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. 2021 Nov 17;116(4):220–235. doi: 10.1080/20477724.2021.1989185

Global meta-analysis on Babesia infections in human population: prevalence, distribution and species diversity

Solomon Ngutor Karshima a,✉, Magdalene Nguvan Karshima b, Musa Isiyaku Ahmed c
PMCID: PMC9132453  PMID: 34788196

ABSTRACT

Human babesiosis is an emerging tick-borne protozoan zoonosis caused by parasites of the genus Babesia and transmitted by ixodid ticks. It was thought to be a public health problem mainly for the immunocompromised, however the increasing numbers of documented cases among immunocompetent individuals is a call for concern. In this systematic review and meta-analysis, we reported from 22 countries and 69 studies, an overall pooled estimate (PE) of 2.23% (95% CI: 1.46–3.39) for Babesia infections in humans. PEs for all sub-groups varied significantly (p < 0.05) with a continental range of 1.54% (95% CI: 0.89–2.65) in North America to 4.17% (95% CI: 2.11–8.06) in Europe. PEs for country income levels, methods of diagnosis, study period, sample sizes, Babesia species and targeted population ranged between 0.43% (95% CI: 0.41–0.44) and 7.41% (95% CI: 0.53–54.48). Babesia microti recorded the widest geographic distribution and was the predominant specie reported in North America while B. divergens was predominantly reported in Europe. Eight Babesia species; B. bigemina, B. bovis, B. crassa-like, B. divergens, B. duncani, B. microti, B. odocoilei and B. venatorum were reported in humans from different parts of the world with the highest prevalence in Europe, lower middle income countries and among individuals with history of tick bite and other tick-borne diseases. To control the increasing trend of this emerging public health threat, tick control in human settlements, the use of protective clothing by occupationally exposed people and the screening of transfusion blood in endemic countries are recommended.

Abbreviations AJOL: African Journals OnLine, CI: Confidence interval, CIL: Country income level, df: Degree of freedom, HIC: Higher-income countries, HQ: High quality, I2: Inverse variance index, IFAT: Indirect fluorescent antibody test, ITBTBD: Individuals with tick-bite and tick-borne diseases, JBI: Joanna Briggs Institute, LIC: Lower-income countries, LMIC: Lower middle-income countries, MQ: Medium quality, NA: Not applicable, N/America: North America, OEI: Occupational exposed individuals, OR: Odds ratio, PE: Pooled estimates, PCR: Polymerase chain reaction, Prev: Prevalence, PRISMA: Preferred Reporting System for Systematic Reviews and Meta-Analyses, Q: Cochran’s heterogeneity statistic, QA: Quality assessment, Q-p: Cochran’s p-value, qPCR: Quantitative polymerase chain reaction, S/America: South America, Seq: Sequencing, UMIC: Upper middle-income countries, USA: United States of America

KEYWORDS: Geographic distribution, human babesiosis, prevalence, species diversity, zoonotic Babesia species

Introduction

Zoonotic babesiosis is an emerging tick-borne protozoan disease caused by intraerythrocytic parasites of the genus Babesia, family Babesiidae, order Piroplasmorida and phylum Apicomplexa. The disease is predominantly caused by three parasites namely; Babesia divergens, B. microti and B. venatorum and transmitted by tick vectors. Although these zoonotic Babesia species are capable of infecting a wide range of vertebrate hosts across the globe, they require competent vertebrates and arthropod vectors; particularly ticks to complete their life cycle [1]. The sexual stage of the life cycle occurs in the tick vectors while the asexual stage occurs within the erythrocytes of the vertebrate host [2,3].

Babesia species have distinct geographic distributions. Transmission primarily occurs through bites of ticks of the family Ixodidae particularly those of the genus Ixodes. However, transfusion-associated [4,5] and vertical transmission from mothers to infants particularly for B. microti [6,7] are well documented. Quarter to half of infections are usually asymptomatic; usually confused with malaria due to nonspecific symptoms like fever and hemolytic anemia [8]. In immunocompromised population, these parasites infect host’s erythrocytes causing hemolytic anemia, intravascular coagulopathy, hepatomegaly and splenomegaly; leading to complications such as respiratory distress syndrome, heart failure, inflammation of the central nervous system and death [8].

Babesia divergens was the cause of the first human case of babesiosis in Croatia [9]. It is the most common cause of zoonotic babesiosis in Europe [10] and to a lesser extent in North America where the tick vectors are distributed [11]. The parasite is transmitted principally by Ixodes ricinus and cattle are the natural host [12]. Clinical symptoms due to B. divergens in humans appear within 1 to 3 weeks post infected tick bite and may include hemoglobinuria, jaundice resulting from severe hemolysis as well as renal failure and pulmonary edema in severe cases [8].

Babesia microti was first reported in 1966 [13] and is the principal cause of zoonotic babesiosis in the North America [14], however, an expanding geographic range to all New England states, north into Maine, west into the upper Hudson River valley, eastern Pennsylvania and New Jersey and as far south as Maryland has also been reported [15–18]. The principal vector of B. microti in the North America is Ixodes scapularis [19] and rodents are the reservoirs of infection [12]. Clinically, B. microti causes asymptomatic to severe disease with multi-organ failures and up to 20% fatality rates among the elderly, immunocompromised and asplenic patients [20,21].

Babesia venatorum is associated with zoonotic babesiosis in Asia and Europe [22] and is transmitted by the vectors Ixodes persulcatus in China [23] and Ixodes ricinus in Austria and Italy [24]. The roe deer serve as the primary vertebrate host of the parasite [22,25]. The first three reported cases of Babesia venatorum (formally known as Babesia sp. EU1) were in splenectomized occupational hunters from Austria, Italy [24] and Germany [26] who were above 50 years of age.

It is speculated that zoonotic babesiosis has suffered neglect and underestimation of burden as a result of misdiagnosis especially in resource limited countries with limited diagnostic capabilities. Though this disease is asymptomatic in immunocompetent population, the risk of fatality associated with old age [27], splenectomy [28], HIV infection [29] and malignancy [28] suggest the need for more attention to this emerging public health threat. Furthermore, the possibility of transmission to non-endemic countries as a result of asymptomatic blood donors may also be an important epidemiologic risk. For a better understanding of the worldwide burden of zoonotic babesiosis in humans, we undertook a systematic review and meta-analysis to determine its global prevalence, distribution and Babesia species diversity in humans.

Materials and methods

Study protocol and eligibility criteria

This systematic review and meta-analysis was performed and documented in accordance with the recommendations published by Moher et al. [30]. Studies were incorporated based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist available from https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000097. The review protocol was registered on PROSPERO international prospective register of systematic reviews with registration number CRD42020153018 and available from https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020153018.

Data sources and search strategy

We systematically searched African Journals OnLine (AJOL), Google Scholars, PubMed, Science Direct, Scopus and Web of Science for a period of 18 months (1 March 2020–31 August 2021) for articles published on human Babesia infections worldwide from inception to 31 August 2021. References of retrieved studies were manually searched for additional articles. We requested full texts of relevant articles with only visible online titles and abstracts through texting and e-mailing of authors and editors of the publishing journals. We employed the MeSH search string ‘prevalence’ OR ‘sero-prevalence’ OR ‘epidemiology’ OR ‘sero-epidemiology’ OR ‘detection’ OR ‘molecular detection’ AND ‘zoonotic babesiosis’ OR ‘human babesiosis’ OR ‘human babesiasis’ OR ‘zoonotic Babesia species’ OR ‘Babesia (B.) divergens’ OR ‘B. microti’ OR ‘B. venatorum’ OR ‘B. duncani’ OR ‘B. crassa’ AND ‘humans’ OR ‘man’ OR ‘people’.

Study selection

All the authors (SNK, MNK and MIA) screened the title and abstract of each article and removed irrelevant and duplicate articles. Apparently relevant articles were further subjected to full text review for the identification and extraction of relevant information. A study was considered eligible only if it fulfill the following conditions: (i) it investigated human infections with Babesia species, (ii) was published in English, (iii) it stated numbers of positive cases and sample size, (iv) it stated study location, (v) was published until 31 August 2021, (vi) it stated the method of diagnosis used and (vii) it identified Babesia parasites to species level.

Data extraction

Data extraction was conducted by all authors (SNK, MNK and MIA) independently using a database developed in Microsoft Excel (Supplementary file 1). In cases of discrepancies, all authors double checked data simultaneously and discuss issues until unanimity was reached. From each of the articles, we extracted data including author’s name, year of conduct and publication, number of positive cases, sample sizes, study location, study design, method of diagnosis, Babesia species associated with the infection and where stated, the targeted population.

For the purpose of our analysis, studies which used diagnostic methods targeting antibodies or antigens were grouped as studies diagnosed by serology, while those that utilized polymerase chain reaction (PCR) either alone or in combination with sequencing were grouped as diagnosed by molecular methods. Individuals with tick bite history and/or tick-borne diseases (ITBTBD) referred to people that had history of tick bite and those who tested positive for human granulocytic anaplasmosis and/or Lyme borreliosis as well as those with tick-borne disease symptoms like erythema migrans. Occupational exposed group referred to people whose occupations put them at high risk of infection with tick-borne diseases like foresters, hunters, farmers, livestock owners and veterinarians. The category others included all normal individuals, hospitalized individuals without any specified disease and individuals with conditions other than tick-borne diseases targeted by the individual studies. More so, zoonotic Babesia species refer to species of Babesia like B. divergens, B. microti and B. venatorum which are infective to man and animals under natural conditions. Analysis for country-based pooled estimates were only performed for countries that reported at least two studies. We grouped countries income levels based on the World Bank year 2020 classifications [31].

Quality assessment for individual studies

All authors (SNK, MNK and MIA) independently screened articles explicitly for quality based on the checklist of the Joanna Briggs Institute (JBI) critical appraisal instrument for studies reporting prevalence data published by Munn et al. [32]. This was carried out on a database developed in Microsoft Excel (Supplementary file 2), and discrepancies in data collected were simultaneously doubled checked by all authors and discussed until consensus was reached. Each article was examined for appropriateness of sample frame and the way the study participants were sampled, completeness of the description of study subjects and settings as well as the sufficiency of data analysis of the identified sample. The articles were also examined for, validity of the methods employed for the detection of Babesia infections, reliability of the measurement of the condition in all participants, appropriateness of the statistical analysis used and adequacy of the response rate and its management. We assigned scores of 0 or 1 for no or yes answers and NA when the item was not applicable for any given article. We slightly modified the grading by grouping studies based on total scores earned as follows; 0–3 (low quality), 4–6 (medium quality) and 7–9 (high quality).

Pooling and heterogeneity analysis

Data were managed in Microsoft Excel and transferred to Graph-Pad Prism version 4.0 and Comprehensive Meta-Analysis version 3.0 for statistical and meta-analysis respectively. Prevalence of each included study was determined by expressing the proportion of positive cases and sample size as a percentage. We used the random-effects model to determine pooled estimates of human Babesia infections and their 95% Confidence interval [33]. Furthermore, we used the Cochran’s Q-test to determine variations across studies and quantified the percentage variations among studies due to heterogeneity using the inverse variance index (I2); which is expressed as I2 = 100(Q-df)/Q; where Q represents Cochran heterogeneity statistic and df, the degree of freedom; which is equal to number of studies analyzed minus 1. I2 values of 0, 25, 50 and 75% represented absence of, low, moderate and substantive heterogeneities respectively [34,35].

Publication bias, sensitivity, sub-group and meta-regression analyses

Across study bias was investigated by the funnel plots, while its statistical significance was examined using Egger’s regression asymmetry test [36]. We also employed the Duval and Tweedie non-parametric ‘fill and trim’ linear random method to test for unbiased estimates [37]. We used one study deletion analysis at a time to test the effect of each eligible study on the pooled estimate of human Babesia infections, and a study was considered to have no influence if the pooled estimate without it was within the 95% confidence limits of the overall PE [38].

We performed sub-groupings for continents (Africa, Asia, Australia, Europe, North America and South America), country income levels (high-income countries; HIC, low-income countries; LIC, lower middle-income countries; LMIC, and upper middle-income countries; UMIC), methods of diagnosis (serology and molecular), study period (1975–1990, 1991–2005 and 2006–2021), sample sizes (≤500, 501–1000 and >1000), Babesia species (B. bigemina, B. bovis, B. crassa-like, B. divergens, B. duncani, B. microti, B. odocoilei, and B. venatorum) as well as targeted population (blood donors, individuals with tick-bite and/or tick-borne diseases; ITBTBD, occupationally exposed individuals; OEI and others).

To identify possible sources of heterogeneity in our analysis, we performed meta-regression for different strata by comparing South America with other continents (Africa, Asia, Australia, Europe and North America) where studies were reported, UMIC with other country income level groups (HIC, LIC and LMIC), serological methods with molecular methods, 2006–2021 with other study periods (1975–1990 and 1991–2005), sample sizes >1000 with other sample sizes (≤500 and 501–1000), Babesia venatorum with other species (B. bigemina, B. bovis, B. crassa-like, B. divergens, B. duncani, B. microti and B. odocoilei) and others with other target populations (blood donors, ITBTBD and OEI).

Results

Study selection

Overall, our literature search revealed a total of 1027 studies (1003 form databases and 24 from manual search of references). A total of 792 duplicates were excluded after title screening and another 142 animal-based studies were excluded after scrutinizing abstracts. We finally subjected 93 studies to full text review and 24 studies were excluded for the following reasons; case reports (n = 16) and insufficient data on prevalence (n = 8). We included in this quantitative synthesis a total of 69 studies (Figure 1).

Figure 1.

Figure 1.

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Flow chart for the selection of eligible studies

Study characteristics, quality assessment and distribution of Babesia species

Table 1 shows the baseline characteristics of eligible studies and is ordered by continent/country. Studies were reported from six continents: Africa and Australia reported one study each, South America (2/69) Asia (9/69), Europe (22/69) and North America (34/69). Individual countries with the highest concentration of studies across continents were China in Asia (7/69; 10.14%), Poland in Europe (10/69; 14.49%) and the USA in North America (33/69; 47.83%). The 2 studies in South America were from Bolivia (n = 1) and Colombia (n = 1), while the only study in Africa was from Tanzania. Prevalence of zoonotic Babesia in individual studies analyzed ranged between 0.00 and 81.91%. Studies were reported from LIC (1/69), LMIC (3/69), UMIC (8/69) and HIC (57/69). Forty studies diagnosed babesiosis using serological methods, while the remaining 29 utilized molecular techniques Figure 2. The majority of studies were conducted during 2006–2021 (49/69; 71.01%) with the remainder during 1991–2005 (14/69; 20.29%) and 1975–1990 (6/69; 8.70%). Furthermore, 37 studies had sample sizes of ≤500, 9 had sample sizes of 501–1000 and 23 had sample sizes of >1000. Babesia bigemina, B. bovis, B. crassa-like and B. odocoilei were reported by one study each, B. duncani (2 studies), B. venatorum (3 studies), B. divergens (11 studies) and B. microti (57 studies). Overall, B. microti had the widest geographic distribution globally, while continental distribution revealed predominance of B. divergens and B. microti in Europe and North America respectively. In addition, 2 of the 3 reports on B. venatorum infections in humans were from Asia. The population targeted by the 69 eligible studies were blood donors (n = 23), ITBTBD (n = 26), OEI (n = 11) and other individuals (n = 11) as shown in Table 1. No study was excluded for lack of merit based on assessment of quality. The majority of studies (62/69; 89.86%) were studies of medium quality (4–6 points) and the remainder (7/69; 10.14%) were of high quality (7–9 points) as shown in Table 1.

Table 1.

List and baseline characteristics of studies on Babesia infections in humans

Continent/Country CIL Study year Targeted population MOD Babesia species Sample size Cases Prev. (%) 95% CI QA Study reference
Africa                      
Tanzania LIC 2017 Normal children and adults IFAT B. microti 299 4 1.34 0.37–3.39 MQ [39] Bloch et al., 2019b
Asia                      
China UMIC 2011–14 Individuals with recent tick-bite Npcr B. venatorum 2912 48 1.65 1.22–2.18 MQ [123] Jiang et al., 2015
China UMIC 2016 Blood donors IFAT B. microti 1000 13 1.30 0.69–2.21 MQ [40] Bloch et al., 2018
China UMIC 2015/16 Individuals with recent tick-bite Mic & PCR/Seq B. crassa-like 1125 58 5.16 3.94–6.61 MQ [124] Jia et al., 2018
China UMIC 2010/11 Individuals bitten by ticks PCR/Seq B. venatorum 180 2 1.11 0.13–3.96 MQ [41] Liu et al., 2019
China UMIC 2009 Anemic patients PCR/Seq B. divergens 377 2 0.53 0.06–1.90 MQ [113] Qi et al., 2011
China UMIC 2018 Individuals with history of tick bite PCR/Seq B. divergens 754 10 1.33 0.64–2.43 HQ [114] Wang et al., 2019
China UMIC 2013 Humans with malaria-like symptoms PCR/Seq B. microti 449 10 2.23 1.07–4.06 MQ [112] Zhou et al., 2013
Japan HIC 1985 Individuals from a tick-borne disease endemic area IFAT B. microti 1335 18 1.35 0.80–2.12 MQ [42] Arai et al., 2003
Mongolia LMIC 2011 Stock farmers PCR B. microti 100 3 3.00 0.62–8.52 MQ [117] Hong et al., 2014
Australia                      
Australia HIC 2009–11 Self-referred patients for LD FISH, IFA & PCR All species 41 13 31.71 18.08–48.09 MQ [43] Mayne, 2011
          B. duncani 41 10 24.39 12.36–40.30    
          B. microti 41 7 17.07 7.15–32.06    
Europe                      
Austria HIC 2009 Blood donors IFAT All species 988 26 2.63 1.73–3.83 MQ [44] Sonnleitner et al., 2014
          B. divergens 988 21 2.13 1.32–3.23    
          B. microti 988 5 0.51 0.16–1.18    
Belgium HIC 2010 Humans with tick bite and tickborne disease-like symptoms IFAT All species 199 163 81.91 75.85–87.00 MQ [95] Lempereur et al., 2015
          B. divergens 199 66 33.17 26.67–40.17    
          B. microti 199 18 9.05 5.45–13.92    
          B. venatorum 199 79 39.70 32.85–46.86    
Croatia HIC 1999 Individuals with history of tick bite IFAT B. microti 102 1 0.98 0.02–5.34 MQ [96] Topolovec et al., 2003
Finland, Norway, Sweden HIC 2007 High risk tick bitten individuals IFAT B. microti 86 0 0.00 0.00–4.20 MQ [97] Ocias et al., 2020
Finland, Sweden HIC 2019 Humans bitten by Babesia species positive ticks IFAT B. microti 159 7 4.40 1.79–8.86 MQ [98] Wilhelmsson et al., 2020
France HIC 2003 Foresters IFAT All species 810 21 2.59 1.61–3.94 MQ [99] Rigaud et al., 2016
          B. divergens 810 1 0.12 0.00–0.69    
          B. microti 810 20 2.47 1.51–3.79    
Germany HIC 1999 Blood donors IFAT All species 467 42 8.99 6.56–11.96 MQ [45] Hunfeld et al., 2002
          B. divergens 467 17 3.64 2.13–5.76    
          B. microti 467 25 5.35 3.49–7.80    
Italy HIC 2009 Farmers, livestock keepers, veterinary practitioners and hunters IFAT All species 432 37 8.56 6.10–11.61 MQ [100] Gabrielli et al., 2014
          B. divergens 432 17 3.94 2.31–6.23    
          B. microti 432 20 4.63 2.85–7.06    
Netherlands HIC 2008 Individuals with tick bites history and erythema migrans PCR/Seq B. divergens 291 1 0.34 0.01–1.90 MQ [101] Jahfari et al., 2016
Norway HIC 2016 Healthy adults IFAT B. microti 1537 33 2.15 1.48–3.00 MQ [102] Thortveit et al., 2020
Poland HIC 2008 Farmers, foresters, blood donors IFAT B. microti 190 10 5.26 2.55–9.74 MQ [103] Chmielewska-Badora et al., 2012
Poland HIC 2012 Tick-borne encephalitis patients PCR/Seq B. microti 110 1 0.91 0.02–4.96 MQ [104] Moniuszko et al., 2014
Poland HIC 2013 Individual with history of tick bite PCR/Seq B. microti 548 6 1.09 0.40–2.37 MQ [105] Moniuszko-Malinowska et al., 2016
Poland HIC 2010 Foresters IFAT B. microti 114 5 4.39 1.4–-9.94 MQ [106] Pancewicz et al., 2011
Poland HIC 2013 Farmers and foresters IFAT B. microti 93 1 1.08 0.03–5.85 MQ [107] Panczuk et al., 2016
Poland HIC 2018 HIV-patients and blood donors IFAT B. microti 426 23 5.40 3.45–7.99 MQ [46] Pawelczyk et al., 2019
Poland HIC 2008 Lyme disease patients PCR/Seq B. divergens 24 1 4.17 0.11–21.12 MQ [108] Welc-Faleciak et al., 2010
Poland HIC 2011 Foresters PCR/Seq B. microti 58 2 3.45 0.42–11.91 MQ [109] Welc-Faleciak et al., 2015
Poland HIC 2013 Foresters IFAT B. microti 216 50 23.15 17.70–29.35 MQ [110] Zukiewicz-Sobczak et al., 2014
Sweden HIC 2015 Lyme disease patients IFAT All species 283 19 6.71 4.09–10.29 HQ [47] Svensson et al., 2019
          B. divergens 283 8 2.83 1.23–5.49    
          B. microti 283 11 3.89 2.96–6.85    
Switzerland HIC 1998 Blood donors IFAT B. microti 396 6 1.52 0.56–3.27 MQ [48] Foppa et al., 2002
Ukraine LMIC 2020 Blood donors as well as HIV and LD patients IFA All species 145 15 10.34 5.91–16.49 MQ [49] Bondarenko et al., 2021
          B. divergens 145 10 6.90 3.36–12.32    
          B. microti 145 5 3.45 1.13–7.86    
N/America                      
Canada HIC 2018 Blood donors TMA B. microti 50,752 1 0.00 0.00, 0.00 MQ [50] Tonnetti et al., 2019a
USA HIC 1999–07 Patient records Mic/PCR Unspecified 326,081 353 0.11 0.10–0.12 MQ [51] Asad et al., 2009
USA HIC 2013 Blood donors PCR B. microti 26,702 134 0.50 0.42–0.59 MQ [52] Bloch et al., 2016
USA HIC 1985 Children on an Indian reservation in North Carolina IFA B. microti 185 6 3.24 1.20–6.92 MQ [53] Chisholm et al., 1986
USA HIC 2015 Lyme disease patients IFAT B. microti 130 35 26.92 19.52–35.40 MQ [54] Curcio et al., 2016
USA HIC 1978 Healthy individuals IFAT B. microti 136 6 4.41 1.64–9.36 MQ [111] Filstein et al., 1980
USA HIC 1995 High risk adult population IFAT B. microti 671 7 1.04 0.42–2.14 MQ [55] Hilton et al., 1999
USA HIC 2007 Blood donors IFAT B. microti 17,465 267 1.53 1.35–1.72 MQ [56] Johnson et al., 2009
USA HIC 2005 Blood donors PCR B. microti 17,422 208 1.19 1.04–1.37 MQ [57] Johnson et al., 2012
USA HIC 2009 Blood donors PCR B. microti 1002 3 0.30 0.06–0.87 MQ [118] Johnson et al., 2013
USA HIC 2004–13 Patient records Mic & PCR B. microti 3138 22 0.70 0.44–1.06 MQ [58] Kowalski et al., 2015
USA HIC 1989 Lyme disease patients, randomly selected outpatients, college students and healthy individuals IFAT B. microti 1285 81 6.30 5.04–7.77 MQ [59] Krause et al., 1991
USA HIC 1991 Children and adults IFAT B. microti 574 52 9.06 6.84–11.71 HQ [60] Krause et al., 1992
USA HIC 1990–94 Long-term residents of island community and LD patients Serology Unspecified 1396 40 2.87 2.05–3.88 MQ [61] Krause et al., 1996
USA HIC 1998 Blood donors IFAT B. microti 2006 9 0.45 0.21–0.85 MQ [62] Leiby et al., 2002
USA HIC 1999 Blood donors IFAT B. microti 3490 30 0.86 0.58–1.22 MQ [63] Leiby et al., 2005
USA HIC 2012 Blood donors IFAT B.microti 1272 14 1.10 0.60–1.84 HQ [64] Levin et al., 2014
USA HIC 2013 Blood donors EIA, IFA, Mic & PCR B. microti 26,703 56 0.21 0.16–0.27 MQ [65] Levin et al., 2016
USA HIC 1997 Healthy blood donors from a highly endemic area IFA/PCR B. microti 150 5 3.33 1.09–7.61 MQ [66] Linden et al., 2000
USA HIC 1990 Lyme disease patients and normal individuals IFAT B. microti 172 3 1.74 0.36–5.01 MQ [67] Magnarelli et al., 1995
USA HIC 1996 Human granulocytic ehrlichiosis patients IFAT B. microti 494 47 9.51 7.0–12.45 MQ [68] Magnerelli et al., 1998
USA HIC 1995 LD and HGE patients IFA B. microti 115 6 5.22 1.94–11.01 MQ [69] Mitchell et al., 1996
USA HIC 2014 Blood donors PCR B. microti 84,209 331 0.39 0.35–0.44 MQ [70] Moritz & Stramer, 2015
USA HIC 2011 Blood donors AFIA B. microti 13,269 44 0.33 0.24–0.45 HQ [71] Moritz et al., 2014
USA HIC 2014 Blood donors PCR B. microti 89,152 67 0.08 0.06–0.10 MQ [72] Moritz et al., 2016
USA HIC 1984 Blood donors IFAT B, microti 779 29 3.72 2.51–5.30 MQ [73] Popovsky et al., 1988
USA HIC 2017 Individual with history of tick bite Qpcr B. microti 192 92 47.92 40.67–55.23 MQ [74] Primus et al., 2018
USA HIC 2008/09 Blood donors and individuals requesting for B. duncani test IFA All species 900 22 2.44 1.54–3.68 MQ [75] Prince et al., 2010
          B. duncani 900 18 2.00 1.19–3.14    
          B. microti 900 4 0.44 0.12–1.13    
USA HIC 2000–16 Patients who received medical care within 2000–2016 Mic & PCR B. microti 2956 213 7.21 6.30–8.20 HQ [76] Rau et al., 2020
USA HIC 2020 Humans with babesiosis symptoms PCR/Seq B. odocoilei 19 2 10.53 1.30–33.14 MQ [77] Scott et al., 2021
USA HIC 2001 Patients with erythema migrans PCR B. microti 93 2 2.15 0.26–7.55 MQ [78] Steere et al., 2003
USA HIC 2010/11 Blood donors IFA/RT-PCR B. microti 2150 42 1.95 1.41–2.63 MQ [79] Tonnetti et al., 2013
USA HIC 2018 Blood donors AFIA B. microti 506,540 1299 2.96 2.43–2.71 MQ [80] Tonnetti et al., 2019b
USA HIC 2015 Lyme disease patients IFAT B.microti 52 4 7.69 2.14–18.54 MQ [81] Wormser et al., 2019
S/America                      
Bolivia LMIC 2013 Healthy rural residents PCR B. microti 271 9 3.32 1.53–6.21 MQ [82] Gabrielli et al., 2016
Colombia UMIC 2014/15 Herders ELISA, IFA & nPCR All species 300 6 2.00 0.74, 4.30 HQ [83] Gonzalez et al., 2018
          B. bigemina 300 2 0.67 0.08–2.39    
          B. bovis 300 4 1.33 0.36–3.38    
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CI (Confidence interval), CIL (Country income level), HIC (Higher income countries), HQ (High quality), IFAT (Indirect fluorescent antibody test), LIC (Lower income countries), LMIC (Lower middle income countries), MOD (Method of diagnosis), MQ (Medium quality), N/America (North America), PCR (Polymerase chain reaction), Prev. (Prevalence), QA (Quality assessment), qPCR (Quantitative polymerase chain reaction), S/America (South America), Seq (Sequencing), UMIC (Upper middle income countries), USA (United States of America)

Figure 2.

Figure 2.

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Global distribution of studies on human babesiosis

Pooled estimates, sub-group and heterogeneity analyses

Pooled estimates of human Babesia infections and heterogeneities among studies are presented in Tables 2 and 3 as well as Figures 3 and 4. Exactly 4198 of 1,198,469 individuals examined during the period under review were positive for Babesia infections, yielding an overall PE of 2.23% (95% CI: 1.46–3.39). PEs of human Babesia infections were 1.54% (95% CI: 0.89–2.65) in North America, 1.76% (95% CI: 1.07–2.87) in Asia, 2.71% (95% CI: 1.64–4.45) in South America and 4.17% (95% CI: 2.11–8.06) in Europe. Single studies reported prevalence of 1.34% (95% CI: 0.50–3.51) in Africa and 31.71% (95% CI: 19.39–47.27) in Australia. Based on country income level, the highest PE was in LMIC (5.03%; 95% CI: 2.04–11.89), followed by HIC (2.26%; 95% CI: 1.41–3.60) and then UMIC (1.76%; 95% CI: 1.03–2.98). A single study from LIC reported a prevalence of 1.34% (95% CI: 0.50–3.51). PE by molecular techniques was 1.30% (95% CI: 0.65–2.57), while that by serological methods was 3.24% (95% CI: 1.78–5.81). The prevalence of human Babesia infections decreased by 2.74% during the 45 years under review. The highest occurred during 1975–1990 (3.17%; 95% CI: 1.79–5.56), followed by 1991–2005 (2.44%; 95% CI: 1.56–3.18) and then 2006–2021 (0.43%; 95% CI: 0.42–0.44).

Table 2.

Sub-group analysis for the pooled estimates of Babesia infections in humans

Variables No. of
Studies		 Pooled Estimates
 (95% CI)  
 Heterogeneity
 Meta-regression
Sample size Cases Prev. (%) P-value Q-value I2 (%) Q-p P- value OR (95% CI)
Continent                      
Africa 1 299 4 1.34 0.50–3.51 <0.001 0.00 0.00 1.000 0.1091 −0.67 (−4.62, 3.28)
Asia 9 8232 164 1.76 1.07–2.87   62.27 87.15 <0.001   −0.45 (−2.94, 2.04)
Australia 1 41 13 31.71 19.39–47.27   0.00 0.00 1.000   2.86 (−1.02, 6.74)
Europe 22 7674 470 4.17 2.11–8.06   729.37 97.12 <0.001   0.49 (−1.86, 2.85)
North America 34 1,181,652 3532 1.54 0.89–2.65   7310.19 99.55 <0.001   −0.53 (−2.84, 1.79)
South America 2 571 15 2.71 1.64–4.45   0.95 0.00 0.329   Reference
Income level                      
HIC 57 1,190,557 4018 2.26 1.41–3.60 <0.001 10,280.30 99.46 <0.001 0.8216 0.34 (−1.00, 1.68)
LIC 1 299 4 1.34 0.50–3.51   0.00 0.00 1.000   0.09 (−3.89, 4.06)
LMIC 3 516 27 5.03 2.04–11.89   9.57 79.11 0.008   1.12 (−1.29, 3.52)
UMIC 8 7097 149 1.76 1.03–2.98   56.09 87.52 <0.001   Reference
MOD                      
Molecular 29 636,111 1661 1.30 0.65–2.57 <0.001 4661.85 99.40 <0.001 0.0491 0.94 (0.00, 1.87)
Serology 40 562,358 2537 3.24 1.78–5.81   5974.95 99.35 <0.001   Reference
Study period                      
1975–1990 6 3892 143 3.17 1.79–5.56 <0.001 41.18 87.86 <0.001 0.8595 0.39 (−1.11, 1.89)
1991–2005 14 28,186 476 2.44 1.56–3.18   458.52 96.95 <0.001   0.15 (−0.91, 1.21)
2006–2021 49 1,166,391 3579 0.43 0.42–0.44   9845.20 99.50 <0.001   Reference
Sample size                      
≤500 37 7546 641 4.90 3.00–7.91 <0.001 905.48 96.02 <0.001 <0.001 1.97 (1.25, 2.70)
501–1000 9 7024 186 2.28 1.35–3.82   96.67 91.72 <0.001   1.14 (0.08, 2.19)
>1000 23 1,183,899 3371 0.73 0.42–1.26   4926.18 99.55 <0.001   Reference
Overall 69 1,198,469 4198 2.23 1.46–3.39   10,678.92 99.36 <0.001    
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CI (Confidence interval), HIC (High income countries), I2 (Inverse variance index), IFAT (Indirect fluorescent antibody technique), LIC (Low income countries), LMIC (Lower middle income countries), OR (Odds ratio), PCR (Polymerase chain reaction), Prev. (Prevalence), Q-p (Cochran’s p-value), UMIC (Upper middle income countries)

Table 3.

Pooled estimates of human Babesia infections in relation to target population and species

Variables No. of
Studies		 Pooled Estimates
 95% CI  
 Heterogeneity
 Meta-regression
Sample size Cases Prev. (%) P-value Q-value I2 (%) Q-p P- value OR (95% CI)
Target population                    
Blood donors 23 847,300 2672 0.87 0.55–1.36 <0.001 2237.12 99.01 <0.001 <0.001 −1.03 (−2.13, 0.07)
ITBTBD 26 12,127 665 5.00 2.62–9.35   1166.74 97.86 <0.001   0.82 (−0.27, 1.91)
OEI 11 3169 149 3.80 1.88–7.53   147.29 93.21 <0.001   0.49 (−0.81, 1.78)
Others 11 335,848 712 2.31 0.51–9.75   2894.13 99.65 <0.001   Reference
Babesia species                      
B. bigemina 1 300 2 0.67 0.17–2.63 <0.001 0.00 0.00 1.000 0.7823 0.18 (−4.14, 4.50)
B. bovis 1 300 4 1.33 0.50–3.50   0.00 0.00 1.000   0.88 (−3.33, 5.08)
B. crassa-like 1 1125 58 5.16 4.01–6.61   0.00 0.00 1.00   2.27 (−1.83, 6.37)
B. divergens 11 4770 154 2.39 0.89–6.27   279.36 96.42 <0.001   1.46 (−1.13, 4.05)
B. duncani 2 941 28 7.41 0.53–54.48   40.33 97.52 <0.001   2.65 (−0.71, 6.02)
B. microti 57 864,895 3460 2.10 1.36–3.24   7638.00 99.27 <0.001   1.34 (−1.07, 3.75)
B. odocoilei 1 19 2 10.53 2.65–33.74   0.00 0.00 1.000   3.04 (−1.30, 7.39)
B. venatorum 3 3291 129 4.91 0.28–49.02   329.24 99.39 <0.001   2.26 (−0.83, 5.34)
Unspecified spp. 2 327,477 393 0.56 0.02–12.55   382.03 99.74 <0.001   Reference
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CI (Confidence interval), I2 (Inverse variance index), ITBTBD (Individuals with tick-bite and tick-borne diseases), OEI (Occupational exposed individuals), OR (Odds ratio), Prev. (Prevalence), Q-p (Cochran’s p-value)

Figure 3.

Figure 3.

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Country-based pooled estimates of Babesia infections in humans

Figure 4.

Figure 4.

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Forest plot for the global pooled estimates of Babesia infections in humans

Prevalence of human Babesia infections decreased with increasing sample size, with the highest among studies with sample size ≤500 (4.90%; 95% CI: 3.00–7.91), followed by studies with sample size 501–1000 (2.28%; 95% CI: 1.35–3.82) and then those with sample size >1000 (0.73%; 95% CI: 0.42–1.26). Babesia infections were most prevalent among ITBTBD (5.00%; 95% CI: 2.62–9.35), with OEI in second place (3.80%; 95% CI: 1.88–7.53). PE among the others category was 2.31% (95% CI: 0.51–9.75), with the lowest observed among blood donors (0.87%; 95% CI: 0.55–1.36). Eight different Babesia species were reported in humans during the period under review. The highest PE was recorded by B. duncani (7.41%; 95% CI: 0.53–54.48), followed by B. venatorum (4.91%; 95% CI: 0.28–49.01), then B. divergens (2.39%; 95% CI: 0.89–6.27) and finally B. microti (2.10%; 95% CI: 1.36–3.24). Single studies reported the prevalence of 0.67% (95% CI: 0.17–2.63) for B. bigemina, 1.33% (95% CI: 0.50–3.50) for B. bovis, 5.16% (95% CI: 4.01–6.61) for B. crassa-like and 10.53% (95% CI: 2.65–33.74) for B. odocoilei. Country-based PEs ranged from 1.72% (95% CI: 0.95–3.08) in China to 4.95% (95% CI: 2.55–9.46) in Sweden. Overall heterogeneity was 99.36%, with a range of 0.00–99.74% across sub-groups.

Across study bias, sensitivity and meta-regression analyses

The funnel plot (Figure 5) and its respective bias coefficient for studies published worldwide on human Babesia infections (b = 7.84, 95% CI = 4.10–11.59, p = 0.00009) showed significant publication bias at α 0.05. We also observed that all the PEs following one study deletion analysis remained within the 95% confidence limits of the overall pooled estimate (Supplementary file 3). Results of meta-regression analysis (Tables 2 and 3) for sub-groups excluded study locations (Q = 9.00, df = 5, p = 0.1091), country income level (Q = 0.92, df = 3, p = 0.8216), study periods (Q = 0.30, df = 2, p = 0.8595) and Babesia species diversity (Q = 4.77, df = 8, p = 0.7823) as significant causes of heterogeneity. However, methods of diagnosis (Q = 3.87, df = 1, p = 0.0491), sample sizes of the individual studies (Q = 28.19, df = 2, p < 0.001) and targeted population (Q = 18.48, df = 3, p = 0.0004) were shown to contribute to the heterogeneity.

Figure 5.

Figure 5.

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Funnel plot of standard error vs logit event rate for studies published on human Babesia infections worldwide

Discussion

Several surveillance studies reported zoonotic babesiosis in humans in different countries, however, no study harmonized these individual surveillance studies to provide the global situation of this emerging public health problem. We reported here, the global status of Babesia infections in humans in terms of prevalence, distribution and species diversity. To our knowledge, this is the first systematic review and meta-analysis to report the global prevalence of zoonotic babesiosis in humans. This study became pertinent following increased numbers of asymptomatic [84,85] and fatal [27,86–88] case reports of zoonotic Babesia from different countries in both immunocompromised [28,29] and immunocompetent [89–91] individuals as well as the risk of misdiagnosis and possible transmission by travelers to non-endemic countries [91,92].

The overall low global prevalence of 2.23% revealed by the present study may be attributable to factors including low trans-stadial transmission of zoonotic Babesia species which last for 2–3 years, very low parasitemia which can be easily missed by researchers and under-diagnosis in non-or-newly endemic areas [21,91,92]. Although the present study reported low global prevalence of these emerging pathogens, the fatality caused among immunocompromised population calls for concern, especially with the increasing numbers of people living with immunocompromised conditions.

Pooled estimates of Babesia infections in humans varied across geographic regions with the highest in Europe and the lowest in North America. These variations across regions may be attributed to the abundance of competent tick vectors [93] and reservoirs which are capable of maintaining these parasites [94]. The fact that over 76% of the studies published from Europe targeted occupationally exposed populations (foresters, farmers, livestock keepers, veterinarians) as well as individuals with history of tick bites and those with other tick-borne diseases [95–110] may be another possible reason for the higher prevalence in the region. Substantive evidence showed that the prevalence of human Babesia infections can vary even within a country. For instance, the prevalence of 1.1, 3.1 and 4.2% were reported from the North east [111], Eastern [112] and South eastern Poland [108] while in China, prevalence of 0.5, 1.3 and 2.2% were reported from the Shandong [113], Heilongjiang [114] and Yunnan [112] Provinces respectively.

We observed the highest prevalence of human Babesia infections in lower middle-income countries like Bolivia and Mongolia, which we attributed to limited resources for vector control and the poor living conditions of the lower class in these countries [115]. The high sensitivity (88–96%) and specificity (90–100%) of the immunofluorescence antibody technique [116] utilized by over 90% of the serology-based studies included in the analysis may be a possible explanation for the higher prevalence revealed by studies diagnosed using serology. The fact that serology detects both active and convalescent infections may be another factor. Similar findings were reported even at country levels like in Mongolia [117] and the United States of America [118].

The higher prevalence observed among individuals with history of tick bites and other tick-borne diseases suggests bites from infected ticks and possible transmission of multiple infections by ticks. Exposure of foresters, farmers, veterinarians and herders to tick bites at work places may explain the high prevalence among occupationally exposed population. The detection of zoonotic Babesia among blood donors suggests possible risk of transfusion-associated babesiosis which is a growing problem in areas endemic for zoonotic babesiosis [5,119].

The majority of studies we included in our analysis were published between 2006 and 2021, probably due to increased understanding of the public health significance of the pathogen. Overall, the prevalence of human Babesia infections decreased by 2.74% during the period of 45 years under review. Further analysis revealed a 0.73% initial decline between 1990 and 2005, which was followed by a 2.01% decline between 2006 and 2021. This consistent decline is suggestive of possible successes of existing control programmes targeting human babesiosis, especially with the increasing number of prevalence studies and improvement in current diagnostic techniques. Babesia microti showed the widest geographic distribution globally and was the predominant species reported across North America, while B. divergens was predominantly reported in Europe, concurring with reports from existing literature [10,120–122]. On the other hand, two of the three reports on Babesia venatorum were from Asia [123,124] and one from Belgium [95].

We found significant publication bias by the funnel plot. This publication bias might be due to gap in literature arising from non-publication of results that contradict existing knowledge as well as dependence of research publication on the nature and direction of study results [125] and its statistical significance [126]. From the results of one study deletion analysis performed, all the pooled estimates were within the 95% CI of the overall PE, suggesting that no single study influenced the PE in our analysis. We observed substantive heterogeneity across studies which persisted even after sub-group analysis. Meta-regression for sub-groups showed that the sample sizes of the eligible studies, the methods of diagnosis as well as the population targeted by the individual studies were the possible sources of heterogeneity in the present analysis.

The present study has a number of implications on public health. First, the detection of zoonotic Babesia among blood donors in different countries may influence transfusion-associated babesiosis. Second, for travelers from endemic to non-endemic areas, there is the risk of misdiagnosis by physicians and possible transmission by available ticks to susceptible individuals. Third, asymptomatic individuals may serve as reservoirs of infections thereby initiating transmission through activities of peri-domestic ticks.

A number of limitations are associated with our study. We could not include a number of studies which would have increased our understanding of the global status of human babesiosis due to insufficient prevalence data. Again, over 80% (56/69) of the studies were concentrated in two continents namely; Europe (22) and North America (34) giving an uneven distribution of studies. Studies on human Babesia infections were available from only 22 of 249 countries of the world. In addition, over 57% (40/69) of the studies included in this analysis were diagnosed using serological techniques, which are limited in their cross reactivity between species, and inability to differentiate active from convalescent infections. This suggest that the results of the present study must be applied with caution. Finally, we considered only studies published in English, resulting in language bias and the possibilities of omitting credible studies published in other languages which would have provided a better insight on human babesiosis.

Conclusion

Eight Babesia species (B. bigemina, B. bovis, B. crassa-like, B. divergens, B. duncani, B. microti B. odocoilei and B. venatorum) were reported in humans from 22 countries of the world, with the highest prevalence in Europe. Babesia microti had the widest geographic distribution across the globe and was predominantly reported from the North America. To control this emerging zoonosis, we suggest the control of tick vectors around human settlements, the use of repellants and appropriate protective clothing by occupationally exposed population. The screening of blood for this parasites will also reduce the risk of transfusion-associated babesiosis.

Supplementary Material

Supplemental Material
Click here for additional data file. (38KB, zip)

Acknowledgments

We are grateful to all authors whose articles are included in this study. We also appreciate Mrs Juliana Tije for assisting in literature search.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Disclosure statement

The authors declare that they have no competing interests.

Availability of data and materials

The data supporting the conclusion of this article are all included in the article and supplementary files 1 and 2.

Authors’ contributions

SNK: Conceived and designed the study, SNK, MNK, MIA: conducted literature search, identified articles, screened articles and extracted data. SNK: Conducted statistical and meta-analyses and wrote the manuscript. Both authors read and approved the final manuscript.

Consent for publication

Not applicable

Ethics approval and consent to participate

Not applicable

Supplementary material

Supplemental data for this article can be accessed here.

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