Introduction

Blood transfusion is a medical intervention during which whole blood or its components (e.g., platelets) are taken from an individual (i.e., the donor) to another individual (i.e., the recipient). An estimated ~118.5 million blood donations, of which 40% were from developed regions, were recorded by the World Health Organization (WHO) [1]. Each year, several million lives are saved through blood transfusions, along with corollaries such as improved health and greater welfare. In practice, the reasons and recipient groups for blood transfusion are diverse between developing and developed areas. While blood transfusion is commonly administered in the elderly (~60% of all transfusions) in high-income countries, children under five years of age are the primary recipients in low-income countries [2].

Blood safety is crucial to guarantee efficient blood transfusion in recipients. Developing regions in Africa, the Americas, and Asia are striving to improve their blood transfusion practices and guidelines, given the increasing demand for blood [1]. Till now, especially in these regions, blood transfusion is associated with a higher risk of transfusion-transmitted infections (TTIs), which can compromise recipients’ health outcomes. Aside from their natural routes of transmission, several pathogens of diverse origins can be transmitted through blood transfusion. These include prions, viruses (e.g., hepatitis C and B viruses – HCV/HBV, human immunodeficiency virus – HIV), bacteria (e.g., Treponema pallidum), fungi (e.g., Candida spp.), and parasites (e.g., Plasmodium spp., Toxoplasma gondii) [3,4]. In practice, priority is generally given to HIV, HCV, HBV, and T. pallidum in Africa, especially in countries such as Cameroon. The main reason is the higher dangerousness, chronicity, and long-term deleterious impact on individuals.

Little attention is given to other blood-transmitted pathogens, especially to Apicomplexans such as Plasmodium spp., and T. gondii. Other major life-debilitating pathogens (e.g., Loa loa, dengue virus, parvovirus B9, Candida spp., Histoplasma capsulatum, Cryptococcus neoformans) are also routinely overlooked in blood banks from health facilities of several countries (e.g., Cameroon, India), and not integrated in national blood safety policies and surveillance, despite their potential for transfusion transmission [4,5]. In addition, insufficient epidemiological data and a lack of integration into national blood safety policies and surveillance frameworks further contribute to their under-recognition and inadequate monitoring. Some of them, e.g., Plasmodium spp., T. gondii, are highly endemic in several parts of the globe, including Cameroon. These pathogens can survive for long periods in unscreened blood bags and asymptomatically in infected recipients. Plasmodium spp. parasites can provoke clinical malaria, often leading to severe malaria and deaths [6]. Given their clinical impact in the general population, it is also crucial to determine the blood transfusion risk associated with these ‘neglected’ pathogens in developing countries such as Cameroon.

To date, to the best of the authors’ knowledge, there are no systematic reviews and meta-analyses (SRMA) on the epidemiology and clinical impact of these neglected TTIs in Cameroon. This review was designed to address this gap and propose solutions to the current identified blood transfusion-related challenges in Cameroon.

Materials and methods

Results

Characteristics of the included studies

A total of 531 records were identified via database search strategies, of which 186 were excluded. Thus, the full-texts of 345 records were screened for eligibility. Several records were excluded for various reasons (e.g., studies focused on HIV, HCV, HBC, and T. pallidum). Fifteen papers were judged eligible for the study, in addition to three papers identified after inspection of bibliographies. We therefore included 18 studies in the systematic review, of which 14 were relevant for meta-analysis (Fig 1A) [13–30]. Most of the studies were cross-sectional (94.4%), conducted in a single study site (94.4%), conducted in the town of Yaoundé (38.9%), and in a clinical setting (88.9%) (Fig 2 & Table 1). Regarding blood donors, 41.2% of studies included family and voluntary donors, and the donor type was not specified in 4 studies (Table 1). Plasmodium spp. parasites (68.4%) were mainly targeted in the included studies (Fig 1B), followed by the SARS-CoV-2 (10.5%). It should be noted that the filarial parasite Loa loa was accidentally found, i.e., its detection was not included in the predefined study protocols, by the authors of two included studies [26,28]. Peripheral blood film (PBF) (42.3%) and rapid diagnostic tests (RDT) (34.6%) were the main screening techniques (Fig 1C). The bias risk of the studies was good for four criteria related to the objective definition and measurement of exposure and outcome (i.e., clear description of inclusion criteria, valid and reliable diagnostic tools, and utilization of standard criteria to assess neglected TTIs). However, 94.4% of the studies failed to provide site details (i.e., related to blood transfusion), and 66.7% did not use an appropriate statistical analysis to correctly address their defined objectives (S2 Table).

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Table 1. Characteristics of studies included in the systematic review and meta-analysis.

https://doi.org/10.1371/journal.pntd.0014378.t001

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Fig 1. Study inclusion process as per PRISMA guidelines.

AJOL: African Journals Online, ELISA: Enzyme-Linked Immunosorbent Assay, HIV: Human immunodeficiency virus, HBV: Hepatitis B virus, HCV: Hepatitis C virus, PBF: Peripheral blood film, PCR: Polymerase chain reaction, RDT: Rapid diagnostic test, RT-LAMP: Reverse transcription loop-mediated isothermal amplification, SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2, TMA: Transcription-mediated amplification, WHO: World Health Organization.

https://doi.org/10.1371/journal.pntd.0014378.g001

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Fig 2. Map of Cameroon depicting the geographical distribution of the studies.

The Cameroon basemap was downloaded from Natural Earth (Base layer of the map available from: http://www.naturalearthdata.com) and visualized using the QGIS software v3.36.1 (https://qgis.org/en/site/). The regions where the included studies are highlighted in magenta. The total number of studies in each region is shown in the yellow shape. The total number of studies is > 18 because one study was conducted in two regions.

https://doi.org/10.1371/journal.pntd.0014378.g002

Pooled overall prevalence of neglected TTIs

Meta-analysis to compute pooled overall proportions was possible for Plasmodium spp., L. loa, and SARS-CoV-2. The pooled proportion of Plasmodium spp. infection in blood donors was 16.6% (95%CI 10.1 – 24.2%, I² = 97.6%, p < 0.001) (Fig 3A). Publication bias was identified across studies on Plasmodium spp. (p = 0.004) (S1 Fig). Higher estimates were found for SARS-CoV-2 infection (17.7%, 95%CI 0.0 – 100%, I² = 85.2%, p = 0.009) (Fig 3B). In contrast, the pooled proportion of L. loa infection in blood donors was 0.5% (95%CI 0.1 – 1.1%, I² = 0.0%, p = 0.90) (Fig 3C). Prevalence data for dengue virus (24.8%), human T-lymphotropic virus 1 (HTLV-1, 5.6%), and T. gondii (4.7%) were available for only one study each (Fig 3D).

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Fig 3. Pooled proportions of Plasmodium spp. (A), SARS-CoV-2 (B), and Loa loa (C) in blood donors.

Prevalence of HTLV-1 and Dengue viruses in blood donors (D). 95%CI: Confidence interval at 95%, I²: Heterogeneity, HTLV-1: Human T-lymphotropic virus 1, SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2, ELISA: Enzyme-Linked Immunosorbent Assay, RDT: Rapid diagnostic test. ***SARS-CoV-2 was included in the analysis, even though there is limited evidence of transfusion-transmitted infection cases with this virus via human blood products. However, we kept this virus in the analysis, given the many dark areas of the natural history of this virus.

https://doi.org/10.1371/journal.pntd.0014378.g003

Discussion

Blood supply is already a public issue in African countries. This section summarizes the most urgent challenges associated with ‘neglected’ TTIs in Cameroon.

• The reviewed studies were mainly conducted in three regions (i.e., Centre, Littoral, and Northwest). This regional gap, pinpointed in the present study, is the missing link to understanding the epidemiology of these ‘neglected’ TTIs, and this warrants the need for further studies in the country, especially in regions with little or no data.
• The lack of data on these ‘neglected’ TTIs, as well as field evidence, especially for dengue, HTLV-1, or filariasis, is the main challenge. In the present SRMA, we have shown that pooled estimates of Plasmodium spp. and T. gondii infections can be similar to or exceed those of major TTIs. This assumption is supported by findings of a recent SRMA of major blood-transmitted pathogens in Cameroon, which reported pooled proportions of 2.4%, 8.9%, 2.2%, and 3.6% for HIV, HBV, HCV, and T. pallidum, respectively [5]. There are limited or no data on the epidemiology of the above-mentioned non-malarial pathogens (i.e., dengue virus, HTLV-1, filariae). Such epidemiological data are instrumental in evaluating the real danger posed by these pathogens and in guiding blood safety policies in blood transfusion services.
• In individuals qualified for blood donations following screening for major pathogens, these ‘neglected’ pathogens exist asymptomatically, often at low density malaria infections (LDMIs) [31], can be transmitted to recipients and then elicit a clinical episode. It should be interesting to conduct clinical impact and longitudinal studies in recipients in future to inform healthcare personnel and policymakers. These would be helpful to assess the fraction of Plasmodium spp. infections attributed to blood transfusion, as well as their clinical impact.
• It is well known that the infectious risk varies by blood donor types (family, paid, voluntary) for primarily targeted TTIs (e.g., viral hepatitis), with the highest risks commonly reported in family donors. This aspect was recently reported in an earlier investigation in Cameroon [5]. In the present study, it was tricky to address the patterns of the proportion of Plasmodium spp. infections by type of donor, and this outlines the need for further studies to address this aspect. The current available data on the association between Plasmodium spp. infections and donor type are conflicting. For instance, no significant association was found in Nigeria [32], while in Saudi Arabia, a higher risk of Plasmodium spp. infections in family donors compared to voluntary donors [33].
• RDT and PBF are the main techniques used in health facilities in Cameroon. Even though blood bank personnel are aware of malaria risk, Plasmodium spp. parasites can still be missed during screening with RDTs due to false negative results for reasons such as LDMIs, non-P. falciparum species (e.g., P. vivax, P. ovale spp.), and the presence of P. falciparum parasites with deletions in the histidine-rich protein 2 (pfhrp2) gene. The bulk of commercial RDTs are designed to target the histidine-rich protein 2, which is only produced by P. falciparum parasites [34]. The emergence and spread of pfhrp2-deleted P. falciparum parasites is a threat to RDT-based diagnosis, given the ability of these parasites to escape PfHRP2-targeting RDTs, and thus leading to false negative RDT results [35]. Several Cameroonian authors have reported these threats in the territory [36,37]. Additionally, cost and resource constraints associated with PBF are cumbersome, thereby reducing the likelihood of additional testing at blood banks. Personnel at blood banks in Cameroon and other African countries are facing significant work-related pressure. In such settings, priority is often given to mandatory tests for the major TTIs (e.g., HIV, HBV, HCV, and syphilis) in the country. The introduction of additional tests, such as those for Plasmodium spp. parasite detection requires more time, resources, and technical capacity. Thus, testing of neglected TTIs is not routinely performed at blood banks of developing settings, such as Cameroon. Besides, point-of-care molecular tests (e.g., Truenat) are available and have shown promising field performance in detecting P. falciparum and P. vivax LDMIs in other malaria-endemic settings [38]. In this context, it would be interesting to reinforce blood safety via the integration of these point-of-care molecular diagnostic approaches. It is also needed to improve quality assurance systems, enhance staff training, and ensure adequate resource allocation for malaria screening in blood banks. These call for cost-effectiveness and qualitative studies to evaluate the potential impact of these solutions in the Cameroonian context.
• Many co-infection cases were reported across the reviewed studies, mainly P. falciparum with viral infections (i.e., HBV, HCV, HIV). These viral infections, especially HIV, are well known to be a risk factor for malaria severity and deaths [39,40]. Conversely, Plasmodium spp. infection is associated with higher HIV viral load and inflammatory responses [39,40]. In a context where persons living with HIV, which could also include pregnant women, can also benefit from blood transfusion, preventing transfusion-transmitted malaria is crucial. In addition, even though limited evidence is available on the impact of anti-retroviral treatment on P. falciparum-related antimalarial drug treatment efficacy [41], it is still important to prevent post-transfusion P. falciparum malaria in HIV-infected recipients.
• Training of health personnel of blood banks for the screening of these ‘neglected’ pathogens is essential. Awareness campaigns and periodical training sessions should be implemented and/or scaled up to increase testing rates for these ‘neglected’ pathogens. A recent study by Nguemnang et al. pinpointed very low testing rates for Plasmodium spp. and T. gondii in blood donors (7% and 4.7%) and recipients (0% and 2.3%) of health facilities in the West region [42].
• Targeting additional pathogens could worsen the blood supply and increase the risk of shortages. There is a balance to find between blood supply and safety. For malaria, it was proposed to give recipients a preventive antimalarial drug. Currently available data indicate a very low rate (9.1%) of prophylactic treatment for post-transfusion malaria in Cameroon health facilities [20]. However, to be more effective, this approach requires access to updated data on drug resistance epidemiology and therapeutic efficacy studies.

Conclusion

This study was designed to conduct a systematic review and meta-analysis of less prioritized blood-borne pathogens in blood blanks of Cameroon. The study revealed a dearth of epidemiological data, with an overrepresentation in three regions of the country. The prevalence of pathogens, such as Plasmodium spp. and T. gondii, can often outnumber that of major TTIs. Also, we argue that the most critical challenge is to produce high-quality epidemiological data on the residual risk, burden, extent, and determinants of these ‘neglected’ transfusion-transmitted pathogens. Disposing of such data is pivotal to addressing the other challenges identified in the review.

Supporting information