key: cord-323141-6z750avb
authors: Kuroda, Naoto
title: Demand for BCG Vaccine Due to Unproven Claims of its Role in Preventing COVID-19 Is Causing Shortages of Vaccines for Infants in Japan
date: 2020-12-05
journal: Pediatr Infect Dis J
DOI: 10.1097/inf.0000000000002724
sha: 
doc_id: 323141
cord_uid: 6z750avb

nan

Apart though from the management of febrile children, pediatricians and the pediatric infectious diseases specialists will also have to face challenges with the infection during the neonatal period. Undoubtedly close monitoring of at-risk neonates is essential in the neonatal wards, but there are issues where evidence-based guidance is needed. The first priority is identifying the timing of infection (antenatally, perinatally or postnatally) and confirming its presence. Two recent reports from China suggest that in utero infection could be possible based on the measurement of IgM levels in neonates shortly after birth but no further confirmation of this with a positive reverse transcriptase-polymerase chain reaction test. 2, 3 Therefore, although in utero transmission is possible, larger studies on infected women will bring further insight in the field. In the case of the in utero infected neonate, the timing of infection may have an impact on fetal development and possibly on long-term outcomes. We do not know as yet whether acquisition during first trimester of pregnancy is associated with birth defects and whether fetal infection is more likely in the advanced pregnancy stages following the patterns of other congenital infections. What we do know though is that antenatal infection with other coronaviruses (severe acute respiratory syndrome and Middle East respiratory syndrome) is associated with possible miscarriage, intrauterine growth retardation prematurity and low birth weight. 4 Moreover, at present, we do not know how many molecular tests we need to perform and whether 2 tests are enough to rule out neonatal infection given that serology is not always reliable, as observed with other congenital infections. In addition to that, uncertainty exists as to whether respiratory specimens are enough or blood, stool or urine samples would offer more accurate results.

Last but not least separation of an infected mother from her offspring and feeding options are issues for further consideration. Some guidelines suggest complete separation of a COVID-19-positive mother and her baby for at least 14 days or until viral shedding clears, during which time direct breast-feeding is not recommended. 5 On the other hand, the Centre for Disease Control and Prevention and the Royal College of Obstetricians and Gynecologists recommend breast-feeding with strict contact precautions based on the fact that so far there is no evidence that the virus can be transferred via breast milk. For those women who are too sick to breast-feed, the recommendation is breast milk expression and avoidance of any contact with the baby.

In conclusion, the current pandemic poses several challenges to the pediatricians from the neonatal period throughout adolescence. Evidence-based recommendations The authors have no funding or conflicts of interest to disclose. N.K. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. N.K. contributed to the study concept and design; drafting of the article; Critical revision of the article for important intellectual content. 

originated in China and has rapidly spread worldwide. Currently, supportive therapy is the most effective treatment. Vaccination is one of the best options for the prevention of infectious diseases. However, a vaccine, as well as a specific proven treatment, remains elusive.

The Bacillus Calmette-Guérin (BCG) vaccine is administered to more than one million children annually in countries with a high prevalence of tuberculosis. Recently, researchers hypothesized that it might also combat COVID-19 because of its broad ability to stimulate the immune system. 1 This is based on the fact that countries without universal policies of BCG vaccination (ie, Italy, the Netherlands, and the United States) have been more severely affected compared with countries with universal and long-standing BCG policies. 2 Therefore, some researchers are investigating the vaccine's effectiveness against COVID-19. 3 However, it should be emphasized that the causality is not yet proven; there is only one study predicting an association. 3 Generally, to clarify the causality between two variables, the Bradford Hill criteria is used. 4 To show the causality between the BCG vaccine and the severity of COVID-19, we have to confirm the following Bradford Hill criteria: specificity, temporality, reversibility, and experiment. Until the results of interventional studies are published, we cannot conclusively establish the utility of BCG against COVID-19.

However, many people have misinterpreted this association as causation. This excessive expectation increases individual desire to be vaccinated with BCG. This will cause a big problem for Japanese infants, who, owing to the shortage of BCG, may not get the necessary vaccination. Producing adequate amounts of BCG to meet demands besides that for infant vaccination will take half a year because, at present, only the amount necessary for use in infants is manufactured. Apprehension regarding BCG shortage led the Japanese Society for Vaccinology to officially state that it does not recommend the use of BCG vaccine for the prevention of COVID-19. 5 However, under the current Japanese health care system, individuals willing to pay for individual vaccination cannot be prohibited from doing so. Therefore, emphasizing the lack of evidence and the cooperation of Japanese citizens is necessary. If infants in Japan do not receive BCG vaccines, tuberculosis might spread. We must prevent this from happening by publicizing inadequate evidence of causality between the BCG and prevention of the COVID-19. We also need to highlight the concern that a shortage of BCG would exacerbate the tuberculosis crisis among the infants in Japan.

A t the end of December 2019, the coronavirus disease 2019 (COVID-19) epidemic started in China and then expanded worldwide. Thereafter, many clinical studies have been reported, but most of them concerned the Chinese people. Clinical data regarding the Italian pediatric population are still lacking.

In February 2020, the COVID-19 pandemic flared up across Italy, the first cluster started in South-Lombardy, which is still the most affected area. 1 caused about 19,000 deaths, including more than 110 doctors, so far (April 11).

Based on this background, we analyzed the data concerning all pediatric patients with COVID-19 (0-18 years old) admitted to the San Matteo Hospital of Pavia until April 4. The Province of Pavia (about 550,000 residents) belongs to Lombardy Region and is the catchment-area of this hub hospital. Patients were stratified in 4 subgroups according to the severity of the disease, classified as requiring home isolation, admission to low-intensity care, sub-intensive care unit or intensive care unit (ICU). We also considered the data of all patients with COVID-19 living in Lombardy, evaluating the same classification adding the death rates. Table 1 shows the demographic and clinical data. As of today (April 11), 17 children had COVID-19 diagnosis based on clinical data and positive swab (RT-PCR analysis). There was a slight predominance of males (58.8%), the median age was 4 years. Five children required the home isolation as the symptoms were very mild; 12 were admitted at the hospital: 3 (25%) required low-intensity care, 8 (66.7%) subintensive care and 1 (8.3%) ICU admission.

Analyzing the data concerning the whole Lombardy population, 29.3% of patients with COVID-19 had home isolation, 21.5% required low-medium-intensity care, 2.3% ICU admission, and 18.3% died. Therefore, there is, presently, convincing evidence that COVID-19 causes a mild-moderate disease in childhood. Consistently, no child has died so far in Italy. Indeed, disease severity, namely intensity of requested care and mortality rate, progressively increased with age. These findings could be interpreted as reassuring for the pediatric age and young adulthood. On the other hand, COVID-19 may seriously affect elderly people, requiring an outstanding care concentration.

These outcomes were consistent with the literature data. 2, 3 Several hypotheses were envisaged, including the different frequency of angiotensin converting enzyme 2 (ACE2) expression on pneumocytes, which is higher in the elderly and male. ACE2 is the receptor for coronavirus, thus overexpression promotes infection. Hypertension, chronic respiratory diseases, cancer and metabolic disorders were also reported frequent comorbidity, common in older subjects. 4, 5 However, no conclusive factors have been defined still now. On the other hand, children seem to be protected thanks to some probable mechanisms. Children have usually fewer comorbidity, ACE2 is under-expressed and do not smoke (smoking is associated with increased expression of ACE2), have a large thymic repertoire and sustained innate immunity, more T and B regulatory lymphocytes than adults, and received a wide vaccination program. As a result, children could have a more protective immune response than adults.

Therefore, the current data confirm the good prognosis in children. An ongoing study is investigating more detailed risk factors in this population.

SARS-CoV-2 infection in a pediatric department in Milan: a logistic rather than a clinical emergency

Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn

Antibodies in infants born to mothers with COVID-19 pneumonia

Coronavirus infections in children including COVID-19 an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children

Guidelines for pregnant women with suspected SARS-CoV-2 infection

Can a century-old TB vaccine steel the immune system against the new coronavirus?

Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study

Immune boost against the corona virus [Max-Planck-GesellSchaft web site

The environment and disease: association or causation

Opinion about effectiveness of BCG vaccine against COVID-19 [The Japanese Society for Vaccinology web site

The early phase of the COVID-19 outbreak in Lombardy

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease

Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis

Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19

Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19

TABLE 1. Demographic and COVID-19 Data in Lombardy Region and Pediatric Patients with COVID-19+ living in Pavia District Lombardy Region Total population 10

Age (years)* 62

Males (%) 67 % Home isolation, n (%)

3%) Pavia District Total population

Pediatric population, ≤18 years, n (% total population)

*Figures represent median values and figures in squared parentheses represent first and third quartiles. COVID-19, coronavirus disease 2019; ICU, intensive care unit. Figures in round parentheses represent percentages

The authors have no funding or conflicts of interest to disclose.Ilaria Brambilla, PhD,* Riccardo Castagnoli, PhD,* Silvia Caimmi, MD,* Giorgio Ciprandi, MD, † Gian Luigi Marseglia, MD*