key: cord-0956984-rk6eq4ax
authors: Chen, Fan; Chen, GuoXi; Zhou, Jing; Xue, Yun; Wu, Mei X.
title: Childhood Bacillus Calmette–Guérin Vaccination and Its Association With Less Severe COVID-19 Pneumonia
date: 2021-04-12
journal: Am J Prev Med
DOI: 10.1016/j.amepre.2021.02.025
sha: 2d4244010a7265e0402f3d82850d2d24d582e594
doc_id: 956984
cord_uid: rk6eq4ax

Introduction The potential for bacillus Calmette–Guérin (BCG) vaccination to mitigate coronavirus disease 2019 (COVID-19) severity and perhaps infection susceptibility has been hypothesized, attracting global attention given its off-target benefits demonstrated in several respiratory viral infections. Methods In this retrospective study, patients with laboratory-confirmed COVID-19 from Wuhan Pulmonary Hospital, China were categorized into BCG vaccination and non-vaccination groups. Clinical records, demography, laboratory results, and chest computed tomography scans were extracted from electronic medical records and compared between the 2 groups. Results No adverse events were observed, except for an increased frequency of chills in the BCG-vaccinated group versus the unvaccinated group (p=0.014). There were no significant differences in oxygen demand for breathing, computed tomography scans, treatments, or outcomes between the 2 groups. However, BCG vaccination was associated with significantly less severe pneumonia (p=0.028) and milder deficiency in liver function, consistent with a lower death rate in comparison with the unvaccinated group. Conclusions BCG vaccination received in childhood is associated with less severe COVID-19 pneumonia and milder liver function deficiency in addition to a lower death rate in BCG-vaccinated patients versus non-vaccinated individuals.

Coronavirus disease 2019 , caused by SARS-CoV-2, has become a global public health and economic crisis since its initial appearance in Wuhan, China in December 2019. 1, 2 Various resources worldwide have been allocated to the development of COVID-19 vaccines and searching for effective treatments to manage this devastating disease. 3, 4 Although COVID-19 vaccines and effective therapeutics are emerging, repurposing available medical regimens against this disease remain vital strategies for the current and future pandemics.

Among these, the potential for bacillus Calmette-Guérin (BCG) vaccination to mitigate COVID-19 severity and perhaps susceptibility has attracted attention worldwide for the following reasons. First, BCG, a live attenuated vaccine, was developed to prevent tuberculosis 100 years ago and has been since administered to infants worldwide with a proven safety record over the last century. It is the most used vaccine in the world and 130 million children receive the vaccine each year owing to its effectiveness and low cost. Second, epidemiological, preclinical, and clinical studies have found a wide range of off-target benefits of the vaccine, especially with regard to respiratory tract viral infections-including those from respiratory syncytial virus, influenza A virus, and herpes simplex virus type 2. 5, 6 Finally, the number of confirmed COVID-19 cases appear to be fewer and the death toll seems to be lower in countries with universal BCG vaccine coverage than those in countries without it. 7, 8 These observations boost hopes for use of BCG vaccination as a bridging strategy to protect against a wide range of emerging pathogens including SARS-CoV-2, mutations thereof, or future new SARS viruses, before specific vaccines are developed.

However, definitive proof of its benefit is required to validate this broad approach, which remains lacking. Most current ecological studies fail to consider some major confounding factors in the linkage between COVID-19 heterogenicity and the prevalence of BCG childhood vaccination program in different countries. These confounding factors include differences in demography, ethnicity, time of infections, age, sex, BMI, chronic underlying medical conditions, non-pharmaceutical interventions, and diagnosis and reporting of COVID-19 cases. As a consequence, conflicting results are reported with either positive or no real correlation between BCG vaccination and reduced COVID-19 incidence and fatality rates. 9,10 When COVID-19 infection rates were investigated in young adults aged 35-41 years differing only in BCG status in Israel, BCG vaccination in childhood was found to have no effect on COVID-19 infection rates. 11 Effects of BCG vaccination on the severity of COVID-19 was not assessed in that study as those young adults exhibit mostly mild or moderate disease.

The BCG vaccination program was initiated in China in 1950, but did not become a routine vaccination until 1982, which provides a unique opportunity to investigate the influence of BCG vaccination on COVID-19 severity and infection rates in the same demographic, ethnic, epidemiological infection curve, social, cultural, and climate environment. Accordingly, this study analyzed a cohort of COVID-19 patients from the same hospital in the same period of the pandemic curve to eliminate any of the aforementioned inherent biases and determine the beneficial effects of BCG vaccination on COVID-19 severity between 2 similar groups of patients with only 1 variable: BCG immunization history. The investigation provides the first direct evidence that BCG vaccination in childhood may attenuate COVID-19 pneumonia severity and improve liver function in association with a lower death rate. 

Basic information, medical history, clinical symptoms, clinical laboratory tests, treatments, and outcome data were extracted from electronic medical records. All information was obtained and curated with a customized data collection form. Pneumonia severity was determined according to the Chinese COVID-19 diagnosis and treatment protocol (7th edition). Briefly, mild disease is defined as no signs of pneumonia on computed tomography (CT) imaging; moderate refers to symptoms such as fever, respiratory tract lesion, and manifestations of pneumonia on CT imaging; severe must have 1 of the following: onset of shortness of breath, respiration rate ≥30 times/minute, finger oxygen saturation ≤93% when at rest, partial arterial oxygen pressure/fraction of inspiration oxygen ≤300 mmHg, or pulmonary imaging showing significant progression of lesions within 24-48 hours (50%); and critical is defined by any of the following: respiratory failure and mechanical ventilation required, or shock alone or combined with other organ failure, requiring intensive care unit admission. Two investigators independently reviewed the data collection forms to ensure that the data collection was unbiased.

Continuous variables are presented as median (IQR) and categorical variables as n (%). The

Mann-Whitney U test, Wilcoxon signed rank test, independent-samples t-test, Fisher's exact test, or chi-square test were initially used to compare differences between BCG vaccination and non-vaccination groups as appropriate. Variables that were significant in univariate analysis were further examined with the multivariate logistic regression model to ascertain independent factors after adjusting age, sex, and BMI. A p-value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS, version 22.

From February 1 to March 30, 2020, a total of 428 COVID-19 patients were admitted to the Wuhan Pulmonary Hospital in China. SARS-CoV-2 viral infection was confirmed with at least 2 real-time polymerase chain reaction tests. Patients (n=20) with incomplete medical records were removed from the study. Overall, the death rate was significantly lower in the BCG-vaccinated group (4.2%, 5/118) than in the unvaccinated group (19.0%, 55/290) (p=0.00014, chi-square test). However, young patients aged <39 years were all BCG vaccinated, as BCG vaccination became mandatory in China in 1982, and they are less likely to die of COVID-19. On the other hand, none of older patients (n=189) aged >62 years received the BCG vaccine because the BCG vaccine was seldom administered in China before 1958. It has been well documented that elderly patients died of or with the disease at a relatively high mortality rate. Therefore, patients in these 2 groups were excluded from the investigation to circumvent any influence of age on COVID-19 ( (Table 1 ). There was no significant difference in age or sex between the 2 groups.

Clinical symptoms such as fever, cough, sore throat, stuffy nose, fatigue, muscle aches, chest tightness, difficult breathing, breath-holding spells, digestion, dizziness, or heart palpitations also did not differ significantly between the 2 groups (Table 1) . BMI and chronic underlying conditions including pulmonary disease, cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic liver disease, chronic gastropathy, hyperlipidemia, diabetes, cancer, surgery history, and other diseases were all similar irrespective of BCG vaccination history (Table 1) . However, a significantly higher percentage of patients experienced chills in the BCG-vaccinated group than in the unvaccinated group (p=0.014) ( Table 1 ).

There were 10 deaths (9.9%) in the unvaccinated group and 5 deaths among BCG-vaccinated patients (5.9%), a 40% reduction (Figure 1 ). In continuation of this positive trend, percentages of patients suffering from severe and critical pneumonia were significantly lower in the BCG-vaccinated group than in the non-vaccinated group. Only 1 patient was in critical condition (1.18%) in the BCG-vaccinated group, whereas 6 patients were critically ill (5.94%) in the unvaccinated group (Table 2) . Concomitantly, more patients or a higher proportion of patients with mild or moderate pneumonia were identified in the BCG-vaccinated group than in the unvaccinated group ( Table 2 ). The higher percentage of patients with mild and moderate pneumonia, along with a lower proportion of severe and critical COVID-19 patients, suggested a significant reduction of COVID-19 pneumonia severity in BCG-vaccinated compared with non-vaccinated groups (p=0.028) ( Table 2) . Moreover, a significant decrease in the mean concentration of serum lactate dehydrogenase (p=0.031) ( Figure 2 ) and a declining trend in lactate dehydrogenase levels were observed in the BCG-vaccinated group compared with unvaccinated patients (Table 2) . Lactate dehydrogenase has been reported to be an independent risk factor for lung injury and severe COVID-19 because it is released from injured cells. 12 Finally and unexpectedly, investigators found significantly lower percentages of patients producing abnormal levels of alanine aminotransferase (p=0.005) or aspartate transaminase (p=0.029) in the BCG-vaccinated group compared with the unvaccinated group ( Table 2 ).

The beneficial effects of BCG vaccination were independent of age or chronic underlying health conditions (Table 1) . Moreover, the oxygen demand for breathing was assessed by any need for supplemental oxygen or requiring low flow nasal cannula oxygen therapy, high flow nasal cannula oxygen therapy, noninvasive mechanical ventilation, extracorporeal membrane oxygenation, or invasive mechanical ventilation, none of which were discriminable statistically in the presence or absence of BCG vaccination ( Table 2 ). CT scans also demonstrated no difference between the 2 groups while comparing ground glass opacities in the lung, number of affected lung lobes, patches, stripe shadows, pleural adhesion, thickening, or effusion (Table 2 ). In accordance with the CT scans, there were no significant differences between these 2 groups when examining white cell counts, lymphocyte counts, or levels of hypersensitive C-reactive protein, creatine kinase MB isoenzyme, myoglobin, troponin I, erythrocyte sedimentation rate, procalcitonin, or D-dimer ( Table 2 ). The investigation also failed to identify any significant differences in treatment options patients received during hospitalization or in the subsidiary cabin medical facility irrespective of BCG vaccination history.

The current study provides the first direct clinical evidence that BCG vaccination received in childhood is associated with less severe COVID-19 pneumonia and milder deficiency in liver function in connection with a lower death rate in BCG-vaccinated patients compared with non-vaccinated individuals. This finding is in agreement with recent ecological studies and the well-recognized benefits of BCG vaccination leading to a decreased number of infections of all causes, especially respiratory tract infections, in people of all ages. 5, 6, 13, 14 Similar to the BCG vaccine, measles, mumps, and rubella vaccines and the oral polio vaccine have exhibited off-target benefits. 14, 15 The broad protective and lifelong benefit of BCG vaccination is intriguing and could serve a desperately urgent need for protecting people from a wide range of emerging pathogens. For instance, if a more lethal SARS virus or mutated SARS-CoV-2 transmit among humans in the future, the world could experience another emerging pathogen with potentially devastating consequences. This possibility cannot be ruled out because SARS-CoV-2 is mutating and the SARS-CoV-2 D614G variant is reported to be 10 times more contagious than the original virus. 16 Conceivably, BCG vaccination could protect people to some degree at the beginning of a pandemic, bridging the 1 to 2-year period until a specific vaccine is developed in case this occurs.

Apart from COVID-19 severity, a previous investigation suggests that BCG vaccination in childhood provides little prophylaxis against SARS-Cov-2 infection. 11 The authors could not determine any prophylactic effect of BCG vaccination on SARS-Cov-2 viral infection in the current study because the BCG vaccination rate among people aged 39-62 years is unknown.

Yet, in the authors' view, any conclusion on the impact of childhood BCG vaccination on infection should not serve as a reference to predict whether single or multiple doses of BCG vaccination in adults, as proposed in ongoing clinical trials, may prevent SARS-Cov-2 infection. 17 In fact, BCG revaccination may decrease susceptibility to SARS-CoV-2, as recently shown. 18 BCG vaccination could induce "trained immunity" by activation and reprogramming of innate immune cells via histone modifications and epigenetic reprogramming at the regulatory sites of genes encoding inflammatory cytokines in cells. 19, 20 Hematopoietic stem cells and myeloid progenitors in the bone marrow or microbiota in the gut may be also imprinted by BCG-mediated metabolic and epigenetic processes either directly or indirectly and involved in trained immunity, especially when the BCG vaccine is administered at birth. 21, 22 Epigenetically trained monocytes and natural killer cells can respond to bacterial or viral pathogens more strongly via pathogen-associated molecular patterns or other mechanisms and promote host defense. 20 Although trained immunity is thought to be long lasting, whether it can be fully or only partially sustained throughout life is unknown. Therefore, recent BCG vaccination, especially multiple doses, may confer much stronger trained immunity than childhood BCG vaccination does, an assumption that remains to be tested, however. 23 One concern has been raised with respect to whether non-specific augmentation of the innate immune response by BCG can deteriorate the exaggerated cytokine responses associated with complications in patients with COVID-19. This concern can be eased, at least in part, by the current investigation showing that BCG's imprint exerts no significant adverse events except for an increased chill response, which may be due to an enhanced innate immune response, 24 although the mechanism underlying the chill response remains to be determined.

Nevertheless, this response is minor and greatly outweighed by the benefits of BCG vaccination. Another unexpected finding is less liver dysfunction in COVID-19 patients with BCG immunization history, which is likely associated with metabolic reprogramming that alters certain metabolites that can function as cofactors in some liver enzymes. 25 

In spite of extensive adjustment, it is still possible that some unmeasured factors may play a role and some data may be missing or inaccurate in some patients' electronic health records.

For instance, patients with tuberculosis infection history, irrespective of whether it was latent or active, may be categorized into the unvaccinated group, and the significance of BCG vaccination might be underestimated. Moreover, the effect may be more predominant in patients with mild or no symptoms who were not admitted to the hospital or included in the current study, as suggested by a recent study showing a significant decrease of hospital admission rate (3.7% vs 15.8%) in people with versus without BCG vaccination history. 26 

The current investigation suggests that BCG vaccination in children is associated with less severe COVID-19 pneumonia, milder liver function deficiency, and a lower death rate when compared with unvaccinated patients. This conclusion is supported after controlling for major confounding factors including age, sex, ethnicity, BMI, the pandemic curve, demography, diabetes, and other underlying medical conditions. Notes: Each symbol represents data from one patient. *p0.05.

BCG, Bacillus Calmette-Guérin. LFNC, low flow nasal cannula oxygen therapy; HFNC, high flow nasal cannula oxygen therapy; NIMV, noninvasive mechanical ventilation; ECMO, extracorporeal membrane oxygenation; IMV, invasive mechanical ventilation; CRP, C-reactive protein; ALT, alanine aminotransferase; AST, aspartate transaminase; MB, muscle and brain; ESR, erythrocyte sedimentation rate. 

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We acknowledge the sacrifice, devotion, and commitment of all healthcare workers. This study is dedicated to the memory of those who have given their lives in the care of patients with COVID-19. The study is supported in part by Wellman Center discretionary fund, Massachusetts General Hospital, Dermatology Department, Harvard Medical School.No financial disclosures were reported by the authors of this paper.