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Immunological deficiencies: more frequent than they seem to be

Abstract

Objective:

A review article was carried out, addressing the clinical and epidemiological characteristics of immune system deficiencies, which are associated with or predispose to recurrent infectious processes, autoimmune diseases, auto inflammatory diseases, or neoplasms, and which are classified as inborn errors of immunity (IEI) and secondary immunodeficiencies (SID). Emphasis was placed on the classification of the main signs and symptoms for each organ and system, which will serve as warning signs, to guide the pediatrician in the investigation of the main IEI. In addition, the main secondary changes in the immune system triggered by infections (with emphasis on COVID-19), drugs, chronic diseases, metabolic and nutritional disorders were identified.

Sources of data:

This review included articles published in the last five years and that were identified in the MEDLINE platform (PubMed).

Summary of findings:

The recurrence of infectious processes, associated with the severity of the condition and/or unusual profile of the infectious agent, always related to the age range of symptom onset, are the most important findings for suspected diagnosis.

Conclusions:

Considering this scenario, immunity disorders should be part of the investigation carried out by the general pediatrician, whether they are the innate errors of immunity (primary immunodeficiencies) or secondary immunodeficiencies, so that the diagnosis is attained as early as possible and therapeutic measures are implemented, reducing the morbidity and mortality of these patients.

KEYWORDS
Primary immunodeficiency disorders; Immunodeficiency disorders; Classification; Epidemiology; COVID-19; SARS-CoV-2

Introduction

Immunodeficiencies (IDs) are a group of diseases that present with quantitative and/or functional alterations in the elements that comprise the inborn and adaptive immune response. They are classified as primary when their origin is genetic, also currently called inborn errors of immunity (IEI), and secondary when they are acquired. Both situations are associated with or predispose to recurrent infectious processes, autoimmune or auto inflammatory diseases, typical of immune dysregulation processes, in addition to lymph proliferative and/or neoplastic processes.11 Sánchez-Ramón S, Bermudez A, González-Granado LI, Rodríguez-Gallego C, Sastre A, Soler-Palacín P, et al. Primary and secondary immunodeficiency diseases in oncohaematology: warning signs, diagnosis, and management. Front Immunol. 2019;10:586.

Primary immunodeficiencies

Primary immunodeficiencies (PIDs), more recently called inborn errors of immunity (IEI), include approximately 420 monogenic diseases that are more susceptible to infections, immune dysregulation leading to severe types of allergies, autoimmunity or auto inflammation, susceptibility to cancer, or integrate complex syndromes that affect different organs and systems, including developmental disorders, autism, intellectual disability, epilepsy, gastroenteropathies, pneumopathies, dermatoses, skeletal and renal abnormalities, among other clinical events. The estimated prevalence of IEI worldwide is 1:10,000 individuals. This number is increasing, especially with the advances in knowledge, diagnostic resources, and also in communities with a high rate of inbreeding. In a global context, within the classification of primary immunodeficiencies we found the following frequencies, confirmed by specialization societies (Fig. 1).22 Rezaei N, Bonilla FA, Seppänen M, de Vries E, Bousfiha AA, Puck J, et al. Introduction on primary immunodeficiency diseases. In: Rezaei N, Aghamohammadi A, Notarangelo L, editors. Primary immunodeficiency diseases. Berlin, Heidelberg: Springer; 2017. p. 1-81.,33 Bousfiha A, Jeddane L, Picard C, Al-Herz W, Aital F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40:66-81.

The implementation of neonatal screening for immunodeficiencies with T and B lymphopenias, particularly the group of severe combined immunodeficiencies and agammaglobulinemia, which is now universal in the United States of America, and the implantation in several European countries and in Brazil has contributed to a significant change in the epidemiological profile of PIDs.44 Tangye SC, Al-Herz W, Bousfiha A, Chatila C, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40:24-64.

Figure 1
Classification of primary immunodeficiencies and their relative frequencies. Data extracted from the main specialized societies (ESID, LASID, USID net) and records from Asia, Africa and Australia.

The immune system is anatomically distributed throughout the body, especially in the barrier areas such as the skin, gastrointestinal and respiratory mucosa. This explains why the clinical picture of recurrent infections occurs at these barriers. However, in the case of the most severe immunodeficiencies, they become more invasive and manifest themselves as deep abscesses, sepsis, osteoarticular infections, meningitis, and encephalitis. This brings an interdisciplinary characteristic to the study of immunodeficiencies, since the infection, allergy, and autoimmunity aspects affect the different organs and systems. In practice, the patient with IEI is initially seen by general pediatricians, pulmonologists, otorhinolaryngologists, gastroenterologists, infectologists, hematologists, dermatologists and rheumatologists.33 Bousfiha A, Jeddane L, Picard C, Al-Herz W, Aital F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40:66-81.,44 Tangye SC, Al-Herz W, Bousfiha A, Chatila C, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40:24-64.

Tables 1-7 show the main signs and symptoms for each organ and system, constituting a warning sign that directs the physician to the investigation of IEI.55 Costa-Carvalho BT, Grumach AS, Franco JL, Espinosa-Rosales FJ, Leiva LE, King A, et al. Attending to warning signs of primary immunodeficiency diseases across the range of clinical practice. J Clin Immunol. 2014;34:10-22.

Table 1
Screening laboratory tests for the non-immunology specialist to detect patients with possible primary immunodeficiency.
Table 2
Infections as general warning signs for primary immunodeficiency.
Table 3
Warning signs of primary immunodeficiency for infectious disease specialists.
Table 4
Warning signs of primary immunodeficiency for pulmonologists.
Table 5
Warning signs of primary immunodeficiency for gastroenterologists.
Table 6
Warning signs of primary immunodeficiency for dermatologists.
Table 7
Warning signs of primary immunodeficiency for hematologists.

Secondary immunodeficiencies

There are several causes of secondary immunodeficiencies (SIDs), among which we can highlight: chronic protein-losing diseases (e.g. nephrotic syndrome); autoimmune and onco-hematological diseases, associated or not with the use of immunosuppressant drugs; nutritional alterations, whether malnutrition or obesity/metabolic syndrome; post-trauma splenectomy or autosplenectomy (sickle-cell anemia),which increase the risk of sepsis and chronic or prolonged viral infections, such as HIV, HTLV, cytomegalovirus, mononucleosis virus and, more recently, the SARS-CoV-2 that has caused immunological alterations both in the short term and in the medium and long terms.11 Sánchez-Ramón S, Bermudez A, González-Granado LI, Rodríguez-Gallego C, Sastre A, Soler-Palacín P, et al. Primary and secondary immunodeficiency diseases in oncohaematology: warning signs, diagnosis, and management. Front Immunol. 2019;10:586.,66 Dhar D, Mohanty A. Gut microbiota and Covid-19 - possible link and implications. Virus Res. 2020;285:198018.

Nutritional alterations

Malnutrition has traditionally been the focus of nutrition agendas in underdeveloped or developing countries. However, rapid economic growth and urbanization have given rise to a nutritional transition where energy-dense diets have replaced traditional diets and sedentary lifestyles prevail. In this sense, childhood obesity rates have increased dramatically. The global prevalence of overweight or obesity has increased in all regions, from 4.2% in 1990 to 6.7% in 2010. Although the prevalence is higher in developed countries, developing countries have a higher absolute number of affected children and higher relative increases. It is estimated that these growing trends will continue to increase, now in 2020, with 60 million overweight or obese children under the age of five.77 Tzioumis E, Adair LS. Childhood dual burden of under- and over-nutrition in low- and middle-income countries: a critical review. Food Nutr Bull. 2014;35:230-43.

In malnourished children, common infections are the main causes of death, which shows a probable underlying, inborn and adaptive immune deficiency, even in mild forms of malnutrition. The altered mechanisms of immune function include: alteration of the cutaneous and intestinal epithelial barrier; reduced granulocyte microbicidal activity; quantitative decrease in circulating dendritic cells, B lymphocytes and complement system proteins; reduced levels of soluble IgA in saliva and tears; atrophy of lymphoid organs; impaired late hypersensitivity responses; lymphocyte hyper responsiveness with a predominance of Th2 response. Despite that, most malnourished children seem to respond adequately to vaccination, although the timing, quality and longevity of specific vaccine responses may be impaired.88 Bourke CD, Berkley JA, Prendergast AJ. Immune dysfunction as a cause and consequence of malnutrition. Trends Immunol. 2016;37:386-98.

At the other end of nutritional disorders, obese individuals have a higher number of infections, which are more severe. This fact is corroborated by recent studies that show a strong association between obesity and the severity of SARS-CoV-2 infection, in the absence of other comorbidities. The dysfunctional hypertrophic adipocytes present in obesity produce an excessive amount of proinflammatory cytokines, such as IL-6, IL-8, monocyte-1 chemo attractant protein, leptin and plasminogen activator inhibitor-1, which lead to an increase in the recruitment of macrophages, especially polarized M1 macrophages. These cells, together with free fatty acids, maintain a high production of pro-inflammatory molecules. This cumulative effect generates a state of chronic inflammation and hypercytokinemia, which leads to defective inborn immunity and creates a breeding ground for the hyper inflammatory response mediated by macrophage activation in severe cases of COVID-19.99 Korakas E, Ikonomidis I, Kousathana F, Balampanis K, Kountouri A, Raptis A, et al. Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes. Am J Physiol Endocrinol Metab. 2020;319:E105-9.

Nephrotic syndrome

Primary nephrotic syndrome (NS) in childhood is a disease characterized by the presence of high proteinuria, clinically significant edema, hypoalbuminemia and hyperlipidemia. It occurs at the proportion of 2-7 cases for every 100,000 children per year. Inside the spectrum of possible complications of NS are recurrent infections, which vary in incidence between 8 and 84% and occur mainly due to defects in cell-mediated immunity, use of immunosuppressive therapy, malnutrition and specific urinary protein losses, such as immunoglobulins, properdin factor B and complement factors.1010 Alfakeekh K, Azar M, Sowailmi BA, Alsulaiman S, Makdob SA, Omair A, et al. Immunosuppressive burden and risk factors of infection in primary childhood nephrotic syndrome. J Infect Public Health. 2019;12:90-4.

Sickle-cell anemia

Until the 1990s, in the United States, up to 30% of young children with sickle-cell anemia (SCA) died of infections, mainly caused by encapsulated bacteria, due to the deficiency in the immune response to polysaccharide antigens, exacerbated by the deficient blood elimination of these bacteria, since there is functional asplenia. Prophylactic penicillin is a safe and beneficial strategy in patients under five years of age, and its introduction reduced the incidence of pneumococcal bacteremia associated with impaired splenic function by 85%. However, the universal use of anti-pneumococcal vaccines has also greatly helped reduce mortality from these infectious diseases. With the introduction of the first pneumococcal conjugate vaccine, there was a decrease in the rate of pneumococcal bacteremia in children under 3 years of age by 93.4%, in addition to further protection for those patients who have low adherence to prophylactic therapy with penicillin.1111 Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti K, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.

Medications

In the last decades, we have seen an increase in the use of drugs to suppress the body's undesirable immune responses, mainly in the control of autoimmune diseases, allergic diseases and in the prevention of the rejection of transplanted organs. Such drugs are able to control the exacerbated immune response; however, they leave the individual more susceptible to infections, through several mechanisms.

Glucocorticoids are widely used in clinical practice to treat immune-mediated diseases, either as monotherapy or combined with other immunosuppressants. Their effects on the immune system are secondary to two mechanisms: immunosuppression with increased susceptibility to viral, fungal and bacterial infections, and the anti-inflammatory action, masking infectious signs and symptoms, delaying the diagnosis and the start of treatment.1212 Becker ML, Lovell D, Leeder SJ. Pharmacology and drug therapy: nonbiologic therapies. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn L, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia: Elsevier; 2016. p. 140-59.,1313 Van der Goes MC, Jacobs JW, Bijlsma JW. The value of glucocorticoid co-therapy in different rheumatic diseases - positive and adverse effects. Arthritis Res Ther. 2014;16:S2. The mechanism of action occurs mainly in T cells, especially with decreased cytokine production, reduced lymphocyte chemotaxis, cell adhesion and phagocytosis.1414 Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125:S195-203. Therefore, interference with the tuberculin skin test is also observed, in addition to restrictions regarding the use of vaccines consisting of live attenuated microorganisms.1313 Van der Goes MC, Jacobs JW, Bijlsma JW. The value of glucocorticoid co-therapy in different rheumatic diseases - positive and adverse effects. Arthritis Res Ther. 2014;16:S2.

Another class of drugs widely used in immunosuppressive treatment are calcineurin inhibitors (Cyclosporine, Tacrolimus), which inhibit T-cell activation and IL-2 production. They are considered glucocorticoid-sparing drugs and have the advantage of not interfering with macrophage and neutrophil action, but they increase susceptibility to skin infections and viral airway infections.1414 Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125:S195-203.,1515 Loechelt BJ, Green M, Gottlieb PA, Blumberg E, Weinberg A, Quinlan S, et al. Screening and monitoring for infectious complications when immunosuppressive agents are studied in the treatment of autoimmune disorders. J Pediatric Infect Dis Soc. 2015;4:198-204.

As for cytotoxic drugs (Azathioprine, Cyclophosphamide, Methotrexate, Leflunomide, and Mycophenolate mofetil), they are highly effective in suppressing the immune response, inhibiting the proliferation and activation of T and B cells. Additionally, these drugs lead to cytopenia, further contributing to secondary immunosuppression and susceptibility to infections.1212 Becker ML, Lovell D, Leeder SJ. Pharmacology and drug therapy: nonbiologic therapies. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn L, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia: Elsevier; 2016. p. 140-59.,1414 Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125:S195-203.

In recent years, immunosuppressive agents with more specific targets have been developed, seeking to obtain less harmful and highly effective drugs in the treatment of autoimmune diseases and in the prevention of transplanted organ rejection (Table 8).1212 Becker ML, Lovell D, Leeder SJ. Pharmacology and drug therapy: nonbiologic therapies. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn L, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia: Elsevier; 2016. p. 140-59.,1616 Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016;11:322-43.,1717 da Mota LM, Cruz BA, Brenol CV, Pollak DF, Pinheiro GR, Laurindo LM, et al. Segurança do uso de terapias imunobiológicas para o tratamento de artrite reumatoide e espondiloartrites. Rev Bras Reumatol. 2015;55:281-309.

Table 8
Immunobiological agents and risk of infection.

Taking into account the innumerable immunosuppression pathways secondary to the use of medications to control autoimmune diseases, the immunization recommendations should be followed, updating the vaccination schedule before the start of treatment whenever possible. It is important to recommend follow-up at Special Immunobiological Reference Centers (CRIE), keeping the immunization against Influenza, pneumococcal infections, meningitis, HPV, and Hepatitis B updated and individually assessing the risk of vaccines consisting of live attenuated microorganisms, according to the drug and doses used.1818 Bühler S, Hatz C. Vaccinations in patients with autoimmune diseases. Ther Umsch. 2016;73:275-80.,1919 Subesinghe S, Bechman K, Rutherford AI, Goldblatt D, Galloway JB. A systematic review and metaanalysis of antirheumatic drugs and vaccine in rheumatoid arthritis. J Rheumatol. 2018;45:733-44.

Infections

Since the last century, it has been observed that the measles virus leads to a condition of transient immunosuppression with anergy and greater susceptibility to infections by other microorganisms, due to changes in the function of T cells and dendritic cells.1414 Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125:S195-203. Since then, several microorganisms have been implicated in transient immunosuppression, such as cytomegalovirus (due to changes in T cells) and the Epstein-Barr virus (due to B-cell depletion). Other agents that cause frequent diseases in some Brazilian regions may also increase the risk of opportunistic infections with increased morbidity and mortality, such as: Leishmaniasis, which leads to macrophage dysfunction, decreased production of cytokines and cytopenias, and Malaria, by altering the function of Tcells.2020 Bonagura VR, Rosenthel DW. Infections that cause secondary immune deficiency. In: Sullivan KE, Stiehm RE, editors. Stiehm's immune deficiencies. 2nd ed. Elsevier; 2020. p. 1035-58.

In the 1980s, the human immunodeficiency virus (HIV) was recognized as a cause of acquired and permanent immunodeficiency, where there is progressive involvement of CD4+ T cells, leading the infected individual to death by opportunistic infections if not treated. This occurs when the peripheral CD4+ T cell count is less than 200 cells/mL, and thus the patient can acquire any of the various opportunistic infections present in acquired immunodeficiency syndrome (AIDS), such as pneumonia caused by Pneumocystis jirovecii, histoplasmosis, toxoplasmosis, and tuberculosis.1414 Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125:S195-203.

Recently, after the pandemic caused by the new Coronavirus (SARS-CoV-2), the association between secondary infections and increased mortality in patients with the severe form of COVID-19 has been demonstrated. The greater susceptibility to these infections is probably due to dysregulation of the immune system and alterations in the intestinal microbiota, in addition to direct tissue damage caused by the SARS-CoV-2 virus.66 Dhar D, Mohanty A. Gut microbiota and Covid-19 - possible link and implications. Virus Res. 2020;285:198018.,2121 Zhang H, Zhang Y, Wu J, Li Y, Zhou X, Li X, et al. Risks and features of secondary infections in severe and critical ill COVID-19 patients. Emerg Microbes Infect. 2020;9:1958-64.

In this context of COVID-19, unfortunately, there are no studies that analyze the immune response in asymptomatic infected individuals and compare them with individuals with mild, moderate or severe symptoms. Therefore, the information on the following immunological alterations is based on the symptomatic ones, as follows:

  • Cytopenia: The most evident cell decrease would be lymphopenia, which is more marked in severe symptomatic patients and mainly includes a decrease in T cells (CD8, which when present exhibits abnormal functional phenotype; CD4, especially subtypes Th1 and Treg). NK cells and monocytes may also show decreased rates, especially in moderate and severe cases.2222 García LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020;11:1441.

  • Alterations in cytokine levels: There is an increase in cytokine levels, especially in severe cases of SARS-CoV-2 infection, especially of: IL-2, IL-2r, IL-6, IL-7, IL-8, IL-10, MP-10, MP-1A, and TNF-α. Of all these cytokines, IL-6 has shown the highest correlation with severity and therefore can be used as a good biomarker to monitor the evolution of the clinical picture.2222 García LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020;11:1441.

Clearly, the immunological alterations described above directly influence the evolution of the disease from a mild or even asymptomatic profile to severe situations with a high mortality rate. Moreover, these immunological alterations caused by the virus favor the onset of secondary infectious processes in the short term and have favored the emergence of autoimmune and inflammatory dysregulations, such as the Kawasaki-like Pediatric Multisystem Inflammatory Syndrome (PMIS), in the medium and long terms.2222 García LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020;11:1441.,2323 Kaushik S, Aydin SI, Derespina KR, Bansal PB, Kowalsky S, Trachtman R, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory Syndrome Coronavirus 2 Infection (MIS-C): a multi-institutional study from New York city. J Pediatr. 2020;224:24-9.

In conclusion, considering the recurrent infectious and/or inflammatory clinical conditions, especially those that escape the age range normality, immunity disorders, whether primary (inborn errors of immunity) or secondary (secondary immunodeficiencies) alterations, should be part of the investigation of the general pediatrician so that the diagnosis can be made as soon as possible and therapeutic measures can be implemented, thus preventing the repetition of events and functional sequelae as well as promoting an adequate quality of life for these patients.

References

  • 1
    Sánchez-Ramón S, Bermudez A, González-Granado LI, Rodríguez-Gallego C, Sastre A, Soler-Palacín P, et al. Primary and secondary immunodeficiency diseases in oncohaematology: warning signs, diagnosis, and management. Front Immunol. 2019;10:586.
  • 2
    Rezaei N, Bonilla FA, Seppänen M, de Vries E, Bousfiha AA, Puck J, et al. Introduction on primary immunodeficiency diseases. In: Rezaei N, Aghamohammadi A, Notarangelo L, editors. Primary immunodeficiency diseases. Berlin, Heidelberg: Springer; 2017. p. 1-81.
  • 3
    Bousfiha A, Jeddane L, Picard C, Al-Herz W, Aital F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS Phenotypical Classification. J Clin Immunol. 2020;40:66-81.
  • 4
    Tangye SC, Al-Herz W, Bousfiha A, Chatila C, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40:24-64.
  • 5
    Costa-Carvalho BT, Grumach AS, Franco JL, Espinosa-Rosales FJ, Leiva LE, King A, et al. Attending to warning signs of primary immunodeficiency diseases across the range of clinical practice. J Clin Immunol. 2014;34:10-22.
  • 6
    Dhar D, Mohanty A. Gut microbiota and Covid-19 - possible link and implications. Virus Res. 2020;285:198018.
  • 7
    Tzioumis E, Adair LS. Childhood dual burden of under- and over-nutrition in low- and middle-income countries: a critical review. Food Nutr Bull. 2014;35:230-43.
  • 8
    Bourke CD, Berkley JA, Prendergast AJ. Immune dysfunction as a cause and consequence of malnutrition. Trends Immunol. 2016;37:386-98.
  • 9
    Korakas E, Ikonomidis I, Kousathana F, Balampanis K, Kountouri A, Raptis A, et al. Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes. Am J Physiol Endocrinol Metab. 2020;319:E105-9.
  • 10
    Alfakeekh K, Azar M, Sowailmi BA, Alsulaiman S, Makdob SA, Omair A, et al. Immunosuppressive burden and risk factors of infection in primary childhood nephrotic syndrome. J Infect Public Health. 2019;12:90-4.
  • 11
    Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti K, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.
  • 12
    Becker ML, Lovell D, Leeder SJ. Pharmacology and drug therapy: nonbiologic therapies. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn L, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia: Elsevier; 2016. p. 140-59.
  • 13
    Van der Goes MC, Jacobs JW, Bijlsma JW. The value of glucocorticoid co-therapy in different rheumatic diseases - positive and adverse effects. Arthritis Res Ther. 2014;16:S2.
  • 14
    Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125:S195-203.
  • 15
    Loechelt BJ, Green M, Gottlieb PA, Blumberg E, Weinberg A, Quinlan S, et al. Screening and monitoring for infectious complications when immunosuppressive agents are studied in the treatment of autoimmune disorders. J Pediatric Infect Dis Soc. 2015;4:198-204.
  • 16
    Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016;11:322-43.
  • 17
    da Mota LM, Cruz BA, Brenol CV, Pollak DF, Pinheiro GR, Laurindo LM, et al. Segurança do uso de terapias imunobiológicas para o tratamento de artrite reumatoide e espondiloartrites. Rev Bras Reumatol. 2015;55:281-309.
  • 18
    Bühler S, Hatz C. Vaccinations in patients with autoimmune diseases. Ther Umsch. 2016;73:275-80.
  • 19
    Subesinghe S, Bechman K, Rutherford AI, Goldblatt D, Galloway JB. A systematic review and metaanalysis of antirheumatic drugs and vaccine in rheumatoid arthritis. J Rheumatol. 2018;45:733-44.
  • 20
    Bonagura VR, Rosenthel DW. Infections that cause secondary immune deficiency. In: Sullivan KE, Stiehm RE, editors. Stiehm's immune deficiencies. 2nd ed. Elsevier; 2020. p. 1035-58.
  • 21
    Zhang H, Zhang Y, Wu J, Li Y, Zhou X, Li X, et al. Risks and features of secondary infections in severe and critical ill COVID-19 patients. Emerg Microbes Infect. 2020;9:1958-64.
  • 22
    García LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020;11:1441.
  • 23
    Kaushik S, Aydin SI, Derespina KR, Bansal PB, Kowalsky S, Trachtman R, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory Syndrome Coronavirus 2 Infection (MIS-C): a multi-institutional study from New York city. J Pediatr. 2020;224:24-9.

Publication Dates

  • Publication in this collection
    26 Apr 2021
  • Date of issue
    Mar-Apr 2021

History

  • Received
    2 Oct 2020
  • Accepted
    13 Oct 2020
  • Published
    22 Nov 2020
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