SciELO - Scientific Electronic Library Online

vol.75Medical care for spinal diseases during the COVID-19 pandemicLung transplantation during the COVID-19 pandemic author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand




Related links



Print version ISSN 1807-5932On-line version ISSN 1980-5322

Clinics vol.75  São Paulo  2020  Epub May 15, 2020 


Why is SARS-CoV-2 infection milder among children?

Patricia PalmeiraI

José Alexandre M. BarbutoII

Clovis Artur A. SilvaIII

Magda Carneiro-SampaioI  III  *

ILaboratorio de Investigacao Medica (LIM-36), Departamento de Pediatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR

IIDepartamento Imunologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR

IIIDepartamento de Pediatria, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR

Acute respiratory viral diseases, like most other infectious diseases, affect mainly infants and young children, who present with 6-8 episodes per year and usually develop more severe manifestations than in adults. It is well-documented that innate antiviral immune responses in early life are characterized by lower type I interferon (IFN) responses (1) and reduced natural killer cell activity, which despite their higher numbers exhibit lower cytotoxic capacity and reduced number of cytoplasmic granules and degranulation ability (2). Additionally, lower cytotoxic T lymphocyte activity and numbers of effector and memory CD8+ T cells have also been described at younger ages (3).

Most data indicate a significant role for innate immunity and T-cell cytotoxicity in the control of viral infections. Surprisingly, however, as seen in the severe acute respiratory syndrome-related coronavirus (SARS-CoV) (4) and Middle East respiratory syndrome-related coronavirus (MERS) (5) outbreaks, the current SARS-CoV-2 pandemic shows low morbidity and near-absent mortality in previously healthy children. On February 28, 2020, in one of the first publications on the clinical features of SARS-CoV-2 infection, Guan et al. (6) analyzed 1,099 laboratory-confirmed patients from Wuhan, China. Among these, only nine were under 14 years (0.9%) and only one had a severe course. Shortly thereafter, a review of 72,314 cases, conducted by the Chinese National Center for Disease Control and Prevention, showed that less than 1% of cases were in children under 10 years of age (7). Similarly, reports from Italy, Brazil, and the USA confirm a lower incidence of serious infections among younger individuals (8-10).

In late March 2020, the Chinese Center for Disease Control and Prevention reported the epidemiological characteristics of a nationwide case series of 2,143 pediatric patients (<18 years old) with COVID-19, including 731 laboratory-confirmed cases and 1,412 suspected patients (11). Among the confirmed cases, 12.9% were asymptomatic, and symptomatic disease was mild in 43.1%, moderate in 41%, and severe in 2.5% of cases. Only 0.4% (3 patients) were classified as critical. Considering the available data for the whole series, the most severe cases were more frequent among those under 5 years old. Clinical data for 171 confirmed cases (1 day to 15 years old) from the Wuhan Children’s Hospital were described in more detail (12). Like in adults, there was a predominance of males (60.8%), and the clinical manifestations were quite similar: fever was present in 41.5% of the children and adolescents at any time during the illness, and other common features were cough and pharyngeal erythema. Pneumonia was diagnosed in 111 patients (64.9%), 33 (19.3%) presented only upper respiratory tract manifestations, and 27 (15.8%) had asymptomatic infection. Bilateral ground-glass opacities were the most common radiologic finding, observed in 32.7% of the cases. Three patients required intensive care support and invasive mechanical ventilation (1.75%). These patients had co-existing morbidities (hydronephrosis, leukemia in maintenance chemotherapy, and bowel intussusception), and the only death in the series occurred in a 10-month-old patient with intussusception.

As with SARS-CoV, COVID-19 is believed to be initiated by the binding of the SARS-CoV-2 envelope-anchored spike protein to the outer surface of the angiotensin-converting enzyme 2 (ACE2) catalytic domain (13), promoting endocytosis where viral and host membranes fuse and consequent entry of the virus into the host cell. Angiotensin-converting enzyme (ACE) and its later described homolog ACE2 are critical proteases for regulating the renin-angiotensin system (RAS), exerting opposite roles. Whereas ACE generates angiotensin II, promoting vasoconstriction, ACE2 cleaves angiotensin II to generate Ang1-7, which acts as a negative regulator and exerts an antihypertensive effect (14,15). Zhao et al. (16) reported that ACE2 pulmonary expression is concentrated mainly in type II alveolar cells, which express many other genes that could favor viral replication, thus offering an explanation for the severe alveolar damage associated with SARS-CoV-2 infection. However, one should remember that, in addition to the lung, ACE2 is highly expressed in the kidneys, heart, and testes and is expressed at a lower level in the colon and liver (17). Furthermore, ACE2 may not be the only cellular receptor for the virus. Infection of T lymphocytes, which express very low levels of ACE2, has been described and attributed to the binding of the virus spike protein to CD147, another cell surface molecule (18).

Nevertheless, considering ACE2 as the main gate for infection, the first hypothesis for the diminished susceptibility of children to SARS-CoV-2 suggests a different ACE2 configuration, concentration, or binding capacity or a less harmful alveolar epithelial cell response to ACE2 in children when compared with that in adults (19). Although attractive and supported by observations that some comorbidities associated with a more severe evolution of COVID-19 may be also associated with modifications of ACE2 expression (20-23), the role of ACE2 modulation in this infection is far from clear. Reports suggesting a protective role against severe COVID-19 by increased ACE2 expression are paralleled by others that indicate otherwise (24). In agreement with the hypothesis that ACE2 expression levels have a significant role in acute respiratory distress syndrome (ARDS), which also occurs in COVID-19, an experimental mouse model of H5N1 virus-induced lung injury and death showed ACE2 downregulation following infection (25). In this context, however, one should add a confounding observation: arterial hypertension, a condition that is associated with modified ACE2 expression (26) and was one of the main comorbidities in the Chinese population with severe COVID-19, is barely present among the first North American series reported by the CDC (27). However, it is possible that the increased representation of male individuals among patients with confirmed COVID-19 might be because of decreased ACE2 expression caused by testosterone in contrast to the enhancement caused by estrogens (28,29), a phenomenon that, although not explored in children, might take part in their relative resistance.

Finally, a recently released news report of a fatal case of COVID-19 in a 3-month-old infant with Bartter's syndrome has indicated that ACE2 does have a significant role in COVID-19. This is an interesting example of how rare genetic disorders may contribute to understanding the pathophysiology of common diseases: patients affected with this autosomal recessive tubulopathy have increased ACE2 levels and elevated renin and aldosterone levels (30). However, how these factors actually interact in the case of a SARS-CoV-2 infection remains to be determined.

The aforementioned suggestion by Fang and Luo (19) that the intracellular response induced by ACE2 is different in children than in adults, especially in the elderly, leads us to another hypothesis. In animal models, as age increases, there is a shift in the balance between the pulmonary RAS enzymes, ACE and ACE2. As ACE levels increase, so do the angiotensin II levels, leading to more intense inflammation and increased lung injury (31). Although the same ACE/ACE2 imbalance was not observed in humans in a later study by the same group (32), the incidence, susceptibility, course, and mortality from ARDS do tend to increase progressively with age (33-35). It is well-known that aging is associated with a process called immunosenescence, that is, the decline in the efficiency of the immune systems with age (36). Increasing age is associated with increased neutrophil elastase activity, primary granule release, inaccurate migration, and increased oxidative stress, leading to a state of systemic inflammation (37) with impaired repair mechanisms, thus contributing to exaggerated responses and tissue injury in the elderly (35). In contrast, could the relative resistance of children be due to an immature immune system?

Unlike other respiratory viruses, such as influenza, respiratory syncytial virus, adenovirus, and others, one very intriguing aspect is that the current SARS-CoV-2 pandemic (like with SARS-CoV and MERS) may not cause a more serious illness in immunosuppressed patients in addition to being milder in immature hosts. In a recent letter from a pediatric liver transplantation unit in Bergamo, Italy, D’Antiga (38) noted that there were no cases of ARDS in patients immunosuppressed because of transplantation, chemotherapy, or other immunosuppressive treatments. However, some of these cases were positive for SARS-CoV-2, suggesting that immunosuppressed patients may not be at higher risk of severe pulmonary disease compared with the general population. Nevertheless, this is still purely observational, as is a report of fatal COVID-19 pneumonia in two transplanted patients in China (39). Additionally, another Italian study reported 4% of adults with chronic arthritis diseases under immunosuppressive treatment had suspected or confirmed COVID-19, with no deaths (40).

This brings us to what may prove to be the crucial point in understanding COVID-19 pathophysiology. As in most (if not all) infectious diseases, this disease is not a direct and simple result of the infection, but the consequence of both the presence of the pathogen and its interaction with the patient’s immune system. Thus, even if we unveil, as we are indeed unveiling, many characteristics of the virus that contribute to and are coherent with the clinical manifestations and course of COVID-19 without adding to the picture the immune reaction to the virus, we will be missing the target. In addition, by taking into account the immune response, we need to consider that the response in a patient will not be independent of the individual immunological history, where previous infections and momentary immune status will drive the response to one pattern or another and, possibly, to different clinical evolutions of the disease.

Currently, however, we are only beginning to describe the immune response of patients to SARS-CoV-2, and we are unclear about the most effective immune response pattern against the virus. A prospective observation of a 47-year-old female patient with mild-to-moderate COVID-19 showed increased numbers of antibody-secreting cells, follicular helper T cells, activated CD4+ T cells and CD8+ T cells, as well as antiviral IgM and IgG antibodies in blood before symptomatic recovery (41). This study indicates that early robust adaptive immune responses were elicited against SARS-CoV-2, as should occur in other viral diseases, but we cannot conclude from it whether humoral or cellular responses are more relevant. In contrast, patients who had recovered from SARS showed potent antibody responses specific to the SARS-CoV spike protein with robust neutralizing activity, which persisted at high titers over a three-year follow-up (42). In addition, the IgG level in patients with mild SARS-CoV infection was significantly higher than that in patients with severe infection (43).

If the antibody response is responsible for the severity of COVID-19, we should consider that adults would have come into contact with and have produced antibody responses against several antigens from related viruses throughout their lives on a much larger scale than in children (44). These antibodies could cross-react with SARS-CoV-2 with a low affinity and could induce activation of an inflammatory response, either by local deposition of immune complexes or by binding to Fc receptors present on pulmonary antigen-presenting cells, instead of promoting an effective viral neutralization. In fact, in patients with COVID-19, the innate immune response shows an increase in neutrophil numbers and C-reactive protein (CRP), D-dimer, and IL-6 levels (43,45).

Another possible mechanism through which antibodies could contribute to the severity of the disease is the antibody-dependent enhancement, which is well-described in dengue virus infections (46). This was also, in fact, demonstrated by Yip et al. (47) in SARS-CoV infection of human macrophages in vitro. Nevertheless, although murine anti-spike antibodies facilitated human macrophage infection via the Fcγ receptor II (CD32), this resulted in neither SARS-CoV replication nor alteration of pro-inflammatory cytokine/chemokine production or apoptosis-induced ligands by these infected cells. This is relevant because other clinical studies indicate that COVID-19 patients have lymphocytopenia with high levels of several cytokines and chemokines, such as G-CSF, IP-10, MCP-1, MIP-1α, and TNF-α (48,49). Therefore, the increased production of pro-inflammatory cytokines could be the cause of both viral sepsis and damage to tissues or organs, resulting in septic shock, disseminated intravascular coagulation, and multi-organ dysfunction syndrome. These phenomena of a cytokine storm syndrome in COVID-19 are similar to those in hemophagocytic lymphohistiocytosis (50) and in the macrophage activation syndrome associated with systemic-onset juvenile idiopathic arthritis or juvenile systemic lupus erythematosus (51-53), indicating that COVID-19 is, at least in some cases, a disease of immune dysregulation.

Another observation deserves to be highlighted: in the description of the clinical characteristics of coronavirus disease in China, lymphocytopenia (<1.2×109 per liter) was present in only 3.5% of pediatric patients in contrast to 83.2% of the 1,099 patients of all age groups analyzed (6). The characteristically higher numbers of total lymphocytes and their main subpopulations in healthy infants and young children (54) attracts attention and warrants further investigations, although we cannot determine whether this lack of lymphocytopenia is a cause or consequence of a diminished disease severity.

Another hypothesis related to the immune history of patients has been proposed, that is, a “protective” effect of BCG (Bacille Calmette-Guérin) vaccination against tuberculosis, as countries where BCG is compulsorily administrated in the first few days of life, like Brazil, have a seemingly more controlled dissemination of the SARS-CoV-2 virus (55). A recent review discussed the possible non-specific mechanisms of action of BCG or muramyl dipeptide (MDP) against viral infections in animal models and humans (56). The proposed mechanisms were an induction of CD4 and CD8 T-cell responses, mainly of the Th1 and Th17 subtypes, to secondary unrelated viruses (57); an increased functional cross-reactive antibody response (58); and increased production of pro-inflammatory cytokines, such as IL-1β and TNF-α, by epigenetic reprogramming of monocytes and macrophages (“trained immunity”), probably as a consequence of greater activation of CD11b, TLR4, and CD14 on these cells (59,60). Faced with a disease where most pathogenetic mechanisms seem to rely on “excessive” immune responses, these hypotheses would have to be adjusted before one could incorporate them into the picture of the natural history of COVID-19.

As is evident, the pathophysiology of SARS-CoV-2 infection is far from being understood. Most data indicate that it is, in fact, a multisystemic disease and not only a respiratory disorder. Hematologic, cardiac, renal, neurologic, gastrointestinal, and other alterations are being described as parts of a conundrum that needs to be clarified. Understanding the reasons for the consistent observations that immune-immature and some immunosuppressed hosts are spared from severe manifestations could contribute to elucidating COVID-19 aggression mechanisms and indicate pathways to offer better and more efficient treatment to infected patients. Interestingly, after the acceptance of this manuscript, there have been warnings from pediatric associations in Spain, the UK and the USA about cases of children with confirmed COVID-19. These patients developed septic shock and Kawasaki-like features, after initial gastrointestinal manifestations and without flu-like symptoms (61). It is noteworthy that vascular lesions and dysregulated inflammatory responses, which seem to be characteristics of COVID-19 in adults, may also occur in children.

On the last April 27th, Bi et al. (62) published a retrospective cohort study from Shenzhen, China demonstrating that the rate of infection in children below 10 years was similar to the population average, although children are less likely to develop severe symptoms.


This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 409825/2016-6 and 308053/2017-6 to JAMB, CNPq 303422/2015-7 to CAS; and 308627/2016-4 to MCS), Fundação de Amparo è Pesquisa do Estado de São Paulo (FAPESP 2015/03756-4 to CAS and 2014/50489-9 to MCS) and by Núcleo de Apoio è Pesquisa “Saúde da Criança e do Adolescente” from USP (NAP-CriAd) to CAS and MCS.


1. Heinonen S, Rodriguez-Fernandez R, Diaz A, Oliva Rodriguez-Pastor S, Ramilo O, Mejias A. Infant Immune Response to Respiratory Viral Infections. Immunol Allergy Clin North Am. 2019;39(3):361-76. [ Links ]

2. Guilmot A, Hermann E, Braud VM, Carlier Y, Truyens C. Natural killer cell responses to infections in early life. J Innate Immun. 2011;3(3):280-8. [ Links ]

3. Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint JP, Labalette M. Accumulation of memory T cells from childhood to old age: central and effector memory cells in CD4(+) versus effector memory and terminally differentiated memory cells in CD8(+) compartment. Mech Ageing Dev. 2006;127(3):274-81. [ Links ]

4. Stockman LJ, Massoudi MS, Helfand R, Erdman D, Siwek AM, Anderson LJ, et al. Severe acute respiratory syndrome in children. Pediatr Infect Dis J. 2007;26(1):68-74. [ Links ]

5. Hui DS, Azhar EI, Kim YJ, Memish ZA, Oh MD, Zumla A. Middle East respiratory syndrome coronavirus: risk factors and determinants of primary, household, and nosocomial transmission. Lancet Infect Dis 2018;18(8):e217-e227. [ Links ]

6. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020. [ Links ]

7. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020. [ Links ]

8. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA. 2020. [ Links ]

9. Boletim Epidemiológico no 6 da Secretária de Vigilância em Saúde, Ministério da Saúde, COE-COVID, 3 abril 2020. Available from: ]

10. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):422-6. [ Links ]

11. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. Pediatrics. 2020. [ Links ]

12. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020. [ Links ]

13. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8. [ Links ]

14. Perlot T, Penninger JM. ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect. 2013;15(13):866-73. [ Links ]

15. Ferrario CM. ACE2: more of Ang-(1-7) or less Ang II? Curr Opin Nephrol Hypertens. 2011;20(1):1-6. [ Links ]

16. Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. bioRxiv. 2020. [ Links ]

17. Imai Y, Kuba K, Ohto-Nakanishi T, Penninger JM. Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circ J. 2010;74(3):405-10. [ Links ]

18. Wang X, Xu W, Hu G, Xia S, Sun Z, Liu Z, et al. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cell Mol Immunol. 2020. [ Links ]

19. Fang F, Luo XP. [Facing the pandemic of 2019 novel coronavirus infections: the pediatric perspectives]. Zhonghua Er Ke Za Zhi. 2020;58(2):81-85. [ Links ]

20. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8(4):e21. [ Links ]

21. Sommerstein R, Gräni C. Preventing a COVID-19 pandemic: ACE inhibitors as a potential risk factor for fatal COVID-19. BMJ. 2020. Available from ]

22. Esler M, Esler D. Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? J Hypertens. 2020;38(5):781-2. [ Links ]

23. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med. 2020. pii: taaa041. ]

24. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020;382(17):1653-9. [ Links ]

25. Zou Z, Yan Y, Shu Y, Gao R, Sun Y, Li X, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014;5:3594. [ Links ]

26. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017;125 (Pt A):21-38. [ Links ]

27. CDC COVID-19 Response Team. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 - United States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):382-386. [ Links ]

28. Schunkert H, Danser AH, Hense HW, Derkx FH, Kürzinger S, Riegger GA. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation. 1997;95(1):39-45. [ Links ]

29. Hilliard LM, Sampson AK, Brown RD, Denton KM. The “his and hers” of the renin-angiotensin system. Curr Hypertens Rep. 2013;15(1):71-9. [ Links ]

30. Besouw MTP, Kleta R, Bockenhauer D. Bartter and Gitelman syndromes: Questions of class. Pediatr Nephrol. 2019. [ Links ]

31. Schouten LR, Helmerhorst HJ, Wagenaar GT, Haltenhof T, Lutter R, Roelofs JJ, et al. Age-Dependent Changes in the Pulmonary Renin-Angiotensin System Are Associated With Severity of Lung Injury in a Model of Acute Lung Injury in Rats. Crit Care Med. 2016;44(12):e1226-35. [ Links ]

32. Schouten LR, van Kaam AH, Kohse F, Veltkamp F, Bos LD, de Beer FM, et al. Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study. Ann Intensive Care. 2019;9(1):55. [ Links ]

33. Johnston CJ, Rubenfeld GD, Hudson LD. Effect of age on the development of ARDS in trauma patients. Chest. 2003;124(2):653-9. [ Links ]

34. Villar J, Pérez-Méndez L, Basaldúa S, Blanco J, Aguilar G, Toral D, et al. A risk tertiles model for predicting mortality in patients with acute respiratory distress syndrome: age, plateau pressure, and P(aO(2))/F(IO(2)) at ARDS onset can predict mortality. Respir Care. 2011;56(4):420-8. [ Links ]

35. Schouten LR, Schultz MJ, van Kaam AH, Juffermans NP, Bos AP, Wösten-van Asperen RM. Association between Maturation and Aging and Pulmonary Responses in Animal Models of Lung Injury: A Systematic Review. Anesthesiology. 2015;123(2):389-408. [ Links ]

36. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217. [ Links ]

37. Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood. 2014;123(2):239-48. [ Links ]

38. D'Antiga L. Coronaviruses and Immunosuppressed Patients. The Facts During the Third Epidemic. Liver Transpl. 2020. [ Links ]

39. Huang J, Lin H, Wu Y, Fang Y, Kumar R, Chen G, et al. COVID-19 in posttransplant patients—report of 2 cases. Am J Transplant. 2020. [ Links ]

40. Monti S, Balduzzi S, Delvino P, Bellis E, Quadrelli VS, Montecucco C. Clinical course of COVID-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies. Ann Rheum Dis. 2020;79(5):667-8. [ Links ]

41. Thevarajan I, Nguyen THO, Koutsakos M, Druce J, Caly L, van de Sandt CE, et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat Med. 2020;26(4):453-5. [ Links ]

42. Cao Z, Liu L, Du L, Zhang C, Jiang S, Li T, et al. Potent and persistent antibody responses against the receptor-binding domain of SARS-CoV spike protein in recovered patients. Virol J. 2010;7:299. [ Links ]

43. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020;9(1):727-32. [ Links ]

44. Huang AT, Garcia-Carreras B, Hitchings MDT, Yang B, Katzelnick LC, Rattigan SM, et al. A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease. MedRxiv. [ Links ]

45. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3. [ Links ]

46. St John AL, Rathore APS. Adaptive immune responses to primary and secondary dengue virus infections. Nat Rev Immunol. 2019;19(4):218-30. [ Links ]

47. Yip MS, Leung HL, Li PH, Cheung CY, Dutry I, Li D, et al. Antibody-dependent enhancement of SARS coronavirus infection and its role in the pathogenesis of SARS. Hong Kong Med J. 2016;22(3 Suppl 4):25-31. [ Links ]

48. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. [ Links ]

49. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420-2. [ Links ]

50. Barbuto JA. Hemophagocytic lymphohistiocytosis: a rare diagnosis, an even rarer opportunity to appraise our understanding of the immune system. Autops Case Rep. 2015;5(1):1-5. [ Links ]

51. Davi S, Minoia F, Pistorio A, Horne A, Consolaro A, Rosina S, et al. Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2014;66(10):2871-80. [ Links ]

52. Gormezano NW, Otsuzi CI, Barros DL, da Silva MA, Pereira RM, Campos LM, et al. Macrophage activation syndrome: A severe and frequent manifestation of acute pancreatitis in 362 childhood-onset compared to 1830 adult-onset systemic lupus erythematosus patients. Semin Arthritis Rheum. 2016;45(6):706-10. [ Links ]

53. Minoia F, Bovis F, Davì S, Horne A, Fischbach M, Frosch M, et al. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2019;78(10):1357-62. [ Links ]

54. van Gent R, van Tilburg CM, Nibbelke EE, Otto SA, Gaiser JF, Janssens-Korpela PL, et al. Refined characterization and reference values of the pediatric T- and B-cell compartments. Clin Immunol. 2009;133(1):95-107. [ Links ]

55. Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRXiv. 2020. [ Links ]

56. Moorlag SJCFM, Arts RJW, van Crevel R, Netea MG. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019;25(12):1473-8. [ Links ]

57. Mathurin KS, Martens GW, Kornfeld H, Welsh RM. CD4 T-cell-mediated heterologous immunity between mycobacteria and poxviruses. J Virol. 2009;83(8):3528-39. [ Links ]

58. Leentjens J, Kox M, Stokman R, Gerretsen J, Diavatopoulos DA, van Crevel R, et al. BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis. 2015;212(12):1930-8. [ Links ]

59. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci USA. 2012;109(43):17537-42. [ Links ]

60. Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang SY, Oosting M, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018;23(1):89-100.e5. [ Links ]

61. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J, et al. COVID-19 and Kawasaki Disease: Novel Virus and Novel Case. Hosp Pediatr. 2020. pii: hpeds.2020-0123. [ Links ]

62. Bi Q, Wu Y, Mei S, Ye C, Zou X, Zhang Z, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect Dis. 2020. [ Links ]

Received: April 22, 2020; Accepted: April 23, 2020

*Corresponding author. E-mail:

No potential conflict of interest was reported.

All the authors contributed substantially to the conception and design of the study and in the analysis and interpretation of data. All authors revised the work critically and approved the final version.

Creative Commons License This is an Open Access article distributed under the terms of the Creative Commons License ( which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.