key: cord-0831087-7j1edahe authors: Velavan, Thirumalaisamy P.; Meyer, Christian G.; Esen, Meral; Kremsner, Peter G.; Ntoumi, Francine title: COVID-19 and Syndemic challenges in ‘Battling the Big Three’: HIV, TB and malaria date: 2021-03-26 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.03.071 sha: 686665c763279b168234cf4a10f0c341c3fa9c1a doc_id: 831087 cord_uid: 7j1edahe Indirect effects of the COVID-19 pandemic have the potential to seriously undermine the health system in sub-Saharan Africa with an increase in the incidences of malaria, tuberculosis (TB) and HIV infections. Based on current evidence in the African region the collateral impact of COVID-19 on the “big three diseases” shall be addressed in the following. significant increase in malaria cases and even doubling malaria mortality in 2020, with still greater increases in subsequent years [10] . Another study on the interruption of prevention activities by using malaria transmission models predicted also that the malaria burden could have doubled in 2020, compared to 2019 [11] . Estimates indicate that reducing case management for six months and delaying the distribution of long-lasting insecticidal bednets campaigns in Nigeria could lead to 81,000 additional fatalities; corresponding figures apply to other countries [11] . SARS-CoV-2 infects lung alveolar cells using receptor-mediated endocytosis via the angiotensin-converting enzyme II (ACE2) as entry receptor [12] , and SARS-CoV-2 infection depends on the receptors ACE2, TMPRSS2, and CD147 [13] . A genetic deletion/insertion of a 285 bp Alu repeat sequence in intron 16 of the ACE gene fragment insertion (I allele) or its absence (D allele) is of particular importance. Insertion of the extra fragment (ACE I allele) is associated with lower ACE activity, whereas its absence (ACE D allele) leads to higher ACE activity [14, 15] and angiotensin II levels [16] . While the ACE I/D genotype modulates ACE2 expression and the ACE D allele is associated with the infection course and mortality due to COVID-19 [17, 18] , an earlier study has shown that the ACE I/D and ACE D/D genotypes provide relative protection from cerebral malaria in an Indian cohort [19] . The protective association of the D allele is conclusive, as angiotensin II and its analogues have antimalarial effects in Plasmodium falciparum infection [20, 21] . The ACE I/D allele distribution (rs4646994, ACE I/D polymorphism) as retrieved from the Allele Frequency Database (ALFRED) (https://alfred.med.yale.edu/alfred/index.asp) from 199 populations indicates that the ACE D frequency is high among African ethnic groups. Studies have indicated that the D allele occurs more frequently among African Americans (89%) compared to Asian populations (33%-50%) [22] . The enormous spread of the ACE II deletion among many African ethnic groups with asymptomatic submicroscopic malarial infections could presumably help to resolve the link between malaria and COVID-19 susceptibility. Evidence suggests a link between Glucose-6-phosphate dehydrogenase (G6PD) deficiency and increased susceptibility to COVID-19 infection and the severity of the disease [23] . Several observations support the hypothesis that G6PD deficiency increases the risk of developing severe COVID-19 [24, 25] . A retrospective chart review on 17 COVID-19 patients from Houston Methodist Hospital, six of which had G6PD deficiency, found prolonged PaO2/FiO2 ratio and more days on mechanical ventilation in the G6PD deficient group, along with lower J o u r n a l P r e -p r o o f hemoglobin and hematocrit values as indicators of hemolysis [26] . Both G6PD deficiency and SARS-CoV-2 compromise the antioxidant system through the same pathways, indicating that the evolutionary antimalarial advantage of G6PD deficient individuals can be a disadvantage in SARS-CoV-2 infection. With high prevalences in Africa, the Mediterranean region and in Asia, this recessive trait affects about 400 million people worldwide. G6PD deficiency was shown to enhance infection of human coronavirus 229E (HCoV 229E) in human lung epithelial cells and G6PD-deficient cells showed increased viral replication and progression of HCoV 229E-mediated cell death. SARS-CoV-2 may have a similar effect [27] . The selection pressure exerted by P. falciparum has resulted in blood group O being most common in malaria endemic areas [28] , especially in Africa. Blood group O provides a selective advantage against severe malaria through the mechanism of reduced rosetting [29] . Recent findings suggest that the ABO blood groups modulate COVID-19 susceptibility and progression, with individuals carrying blood group A being more susceptible to infection and severe clinical manifestations [30, 31] . A recent study has shown that the distribution and modulation of sialic acid-containing receptors on host cell surfaces is crucial, and this is induced by ABO antigens through carbohydrate-carbohydrate interactions, thus influencing the virus spike protein binding to the host cells [32] . Given the selective advantage offered by malaria through a wide distribution of blood group O in Africa, reduced COVID-19 susceptibility can be assumed. Although the World Health Organization (WHO) has provided technical guidance [33] specifically aimed at prevention of infection, testing, treatment and interventions, several African countries have meanwhile suspended the implementation of vector control activities. This applies especially to the use of insecticide-treated bed-nets and indoor residual spraying. Such a scale-back leaves vulnerable populations, in particular young children and pregnant women, at a greater malaria risk. Taken together, the potential consequences in malaria intervention coverage, morbidity, and mortality during the Covid-19 pandemic in malariaendemic regions should be addressed in a timely manner. Both tuberculosis (TB) and COVID-19 exhibit overlapping clinical signs and symptoms, however clear differences in their incubation periods and the onset of the disease. Despite being J o u r n a l P r e -p r o o f a curable disease, approximately 10 million persons were newly infected by TB in 2019, with an estimated 1.2 million deaths in HIV-negative individuals and an additional 208,000 deaths among HIV-positive individuals [34] . Men accounted for 56%, women for 32% and children for 12% of TB cases in 2019. Among those affected, 8.2% were people living with HIV [34] . The cumulative reduction in incidences from 2015 to 2019 was 9% (from 142 to 130 new cases per 100,000 individuals), with the African Region having made substantial progress (reduction of 16% between 2015 and 2019) [34] . The COVID-19 pandemic threatens to reverse recent progress in reducing the global burden of TB. COVID-19 is expected to have a significant impact on TB patients, undiagnosed TB patients and TB survivors due to disruption of health services [35] . Access to diagnostic TB tests will likely be limited because of the stigma associated with coughing or malaise. This stigma might be enhanced during the current pandemic, driving individuals with TB to hide their disease and delaying access to healthcare facilities until disease and infectivity have progressed [36] . WHO reports that about one third of people living with TB were either not diagnosed or reported [37] and may be major contributors for ongoing transmission with a high risk of related morbidity and mortality. For instance, there were large drops in the reported number of people diagnosed with TB between January and June 2020 [37] . Estimates of global TB detection and care in terms of TB mortality for 2020 indicate a 25% decline in TB case detection, with a predicted 13% increase in TB deaths (an additional 190,000 TB deaths) and an estimated total of 1.66 million TB deaths in 2020, consistent with the number of global TB deaths in 2015 [38] . A potential relation between BCG vaccination and COVID-19 is not completely clear. BCG vaccination has been reported to offer protection from infections other than TB [39] , including viral infections and sepsis [40] . Studies correlating BCG vaccination and reduced mortality due to COVID-19 conclude that countries without a policy of BCG vaccination have been more severely affected compared to countries with universal and long-standing BCG vaccination programs [39] . However, these comparisons are difficult to validate due to large differences between countries with regard to socioeconomic status, demographics, outbreak periods, number of diagnostic tests performed and test criteria [41] . A meta-analysis using 2932 data sets has shown that TB patients are not more likely to contract COVID-19, but are more prone to develop severe complications of COVID-19 [42, 43] . Clinical TB remains a cause of death related to COVID-19 co-infection. As in HIV infection, COVID-19 has had a major impact on women with a higher risk of infection, especially in Africa. In 2019, adolescent girls and young women were estimated to represent 10% of the population in Sub-Saharan-Africa, but disproportionately affected with 59% of new HIV infections [45, 46] . It was also shown that lesbian, gay, bisexual, transgender and queer (LGBTQ) populations had an increased vulnerability due to COVID-19 and an increased risk for complications due to COVID-19 [45, 47] . In Uganda, maternal mortality increased by 82% between January and March 2020, and there is evidence that rates of HIV diagnoses and of people starting ART and treatment to prevent TB will fall by 75% [48, 49] . Between January and June 2020, data from UNAIDS indicate a sharp reduction in HIV testing during first antenatal care visits in 17 countries [46] and equally a reduced treatment access in pregnant women in 15 countries [46] . Also, until October 22 nd 2020, Botswana, South Africa, Sierra Leone, and Togo had not recovered yet to provide routine treatment [45, 46] . Models concluded that fatalities due to HIV infections could increase substantially during the COVID-19 pandemic with interruptions of HIV services in South Africa, Malawi, Zimbabwe, and Uganda [50] . These models likely apply to other African countries as well. Also, in countries with high HIV burden, the continuity of ART during the J o u r n a l P r e -p r o o f pandemic is a considerable challenge and it is predicted that 40% of those currently on ART are forced to temporarily suspend ART [50] . Actions are urgently required in Africa to minimize the widening inequalities in fair access to treatment [51] . It is also evident now that use of lopinavir and ritonavir is not associated with mortality reduction, duration of hospitalization and risk of progression to mechanical ventilation [52] [53] [54] . A systematic review and meta-analysis found increased and frequent adverse events for lopinavir and ritonavir when administered in non-antiviral treatment [55] . Another postulate was that HIV-infected patients receiving standard anti-HIV drugs might not have an increased risk of SARS-CoV-2 infection [56] . A HIV transmission model predicted on implementing HIV tests alongside SARS-CoV-2 testing has the potential to reduce the number of HIV infections substantially in six US cities [57] . Policymakers might consider a combined strategy of health testing and reducing the widespread and long-lasting disruption to ART care, which could cause an increase in the number of deaths that could be saved by interventions. Policy changes could minimize these interruptions through adjustments such as multi-month ART prescriptions. The indirect effects of the COVID-19 pandemic will severely intensify the burden of HIVinfections, malaria and tuberculosis in Africa, where millions of people live with a potentially life-threatening diseases. The increase of the disease burden will most likely also apply to noncommunicable diseases. 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