Potential histopathological and immunological effects of SARS-CoV-2 on the liver / Efeitos histopatológicos e imunológicos potenciais do SARS-CoV-2 no fígado

The coronavirus disease outbreak of 2019 (COVID-19) poses a serious threat to public health worldwide. Lung injury is the most common complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. However, other organs, including the liver, can also be affected. Currently, there is limited evidence that liver impairment is associated with severe SARS-CoV-2 infection. Clinicians will need to determine whether liver injury is caused by an underlying liver condition, COVID-19 therapy, the virus directly, or immune-mediated inflammation or represents a complicated disease course in the context of COVID-19. To address the scarcity of data on histopathological changes and immunological effects on the liver with COVID-19 positivity, we analyze and summarize recent findings. We searched PubMed, Medline, Google Scholar, Science Direct, Scopus, and Web of Science databases up to December 1, 2021, identifying published studies with the search terms "Histopathology in COVID-19," "COVID-19," "Pathological changes in liver in COVID-19," "Liver pathology in COVID-19," "immunological effects in liver in COVID-19," and "SARS-CoV-2." This concise review will aid clinicians and researchers in better understanding the tissue histopathology and immunological consequences of SARS-CoV-2 on the liver, enabling improved care planning and avoiding future dangers.

O surto de doença por coronavírus de 2019 (COVID-19) representa uma séria ameaça à saúde pública em todo o mundo. A lesão pulmonar é a complicação mais comum da infecção por Coronavírus 2 da Síndrome Respiratória Aguda Grave (SARS-CoV-2). No entanto, outros órgãos, incluindo o fígado, também podem ser afetados. Atualmente, há evidências limitadas de que a insuficiência hepática está associada à infecção grave por SARS-CoV-2. Os médicos precisarão determinar se a lesão hepática é causada por condição hepática subjacente, terapia COVID-19, vírus diretamente, inflamação imunomediada ou se representa um curso complicado da doença no contexto da COVID-19. Para abordar a escassez de dados sobre alterações histopatológicas e efeitos imunológicos no fígado com positividade para COVID-19, analisamos e resumimos os achados recentes. Pesquisamos os bancos de dados PubMed, Medline, Google Scholar, Science Direct, Scopus e Web of Science até 1º de dezembro de 2021, identificando estudos publicados com os termos de pesquisa "Histopatologia em COVID-19", "COVID-19", "Alterações patológicas no fígado em COVID-19", "Patologia hepática em COVID-19", "Efeitos imunológicos no fígado em COVID-19" e "SARS-CoV-2". Esta revisão concisa ajudará médicos e pesquisadores a entender melhor a histopatologia do tecido e as consequências imunológicas do SARS-CoV-2 no fígado, permitindo um melhor planejamento de cuidados e evitando perigos futuros.

Brazilian report on primary immunodeficiencies in children: 166 cases studied over a follow-up time of 15 years.

One hundred sixty-six cases of primary immunodeficiency diseases (PID) (95 males, 71 females), diagnosed according to WHO criteria, have been registered at the Children's Hospital, University of São Paulo, Brazil. The following frequencies were found: predominantly humoral defects, 60.8% (n = 101); T cell defects, 4.9% (n = 8); combined ID, 9.6% (n = 16); phagocyte disorders, 18.7% (n = 31); and complement deficiencies, 6% (n = 10). IgA deficiency was the most frequent disorder (n = 60), followed by transient hypogammaglobulinemia (n = 14), chronic granulomatous disease (n = 14), and X-linked agammaglobulinemia (n = 9). In comparison to other (national) reports, we observed higher relative frequencies of phagocyte and complement deficiencies. Recurrent infections were the cause of death in 12.7%. Allergic symptoms were observed in 41%, mainly in IgA-deficient, hypogammaglobulinemic, or hyper-IgE patients, and autoimmune disorders in 5%, predominantly in IgA and complement deficiencies. Five patients suffered from BCG dissemination; two of them died. This is the first Brazilian report on PID over an observation time of 15 years.

PIP: Over a 15-year observation period (1981-96), 166 cases of primary immunodeficiency disease (PID) were registered at the Department of Pediatrics, University of Sao Paulo, Brazil. PID was diagnosed according to World Health Organization criteria and only children with well-established deficiencies were included. The following frequencies were noted by PID classification: predominantly humoral defects (60.8%), T cell defects (4.9%), combined immunodeficiency (9.6%), phagocyte disorders (18.7%), and complement deficiencies (6%). The male to female ratio was 1.3 to 1. Immunoglobin A deficiency was the most frequent disorder (60 cases), followed by transient hypogammaglobulinemia (14 cases), chronic granulomatous disease (14 cases), and X-linked agammaglobulinemia (9 cases). Allergic symptoms occurred in 41% of cases. During the observation period, 23 children (13.8%) died, primarily of recurrent infections. Although improved diagnostic facilities have facilitated the recognition of immunodeficient children, the true incidence is likely to be higher than that detected in this study. Increased international collaboration is urged to improve the early detection of PID.

Safety and immunogenicity of oral killed whole cell recombinant B subunit cholera vaccine in Barranquilla, Colombia.

In January and February 1992, an assessment was conducted of the safety and immunogenicity of two doses of a new oral cholera vaccine prepared from the recombinant B subunit of the toxin and from killed whole cells (rBS/WC) in 1,165 individuals between the ages of 12 months and 64 years in Barranquilla, Colombia. This was a randomized, double-blind placebo-controlled study. Participants received two doses of either the vaccine or a placebo (killed Escherichia coli K12) over a two-week interval. Few symptoms were detected during the three days following administration of the initial dose and even fewer following the second. Sera obtained upon administration of the first dose and two weeks after administration of the second were tested for Vibrio cholerae 01 Inaba vibriocidal antibodies and antitoxins. Geometric mean titers (GMT) of vibriocidal antibodies were found to increase two-fold in subjects receiving the vaccine. In the paired samples taken from vaccinated subjects, two-fold or greater increases were observed in 44% and four-fold or greater increases were observed in 34%, as compared to similar increases in 9.2% and 2.2% of the sera taken from those receiving the placebo (P < 0.05). The GMTs of IgG and IgA antitoxins, as determined by ELISA, increased by factors of 4 and 3.2, respectively, in those receiving the vaccine, as compared to factors of 1.1 and 1.1 in those given the placebo (P < 0.001 for IgG, P < 0.01 for IgA). Approximately 80% of the paired samples from the vaccinated group showed an increase of both IgG and IgA antitoxins > or = 1.5, as compared to only about 20% of those in the placebo group (P < 0.000001). Belonging to the O blood group did not significantly affect the immune response. Children under age four tended to show a weaker vibriocidal antibody response and a stronger antitoxin response than older subjects. The two doses of oral vaccine were found to be safe and without attributable side-effects. The vibriocidal antibody and antitoxin responses were similar to those obtained previously with the conventional oral killed whole cell B subunit cholera vaccine.

PIP: In a randomized, double-blind, placebo-controlled study in January and February 1992, the safety and immunogenicity of two doses of a new oral cholera vaccine was assessed. The vaccine was prepared from the recombinant B subunit of the toxin and from killed whole cells (rBS/WC) in 1165 individuals between the ages of 12 months and 64 years in Barranquilla, Colombia. Participants received two doses of either the vaccine or a placebo (killed Escherichia coli K12) over a 2-week interval. Few symptoms were detected during the 3 days following administration of the initial dose and even fewer following the second one. Sera obtained upon administration of the first dose and 2 weeks after administration of the second dose were tested for Vibrio cholera 01 Inaba vibriocidal antibodies and antitoxins. Geometric mean titers (GMTs) of vibriocidal antibodies were found to increase two-fold in subjects receiving the vaccine. In the paired samples taken from vaccinated subjects, two-fold or greater increases were observed in 44% and four-fold or greater increases were observed in 34%. In comparison, similar increases were found only in 9.2% and 2.2% of the sera taken from those receiving placebo (p .05). The GMTs of IgG and IgA antitoxins, as determined by ELISA, increased by factors of 4 and 3.2, respectively, in those receiving the vaccine as compared with factors of 1.1 and 1.1, respectively, in those given the placebo (p .001 for IgG and p .01 for IgA). Approximately 80% of the paired samples from the vaccinated group showed an increase of both IgG and IgA antitoxins or= 1.5 as compared with only about 20% of those in the placebo group (p .000001). Belonging to the O blood group did not significantly affect the immune response. Children under the age of 4 years tended to show a weaker vibriocidal antibody response and stronger antitoxin response than did older subjects. The two doses of oral vaccine were found to be safe and without attributable side effects.

[Antimicrobial and immunological properties of human milk]. / Leche humana: propiedades immunologicas y antimicrobianas

PIP: Human milk is the ideal food for newborns because of its content of nutrients, immunoprotective factors and their associated antimicrobic properties. Milk is unique because it is made up of cellular components (non-soluble) and soluble components that include 3 types of organic nutrients: 1) proteins which protect the system; 2) lipids which contain antiviral and antiprotozoan properties; and 3) carbohydrates which modify bacterial growth and prevent the adhesion of microorganisms to the epithelial cells along the respiratory and gastrointestinal tracts. These 3 antibacterial, antiviral and antiparasitic components help to reduce incidence of morbidity and mortality due to infectious diseases.^ieng

Does breast feeding help protect against atopic disease? Biology, methodology, and a golden jubilee of controversy.

To help shed some light on the 50-year-old controversy concerning the possible protective effect of breast feeding on subsequent atopic disease, I developed 12 standards pertaining to both biologic and methodologic aspects of exposure (infant feeding), outcome (atopic conditions), and statistical analysis for studies of atopic eczema, asthma, allergic rhinitis, cow milk allergy, and other food allergy. Among the published studies on atopic eczema, the nine claiming a protective benefit of breast feeding performed less well than the 12 not making such a claim on "methodologic" standards relating to strict diagnostic criteria and blind ascertainment of outcome. The positive studies were somewhat stronger, however, on the "biologic" standards bearing on sufficient duration and exclusivity of breast feeding and on separate analysis of children at high risk. For the other atopic conditions, there were no important differences between positive and negative studies. In few negative or positive studies was there adequate control for confounding variables or examination of potential benefits relating to the severity or age at onset of atopic disease. To avoid another 50 years of unresolved controversy, future studies should improve both the biologic and methodologic aspects of their design and analysis.

PIP: In the last 50 years many studies have been published that purportedly prove or refute the hypothesis that breast feeding protects infants against 6 immediate hypersensitivity-mediated disease states -- atopic eczema, asthma, allergic rhinitis, cow milk allergy, other food allergy, and combinations of these. A MEDLINE search for articles published between 1983 and 1986 and an examination of end references back to 1936 provided a supply of articles on both sides of the debate. These articles were rated against 12 biological and methodological standards to determine whether their conclusions were based on rigorous examination of the facts. The 12 standards were: nonreliance on recall, blind ascertainment of infant feeding history, breast feeding duration of at least 2 months, specifically stated exclusivity of breast feeding, strict diagnostic criteria for the atopic diseases, blind ascertainment of outcome, measured severity of disease outcome, age at onset of disease, control for confounding variables, assessment of dose-response effect, assessment of genetic of risk factors for atopic disease, and rigorous statistical methods. The total retrieval included 22 studies of atopic eczema, 13 studies of asthma, 7 studies of rhinitis, 3 studies of cow milk allergy, 4 studies of other food allergy, and 8 studies of mixtures of 2 or more atopic diseases. These studies were rated against the 12 standards. Serious flaws reduced the value of all studies in greater or lesser degree. Nonblind ascertainment of outcome, failure to control for confounding variables, failure to ascertain disease severity, and failure to record age at onset of disease were the most common drawbacks. It is not possible to determine from these studies whether or not breast feeding has a prophylactic effect on atopic disease. More research is obviously necessary, but a rigorous study design must come first.

Defective humoral immunity in pediatric acquired immune deficiency syndrome.

Specific antibody production was assessed in six young children with the acquired immune deficiency syndrome (AIDS). All patients were immunized with bacteriophage phi X 174, a T cell-dependent neoantigen. In addition, antibody responses to pneumococcal vaccine and tetanus toxoid, lymphocyte responses to mitogens, and serum immunoglobulin levels were determined. Polyclonal hypergammaglobulinemia was documented in three patients. Responses to bacteriophage phi X 174 were abnormal in all patients: primary responses were blunted, secondary responses were markedly decreased, and the class switch (IgM-IgG) was absent in five of six patients. Antibody formation to pneumococcal vaccine and tetanus toxoid was also diminished. Lymphocyte mitogenic responses to phytohemagglutinin, concanavalin A, pokeweed mitogen, and staphylococcal Cowan A were generally decreased. These findings confirm that pediatric patients with AIDS have significant abnormalities in humoral immunity. Dysfunction of both T cells and B cells plays a role in the resultant poor specific antibody production.

Opportunistic infections and Kaposi's sarcoma among Haitians: evidence of a new acquired immunodeficiency state.

Twenty Haitian patients, hospitalized from 1 April 1980 to 20 June 1982, had Pneumocystis carinii pneumonia, central nervous system toxoplasmosis, esophageal candidiasis, cryptococcosis, disseminated cytomegalovirus, progressive herpes simplex virus, chronic enteric coccidiosis, or invasive Kaposi's sarcoma. Ten patients died. Opportunistic infections were frequently multiple and were recurrent in three patients. In seven patients disseminated tuberculosis preceded the other infections by 2 to 15 months. There was no evidence of an underlying immunosuppressive disease, and no history of homosexuality or intravenous drug abuse. At least three patients probably acquired the syndrome in Haiti. Lymphadenopathy was common. Seventeen patients tested had anergy, and 18 had lymphopenia. Monoclonal antibody analysis of peripheral-blood T-cell subsets done on 11 patients showed a marked decrease in T-helper cells and an inversion of the normal ratio of T-helper cells to T-suppressor cells. This syndrome among heterosexual Haitians is strikingly similar to the syndrome of immunodeficiency described recently among American homosexuals.

Host resistance factors in human milk.

PIP: This paper discusses the nature of host resistance factors in human milk and epidemiologic studies regarding infections and mortality rates in breastfed and nonbreastfed babies. The defense factors and their proposed modes of action are: 1) a growth enhancer of lactobacilli, which interferes with intestinal colonization of enteric pathogens; 2) antistaphylococcal factors, which inhibit staphylococci; 3) secretory IgA and other immunoglobulins, which protect the gut and respiratory tract; 4) C4 and C3 (complement components; C3 fragments have opsonic, chemotactic, and anaphylatoxic activities); 5) lysozome, lysis of bacterial cell wall; 6) lactoperoxidase, killing of streptococci; 7) lactoferrin, kills microorganism by chelating iron, and 8) macrophages and lymphocytes, phagocytosis and cell-mediated immunity. Although it can be postulated that the breastfed infant's resistance to infection would be superior on account of the greater presence of these factors in human milk compared to cow's milk, little is known about the effects of these defense factors on the infant. Epidemiologic studies have reported on the lower morbidity and mortality rates of breastfed infants as compared to bottlefed infants. Other studies have focused on the protective effects of human milk upon the infant, but these have been inconclusive. In countries with poor sanitation and high infection rates, the incidence of bacterial infections is lowest in breastfed infants. The advantages of human milk however are difficult to demonstrate in societies with high standards of sanitation and low infection rates. Infection and mortality rates in infants have in fact declined in developed countries as the practice of breastfeeding declined. Until it is established that immunity to common pathogens is transmitted to the infant by human milk, it will not be known whether human milk does have protective effects.^ieng