with appropriate antimicrobial coverage, even in the absence of typical lung findings.
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BACKGROUND: Sepsis is a global health challenge associated with significant morbidity and mortality. Detrimental sepsis effects are attributed to excessive inflammation or a "cytokine storm." However, anti-inflammation therapies have failed to lower sepsis mortality. We aim to characterize levels of key inflammatory cytokines in patients with sepsis and compare levels with those in healthy individuals and relate tumor necrosis factor (TNF) α levels to patient characteristics and outcomes. METHODS: We performed a systematic review and meta-analysis. Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched between 1985 and May 2020. Analysis was restricted to studies in English. We included randomized controlled trials (RCTs), controlled trials, cohort studies, case series, and cross-sectional studies that reported mean levels of cytokines in the circulation thought to be relevant for sepsis pathogenesis. We also evaluated concentrations of these cytokines in healthy individuals. The Quality in Prognosis Studies tool was used to assess the methodological quality of included studies. We extracted summary data from published reports. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) with 95% confidence intervals for cytokine levels and mortality. This systematic review is registered in PROSPERO (CRD42020179800). FINDINGS: We identified 3654 records, and 104 studies were included with a total of 3250 participants. The pooled estimated mean TNFα concentration in sepsis patients was 58.4 pg/ml (95% Confidence Interval or CI 39.8-85.8 pg/ml), and in healthy individuals was 5.5 pg/ml (95% CI 3.8-8.0 pg/ml). Pooled estimate means for IL-1ß and IFN-γ in sepsis patients were 21.8 pg/ml and 63.3 pg/ml, respectively. Elevated TNFα concentrations associated with increased 28-day sepsis mortality (p = 0.001). In subgroup analyses, we did not detect an association between TNFα levels and sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score. A TNF-α cutoff level ≥14.7 pg/ml separated sepsis patients from healthy individuals with a sensitivity of 82.6%, a specificity of 91.7%, and a likelihood ratio of 9.9. INTERPRETATION: Sepsis mean TNFα concentration is increased approximately 10-fold compared to mean concentration in healthy individuals, and TNFα associated with sepsis mortality but not sepsis severity. The concept that elevated cytokines cause sepsis should be revisited in the context of these data. FUNDING: None.
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Citocinas , Sepsis , Factor de Necrosis Tumoral alfa , Citocinas/sangre , Voluntarios Sanos , Humanos , Inflamación , Pronóstico , Sepsis/complicaciones , Sepsis/diagnóstico , Sepsis/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Sepsis is infection sufficient to cause illness in the infected host, and more severe forms of sepsis can result in organ malfunction or death. Severe forms of Coronavirus disease-2019 (COVID-19), or disease following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are examples of sepsis. Following infection, sepsis is thought to result from excessive inflammation generated in the infected host, also referred to as a cytokine storm. Sepsis can result in organ malfunction or death. Since COVID-19 is an example of sepsis, the hyperinflammation concept has influenced scientific investigation and treatment approaches to COVID-19. However, decades of laboratory study and more than 100 clinical trials designed to quell inflammation have failed to reduce sepsis mortality. We examine theoretical support underlying widespread belief that hyperinflammation or cytokine storm causes sepsis. Our analysis shows substantial weakness of the hyperinflammation approach to sepsis that includes conceptual confusion and failure to establish a cause-and-effect relationship between hyperinflammation and sepsis. We conclude that anti-inflammation approaches to sepsis therapy have little chance of future success. Therefore, anti-inflammation approaches to treat COVID-19 are likewise at high risk for failure. We find persistence of the cytokine storm concept in sepsis perplexing. Although treatment approaches based on the hyperinflammation concept of pathogenesis have failed, the concept has shown remarkable resilience and appears to be unfalsifiable. An approach to understanding this resilience is to consider the hyperinflammation or cytokine storm concept an example of a scientific paradigm. Thomas Kuhn developed the idea that paradigms generate rules of investigation that both shape and restrict scientific progress. Intrinsic features of scientific paradigms include resistance to falsification in the face of contradictory data and inability of experimentation to generate alternatives to a failing paradigm. We call for rejection of the concept that hyperinflammation or cytokine storm causes sepsis. Using the hyperinflammation or cytokine storm paradigm to guide COVID-19 treatments is likewise unlikely to provide progress. Resources should be redirected to more promising avenues of investigation and treatment.
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INTRODUCTION: It is widely assumed that sepsis is a life-threatening systemic inflammation caused by a dysregulated host response to infection mediated by an increase in multiple proinflammatory cytokines. The levels of key proinflammatory cytokines tumour necrosis factor, interleukin-1ß and interferon γ are poorly characterised during sepsis. We believe this project will produce a 'gold-standard' document to which other reports on cytokine levels will be compared. The objective of this systematic review will be to identify key cytokine circulating levels in patients with sepsis and assess the association between these levels and morbidity and mortality outcomes related to sepsis. METHODS AND ANALYSIS: We would include reports of any design except for case reports. Sepsis patients will comprise those with a diagnosis of sepsis, severe sepsis or septic shock. The primary exposure is levels of three proinflammatory cytokines. The primary outcome is mortality at 28 or 30 days. Study subjects can be of any age, sex or ethnicity. Studies will be restricted to the English language. Medline, Embase, Cochrane Library and Web of Science Core Collection will be searched for eligible studies. A database search will include studies from 1985 to May 2020. Two reviewers will independently screen and select studies, assess methodological quality and extract data. A meta-analysis will be performed, if possible, and the Grading of Recommendations Assessment Development and Evaluation Summary of Findings presented. ETHICS AND DISSEMINATION: Formal ethical approval is not required as data will be extracted from existing literature. This systematic review will be disseminated through a peer-reviewed publication and at conference meetings. PROSPERO REGISTRATION NUMBER: CRD42020179800.
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Sepsis , Choque Séptico , Citocinas , Humanos , Metaanálisis como Asunto , Proyectos de Investigación , Revisiones Sistemáticas como Asunto , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: There is an urgent need for accurate, rapid, inexpensive biomarkers that can differentiate coronavirus disease 2019 (COVID-19) from bacterial pneumonia. We assess the role of the ferritin-to-procalcitonin (F/P) ratio to classify pneumonia cases into those due to COVID-19 vs those due to bacterial pathogens. METHODS: This multicenter case-control study compared patients with COVID-19 with those with bacterial pneumonia, admitted between March 1 and May 31, 2020. Patients with COVID-19 and bacterial pneumonia co-infection were excluded. The F/P in patients with COVID-19 vs with bacterial pneumonia were compared. Receiver operating characteristic curve analysis determined the sensitivity and specificity of various cutoff F/P values for COVID-19 vs bacterial pneumonia. RESULTS: A total of 242 COVID-19 pneumonia cases and 34 bacterial pneumonia controls were included. Patients with COVID-19 pneumonia had a lower mean age (57.1 vs 64.4 years; Pâ =â .02) and a higher body mass index (30.74 vs 27.15 kg/m2; Pâ =â .02) compared with patients with bacterial pneumonia. Cases and controls had a similar proportion of women (47% vs 53%; Pâ =â .5), and COVID-19 patients had a higher prevalence of diabetes mellitus (32.6% vs 12%; Pâ =â .01). The median F/P was significantly higher in patients with COVID-19 (4037.5) compared with the F/P in bacterial pneumonia (802; Pâ <â .001). An F/P ≥877, used to diagnose COVID-19, resulted in a sensitivity of 85% and a specificity of 56%, with a positive predictive value of 93.2% and a likelihood ratio of 1.92. In multivariable analyses, an F/P ≥877 was associated with greater odds of identifying a COVID-19 case (odds ratio, 11.27; 95% CI, 4-31.2; Pâ <â .001). CONCLUSIONS: An F/P ≥877 increases the likelihood of COVID-19 pneumonia compared with bacterial pneumonia.
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BACKGROUND: The survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined. METHODS: This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America. RESULTS: Sixty-four patients with proven (nâ =â 47) or probable (nâ =â 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmBâ +â posaconazole (25%), AmBâ +â echinocandin (13%), AmBâ +â isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (nâ =â 28) was associated with a trend toward lower treatment failure compared with AmB (nâ =â 21) (42% vs 64%, Pâ =â .136). CONCLUSIONS: Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmBâ +â azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.
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IMPORTANCE: There is a need to develop tools to differentiate COVID-19 from bacterial pneumonia at the time of clinical presentation before diagnostic testing is available. OBJECTIVE: To determine if the Ferritin-to-Procalcitonin ratio (F/P) can be used to differentiate COVID-19 from bacterial pneumonia. DESIGN: This case-control study compared patients with either COVID-19 or bacterial pneumonia, admitted between March 1 and May 31, 2020. Patients with COVID-19 and bacterial pneumonia co-infection were excluded. SETTING: A multicenter study conducted at three hospitals that included UCHealth and Phoebe Putney Memorial Hospital in the United States, and Yichang Central People's Hospital in China. PARTICIPANTS: A total of 242 cases with COVID-19 infection and 34 controls with bacterial pneumonia. MAIN OUTCOMES AND MEASURES: The F/P in patients with COVID-19 or with bacterial pneumonia were compared. Receiver operating characteristic analysis determined the sensitivity and specificity of various cut-off F/P values for the diagnosis of COVID-19 versus bacterial pneumonia. RESULTS: Patients with COVID-19 pneumonia had a lower mean age (57.11 vs 64.4 years, p=0.02) and a higher BMI (30.74 vs 27.15 kg/m 2 , p=0.02) compared to patients with bacterial pneumonia. Cases and controls had a similar proportion of women (47% vs 53%, p=0.5) and COVID-19 patients had a higher prevalence of diabetes mellitus (32.6% vs 12%, p=0.01). The median F/P was significantly higher in patients with COVID-19 (4037.5) compared to the F/P in bacterial pneumonia (802, p<0.001). An F/P ≥ 877 used to diagnose COVID-19 resulted in a sensitivity of 85% and a specificity of 56%, with a positive predictive value of 93.2%, and a likelihood ratio of 1.92. In multivariable analyses, an F/P ≥ 877 was associated with greater odds of identifying a COVID-19 case (OR: 11.27, CI: 4-31.2, p<0.001). CONCLUSIONS AND RELEVANCE: An F/P ≥ 877 increases the likelihood of COVID-19 pneumonia compared to bacterial pneumonia. Further research is needed to determine if obtaining ferritin and procalcitonin simultaneously at the time of clinical presentation has improved diagnostic value. Additional questions include whether an increased F/P and/or serial F/P associates with COVID-19 disease severity or outcomes.
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Enfermedades Transmisibles Emergentes , Infecciones por Coronavirus , Medicina Basada en la Evidencia/historia , Errores Médicos/historia , Pandemias/historia , Seguridad del Paciente , Neumonía Viral , Betacoronavirus/aislamiento & purificación , COVID-19 , Enfermedades Transmisibles Emergentes/tratamiento farmacológico , Enfermedades Transmisibles Emergentes/historia , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Historia del Siglo XVII , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Errores Médicos/prevención & control , Mortalidad , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , SARS-CoV-2RESUMEN
Cytomegalovirus (CMV) is a DNA virus of the Herpesviridae family and is estimated to affect 15%-30% of high-risk solid organ transplant recipients. Typical manifestations of CMV end-organ disease in this population include colitis, esophagitis, and pneumonitis, and myocarditis is a rarely reported manifestation. We describe two cases of CMV myocarditis in solid organ transplant recipients and review the literature regarding previously published cases of CMV myocarditis.
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Infecciones por Citomegalovirus/diagnóstico , Miocarditis/virología , Trasplante de Órganos/efectos adversos , Receptores de Trasplantes , Anciano , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocarditis/diagnósticoRESUMEN
The risk of toxoplasmosis in high-risk cardiac transplant recipients is well recognized prompting universal donor and candidate screening with administration of targeted post-transplant chemoprophylaxis in high-risk (D+/R-) cardiac transplant patients. In contrast, until recently, there have been neither well-defined recommendations nor consensus regarding toxoplasmosis preventive strategies among non-cardiac solid organ transplant recipients. We report 3 cases of post-transplant toxoplasmosis in non-cardiac transplant recipients (one lung and two liver); all 3 infections presumed to be donor-derived. Not surprisingly, pre-transplant Toxoplasma serology was negative in all the patients. None of the patients were on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at the time of diagnosis of toxoplasmosis. The median time from transplant to onset of infection was 90 days (range: 30-120 days). Clinical presentations included cerebral (n = 1) and disseminated infections (n = 2). Two of the 3 patients, both with disseminated infection died (mortality ~ 67%).