Ehrlichiosis-Associated Hemophagocytic Lymphohistiocytosis: A Case Series and Review of the Literature.

Background: Human monocytic ehrlichiosis (HME) is a potentially life-threatening tick-borne illness. HME-associated hemophagocytic lymphohistiocytosis (HLH) is a rare entity with a paucity of published literature regarding treatment and outcome. We present the clinical features, treatment, and outcomes of 4 patients at our institutions with HME-associated HLH. This review also summarizes the current literature regarding the presentation, treatment, and outcome of this infection-related HLH. Methods: We searched the PubMed database for case reports and case series. All cases were diagnosed according to the HLH-04 criteria. Results: Four cases of HME-associated HLH were included from our institutions. The literature review yielded 30 additional cases. About 41% of the cases were in the pediatric population; 59% were female; and all patients had fever, cytopenia, and elevated ferritin. Most patients were immunocompetent; all but one patient with available data were treated with doxycycline, and eight of the patients with available data received the HLH-94 treatment protocol. The mortality rate was 17.6%. Conclusions: HME-associated HLH is a rare but serious syndrome with significant mortality. Early treatment with doxycycline is critical, but the role of immunosuppressive therapy is individualized.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

Ehrlichiosis mimicking acute leukemia.

Human monocytic ehrlichiosis is a tickborne disease with a spectrum of presentations ranging from asymptomatic, mild to fatal. Ehrlichiosis can transiently cause white blood cells abnormalities that mimic leukemia/lymphoma and cases have been, on rare occasions, initially mistaken for hematological malignancies. We report a case of Ehrlichia chaffeensis infection suspected to be acute promyelocytic leukemia at presentation, prompting therapy with all-trans-retinoic acid. Physicians should keep tickborne transmitted illnesses on the differential in patients presenting with pancytopenia, especially in endemic areas.

Assessing Provider Utilization of COVID-19 Inflammatory Marker Trends in Hospitalized Patients and Implications in Optimizing Value-Based Care During a Pandemic.

Introduction: Numerous inflammatory markers may serve a role in prognostication of patients hospitalized with COVID-19 infection. Early in the pandemic, our health system created an admission order set which included daily d-dimer, c-reactive protein (CRP), lactate dehydrogenase (LDH), and ferritin. Given more available outcomes data, limiting standing order of labs that do not affect daily management could result in significant cost savings to the health system without adverse patient outcomes. The purpose of this study was to determine ordering and utilization patterns of inflammatory markers by physicians caring for patients hospitalized with COVID-19 infection. Methods: An anonymous 10-question survey was distributed to 125 physicians (Infectious Disease, Hospitalist, Pulmonary and Critical Care faculty). Responses were tallied and values greater than 50% were identified as the majority of the surveyed group. Results: Of the 125 physicians surveyed, 77 (62%) responded. A total of 57.1% (44/77) of physicians reported ordering daily inflammatory markers for 3 - 10 days from admission. Another 31.2% (24/77) ordered markers until clinical improvement or hospital discharge. D-dimer was used for care decisions by 83.1% (64/77) of respondents; 93.8% (60/64) of those reported utilizing it in determining anticoagulation dose. CRP was used by 61% (47/77) of physicians to help identify a secondary infection or determine steroid dose or duration. LDH and ferritin were not used for management decisions by the majority of physicians. Inflammatory markers were not used routinely after isolation precautions had been discontinued, even when ongoing care required mechanical ventilation. Conclusions: Of the markers studied, both d-dimer and CRP were considered useful by most respondents. LDH and ferritin were used less frequently and were not considered as useful in guiding medical decision making. Discontinuation of standing daily LDH and ferritin orders is believed to have potential to result in cost savings to the health care system with no adverse patient outcomes.

Culture Yield in the Diagnosis of Native Vertebral Osteomyelitis: A Single Tertiary Center Retrospective Case Series With Literature Review.

BACKGROUND: Vertebral osteomyelitis is a serious condition that requires prompt diagnosis to avoid delays in proper management. There is no well-defined gold standard for diagnosis. We describe the current diagnostic approach at our institution, with a focus on the yield of image-guided vertebral biopsy. METHODS: We performed a single-centre 10-year retrospective case series, including adults with imaging suggestive of vertebral osteomyelitis/discitis, with either positive blood cultures, and/or a vertebral biopsy. We defined positive histopathology as our gold standard for test characteristic evaluation of biopsy cultures. RESULTS: Out of 694 patients identified, 221 met our inclusion criteria, and 173/221 (78.2%) patients underwent a spinal biopsy. Of those patients with biopsies, 113 (65%) had received antibiotics within 2 weeks preceding their evaluation. Six of 43 (13.9%) bone specimens were positive by culture, while 66/152 (43.4%) of disc specimens were culture positive. Forty-seven of 84 (55.9%) histopathology (bone or disc) specimens were diagnostic for osteomyelitis/discitis. The sensitivity of bone and disk culture were 30.0% and 56.0%, respectively, with specificities of 92.8% and 75.0%, respectively. Twenty-three (13.4%) patients had repeat biopsies, including 10 bone specimens and 14 disc specimens, and 11 (47.8%) specimens had histopathology performed which diagnosed an additional 3/23 patients (13% additional diagnostic yield). CONCLUSIONS: Culture of percutaneous biopsy of disc resulted in the highest diagnostic yield. Histopathology added to the diagnostic yield in culture-negative specimens. Histopathologic evaluation of bone had better yield than bone culture. A repeat biopsy can add to the diagnostic yield.

Point-of-care program in HIV, tuberculosis, and associated conditions: A virtual global technical assistance platform to strengthen HIV and tuberculosis workforce capacity.

A global multi-disciplinary faculty was established to work collaboratively and provide virtual technical assistance, using a point-of-care continuing education model, to clinicians across the world engaged in the care of patients with either HIV infection or tuberculosis. Ancillary offerings included live or virtual lectures, case-based conferences, and courses. In spite of the considerable disruption of the program due to the COVID-19 pandemic, we engaged and assisted a substantial number of clinicians across the world and provided meaningful contributions to their continuous professional development and patient care. In light of the ongoing pandemic, virtual technical assistance models such as this should be scaled to continue essential high-quality HIV/TB services.

Clostridioides difficile Infection and Risk of Acute Graft-versus-Host Disease among Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Clostridioides difficile infection (CDI) is a major cause of infectious diarrhea among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. The relationship between CDI and acute graft-versus-host disease (aGVHD) has been a topic of interest, as these 2 conditions may influence each other. We studied the temporal relationship of CDI to aGVHD in the first 100 days post-transplantation in a large cohort of allo-HSCT recipients. We performed a retrospective cohort study of adult patients undergoing their first allo-HSCT at our tertiary care medical center between January 1, 2010, and December 31, 2016. Patients were followed for CDI diagnosis, development of aGVHD, and vital status up to day +100 post-transplantation. Descriptive statistics and multivariate Cox models with CDI as a time-varying covariate and aGVHD and high-grade aGVHD as outcomes were used for data analyses. A total of 656 allo-HSCT recipients were included in the analysis. Of these, 419 (64%) developed aGVHD, and 111 (17%) were diagnosed with CDI within the first 100 days post-transplantation. CDI developed before the onset of aGVHD in 72 of the 84 allo-HSCT recipients (85%) with both CDI and aGVHD. Fidaxomicin was used in the treatment of 57 of the 111 CDI cases (50%), whereas vancomycin was used in 52 (47%). Most of the CDI cases (88%) were diagnosed in the peritransplantation period (between day -10 and day +10). The median time to the development of CDI and aGVHD was 3.5 days (range, -7 to 95 days) and 33 days (range, 9 to 98 days) post-transplantation, respectively. Using multivariate Cox model, the following predictors were significantly associated with the development of aGVHD: CDI (adjusted hazard ratio [aHR], 1.52; 95% confidence interval [CI], 1.17 to 1.97; P = .0018), transplantation from a matched related donor (MRD) compared with a matched unrelated donor (aHR, 0.68; 95% CI, 0.54 to 0.85; P = .0003), and myeloablative versus nonmyeloablative conditioning (aHR, 2.45; 95% CI, 1.80 to 3.34; P < .0001), adjusting for age, sex, race, underlying disease, cytomegalovirus CMV serostatus, transplant source, and receipt of antithymocyte globulin (ATG). There was no association between CDI and high-grade aGVHD after adjustment for age, underlying disease, transplant type, intensity of conditioning, and receipt of ATG (aHR, 1.59; 95% CI, 0.95 to 2.66; P = .0755). CDI after allo-HSCT is associated with increased risk of GVHD when no CDI prophylaxis was used. Further studies examining CDI preventive measures, including prophylaxis, as well as the preservation or reconstitution of the gastrointestinal microbiome in the setting of HSCT are warranted.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

BACKGROUND: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. METHODS: The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. DISCUSSION: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

Background: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods: The Pass ive I mmunity T rial for O ur N ation (PassITON), is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the United States to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial Registration: ClinicalTrials.gov: NCT04362176. Date of trial registration: April 24, 2020, https://clinicaltrials.gov/ct2/show/NCT04362176.

Fatal disseminated Mycobacterium haemophilum infection involving the central nervous system in a renal transplant recipient.

Mycobacterium haemophilum is a slow growing nontuberculous mycobacterium which prefers cooler temperatures and requires iron for growth. It usually causes skin and soft tissue infections in immunocompromised hosts and cervical lymphadenitis in healthy children. We present the case of fatal disseminated M. haemophilum in an immunocompromised host with central nervous system (CNS) involvement. Our case is a 65-year-old Hispanic male with history of end-stage renal disease status post renal transplantation six years prior (on maintenance immunosuppression with mycophenolate, tacrolimus and prednisone), diabetes mellitus type 2, coronary artery disease, ventricular arrhythmias with implantable cardioverter defibrillator, prior stroke and cochlear implant. In the four months preceding admission to our institution he had frequent hospitalizations for altered mental status (AMS), sepsis syndromes and failure to thrive. Two months prior to presentation he developed progressive swelling and redness of the wrists, right third and left fifth digits. Computed tomography (CT) showed extensive cellulitis in distal right forearm and hand with chronic osteomyelitis. Serial incision and drainage (I&D) of right wrist yielded positive AFB stain and growth on AFB culture. PCR was negative for Mycobacterium tuberculosis. Patient was started on rifampin, clarithromycin and ethambutol. Two days later patient developed AMS and severe septic shock requiring transfer to our facility. CT head revealed indeterminate lesion in the left frontal lobe along with nonspecific hypodensities in the pons and thalamus. Repeat CT upper extremities showed osteomyelitis of distal radius and small hand bones with adjacent abscesses. I&D also revealed bilateral tenosynovitis. Cultures were resent. With suspicion for rapidly growing mycobacterial infection, the regimen was changed to linezolid, imipenem and azithromycin. Several changes in antimicrobials were necessary throughout hospitalization due to complicated hospital course. Unfortunately, despite aggressive measures, patient developed multiorgan failure culminating in death 10 days after starting anti-mycobacterial drugs. On the day of death, the organism was identified as M. haemophilum. Susceptibilities were not done as patient had died. On autopsy the brain was noted to have multiple abscesses containing AFB. The organism also grew from the wrists and right finger cultures. M. haemophilum of the CNS is extremely rare and has been reported in HIV or AIDS patients. To our knowledge this is the first reported case of M. haemophilum brain abscesses in a patient without HIV/AIDS. Because of its fastidious growth requirements, M. haemophilum usually shows on acid fast stains but does not grow on routine AFB cultures. Although it prefers lower temperatures for growth and is usually limited to skin and soft tissues, disseminated disease occurs in immunocompromised patients and has high mortality. It is usually treated with a multi drug regimen including clarithromycin, rifampin, ciprofloxacin and amikacin.

Seronegative ocular toxoplasma panuveitis in an immunocompetent patient.

PURPOSE: Toxoplasma gondii is the most common cause of infectious posterior uveitis worldwide in immunocompetent patients. Despite its prevalence, diagnosis can still be challenging and vision-threatening in cases with atypical presentations. This case exemplifies the importance of clinical exam and additional workup when required despite negative initial serology results. OBSERVATIONS: A 73-year-old immunocompetent woman presented with a 2-year history of recurrent panuveitis and retinal necrosis not responsive to systemic antiviral therapy. Toxoplasma serum antibodies (IgG and IgM) were not detected on systemic workup one year prior. The slit-lamp exam revealed mutton fat keratic precipitates, panuveitis, and necrotic retinal lesions adjacent to a retinal scar. Repeated Toxoplasma serum antibodies (IgG and IgM) were again negative. However, aqueous fluid testing by polymerase chain reaction (PCR) was highly positive for Toxoplasma gondii. The patient improved after starting systemic anti-toxoplasma therapy. CONCLUSION/IMPORTANCE: To our knowledge, this is the first report in the literature of an immunocompetent patient with ocular toxoplasmosis and undetectable serum IgG and IgM. Aqueous fluid PCR testing is useful in suspected ocular toxoplasmosis in patients with vision-threatening lesions despite negative serology.

De Novo Acute Myeloid Leukemia with Combined CBFB-MYH11 and BCR-ABL1 Gene Rearrangements: A Case Report and Review of Literature.

Acute myeloid leukemia (AML) with inv(16)(p13.1q22) resulting in CBFB-MYH11 fusion is associated with a favorable prognosis. The presence of a KIT mutation modifies it to an intermediate prognosis. Additionally, inv(16) can cooperate with other genetic aberrations to further increase cell proliferation. Coexistence of inv(16) and t(9;22) is extremely rare (20 cases). We present a case of a 55-year-old male with elevated white blood cell count. Bone marrow evaluation and flow cytometry analysis were compatible with AML with monocytic features. Cytogenetic studies revealed two-related clones, a minor clone with inv(16) and a major clone with concurrent inv(16) and t(9;22) rearrangements. Fluorescent in situ hybridization studies confirmed these rearrangements. Molecular analysis detected a p190 BCR-ABL1 transcript protein. KIT mutations were negative. The patient was initially treated with standard induction regimen; 7 daily doses of cytarabine from day 1-day 7, 3 daily doses of daunorubicin from day 1-day 3, and 1 dose of Mylotarg (gemtuzumab ozogamicin) on day 1. The detection of t(9;22) led to the addition of daily doses of dasatinib (tyrosine kinase inhibitor) from day 7 onwards. The patient achieved complete remission on day 45. During his treatment course, he acquired disseminated Fusarium infection. Day 180 bone marrow evaluation revealed florid relapse with 64% blasts. Cytogenetic study showed clonal evolution of the inv(16) clone with no evidence of the t(9;22) subclone. Eventually, bone marrow transplantation was contraindicated, and the patient was transferred to palliative care. Literature review revealed that AML with co-occurrence of CBFB-MYH11 and BCR-ABL1 gene rearrangements was involved by only a small number of cases with de novo and therapy-related AML. Most cases were in myeloid blast crisis of chronic myeloid leukemia (CML). Treatment and prognosis among the de novo AML cases varied and majority of them achieved clinical remission. In contrast, these cytogenetic abnormalities in the blast phase of CML had a poor prognosis. As the prognosis and management of AML is dependent upon the underlying genetic characteristics of the neoplasm, it is imperative to include clinical outcome with such rare combinations of genetic alterations.

Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Review of the Literature.

BACKGROUND: Histoplasmosis is an endemic fungal disease with diverse clinical presentations. Histoplasmosis-associated hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with limited data regarding treatment and outcome. We described the clinical features, treatment, and outcomes of five patients in our institution with histoplasmosis-associated HLH. This review also summarizes the current literature about presentation, treatment, and outcome of this infection-related HLH entity. METHODS: We searched the electronic medical records for patients with histoplasmosis-associated HLH at our institution from 1/1/2006 to 9/30/2017. Diagnosis of HLH was confirmed by chart review using the HLH-04 criteria. We also searched the current literature for case reports and case series. RESULTS: Five cases of histoplasmosis-associated HLH were included from our institution. All five patients were diagnosed after 2010. The literature review yielded 60 additional cases of histoplasmosis-associated HLH. The most common underlying condition was HIV in 61% of cases. The majority of histoplasmosis patients (81%) were treated with amphotericin B formulations. Documented specific treatments for HLH were as follows: nine patients received steroids only, six patients received intravenous immunoglobulin (IVIG) only, three patients received dexamethasone and etoposide, two patients received etoposide, dexamethasone, and cyclosporine, two patients received steroids and IVIG, and one patient received Anakinra and IVIG. The inpatient case fatality rate was 31% with most of the deaths occurring within two weeks of hospital admission. CONCLUSIONS: Histoplasmosis-associated HLH among adults is an uncommon but serious complication with high associated mortality. Early antifungal therapy with a lipid formulation amphotericin B is critical. The initiation of immunosuppressive therapy with regimens like HLH-04 in this disease entity should be individualized.

Peers Keep It Real: Re-engaging Adults in HIV Care.

BACKGROUND: After diagnosis, a substantial number of people with HIV disease fall out of care. Effective interventions are needed for this priority population. METHODS: The "Peers Keep It Real" study aimed to help adults who were disengaged from HIV treatment. Peers, lay individuals living with HIV, facilitated intervention sessions. Participants were randomized to immediately receive the peer-facilitated intervention or were wait-listed. RESULTS: Considerable attrition occurred in the control group. Pre-/postanalyses showed that among participants (n = 23) who received the intervention, 65% had viral load suppression and 100% remained in care at 12 months postintervention. Impact on viral load was significant ( P = .0326), suggesting that peers are effective change agents who positively impacted outcomes for individuals struggling with adherence to HIV treatment. CONCLUSION: Future endeavors should consider providing all individuals from this priority population with an active peer intervention from the onset to enhance retention and adherence.

Isolated Sporothrix schenckii Monoarthritis.

Sporothrix schenkii sensu lato is a rare cause of arthritis. Its course is indolent with lack of constitutional symptoms resulting in delayed presentation and diagnosis. It is a dimorphic fungus found ubiquitously in sphagnum moss, decaying vegetation, soil, and hay. Inoculation of dirt into the skin and soft tissues and, in rare instances, inhalation of aerosolized conidia from soil and plants can lead to infection. Subacute and chronic involvement of skin and subcutaneous tissues is the most common manifestation of sporotrichosis in immunocompetent hosts. In patients with underlying risk factors (HIV, alcoholism, diabetes mellitus, organ transplant patients, immunosuppressive medications, steroids, and malignancies), it can often have disseminated visceral, osteoarticular, meningeal, and pulmonary involvement. Sporothrical arthritis most commonly infects knee joint followed by hand and wrist joints. A culture of Sporothrix schenkii sensu lato is the gold standard for the diagnosis of sporotrichosis. Itraconazole is the drug of choice for osteoarticular sporotrichosis. We present a case of sporotrichal arthritis in a patient without skin or lymph node involvement who underwent treatment with itraconazole resulting in resolution of his symptoms.