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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 2  |  Page : 88-97

The risk of transfusion transmissible infections. Where do we stand in 2018?


Department of Laboratory Medicine (Microbiology), Manipal Hospital, Bengaluru, Karnataka, India

Date of Web Publication24-Oct-2018

Correspondence Address:
Dr. Ranjeeta Adhikary
Department of Laboratory Medicine (Microbiology), Manipal Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GJTM.GJTM_33_18

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  Abstract 


Blood transfusion is an important aspect of medicine and patient safety plays a very important role. A myriad of blood-borne infectious agents can be potentially transmitted through transfusion of blood and blood products donated by apparently healthy and asymptomatic donors. The diversity of infectious agents includes human immunodeficiency viruses 1 and 2, hepatitis B virus, hepatitis C virus, malaria, syphilis, human T-lymphotropic virus types 1 and 2 and in certain circumstances, hepatitis A virus, cytomegalovirus, parvovirus B19, and many more. Besides the established viral, bacterial, and parasitic diseases, novel agents have now appeared and are still emerging as potential threats in transfusion medicine. While transmission of prion protein causing variant Creutzfeldt–Jakob disease is of prime concern in countries like the United Kingdom (UK), bacterial infections and viruses such as Dengue and Chikungunya are of prime concern in the Asian region. Transfusion centers employ three levels of screening to ensure blood safety: donor screening interventions to exclude high-risk donors, testing for infectious markers by serology, nucleic acid testing methods and processing technologies like leukoreduction, use of diversion pouch in blood collection, and use of aseptic blood collection technique. Implementing new technologies like pathogen reduction to destroy/inactivate pathological substances in blood components using chemicals or UV lights coupled with expanding testing for emerging diseases will certainly increase the safety of blood. The ultimate aim is to minimize the risks of transfusion-transmitted infection during the window period of infectious agent in a cost-effective and efficient manner. Although considerable effort and resources have been invested, no single technique is yet effective and we are far from achieving zero risk. The main challenges are faced by developing countries due to limited resources.

Keywords: Emerging infection, existing infection, transfusion-transmitted infection


How to cite this article:
Adhikary R, Bhavana MV. The risk of transfusion transmissible infections. Where do we stand in 2018?. Glob J Transfus Med 2018;3:88-97

How to cite this URL:
Adhikary R, Bhavana MV. The risk of transfusion transmissible infections. Where do we stand in 2018?. Glob J Transfus Med [serial online] 2018 [cited 2018 Nov 20];3:88-97. Available from: http://www.gjtmonline.com/text.asp?2018/3/2/88/243926




  Introduction Top


One of the major concerns throughout the history of transfusion medicine has been the transmission of infectious diseases during the process. The earliest reports of transfusion-transmitted infections (TTIs) were that of malaria in 1911, syphilis in 1915, and hepatitis in 1945.[1] This was followed by the human immunodeficiency virus (HIV) in 1980's and hepatitis C in the mid-90's.[2],[3] More stringent processes were then brought into force for screening of donors and donated blood for these infectious agents. These processes have made blood transfusion a relatively safe procedure in the present date. Adoption of advanced molecular methods in infectious disease monitoring has considerably improved the safety of blood supply. A new scenario has arisen in recent years with the appearance of emerging infectious agents. Hence, transfusion-associated infections still continue to be an important concern.


  Existing Infections Top


  1. Viral
  2. Bacterial and parasitic.


a. Existing transfusion-transmitted viral infections

In the last two decades, the scientific community has given much attention to the prevention of TTIs. The challenges faced are due to its prevalence among asymptomatic carriers in the general population and potential transmission of viruses during the immunological window period of infections. To address these issues, novel non-serology-based approaches such as viral nucleic acid testing (NAT) have been established. However, blood components with very low viral load can even escape detection by NAT and cannot completely prevent transmission.

Human immunodeficiency virus

The transmission of HIV through blood transfusion has been a major concern. The etiological agents are HIV-1 and HIV-2. HIV is known to have a high genetic diversity which enables the virus to undergo in vivo selective pressures leading to rapid development of immunological and drug-resistant mutants.[4] Besides, HIV has several subtypes and blood centers should use updated commercial kits that contain both natural and recombinant antigens to increase their sensitivity to newly discovered species, such as group O viruses.[5] The fourth-generation enzyme-linked immunosorbent assay (ELISA) kit detects both HIV antigen (p24) and antibodies, IgM and IgG and is recommended as it reduces the window period to 14 days.[6] Molecular epidemiological analysis has identified the predominance of HIV-1 subtype C in Indian population.[7] Similarly, HIV-2 has six subtypes with different geographic distribution.[8] It is mainly restricted to West Africa and is also present in Europe, mainly Portugal and France, India, and the United States of America (USA).[9] The residual risk for TT HIV 1 and 2 infections among Chinese blood donors was reported as 5.4 infections per million blood donations.[10] The seroprevalence of HIV in Indian scenario is between 0.2% and 1%.[11] The risk of acquiring HIV from a donor during window period based on antibody detection has been reported to be 1 in 493,000 units transfused.[12] Introduction of HIV-NAT has reduced the window period from 16 days to 10 days.[11]

Hepatitis viruses

TT hepatitis is almost exclusively due to viruses. These viruses include hepatitis viruses A through E, cytomegalovirus (CMV), Epstein–Barr virus (EBV), and other newly described viruses.

  1. Hepatitis A, endemic in many parts of the developing world, is rarely transmitted by transfusion with a risk of <1 per million units of blood transfused.[11],[13] This rarity is due to short duration of viremia and absence of chronic carrier state. Although there are occasional reports of TTI, routine testing for hepatitis A virus (HAV) does not appear to be warranted.[14]
  2. Hepatitis B virus (HBV) infection has greater risk of transmission than HAV and is estimated in the USA to be 1:63,000 units transfused.[12] The seroprevalence of HBV infection among blood donors in India was 0.62%–1.61%.[15],[16] Donated blood is screened for HBsAg and IgM antibody to hepatitis B core antigen (anti-HBc).[11] It is recommended to do HBV-NAT of all blood units before transfusion. As of 2012, 30 countries have implemented NAT in their routine screening.[17] Other alternative is the inclusion of anti-HBc IgM, which will help in the diagnosis during the “window period” before the appearance of antibody to HBsAg and disappearance of HBsAg.[18] Moreover, anti-HBc IgM can detect recent HBV infection in rare HBV mutants with altered HBsAg epitopes and occult HBV infection (OBI).[11] According to a 2008 international survey, the prevalence of OBI in blood donors was estimated to be 8.55/million donations.[17]
  3. Hepatitis C virus (HCV) is transmitted mainly through blood exposure. The risk of acquiring HCV through transfusion is approximately 1 in 2,000,000 units.[13] Blood donation units are tested for antibodies to HCV and HCV RNA. The prevalence of HCV antibodies in blood donors in developed countries ranges from 0.4% to 2%.[19] Countries with the high prevalence rates are located in Africa and Asia. HCV antibodies are typically not detectable until 2 months or longer after acquisition of infection when ELISA is used for screening. NAT, with a window period of approximately 7 days, reduces the risk of window period HCV infection from approximately 3 in 100 to 3 in 1000 among injectable drug users when compared to ELISA.[20]
  4. Hepatitis D virus (HDV) requires HBV for its replication and cannot be expressed in the absence of HBV. Therefore, the chance that a blood donor screened and found to be negative for HBsAg and anti-HBc could harbor HDV is extremely rare. Hence, additional tests for screening of HDV among blood donors are not employed.[11]
  5. Hepatitis E virus (HEV) is not normally transmitted by blood transfusion. There are reports of TT HEV in endemic areas, in high-risk groups, such as patients with chronic hemodialysis.[21] HEV viremia is most commonly associated with anti-HEV IgM antibodies than with anti-HEV IgG antibodies. Therefore, HEV screening of these antibodies among blood donors should be considered in endemic areas and in high-risk population.[22] Moreover, HEV RNA screening might also be effective for its prevention.[23]
  6. Hepatitis due to CMV or EBV: This is generally very mild in the absence of severe immune suppression. Hence, routine screening is not performed for CMV or EBV. However, CMV should be screened for transfusion to immunosuppressed individuals, neonates, and pregnant women.[11] The prevalence of anti-CMV (IgG) in the Indian scenario is about 95% and about 5% of donor population is IgM antibody positive which carries the eminent threat of transmitting CMV infection. Due to the wide prevalence of CMV infection, it is not possible to screen blood donors. Hence, in the absence of screening, leukoreduced (by third-/fourth-generation filters) blood products should be supplied to high-risk patients.[11],[24],[25]


Human T-cell lymphotrophic virus

Human T-lymphotropic virus types-1 and -2 (HTLV-1 and -2) were discovered in the early 1980s and soon after that it was realized to cause TTI due to the infusion of infected lymphocytes. HTLV-1 is associated with myelopathy and adult T-cell leukemia/lymphoma. It may present a greater risk in certain regions and countries like Japan, Sub-Saharan Africa, and Central and South America.[24] HTLV-2 is found to be more common among Native American blood donors. In a study from China, it was found that among 253,855 blood donors, 43 were confirmed to be seropositive for HTLV-1 (16.9/100,000), whereas HTLV-2 infection was not found.[26]

b. Existing transfusion-transmitted bacterial and parasitic infections

Bacterial contamination

The American Association of Blood Banks (AABB) in 2008 reported that the second most common problem faced by them is the bacterial contamination of blood products.[27] In the Indian scenario, of the 735 adverse recipient reactions reported to National Institute Biologicals that monitors National Haemovigilance Program, between February and November 2013, nine cases were due to infectious causes.[28]

Sources of contamination include the skin, blood, disposables, and the environment. Gram-positive skin flora such as  Staphylococcus epidermidis Scientific Name Search most often recovered from donated blood which is responsible for its contamination. This occurs principally during phlebotomy, as a result of incomplete disinfection of the skin. These organisms typically do not grow at 1°C–6°C but survive at the platelet storage temperature of 20°C–24°C. As per the United States (US) data, rate of bacterial contaminants of platelets has been estimated approximately as 1 in 6015 collected units with one death.[29] In the case of Gram-negative bacteria such as  Escherichia More Details coli, Klebsiella, Pseudomonas species, asymptomatic donors with transient bacteremia are presumed to be responsible. Of particular interest is this Gram-negative bacterium,  Yersinia More Details enterocolitica, which is implicated in 46% of clinical cases of sepsis due to contaminated blood units. This organism grows well in red cell concentrates since it uses citrate as the source of iron and can survive at 4°C.[30],[31] Most of the reports pertaining to Y. enterocolitica are from the West, and there is a paucity of data from the Asian subcontinent. Approximately 80% of the reported cases of bacteria transmitted by transfusion are due to psychrophilic organisms, which are capable of surviving at low temperatures.[31]

Appropriate skin disinfection, continuous training, and supervision of the responsible personnel for donation; proper product processing; and optimum storage are key elements for blood safety.[32] Implementing appropriate and advanced diagnostics for early detection of these organisms and effective pathogen reduction techniques of the donated blood also add to the success of this procedure.[33] Donor deferral (especially in the case of Y. enterocolitica) and use of blood bags with diversion pouches are other alternatives to reduce bacterial infections in donated blood.

Malaria

Transfusion-transmitted malaria (TTM) was described for the 1st time by Woolsey in 1911.[34] The impact of this infection on transfusion is huge. As per the literature, Plasmodium species were detected in 100 TTM case reports with a different frequency: 45% Plasmodium falciparum,30% Plasmodium malariae,16% Plasmodium vivax, 4% Plasmodium ovale, 2% Plasmodium knowlesi,1% mixed infection with P. falciparum/P. malariae. The majority of fatal outcomes (11/45) were caused by P. falciparum, while the other fatalities occurred in individuals infected by P. malariae (2/30) and P. ovale (1/4).[35] Infected blood transfusions directly release malaria parasites in the recipient's bloodstream triggering the development of high-risk complications and potentially leading to a fatal outcome. The parasites are stable in plasma and whole blood for at least 18 days when stored at 4°C and for extended periods in frozen state.[24] Criteria for hemovigilance are defined by the World Health Organization and are adapted to the needs of each country. Some countries such as the USA rely on a predonation questionnaire for the screening of potential infected donors, whereas some others, including France, UK and Australia, use antibody testing on high-risk donors.[36] In malaria endemic countries, antigen detection is the recommended mode of screening.[24]

 Babesiosis More Details

TT babesiosis was first recognized in 1979. This is the most common TTI in the West.[37] Babesiosis is difficult to identify in donors as most of the adults experience asymptomatic infection, which also persists for months following antibiotic therapy. The preventive strategies include pathogen inactivation of blood products and laboratory screening to identify and remove infected donations.  Babesia More Details inactivation has been shown to be possible with methods that are in use for other pathogens, but no licensed commercial products are yet available for this purpose. Babesia microti antibody and/or polymerase chain reaction (PCR) assays can also be effective screening tools for preventing this infection.[37]

Leishmaniasis

TT leishmaniasis continues to be a major problem in endemic areas. Most of these cases manifest atypically.[38] The parasites may already be circulating in the peripheral blood in an asymptomatic individual. The first report of two TT kala-azar came from China in 1948.[39] Ten cases of transfusion-associated leishmaniasis are reported from Asia and Europe and one case report was from India.[38],[40] ELISA can be used for mass screening of donor blood samples in endemic areas. Individuals who have spent extended periods in endemic areas are deferred from donation for at least 12 months since their last return.[41]

Trypanosomal infection (Chagas' disease)

Transmission of this infection through blood transfusion has been recognized since 1952.[42] The affected individual is asymptomatic, but parasitemic in the chronic phase can transmit the infection by transfusion. The parasites are stable in plasma and whole blood for at least 30 days when stored at 4°C and for extended periods in frozen state. They can also withstand freezing and thawing.[11] However, platelets are the most frequent cause of transfusion-related transmission. This disease is a major concern in endemic countries and in some nonendemic countries to which significant numbers of blood donors migrate from endemic regions. Screening involves the detection of antibodies in the donated blood. Blood component leukoreduction by filtering could reduce the amount of parasites present.[43]

Syphilis

Syphilis, caused by Treponema pallidum subspecies pallidum, is one of the oldest recognized infectious risks of blood transfusion. This has become extremely rare because of improved donor selection processes, universal screening of donors for this infection, and the shift from transfusion of fresh blood components to refrigerated products. These stringent processes have resulted in only three reported cases of TT syphilis over the past four decades although antibodies to T. pallidum are found occasionally in blood donors.[44] All reported cases were linked to transfusion of fresh blood products, and only one case, which was reported >30 years ago, involved blood products received in the US.[45]


  Emerging Infections Top


Hepatitis virus non-A-E

  1. GB virus-C (GBV-C), formerly known as hepatitis G virus (HGV), is a recently discovered RNA virus and is distantly related to HCV. It has been found to be associated with hepatitis and transmitted through parenteral and sexual route.[46] The prevalence of HGV in the general population in India was found to be 4%, but a significantly higher frequency of 46.6% was observed in commercial blood donors.[47] It is detected by PCR technology. As yet there is no conclusive evidence that HGV produces hepatitis, but the presence of HGV in hepatitis cases creates a doubt on this finding.[46]
  2. Teno virus: Novel DNA virus, named TTI virus, also known torque teno virus (TTV) has been isolated from sera of patients with non-A-G hepatitis. It has been reported worldwide with high prevalence. TTV infection rates in the healthy blood donors by PCR technology were found to be 72%–81.4%[48],[49],[50]
  3. SEN virus (SENV): Another novel nonenveloped DNA virus, designated as SENV was discovered as a blood-borne pathogen causing hepatitis. TTI has been confirmed by the detection of more than 99% homology between SEN-V in donor and recipient sera.[51] It has a worldwide incidence with varying prevalence rate. SENV DNA was detected by PCR technology in 10% of blood donors from a study in Japan.[52]


Screening of GBV-C, TTV, and SENV is not currently recommended among blood donors, as disease association is yet to be confirmed.[11]

Human herpesvirus

Human herpesvirus (HHV) infection transmitted through infected healthy blood donors pose a danger to immunocompromised recipients. HHV-8 is the causative agent of Kaposi's sarcoma. Although HHV-8 seroprevalence among blood donors have been reported from different countries, further studies are needed to clarify the potential risk of TT HHV infection in immunocompetent patients.[32] There is insufficient information on the epidemiology of HHV-8 infection from India. A study has reported the seroprevalence of HHV-8 as 4.7% in the South Indian population.[53] A study from China has reported significantly high HHV-8 seroprevalence ranging from 18.6% to 36.8% among blood donors in various ethnic groups.[54]

West Nile virus

West Nile virus (WNV), a documented TTI in 2002, is a mosquito-borne RNA virus of the flavivirus family. It is detected using NAT.[13] No study proves the association of WNV to transfusion in the Indian subcontinent.[19] In 1999 through 2003, WNV spread was documented as TTI in the US. The mean risk of transmission through blood components ranged from 1.46 to 12.33/10,000 donations during the 2002 epidemic.[11] Hence, routine screening has been included from 2003 in the US.[13]

Dengue virus

Dengue (DENV) is an arbovirus transmitted through the bite of mosquitoes of the genus Aedes. So far, only five cases of TT dengue, including one case of dengue hemorrhagic fever, have been documented. The present global burden of dengue is enormous. About 2.5 billion people over more than 100 countries are concerned; with approximately 20,000 fatal cases. Although frequently asymptomatic or limited to a mild fever, dengue is responsible for severe cases that can lead to shock and death, notably in children from poor resource settings. In 2009, the AABB placed DENV in the highest category of emerging infectious agents for their potential impact on transfusion recipient safety in North America.[55]

Parvovirus B19

Parvovirus B19 (PV-B19) was discovered in 1975 during HBsAg screening of blood samples.[11],[56] This virus shows tropism for erythroid precursors and inhibits both erythrocyte production and maturation.[13] PV-B19 infection may result in a life-threatening aplastic crisis in patients with a high erythrocyte turnover, and acutely infected pregnant women can transmit to their unborn child, resulting in a hydrops fetalis and fetal death. There is a paucity of reports on PV-B19 infection in India. A study from North India has shown about 40% prevalence or evidence of IgG PV-B19 which is too high to frame any selection criteria. Moreover, this infection is not fatal in immune-competent patients. Hence, PV-B19 screening of blood donors has not been a high priority.[11],[25]

Chikungunya virus

Chikungunya virus (CHIKV), a mosquito-borne arbovirus, is a matter of concern because of high population involvement during outbreaks and high viremia lasting approximately 6 days. TT risk is estimated to be as high as 150/10,000 donations during outbreaks. Due to sporadic and low prevalence infections, the possible screening measures to prevent CHIKV TT are by deferral of symptomatic donors and discontinuing blood collections in affected areas.[25],[57]

Severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is a newly recognized infectious disease caused by a novel coronavirus (CoV). The detection of the SARS-CoV viremia in low titers for approximately 10 days after the onset of symptoms from probable SARS patients has led to the theoretical risk of transfusion transmission, although no cases have yet been identified or proven.[24],[58]

Yellow fever

There is a theoretical risk for transmission of yellow fever from viremic travelers and active duty military members visiting endemic areas of Sub-Saharan Africa and Central/South America following yellow fever vaccination for 2 weeks. They should defer blood donation for 2 weeks.[59]

Zika virus

Zika virus can also be transmitted through blood transfusion as large number of infected people may be asymptomatic and present as a healthy donor. CDC has reported possible blood transfusion transmission cases in Brazil.[60]

Anaplasmosis

Human granulocytic anaplasmosis is an emerging tick-borne illness caused by intracellular bacteria called Anaplasma phagocytophilum. It can cause asymptomatic infection and can survive blood component refrigeration for at least 18 days. The reported cases of transfusion-acquired infection are attributed to leukoreduced red blood cell units and apheresis platelet unit and whole-blood-derived platelet pool. Although transfusion-associated transmission of this pathogen appears to be rare, reported incidences of anaplasmosis and other tick-borne diseases are on the rise, especially in the endemic regions such as the US.[61] Since it is rare, routine screening of blood donors for the presence of this organism is not likely to be cost-effective. Nevertheless, when febrile illness associated with leukopenia or thrombocytopenia develops in a patient after transfusion, testing for this infection may be beneficial.[62]

Lyme disease

This is a tick-borne infection, caused by the bacterium, Borrelia burgdorferi. This is a common vector-borne infection in North America and Europe. Although no cases of Lyme disease have been linked to blood transfusion, research has shown that B. burgdorferi can survive in stored blood. Individuals being treated with an antibiotic for this infection should not donate blood.[63]

Other tick-borne pathogens such as R. rickettsii, Colorado tick fever virus, and tick-borne encephalitis virus also have been transmitted by transfusion but are extremely rare in incidence.[64] Avian flu virus, which is known to have a viremic phase, may be associated with blood transfusion but is yet to be proved.[65] Of future interest will be whether other viruses such as Nipah and Hendra virus are blood-borne and involved in TTI.[66]

Prions

The word prion is derived from “proteinaceous infectious particle.” They are misfolded proteins that are associated with several fatal neurodegenerative diseases in animals and humans. No transmission through transfusion has been reported for classic Creutzfeldt–Jakob disease (CJD).[67] As per an ongoing study in the UK, three cases of probable transfusion transmission of variant CJD (vCJD) infection were reported, including two confirmed clinical cases and one pre- or sub-clinical infection.[68] All three infected patients received nonleukodepleted red blood cells. Leukodepletion may reduce the possibility of vCJD transmission.


  Conclusion Top


In a nutshell, the bugs that can threaten blood transfusion and the ways to tackle them are summarized in [Table 1].[69],[70],[71] This fear of infectious agents entering the blood products is ongoing and may evolve as new pathogens emerge or as old ones change their epidemiological pattern. The goal of a safe blood supply is reached by the coordinated optimization of each step in the transfusion chain. In the present situation, new technologies are being explored to achieve pathogen reduction in donated blood, some of which are highlighted in [Table 1]. This provides a ray of hope, with advancement in science and technology paving the way to achieve complete safety in blood transfusion. To sum it up, selection of appropriate and risk-free donors, usage of optimal screening tests, and elimination of residual pathogens help in ensuring the safety of blood, the “liquid gold.”
Table 1: An overview of existing and emerging transfusion-transmitted infections with various modalities for prevention of transmission

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Conflicts of interest

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