Economic Impact of Progression from Mild Cognitive Impairment to Alzheimer Disease in the United States.

BACKGROUND: Limited evidence exists on the economic burden of individuals who progress from mild cognitive impairment (MCI) to Alzheimer disease and related dementia disorders (ADRD). OBJECTIVES: To assess the all-cause health care resource utilization and costs for individuals who develop ADRD following an MCI diagnosis compared to those with stable MCI. DESIGN: This was a retrospective cohort study from January 01, 2014, to December 31, 2019. SETTING: The Merative MarketScan Commercial and Medicare Databases were used. PARTICIPANTS: Individuals were included if they: (1) were aged 50 years or older; (2) had ≥1 claim with an MCI diagnosis based on the International Classification of Diseases, Ninth Revision (ICD-9) code of 331.83 or the Tenth Revision (ICD-10) code of G31.84; and had continuous enrollment. Individuals were excluded if they had a diagnosis of Parkinson's disease or ADRD or prescription of ADRD medication. MEASUREMENTS: Outcomes included all-cause utilization and costs per patient per year in the first 12 months following MCI diagnosis, in total and by care setting: inpatient admissions, emergency department (ED) visits, outpatient visits, and pharmacy claims. RESULTS: Out of the total of 5185 included individuals, 1962 (37.8%) progressed to ADRD (MCI-to-ADRD subgroup) and 3223 (62.2%) did not (Stable MCI subgroup). Adjusted all-cause utilization was higher for all care settings in the MCI-to-ADRD subgroup compared with the Stable MCI subgroup. Adjusted all-cause mean total costs ($34 599 vs $24 541; mean ratio [MR], 1.41 [95% CI, 1.31-1.51]; P<.001), inpatient costs ($47 463 vs $38 004; MR, 1.25 [95% CI, 1.08-1.44]; P=.002), ED costs ($4875 vs $3863; MR, 1.26 [95% CI, 1.11-1.43]; P<.001), and outpatient costs ($16 652 vs $13 015; MR, 1.28 [95% CI, 1.20-1.37]; P<.001) were all significantly higher for the MCI-to-ADRD subgroup compared with the Stable MCI subgroup. CONCLUSIONS: Individuals who progressed from MCI to ADRD had significantly higher health care costs than individuals with stable MCI. Early identification of MCI and delaying its progression is important to improve patient and economic outcomes.

Effect of autologous hematopoietic stem cell transplant on the development of second primary malignancies in multiple myeloma patients.

Autologous stem cell transplant (aHSCT) is associated with improved survival for multiple myeloma (MM) patients but may be associated with second primary malignancy (SPM) development. Using the California Cancer Registry linked to statewide hospitalization data, we determined the cumulative incidence (CMI) of SPMs more than 1 year after MM diagnosis, accounting for the competing risk of death. AHSCT recipients were matched 1:2 to non-aHSCT patients. Adjusted hazard ratios (aHR) were estimated using the Fine and Gray method. Among 16,331 patients, 933 (5.7%) developed a SPM more than 1 year after diagnosis. The 10-year CMI of developing any SPM was 6.6%, 5.7% for solid tumor SPM and 0.9% for hematologic malignancies. The 10-year CMI of developing any SPM was similar among aHSCT [9.1% (7.7-10.7%)] and non-aHSCT [7.5% (6.5-8.6%)] (P = 0.26) recipients and there was no difference in solid-tumor SPMs (P = 0.98). The 10-year CMI of hematologic SPMs was higher among aHSCT recipients [2.1% (1.4-2.9%) vs. 0.8% (0.5-1.2%); P = 0.005], corresponding to a 1.3% absolute increase and an aHR of 1.51 (1.01-2.27). Ten-year myeloma-specific and non-cancer mortality rates were 59% (58.2-60.0%) and 18.1% (17.4-18.8%), respectively. Although aHSCT was associated with a small increase in hematologic SPMs, mortality was driven by MM and non-cancer causes.

Secondary acute lymphoblastic leukemia is a distinct clinical entity with prognostic significance.

The effect of prior malignancy on the risk of developing, and prognosis of, acute lymphoblastic leukemia (ALL) is unknown. This observational study utilized the California Cancer Registry to estimate the risk of developing ALL after a prior malignancy using standardized incidence ratios (SIRs, 95% confidence intervals). ALL occurring after a malignancy with an SIR>1 (increased-risk (IR) malignancies) was considered secondary ALL (s-ALL). Adjusted hazard ratios (aHRs, 95% confidence intervals) compared the effect of s-ALL with de novo ALL on overall survival. A total of 14 481 patients with ALL were identified (1988-2012) and 382 (3%) had a known prior malignancy. Any prior malignancy predisposed patients to developing ALL: SIR 1.62 (1.45-1.79). Hematologic malignancies (SIR 5.57, 4.38-6.98) and IR-solid tumors (SIR 2.11, 1.73-2.54) increased the risk of developing ALL. s-ALL increased the risk of death compared with de novo ALL (aHR 1.38 (1.16-1.63)) and this effect was more pronounced among younger patients (age<40 years: aHR 4.80 (3.15-7.30); age⩾40 years: aHR 1.40 (1.16-1.69)) (interaction P<0.001). This population-based study demonstrates that s-ALL is a distinct entity that occurs after specific malignancies and carries a poor prognosis compared with de novo ALL, particularly among patients <40 years of age.

A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins.

Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology.

CCR5 deficiency and severe polio infection in the 1984 outbreak in Finland.

CCR5, a leukocyte chemoattractant receptor for chemokines CCL3, CCL4, and CCL5, promotes innate and adaptive immune responses by mediating leukocyte trafficking within lymph nodes and to peripheral tissues and is also known as a co-receptor for HIV cell entry. Homozygous inheritance of a complete loss-of-function mutation in CCR5 (CCR5Δ32/CCR5Δ32) is associated with symptomatic neuroinflammatory disease in humans with West Nile and Tickborne Encephalitis flavivirus infections. This study sought to establish whether CCR5 deficiency could also be a determinant of clinical outcome after infection by poliovirus which results in central nervous system damage in only a small proportion of cases. We analyzed serum samples from seven patients and 79 controls, collected during the 1984-1985 polio outbreak in Finland, where CCR5Δ32 is relatively common in the general population. The results excluded CCR5 deficiency as the sole determinant of severe neurologic disease after poliovirus infection in this population.

Immunogenicity of biological therapeutics: a hierarchy of concerns.

CBER considers immune responses to biological therapeutic agents in a hierarchy, structured by clinical effects. The greatest concern regards immediate hypersensitivity responses that cause anaphylactic or anaphylactoid responses. Such responses have been most commonly observed in treatment with bacterial products such as asparaginase, streptokinase, and diptheria toxin-conjugated molecules. Immediate hypersensitivity, as well as more delayed hypersensitivity responses (hours to days) may also be observed in enzyme replacement therapies, wherein a normal mammalian enzyme appears as a foreign protein to deficient patients. More insidious, but nonetheless devastating, antibodies to a recombinant hormone or cytokine have been shown to neutralize not only the product, but also the endogenous factor. When the endogenous factor mediates a unique biological function, a clinical syndrome develops. Such has been observed in immune responses to recombinant erythropoietin and thrombopoietin, with patients exhibiting pure red blood cell aplasia and immune mediated thrombocytopaenia respectively. Of considerable importance, but posing less threat, is generation of binding antibodies which may cause infusion reactions, alter pharmacokinetics and biodistribution, and potentially diminish product efficacy.

Cutaneous indeterminate cell histiocytosis: a new spindle cell variant resembling dendritic cell sarcoma.

BACKGROUND: Cutaneous indeterminate cell histiocytosis is a rare neoplastic disorder. Its varied histological presentation and rarity have limited efforts to determine its pathogenic relationship with other histiocytic lesions and possibly, its recognition. METHODS: We report on an unusual histologic pattern of indeterminate cell histiocytosis that resembled follicular dendritic sarcoma. A battery of immunohistochemical stains and electron microscopy were performed to elucidate the phenotype of the "histiocytic" cells. Based on a review of the literature, reported cases of indeterminate cell histiocytosis are presented and the diagnostic differential of spindle-cell lesions is discussed. RESULTS: Spindling histiocytes were positive for S-100 and CD1a. The monocytic/macrophage marker, CD68, and the dendritic cell marker, CD21, were negative. Electron microscopy failed to reveal Birbeck granules. CONCLUSIONS: Relatively few reports of indeterminate cell histiocytosis exist, some of which include discussion of potential overlaps with the non-X histiocytoses. Although the presence of prominent spindling in our case expanded the differential to include non-histiocytic disorders, the identified histiocytes unequivocally fulfilled the criteria of S-100 and CD1a positivity without demonstrable Birbeck granules.

Disseminated acanthamoebiasis presenting as lobular panniculitis with necrotizing vasculitis in a patient with AIDS.

BACKGROUND: Disseminated acanthamoebiasis is a rare entity, almost exclusively occurring in the immunocompromised host. METHODS: We report an unusual case of a 35-year-old female with recurrent sinusitis and multiple skin nodules demonstrating a necrotizing panniculitis, shown to be due to disseminated acanthamoebiasis. RESULTS: Histologic sections showed a neutrophilic lobular panniculitis with 20- to 30-microm trophozoites consistent with Acanthamoeba species. CONCLUSIONS: A review the literature shows that the histopathological presentation of acanthamoebiasis often eludes initial diagnostic attempts and that central nervous system (CNS) involvement is frequent and ultimately fatal. When amoebiasis is suspected, knowledge of the trophozoite and cyst forms may be helpful in distinguishing Acanthamoeba species from Entamoeba histolytica.

Antigen presentation determines the fate of the T memory response in vivo after sublethal gamma-irradiation.

The survival of memory T cells is critical to vaccination strategies for infectious diseases and cancer, whereas their elimination may be crucial for treatment of autoimmune states. We examined the consequences of gamma-irradiation, which induces apoptosis of memory T cells in vitro, on the memory response to MHC class I alloantigen in vivo. Sublethal gamma-irradiation of primed mice eliminated accelerated rejection of skin allografts but failed to induce tolerance. Accelerated rejection was restored in irradiated mice by infusion of bone marrow cells expressing the priming alloantigen on immunostimulatory APCs (dendritic cells), whereas the memory response was not restored by infusion of bone marrow cells expressing the priming alloantigen on nonstimulatory APCs (B cells). Strikingly, irradiated mice infused with nonstimulatory bone marrow APCs exhibited long-term survival or tolerance to skin grafts expressing the priming MHC class I alloantigen. The mechanism of tolerance in this setting is explored.

Safe and effective regulation of hematocrit by gene gun administration of an erythropoietin-encoding DNA plasmid.

This work examines the effect of delivering a DNA plasmid encoding murine erythropoietin (pVRmEpo) to BALB/c mice by gene gun. Whereas intramuscular injection elicits a rise in hematocrit persisting >8 months, intradermal delivery triggers the dose-dependent secretion of biologically active erythropoietin (Epo) for approximately 1 month. Repeated administration of pVRmEpo by gene gun elicits a stable increase in hematocrit. The source of the Epo produced following gene gun delivery was analyzed by periodically grafting the site of injection onto naive recipients. Results indicate that both stationary cells (presumably keratinocytes) and migratory (presumably dendritic) cells were transfected and secreted biologically active Epo in vivo. Gene gun administration of plasmid DNA appears to be safe, and provides an additional strategy for achieving the regulated secretion of an exogenous gene product.

Induction of antigen-specific hyporesponsiveness by transplantation of hemopoietic cells containing an MHC class I transgene regulated by a lymphocyte-specific promoter.

We explored a novel approach to tolerance induction by the transplantation of bone marrow (BM) cells (BMCs) that themselves do not express a foreign histocompatibility Ag, but which give rise to mature lymphocytes that do so. Lines of transgenic (FVB) mice were generated that contained an MHC class I Dd cDNA regulated by a CD2 promoter. Because the CD2 promoter is lymphocyte-specific and activated relatively late in lymphocyte ontogeny, Dd is expressed on most mature lymphocytes in the periphery but only on developing B cells in the BM of transgenic mice. Transgenic BMCs are tolerogenic and reproducibly engraft in nontransgenic mice using a conditioning regimen that is nonpermissive for the engraftment of conventional (MHC promoter) Dd-transgenic BMCs. Engrafted BMCs generate transgene-expressing lymphocytes and confer a state of Ag-specific hyporesponsiveness on the host that is primarily attributable to a peripheral mechanism. The strategies by which tolerance can be optimized in this system are discussed.

Contribution of cells at the site of DNA vaccination to the generation of antigen-specific immunity and memory.

Gene gun-mediated DNA vaccination stimulates an immune response characterized by the activation of IgG-secreting B cells and IFN-gamma-secreting T cells. To monitor the contribution of cells at the site of vaccination to this process, transfected skin was periodically removed and grafted onto naive recipients. Immediate removal of vaccinated skin abrogated the development of an immune response. Low-level IgG production was stimulated when the vaccination site was left in place for > or = 5 h, with the strength of this response increasing the longer the site remained intact (for up to 2 wk). Measurable primary T cell responses were observed in animals whose vaccination site remained in place for > or = 1 day. Skin grafts transferred 0 to 24 h postvaccination stimulated a primary immune response in naive recipients. Memory B and T cells were generated in animals whose site of vaccination remained intact for 5 to 12 h. Skin transferred within 12 h of vaccination triggered memory B and T cell development in graft recipients, while the removal of skin >12 h postvaccination did not reduce memory in vaccinated mice. These findings suggest that 1) primary immunity is induced by cells that migrate rapidly from the site of immunization, 2) nonmigratory cells influence the magnitude of this primary response, and 3) migratory cells alone are responsible for the induction of immunologic memory.

Fungal infections in patients with acquired immunodeficiency syndrome.

The incidence and severity of fungal infections appear to increase with progression of HIV disease. Because of the significant morbidity and mortality associated with the mycoses discussed, knowledge of the clinical syndromes, early diagnosis, and prompt institution of therapy are crucial for a favorable outcome. For disseminated or invasive fungal infections, suppressive therapy must be continued to prevent relapse.

Genetic variation among 129 substrains: practical consequences.

We designed a series of experiments to define the role of IFN-gamma in cellular interactions mediating graft rejection by assessing the rejection of H-Y disparate grafts in both ligand and receptor knockout mice and their control inbred strain. In the course of these studies it became apparent that neither knockout strain is histocompatible with the putative control and that the putative control is not histocompatible with either knockout strain. In the process of deducing why this might be so, it became apparent that the putative control is not an inbred strain of mouse. Thus, in the absence of rigorous genetic control, the utility of such knockout strains of mice for assessing the effects of cytokines and receptors in transplantation and autoimmunity is limited.

Induction of murine acquired immunodeficiency syndrome (MAIDS) in allophenic mice generated from strains susceptible and resistant to disease.

To examine whether a retroviral disease can be controlled in animals in which cells from a resistant strain coexist in a state of immunological tolerance with cells from a susceptible strain, allophenic mice were constructed and infected with LP-BM5 murine leukemia viruses which induce a fatal disorder, termed murine acquired immunodeficiency syndrome (MAIDS), characterized by lymphoproliferation and immunodeficiency in susceptible inbred strains of mice. We found that in two different strain combinations, resistance to MAIDS was contingent on the presence in individual animals of >50% of lymphocytes of resistant strain origin and correlated with reduction or elimination of retrovirus. In contrast, animals harboring substantial, but less than predominant, numbers of genetically resistant lymphocytes developed disease and died within the same time frame as susceptible control mice with uncontained proliferation of retrovirus.

Assessment of alloreactive T cell subpopulations of aged mice in vivo. CD4+ but not CD8+ T cell-mediated rejection response declines with advanced age.

The present investigation explored age-related alterations in T cell populations mediating allospecific responses in vivo. Healthy aged and young H-2b and H-2bxH-2k mice were engrafted with major histocompatibility complex (MHC) class II-disparate bm12 skin, rejection of which requires CD8+ T cells, and MHC class I-disparate bm1 skin, rejection of which requires CD8+ T cells. Aged mice of both genders exhibited prolonged survival of bm12 skin grafts relative to their young counterparts but rejected bm1 skin grafts at a rate equivalent to that of young mice. Consistent with prolonged survival of bm12 skin grafts, markedly diminished levels of Iabm12 CTL activity were elicited from T cells of aged mice in vitro. However, no such decline was observed in the level of Kbm1 CTL from T cells of aged mice. The alterations in Iabm12 allospecific responses were not attributable to quantitative changes in CD4+ T cells of aged mice, and addition of soluble T cell helper factors to response cultures of aged mice did not augment Iabm12 cytotoxic T lymphocytes activity. These data demonstrate that aging fundamentally affects CD4+ T cell-mediated allospecific responses particularly in vivo, and that deficient generation of soluble T cell helper factors alone cannot explain this deficit.

Infection in the cancer patient.

Neoplastic disease and its treatment lead to specific immune defects that predispose to specific infections. As the management of cancer has changed, so has the spectrum of infection with which it is associated. Neutropenia, T-cell defects, B-cell defects, and splenectomy lead to either specific illnesses or more severe manifestations of infection. Interruption in the normal barriers of the skin and mucous membranes due to the tumor itself or its treatment also predisposes to infection. Investigation is under way to determine the role of newer modalities (e.g., hematopoietic growth factors, interleukins, and interferons) in decreasing the number and severity of such infections.

Cellular basis of skin allograft rejection: an in vivo model of immune-mediated tissue destruction.

Rejection of transplanted tissue allografts results from T-cell recognition of histocompatibility antigens expressed by cells of the donor graft. This review focuses on the phenotype, specificity, and function of the T cells mediating rejection responses against skin allografts, and on the immune mechanisms by which host T cells are either activated or rendered non-responsive by cellular populations within the graft. We review the cellular basis for rejection responses across limited class-I and class-II major histocompatibility differences, as well as the specificity of the rejection response itself.