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BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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Autoanticuerpos , Síndromes de Inmunodeficiencia , Interleucina-23 , Infecciones Oportunistas , Adulto , Humanos , Autoanticuerpos/inmunología , Síndromes de Inmunodeficiencia/inmunología , Interleucina-12/antagonistas & inhibidores , Interleucina-12/inmunología , Interleucina-23/antagonistas & inhibidores , Interleucina-23/inmunología , Micosis/inmunología , Infecciones Oportunistas/inmunología , Timoma/inmunología , Neoplasias del Timo/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones Bacterianas/inmunologíaRESUMEN
BACKGROUND: The immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines is variable in individuals with different inborn errors of immunity or acquired immune deficiencies and is yet unknown in people with idiopathic CD4 lymphopenia (ICL). OBJECTIVE: We sought to determine the immunogenicity of mRNA vaccines in patients with ICL with a broad range of CD4 T-cell counts. METHODS: Samples were collected from 25 patients with ICL and 23 age- and sex-matched healthy volunteers (HVs) after their second or third SARS-CoV-2 mRNA vaccine dose. Anti-spike and anti-receptor binding domain antibodies were measured. T-cell receptor sequencing and stimulation assays were performed to quantify SARS-CoV-2-specific T-cell responses. RESULTS: The median age of ICL participants was 51 years, and their median CD4 count was 150 cells/µL; 11 participants had CD4 counts ≤100 cells/µL. Anti-spike IgG antibody levels were greater in HVs than in patients with ICL after 2 and 3 doses of mRNA vaccine. There was no detectable significant difference, however, in anti-S IgG between HVs and participants with ICL and CD4 counts >100 cells/µL. The depth of spike-specific T-cell responses by T-cell receptor sequencing was lower in individuals with ICL. Activation-induced markers and cytokine production of spike-specific CD4 T cells in participants with ICL did not differ significantly compared with HVs after 2 or 3 vaccine doses. CONCLUSIONS: Patients with ICL and CD4 counts >100 cells/µL can mount vigorous humoral and cellular immune responses to SARS-CoV-2 vaccination; however, patients with more severe CD4 lymphopenia have blunted vaccine-induced immunity and may require additional vaccine doses and other risk mitigation strategies.
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COVID-19 , Linfopenia , Humanos , Persona de Mediana Edad , Vacunas contra la COVID-19 , Vacunas de ARNm , SARS-CoV-2 , COVID-19/prevención & control , Vacunación , Receptores de Antígenos de Linfocitos T , Inmunidad , ARN Mensajero , Anticuerpos AntiviralesRESUMEN
People with HIV (PWH) and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy. The pathophysiology of mycobacterial-IRIS overlaps with primary hemophagocytic lymphohistiocytosis (pHLH). To assess possible genetic predisposition to IRIS, protein-altering variants in genes associated with HLH were evaluated in 82 PWH and mycobacterial infections who developed IRIS (n = 56) or did not develop IRIS (n = 26). Protein-altering variants in cytotoxicity genes were found in 23.2% of IRIS patients compared to only 3.8% of those without IRIS. These findings suggest a possible genetic component in the risk of mycobacterial IRIS in PWH. Clinical Trials Registration. NCT00286767, NCT02147405.
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Infecciones por VIH , Síndrome Inflamatorio de Reconstitución Inmune , Linfohistiocitosis Hemofagocítica , Tuberculosis , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/complicaciones , Tuberculosis/complicaciones , Tuberculosis/genética , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART). Severe mycobacterial IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We evaluated the pathophysiologic similarities between mycobacterial IRIS and HLH to identify clinical and immune predictors of mycobacterial IRIS severity. METHODS: HLH criteria were applied to a longitudinal cohort of 80 patients with HIV (CD4 <100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell subsets were assessed at baseline and IRIS-equivalent time points. RESULTS: HLH-IRIS patients required corticosteroids more frequently (OR: 21.5; 95%CI: 5.6-114.8) and for longer duration (21.2; 95%CI: 10.7-31.7 weeks) than those not meeting HLH criteria. Utilizing decision tree analyses, hemoglobin <9.2 g/dL was the best predictor of HLH-IRIS before ART, whereas ferritin, CXCL9 and sCD25 were most diagnostic for HLH at IRIS onset. At the IRIS timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T cells along with greater production of IFNγ-IL-18 axis biomarkers compared with both IRIS and non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients. CONCLUSIONS: Severe mycobacterial IRIS and HLH have an overlapping pathogenesis involving IFNγ and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS [FIRIS]). Hemoglobin, ferritin, CXCL9, and sCD25 identify high-risk patients and may improve risk stratification and therapeutic strategies for mycobacterial IRIS.
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Infecciones por VIH , Síndrome Inflamatorio de Reconstitución Inmune , Linfohistiocitosis Hemofagocítica , Humanos , VIH , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/diagnóstico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , BiomarcadoresRESUMEN
BACKGROUND: Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion. METHODS: Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed. RESULTS: High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8. CONCLUSIONS: Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses. CLINICAL TRIALS REGISTRATION: NCT04401436.
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COVID-19 , Humanos , SARS-CoV-2 , Ritonavir , Tratamiento Farmacológico de COVID-19 , Antivirales , Inmunoglobulina G , Anticuerpos AntiviralesRESUMEN
The development of effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines has been a significant accomplishment. Adverse events are extremely rare, but continued surveillance is important, especially in at-risk populations. In 5 patients with preexisting immune dysregulation, hyperinflammatory syndromes, including hemophagocytic lymphohistiocytosis, developed after SARS-CoV-2 mRNA vaccination. Early recognition of this rare condition is essential.
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COVID-19 , Coronavirus del Síndrome Respiratorio de Oriente Medio , COVID-19/prevención & control , Humanos , ARN Mensajero/genética , SARS-CoV-2/genética , Vacunación/efectos adversosAsunto(s)
Síndrome de Hipersensibilidad a Medicamentos , Herpesvirus Humano 6 , Linfadenitis , Linfoma , Infecciones por Roseolovirus , Humanos , Herpesvirus Humano 6/aislamiento & purificación , Linfadenitis/virología , Linfadenitis/diagnóstico , Linfadenitis/etiología , Infecciones por Roseolovirus/complicaciones , Infecciones por Roseolovirus/diagnóstico , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Síndrome de Hipersensibilidad a Medicamentos/etiología , Síndrome de Hipersensibilidad a Medicamentos/patología , Linfoma/complicaciones , Diagnóstico Diferencial , Masculino , Femenino , Persona de Mediana EdadRESUMEN
People with HIV (PWH) have a higher age-adjusted mortality due to chronic immune activation and age-related comorbidities. PWH also have higher rates of clonal hematopoiesis (CH) than age-matched non-HIV cohorts; however, risk factors influencing the development and expansion of CH in PWH remain incompletely explored. We investigated the relationship between CH, immune biomarkers, and HIV-associated risk factors (CD4+ and CD8+ T cells, nadir CD4+ count, opportunistic infections [OIs], and immune reconstitution inflammatory syndrome [IRIS]) in a diverse cohort of 197 PWH with median age of 42 years, using a 56-gene panel. Seventy-nine percent had a CD4+ nadir below 200 cells/µL, 58.9% had prior OIs, and 34.5% had a history of IRIS. The prevalence of CH was high (27.4%), even in younger individuals, and CD8+ T cells and nadir CD4+ counts strongly associated with CH after controlling for age. A history of IRIS was associated with CH in a subgroup analysis of patients 35 years of age and older. Inflammatory biomarkers were higher in CH carriers compared with noncarriers, supporting a dysregulated immune state. These findings suggest PWH with low nadir CD4+ and/or inflammatory complications may be at high risk of CH regardless of age and represent a high-risk group that could benefit from risk reduction and potentially targeted immunomodulation.
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Hematopoyesis Clonal , Infecciones por VIH , Humanos , Adulto , Masculino , Femenino , Hematopoyesis Clonal/genética , Infecciones por VIH/inmunología , Infecciones por VIH/complicaciones , Persona de Mediana Edad , Linfocitos T CD8-positivos/inmunología , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Recuento de Linfocito CD4 , Factores de Riesgo , Linfocitos T CD4-Positivos/inmunología , Biomarcadores , Adulto Joven , InflamaciónRESUMEN
Introduction: COVID-19 patients can develop autoantibodies against a variety of secreted and membrane proteins, including some expressed on lymphocytes. However, it is unclear what proportion of patients might develop anti-lymphocyte antibodies (ALAb) and what functional relevance they might have. Methods: We evaluated the presence and lytic function of ALAb in the sera of a cohort of 85 COVID-19 patients (68 unvaccinated and 17 vaccinated) assigned to mild (N=63), or moderate/severe disease (N=22) groups. Thirty-seven patients were followed-up after recovery. We also analyzed in vivo complement deposition on COVID-19 patients' lymphocytes and examined its correlation with lymphocyte numbers during acute disease. Results: Compared with healthy donors (HD), patients had an increased prevalence of IgM ALAb, which was significantly higher in moderate/severe disease patients and persisted after recovery. Sera from IgM ALAb+ patients exhibited complement-dependent cytotoxicity (CDC) against HD lymphocytes. Complement protein C3b deposition on patients' CD4 T cells was inversely correlated with CD4 T cell numbers. This correlation was stronger in moderate/severe disease patients. Discussion: IgM ALAb and complement activation against lymphocytes may contribute to the acute lymphopenia observed in COVID-19 patients.
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Autoanticuerpos , COVID-19 , Activación de Complemento , Inmunoglobulina M , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/sangre , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Masculino , Femenino , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Activación de Complemento/inmunología , SARS-CoV-2/inmunología , Anciano , Adulto , Linfocitos/inmunología , Prevalencia , Linfocitos T CD4-Positivos/inmunología , Linfopenia/inmunología , Linfopenia/sangre , Complemento C3b/inmunologíaRESUMEN
Background: Pneumocystis jirovecii pneumonia (PCP) is one of the most frequent opportunistic infections in people with HIV (PWH). However, there are limited data on long-term outcomes of PCP in the antiretroviral therapy (ART) era. Methods: We conducted a secondary analysis of 2 prospective studies on 307 PWH, 81 with prior PCP, with a median follow-up of 96 weeks. Laboratory data were measured at protocol-defined intervals. We reviewed clinically indicated chest computerized tomography imaging in 63 patients with prior PCP at a median of 58 weeks after PCP diagnosis and pulmonary function tests (PFTs) of patients with (n = 10) and without (n = 14) prior PCP at a median of 18 weeks after ART initiation. Results: After 96 weeks of ART, PWH with prior PCP showed no significant differences in laboratory measurements, including CD4 count, when compared with those without prior PCP. Survival rates following ART initiation were similar. However, PWH with prior PCP had increased evidence of restrictive lung pathology and diffusion impairment in PFTs. Furthermore, on chest imaging, 13% of patients had bronchiectasis and 11% had subpleural cysts. Treatment with corticosteroids was associated with an increased incidence of cytomegalovirus disease (odds ratio, 2.62; P = .014). Conclusions: PCP remains an important opportunistic infection in the ART era. While it did not negatively affect CD4 reconstitution, it could pose an increased risk for incident cytomegalovirus disease with corticosteroid treatment and may cause residual pulmonary sequelae. These findings suggest that PCP and its treatment may contribute to long-term morbidity in PWH, even in the ART era.
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In this study, abnormal levels of myeloid activation, endothelial damage, and innate immune markers were associated with severe coronavirus disease 2019 (COVID-19), while higher levels of metabolic biomarkers (irisin, leptin) demonstrated a protective effect. These data support a model for COVID-19 immunopathogenesis linking robust inflammation and endothelial damage in metabolically predisposed individuals.
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The coronavirus disease-2019 (COVID-19) caused by the SARS-CoV-2 virus may vary from asymptomatic to severe infection with multi-organ failure and death. Increased levels of circulating complement biomarkers have been implicated in COVID-19-related hyperinflammation and coagulopathy. We characterized systemic complement activation at a cellular level in 49-patients with COVID-19. We found increases of the classical complement sentinel C1q and the downstream C3 component on circulating blood monocytes from COVID-19 patients when compared to healthy controls (HCs). Interestingly, the cell surface-bound complement inhibitor CD55 was also upregulated in COVID-19 patient monocytes in comparison with HC cells. Monocyte membrane-bound C1q, C3 and CD55 levels were associated with plasma inflammatory markers such as CRP and serum amyloid A during acute infection. Membrane-bounds C1q and C3 remained elevated even after a short recovery period. These results highlight systemic monocyte-associated complement activation over a broad range of COVID-19 disease severities, with a compensatory upregulation of CD55. Further evaluation of complement and its interaction with myeloid cells at the membrane level could improve understanding of its role in COVID-19 pathogenesis.
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COVID-19/inmunología , Activación de Complemento/inmunología , Proteínas del Sistema Complemento/inmunología , Monocitos/inmunología , Adulto , Biomarcadores/sangre , COVID-19/sangre , COVID-19/virología , Inactivadores del Complemento/inmunología , Citocinas/inmunología , Femenino , Humanos , Factores Inmunológicos/inmunología , Masculino , Persona de Mediana Edad , Monocitos/virología , SARS-CoV-2/inmunologíaRESUMEN
Clinical rebound of COVID-19 after nirmatrelvir/ritonavir treatment has been reported. We performed clinical, virologic, and immune measurements in seven patients with symptomatic rebound, six after nirmatrelvir/ritonavir treatment and one without previous treatment. There was no evidence of severe disease or impaired antibody and T-cell responses in people with rebound symptoms.
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Interferon-γ autoantibodies increase the risk of disseminated nontuberculous mycobacterial infections. Addition of rituximab to antibiotics accelerates and improves outcomes, but refractory infections can occur due to persistent production of autoantibodies. We combined bortezomib with rituximab to reduce autoantibodies leading to clinical and radiographic improvement in infection.
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Anaplasmosis is an emerging infection in the United States and remains under-recognized in many areas including Pennsylvania. Presenting signs and symptoms are often nonspecific, but fulminant infection can occur in vulnerable populations. We present two cases of severe anaplasmosis that progressed to secondary hemophagocytic lymphohistiocytosis (HLH). This severe immune dysregulation syndrome has an extremely high mortality, but anaplasmosis represents one of the few treatable underlying etiologies. It is imperative for physicians to recognize this complication and start empiric doxycycline, as early treatment improves mortality. We also present a case of anaplasmosis-induced HLH successfully treated with a combination of doxycycline, steroids, and anakinra (an IL-1 receptor antagonist), highlighting that this primarily immune-mediated complication is amenable to treatment with both antibiotics and immune suppression.
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Anaplasmosis/complicaciones , Antibacterianos/uso terapéutico , Doxiciclina/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Linfohistiocitosis Hemofagocítica/terapia , Esteroides/uso terapéutico , Anciano , Anciano de 80 o más Años , Humanos , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/etiología , Masculino , Pennsylvania , Resultado del TratamientoRESUMEN
Babesia microti can lead to severe babesiosis in immunosuppressed populations, but due to high numbers of asymptomatic cases, clinical reporting is unable to define its geographic distribution. Although Lyme disease caused by Borrelia burgdorferi is endemic throughout Pennsylvania (PA), human babesiosis is under recognized, despite sharing the same vector and primary reservoir host. Ixodes ticks are known to carry B. microti throughout PA, but information about pathogen prevalence in small mammal reservoirs remains limited. Characterizing B. microti prevalence in these small mammals can elucidate mechanisms of pathogen spread and define geographic areas where humans are at risk of infection. We tested 692 small mammals across eight contiguous counties in central PA for molecular evidence of B. microti and B. burgdorferi. In total, six different small mammal species were collected. The overall prevalence of B. microti was 32% with similar rates observed across all counties. Surprisingly, this was higher than the prevalence of B. burgdorferi at 21%. In fact, high rates of B. microti were found in all six species, and both pathogens were identified in 11% of mammals tested. The prevalence of B. microti was highest in Myodes gapperi (southern red-backed vole) at 39% despite Peromyscus leucopus (white-footed mouse) being considered the primary reservoir host for B. microti. In conclusion, B. microti has a high prevalence across multiple small mammal species throughout central PA. This prevalence is greater than B. burgdorferi despite a much higher incidence of Lyme disease compared to babesiosis in PA. Although it remains unknown how the prevalence of B. microti in small mammal hosts corresponds to human infection rates, the high pathogen prevalence of B. microti suggests that it is an emerging pathogen in this area. Currently, babesiosis is not a reportable disease in PA, and additional studies are warranted to evaluate its clinical significance in this geographic region.
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Babesiosis/epidemiología , Enfermedad de Lyme/epidemiología , Mamíferos/microbiología , Mamíferos/parasitología , Animales , Babesia microti/aislamiento & purificación , Borrelia burgdorferi/aislamiento & purificación , Reservorios de Enfermedades/microbiología , Reservorios de Enfermedades/parasitología , Pennsylvania/epidemiología , PrevalenciaRESUMEN
BACKGROUND: We determined the levels of 11 soluble immune mediators in oral washings of AIDS Clinical Trials Group A5254 participants with varying degrees of plasma viremia and CD4 T-cell counts to characterize the mucosal immune response at different stages of HIV-1 infection. METHODS: A5254 was a multicenter, cross-sectional study in people with HIV (PWH) recruited into 4 strata based on CD4 count and levels of plasma viremia: stratum (St) A: CD4 ≤200 cells/mm3, HIV-1 RNA (viral load [VL]) >1000 cps/mL; St B: CD4 ≤200, VL ≤1000; St C: CD4 >200, VL >1000; St D: CD4 >200, VL ≤1000. Oral/throat washings were obtained from all participants. Soluble markers were tested in oral/throat washings using a multibead fluorescent platform and were compared across strata. Linear regression was used to determine the associations between cytokines and HIV-1 in plasma and oral fluid. RESULTS: St A participants had higher levels of interleukin (IL)-1ß, IL-6, IL-17, tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) compared with St B and D (P = .02; P < .0001) but were not different from St C. IL-8, IL-10, and IL-12 were elevated in St A compared with the other 3 strata (P = .046; P < .0001). Linear regression demonstrated that oral HIV-1 levels were associated with IL-1ß, IL-6, IL-8, and TNFα production (R > .40; P < .001) when controlling for CD4 count and opportunistic infections. CONCLUSIONS: Our results show that high levels of oral HIV-1, rather than low CD4 counts, were linked to the production of oral immune mediators. Participants with AIDS and uncontrolled viremia demonstrated higher levels of pro- and anti-inflammatory soluble immune mediators compared with participants with lower HIV-1 RNA. The interplay of HIV-1 and these immune mediators could be important in the oral health of PWH.
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Aspergillus is a common environmental mold most often recognized as an infectious agent in patients with severe immune compromise. We present a case of an immunocompetent patient presenting with endogenous endophthalmitis in the absence of other infectious symptoms. The search for a systemic source revealed an ascending aortic pseudoaneurysm. Surgical resection and pathology revealed angioinvasive aspergillus aortitis. Recent cardiac surgery has been noted to be a risk factor for angioinvasive aspergillosis. Diagnosis is difficult as symptoms are mild and laboratory studies are often normal. To our knowledge this is the first case of aspergillus aortitis presenting as endogenous endophthalmitis without systemic signs of inflammation. These patients have a high mortality rate therefore early recognition is essential. It is important to consider angioinvasive aspergillus infections in patients with prior cardiac surgery presenting with occult embolic phenomena. Only with early diagnosis and prompt treatment can we improve outcomes of this disease process.