Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children.

OBJECTIVES: Sepsis-associated immune suppression correlates with poor outcomes. Adult trials are evaluating immune support therapies. Limited data exist to support consideration of immunomodulation in pediatric sepsis. We tested the hypothesis that early, persistent lymphopenia predicts worse outcomes in pediatric severe sepsis. DESIGN: Observational cohort comparing children with severe sepsis and early, persistent lymphopenia (absolute lymphocyte count < 1,000 cells/µL on 2 d between study days 0-5) to children without. The composite outcome was prolonged multiple organ dysfunction syndrome (MODS, organ dysfunction beyond day 7) or PICU mortality. SETTING: Nine PICUs in the National Institutes of Health Collaborative Pediatric Critical Care Research Network between 2015 and 2017. PATIENTS: Children with severe sepsis and indwelling arterial and/or central venous catheters. INTERVENTIONS: Blood sampling and clinical data analysis. MEASUREMENTS AND MAIN RESULTS: Among 401 pediatric patients with severe sepsis, 152 (38%) had persistent lymphopenia. These patients were older, had higher illness severity, and were more likely to have underlying comorbidities including solid organ transplant or malignancy. Persistent lymphopenia was associated with the composite outcome prolonged MODS or PICU mortality (66/152, 43% vs 45/249, 18%; p < 0.01) and its components prolonged MODS (59/152 [39%] vs 43/249 [17%]), and PICU mortality (32/152, 21% vs 12/249, 5%; p < 0.01) versus children without. After adjusting for baseline factors at enrollment, the presence of persistent lymphopenia was associated with an odds ratio of 2.98 (95% CI [1.85-4.02]; p < 0.01) for the composite outcome. Lymphocyte count trajectories showed that patients with persistent lymphopenia generally did not recover lymphocyte counts during the study, had lower nadir whole blood tumor necrosis factor-α response to lipopolysaccharide stimulation, and higher maximal inflammatory markers (C-reactive protein and ferritin) during days 0-3 ( p < 0.01). CONCLUSIONS: Children with severe sepsis and persistent lymphopenia are at risk of prolonged MODS or PICU mortality. This evidence supports testing therapies for pediatric severe sepsis patients risk-stratified by early, persistent lymphopenia.

Multicentre observational study on multisystem inflammatory syndrome related to COVID-19 in Argentina.

BACKGROUND: The impact of the pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in low- and middle-income countries remains poorly understood. Our aim was to understand the characteristics and outcomes of PIMS-TS in Argentina. METHODS: This observational, prospective, and retrospective multicenter study enrolled patients younger than 18 years-old manifesting PIMS-TS, Kawasaki disease (KD) or Kawasaki shock syndrome (KSS) between March 2020 and May 2021. Patients were followed-up until hospital discharge or death (one case). The primary outcome was pediatric intensive care unit (PICU) admission. Multiple logistic regression was used to identify variables predicting PICU admission. RESULTS: Eighty-one percent, 82%, and 14% of the 176 enrolled patients fulfilled the suspect case criteria for PIMS-TS, KD, and KSS, respectively. Temporal association with SARS-CoV-2 was confirmed in 85% of the patients and 38% were admitted to the PICU. The more common clinical manifestations were fever, abdominal pain, rash, and conjunctival injection. Lymphopenia was more common among PICU-admitted patients (87% vs. 51%, p < 0.0001), who also showed a lower platelet count and higher plasmatic levels of inflammatory and cardiac markers. Mitral valve insufficiency, left ventricular wall motion alterations, pericardial effusion, and coronary artery alterations were observed in 30%, 30%, 19.8%, and 18.6% of the patients, respectively. Days to initiation of treatment, rash, lymphopenia, and low platelet count were significant independent contributions to PICU admission. CONCLUSION: Rates of severe outcomes of PIMS-TS in the present study agreed with those observed in high-income countries. Together with other published studies, this work helps clinicians to better understand this novel clinical entity.

The Role of the Immune System on the Cardiac Complications Observed in SARS-CoV-2

Abstract An acute respiratory syndrome caused by SARS-CoV2 was declared a pandemic by the World Health Organization. Current data in the world and in Brazil show that approximately 40% of patients who died have some type of cardiac comorbidity. There are also robust reports showing an increase in IL-6 / IL-1B / TNF-alpha and the presence of lymphopenia in patients with COVID-19. Our team and others have shown that increased cytokines are the link between arrhythmias/Left ventricular dysfunction and the immune system in different diseases. In addition, it has been well demonstrated that lymphopenia can not only be a good marker, but also a factor that causes heart failure. Thus, the present review focused on the role of the immune system upon the cardiac alterations observed in the SARS-CoV2 infection. Additionally, it was well described that SARS-CoV-2 is able to infect cardiac cells. Therefore, here it will be reviewed in deep.

Potential impact of SARS-CoV-2 infection on the thymus.

Understanding the pathogenesis of certain viral agents is essential for developing new treatments and obtaining a clinical cure. With the onset of the new coronavirus (SARS-CoV-2) pandemic in the beginning of 2020, a rush to conduct studies and develop drugs has led to the publication of articles that seek to address knowledge gaps and contribute to the global scientific research community. There are still no reports on the infectivity or repercussions of SARS-CoV-2 infection on the central lymphoid organ, the thymus, nor on thymocytes or thymic epithelial cells. In this brief review, we present a hypothesis about lymphopenia observed in SARS patients and the probable pathological changes that the thymus may undergo due to this new virus.

Patients with cirrhosis in the ED: early predictors of infection and mortality.

BACKGROUND: Patients with cirrhosis have high risk of bacterial infections and cirrhosis decompensation, resulting in admission to emergency department (ED). However, there are no criteria developed in the ED to identify patients with cirrhosis with bacterial infection and with high mortality risk. STUDY OBJECTIVE: The objective of the study is to identify variables from ED arrival associated with bacterial infections and inhospital mortality. METHODS: This is a retrospective single-center study using a tertiary hospital's database to identify consecutive ED patients with decompensated cirrhosis. Clinical variables and laboratory results were obtained by chart review. Logistic regression models were built to determine variables independently associated with bacterial infection and mortality. Scores using these variables were designed. RESULTS: One hundred forty-nine patients were enrolled, most of them males (77.9%) with alcoholic cirrhosis (53%) and advanced liver disease (Child-Pugh C, 47.2%). Bacterial infections were diagnosed in 72 patients (48.3%), and 36 (24.2%) died during hospital stay. Variables independently associated with bacterial infection were lymphocytes less than or equal to 900/mm(3) (odds ratio [OR], 3.85 [95% confidence interval {CI}, 1.47-10]; P = .006) and C-reactive protein greater than 59.4 mg/L (OR, 5.05 [95% CI, 1.93-13.2]; P = .001). Variables independently associated with mortality were creatinine greater than 1.5 mg/dL (OR, 4.35 [95% CI, 1.87-10.1]; P = .001) and international normalized ratio greater than 1.65 (OR, 3.71 [95% CI, 1.6-8.61]; P = .002). Scores designed to predict bacterial infection and mortality (Mortality in Cirrhosis Emergency Department Score) had an area under the receiver operating characteristic curve of 0.82 and 0.801, respectively. The Mortality in Cirrhosis Emergency Department Score performed better than Model for End-Stage Liver Disease score. CONCLUSIONS: In this cohort of ED patients with decompensated cirrhosis, lymphopenia and elevated C-reactive protein were related to bacterial infections, and elevated creatinine and international normalized ratio were related to mortality. Scores built with these variables should be prospectively validated.

Risk factors and clinical profile of thrombotic thrombocytopenic purpura in systemic lupus erythematosus patients. Is this a distinctive clinical entity in the thrombotic microangiopathy spectrum?: a case control study.

INTRODUCTION: The association of thrombotic thrombocytopenic purpura (TTP) with systemic lupus erythematosus (SLE) is rare. It is associated with high morbidity and mortality. Information about risk factors and clinical outcomes is scant. MATERIAL AND METHODS: A retrospective case-control study was performed in a referral center in Mexico City between 1994 and 2013. Patients were diagnosed with TTP if they fulfilled the following criteria: microangiopathic haemolytic anaemia, thrombocytopenia, high LDH levels, normal fibrinogen and negative Coombs' test. Patients with SLE were diagnosed with ≥ 4 ACR criteria. We included three study groups: group A included patients with SLE-associated TTP (TTP/SLE; cases n = 22, TTP events n = 24); patients with non-autoimmune TTP (NA-TTP; cases n = 19, TTP events n = 22) were included in group B and patients with SLE without TTP (n = 48) in group C. RESULTS: After multivariate analysis, lymphopenia < 1000/mm3 [OR 19.84, p = 0.037], high SLEDAI score three months prior to hospitalisation [OR 1.54, p = 0.028], Hg <7g/dL [OR 6.81, p = 0.026], low levels of indirect bilirubin [OR 0.51, p = 0.007], and less severe thrombocytopenia [OR 0.98, p = 0.009] were associated with TTP in SLE patients. Patients with TTP/SLE received increased cumulative steroid dose vs. NA-TTP (p = 0.006) and a higher number of immunosuppressive drugs (p = 0.015). Patients with TTP/SLE had higher survival than NA-TTP (p=0.033); however, patients hospitalised for TTP/SLE had a higher risk of death than lupus patients hospitalised for other causes CONCLUSIONS: Lymphopenia is an independent risk factor for TTP/SLE. It is likely that patients with TTP/SLE present with less evident clinical features, so the level of suspicion must be higher to avoid delay in treatment.

Lymphopenia as risk factor for development of severe infections in patients with systemic lupus erythematosus: a case-control study.

OBJECTIVES: Hematological abnormalities, particularly lymphopenia, are common in patients with systemic lupus erythematosus (SLE), whether the disease is active or not. The aim of this study is to assess whether lymphopenia (blood counts ≤1000 K/µl) is a risk factor for severe infections in patients with SLE. METHODS: A retrospective case-control study was performed. We reviewed the clinical records of 167 SLE patients throughout a 5-year period. SLE patients with severe infections were compared with those without infection and the presence of lymphopenia was obtained from the blood count previous to the infection date. Also, other clinical and laboratory features as well as immunosuppressive therapy and SLE disease activity index (SLEDAI) were recorded. RESULTS: Univariate analysis shows multiple risk factors for severe infections in SLE, such as lymphopenia, high SLEDAI index, prednisone (PDN) and mycophenolate mofetil treatment and low levels of C3 and C4. Moreover, hydroxychloroquine treatment conferred protection. However, after multivariate analysis, only lymphopenia [odds ratio (OR) 5.2, 95% confidence interval (CI) 2.39-11.3], PDN treatment (OR 4.8, 95% CI 2.1-11.9) and low levels of C3 (OR 2.97, 95% CI 1.1-7.9) remained as independent risk factors. CONCLUSIONS: Our data suggest that lymphopenia, PDN treatment and low levels of C3 are independent risk factors for the development of severe infections in SLE patients, including diverse microorganisms, not only opportunistic infections.

[Disseminated histoplasmosis, lymphopenia and Sjögren's syndrome]. / Histoplasmosis diseminada, linfopenia, y síndrome de Sjögren.

Sjögren's syndrome is an autoimmune disease characterized by decreased exocrine gland secretions; patients may also present several hematological abnormalities, like lymphopenia. We describe the case of a 28 year old man who complained of headache a month of duration, with fever and vomiting in the last 48 hours. He also presented skin lesions on trunk and face, without neck stiffness. The diagnosis of duration infection was confirmed by culture from the skin biopsy and spinal fluid specimens; in addition, the presence of lymphopenia, positive anti Ro-SSA antibodies, poor concentration of the tracer in scintigraphy and lymphocytic infiltration in salivary glands confirmed the diagnosis of Sjögren's syndrome. the patient was successfully treated with liposomal amphotericin and itraconazole. We report this case to emphasize that opportunistic infections, such as disseminated histoplasmosis, may be an uncommon clinical presentation of Sjögren's syndrome.

Histoplasmosis diseminada, linfopenia, y síndrome de Sj÷gren / Disseminated histoplasmosis, lymphopenia and Sj÷gren´s syndrome

El síndrome de Sj÷gren es una enfermedad autoinmune caracterizada por disminución de las secreciones de las glándulas exocrinas; puede presentar también diversas alteraciones hemáticas, entre ellas linfopenia. Presentamos el caso de un varón de 28 años que consultó por cefalea de un mes de evolución a la que se agregaron en las últimas 48 horas vómitos y fiebre. Presentaba lesiones en piel de tronco y cara; no tenía rigidez de nuca. Se demostró infección por Histoplasma capsulatum var. capsulatum en piel y líquido cefalorraquídeo, linfopenia, anticuerpos anti Ro-SSA positivos, baja concentración del trazador en centellograma de glándulas salivales e infiltración linfocitaria en glándulas salivales, lo que permitió confirmar al diagnóstico de síndrome de Sj÷gren. El tratamiento con anfotericina liposomal e itraconazol mejoró el cuadro clínico. Comunicamos este caso para referir que una infección oportunista, como la histoplasmosis diseminada, puede ser una forma poco común de presentación del síndrome de Sj÷gren.(AU)

Sj÷grens syndrome is an autoimmune disease characterized by decreased exocrine gland secretions; patients may also present several hematological abnormalities, like lymphopenia. We describe the case of a 28 year old man who complained of headache a month of duration, with fever and vomiting in the last 48 hours. He also presented skin lesions on trunk and face, without neck stiffness. The diagnosis of duration infection was confirmed by culture from the skin biopsy and spinal fluid specimens; in addition, the presence of lymphopenia, positive anti Ro-SSA antibodies, poor concentration of the tracer in scintigraphy and lymphocytic infiltration in salivary glands confirmed the diagnosis of Sj÷grens syndrome. The patient was successfully treated with liposomal amphotericin and itraconazole. We report this case to emphasize that opportunistic infections, such as disseminated histoplasmosis, may be an uncommon clinical presentation of Sj÷grens syndrome.(AU)

Histoplasmosis diseminada, linfopenia, y síndrome de Sjögren / Disseminated histoplasmosis, lymphopenia and Sjögren´s syndrome

El síndrome de Sjögren es una enfermedad autoinmune caracterizada por disminución de las secreciones de las glándulas exocrinas; puede presentar también diversas alteraciones hemáticas, entre ellas linfopenia. Presentamos el caso de un varón de 28 años que consultó por cefalea de un mes de evolución a la que se agregaron en las últimas 48 horas vómitos y fiebre. Presentaba lesiones en piel de tronco y cara; no tenía rigidez de nuca. Se demostró infección por Histoplasma capsulatum var. capsulatum en piel y líquido cefalorraquídeo, linfopenia, anticuerpos anti Ro-SSA positivos, baja concentración del trazador en centellograma de glándulas salivales e infiltración linfocitaria en glándulas salivales, lo que permitió confirmar al diagnóstico de síndrome de Sjögren. El tratamiento con anfotericina liposomal e itraconazol mejoró el cuadro clínico. Comunicamos este caso para referir que una infección oportunista, como la histoplasmosis diseminada, puede ser una forma poco común de presentación del síndrome de Sjögren.

Sjögren's syndrome is an autoimmune disease characterized by decreased exocrine gland secretions; patients may also present several hematological abnormalities, like lymphopenia. We describe the case of a 28 year old man who complained of headache a month of duration, with fever and vomiting in the last 48 hours. He also presented skin lesions on trunk and face, without neck stiffness. The diagnosis of duration infection was confirmed by culture from the skin biopsy and spinal fluid specimens; in addition, the presence of lymphopenia, positive anti Ro-SSA antibodies, poor concentration of the tracer in scintigraphy and lymphocytic infiltration in salivary glands confirmed the diagnosis of Sjögren's syndrome. The patient was successfully treated with liposomal amphotericin and itraconazole. We report this case to emphasize that opportunistic infections, such as disseminated histoplasmosis, may be an uncommon clinical presentation of Sjögren's syndrome.

Association of Crohn's disease, thiopurines, and primary epstein-barr virus infection with hemophagocytic lymphohistiocytosis.

OBJECTIVE: To assess the incidence of hemophagocytic lymphohistiocytosis (HLH) in a well-defined population of children with inflammatory bowel disease (IBD) and evaluate the common clinical and laboratory characteristics of individuals with IBD who developed HLH. STUDY DESIGN: We conducted a retrospective study of all children who developed HLH over an 8-year period. The incidence of HLH in patients with IBD was calculated using US census data and a statewide project examining the epidemiology of pediatric IBD. RESULTS: Among children in Wisconsin, 20 cases of HLH occurred during the study period; 5 cases occurred in children with IBD. Common characteristics include: Crohn's disease (CD), thiopurine administration, fever lasting more than 5 days, lymphadenopathy, splenomegaly, anemia, lymphopenia, and elevated serum triglycerides and ferritin. Of the patients, 4 had primary Epstein-Barr virus infections. The incidence of HLH among all children in Wisconsin was 1.5 per 100 000 per year. The risk was more than 100-fold greater for children with CD (P < .00001). CONCLUSIONS: Pediatric patients with CD are at increased risk for developing HLH; primary Epstein-Barr virus infection and thiopurine administration may be risk factors.

Low CD40L levels and relative lymphopenia in narcoleptic patients.

Narcolepsy has been studied as a possible autoimmune disease for many years, and recent findings lend more credence to this belief. Although recent and important advances have been done, no study has analyzed the role of the CD40L in patients with narcolepsy. The purpose of this study was to assess CD40L levels, CD3, TCD4, TCD8, CD19, and CD56 lymphocytes, as well as levels of tumor necrosis factor-α and interleukin-6 in narcoleptic patients. We quantified the levels of CD40L, different types of lymphocytes, and levels of tumor necrosis factor-α and interleukin-6 in narcoleptic patients and control subjects. Narcoleptic patients had lower levels of CD40L. Total lymphocytes; CD3, and TCD4 were lower than in the control group. Our findings highlight the important role of CD40L in narcolepsy.

Quantitative and functional profiles of CD4+ lymphocyte subsets in systemic lupus erythematosus patients with lymphopenia.

Lymphopenia is a common clinical manifestation in patients with systemic lupus erythematosus (SLE). However, its physiopathogenic role and the contribution of different T cell subsets in this setting have not been addressed fully. The aim of this study was to characterize T cell subsets quantitatively and functionally and their association with lymphopenia and azathioprine treatment in SLE. We included 84 SLE patients and 84 healthy controls and selected 20 patients for a 6-month longitudinal analysis. Peripheral blood mononuclear cells were isolated, and T cell subsets were analysed by flow cytometry. Functional analyses included autologous and allogeneic co-cultures of T cells. Our data show persistently lower absolute numbers of CD4(+) CD25(high) T cells [regulatory T cells (T(regs) )] (1·9 versus 5·2, P < 0·01) and CD4(+) CD69(+) T cells (3·2 versus 9·3, P = 0·02) and higher activity scores (4·1 versus 1·5, P = 0·01) in SLE patients with lymphopenia compared with those without lymphopenia. Lymphopenia increased the risk for decreased numbers of CD4(+) CD25(high) cells (relative risk 1·80, 95% confidence interval 1·10-2·93; P = 0·003). In addition, azathioprine-associated lymphopenia was characterized by decreased absolute numbers of CD4(+) CD69(+) and CD4(+) interleukin (IL)-17(+) cells compared to disease activity-associated lymphopenia. Functional assays revealed that SLE effector T cells were highly proliferative and resistant to suppression by autologous T(regs) . In summary, lymphopenia was associated with deficient numbers of CD4(+) CD25(high) and CD4(+) CD69(+) cells and resistance of effector T cells to suppression by T(regs) , which could contribute to the altered immune responses characteristic of SLE. Furthermore, azathioprine treatment was associated with decreased numbers of CD4(+) CD69(+) and CD4(+) IL-17(+) cells and diminished T(reg) suppressive activity.

Autoantibodies against galectin-8: their specificity, association with lymphopenia in systemic lupus erythematosus and detection in rheumatoid arthritis and acute inflammation.

The role of autoantibodies in the pathogenesis of systemic lupus erythematosus (SLE) has not been completely defined. From more than a hundred autoantibodies described in SLE, relatively few have been associated with clinical manifestations. The glycan-binding proteins of the galectin family can modulate the immune system. Anti-galectin autoantibodies thus could have functional and/or pathogenic implications in inflammatory processes and autoimmunity. We previously reported function-blocking autoantibodies against galectin-8 (Gal-8) in SLE. Here we tested these autoantibodies against a series of other human galectins and demonstrated their specificity for Gal-8, being detectable in 23% of 78 SLE patients. Remarkably, they associated with lymphopenia (50% of 18 anti-Gal-8-positive versus 18% of 60 anti-Gal-8-negative cases, Fisher's Exact test two-tailed: P < 0.012). Lymphopenia is a common clinical manifestation in SLE, yet of unknown mechanism. In addition, six of eight patients with both lymphopenia and malar rash had anti-Gal-8 in their sera. Occurrence of these autoantibodies was not confined to SLE as we also found them in sera of patients with rheumatoid arthritis (16%) and septicemia (20%). This study thus establishes occurrence of specific anti-Gal-8 autoantibodies in autoimmune rheumatic diseases and in acute inflammation, with an apparent association to a clinical subset in SLE.

Systemic lupus erythematosus in a multiethnic US cohort, XXXVII: association of lymphopenia with clinical manifestations, serologic abnormalities, disease activity, and damage accrual.

OBJECTIVE: To determine if lymphopenia is associated with clinical/immunologic manifestations, disease activity, and disease damage in systemic lupus erythematosus (SLE). METHODS: The study group comprised 591 patients with SLE participating in a multiethnic, longitudinal outcome study. Cumulative clinical/immunologic (per American College of Rheumatology criteria) and pharmacologic treatment variables were obtained at enrollment (T0) and last visit (TL). Lymphopenia (<1,500/mm3) was scored only when clinically attributable to SLE and not to medications or other causes. Lymphocyte counts were expressed in 4 categories per the Systemic Lupus Activity Measure (SLAM): normal (> or =1,500/mm3), mild (1,000-1,499/mm3), moderate (500-999/mm3), and marked (<500/mm3). Disease activity was assessed with the SLAM and the Physician's Global Assessment (PGA). Disease damage was determined with the Systemic Lupus International Collaborating Clinics Damage Index (SLICC-DI). The relationship of lymphopenia with cumulative clinical/immunologic and pharmacologic treatment variables was first examined, then the association between the SLAM, PGA, and SLICC-DI scores with different categories of lymphopenia was examined by generalized estimating equation (GEE) regression analyses. Ethnicity, age, and sex were entered into all regression models. RESULTS: At T0 and TL, lymphopenia was found to be positively associated with renal involvement, leukopenia, anti-double-stranded DNA antibodies, anti-Ro antibodies, and the use of glucocorticoids, azathioprine, and methotrexate, but was negatively associated with photosensitivity. On GEE analyses, marked lymphopenia at T0 and moderate and marked lymphopenia for all visits were independently associated with higher SLAM, PGA, and SLICC-DI scores. CONCLUSION: Lymphopenia is associated with several clinical/immunologic manifestations in SLE. Moderate and marked lymphopenia are associated with higher disease activity and damage accrual.

Successful bone marrow transplantation in a patient with Schimke immuno-osseous dysplasia.

Early death in Schimke immuno-osseous dysplasia often results from renal failure and/or cell-mediated immunodeficiency. Kidney transplants have improved renal function, but effective therapy for the immunodeficiency has not yet been reported. We describe markedly improved marrow function 2 years after bone marrow transplantation in a boy with Schimke immunoosseous dysplasia.

Neumonía por pneumocystis carinii: factores predisponentes, manifestaciones clínicas y respuesta a tratamiento / Pneumocystis carinii pneumonia: risk factors, clinical manifestations and treatment outcome

Presentamos una serie de 43 pacientes con neumonía por P. carinii confirmada ya sea por anatomía patológica y/o RPC, destacando como patología de base más frecuente el SIDA, pero también se pesquisaron casos en pacientes con otras inmunodeficiencias, leucemia linfoblástica aguda, tratamiento inmunosupresor y linfopenia idiopática. En los pacientes infectados por VIH la evolución del cuadro fue larvada mientras que en los pacinetes leucémicos la presentación clínica del cuadro fue más agresiva. Destacó la tríada sintomática de fiebre, tos y disnea como los hallazgos clínicos más frecuentes, junto a una elevación constante de LDH y un recuento de CD4 inferior a 200 células/mm3. La mayoría de los pacientes presentó un patrón radiológico de tipo retículo nodular, aunque se evidenciaron también condensaciones y radiografías de tórax normales. La mayoría de los pacientes presentó una evolución clínica favorable con pocas reacciones adversas severas a cotrimoxazol, pero sí más frecuentes a pentamidina intravenosa. En el subgrupo de pacientes admitidos en UCI se observó una elevada letalidad