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Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.

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Abstract Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.

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Abstract Introduction: Members of the Herpesviridae family have been described in patients with systemic lupus erythematous (SLE), but the clinical impact on renal function is not well known. Methods: HSV1, HSV2, VZV, EBV, CMV, HHV-6, HHV-7, and HHV-8 were evaluated by molecular biology on admission in blood samples from 40 consecutive SLE patients hospitalized for lupus activity. Results: Patients were 90.0% female, 77.5% non-white, with average age of 32.7 ± 13.6 years. We found positivity for EBV (65.0%), CMV (30.0%), HSV-1 (30.0%), HHV-6 (12.5%), and HHV-7 (7.5%). For all viruses, age, SLEDAI, hematological tests, ferritin, LDH, C-reactive protein, and erythrocyte sedimentation rate (ESR) were not significant. However, EBV positivity was a significant factor for higher serum creatinine (3.0 ± 2.8 vs. 0.9 ± 0.8; P = 0.001) and urea (86 ± 51 vs. 50 ± 46; P = 0.03). Moreover, positive cases for EBV only or with combined co-infections (66.7%-CMV; 58.3%-HSV-1) or negative for EBV only were evaluated by Kruskal-Wallis test again showed statistical significance for serum creatinine and urea (both P ≤ 0.01), with posttest also showing statistical differences for renal dysfunction and EBV presence (alone or in combined co-infections). The presence of EBV viral load was also significant for nephrotic-range proteinuria, renal flare, and the need for hemodialysis. Conclusion: Members of the Herpeviridae family (mainly EBV, HSV-1 and CMV) are common on hospital admission of SLE patients, reaching 65% for EBV, which seems to be associated with renal dysfunction and could reflect a previous association or overlapping disease, which is not well understood.

Resumo Introdução: Membros da família Herpesviridae tem sido descritos em pacientes com lúpus eritematoso sistêmico (LES), mas o impacto clínico na função renal não é bem conhecido. Métodos: Avaliou-se HSV1, HSV2, VZV, EBV, CMV, HHV-6, HHV-7, HHV-8 por biologia molecular na admissão em amostras sanguíneas de 40 pacientes com LES consecutivos hospitalizados por atividade lúpica. Resultados: Pacientes 90,0% mulheres, 77,5% não brancos, idade média 32,7 ± 13,6 anos. Encontramos positividade para EBV (65,0%), CMV (30,0%), HSV-1 (30,0%), HHV-6 (12,5%), HHV-7 (7,5%). Para todos os vírus, idade, SLEDAI, exames hematológicos, ferritina, LDH, proteína C reativa, velocidade de hemossedimentação não foram significativos. Entretanto, positividade para EBV foi estatisticamente significativo para creatinina (3,0 ± 2,8 vs. 0,9 ± 0,8; P = 0,001) e ureia (86 ± 51 vs. 50 ± 46; P = 0,03) séricas mais elevadas. Ademais, casos positivos para EBV isolado ou com coinfecções combinadas (66,7%-CMV; 58,3%-HSV-1) ou negativos apenas para EBV foram avaliados pelo teste Kruskal-Wallis e novamente mostraram significância estatística para creatinina e ureia séricas (ambas P ≤ 0,01), com pós-teste mostrando também diferenças estatísticas para disfunção renal e presença de EBV (sozinho ou em coinfecções combinadas). A presença de carga viral do EBV também foi significativa para proteinúria de faixa nefrótica, inflamação aguda, necessidade de hemodiálise. Conclusão: Membros da família Herpeviridae (principalmente EBV, HSV-1, CMV) são comuns na admissão de pacientes com LES, chegando a 65% para EBV, que parece associar-se à disfunção renal podendo refletir associação prévia ou doença sobreposta, o que não é bem compreendido.

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INTRODUCTION: Members of the Herpesviridae family have been described in patients with systemic lupus erythematous (SLE), but the clinical impact on renal function is not well known. METHODS: HSV1, HSV2, VZV, EBV, CMV, HHV-6, HHV-7, and HHV-8 were evaluated by molecular biology on admission in blood samples from 40 consecutive SLE patients hospitalized for lupus activity. RESULTS: Patients were 90.0% female, 77.5% non-white, with average age of 32.7 ± 13.6 years. We found positivity for EBV (65.0%), CMV (30.0%), HSV-1 (30.0%), HHV-6 (12.5%), and HHV-7 (7.5%). For all viruses, age, SLEDAI, hematological tests, ferritin, LDH, C-reactive protein, and erythrocyte sedimentation rate (ESR) were not significant. However, EBV positivity was a significant factor for higher serum creatinine (3.0 ± 2.8 vs. 0.9 ± 0.8; P = 0.001) and urea (86 ± 51 vs. 50 ± 46; P = 0.03). Moreover, positive cases for EBV only or with combined co-infections (66.7%-CMV; 58.3%-HSV-1) or negative for EBV only were evaluated by Kruskal-Wallis test again showed statistical significance for serum creatinine and urea (both P ≤ 0.01), with posttest also showing statistical differences for renal dysfunction and EBV presence (alone or in combined co-infections). The presence of EBV viral load was also significant for nephrotic-range proteinuria, renal flare, and the need for hemodialysis. CONCLUSION: Members of the Herpeviridae family (mainly EBV, HSV-1 and CMV) are common on hospital admission of SLE patients, reaching 65% for EBV, which seems to be associated with renal dysfunction and could reflect a previous association or overlapping disease, which is not well understood.

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Human herpesvirus-6 (HHV-6) may cause serious diseases in immunocompromised individuals. SARS-CoV-2/HHV-6 coinfection has been emphasized in previous works, mostly case reports, small series, or epidemiological studies, but few are known about its real clinical outcomes. Here we present a real-world pilot study aiming to understand the frequency and the clinical impact of HHV-6 coinfection in moderate to critically ill patients hospitalized due to COVID-19. SARS-CoV-2 and HHV-6 were evaluated in nasopharyngeal samples at the hospital admission of suspected COVID-19 patients. From 173 consecutive cases, 60 were SARS-CoV-2 positive and 13/60 (21.7%) were HHV-6 positive after identified as the HHV-6B species by a Sanger sequencing. The SARS-CoV-2+/HHV-6+ group was younger but not significant for cardiovascular diseases, diabetes, obesity, and cancer, but significant among therapeutic immunosuppressed patients (as systemic lupus erythematosus and kidney transplant patients). In the medical records, only sparse data on cutaneous or neurological manifestations were found. Biochemical and hematological data showed only a trend towards hyperferritinemic status and lymphopenia. In conclusion, despite the impressive high frequency of HHV-6 coinfection in SARS-CoV-2 positive cases, it did not impact general mortality. We suggest larger future prospective studies to better elucidate the influence of HHV-6 reactivation in cases of COVID-19, designed to specific assessment of clinical outcomes and viral reactivation mechanisms.

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INTRODUCTION: Some COVID-19 patients have higher mortality and the responsible factors for this unfavorable outcome is still not well understood. OBJECTIVE: To study the association between ferritin levels at admission, representing an inflammatory state, and hospital mortality in COVID-19 patients. METHODS: From May through July 2020, SARS-CoV-2 positive patients with moderate to severe clinical symptoms were evaluated at admission, regarding clinical and laboratory data on renal and hepatic function, hematologic parameters, cytomegalovirus co-infection, and acute phase proteins. RESULTS: A total of 97 patients were included; mean age=59.9±16.3 years, 58.8% male, 57.7% non-white, in-hospital mortality=45.4%. Age, ferritin, C-reactive protein, serum albumin and creatinine were significantly associated with mortality. Ferritin showed area under the curve (AUC) of 0.79 (p<0.001) for the cut-off of 1873.0ng/mL, sensitivity of 68.4% and specificity of 79.3% in predicting in-hospital mortality. Age ≥60 years had an odds ratio (OR) of 10.5 (95% CI=1.8-59.5; p=0.008) and ferritin ≥1873.0ng/mL had an OR of 6.0 (95% CI=1.4-26.2; p=0.016), both independently associated with mortality based on logistic regression analysis. CONCLUSION: The magnitude of inflammation present at admission of COVID-19 patients, represented by high ferritin levels, is independently predictive of in-hospital mortality.

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ABSTRACT Introduction: Some COVID-19 patients have higher mortality and the responsible factors for this unfavorable outcome is still not well understood. Objective: To study the association between ferritin levels at admission, representing an inflammatory state, and hospital mortality in COVID-19 patients. Methods: From May through July 2020, SARS-CoV-2 positive patients with moderate to severe clinical symptoms were evaluated at admission, regarding clinical and laboratory data on renal and hepatic function, hematologic parameters, cytomegalovirus co-infection, and acute phase proteins. Results: A total of 97 patients were included; mean age = 59.9 ± 16.3 years, 58.8% male, 57.7% non-white, in-hospital mortality = 45.4%. Age, ferritin, C-reactive protein, serum albumin and creatinine were significantly associated with mortality. Ferritin showed area under the curve (AUC) of 0.79 (p < 0.001) for the cut-off of 1873.0 ng/mL, sensitivity of 68.4% and specificity of 79.3% in predicting in-hospital mortality. Age ≥60 years had an odds ratio (OR) of 10.5 (95% CI = 1.8-59.5; p = 0.008) and ferritin ≥1873.0 ng/mL had an OR of 6.0 (95% CI = 1.4-26.2; p = 0.016), both independently associated with mortality based on logistic regression analysis. Conclusion: The magnitude of inflammation present at admission of COVID-19 patients, represented by high ferritin levels, is independently predictive of in-hospital mortality.

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INTRODUCTION: In contrast to organ transplantation, few studies correlate the monitoring of pp65 antigenemia with a diagnosis of cytomegalovirus (CMV) in patients with systemic lupus erythematosus (SLE). OBJECTIVE: To highlight the importance of CMV outside transplantation, we monitored pp65 antigenemia in a series of SLE patients. METHODS: From March 2015 to March 2016, SLE patients presenting kidney involvement, fever, and an unclear infection at hospital admission were monitored through pp65 antigenemia. The pp65 antigenemia assay, revealed by immunofluorescence, was correlated with clinical and laboratory findings. RESULTS: We included 19 patients with a suspected unclear infection. A positivity for pp65 antigenemia was found in seven patients (36.8%). The mean age was 33.5 ± 11.2 years, 16 (84%) were females, and 16 (84%) were black. Lymphopenia, anemia, and higher scores of SLEDAI were significantly more common in pp65-positive patients. Five patients received antiviral therapy with ganciclovir. Although receiving specific CMV treatment, one patient died because of suspected CMV disease. CONCLUSIONS: Pp65 antigenemia might be relevant in SLE patients, and studies with a greater number of patients are needed in order to establish sensitivity and specificity of pp65 antigenemia in different clinical contexts of SLE patients.

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ABSTRACT Introduction: In contrast to organ transplantation, few studies correlate the monitoring of pp65 antigenemia with a diagnosis of cytomegalovirus (CMV) in patients with systemic lupus erythematosus (SLE). Objective: To highlight the importance of CMV outside transplantation, we monitored pp65 antigenemia in a series of SLE patients. Methods: From March 2015 to March 2016, SLE patients presenting kidney involvement, fever, and an unclear infection at hospital admission were monitored through pp65 antigenemia. The pp65 antigenemia assay, revealed by immunofluorescence, was correlated with clinical and laboratory findings. Results: We included 19 patients with a suspected unclear infection. A positivity for pp65 antigenemia was found in seven patients (36.8%). The mean age was 33.5 ± 11.2 years, 16 (84%) were females, and 16 (84%) were black. Lymphopenia, anemia, and higher scores of SLEDAI were significantly more common in pp65-positive patients. Five patients received antiviral therapy with ganciclovir. Although receiving specific CMV treatment, one patient died because of suspected CMV disease. Conclusions: Pp65 antigenemia might be relevant in SLE patients, and studies with a greater number of patients are needed in order to establish sensitivity and specificity of pp65 antigenemia in different clinical contexts of SLE patients.

RESUMO Introdução: Diferentemente do transplante de órgãos, poucos estudos correlacionam o monitoramento da antigenemia pp65 com o diagnóstico de citomegalovírus (CMV) em pacientes com lúpus eritematoso sistêmico (LES). Objetivo: De modo a destacar a importância do CMV para além do transplante, monitorizamos a antigenemia pp65 em uma série de pacientes com LES. Métodos: De março de 2015 a março de 2016, pacientes com LES que apresentaram acometimento renal, febre e infecção indeterminada na internação foram monitorados através da antigenemia pp65. O ensaio de antigenemia, revelada por imunofluorescência, foi correlacionado com achado clínicos e laboratoriais. Resultados: Foram incluídos 19 pacientes com suspeita de infecção indeterminada. Positividade para antigenemia pp65 foi encontrada em sete pacientes (36,8%). A idade média foi de 33,5 ± 11,2 anos; 16 (84%) eram do sexo feminino e 16 (84%) eram negros. Linfopenia, anemia e escore de SLEDAI mais elevado foram significativamente mais comuns em pacientes pp65 positivos. Cinco pacientes receberam terapia antiviral com ganciclovir. Apesar de receber tratamento específico para CMV, um paciente com suspeita de doença por CMV veio a óbito. Conclusões: Antigenemia pp65 pode ser relevante em pacientes com LES, e estudos com maior número de pacientes são necessários para estabelecer a sensibilidade e a especificidade da antigenemia pp65 em diferentes contextos clínicos envolvendo pacientes com LES.

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