David L. Goldman

Bio: David L. Goldman is an academic researcher from Boston Children's Hospital. The author has contributed to research in topics: Cryptococcus neoformans & Cryptococcosis. The author has an hindex of 34, co-authored 87 publications receiving 5322 citations. Previous affiliations of David L. Goldman include Albert Einstein College of Medicine & Yeshiva University.

Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america.

Abstract: Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

Serologic evidence for Cryptococcus neoformans infection in early childhood.

Abstract: Objective. Cryptococcus neoformans is an important cause of central nervous system infection in adults with acquired immunodeficiency syndrome (AIDS) but an unusual cause of disease in children with AIDS. The basis for this age-related difference in incidence is not known but may be caused by differences in exposure or immune response. The objective of this study was to determine whether the low prevalence of cryptococcal disease among children is related to a lack of exposure to C neoformans . Methods. Sera were obtained from 185 immunocompetent individuals ranging in age from 1 week to 21 years who were being evaluated in an urban emergency department. Sera were analyzed for antibodies to C neoformans and Candida albicans proteins by immunoblotting. Immunoblot patterns were compared with those obtained from sera of patients with cryptococcosis ( n = 10) and workers in a laboratory devoted to the study of C neoformans . The specificity of our results was confirmed by several approaches, including antibody absorption and blocking studies. Sera were also analyzed for the presence of cryptococcal polysaccharide by both enzyme-linked immunosorbent assay and latex agglutination assays. Results. Sera from children 1.1 to 2 years old demonstrated minimal reactivity to C neoformans proteins. In contrast, the majority of sera from children >2 years old recognized many (≥6) C neoformans proteins. For children between 2.1 and 5 years old, 56% of sera ( n = 25) reacted with many proteins, whereas for children >5 years old ( n = 120), 70% of samples reacted with many proteins. Reactivity was decreased by absorbing sera with C neoformans extracts or by preincubating blots with sera from experimentally infected but not from control rats. Reactivity to C neoformans proteins did not correlate with reactivity to C albicans proteins, which was common in sera from children between the ages of 1.1 and 2 years. Cryptococcal polysaccharide was detected at a titer of 1:16 (∼10 ng/mL) in the sera of 1 child, a 5.6-year-old boy who presented to the emergency department with vomiting. Conclusions. Our findings provide both indirect and direct evidence of C neoformans infection in immunocompetent children. Our results indicate that C neoformans infects a majority of children living in the Bronx after 2 years old. These results are consistent with several observations: the ubiquitous nature of C neoformans in the environment, including its association with pigeon excreta; the large number of pigeons in urban areas; and the increased likelihood of environmental exposure for children once they have learned to walk. The signs and symptoms associated with C neoformans infection in immunocompetent children remained to be determined. Primary pulmonary cryptococcosis may be asymptomatic or produce symptoms confused with viral infections and, therefore, not recognized as a fungal infection. Our results suggest that the low incidence of symptomatic cryptococcal disease in children with AIDS is not a result of lack of exposure to C neoformans . These findings have important implications for C neoformans pathogenesis and the development of vaccine strategies.

Characterization of a Murine Monoclonal Antibody to Cryptococcus neoformans Polysaccharide That Is a Candidate for Human Therapeutic Studies

Abstract: The murine monoclonal antibody (MAb) 18B7 [immunoglobulin G1(κ)] is in preclinical development for treatment of Cryptococcus neoformans infections. In anticipation of its use in humans, we defined the serological and biological properties of MAb 18B7 in detail. Structural comparison to the related protective MAb 2H1 revealed conservation of the antigen binding site despite several amino acid differences. MAb 18B7 was shown by immunofluorescence and agglutination studies to bind to all four serotypes of C. neoformans, opsonize C. neoformans serotypes A and D, enhance human and mouse effector cell antifungal activity, and activate the complement pathway leading to deposition of complement component 3 (C3) on the cryptococcal capsule. Administration of MAb 18B7 to mice led to rapid clearance of serum cryptococcal antigen and deposition in the liver and spleen. Immunohistochemical studies revealed that MAb 18B7 bound to capsular glucuronoxylomannan in infected mouse tissues. No reactivity of MAb 18B7 with normal human, rat, or mouse tissues was detected. The results show that both the variable and constant regions of MAb 18B7 are biologically functional and support the use of this MAb in human therapeutic trials.

Pathogenesis of pulmonary Cryptococcus neoformans infection in the rat

Abstract: The pathogenesis of Cryptococcus neoformans pulmonary infection in the rat was studied after intratracheal inoculation. Lungs were examined at various times following infection for histopathology in conjunction with macrophage markers, proliferating cell nuclear antigen (PCNA), and capsular glucuronoxylomannan (GXM) antigen. Serum GXM, immunoglobulin M (IgM) and IgG titers and organ fungal burden were compared with pathological findings. C. neoformans organisms were in the lung parenchyma 2 h postinoculation, and GXM antigen was present in surrounding tissues shortly thereafter. Extrapulmonary dissemination occurred early in infection. Two phases of host cellular inflammatory response were discernible: early local macrophage recruitment at 2 to 4 days followed by granulomatous inflammation, which reached maximum intensity 14 days after infection. The granulomatous phase was preceded by lymphocyte influx with macrophage proliferation and maturation into epithelioid histiocytes; this was paralleled by a shift of yeasts from extracellular to intracellular spaces. Tissue IgG deposits, serum IgG to GXM, and localization of tissue GXM immunoreactivity to epithelioid cells were noted at 2 to 4 weeks. A 10-fold decrease in lung fungal burden occurred 25 days postinfection and was associated with resolving granulomas, fewer proliferating cells, and decreased tissue GXM. The present study demonstrates that (i) C. neoformans penetrates the lung parenchyma shortly after infection; (ii) immunocompetent rats control pulmonary cryptococcosis efficiently, with minimal extrapulmonary dissemination and low levels of serum GXM; and (iii) macrophage activation is likely to play a crucial role in limiting C. neoformans infection in the rat lung.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Nitric oxide and macrophage function

Abstract: ▪ Abstract At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxid...

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.