Issues of Concern
Transfusion-transmitted infection risks are numerous and can be characterized as bacterial and non-bacterial. This article attempts to include the most clinically relevant etiologies.
Bacterial Transfusion-Transmitted Infections
Bacterial infection stemming from transfusion is a significant cause of morbidity and mortality and has historically been underappreciated. The 2016 Annual UK Serious Hazards of Transfusion (SHOT) report suggested the main culprit of TTIs was bacterial transmission accounting for more than 10% of transfusion-associated deaths in the USA.[1][2]
The US Centers for Disease Control and Prevention performed a study called ‘The Assessment of the Frequency of Blood Component Bacterial Contamination Associated with Transfusion Reaction Study’ (BaCon), the first study to look at specific characteristics related to bacterial contamination of blood products. The results collected between 1998 and 2000 showed that the risk for bacteremia due to transfusion is 1 in 100,000 units of platelets and 1 in 500,000 units of red blood cells (RBCs). The estimated risk for death from bacterial transfusion-transmitted causes is 1 in 500,000 units of platelets and 1 in 8 million units of RBCs.[3]
Continually, the bacterial contamination risk is highest in platelet components, given their storage at room temperature compared to refrigerated components. It has been postulated that donor arm contamination, donor bacteremia, and equipment contamination are contributing sources. As such, donor health history questionnaires (DHQs), mini-physical exams, donor puncture site preparation, diversion of the initial portion of blood donation, and self-exclusion of unwell bacteremic donors combat these risks.
That said, asymptomatic donor bacteremia, including Yersinia infection, has also been identified, especially given its ability to grow at colder storage temperatures. This risk has largely been reduced since prestorage leukoreduction may prevent/ inhibit Yersinia proliferation. Once introduced in the UK in 2011, platelet bacterial screening has greatly reduced the risk of TTIs due to Gram-negative bacteria previously responsible for most platelet contamination fatalities.[4][5][6]
Despite these efforts, the risk of transfusion transmission - not necessarily septicemia - is relatively high at 1:30,000 for red cells and 1:3,000 for platelets, compared to the residual risk after the modern viral screening. Assuming bacterial contamination at the time of collection, colony-forming units (CFUs) / mL are low, and sepsis does not occur with transfusion.
At the end of storage time, CFU / mL can increase dramatically and lead to sepsis, especially in immunocompromised individuals. Again, apheresis platelets (single-donor) and platelet concentrates (three to six donor pools) are stored at higher temperatures (20 to 24 degrees Celsius) with agitation for up to five days. Skin flora, including Staphylococcus and Streptococcus, thrive in these conditions and are more apt to cause bacterial septicemia once transfused. Serratia, Salmonella, and Bacillus are known to commonly contaminate platelet products as well.[7][8][9]
Gram-negative bacteria initially appeared to be the most common source of contamination based on reports of small case series; however, the BaCon study showed that Gram-negative bacteria are more frequently associated with death and, therefore, were more often reported. Gram-positive bacteria are most likely more associated with contamination.[3]
Attempts to prolong the platelet storage phase beyond five days have been limited due to bacteremic/ septic reactions seen at end storage and the unacceptable rates of bacterial transmission. Visual inspection of products before transfusion should occur. Contaminated red cell units are generally much darker due to bacterial oxygen usage, and platelets have loose “swirling” and lower pH when contamination is potentially present.[7][10] Twenty-four percent of contaminated units were characterized by haziness or discoloration.[3]
Suspect units should be quarantined and examined to evaluate for contamination. Care is necessary to maintain proper storage temperature during transport.
Regarding transfusion complications, bacterial septicemia remains the fourth leading cause of death in the United States. Presentation tends to be in the form of severe sepsis and usually presents as rapid onset fever and circulatory collapse.[4]
Septic reactions should be suspected if the following occur:
- Temperature greater than 102 degrees Fahrenheit (or higher than 2 degrees Fahrenheit or 3 degrees Celsius above baseline temperature)*
- Chills
- Rigors*
- Tachycardia (heart rate greater than 40 beats over baseline)*
- Shock/falling systolic blood pressure (30 mm Hg below systolic)
- Backache
- Nausea/vomiting
- Unexplained bleeding from mucous membranes or the infusion site
- Renal failure may follow[7][10] (*In 75% of cases, fever, rigors, or tachycardia were present within 4 hours of transfusion.)[3]
The following steps should occur if suspected:
- Transfusion is immediately halted
- Respiratory support and institute mechanical ventilation as needed
- Cardiovascular support with vasopressors as indicated
- Start transfusion reaction workup (i.e., blood, post-transfusion urine, blood unit, and administration set sent to the lab.)
- Perform gram stain and culture from implicated unit and administration set as well as two site blood culture from patient to establish the diagnosis
- Prompt broad-spectrum antibiotics initiation with narrowing from gram stain and cultures/ sensitivities[7][10]
The differential diagnosis for transfusion pyrexia - defined as an increase in temperature greater than one degree Celsius from baseline or greater than 38 degrees Celsius with or without rigors/ chills occurring in the blood recipient of a unit of blood or blood component without other explanation – is broad and includes the following:
- Febrile non Hemolytic transfusion reaction
- Hemolytic transfusion reactions (Immediate and Delayed)
- Transfusion transmitted malaria
- Transfusion-related acute lung injury (TRALI)
- Transfusion-associated graft versus host disease (TAGVHD)
The clinician often requires a high index of suspicion to suspect the transfusion as the culprit of a fever. It should not be overlooked during the evaluation of pyrexia, especially after a reasonable interval from the transfusion has elapsed.[11]
Non-Bacterial Transfusion-Transmitted Infections
Viruses
Again, syphilis was recognized as the first TTI in the 1930s. Since then, numerous infectious entities associated with blood transfusions have been identified.[12] Although it was not known that the agent of transmission for hepatitis was viruses, transfusion transmission of hepatitis has been recognized since the 1940s.[13]
The first major viral infection recognized as causing transfusion-transmitted hepatitis was the hepatitis B virus (HBV). This was followed by “non-A” and “non-B” infection, which was later identified as hepatitis C virus (HCV), as well as human immunodeficiency virus (HIV).[2]
Since the 1950s, safeguards to prevent hepatitis-causing TTIs have been in place, such as donor health questionnaires. Laboratory screening advanced, and tests developed in the 1990s could detect antibodies to, as well as antigens of, hepatitis viruses. Ultimately, nucleic acid testing (NAT) was created to detect genetic material from viruses in the donor. These tests and other mitigation strategies ultimately paved the way for the low risk of transmission of infection seen in modern times.[14][15]
HBV
- As above, HBV was a serious transfusion risk before the development of sensitive and specific tests many years ago, which led to a dramatic reduction in transmission via transfusion.[16][17][18]
- NAT testing has further decreased the risk of HBV transmission from donors during the early stages of acute infection (i.e., window period); however, transmission is still possible as donor viral loads may be below the test level of detection.[18]
- In the United Kingdom, routine blood donation screening may fail to detect one to two HBV infection donations per year.
- Despite most cases of acute infection clearing spontaneously in immunocompetent adults, immunocompromised individuals will likely remain infected long-term, and infection from HBV can impact the treatment of the underlying condition.[2]
HCV
- As with HBV, careful donor selection, as well as HCV antibody screening, greatly reduced the rate of TTIs due to HCV in the early 1990s.
- In the late 1990s, HCV NAT screening in the developed world further reduced the risk.
- The last reported TTI due to HCV in the United Kingdom was in 1997.[2]
- The risk of lab screening not detecting HCV-infected blood donation remains at one in many millions, and HCV TTI is exceedingly low.[19]
HIV
- Although initially thought to be rare, the ease of transmission of HIV via blood transfusion became more appreciated, especially with the spread of HIV in the 1980s and the gravity of acquired immunodeficiency syndrome prognosis.[14][20]
- By 1985 HIV antibody assays allowed for screening of blood donations; however, many TTIs due to HIV had occurred.[21][22]
- Implementation of pre-donation screening has proven to be 98% effective in preventing HIV-positive donor units and coupled with the 95% effectiveness of antibody testing, the two combine for a 99.9% chance of reducing HIV TTIs.[20]
- NAT has decreased the risk of HIV TTIs to 1:1.9 x 106.
- Window period transmission is rare, but it can occur. This risk varies with the epidemiology of HIV infection in the donor pool.[23]
- Four cases of transfusion transmission of HIV occurred from 1999 to 2009; the last case in the United States was in 2008.[24]
Hepatitis E Virus (HEV)
- Since the 1980s, HEV has been a significant cause of acute hepatitis; however, it has only recently been recognized as an important issue in developed countries.
- Four genotypes exist:
- G1 and G2 are water-borne, endemic, and cause large sporadic infections in the developing world
- G3 and G4, which are primarily viruses of swine, are transmitted via foodborne zoonosis via consumption of undercooked pork products.[25]
- HEV cases have been rising in the UK since 2010; G3 is the most common cause.[26]
- Acute infection in immunocompromised individuals may lead to chronic hepatitis and cirrhosis, but most HEV infections are clinically asymptomatic.[27]
- The virus is cleared the majority of the time quickly in the immunocompetent.
- Assuming viremic donation, the risk of HEV TTI is 40 to 50% in the recipient.
- Unless transfusion recipients take dietary precautions, 13 donor exposures are approximately the same risk of infection as dietary exposure for one year.[28]
Human T-Lymphotropic Virus (HTLV)
- HTLV is transmitted through sexual partners, breastfeeding, and transfusion.
- It is a white-cell-associated virus, and although most infections are asymptomatic, a small number of individuals infected will develop clinical sequelae in the form of increased lifetime risk of adult T-cell leukemia/ lymphoma or HTLV-associated myelopathy/ tropical spastic paraparesis (4 to 5%).[29][30]
- Areas with relatively high prevalence include Japan and the Caribbean, as well as areas of the Middle East, South America, and western and southern Africa.
- High infection rates in the Japanese population in the 1980s led to antibody screening.[31]
- In the United States, universal antibody screening began in 1988, followed by France in 1991 and the UK in 2002.[32]
- in an attempt to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD), leukodepletion of donor units in the UK in the 1990s led to a risk reduction of 93% of HTLV infection.[33]
- HTLV is not believed to exhibit the traditional window period of infectious viremia as it is a cell-associated virus. Transmission requires an infected white cell to come into contact with a white recipient cell.[34]
- Leukodepletion, therefore, ultimately leads to a remote risk of HTLV TTI in countries where prevalence is relatively infrequent, especially in a previously tested donor
- There is a low, 1:5.1 x 105 prevalence in the United States for first-time tested donors, and there is a 1:2.9 x 106 chance of TTI.[35][2]
- The conversion rate is 25 to 63% for those receiving seropositive blood products.[36]
- NAT is not performed for HTLV, and no similar tests are under development.[35]
Cytomegalovirus (CMV)
- Iatrogenic transmission via blood transfusion or tissue/ organ transplantation is possible; however, person-to-person contact through respiratory secretions is the primary mechanism of infection.
- Following initial infection, which is often subclinical or results in mild flu-like symptoms, there is lifelong persistence of the virus within mononuclear white cells or hematopoietic progenitor cells within bone marrow following antibody development.[37][38]
- Secondary infection can occur as the virus can be re-activated.[39]
- The vertical transmission rate during pregnancy is 40% and can affect neurodevelopment.
- 50 to 60% of the UK population is estimated to be seropositive.[2]
- 1.1% of CMV-negative donors will seroconvert per year.[40]
- Patients most at risk of severe infection are solid organ/ hematopoietic stem cell transplant patients, preterm infants, congenital or acquired immunodeficiency, and those undergoing chemo-/radio-therapy; symptoms can include fever, pneumonitis, hepatitis, retinitis, colitis, and meningoencephalitis; this is most relevant in immunocompromised individuals.[41]
- Traditionally, transfusion of seronegative blood components to those at risk of infection was the primary mode of reducing transmission.[42]
- Modern leukocyte reduction techniques are now known to significantly reduce or even eliminate CMV transmission from blood products.[43]
Emerging Viral Infections
This term is generally used to describe either newly identified infections or ones that have spread from a previous location to affect new or larger areas. Factors and conditions that promote emerging infections include air travel and increasing population mobility, asymptomatic carriers, vector existence in a new area, and climate warming. West Nile Virus in North America, Zika virus in Brazil, Chikungunya virus in Reunion, and dengue in areas such as southern France are all relatively recent examples. Interestingly, these instances of emerging infections have in common that they are arboviruses transmitted by mosquitos. As there is often a symptom-free period despite viremia, infected donors could unknowingly donate blood resulting in the risk, albeit small, of TTI.[44]
Travel history, temperature measurement, and donor health questionnaires screen out roughly 99.5% of potentially infectious donors; however, other viruses are still not screened by history or tested for in the blood donor setting. Luckily, these tend to produce mild symptoms, be geographically isolated, or have yet to be identified as causing TTIs.[12]
West Nile Virus (WNV)
- Mosquitos spread the virus with birds serving as the prime reservoir, but mammals are also an end host.
- Infection in the majority of cases is either asymptomatic or results in mild symptoms, including headache, fever, and myalgias.
- There is a small, possibly 1%, risk of central nervous system involvement resulting in meningitis/ encephalitis.[45]
- Although previously an unaffected WNV area, the virus spread to North America, with the first cases being identified in New York City in 1999.[46]
- Global spread continued over the next five years across North America, north into Canada, and south to Latin America and the Caribbean; European spread also continued to previously unaffected areas.[47]
- Twenty-three patients were confirmed to have transfusion-transmitted WNV during the 2002 United States epidemic.
- The average period of viremia for WNV infection only lasts six days; however, 80% of those infected are asymptomatic, resulting in symptom-free blood donation.[47][2]
- The development of WNV genomic screening was rapid, and permanent NAT testing was put in place in the United States by 2002.[35]
Zika
- First evident in Africa in 1947, infection by Zika virus has been newly documented as transfusion transmissible.
- The virus spread across Africa and Asia through the 1980s; at least 56 countries are known to have active Zika infections.
- More recently, in Brazil in 2015, in vivo-infected fetuses of mothers who had contracted the virus were found to exhibit microcephaly.
- Viremia generally lasts 1-2 weeks during primary infection.
- By 2016 NAT testing was well underway in the United States and should decrease transfusion transmission risk to <1:1 x 106 as with HCV and HIV testing [Guidance for Industry: Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components (2016)].
Parasites
There is a risk of TTI due to parasites; several cases of babesiosis, malaria, trypanosomiasis, toxoplasmosis and other parasites have been reported. Careful screening of donors, such as recognizing travel history to endemic areas, is the primary means of mitigating the risk of TTI due to these organisms.[48]
Syphilis
- No cases due to blood transfusion have been reported since 1969.
- Refrigeration of blood products is thought to kill spirochetes within 1-2 days.[1]
- Malaria contributes to significant morbidity and mortality following blood transfusion, especially in developing countries.[2]
- This plasmodium species, with the Anopheles mosquito serving as its vector, spends part of its life cycle in hepatocytes and is an intracellular erythrocyte protozoan pathogen.
- Leukocyte reduction does not seem to decrease the risk of transmission, and survival for 7-10 days for this protozoan is possible in blood containers.
- Travel history and donor deferral are the primary means of reducing TTI risk as there are no FDA-approved screening tests for malaria; however, this can lead to the unnecessary exclusion of many donors.[12]
- Individuals born and raised in endemic areas, not travelers, resulting in the majority of risk as they may remain infected, semi-immune, and seemingly healthy.
- An effective tool to retain donors is to perform antibody screening after the last exposure, usually four months, as a surrogate for transmission risk.[2]
- Studies are ongoing regarding pathogen reduction in blood products before transfusion.[12]
Babesia
- Babesiosis is caused by babesia, intracellular erythrocyte protozoa closely related to Plasmodium, with humans being an accidental host.
- TTI has been documented in at least 162 red cell component transfusion events.[14][49]
- Although the areas where the disease is endemic are limited, babesiosis is the most prevalent TTI in the United States.[50]
- Babesia microti is spread by the ixodid tick in the United States; North Midwest states and New England are the most commonly cited areas.
- Incubation and infectivity periods are prolonged at 1 to 6 weeks and 1 to 9 weeks, respectively.
- The disease is usually mild with fevers; however, presentation in the immunocompromised can result in disseminated intravascular coagulation, hemolysis, or multi-organ dysfunction.[14][49]
- NAT and serologic studies can assess transfusion risk, but cost-effectiveness models have shown varying results.[50]
Trypanosomiasis
- Trypanosomiasis cruzi, the organism responsible for Chagas disease, is endemic in South and Central America.
- Risk mitigation is managed similarly to malaria with antibody screening to detect prior exposure and/or geographic donor deferral.
- The use of pathogen inactivation can further reduce risk.[2]
Leishmania
- Intracellular macrophage/ monocyte protozoans cause leishmaniasis, with the sandfly as the vector.
- In the United States, several cases of TTIs have been reported.
- Given the pathogens reside in red blood cells, it is likely that leukocyte reduction significantly decreases transfusion transmission risk.
- Pathogen reduction technology and donor deferral based on travel history are the main risk mitigators.[12]
Transmissible spongiform encephalopathies (TSEs)
Also known as prion diseases, TSEs are fatal diseases affecting the neurologic system of mammals. Prions are not infectious per se; however, they are proteins that act as infectious particles, causing normal cellular isoforms to create disease-causing ones.[12]
Recognized for approximately 100 years, sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of human prion disease. Familial types are far less common and are due to mutations in prion-related protein genes.[2] TTI from sCJD is of little concern, and there have not been any documented human cases of transfusion transmission.[12]
Variant CJD (vCJD), from which there have been TTIs documented, was recognized as a new form of human prion disease in 1996 and was a result of the foodborne transmission of the prion of bovine spongiform encephalopathy (mad cow disease). There have been reports of 230 vCJD cases in 12 countries.[2]
The vector of the disease is unknown, but humans and cattle serve as reservoirs. There is an intravascular phase before symptoms, and widespread replication and deposition in lymphoreticular tissues follow, at least in animal experiments. The physiochemical characteristics likely allow the prion to survive in most storage conditions. Infection is followed by incubation of 5-15 years, but incubation with transfusion is faster at 5 to 8 years. Leukocyte reduction, nanofiltration, and affinity-based prion removal have been explored to decrease disease transfusion risk.[12]
Risks in Developing Countries
In high-income countries, the availability and safety of blood transfusion are often taken for granted. However, the safe blood supply in many parts of the world is far from reliable. Many hurdles exist, including social, cultural, and medical infrastructure, donor pool and recruitment, organization of the collection, blood testing, required clinical and laboratory skills for blood use, and disease prevalence, to name a few.
For example, in sub-Saharan Africa, which is characterized by many of these issues, the overall prevalence of HIV antibody is between 0.5 and 16%.; chronic hepatitis prevalence ranges between 5 to 25%; plasmodium species, such as malaria, is often in 16 to 55% of donor blood.
However, substantial efforts have been made to improve coverage and test sensitivity and quality. This international push has resulted in the number of countries screening for HBV and HCV to at least 95%. The national median prevalence for HBV and HCV reactive blood donations decreased between 2004 and 2011. Also, across Africa, there has been a reduction in HCV prevalence in chronically transfused patients, suggesting improvement on these fronts. Despite these improvements, the risk of blood donation during the window period of infection remains a possibility, and donor deferral to limit TTIs is not always practical, given the limited donor pool and high disease prevalence.
Maintaining a volunteer donor pool is often challenging given the complexity and expense of the collection teams, education programs, vehicles, and cold storage involved. As such, it was estimated by the World Health Organization (WHO) in 2002 that over 60% of blood in Africa originated from family, also known as replacement donors; this proportion is almost certainly higher in sub-Saharan Africa.
Many patients in developing countries also present late in their disease course, and urgent transfusion needs coupled with shortages of blood result in the possibility that patients may die before blood products can be acquired and prepared. Taken together, the WHO has identified four key objectives for blood services to ensure that blood is safe for transfusion:
- Establish a coordinated national blood transfusion service that can provide adequate and timely supplies of safe blood for all patients in need.
- Collect blood only from voluntary nonremunerated blood donors from low-risk populations, and use stringent donor selection procedures.
- Screen all blood for transfusion-transmissible infections, and have standardized procedures in place for grouping and compatibility testing.
- Reduce unnecessary transfusions through the appropriate clinical use of blood, including the use of intravenous replacement fluids and other simple alternatives to transfusion, wherever possible.”
Each of these objectives has its challenges when applied to developing countries; however, work is ongoing to ensure a safe blood supply on the global level.[51]
Cost
In the United States, it is the role of the Food and Drug Administration (FDA) to ensure patients who are to receive blood transfusions are protected by multiple overlapping safeguards, including donor screening, blood testing, donor deferral lists, and identification of problems and deficiencies with blood centers.
All of this carries with it significant monetary costs. For example, tests on blood products include those for HBV, HCV, HIV, HTLV, and syphilis, as well as recommended testing for WNV and Chagas disease; this has brought blood donor center costs regarding infectious disease testing from $30 in 1994 for one unit of red cells to $193 for one unit of leukocyte reduced red cells (Fatalities Reported to FDA Following Blood Collection and Transfusion Annual Summary for Fiscal Year 2014).
Clinical Challenges
Measuring Risk Due to Viral TTIs
Viral infections due to blood transfusion are exceedingly uncommon in developed countries, and screening questionnaires and NAT have worked to create the safest blood components transfused to date. But there remain additional challenges that must be tackled. For one, it is difficult to estimate the residual risk of viral TTIs, and risk estimates can now only be estimated statistically with mathematical models.
Additionally, the modeling estimates often overestimated the number of cases seen, suggesting both the success of advances in laboratory screening and the challenges in identifying TTIs from viruses in the clinical setting. There is also considerable lag time, assuming correctly identified, from transfusion to recognition of viral blood-borne pathogen infection; therefore, clinicians need to ascertain transfusion history in those contracting viral blood-borne pathogens for reporting purposes.[52]
The Window Period and Balancing Cost with Safety
With the newest NAT screening capabilities, the “window period,” or the time from infection to seroconversion, has been greatly reduced. For example, the window for HIV has decreased to 11 days and 8 to 10 days for HCV. This is a remarkable feat in modern transfusion medicine, further reducing the risk of viral TTIs.[53]
However, as discussed above, with each new screening assay/ safety initiative, there are costs involved and the possibility of diminishing returns given the very low current risks. It is a constant challenge for health services, blood banks, and governments to constantly balance the improvement in safety against the price incurred.[2]
For example, in low prevalence areas, the cost-effectiveness of NAT testing is uniformly poor. In other areas where the window period donation risk is judged high enough, such as the HIV window period in South Africa and Thailand, testing may be utilized.[54][55]
To further obfuscate the issue, these entities entrusted with transfusion safety must combat the risks constantly posed by emerging infections. Some have little or unknown clinical significance, even if associated with transfusion transmission.
Special Populations
It is no surprise that populations in need of frequent blood transfusions are at increased risk for TTIs. Special attention and a high index of suspicion for TTIs should be applied to patients with blood dyscrasia, such as sickle cell anemia, thalassemia, and hemophilia, or cancer patients undergoing chemotherapy, given their possible exposure to many donor units. Initial presentation of TTI may be more severe and affect the underlying treatment of ongoing disease compared to their immunocompetent counterparts.
COVID-19 Considerations
The COVID-19 pandemic has had several repercussions on maintaining a safe blood supply. These challenges have largely resulted in decreased supply attributed to additional screening procedures for donors. To combat this, deferral guidelines were eased in some regards, and elective surgeries were recommended to be postponed at times, pending the burden of the pandemic on the health care system as a whole.
The parity of blood supply and donation was also improved with stringent transfusion appropriate guidelines, blood-sparing strategies (i.e., cell salvage, hemodilution, and minimally invasive surgery), and pharmaceutical products. Luckily, respiratory viruses are not considered TTIs, and coronaviruses have not been reported as being transfusion permissible. Regardless, donors must be healthy before donation, meet existing screening measures, and report the development of symptoms of COVID-19 post-donation, which may result in the recall of donated units to maintain blood product safety.
Infectious Complications of Blood Transfusion