ABSTRACT
Severe pulmonary or disseminated histoplasmosis often necessitates presumptive antifungal treatment while awaiting definitive diagnosis. Histoplasma antigen assays have improved sensitivity but results may lag up to 7 days. In order to increase diagnostic certainty, "soft clues" may be looked for in laboratory and radiologic data, such as elevated alkaline phosphatase or ferritin levels and findings of mediastinal adenopathy or hepatosplenomegaly. To determine if elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is specific to histoplasmosis or a non-specific marker for disseminated fungal infection or sepsis in general, we retrospectively examined records of all patients diagnosed with an endemic fungal infection (EFI) at Rush University Medical Center from January of 1997 to October of 2012, and a cohort of septic patients with elevated liver enzymes. We identified 90 cases of EFIs during the study period that met all inclusion criteria (Histoplasma 21, Blastomyces 56, Coccidioides 12, Paracoccidioides 1). We also evaluated 10 control patients with bacterial sepsis. The mean ratio of AST to ALT in patients with disseminated histoplasmosis was 2.69 (95% CI:1.22, 4.16) while for other EFIs, the mean ratio ranged from 0.38 to 1.14 with disseminated coccidioidomycosis and blastomycosis respectively (P < 0.0001). The ratio in patients with bacterial sepsis was 0.84. We propose the use of the AST/ALT ratio as a clinical "soft clue" suggestive of disseminated histoplasmosis in the appropriate host, and to possibly distinguish cross reactivity of the Histoplasma antigen assay with other EFIs.
Subject(s)
Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Histoplasmosis , Lung Diseases, Fungal , Mycoses , Aged , Cohort Studies , Endemic Diseases , Female , Histoplasma , Histoplasmosis/blood , Histoplasmosis/enzymology , Humans , Lung Diseases, Fungal/blood , Lung Diseases, Fungal/enzymology , Male , Middle Aged , Mycoses/blood , Mycoses/enzymology , Retrospective StudiesABSTRACT
The proteasome catalytic beta subunits LMP2, LMP7, and MECL-1 and two proteasome activator proteins, PA28 alpha and beta, are induced following exposure to IFN-gamma in vitro. Induction of these immunosubunits and the PA28 alpha/beta hetero-oligomer alters proteasome catalytic functions and specificity and enhances production of certain MHC class I epitopes. We sought to determine whether and to what extent proteasome subunit composition is regulated in vivo and to elucidate the mechanisms of such regulation. We analyzed basal expression levels of these inducible genes in normal, IFN-gamma-deficient, and Stat-1-deficient mice. Mice of all three genotypes display constitutive expression of the immunosubunits and PA28, demonstrating that basal expression in vivo is independent of endogenous IFN-gamma production. However, basal expression levels are reduced in Stat-1(-/-) mice, demonstrating a role for Stat-1 independent of IFN-gamma signaling. To demonstrate that IFN-gamma can induce these genes in vivo, mice were infected with Histoplasma capsulatum. Elevated expression of these genes followed the same time course as IFN-gamma expression in infected mice. IFN-gamma-deficient mice did not display elevated protein expression following infection, suggesting that other inflammatory cytokines produced in infected mice are unable to influence proteasome expression. Cytokines other than IFN-gamma also failed to influence proteasome gene expression in vitro in cell lines that had no basal expression of LMP2, LMP7, or MECL-1. Thus, both in vitro and in vivo data demonstrate that IFN-gamma is essential for up-regulation, but not constitutive expression, of immunoproteasome subunits in mice.
Subject(s)
Cysteine Endopeptidases/biosynthesis , Histoplasma/immunology , Histoplasmosis/enzymology , Histoplasmosis/immunology , Multienzyme Complexes/biosynthesis , Protein Subunits , Animals , Cell Line , Gene Expression Regulation/immunology , Histoplasmosis/genetics , Interferon-gamma/biosynthesis , Interferon-gamma/deficiency , Interferon-gamma/genetics , Interferon-gamma/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Proteasome Endopeptidase Complex , Protein Biosynthesis , Tumor Cells, CulturedABSTRACT
The purpose of this study was to determine whether serum lactate dehydrogenase (LDH) level could be used as an adjunct clinical marker to differentiate between histoplasmosis and Pneumocystis carinii pneumonia (PCP). In a retrospective, case-controlled study, 30 patients with a diagnosis of histoplasmosis (all but 1 with disseminated disease) were compared with 120 patients with PCP (33 patients with definitive PCP, 87 with presumed PCP). Groups were matched for CD4+ lymphocyte counts, sex, and year of diagnosis. The mean LDH level for patients with histoplasmosis was 1068 +/- 197 IU/L; for PCP, it was 375 +/- 23. An LDH level of more than 450 IU/L was 9.33 times more likely to be associated with a diagnosis of histoplasmosis than with PCP (odds ratio [OR], 9.33; 95% confidence interval [CI], 3.50-25.47; P < .01), and an LDH level of more than 600 IU/L was 9.41 times more likely to be so (OR, 9.41; 95% CI, 3.43-26.31; P < .01). An LDH level of 450 IU/L or greater had a sensitivity and specificity of 70% and 80%, respectively; a value of 600 IU/L or greater had sensitivity and specificity of 50% and 89%. Thus, serum LDH levels of 600 IU/L or greater are suggestive of histoplasmosis rather than PCP in appropriate clinical settings. Serum LDH may serve as an adjunct laboratory marker in the diagnosis of histoplasmosis. Elevated levels may prompt the physician to look for a diagnosis other than PCP early in the course of the illness.
Subject(s)
AIDS-Related Opportunistic Infections/diagnosis , Histoplasmosis/diagnosis , L-Lactate Dehydrogenase/blood , AIDS-Related Opportunistic Infections/blood , AIDS-Related Opportunistic Infections/enzymology , Histoplasmosis/blood , Histoplasmosis/enzymology , HumansABSTRACT
BACKGROUND: The purpose of this study was to determine the association of serum lactate dehydrogenase (LDH) levels with certain opportunistic infection and to determine an association between LDH levels and CD4+ lymphocyte counts. METHOD: We studied 352 patients retrospectively with HIV infection and one of the following infections: histoplasmosis; toxoplasmosis; tuberculosis (pulmonary and disseminated); bacterial pneumonia; Pneumocystis carinii pneumonia. Demographic and clinical data were obtained from the Adult Spectrum of Diseases (ASD) database in New Orleans. Bivariate and multivariate analysis were used to determine the association between LDH levels and opportunistic infections and CD4+ lymphocyte counts. RESULTS: Patients with a serum LDH level <225 IU/L had a mean CD4+ lymphocyte count of 159/dl (SE 19.3) as compared to patients with a serum LDH level > or =225 IU/L, who had a mean CD4+ lymphocyte count of 58/dl (SE 6.9) (P<0.01). Non-Caucasian race, a diagnosis of histoplasmosis, disseminated tuberculosis or Pneumocystis carinii pneumonia, and CD4+ lymphocyte count were significantly associated with a serum LDH level > or =225 IU/L in the bivariate analysis. In a multivariate analysis, after controlling for race and CD4+ lymphocyte count, the only diagnoses that were significantly associated with the serum LDH level were definitive Pneumocystis carinii pneumonia and toxoplasmosis. Having a higher LDH level was not associated with early mortality. CONCLUSIONS: Although not diagnostic, serum LDH levels could be used as an adjunctive marker in certain opportunistic infections. There is an inverse relationship between serum LDH levels and CD4+ lymphocyte counts in this group.
Subject(s)
AIDS-Related Opportunistic Infections/diagnosis , Histoplasmosis/diagnosis , L-Lactate Dehydrogenase/blood , Pneumonia, Pneumocystis/diagnosis , Tuberculosis/diagnosis , AIDS-Related Opportunistic Infections/enzymology , Adult , CD4 Lymphocyte Count , Disease Progression , Female , HIV Infections/complications , Histoplasmosis/enzymology , Humans , Male , Middle Aged , Pneumonia, Pneumocystis/enzymology , Retrospective Studies , Tuberculosis/enzymologyABSTRACT
BACKGROUND: Histochemical staining of bone marrow biopsy samples for microorganisms may provide a presumptive diagnosis weeks before culture. METHODS: To identify predictors of histochemical positivity, we reviewed 161 bone marrow biopsies from febrile patients with human immunodeficiency virus (HIV) infection. RESULTS: By multivariate analysis, both hematocrit value <30% and white blood cell count <4,000/mm3 predicted biopsy positivity by culture or staining, but only anemia predicted histochemical stain positivity. Of cases with serum lactate dehydrogenase (LDH) levels >600 U/L, histoplasmosis was diagnosed in 31.6% versus 7.8% with lower LDH levels. Among histoplasmosis cases, staining showed fungi in all, with LDH levels >600 U/L versus 44.4% with lower levels. CONCLUSIONS: Bone marrow biopsy will most likely provide a rapid diagnosis in patients with anemia. Markedly elevated LDH levels suggest stain positivity for Histoplasma capsulatum. Histopathologic patterns may also guide empiric therapy.
Subject(s)
AIDS-Related Opportunistic Infections/diagnosis , Bone Marrow/pathology , Fever/diagnosis , Adult , Anemia/microbiology , Anemia/pathology , Biopsy , Bone Marrow/microbiology , Bone Marrow Examination , Chi-Square Distribution , Coloring Agents , Female , Forecasting , HIV Infections/complications , Hematocrit , Histocytochemistry , Histoplasma/classification , Histoplasmosis/diagnosis , Histoplasmosis/enzymology , Humans , L-Lactate Dehydrogenase/blood , Leukocyte Count , Logistic Models , Lymphoma, AIDS-Related/diagnosis , Male , Microbiological Techniques , Multivariate Analysis , Mycobacterium avium-intracellulare Infection/diagnosis , Pneumonia, Pneumocystis/diagnosis , Prospective Studies , Retrospective StudiesABSTRACT
Splenic macrophages from Histoplasma capsulatum-infected mice express inducible nitric oxide synthase (iNOS), and the iNOS expression correlates with severity of the infection. We examined whether production of NO is responsible for apoptosis and the anti-lymphoproliferative response of splenocytes from mice infected with H. capsulatum. In situ terminal deoxynucleotidyl transferase nick end labeling revealed apoptotic nuclei in cryosections of spleen from infected but not normal mice. Splenocytes of infected mice were unresponsive to stimulation by either concanavalin A or heat-killed H. capsulatum yeast cells. Splenocyte responsiveness was restored by addition to the medium of NG-monomethyl-L-arginine, a known inhibitor of NO production. The proliferative response of splenocytes from infected mice was also restored by depletion of macrophages or by replacement with macrophages from normal mice. In addition, expression of iNOS returned to its basal level when the animals had recovered from infection. These results suggest that suppressor cell activity of macrophages is associated with production of NO, which also appears to be an effector molecule for apoptosis of cultured splenocytes from infected mice.
Subject(s)
Apoptosis/immunology , Histoplasmosis/immunology , Histoplasmosis/pathology , Immune Tolerance , Macrophages/enzymology , Nitric Oxide Synthase/biosynthesis , Spleen/enzymology , Animals , Concanavalin A/pharmacology , Histoplasma/immunology , Histoplasmosis/enzymology , Macrophage Activation/immunology , Macrophages/immunology , Macrophages/pathology , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type IIABSTRACT
Disseminated histoplasmosis is a common late manifestation of AIDS, but the diagnosis may be unsuspected in some patients because the clinical presentation of histoplasmosis may mimic other opportunistic infections. High serum lactate dehydrogenase (LDH) levels have been associated with disseminated histoplasmosis. We therefore evaluated whether markedly increased LDH levels were useful for making a diagnosis of disseminated histoplasmosis by comparing admission LDH levels for 15 patients with culture-proven disseminated histoplasmosis with those for 30 patients with advanced AIDS who were admitted to the hospital for evaluation of pulmonary infiltrates and fever. The mean admission LDH level in patients with disseminated histoplasmosis was 1,356 IU/L (range, 145-5,410 IU) whereas it was 332 (range, 77-832 IU) in the patients with other pulmonary processes. Admission LDH levels were >600 IU in 11 (73%) of the 15 patients with disseminated histoplasmosis vs. 3 (10%) of controls (P < .001). We conclude that markedly elevated admission LDH levels may be a clinical clue to the diagnosis of disseminated histoplasmosis in patients with AIDS.
Subject(s)
AIDS-Related Opportunistic Infections/diagnosis , Fungemia/diagnosis , Histoplasmosis/diagnosis , L-Lactate Dehydrogenase/blood , AIDS-Related Opportunistic Infections/enzymology , Biomarkers/blood , Fungemia/enzymology , Histoplasmosis/enzymology , Humans , Odds Ratio , Sensitivity and Specificity , Survival RateABSTRACT
This paper describes the clinical course of four patients with AIDS who were found to have H capsulatum in peripheral blood. The evolution of the infection was fulminant and all died within the first 96 hours following hospitalization. In every case the presence of the characteristic mycelium and "tuberculate" macroconidia of Histoplasma was established in cultures. All cases showed the hematological abnormalities common in other AIDS associated diseases. In addition, there was an increase in serum lactic dehydrogenase over ten times our normal level: the lowest LDM assay was 2137 IU/mL and the highest 4839 IU/mL. This clinical course resembling septicemia and the demonstration of H capsulatum in a peripheral blood smear has had a rate of 12% in our experience (four out of the 34 cases of AIDS with histoplasmosis seen in our institution from January 1984 to March 1991).
Subject(s)
AIDS-Related Opportunistic Infections/microbiology , Acquired Immunodeficiency Syndrome/complications , Fungemia/microbiology , Histoplasma/isolation & purification , Histoplasmosis/complications , L-Lactate Dehydrogenase/blood , AIDS-Related Opportunistic Infections/enzymology , Adult , Biomarkers/blood , Blood/microbiology , Fungemia/complications , Fungemia/enzymology , Histoplasmosis/enzymology , Humans , Male , Middle AgedABSTRACT
In this study we evaluated the disease specificity of bronchoalveolar lavage fluid angiotensin-converting enzyme (BALF-ACE), its correlation with cellular constituents of bronchoalveolar lavage fluid (BALF), and for sarcoidosis, with other proposed markers of disease activity. Furthermore, the question of the clinical value of BALF-ACE determinations in in interstitial lung diseases or any of its subgroups was addressed. The study population consisted of 222 patients, 69 with biopsy proven sarcoidosis, 3 with hypersensitivity pneumonitis, 4 with acute histoplasmosis, 27 with idiopathic pulmonary fibrosis (IPF), 4 with rheumatoid arthritis-related interstitial fibrosis, 9 with pulmonary drug toxicity, 16 with pulmonary malignancies, 26 with other parenchymal lung disease entities, and 30 in whom the final diagnosis remained indeterminate. Elevated BALF-ACE concentrations were seen in all diagnostic categories. In sarcoidosis BALF-ACE levels correlated well with lavage lymphocyte counts (r = 0.49; p less than 0.0001), in contrast to IPF where they correlated well with lavage neutrophil counts (r = 0.51; p less than 0.007). The correlation of BALF-ACE and serum-ACE was significant. In sarcoidosis the mean BALF-ACE level was lower for patients with Stage-I chest roentgenographic patterns (0.664 U/L), compared to those with Stage II (1.112 U/L) and Stage III (1.083 U/L). It was concluded that elevated BALF-ACE levels are not specific for sarcoidosis. The correlations of BALF-ACE levels with different cellular constituents of BALF suggest a different cellular origin of BALF-ACE. In sarcoidosis BALF-ACE levels correlate well with other proposed markers of disease activity and seem to reflect pulmonary activity better than serum ACE.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Bronchoalveolar Lavage Fluid/enzymology , Peptidyl-Dipeptidase A/analysis , Pulmonary Fibrosis/enzymology , Alveolitis, Extrinsic Allergic/diagnosis , Alveolitis, Extrinsic Allergic/enzymology , Arthritis, Rheumatoid/complications , Bronchoalveolar Lavage Fluid/cytology , Clinical Enzyme Tests , Diagnosis, Differential , Histoplasmosis/diagnosis , Histoplasmosis/enzymology , Humans , Lung/diagnostic imaging , Lung Diseases, Fungal/diagnosis , Lung Diseases, Fungal/enzymology , Lung Neoplasms/complications , Middle Aged , Peptidyl-Dipeptidase A/blood , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/etiology , Radiography , Sarcoidosis/diagnosis , Sarcoidosis/diagnostic imaging , Sarcoidosis/enzymologyABSTRACT
Systemic infection with Histoplasma capsulatum induced a granulomatous inflammatory response in the lymphoreticular organs of C57BL/6 mice that was associated with elevated levels of angiotensin-converting enzyme (ACE) in the spleens. To determine the influence of ACE on the granulomatous response, either captopril or MK 421, two inhibitors of ACE, were administered intraperitoneally to mice 6 h after intravenous injection of H. capsulatum and then daily for 1 week. Each ACE inhibitor sharply reduced ACE activity in the spleens of infected mice. Both drugs worsened the clinical severity of infection and significantly increased the growth of H. capsulatum in livers and spleens of mice infected for 1 week. The histopathological changes in mice given captopril were more severe, with massive infiltrates of macrophages in proximity to large aggregates of yeasts. Conversely, the administration of captopril for 2 weeks during the resolving phases of infection did not slow the healing of the granulomatous lesions, nor did it provoke a relapse of infection. Captopril did not promote the growth of H. capsulatum in artificial medium. This drug was not cytotoxic to peripheral blood leukocytes or to splenic leukocytes from normal and infected mice. Administration of captopril to normal mice for 1 week did not depress the response of splenocytes of concanavalin A or to phytohemagglutinin, nor did it diminish delayed-type hypersensitivity responses in vivo. Finally, captopril did not augment the growth of H. capsulatum within macrophages. Our results suggest that ACE may participate in the regulation of the granulomatous inflammatory response to H. capsulatum and that ACE inhibition impairs the protective effects of granulomatous inflammation during acute H. capsulatum infection.
Subject(s)
Captopril/pharmacology , Dipeptides/pharmacology , Granuloma/enzymology , Histoplasmosis/enzymology , Peptidyl-Dipeptidase A/physiology , Proline/analogs & derivatives , Angiotensin-Converting Enzyme Inhibitors , Animals , Enalapril , Granuloma/immunology , Histoplasma/growth & development , Histoplasmosis/immunology , Histoplasmosis/pathology , Hypersensitivity, Delayed , Inflammation , Liver/microbiology , Lymphocyte Activation/drug effects , Macrophages/microbiology , Male , Mice , Mice, Inbred C57BL , Spleen/enzymology , Spleen/microbiology , Spleen/pathologyABSTRACT
Serum angiotensin-converting enzyme (SACE) levels were measured in 44 subjects six weeks after acute pulmonary histoplasmosis. All patients were infected in a common-source outbreak of histoplasmosis which occurred on one day. All patients had both strictly defined clinical and serologic evidence of infection. The SACE activity was elevated at six weeks compared to normal controls, and seven of the 44 had levels more than 2 SD above the normal mean. SACE levels were also measured at three and 24 weeks after acute infection in a smaller number of the same subjects. Serial observations demonstrated that all subjects (including those with normal and elevated SACE at six weeks) had a rise and fall in SACE activity following symptomatic acute pulmonary histoplasmosis. Our findings suggest that elevated SACE does not reliably separate sarcoidosis from histoplasmosis, although elevations in histoplasmosis are much less common and may occur only briefly following acute pulmonary histoplasmosis. More important, it seems that SACE activity rises acutely in all patients with symptomatic acute histoplasmosis and then falls gradually toward baseline over several months, coinciding temporally with the granulomatous response.
Subject(s)
Histoplasmosis/enzymology , Lung Diseases, Fungal/enzymology , Peptidyl-Dipeptidase A/blood , Acute Disease , Adult , Diagnosis, Differential , Granuloma/pathology , Histoplasmosis/diagnosis , Humans , Lung Diseases, Fungal/diagnosis , Sarcoidosis/diagnosisABSTRACT
The association between increased serum angiotensin converting enzyme (ACE) activity and active sarcoidosis is well documented. During a recent outbreak of acute histoplasmosis, a disease that shares many of the clinical and roentgenographic features of sarcoidosis, we examined serum ACE activity. Twenty-one (25%) of 86 patients with histoplasmosis had increased serum ACE activity. There were neither roentgenographic nor other substantive clinical differences between the groups of patients with increased and normal ACE values. Therefore, an increase in serum ACE activity must not be assumed to be caused by sarcoidosis unless histoplasmosis had been excluded.