Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects.

Several diseases (such as diabetes, cancer, and neurodegenerative disorders) affect the morpho-functional aspects of red blood cells, sometimes altering their normal metabolism. In this review, the hematological changes are evaluated, with particular focus on the morphology and metabolic aspects of erythrocytes. Changes in the functionality of such cells may, in fact, help provide important information about disease severity and progression. The viral infection causes significant damage to the blood cells that are altered in size, rigidity, and distribution width. Lower levels of hemoglobin and anemia have been reported in several studies, and an alteration in the concentration of antioxidant enzymes has been shown to promote a dangerous state of oxidative stress in red blood cells. Patients with severe COVID-19 showed an increase in hematological changes, indicating a progressive worsening as COVID-19 severity progressed. Therefore, monitored hematological alterations in patients with COVID-19 may play an important role in the management of the disease and prevent the risk of a severe course of the disease. Finally, monitored changes in erythrocytes and blood, in general, may be one of the causes of the condition known as Long COVID.

Anaemia and enhancement of coagulation are associated with severe COVID-19 infection.

Coagulation disturbances are common in severe COVID-19 infection. We examined laboratory markers in COVID-19 patients during the first wave of the pandemic in Finland. We analysed a wide panel of coagulation tests (IL ACL TOP 750/500®) from anonymously collected samples of 78 hospitalized COVID-19 patients in intensive care units (ICUs; n = 34) or medical wards (n = 44) at Helsinki University Hospital in April-May 2020. These coagulation data were supplemented with the laboratory information system results, including complete blood count and C reactive protein (CRP). Coagulation and inflammatory markers were elevated in most: FVIII in 52%, fibrinogen 77%, D-dimer 74%, CRP 94%, platelet count 37%. Anaemia was common, especially in men (73% vs. 44% in women), and overall weakly correlated with FVIII (women R2 = 0.48, men R2 = 0.24). ICU patients had higher fibrinogen and D-dimer levels (p < .01). Men admitted to the ICU also had higher platelet count, leukocytes and FVIII and lower haemoglobin than the non-ICU patients. None of the patients met the disseminated intravascular coagulation (DIC) criteria, but 31% had a D-dimer level of at least 1.5 mg/L. Presence of both anaemia and high D-dimer together with FVIII is independently associated with ICU admission. Antithrombin was reduced in 47% of the patients but did not distinguish severity. Overall, CRP was associated with coagulation activation. Elevated FVIII, fibrinogen and D-dimer reflected a strong inflammatory response and were characteristic of hospitalized COVID-19 patients. The patients were often anaemic, as is typical in severe inflammation, while anaemia was also associated with coagulation activity.

Severe Malnutrition and Anemia Are Associated with Severe COVID in Infants.

BACKGROUND: COVID-19 is uncommon and less severe in children than adults. It is thought that infants may be at higher risk for severe disease than older children. There is a paucity of literature on infants with COVID, particularly those with severe disease. OBJECTIVE: We describe demographic, epidemiologic, clinical, radiological, laboratory features and outcomes of infants with confirmed SARS-CoV-2 infection admitted to a tertiary care teaching hospital in Pune, India. METHODOLOGY: Infants who tested positive for SARS-CoV-2 and were admitted between 1 April 2020 and 7 August 2020 were included in the study. RESULTS: A total of 13 infants were admitted during the study period. The median age was 8 months (IQR 6) and nine were male. Common presenting features were fever (n = 8, 62%), poor feeding, irritability, and runny nose (n = 3, 23%). Comorbidities noted were severe acute malnutrition (SAM) in three cases (23%) and nutritional megaloblastic anemia, iron deficiency anemia, sickle thalassemia and renal calculi in one case (8%) each. There was a history of low birth weight in two cases (15%). Pallor was noted in three cases (23%), SAM in three cases (23%) and tachypnea and respiratory distress in four cases (30%). Severe anemia, thrombocytopenia, elevated ferritin, abnormal procalcitonin, abnormal C Reactive Protein and deranged D-dimer was noted in three cases (23%) each. Neutrophil-lymphocyte ratio was normal in all cases. Three infants (43%) had evidence of pneumonia on the chest radiograph, of which one had adult respiratory distress syndrome (ARDS) like pattern, one infant had cardiomegaly and perihilar infiltrates. Hydroxychloroquine and azithromycin were given to five patients (38%), Intravenous Immunoglobulin and methylprednisolone were administered to one patient (8%). One infant died of ARDS with multi-organ dysfunction with refractory shock and hemophagocytic lymphohistiocytosis. CONCLUSION: SAM and anemia may be associated with severe COVID in infants.

Does recombinant human erythropoietin administration in critically ill COVID-19 patients have miraculous therapeutic effects?

An 80-year-old man with multiple comorbidities presented to the emergency department with tachypnea, tachycardia, fever, and critically low O2 saturation and definitive chest computerized tomography scan findings in favor of COVID-19 and positive PCR results in 48 hours. He received antiviral treatment plus recombinant human erythropoietin (rhEPO) due to his severe anemia. After 7 days of treatment, he was discharged with miraculous improvement in his symptoms and hemoglobin level. We concluded that rhEPO could attenuate respiratory distress syndrome and confront the severe acute respiratory syndrome coronavirus 2 virus through multiple mechanisms including cytokine modulation, antiapoptotic effects, leukocyte release from bone marrow, and iron redistribution away from the intracellular virus.

Anemia measurements to distinguish between viral and bacterial infections in the emergency department.

The clinical diagnosis of acute infections in the emergency department is a challenging task due to the similarity in symptom presentation between virally and bacterially infected individuals, while the use of routine laboratory tests for pathogen identification is often time-consuming and may contain contaminants. We investigated the ability of various anemia-related parameters, including hemoglobin, red cell distribution width (RDW), and iron, to differentiate between viral and bacterial infection in a retrospective study of 3883 patients admitted to the emergency department with a confirmed viral (n = 1238) or bacterial (n = 2645) infection based on either laboratory tests or microbiological cultures. The ratio between hemoglobin to RDW was found to be significant in distinguishing between virally and bacterially infected patients and outperformed other anemia measurements. Moreover, the predictive value of the ratio was high even in patients presenting with low C-reactive protein values (< 21 mg/L). We followed the dynamics of hemoglobin, RDW, and the ratio between them up to 72 h post emergency department admission, and observed a consistent discrepancy between virally and bacterially infected patients over time. Additional analysis demonstrated higher levels of ferritin and lower levels of iron in bacterially infected compared with virally infected patients. The anemia measurements were associated with length of hospital stay, where all higher levels, except for RDW, corresponded to a shorter hospitalization period. We highlighted the importance of various anemia measurements as an additional host-biomarker to discern virally from bacterially infected patients.

Relationship Between Anemia, Malaria Coinfection, and Kaposi Sarcoma-Associated Herpesvirus Seropositivity in a Population-Based Study in Rural Uganda.

We examined anemia and malaria as risk factors for Kaposi sarcoma-associated herpesvirus (KSHV) seropositivity and antibody levels in a long-standing rural Ugandan cohort, in which KSHV is prevalent. Samples from 4134 children, aged 1-17 years, with a sex ratio of 1:1, and 3149 adults aged 18-103 years, 41% of whom were males, were analyzed. Among children, malaria infection was associated with higher KSHV prevalence (61% vs 41% prevalence among malaria infected and uninfected, respectively); malaria was not assessed in adults. Additionally, lower hemoglobin level was associated with an increased prevalence of KSHV seropositivity, both in children and in adults.

Parvovirus B19 Is Associated with a Significant Decrease in Hemoglobin Level among Children <5 Years of Age with Anemia in Northwestern Tanzania.

Parvovirus B19 (B19) can cause transient aplastic crisis and lead to acute severe anemia. This study investigated the relationship between B19 and anemia among children <5 years old in the city of Mwanza, Tanzania. An enzyme immunoassay was used to detect B19 IgM- and IgG-specific antibodies among children with various categories of anemia according to the World Health Organization (WHO) guidelines. A total of 265 children with median age of 28.5 months (interquartile range 18-39.5) were investigated. Eighty-six children (32.5%) had severe anemia. B19-specific IgM and IgG antibodies were detected in 24 (9%) and 46 (17.4%) children, respectively. Low hemoglobin (Hb) level (p = 0.031), Plasmodium falciparum infection (p = 0.001) and residing in rural areas (p = 0.025) independently predicted B19 IgM seropositivity. Acute B19 infection decreased Hb level by 1.1 g/dl (p = 0.003). In malaria endemic areas, acute B19 infections should be considered among children with severe anemia from rural areas.

Early Intrauterine Transfusion in Fetuses with Severe Anemia Caused by Parvovirus B19 Infection.

OBJECTIVE: To describe procedure-related complications and perinatal survival after intrauterine transfusion (IUT) before 20 weeks of gestation in fetuses with severe anemia due to human parvovirus B19 infection. MATERIALS AND METHODS: A retrospective study was conducted of all fetuses requiring IUT before 20 weeks of gestation in two tertiary referral centers between January 2002 and July 2015. Gestational age (GA) at first IUT, fetal blood sampling results, and presence of hydrops were related to procedure-related complications, fetal death (FD), and perinatal outcome. RESULTS: A total of 93 IUTs was performed on 55 fetuses. The mean GA at first IUT was 16+6 (13+0-19+6) weeks. FD occurred in 11 (20.0%) of the 55 fetuses. Overall survival was 80.0% (44/55). Hydrops was present in 38.2% (21/55) and was strongly associated with FD (p = 0.001). There was no difference with regard to FD, hydrops, or hemoglobin concentration at first IUT in fetuses with transfusion before or after 16+0 weeks. CONCLUSION: Severe anemia due to parvovirus B19 infection in the early second trimester can be treated successfully by IUT before 20 weeks of gestation in specialized centers with sufficient expertise.

Retrovirus-specificity of regulatory T cells is neither present nor required in preventing retrovirus-induced bone marrow immune pathology.

Chronic viral infections of the hematopoietic system are associated with bone marrow dysfunction, to which both virus-mediated and immune-mediated effects may contribute. Using unresolving noncytopathic Friend virus (FV) infection in mice, we showed that unregulated CD4(+) T cell response to FV caused IFN-gamma-mediated bone marrow pathology and anemia. Importantly, bone marrow pathology was triggered by relative insufficiency in regulatory T (Treg) cells and was prevented by added Treg cells, which suppressed the local IFN-gamma production by FV-specific CD4(+) T cells. We further showed that the T cell receptor (TCR) repertoire of transgenic Treg cells expressing the beta chain of an FV-specific TCR was virtually devoid of FV-specific clones. Moreover, anemia induction by virus-specific CD4(+) T cells was efficiently suppressed by virus-nonspecific Treg cells. Thus, sufficient numbers of polyclonal Treg cells may provide substantial protection against bone marrow pathology in chronic viral infections.

Circulating autoantibodies to endogenous erythropoietin are associated with chronic hepatitis C virus infection-related anemia.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with autoimmune phenomena and is often complicated by anemia. Circulating autoantibodies to endogenous erythropoietin (anti-EPO) have been detected in patients with chronic viral infections and were correlated to anemia. The present study aimed to determine anti-EPO prevalence in patients with chronic HCV infection and investigate its possible association with anemia. METHODS: Ninety-three consecutive patients (62 males and 31 females) with chronic HCV infection, who had never received antiviral therapy or recombinant EPO, were enrolled in the study. Circulating anti-EPO were detected in the serum by using an ELISA assay. Quantitative determination of serum EPO levels was done by radioimmunoassay. HCV RNA viral load measurement and genotype sequencing were also performed. RESULTS: Circulating anti-EPO were detected in 10.8% of HCV-infected patients and the prevalence of anti-EPO was significantly higher in patients with anemia (19.4% vs 5.3%, P=0.040) compared to that in those without anemia. Compared to anti-EPO negative cases, anti-EPO positive patients had higher frequency of anemia (70.0% vs 34.9%, P=0.030), lower EPO concentrations (median 16.35 vs 30.65 mU/mL, P=0.005), and higher HCV RNA viral load (median 891.5X103 vs 367.5X103 IU/mL, P=0.016). In multivariate regression analysis the presence of anti-EPO remained an independent predictor of anemia (adjusted OR: 14.303, 95% CI: 1.417-36.580, P=0.024). EPO response to anemia was less prominent among anti-EPO positive patients (P=0.001). CONCLUSIONS: Circulating anti-EPO are detected in a significant proportion of treatment-naive HCV-infected patients and are independently associated with anemia, suggesting a further implication of autoimmunity in the pathophysiology of HCV-related anemia.

Relationship Between Blood Concentrations of Hepcidin and Anemia Severity, Mycobacterial Burden, and Mortality Among Patients With HIV-Associated Tuberculosis.

BACKGROUND: Anemia is very common in patients with human immunodeficiency virus (HIV)-associated tuberculosis, and hepcidin may be key in mediating this. We explored the relationship between blood hepcidin concentrations and anemia severity, mycobacterial burden and mortality in patients with HIV-associated tuberculosis. METHODS: Consecutive unselected HIV-infected adults in South Africa were systematically investigated for tuberculosis. Three groups were studied: 116 hospitalized inpatients with HIV infection and tuberculosis (hereafter, "hospitalized patients"), 58 ambulatory outpatients with HIV infection and newly diagnosed tuberculosis (hereafter, "ambulatory patients with tuberculosis"), and 58 ambulatory outpatients with HIV infection and without tuberculosis (hereafter, "ambulatory patients without tuberculosis"). Blood hepcidin concentrations were determined for all patients. Vital status at 3 months was determined, and independent predictors of mortality were identified. RESULTS: Median hepcidin concentrations were 38.8 ng/mL among hospitalized patients, 19.1 ng/mL among ambulatory patients with tuberculosis, and 5.9 ng/mL among ambulatory patients without tuberculosis (P < .001). In both groups with HIV-associated tuberculosis, hepcidin concentrations were strongly associated with greater anemia severity. Additionally, strong, graded associations were observed between hepcidin and composite indices of mycobacterial burden and dissemination. Patients dying within 3 months had significantly higher hepcidin concentrations, which independently predicted mortality. CONCLUSIONS: High hepcidin concentrations were strongly associated with disseminated disease, anemia, and poor prognosis in patients with HIV-associated tuberculosis. Hepcidin may be a mechanistically important mediator underlying the high prevalence of severe anemia in these patients.

Epidemiologic study of human parvovirus B19 infection in East China.

Human parvovirus B19 (B19V) infection causes a number of diseases in humans, and, in some circumstances, can be life threatening. To understand the epidemiology of B19V infection in the greater metropolitan area of Hangzhou, East China, we performed surveys of IgM and IgG antibodies against B19V and quantification of B19V DNA, by using enzyme-linked immunosorbent assay and quantitative PCR, respectively, in plasma samples from diverse groups. These groups included anemia patients, Mycoplasma pneumonia- and Treponema pallidum-infected patients, HIV-positive individuals, and healthy blood donor volunteers. Our results demonstrated a low level of B19V IgG antibody presence, ranging from 21.9% to 41.8% in all the groups tested, suggesting a low prevalence of B19V infection in the area. Of note, we found that two healthy blood donors and one Mycoplasma pneumonia-infected patient had B19V IgM antibody among 1,290 plasma samples tested. The Mycoplasma pneumonia-infected patient had viremia with viral genome copies of 2.86 × 10(6) per ml of plasma. We detected a high rate of B19V DNA (7.1%) in HIV-positive injection drug users. Importantly, an amino acid mutation of P558S in the large non-structural protein NS1 was identified to be conserved among 14 B19V isolates from the HIV-positive group but not in the B19V isolate of the Mycoplasma pneumonia-infected patient, representing a hallmark of B19V isolates that circulate in HIV1-positive patients in the greater metropolitan area of Hangzhou, East China.

Extrahepatic manifestations of hepatitis E virus.

Hepatitis E virus can cause acute, fulminant and chronic hepatitis and has been associated with a range of extrahepatic manifestations. Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis are the main neurological manifestations associated with acute and chronic hepatitis E virus infection. Renal injuries have been also reported, including membranoproliferative glomerulonephritis with or without cryoglobulinemia and membranous glomerulonephritis. Acute pancreatitis, haematological disorders and other autoimmune extrahepatic manifestations of hepatitis E virus, such as myocarditis and thyroiditis, have been also reported. In this comprehensive article, we review all published reports describing hepatitis E virus-associated extrahepatic manifestations.

Frequency and Genotype of Human Parvovirus B19 among Iranian Hemodialysis and Peritoneal Dialysis Patients.

OBJECTIVES: The aim of this study was to evaluate the frequency and genotype of human parvovirus B19 and its relation with anemia among Iranian patients under dialysis. METHODS: Fifty hemodialysis (HD) and 33 peritoneal dialysis (PD) patients were enrolled. B19 IgG and IgM antibodies were assessed by ELISA, and the presence of B19 DNA was evaluated by nested PCR. PCR products were sequenced directly and phylogenetic analysis was performed. RESULTS: In the HD group, the prevalence of B19 antibodies was 54% for IgG and 4% for IgM. B19 DNA was detected in 10% of the cases, and 10% showed B19 IgG and viremia simultaneously. In the PD group, the prevalence of B19 IgG and IgM was 57.6 and 0% respectively, whereas B19 DNA was found in 12.1% of the group. A total of 9.1% showed B19 IgG and viremia concurrently. There was no significant difference regarding anemia and B19 infection in either group. All B19 isolates were clustered in genotype 1A. CONCLUSION: Our findings indicate that B19 infection plays no role in leading chronic anemia in dialysis patients. However, persistent B19 viremia and the circulation of the same strains in dialysis patients may indicate a potential risk for the contamination of dialysis equipment and nosocomial spread of B19 infection within dialysis units.

Retroviral DNA--the silent winner: blood transfusion containing latent feline leukemia provirus causes infection and disease in naïve recipient cats.

BACKGROUND: The feline leukemia virus (FeLV) is a gamma-retrovirus of domestic cats that was discovered half a century ago. Cats that are infected with FeLV may develop a progressive infection resulting in persistent viremia, immunodeficiency, tumors, anemia and death. A significant number of cats mount a protective immune response that suppresses viremia; these cats develop a regressive infection characterized by the absence of viral replication and the presence of low levels of proviral DNA. The biological importance of these latter provirus carriers is largely unknown. RESULTS: Here, we demonstrate that ten cats that received a transfusion of blood from aviremic provirus carriers developed active FeLV infections, some with a progressive outcome and the development of fatal FeLV-associated disease. The infection outcome, disease spectrum and evolution into FeLV-C in one cat mirrored those of natural infection. Two cats developed persistent antigenemia; six cats were transiently antigenemic. Reactivation of infection occurred in some cats. One recipient developed non-regenerative anemia associated with FeLV-C, and four others developed a T-cell lymphoma, one with secondary lymphoblastic leukemia. Five of the ten recipient cats received provirus-positive aviremic blood, whereas the other five received provirus- and viral RNA-positive but aviremic blood. Notably, the cats that received blood containing only proviral DNA exhibited a later onset but graver outcome of FeLV infection than the cats that were transfused with blood containing proviral DNA and viral RNA. Leukocyte counts and cytokine analyses indicated that the immune system of the latter cats reacted quicker and more efficiently. CONCLUSIONS: Our results underline the biological and epidemiological relevance of FeLV provirus carriers and the risk of inadvertent FeLV transmission via blood transfusion and demonstrate the replication capacity of proviral DNA if uncontrolled by the immune system. Our results have implications not only for veterinary medicine, such as the requirement for testing blood donors and blood products for FeLV provirus by sensitive polymerase chain reaction, but are also of general interest by revealing the importance of latent retroviral DNA in infected hosts. When aiming to eliminate a retroviral infection from a population, provirus carriers must be considered.

Fetal Intracardiac Transfusions in Hydropic Fetuses with Severe Anemia.

INTRODUCTION: Fetal anemia can have significant perinatal morbidity and mortality, particularly with onset prior to 20 weeks of gestation. MATERIALS AND METHODS: We detail a case-cohort study (n = 8) of all women who underwent fetal in-utero, intracardiac transfusion prior to 24 weeks of gestation (7 women before 20 + 1 weeks), between March 2004 and September 2014, in a supraregional Fetal Medicine Center in the United Kingdom, comprising 2.2% of all transfusions performed during this period. All the fetuses were hydropic, with high maternal BMI, and had severe anemia as an indicator for transfusion. It was an attempt to perform intravascular transfusion when other common routes of fetal vascular access had failed. RESULTS: There were 2 intrauterine deaths (25%), both of which were associated with in-utero transfusion and fulminant parvovirus B19 infection. The perinatal survival rate was 75% (6/8). DISCUSSION: Fetal in-utero, intravascular transfusion by the intracardiac route may be used to correct severe early-onset anemia. It is particularly useful when technical issues of fetal size, early gestation (<20 weeks), maternal adiposity, and hydrops fetalis make umbilical cord or intrahepatic vein puncture technically difficult. Survival rates appear comparable to other series of pregnancies where in-utero transfusion is performed at early gestation.

Health-related quality of life and severity of fatigue in HIV/HCV co-infected patients before, during, and after antiviral therapy with pegylated interferon plus ribavirin.

UNLABELLED: The aim of this study was to prospectively assess health-related quality of life (HRQL) and severity of fatigue before, during and after antiviral therapy in HIV/HCV co-infected patients. DESIGN: 59 HIV/HCV co-infected patients receiving pegylated interferon plus ribavirin (PEGIFN+RBV) in the HIVCOPEG study were included in this substudy evaluating the secondary endpoints HRQL and severity of fatigue. METHODS: HRQL and severity of fatigue were assessed using SF36 and FSS, respectively. Advanced liver fibrosis was defined as METAVIR F3/F4 or liver stiffness >9.5 kPa. RESULTS: At baseline, advanced liver fibrosis was associated with worse physical health. Mental health was impaired in female patients and in patients with a history of intravenous drug abuse, while a history of depression was associated with higher severity of fatigue. Female gender was associated with a more pronounced relative decrease in mental health during therapy. At follow-up, 24 weeks after the end of therapy, both physical health and fatigue symptoms had improved. Virological response was associated with better physical and mental health, as well as with reduced severity of fatigue. A correlation between anemia grade and the relative impairments in physical health, mental health and fatigue was observed. CONCLUSIONS: Antiviral therapy with PEGIFN+RBV impairs physical and mental health and increases severity of fatigue, while virological response is associated with improvements in physical health and fatigue symptoms. The optimization of anemia management is essential for reducing the burden of impaired HRQL and fatigue in HIV/HCV co-infected patients receiving antiviral therapy with PEGIFN+RBV.