Blood safety in Mexico and a perspective on Latin America

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Review

Blood safety in Mexico and a perspective on Latin America Bárbara Novelo-Garzaa, Jorge Duque-Rodríguezb,*, Ana-María Mejía-Domínguezc, María-Rita Rivas-Gonzálezd, Oscar Torres-Torrese a

Central Blood Bank, Centro Médico Nacional La Raza [La Raza National Medical Centre], Mexico City, Mexico Postgraduate Department, Faculty of Medicine and Biological Sciences, Universidad Autónoma de Chihuahua, State Blood Transfusion Centre, Chihuahua, Mexico Blood Bank, Instituto Nacional de Cardiología “Ignacio Chávez” [“Ignacio Chávez” National Institute of Cardiology], Mexico City, Mexico d Blood Bank, Hospital de Alta Especialidad “Centenario de la Revolución Mexicana” [“Centenary of the Mexican Revolution” Highly Specialised Hospital], Morelos, Mexico e Central Blood Bank, Centro Médico Nacional de Occidente [National Medical Centre of the West], Guadalajara, Mexico b c

ARTICLE INFO

ABSTRACT

Keywords: Blood transfusion blood safety Mexico Voluntary donation Donor screening

Blood safety has been of paramount concern worldwide over the last decades, and Latin America and Mexico are no exception. Factors of utmost importance include the use of highly efficient screening tests and the encouragement of voluntary donation. This review summarizes the current situation in Latin America and particularly in Mexico with respect to these key issues. Except for some specific regions, there is a lack of progress of voluntary donation in Mexico compared with other Latin American countries. A more efficient voluntary donation system could provide donors with lower prevalence of infectious agents such as human immunodeficiency, hepatitis B, and hepatitis C viruses. In Latin America, and specifically in countries such as Argentina, Brazil and Nicaragua, voluntary donation and blood safety are strongly encouraged. However, to date, in Mexico there has not been a specific blood safety project because of fragmentation of the health system model with structural differences among organisations. Although national policies are established to grant health coverages in Mexico, blood safety is still limited and outdated because of oversights in technical fields and regulations. Individual molecular biological tests for donor screening have recently been incorporated into the Mexican national regulations. Although the routine use of these tests as part of effective donor screening is still not compulsory, it is enabling a progressive improvement of blood safety.

1. Introduction One of the greatest concerns worldwide has been the ability to rely on optimal blood products. Their quality and safety have therefore been designated as a public health problem [1,2]. Blood transfusions save lives and improve health, but many patients who need transfusions do not have access to safe blood when they need it. For this reason, in 2001, the World Health Organisation’s (WHO) Department of Transfusion Safety and Clinical Technology presented a questionnaire to obtain information for the Global Database on Blood Safety. The questionnaire covers the four main components of the WHO’s integrated blood safety strategy, i.e.:

• The establishment of a well-organised and nationally coordinated blood transfusion service (BTS) • Collection of blood only from voluntary non-remunerated donors

from low risk populations

• Screening of all donated blood for transfusion-transmitted infec•

tions, including HIV, the hepatitis viruses, syphilis and other infectious agents. The reduction of unnecessary transfusions through the effective clinical use of blood, including the use of simple alternatives to transfusions (crystalloids and colloids) wherever possible [3].

The global survey uncovered the following: The World Health Organization recommends that all activities relating to the collection, verification, processing, storage and distribution of blood be coordinated nationally through an effective organisation and integrated blood supply networks. The national transfusions system should also be regulated by national policies and legislative frameworks on blood transfusion in order to promote uniformity of quality and safety standards for blood and blood products [4].

⁎ Corresponding author at: Departamento de Postgrado, Facultad de Medicina y Ciencias Biológicas, Universidad Autónoma de Chihuahua; Centro Estatal de la Transfusión Sanguínea, Matamoros 2239, Jardines del Santuario, 31206 Chihuahua, Mexico. E-mail address: [email protected] (J. Duque-Rodríguez).

https://doi.org/10.1016/j.transci.2019.10.003 Received 18 July 2019; Received in revised form 8 October 2019; Accepted 16 October 2019 1473-0502/ © 2019 Published by Elsevier Ltd.

Please cite this article as: Bárbara Novelo-Garza, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.10.003

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Table 1 National Blood Donation Programmes in Latin America. Year

Countries

Specific law

Responsible body

Specific budget

National Policy

National Commission

2006 2015

14 19

13 12

13 17

5 12

11 14

11 8

It was found that, for the year 2013, 68 % of countries that reported figures (122 out of 179) had a national policy on blood. In addition, 58 % of countries (105 out of 181) had specific legislation on the safety and quality of blood transfusions [5]. With regard to the supply of blood, around 117.4 million units of blood were collected worldwide, 42 % of these are collected in highincome countries that are home to just 16 % of the world’s population. In the approximately 13,000 blood donation centres distributed in 170 countries that reported figures, 100 million donations were collected. The annual average per centre is 5,400 donations in low- and middleincome countries and 23,000 in high-income countries [4]. Based on the data collected by the WHO, significant increases in blood donations from voluntary non-remunerated donors have been recorded in low- and middle-income countries. According to the information contributed by 159 countries, between 2008 and 2013 there was an increase of 10.7 million units donated by voluntary non-remunerated donors. Seventy-four countries collect more than 90 % of their supply of blood from voluntary non-remunerated donors (39 highincome countries, 26 middle-income countries and 9 low-income countries). Of these, 57 countries obtained 100 % (or more than 99 %) of their supply from voluntary non-remunerated donors [5]. In 71 countries, more than 50 % of the supply of blood continues to be dependent on donations from friends and relatives and paid donors (11 high-income countries, 44 middle-income countries and 16 lowincome countries) [5]. The WHO recommends that all blood donated be analysed for infections before it is used. Blood must undergo compulsory testing for HIV, hepatitis B and C and syphilis. Blood screening must be performed in accordance with the requirements of the quality system [5]. Some 99.6 % of blood donated in high-income countries undergoes screening in accordance with basic quality procedures, in comparison with 97 % in upper middle-income countries, 81 % in lower middle-income countries and 66 % in low-income countries. This means that the prevalence of transfusion-transmitted infections is lower in high-income countries than in middle- and low-income countries [5]. In response to the risk of transmitting serious infections including HIV and hepatitis through unsafe blood and the chronic scarcity of blood, the WHO has drawn the world’s attention to the importance of the safety of blood. With the aim of guaranteeing universal access to safe blood and blood products, the WHO has led the way in improving safety, and recommends the following five integrated strategies for blood safety [5]:

plasma) where applicable, to meet the needs of medical care. 4 Rational use of blood and blood products to reduce unnecessary transfusion and minimise the risks associated with transfusion, use of alternatives to transfusion where possible, and good, safe clinical transfusion practices, including the handling of blood by the patient. 5 The progressive implementation of effective quality systems, including quality management, standards, good manufacturing practices, documentation, training of all personnel and quality assessment. 2. What has happened in Latin America and Mexico in particular? For 2006 [6], only 14 of the 19 countries in Latin America provided data, while for 2015 [7] 100 % provided data on national programmes, as is shown in Table 1. In terms of national blood coordination, a total of 17 countries in Latin America have a specific functional body within the Ministry of Health that is responsible for planning, monitoring and assessing the national blood system, which highlights the importance of strengthening capacities for oversight and governance of national blood systems. Meanwhile, if we look at allocation of resources, only 12 countries have a specific budget. With regard to the existence of National Commissions, for the year 2015, only eight countries in Latin America possessed such a resource. This represents a backwards step in comparison to 2006, when 11 countries had one. These findings are not surprising as in some ways they may reflect the weakness of functional bodies within Ministries of Health [7]. Mexico has never had a National Commission and any specific budget is relative. During the 80 s, in response to the high prevalence of HIV, which was over 14 % in family or paid donation [8], the national regulatory system was reformed, primarily with regard to specification of donor type and categorisation, eliminating paid donation. In previous years, the National Blood Transfusion Centre (Centro Nacional de la Transfusión Sanguínea—CNTS) had been established nationally as a coordinating and potentially an oversight body, followed at the end of the 80 s by the State Blood Transfusion Centres (Centros Estatales de Transfusión Sanguínea—CETS), in an attempt at regulation and national coordination of blood donation and transfusion [9]. However, this was in the context of a very fragmented health system. Moreover, in this fragmented model, each institution within the national health system establishes its own donation policies and specific budgets for the operation of its establishments, without, to date, including specific resources for a voluntary donation programme or having a comprehensive inter-institutional national programme. As an exception, in 2011 the Mexican Social Security Institute (IMSS) established an internal policy, organising its establishments by region. As a result of changes to Mexican healthcare in this field in 1984 and 1985, more than 556 blood banks were established, mostly in the private sector, with very patchy compliance with international quality standards [10]. In the state of Chihuahua, as cooperation was being established between the PAHO and the blood bank in El Paso, Texas (United Blood Services and Latin America), to encourage voluntary donation in the region, a state / regional voluntary donation and regional blood tissue analysis project was launched. Nowadays, the CETS studies an average of 21,000 units of blood per year from the medical units, blood donation posts and blood banks (20 hospitals) of just the state health services, with an average of around 55 % voluntary donation. However, on a state level, taking into account other public and private sector

1 The establishment of a national blood system with well-organised and coordinated transfusion services; ethical, evidence-based and effective national policies on blood; and legislation and regulation capable of providing sufficient and timely supplies of safe blood and blood products to meet the transfusion needs of all patients. 2 Collection of blood, plasma and other blood products from low-risk non-remunerated regular donors through the strengthening of donation systems and the effective management of donors, including care and counselling. 3 Guaranteed-quality testing of all blood donated for transfusiontransmitted infections including HIV, hepatitis B, hepatitis C and syphilis, confirmatory tests for all donors whose blood is reactive to a screen for infection markers, blood groups and compatibility tests, and systems for processing blood into blood products (components of blood used for transfusion and medicinal products derived from 2

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Table 2 Evolution of the percentage of voluntary donation in some Latin American countries. Country

2006

2008

2010

2015

Argentina Brazil Chile Cuba Colombia Nicaragua

11 58 ND 100 61 46

14.91 52.99 ND 100 71.24 47.6

27.23 64.49 22.33 100 77.94 100

45.66 61.25 28.46 100 91.14 100

Table 4 Donation rate in Latin America. Country

Donation rate per 1,000 inhabitants

Argentina Brazil Cuba Mexico Uruguay

24.36 15.21 37.06 17.37 26.43

Table 5 Average annual collection in Mexico.

ND: no data.

institutions, voluntary donation is not above 30%. Similarly to the national situation, there is no specific budget allocated, nor has it been possible to reduce the number of banks given the national regulatory framework and the different visions between the technical fields, the CNTS, regulatory discipline and the Federal Commission for Protection against Sanitary Risk (COFEPRIS) [11–13]. With regard to voluntary donation, as examples, we can observe increasing percentages in some Latin American countries, as shown in Table 2. Overall, between 2013 and 2015 Latin America saw a 43.28 % increase [7], while in Mexico there has been no percentage increase since records began, as can be seen in Table 3. This lack of progress in Mexico with regard to voluntary donation has put us in last place in Latin America in the last 10 years. On the other hand, there has been an increase of 62 % in the number of units collected in Mexico. If we consider only the total amount of blood, Mexico comes in second, with Brazil as the Latin American country collecting the most blood, at 3,098,338 units in 2015 [14]. If we consider the donation rate per thousand inhabitants, the situation changes, as can be seen in Table 4. While Latin America has seen an increase in the number of units processed per blood bank, in Mexico there has been no significant change in the last 10 years (Table 5). It should be noted that, although there are institutions in Mexico such as the IMSS, whose regional organisation efforts have led to reductions from more than 100 blood banks in 2007 to 54 in 2015, this figure does not reflect an increase in blood banks in both the public and private sectors. Blood supplies in Mexico come from various organisations with different structures, philosophies and health policies. The Mexican health system straddles two sectors, public and private. The public sector includes social security institutes (the Mexican Social Security Institute [IMSS], the Institute for Social Security and Services for State Workers [ISSSTE], Petróleos Mexicanos [PEMEX], the Defence Secretariat [SEDENA], the Naval Secretariat [SEMAR] and others) and the institutions and programmes covering the population without social security (the Health Secretariat [SALUD/SSa], State Health Services [SESA], the IMSS-Opportunities programme [IMSS-O] and Seguro Popular de Salud [SPS—a subsidised health insurance scheme]). The private sector includes insurance companies and service providers working in private practices, clinics and hospitals, including alternative medicine providers. The supply of blood is governed by this fragmentation in the system. Firstly, public sector institutions covering the affiliated population

Total donations

Voluntary donations

% of voluntary donations

2005 2007 2009 2011 2014 2015

1,351,204 1,501,614 1,602,071 1,768,065 1,939,060 2,170,002

ND 47,041 43,943 43,297 49,794 82,395

4 3 2.75 2.45 2.57 3.89

No. of blood banks

Average annual collection per bank

2005 2009 2011 2014 2015

550 560 558 556 572

2,457 2,857 3,169 3,448 3,794

establish their own institutional policies with specific operating budgets, but no voluntary donation or transfusional medicine projects as such. Although the work is coordinated by a national board, there is no observable coordination or single vision. Secondly, the sector known as the “open population” has coverage through the health secretariat and state services, national institutions, the CNTS, CETS and SESA, with poorly defined coverage in terms of costs due to subsidised insurance without a programme and specific budget for transfusional medicine. Finally a large, unregulated private sector spends whatever patients will pay [15]. For 2010, the total amount of blood collected by the country’s health sector was 1,698,124 distributed by Social Security, SSa/SESA and private sector (Table 6). In addition, the number of blood banks distributed by sector and the average number of units collected by blood bank and the sector to which they belong are also shown. Noticeably, although the private sector has 47% of the total number of blood banks, it only collects 13% of the total units of blood, and only the 8% per year. The average annual production of banks in Mexico is 3.071 units of whole blood. Regarding social security coverage, which 87% of the population have, the IMSS is the biggest provider, accounting for 47%. In this latter sector, the cost of collections is fully absorbed by each institution (IMSS, ISSSTE, PEMEX, etc.), while in the population without social security, the Health Secretariat, state health services, CETS and CNTS account for the other 40 %. Coverage of blood is also poorly defined in subsidised insurance, in terms of the various causes and catastrophic costs, resulting in variable recovery quotas. However, since 2006 and probably at a national level, the cost of covering tissues used in the population with subsidised insurance is absorbed by state services through a very heterogeneous process. The size of the profits obtained by the private sector is not known, as there are no legally established prices or price regulation. Table 6 Units of blood collected by health sector, distribution of blood banks, and average units of blood collected per blood bank and year in Mexico.

Table 3 Percentage of voluntary donation in Mexico from 2005 to 2015. Year

Year

Sector

Units of blood collected, n (%)

Number of blood banks, n (%)

Units of blood collected per blood bank and year, n (%)

Social Security SSa/SESA Private Sector Total

789,131 (47) 687,247 (40) 221,746 (13) 1,698,124 (100)

156 137 262 555

5,059 (46) 5,053 (46) 850 (8) 10,962 (100)

SSa: health secretariat. SESA: state health services.

ND: no data. 3

(28) (25) (47) (100)

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Table 7 Percentage of blood screened over time in Mexico.

Table 9 Hepatitis B surface antigen prevalence in some Latin American countries.

Year

HIV

HBsAg

HC

Syphilis

T cruzi

Country

2006

2008

2010

2015

2005 2007 2009 2011 2014 2015

ND 98.70 100 99 100 100

ND 94.83 100 99 100 100

ND 95.37 100 99 100 100

ND 91.63 100 99 100 100

36.34 53.31 82.10 89.00 96.45 99.94

Argentina Brazil Chile Cuba Colombia Nicaragua

0.47 ND ND 0.49 0.35 1.32

0.33 0.35 ND 0.37 0.24 0.33

0.3 0.2 0.02 0.41 0.19 0.24

0.51 0.21 0.01 0.58 0.15 0.18

HBsAg: hepatitis B surface antigen; HC: hepatitis C; T cruzi: Trypanosoma cruzi; ND: no data.

ND: no data. Table 10 Hepatitis C virus prevalence in some Latin American countries.

With regard to screening coverage, all of Latin America achieved 100 % in 2015, with the exception of Mexico, where 99.94 % of units were screened for Trypanosoma Cruzi (Table 7). Between 2007 and 2015, approximate screening for the first 4 markers was in fact used in 100% of cases. The impact over the last 10 years has been the detection of T cruzi, which has increased by 64 %. The action driving this acceleration was the introduction of comprehensive medical services for blood banks in the IMSS, which standardised all its blood banks, enabling them to test for T cruzi, in 2008 [16]. In parallel on the national level, the CNTS, Health Secretariat, ISSSTE, CETS and the public sector in general included T cruzi in tissue studies, and this was gradually taken up by other institutions until it was included as compulsory in the Mexican Official Standard. One of the serious problems affecting blood banks in Mexico is the number of private establishments with blood banks collecting low tissue volumes. Mexico has more than 4500 hospitals, 65% of which are private. Mexican standards and regulations oblige private sector facilities to have a blood bank, with no single vision or oversight of technical fields and regulations on a national level and no public planning or policy. This has led to the establishment of a significant number of banks with lessthan-optimal quality standards and severe fragmentation [17]. We noted that in Latin American countries, the prevalence of these bloodborne diseases has fallen over the last years and may be related to an increase in voluntary donation. Some examples can be seen in Tables 8, 9 and 10. It is extremely telling that, in spite of the progress in voluntary donation in Latin America, behaviour is very heterogeneous, as can be seen from the following examples. For HIV, in Cuba we know of government efforts to control the epidemic, and this is reflected in a very low prevalence among blood donors. In countries such as Colombia and Nicaragua, the drop in prevalence is in proportion to the increase in voluntary donations, an effect that is also observed in the other screening tests. For hepatitis B, there are countries where the prevalence has stayed at the same level or even increased slightly. Hepatitis C is the most heterogeneous marker, with increased prevalence in some voluntary donation systems that have been very well-established for some time, while in others prevalence is stable or even shows a downward trend. For Mexico, the evolution of seroprevalence has remained stable: for HIV it is practically unchanged; for HBsAg there has been a slight decrease over the last 10 years, possibly thanks to the immunisation programme in newborns and the at-risk population; for HC the slight

2006

2008

2010

2015

Argentina Brazil Chile Cuba Colombia Nicaragua

0.30 ND ND 0.02 0.46 0.84

0.21 0.40 ND 0.02 0.38 0.39

0.34 0.36 0.04 0.03 0.29 0.06

0.21 0.23 0.04 0.01 0.20 0.09

2006

2008

2010

2015

Argentina Brazil Chile Cuba Colombia Nicaragua

0.95 ND ND 0.53 0.57 0.47

0.63 0.37 ND 1.20 0.61 0.69

0.47 0.29 0.03 1.34 0.50 0.33

0.34 0.33 0.02 1.19 0.35 0.34

ND: no data.

decrease is due to a dilution effect, as this screening test’s coverage has been variable in Mexico; this dilution effect can also be seen with T cruzi, with just 36.34% screened in high-prevalence regions in 2005, while in 2015 screening was performed in all regions. Finally, the seroprevalence of syphilis has actually been increasing. It is important to note that in 2008 and 2009, laboratories were starting to switch from the VDRL test to the ELISA test. The latter technique had a higher rate of false positives, while the number of confirmed cases remained unchanged (Table 11). Due to the heterogeneity of the results, it was necessary to correlate prevalence in blood donors with that observed in the general population to verify whether or not differences exist. The statistics used were those used as references in WHO publications for hepatitis [18–21] and HIV [2,10,22–33]. The data for hepatitis B can be found in Table 12, while Table 13 shows the results of the comparison of the lower of the two prevalence figures in the general population with the prevalence in blood units. No such detailed results are available for hepatitis C seroprevalence in the general population, so the data obtained for the region have been used (Table 14). The results of the analysis of the difference in HC prevalence between the general population (the lowest prevalence) and donors are shown in Table 15. Meanwhile, Table 16 shows a comparison of HIV prevalence versus the general population for 2015–2016, and the results of the analysis of the difference in HIV prevalence between the general population (the lowest prevalence) and donors can be seen in Table 17. Prevalence is predominantly lower among both blood donors and the general population when donation is voluntary; a further factor is education of the population. Disgracefully, the only country where no difference can be seen is Mexico. Table 11 Seroprevalence in blood donors in Mexico.

Table 8 Human immunodeficiency virus prevalence in some Latin American countries. Country

Country

Year

HIV

HBsAg

HC

Syphilis

T cruzi

2005 2007 2008 2009 2010 2011 2014 2015

0.10 0.28 0.17 0.15–0.4 0.26 0.22 0.24 0.17

0.22 0.19 0.19 0.19 0.17 0.16 0.16 0.15

0.64 0.56 0.62 0.59 0.56 0.56 0.68 0.48

0.24 0.32 0.39 0.45 0.45 0.51 0.58 0.56

0.50 0.41 0.45 0.41 0.39 0.36 0.48 0.37

HIV: human immunodeficiency virus; HBsAg Viruses: hepatitis B surface antigen; HC: hepatitis C; T cruzi: Trypanosoma cruzi.

ND: no data. 4

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Table 12 Hepatitis B seroprevalence in Latin America. Country

Argentina Brazil Chile Colombia Cuba Nicaragua Mexico

% seroprevalence of HBsAg Schweltzer calculation (1965-2013)

CDA calculation (2016)

0.77 (0.77–0.78) 0.65 (0.65–0.66) 0.68 (0.34–1.35) 2.29 (1.86–2.82) 1.3 (0.62–2.70) 0.55 (0.28–1.10) 0.20 (0.19–0.21)

0.3 0.3 0.1 0.3 0.6 0.9 0.1

Table 17 Prevalence of HIV in donors compared with the general population in Latin America.

Blood units reactive to HBsAg (2013)

(0.3–1.0) (0.3–0.8) (0.1–0.3) (0.2–0.5) (0.5–0.8) (0.9–1.2) (0.1–0.37)

0.17 0.16 0.01 0.16 0.51 0.21 0.18

Country

Prevalence in donors vs prevalence in the general population

Argentina Brazil Chile Colombia Nicaragua Mexico

Half Just over one-third One-tenth Half Lower prevalence in volunteer donors No difference

Table 18 Sensitivity of the different tests used for human immunodeficiency virus screening.

HBsAg: hepatitis B surface antigen; CDA: Center for Disease Analysis. Table 13 Prevalence of Hepatitis B in donors compared with the general population in Latin America. Country

Prevalence in donors vs prevalence in the general population

Argentina Brazil Colombia Cuba Nicaragua Mexico

Half Half Half No difference No difference No difference

Method

1st time donors

Lapsed donors

Repeat donors

NAT (ID) + serology NAT (p8) + serology NAT (p16) + serology Serology Combo Serology

99.78 99.59 99.54 99.05 98.73

99.68 99.40 99.32 98.60 97.64

97.68 95.64 95.20 89.79 86.78

% % % % %

% % % % %

% % % % %

NAT: nucleic acid test.

The results from correlating the sensitivity of the different methods used with the RR in Mexico are shown in Tables 19 and 20 [36]. To date in our country, although voluntary donation is very low (less than 3 %), there are some regions or banks that have sought to increase it in their area, such as the state of Chihuahua with 21.5 % and the Health Secretariat with 55 %. Nuevo León and Coahuila, among other states, have also made efforts. However, perhaps due to the low rate of voluntary donation, prevalence results for reactive infection markers between nonvolunteer and volunteer donors have so far shown little difference. The exception to this is Chihuahua, where slight differences were reported in volunteer donors, with greater safety in voluntary donation [11,37]. Starting in the late 1990s and early 2000s, molecular biology tests (NAT, nucleic acid test) were developed. These new technologies are faster, more sensitive, and have been found to be more effective at detecting viruses, primarily human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), significantly shortening window periods. Prior to the NAT, serology offered a safety margin for transfusions but was not required. The risk associated with transfusion transmitted infection (TTI) varies depending on certain factors, a very significant one of which is the disease’s prevalence. With serology, even with the improvements to the antigen and antibody detection process, the residual risk was very high (Table 21). Using mathematical tests together with molecular biology and PCR (polymerase chain reaction) technology, it became possible to determine other factors that might affect the likelihood of viral transmission such as infectious dose, number of copies or virions, product used and volume, presence or absence of neutralising antibodies, knowledge of viral dynamics and, in particular, identifying the stages of the infection as eclipse, pre-ramp-up and ramp-up, determining viral replication and the inherent risk of the viral dynamics. NAT has also allowed different viral patterns of transfusion risk to be identified, such as occult hepatitis B or so-called elite controllers in the case of HIV [38–40]. In the 2000s, through the use of NAT technology to study donors, the USA saw a reduction in the risk associated with transfusion for HCV and HIV of 1:2,000,000 [41].

Table 14 Hepatitis C seroprevalence in some Latin American countries. Country

Prevalence in blood donors

Calculated prevalence of viremia in Latin America in 2016

Argentina Brazil Colombia Cuba Nicaragua Mexico

0.34 0.33 0.35 1.19 0.34 0.48

0.66 0.66 0.66 0.66 0.66 0.66

(0.45–0.72) (0.45–0.72) (0.45–0.72) (0.45–0.72) (0.45–0.72) (0.45–0.72)

Table 15 Prevalence of Hepatitis C in donors compared with the general population in Latin America. Country

Prevalence in donors vs prevalence in the general population

Argentina Brazil Colombia Cuba Nicaragua Mexico

No difference No difference No difference Twice No difference No difference

The residual risk (RR) is defined as the risk that remains after all preventive measures have been taken. Calculating the RR in Mexico for bloodborne diseases using Dr Sergio Sánchez Guerrero’s method [34] gave the following RR for the three viruses: 1: 9,969 for HIV; 1: 2,781 for hepatitis C; and 1: 3,185 for hepatitis B. The sensitivity of the test used is a well-known variable, and one that is important whether in increasing or decreasing the RR of bloodborne diseases. For HIV, this variable is well-known [35] (Table 18). Table 16 Seroprevalence of human immunodeficiency virus in Latin America.

Blood donors Open population

Argentina

Brazil

Chile

Cuba

Colombia

Nicaragua

Mexico

0.21 0.4

0.23 0.6

0.04 0.4

0.01 0.4

0.20 0.4

0.09 0.2

0.25 0.3

5

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Table 19 Sensitivity of human immunodeficiency virus screening methods. Blood collected by IMSS 20122013

RR

Estimated blood based on the RR

Method

Efficacy

Probability of not infecting

Individual infected per unit (2.3)

1,402,441

1: 9,969

140

NAT Pi + Serology Serology Combo Serology

99.78 % 99.05 % 98.00 %

0 in 100 1 in 100 2 in 100

0 2.3 4.6

IMSS: Mexican Social Security Institute; RR: Residual Risk.

In 2012, an international forum organised a review of the implementation of NAT tests from 1999 to 2009 in various countries, finding that donor studies using this technology significantly increase blood safety. Three hundred and thirty million donors were studied, with a risk of 1: 447,000 for HCV, 1: 111,000 for HIV and 1: 66,000 for HBV [42]. NAT tests have evolved with time from their initial form that used large sample pools (more than 24) to mini-pools and individual samples. Reports on their application reveal greater sensitivity when using individual samples versus large sample pools. When results from minipools (fewer than 6 samples) are compared with individual samples, the difference does not appear to be as significant for HCV and HIV, unlike HBV, where individual samples offer greater certainty, especially in areas where the virus is highly prevalent [38,41,43]. Nevertheless, NAT has not been rolled out in all countries and its sensitivity varies depending on prevalence, especially for HBV, with greater benefits demonstrated where prevalence is high. Current window periods with NAT, and the associated risk, have been reduced to 4–5 days for HIV, 2.8 days for HCV and 24 days for HBV, while seroconversion models have estimated viral replication cycles of 0.85 days for HIV, 0.45 days for HCV and 2.56 days for HBV, although the risk varies based on the high prevalence in certain regions. For Mexico, experience of using NAT began in 2007–2008 in some of the country’s main blood banks, primarily in Mexico City, Guadalajara, Nuevo León and essentially within the IMSS. In some of the initial reports, the results did not show the likelihood of detection in the IMSS blood bank in Guadalajara. Of 47,847 donors, none had negative serology and positive NAT [44]. In 2010 in the Chihuahua State Blood Transfusion Centre, one case of HCV with negative serology and positive NAT was reported out of 5,938 samples. This marker is highly prevalent in the state and more recently, one case of HCV and one of HBV have been detected. Similarly, other establishments have demonstrated the capacity to use NAT for detection primarily of HCV and HBV in donors with negative serology. Other blood banks, such as in Monterrey, have demonstrated the efficacy of occult virus detection using NAT, which increases blood safety [23,45–47]. Given this situation, strategies need to be implemented and/or improved that strengthen campaigns to promote voluntary donation, and we must also raise awareness among our representatives of the high risk that donating during the window period entails [48]. Regarding the existence of potential or confirmed window periods, in Mexico we can cite the following examples contributed by the authors of this publication. Blood Bank of the Instituto Nacional de Cardiología “Ignacio Chávez” [“Ignacio Chávez” National Institute of Cardiology] – Mexico City (August 2014 to May 2018 – 38,000 donations) Case 1: a 52-year-old female patient from the state of Sonora, attending to donate as a relative, without other risk factors aside from a

Table 21 Estimated residual risks of blood reserves in different countries. Marker

United States

England

France

Mexico

HIV HBV HBV

1:1,900,000 1:80,000 1:1,600,000

1:8,000,000 1:250,000 1:30,000,000

1:2,000,000 1:205,000 1:1,900,000

1:9,969 1:161,290 1:3,183 1:32,011 1:2,781

HIV: human immunodeficiency virus; HBV: hepatitis B virus; HCV: hepatitis C virus.

dental procedures 4 months earlier (exact date unknown). In July 2015, serology was carried out for the hepatitis C virus (chemiluminescence) with a negative result, however the NAT was reactive (22.77). The discriminatory test was also reactive (26.22). In December 2015, the confirmatory test (Riva) was positive. Case 2: a 23-year-old male patient from the State of Mexico, attending to donate as a relative. He had high-risk sexual practices and was rejected in the first interview. On 10 October 2016, serology was carried out for HIV (chemiluminescence) with a negative results, however the NAT test was reactive (30.19 S/CO) as well as the discriminatory test (31.62 S/CO) performed two days later. On 15 December the same year, a Western Blot test was performed with a positive result. State Blood Transfusion Centre – Chihuahua (September 2009 to December 2016 – 110,300 donors) Case 1: a 32-year-old male patient who reported no risk factors at the time of the interview. On 2 March 2017, he attended to donate blood and was negative for HBsAg (0.16 S/CO). One day later, a reactive NAT result was obtained for HBV. On 10 March, anti-HBsAg antibody testing was carried out with a negative result. Unfortunately, follow-up of patients with reactive results does not take place in the CETS. Patients are referred to Epidemiology, meaning that we do not have evidence of seroconversion. Case 2: an asymptomatic 38-year-old male patient who reported no risk factors during the interview. The donor attended on 7 June 2009 and was found to have negative serology for HCV (0.09 S/CO). On 9 June the same year, a reactive NAT test for the same virus was reported. We do not have the patient follow-up for the same reason as in the case above. Central Blood Bank, Complementary Unit, Highly Specialised Medicine Unit (UMAE) Hospital de Especialidades, Centro Médico Nacional Siglo XXI [21 st Century National Medical Centre] – Mexico City A 59-year old, apparently healthy male donor was identified who attended to donate whole blood, whose only relevant history was working in healthcare (as a doctor). Routine tests were carried out, including NAT for HIV, HBV and HCV, with the NAT-ID for HBV being reactive. On documenting the reactive NAT tests, a discriminatory test was carried out, which was reactive for nucleic acid detection for hepatitis B. It was difficult to contact him, but four months after the

Table 20 Sensitivity of Hepatitis C screening methods. Blood collected by IMSS 2012-2013

RR

Estimated blood based on the RR

Method

Efficacy

Probability of not infecting

Individual infected per unit (2.3)

1,402,441

1:2,781

540

NAT Pi + serology Serology

99.78 % 98.00 %

0 in 100 2 in 100

0 23

IMSS: Mexican Social Security Institute; NAT: nucleic acid test; RR: Residual Risk. 6

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donation, the patient underwent another blood test to look for serological markers of hepatitis B. Anti-HBc, anti-HBe, anti-HBs and anticore (HBc-M) antibodies, HBe antigen and surface antigen (HBsAg) were assessed. The serology was positive for anti-HBc and anti-HBs. The donor reported that after the donation he had in fact presented symptoms of acute hepatitis, although they had completely remitted [46,49]. On the other hand, we have the experience of other centres such as the IMSS Blood Bank of the UMAE No. 34 Hospital de Cardiología, Monterrey, Nuevo León, which reports the case of a 46-year-old man who donated on 18/07/2016 at a donation point in a general hospital in the area. He reported no risk factors in the interview. It was his first donation. The NAT for HBV was reactive (0.61–7.90); however, the serology (chemiluminescence) performed the following morning had a negative result. Finally, the discriminatory NAT carried out that afternoon confirmed that the reactivity (13.0) was exclusively for HBV. All tests for HIV and HCV were negative. The donor was located and confirmatory tests were performed three weeks later. The serology (chemiluminescence and neutralisation) was negative once more, while the NAT tests (Ultrio NAT and discriminatory NAT) again had reactive results (5.53 and 25.31 respectively). The decision was made to conduct follow-up of the patient and a panel of tests was performed for hepatitis B: surface antigen (HBsAg), anti-core antibodies (total HBc), antigen E (HBeAg) and anti-antigen E antibodies (HBeAb). Only total HBc was positive. Subsequently, the viral load was assessed at various timepoints using electrochemiluminescence, giving a result of < 10 UI/ml, which was interpreted as “detected”. Another case from the same centre is that of a 42-year-old woman who donated as a relative on 17/11/2016. She reported no risk factors. It was her first donation. The first reactive result (8.32–8.66) for HCV in the NAT test was obtained on the same day. The serology was negative. The discriminatory NAT test were positive for hepatitis C (26.09). Confirmatory tests were carried out at a second visit, which took place on 24/11/2016. Anti-HCV antibodies were again assessed using chemiluminescence, with a negative result, and the Ultrio NAT and discriminatory NAT for hepatitis C were repeated, both being reactive once again (9.5 and 25.03 respectively). At the third visits on 20/12/ 2016, we found transaminasemia and a discriminatory NAT results of 27, once again reactive. The HCV viral load was found to be over 6,000,000 copies/ml. Eventually, the serology was positive (5.68/5.60) and the donor admitted, confidentially, that her sexual partner had tattoos, that she had undergone surgery before donating, and that she was sexually promiscuous and was suffering from a sexually transmitted infection [49]. At the Central Blood Bank of the Centro Médico Nacional La Raza [La Raza National Medical Centre] in 2010 it was reported that, out of 32,011 donors, one HIV-1 window period and one case of occult HBV were detected. In both cases, follow-up was performed and the results were confirmed in seroconversion laboratory studies. No window period for HCV was detected, in contrast to what was expected in our population. In accordance with the blood bank’s fractionation indices, they estimated that they avoided the transmission of six viral infections via transfusion, 3 due to HIV window periods and 3 due to occult HBV. Both donors did not self-exclude and did not consider themselves to be high-risk, despite having received information on risky behaviours. They were also donating as relatives “for replenishment” [50]. Finally, between January 2011 and July 2017, the IMSS Regional Blood Bank of UMAE No.14, Centro Médico Nacional Adolfo Ruiz Cortines [Adolfo Ruiz Cortines National Medical Centre], Veracruz detected a total of 1,663 samples that were positive for the HIV, HBV and HCV group of viruses using the enzyme-linked immunosorbent assay (ELISA). A total of 678 positive results were then confirmed using NAT, and finally a total of nine window period cases were detected (one for HIV, four for HBV and five for HCV) [49]. In our country, the application of algorithms for handling donors is very heterogeneous. Serology is the foundation of donor acceptance or rejection criteria. As for NAT studies, both methods are available in the

country, as are mini-pool and individual sample techniques. The efficacy and sensitivity of both tests need to be evaluated, especially in regions where prevalence is higher or different to that described. Unfortunately in our country, regulations have not yet made NAT testing obligatory. For this reason, it is only carried out in some IMSS facilities (by region, this corresponds primarily to centralised units in Monterrey, Guadalajara and Mexico City, for example the Centro Médico Nacional siglo XXI), the health Secretariat in some states such as Chihuahua and Guanajuato, some National Health Institute, such as the National Institute of Cardiology or the National Institute of Pediatrics, and some ISSSTE hospitals such as the Hospital de Alta Especialidad “Centenario de la Revolución Mexicana” [“Centenary of the Mexican Revolution” Highly Specialised Hospital]. There are no national figures on detection or efficacy [45,46]. The Mexican regulations and donor follow-up mechanisms make assessing seroconversion complex. Because of this, blood banks in Mexico are not considered epidemiological reporting units; it falls to other areas to make the follow-up and monitoring of donors to assess seroconversion possible. Likewise, with the exception of a few institutions, there is no national hemovigilance and monitoring programme for donors. The most significant aspect of the NAT tests is early detection of reactive individuals with false negative results, significantly reducing the risk associated with transfusion. The risk of transmission of the most clinically relevant viruses, HIV, HBV and HCV, through blood is low when serological analyses are performed routinely at blood banks. However, nucleic acid testing (NAT) technology allows us to bring this risk closer to zero, by directly detecting the viruses in the serological window period [23]. 3. Discussion and conclusions Mexico has a completely different health system to the rest of the countries making up the OECD. It is a highly fragmented system, both intra- and inter-institutionally. Coverage is unequal and concentrated primarily in the working population. Each institution covers its members based on their employment, creating unequal and fragmented medical care policies. Approximately 50% of the population is considered “open”, with care covered through State Health Services and, as a result of decentralisation from 2004 onwards, through subsidised insurance, with unequal coverage of services and a lack of clarity regarding tissues, leaving care policies up to states and to each public, social or private institution. The concept of banking, clinical use and study of blood tissue is essentially included in hospitals, so national policies generally fall to each institution or state government. Although there are regulations to define operational strategies, the legal framework for development and the studies to be conducted for each donor, defining a uniform approach, studies (regulations set the minimum examinations, leaving NAT open to discretion) and selection (the source of exclusively voluntary donors is not well-established) takes priority. On a national level, the Secretariat has been ineffective as a governing body in establishing the bases of national policy, particularly with regard to promotion and prevention. Since the 2000s, with the creation of the CNTS and CETS, a national policy for blood accompanied by a national programme has been expected, but to date there has been no single project that defines this policy with any certainty, nor has a specific budget for such a project been contemplated. Based on the current regulations, blood banks, transfusion services and their objectives and structure have been conceptualised in different ways by the CNTS and COFEPRIS [17,51]. Regarding national external performance evaluation programmes in Latin America, in 2015 a total of 30 countries had external evaluation programmes for serology, 13 in Latin America and 17 in the Caribbean. This translates to a significant increase compared to 2011, when only 22 countries had such programmes. 7

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Moreover, in 2015 a total of 17 countries had national external performance evaluation programmes for immunohematology, seven in Latin America and 10 in the Caribbean, which also represents an increase on 2011, when only 12 countries overall had such programmes. In total, 23 countries have a national policy on blood, 14 in Latin America and nine in the Caribbean, which represents progress from the 2011 total of 18 countries. It should be noted that the implementation and monitoring of these policies has entailed the creation of functional units within Ministries of Health. With regard to national strategic plans on blood and specific budgets, in 2015 a total of 15 countries had such plans, 10 in Latin America and five in the Caribbean; this represents a slight advance, as in 2011 13 countries had these plans and budgets. Furthermore, in 2015 a total of 16 countries had a cross-sector National Commission on blood, eight in Latin America and eight in the Caribbean. This represents progress in comparison to 2011, when just 14 countries had one. These findings are not surprising as in some ways they may reflect the weakness of functional bodies within Ministries of Health. Regarding the reorganisation of blood services into an integrated network, progress has been reported in terms of the number of units of blood processed annually per bank, as well as a reduction in the number of processing sites. A total of 18 countries process more than 5,000 units of blood annually per bank, nine in Latin America and nine in the Caribbean. This is a considerable increase from 2011, when only 12 countries processed more than 5,000 units of blood annually per bank (bearing in mind that due to the geographical characteristics of some Caribbean countries this reorganisation requires different models for blood services). Likewise, in 2015 2,116 processing sites were reported in Latin America, a reduction of 9 % compared to 2011, when there were 2,321. The consolidation and reorganisation into a network of blood services contributes significantly to raising quality and safety, as well as considerably lowering costs. In 2015, 14 countries had established national blood requirements, six in Latin America and eight in the Caribbean; this represents an increase from 2011, when only six in total had done so. Regarding countries that have achieved 100 % voluntary non-remunerated blood donations, in 2015 a total of 10 countries had achieved this goal, two in Latin America and 8 in the Caribbean. This is a slight advance on reports for 2011, when the total was eight countries. It can be seen that more countries are aware of their blood requirements on a national level, which facilitates planning collections with a view to improving availability of and access to blood and blood products. Regarding the rational use of blood and blood products, some progress has been made in the availability of national guidelines for clinical use and the availability of intra-hospital transfusion committees. However, to date we do not have information or monitoring in countries relating to how users/prescribers apply these national guidelines to achieve appropriate use of blood and blood products. With regard to transfusion committees, 19 countries reported having them in 2015, 10 in Latin America and nine in the Caribbean; this reflects considerable progress compared to 2011, when only seven countries had such committees. In addition, in 2015 a total of 23 countries reported having national guidelines on the appropriate use of blood, 14 in Latin America and nine in the Caribbean, reflecting a slight increase in relation to 2011, when 20 countries had such guidelines. Furthermore, in 2015 a total of 25 countries had established a national model for inspection, oversight and control of blood services; 15 in Latin America and 10 in the Caribbean. This is progress compared to 2011, when the total was 20 countries. Additionally, in 2015 a total of nine countries reported having established a national hemovigilance system; five in Latin America and four in the Caribbean. This is an increase from 2011, when there were only two such countries. The above demonstrates that importance of strengthening the oversight, evaluation and follow-up system with the aim of having more information available that will enable appropriate interventions to be identified and

promptly implemented to ensure the sufficient supply, safety, availability and universal access to blood and blood products [7]. Information on both national external performance evaluation programmes for serology and immunohematology and on countries that report plan indicators nationally is included at the beginning of this report. For its part, Mexico continues to have a relatively high risk for some markers. Our country has not really achieved voluntary donation and the serology or prevalence of markers is similar to that reported in other countries such as Argentina [52]. Algorithms are not used systematically, rather their use is based on the Mexican Official Standard, under which nucleic acid testing with PCR technologies is not compulsory [53]. Using NAT, short seroconversion periods become possible, reducing the risk associated with the transmission of pathogens such as HBV, HCV and HIV. Significantly, the viral replication period is estimated at 0.45 days for HCV, 2.6 days for HBV and 0.85 days for HIV. The use of NAT tests in blood banks has been found to offer tremendous benefits, allowing window periods to be set at three to five days for HCV, less than five days for HIV and less than 21 days for HBV. Various factors play a role in the possibility of transmitting an infection, not only nucleic acid concentrations but also the receiver’s immune condition, the viral replication period and dynamics, and concentrate and type of sample, and the NAT technique used. For HIV and HCV, the difference between using individual samples and a minipool of fewer than six samples does not appear to be significant. In contrast, for hepatitis B there is a clear difference in favour of individual samples. The WHO recommends using accessible, user-friendly, robust, rapid, sensitive and specific tests, and that developing countries implement NAT in its current form, which significantly shortens and improves virus detection. To this end, various assays have been authorised for nucleic acid detection as both individual and mini-pool tests. Significant differences exist between the pools used, with the benefit being greatest the lower the number of samples (in the sample pool). A challenge for the future is to implement NAT in all countries and all blood banks, particularly in poorly developed regions. It remains unavailable in more than 39 countries and its use has not yet become systematic in some regions, including in our own country. Globally, there are still 16 million new HBV infection, 5 million new HCV infection and 160,000 new HIV infections [54]. A significant challenge for Mexico will be to establish uniform national policies and a vision focussed on transfusional medicine to improve conditions in blood banks, and to reduce the number of facilities to an optimal level leaving only those blood banks that collect at least 5,000 or ideally 10,000 units. In accordance with the PAHO criteria, uniform algorithms must also be established within the donor study process, primarily implementing the compulsory use of NAT in all donors [55–58]. There needs to be a gradual changeover to safer voluntary donation through uniform policies across institutes, with real oversight by the Health Secretariat and the CNTS, as well as the development of guidelines for the optimal use of tissue in clinics and medical units. A new challenge for blood banks will be posed by emerging diseases and the role that NAT could play in their detection and prevention, above all with the Zika virus among others, in addition to its implementation [54,59]. Sources of funding Not applicable. CRediT author statement All authors participated equally in literature search, data collection, information gathering, and drafting the manuscript. 8

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Informed consent

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B. Novelo-Garza, et al. [47] Duque-Rodríguez J, Rivera-Abaid M, Talamantes Cabrales A, Gómez Y, González L, Ochoa B, et al. Seroprevalencia de hepatitis C en donadores altruistas versus donadores de reposición del Centro Estatal de la Transfusión Sanguínea de Chihuahua. Rev Mex Med Tran 2011;4(2):133. [48] Espinosa-Reséndiz JD, Benítez-Arvizu G, Guerra-Márquez A, Malagón-Martínez A. El riesgo que implica el cumplir un requisito. Rev Mex Med Tran 2010;3(supl 1):s93. [49] Rey JA, Corona JC, Benítez G, González MA. Periodo de ventana en la Medicina Transfusional. Importancia de la tecnología NAT para la seguridad transfusional [Pamphlet]. Grifols, organiser. Symposium. Congress of the Mexican Association of Transfusion Medicine: 2017 Sept 21; Guadalajara. 2018. [50] Malagón-Martínez A, Guerra-Márquez A, Pichardo-Martínez MJ, Gómez-Corona J. Rendimiento del Escrutinio de la prueba de ácidos nucleicos (NAT) en donadores de sangre en la seguridad transfusional. Rev Mex Med Tran 2010;3(supl 1):S118. [51] Organisation for Economic Co-operation and Development (OECD). OECD Perspectives: Mexico Reforms for Change. 2012 [Accessed December 2018]. http:// centro.paot.org.mx/documentos/ocde/49363879.pdf. [52] Cruz JR, Pérez-Rosales MD. Availability, safety, and quality of blood for transfusion in the Americas. Pan J Public Health 2003(13):103–10. [53] Official Gazette of the Federation (DOF). Norma Oficial Mexicana [Mexican Official Standard] NOM 253-SSA1-2012, on the availability of human blood and blood

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[55] [56]

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