Continuing Education Activity

Transfusion-transmitted diseases pose a significant concern in the medical community, with nearly 119 million blood donations collected worldwide each year and approximately 5 million Americans requiring blood transfusions annually. Despite advancements in testing methodologies, donated blood products remain a potential source of bacterial, viral, and parasitic transmission. The most critical risk factor arises during the donor's window period when antibody and antigen levels are too low to be detected by current screening methods. Additionally, the risk of acquiring infection from blood products is influenced by the recipient's geographical location, immune status, and the country's capacity to screen for infectious agents.

This activity addresses the complexities surrounding transfusion-dependent diseases, emphasizing donor selection and adherence to stringent screening protocols to mitigate risks. This activity discusses the potential etiologies of transfusion-transmitted diseases, their epidemiology, clinical manifestations, management, and prevention, and how to differentiate them from other acute transfusion reactions. Additionally, this activity presents how the interprofessional healthcare team and regulatory bodies can implement best practices to ensure the safety of the blood supply and improve patient outcomes. 

Objectives:

• Apply current guidelines for screening blood products to prevent transfusion-transmitted diseases.

• Differentiate between various transfusion-transmitted pathogens and determine appropriate interventions.

• Implement evidence-based practices to improve the overall safety of blood transfusions.

• Collaborate with interdisciplinary team members to establish comprehensive protocols for transfusion safety.

Introduction

Annually, nearly 5 million Americans undergo blood transfusions for various medical conditions such as acute blood loss, surgery, hemophilia, or cancer.[1] In the US alone, approximately 29,000 red blood cell (RBC) units, 5,000 platelets, and 6,500 plasma units are utilized daily. While the risk of transfusion-transmitted diseases (TTD) is extremely low, it persists primarily due to "window-period" donations, where antibodies and antigens remain undetectable by current screening techniques. Furthermore, the blood product supply may be susceptible to contamination by unidentified human pathogens.

Blood products used in transfusions can carry bacterial, viral, and parasitic pathogens. Among these, the risk of transfusion-transmitted bacterial infections (TTBI) exceeds that of transfusion-transmitted viral infections, with platelet transfusion posing the highest risk of TTBI. Viral organisms commonly transmitted through blood transfusions include HIV, hepatitis C (HCV), hepatitis B (HBV), hepatitis A (HAV), West Nile virus (WNV), cytomegalovirus (CMV), severe acute respiratory syndrome coronavirus (SARS-CoV-1), human T-cell lymphotropic viruses (HTLV), Zika virus, and parvovirus B19.[2]

Prions responsible for Creutzfeldt-Jakob disease (CJD) and protozoa from the Plasmodium genus, which causes malaria, are additional potential pathogens. Ongoing enhancements in infectious disease assays, meticulous donor screening, and pathogen inactivation methods contribute to enhancing the safety of the blood supply. Persistent vigilance is crucial to address emerging pathogens and refine current screening practices.

Etiology

The etiology of TTBI typically involves the introduction of bacteria into the bloodstream through contaminated blood products during transfusion. Bacterial contamination can occur at various stages, including during blood collection, processing, storage, or transfusion. Common sources of bacterial contamination include skin flora, collection or storage equipment contamination, and improper handling procedures. The spectrum of pathogenic organisms varies based on the collected blood product.[3]

Bacterial Organisms

Blood collection banks typically store units of RBCs between 34 to 43 °F (1 to 6 °C), favoring the growth of gram-negative rods.[4] The most frequently reported bacterial organisms encountered in units of RBCs are Yersinia enterocolitica, notably associated with sepsis secondary to red blood cell transfusion. Other commonly reported organisms include Pseudomonas fluorescens, Enterobacter, Serratia, and Escherichia coli. However, Babesia microti has emerged as the most frequently associated organism with fatalities after RBC transfusion.[5]

Platelet products stored at room temperature, typically between 68 to 75 °F (20 to 24 °C), carry the highest risk of bacterial contamination among blood products.[6] Gram-positive bacteria are more commonly found in platelet products. The most prevalent bacterial pathogens isolated from platelet products are Streptococcus viridans, Streptococcus bovis, and beta-hemolytic streptococci with an incidence of 39% to 48%, coagulase-negative staphylococcus with an incidence of 21% to 24%, and Staphylococcus aureus with an incidence of 4% to 9%.[7]

Syphilis, caused by the bacterium Treponema pallidum, is primarily transmitted sexually but can be transmitted vertically from mother to fetus across the placenta or through blood transfusions. In blood transfusion-related cases, the risk of syphilis transmission has significantly decreased due to stringent screening protocols and improved testing methods.

Numerous methods exist for evaluating contamination in platelet products. However, some methods may not effectively detect contamination when tested immediately after collection, as sampling typically occurs at least 24 hours after collection.[8]

Other etiologies of TTD may involve viral or parasitic pathogens. Furthermore, emerging infectious agents and novel pathogens pose ongoing challenges to the safety of the blood supply, necessitating continuous surveillance and adaptation of screening protocols.

Viral Organisms

Hepatitis A: HAV is a distinct member of the family Picornaviridae and is characterized by a 27 to 32 nm spherical particle with cubic symmetry containing a linear 7.5 kb single-stranded RNA (ssRNA) genome.[9] HAV exhibits 1 serotype and multiple genotypes. The virus exists in the stool and blood of infected patients and is usually transmitted via the fecal-oral route.[10]  

Hepatitis B virus: HBV is a member of the hepadnavirus, characterized by a 3.2 kb double-stranded DNA (dsDNA) genome.[11] The virus comprises an outer envelope and an inner core. The outer envelope contains the hepatitis B surface antigen (HBsAg) and a surface protein detectable by blood tests. The inner core of the virus is a protein shell referred to as the hepatitis B core antigen (HBcAg), housing the hepatitis B virus DNA and enzymes used in viral replication.[12] HBV transmission occurs through various routes, including sexual activity, breastfeeding, blood products, organ transplantation, and percutaneous exposure.

Hepatitis C virus: HCV is a 60 nm spherical particle, enveloped member of the family Flaviviridae. It contains a 9.4 kb ssRNA genome.[13] The species of HCV are categorized into 6 genotypes, each with multiple subtypes, based on genetic differences among HCV isolates.[14] HCV transmission occurs through blood transfusions, percutaneous exposure, organ transplantation, and, rarely, through sexual activity.

Human immunodeficiency virus: A retrovirus that comprises 2 subtypes, HIV-1 is the most prevalent worldwide and the most common etiological agent of AIDS. HIV-2 is primarily found in West Africa.[15] HIV transmission occurs via sexual activity, percutaneous exposure, blood transfusions, and during the perinatal period.

Human T-lymphotropic virus: A human retrovirus well-known to cause adult T-cell leukemia, lymphoma, and HTLV-I-associated myelopathy (HAM) or tropical spastic paraparesis.[16][17] HTLV-I is primarily transmitted by breastfeeding. Spread via blood transfusion, sharing of needles, and sexual intercourse also occur.[17]  

West Nile virus: An enveloped ssRNA virus within the family Flaviviridae, WNV threatens many transfusion services worldwide.[18] Transmission among humans exists through mosquito bites, blood transfusion, intrauterine exposure, breastfeeding, and organ transplantation.[18] 

Cytomegalovirus: A member of the family Herpesvirus, CMV has a genome of linear dsDNA and contains a viral capsid of icosahedral symmetry and a viral envelope. Cytomegalovirus can be transmitted in utero, perinatally, and postnatally through close contact, blood transfusions, and organ transplantation. 

Zika virus: A flavivirus; transmission of Zika virus occurs via the bite of an infected mosquito, maternal-fetal transmission, sexual activity, transfusion of blood products, and organ transplantation.  

Severe acute respiratory syndrome coronavirus: A member of the family Coronaviridae, SARS-CoV-1 is a medium-sized enveloped positive-stranded RNA virus. SARS predominately spreads via droplets and fomites.

Parvovirus B19: A member of the family Parvoviridae, parvovirus B19 is a 5.6 kb, nonenveloped, ssDNA virus. The only known host for parvovirus B19 is humans. Parvovirus B19 transmission occurs through respiratory, vertical, or hematogenous spread.

Parasitic Organisms

Malaria: An infectious illness caused by parasites of the Plasmodium genus, malaria transmission occurs through bites of female Anopheles mosquitoes. Blood transfusion collected from asymptomatic or infected donors with a low parasite burden may transmit Plasmodium. Erythrocyte concentrate, fresh frozen plasma, cryoprecipitate, and platelet concentrate can all result in transfusion-transmitted malaria.[19] 

Trypanosoma cruzi: The pathogenic cause of Chagas disease, vector-borne transmission is the most likely transmission mode for this disease. Platelet transfusions pose a higher transmission risk than other blood components.[20] 

Babesiosis: Primarily transmitted through the bite of a tick, this protozoa of the genus Babesia can also be transmitted through blood transfusion and solid organ transplantation.  

Prion Diseases

Prions are abnormal proteins that cause central nervous system neurodegenerative diseases called transmissible spongiform encephalopathies like CJD. Prions exhibit a lengthy asymptomatic dormant period and resist typical sterilization methods. Currently, transfusion has only transmitted variant Creutzfeldt-Jakob disease (vCJD). Nevertheless, a theoretical risk exists that blood product transfusion could transmit other forms of CJD.

Epidemiology

Infectious causes currently account for less than 15% of all transfusion-related mortality.[21] Advancements in screening techniques and blood product processing have significantly reduced the incidence of transfusion-related infections, further enhancing the safety of transfusion medicine.

Bacterial Infection

The risk of contamination with bacterial pathogens is 1 in 5,000 for platelets and 1 in 30,000 for RBCs.[22] Despite this prevalence, bacterial contamination may not always result in clinical illness in recipients due to insufficient bacterial inocula or blood contamination during testing. Nevertheless, immunocompromised patients remain the most vulnerable population.[23] 

The World Health Organization estimates that nearly 7.1 million adults between the ages of 15 and 49 acquired syphilis in 2020. The transmission of syphilis via blood products is rare because refrigeration destroys the causal agent, T. pallidum, after 24 to 48 hours. 

Viral Infection

Human immunodeficiency virus: The estimated number of humans living with HIV and AIDS is 36.7 million worldwide as of 2016. The risk of acquiring HIV infection from a blood transfusion is 1 in 1 to 2 million units in the US, 1 in 8 to 10 million units in Canada, and 1 in 1 to 5 million units in parts of Europe.[24][25] Risk factors for acquiring HIV infection include engaging in unsafe sexual practices, particularly among men who have sex with men, the use of intravenous drugs, and receiving blood products contaminated with the virus.[26][27]

Hepatitis: Nearly 240 million individuals worldwide are chronically infected with HBV, leading to over deaths annually from complications like cirrhosis and hepatocellular carcinoma. Additionally, approximately 150 million individuals globally have chronic HCV infection, with nearly 700,000 deaths occurring each year due to liver disease.[13] HBV and HBC infections are widespread, with the highest incidence observed among patients undergoing hemodialysis, those with HIV infection, and individuals with coagulation disorders. The risk of acquiring hepatitis B from a blood transfusion is 1 in 1 to 1.5 million. The risk of acquiring hepatitis C is 1 in 2 to 2.6 million.[28][29]

Human T-lymphotropic virus I: Approximately 15 million people worldwide live with chronic HTLV-I infection. The risk of HTLV-I transmission through a blood transfusion is 1 in 2.7 million.[30]

West Nile virus: Numerous pathogenic isolates of WNV exist, but the two major lineages, L1 and L2, are responsible for most outbreaks. L1 strains predominantly cause infections in North America, Central America, South America, Africa, and the Middle East, while L2 predominates in sub-Saharan Africa, Madagascar, and Eastern Europe. An independent L2 strain, identified in southern Russia in 2004, led to neuroinvasive West Nile disease outbreaks in Romania starting in 2010. The virus primarily circulates between wild birds and mosquitoes. Approximately 1 in 150 WNV infections result in severe neurologic illness, with older individuals being mainly affected.

Cytomegalovirus: The seroprevalence rates of CMV vary between 40% and 100% worldwide. The presence of CMV antibodies increases with age. The estimated risk of contracting CMV is 0.38% per unit of blood. 

Zika virus: Approximately 20% to 25% of patients infected with Zika virus develop symptomatic infection. Although no confirmed cases of Zika virus transmission via blood transfusion have been reported, there have been confirmed cases of transmission via platelet transfusion. While 1 study suggests that women and patients younger than 40 are more likely to develop symptomatic infections, age and sex do not appear to influence overall infection rates. 

Severe acute respiratory syndrome coronavirus: No cases of SARS-CoV-1 have been reported since 2004, but the possibility of its reemergence remains. The outbreak in 2003 involved 8096 cases and resulted in 774 deaths, yielding an overall case-fatality rate of 9% to 12%. 

Parvovirus B19: Parvovirus B19 is prevalent worldwide, with infections peaking in the US in late winter and early summer. Between 50% and 80% of adults in the US show evidence of previous parvovirus B19 infection. Recipients receiving blood products created from large pools have a higher risk of acquiring parvovirus than recipients who receive blood products from a single donor.

Parasitic Infection

Malaria: More than 95% of the world's malaria cases are concentrated in the African region. According to the World Health Organization's 2021 report, there are 247 million malaria cases worldwide.[31] The risk of acquiring malaria through transfusion varies based on the incidence and prevalence of the disease in a particular area. In the US, the risk of malaria transmission through blood products is less than 1 per 1 million units of blood. 

Chagas disease: A prevailing public health issue in Latin America, Chagas disease affects approximately 10 million individuals globally.[31] Previously, platelet transfusion carried a 13% risk of Chagas disease. However, since the implementation of mandated screening in the US, no new cases have been reported since 2007.

Babesiosis: Babesia microtia is the primary species causing human disease in the US, with the highest concentration in the northeastern and upper Midwest portions. In Europe, B divergens predominates, while in Asia, B venatorum, B microti, B crassa-like organisms, and B motasi-like organisms are responsible for disease. Transfusion-transmitted babesiosis most frequently occurs between June and November. To date, more than 250 transfusion-transmitted cases of babesiosis have been reported. Risk factors for developing babesiosis include immunosuppression, travel to endemic areas, and having a blood transfusion within the previous 6 months. 

History and Physical

Recognizing TTBI can be challenging due to similarities with other transfusion reactions or underlying medical conditions. Patients may exhibit symptoms during or within 72 hours of the transfusion, influenced by the inoculum's size and virulence. The clinical presentation of TTBI varies widely, and clinicians must uphold a heightened clinical suspicion. Affected individuals may be asymptomatic or experience septic shock. Indications of a septic transfusion reaction include common clinical signs:

• Temperature >102.2 °F (39 °C)
• A temperature increase of >3.6 °F (2 °C) within a few hours following transfusion
• Rigors
• Heart rate >120 bpm
• A heart rate increase of ≥40 bpm within a few hours following transfusion
• Rise or fall in systolic blood pressure >30 mm Hg

Nausea, vomiting, abdominal pain, back pain, and hypothermia are additional potential symptoms.

Syphilis

Syphilis, when sexually transmitted, manifests as a painless ulcer around the genital, oral, or anal areas. If left untreated, the infection progresses to the secondary stage within 3 to 6 weeks, characterized by a rash on the palms and soles, along with symptoms like lymphadenopathy, fever, weight loss, sore throat, patchy hair loss, headache, and muscle aches. The latent stage follows, with no apparent signs or symptoms. Tertiary syphilis, occurring 10 to 30 years post-infection, can involve the heart, blood vessels, brain, nervous system, eyes, and ears, though most individuals do not develop this stage.

Viral Infection

Hepatitis B 

Subclinical disease occurs in 70% of patients with an acute HBV infection, while the remaining 30% will progress to icteric hepatitis. Fulminant hepatic failure is rare, developing in 0.1% to 0.5% of patients. The incubation period for HBV is typically 1 to 4 months. Alongside icteric hepatitis, individuals may experience additional symptoms such as fatigue, myalgias, nausea, vomiting, jaundice, diarrhea, right upper quadrant pain, dark urine, and clay-colored stools.

Hepatitis C

The majority of patients experiencing an acute HCV infection remain asymptomatic. When symptomatic, affected patients manifest symptoms between 2 and 26 weeks after exposure. The hallmark symptoms are fatigue, low-grade fever, chills, loss of appetite, pruritus, myalgias, mood disturbances, joint pain, dyspepsia, confusion, clay-colored stools, and dark urine.

Human immunodeficiency virus

Primary HIV infection, marked by various symptoms, typically emerges 4 to 10 weeks following exposure.[26] Shallow, sharply demarcated ulcerations with white bases surrounded by a thin area of erythema located on the oral mucosa, anus, penis, or esophagus are characteristic findings associated with an acute HIV infection. The hallmark skin rash consists of 5 to 10-mm red macules most commonly located on the upper chest, collar area, and face. The remaining symptoms may include fever, joint pain, headache, sore throat, fatigue, diarrhea, weight loss, and lymphadenopathy affecting the axillary, cervical, and occipital nodes. The progression of chronic HIV disease can lead to AIDS, which carries a high mortality rate attributed to opportunistic infections and malignant tumors.[26]

Human T lymphotropic virus I 

The majority of individuals with HTLV-I will not exhibit symptoms, leading to disease manifestation in approximately 5% of infected patients.[32][33] HTLV-I infection is known to cause adult T-cell leukemia-lymphoma and HTLV-I-associated myelopathy (HAM) or tropical spastic paraparesis.

• Adult T-cell leukemia-lymphoma: Adult T-cell leukemia-lymphoma, a lymphoproliferative disorder, manifests in various forms listed in decreasing prevalence: acute, lymphomatous, chronic, and smoldering. The acute form is characterized by skin nodules, ulcers, a generalized papular rash, lytic bone lesions, hypercalcemia, and pulmonary infiltrates. The lymphomatous form presents lymphadenopathy, hepatosplenomegaly, and skin lesions. 

• HTLV-I-associated myelopathy or tropical spastic paraparesis: Symptoms of HAM can appear anytime between 4 months and 30 years after the initial infection. Affected patients may present with the following symptoms and physical examination findings:
• Gait difficulties
• Low back pain
• Unexplained falls
• Constipation
• Urinary urgency and incontinence
• Numbness or pain in the lower extremities
• Patellar hyperreflexia
• Bilateral ankle clonus
• Spasticity in both lower extremities
• Loss of vibratory sense [32][33]

West Nile virus

Between 2 and 14 days after infection, 20% to 40% of patients with WNV experience symptomatic presentation. The infection may manifest with various signs and symptoms, including fever, headache, body aches, skin rash, swollen lymph nodes, stiff neck, sleepiness, coma, seizures, and eye pain. In addition, affected patients may develop neuroinvasive diseases like meningitis, encephalitis, flaccid paralysis, or a combination of these conditions. Following the acute phase, many patients experience residual symptoms such as fatigue, memory impairment, weakness, headache, and difficulties with balance.

Cytomegalovirus

During an acute infection, many patients may remain asymptomatic. Congenital CMV infections have the potential to cause complications such as sensorineural hearing loss, hepatosplenomegaly, microcephaly, petechiae, seizures, and intracranial calcification. Premature infants and those with compromised immune systems are particularly susceptible to developing complications like myocarditis, retinitis, encephalitis, or encephalopathy. If symptoms manifest in immunocompetent patients, they might experience prolonged fevers and lethargy, resembling a mononucleosis-type illness associated with the Epstein-Barr virus (EBV). Like EBV, CMV enters a latent phase after resolving the acute infection. Notably, patients with a CMV-related illness are less likely to exhibit pharyngitis, splenomegaly, and lymphadenopathy encountered with EBV.

Zika virus

The Zika virus has an incubation period ranging from 2 to 14 days. Symptoms include the sudden onset of low-grade fever, a pruritic rash affecting the face, trunk, extremities, palms, and soles, arthralgia predominantly in the small joints of the hands and feet, and nonpurulent conjunctivitis. Myalgia, retro-orbital pain, and asthenia are also possible symptoms. Certain patients may report recurring symptoms without a new acute infection.

Severe acute respiratory syndrome coronavirus: 

SARS-CoV-1 is a unique respiratory virus in that the prodrome lasts 3 to 7 days. Patients experience fever, myalgias, and malaise but no respiratory symptoms during the prodrome. A dry, nonproductive cough begins at the end of the prodrome. Affected patients may progress to respiratory failure. The most common symptoms associated with SARS are fever, cough, chills or rigors, myalgias, dyspnea, and headache.

Parvovirus B19:

Nearly 25% of infected patients will remain completely asymptomatic, though 50% will experience malaise, muscle pain, and fever that lasts approximately 3 days. The remaining 25% present will develop either the rash of erythema infectiosum or arthralgias. Children most often develop erythema infectiosum, and adults frequently develop arthralgias. Due to the destruction of erythrocyte progenitor cells, a decrease or absence of reticulocyte count is the hallmark laboratory finding associated with parvovirus B19 infection.

Parasitic Infection

Malaria

Symptoms of malaria typically develop between 12 and 35 days after exposure. Some may become symptomatic as early as 7 days after exposure. Classically, infected patients present with paroxysms of high fevers, profuse sweating, rigors, and headache. Febrile seizures may occur in children. Gastrointestinal symptoms may include nausea, vomiting, abdominal pain, diarrhea, and bloody stools. Lethargy and pallor due to anemia and splenomegaly are classic physical examination findings. 

Chagas disease

The incubation period is generally 1 to 2 weeks. Infected patients develop 2 phases, acute and chronic.[34] The acute phase lasts approximately 8 to 12 weeks. Most patients are asymptomatic or have mild symptoms like malaise, fever, and anorexia. Less common findings during the acute phase are a chagoma, myocarditis, pericardial effusion, or meningoencephalitis.

Patients who do not receive proper treatment enter the chronic phase that lasts the remainder of their life. Most patients develop the indeterminate or asymptomatic form during the chronic phase's first 10 to 30 years. However, 20% to 40% will develop the determinant form involving the cardiac and gastrointestinal systems. Potential symptoms associated with the chronic phase of the Chagas disease are:

• Arrhythmias 
• ECG changes 
• Syncope 
• Palpitations 
• Chronic abdominal pain 
• Chronic constipation 
• Dilated colon  
• Shortness of breath 
• Cardiomyopathy 
• Congestive heart failure  
• Emphysema 
• Stroke  
• Sudden death

Babesiosis

The incubation period after a tick bite is 1 to 4 weeks. Following the transfusion of blood products, the incubation period is 3 to 7 weeks but may be as long as 6 months. Many patients remain asymptomatic. Fever, fatigue, malaise, myalgias, and dry cough are common presenting symptoms. Immunocompromised patients are at risk for progressing to severe disease manifesting as acute respiratory distress syndrome, congestive heart failure, renal failure, disseminated intravascular coagulation, shock, splenic rupture, and coma. Anemia, thrombocytopenia, elevated lactate dehydrogenase, elevated creatinine, and elevated liver enzymes are potential lab abnormalities encountered in patients with babesiosis. 

Evaluation

Thorough evaluation of potential donors and rigorous testing of blood products are essential to safeguard the blood supply's integrity. Donation centers administer a comprehensive donor questionnaire to assess any factors that could compromise the safety of donated blood. This questionnaire covers various aspects, including the history of intravenous drug use, recent travel, current illness or antibiotic usage, HIV or hepatitis infection, as well as vaccine history. In addition to donor screening, blood products undergo screening tests for:

• HBV and HCV
• HIV-1 and HIV-2
• HTLV-I and HTLV-II
• Zika virus
• West Nile virus
• T pallidum
• T cruzi
• Babesia in states where testing is required based on FDA guidance 

Bacterial Testing

Most donation centers perform bacterial cultures on platelet products obtained from 1 donor. The center releases the platelets if the cultures reveal no growth after 24 to 36 hours. Platelets collected from multiple donors may undergo screening for bacterial contamination by hospital transfusion services. 

Screening for syphilis utilizes both treponemal and nontreponemal assays. Nontreponemal tests like the rapid plasma reagin (RPR) test and the venereal disease research laboratory (VDRL) test detect antibodies directed against an antigen called cardiolipin present in patients with active syphilis. The RPR and VDRL can remain positive for 1 to 2 years after treatment in previously infected patients. 

Available treponemal assays are enzyme immunoassays (EIA), fluorescent treponemal antibody absorbed assays (FTA-ABS), Treponema pallidum microhemagglutination assays (MHA-TPA), and Treponema pallidum particle agglutination assays (TP-PA). These assays test for antibodies to antigens that are specific to treponemes. Treponemal assays will remain positive throughout a patient's life regardless of treatment. 

Viral Testing

Donor blood products in most developed countries undergo screening for HBV through HBsAg tests. To address potential challenges in detecting low levels of HBsAg in patients who are chronic carriers of HBV, donation centers may also employ assays to identify anti-HBc. Anti-HBc antibodies emerge early in the infection and remain positive. HBV nucleic acid testing (NAT) becomes crucial for detecting HBV DNA in individuals with chronic infection, undetectable levels of HBsAg, and indeterminate levels of anti-HBc.[11] 

HBsAg establishes a detection window spanning 3 to 40 days, whereas NAT reduces this window to 3 to 4 weeks. Assays targeting anti-HBc may yield positive results within 1 week of infection but are associated with a false positive rate of 1%.

Donation centers screen for HCV using tests for anti-HCV antibodies and NAT detection of HCV RNA. In the US, the standard of care for detecting HCV infection involves mini-pool NAT (MP NAT). This method tests small aliquots from donations of 4 to 16 donors as a single sample.[35] The current method's window period is 1 to 2 weeks. MP NAT also detects HIV RNA and has replaced p24 antigen testing of donor blood. The window period for HIV using MP NAT is approximately 11 days.

NAT is the screening method of choice for WNV and Zika virus. Donation centers utilize individual NAT testing for WNV instead of pooled testing because of the high risk of infection from patients with low-level viremia. Antibody detection assays currently detect CMV, HTLV-I, and HTLV-II.[36] 

Parasite Testing

In Brazilian blood banks, screening for P falciparum relies on examining blood-thick smears. However, a study suggests that employing molecular biology techniques could enhance the efficiency of malaria detection among blood donors. The molecular diagnostic method, utilizing real-time PCR based on mitochondrial DNA (mt-qPCR), has been refined to detect P falciparum, P vivax, and P malariae. The mt-qPCR test demonstrates high analytic sensitivity, proving efficient and effective in identifying potentially infected donors. Incorporation of mt-qPCR testing into the routine screening of asymptomatic carriers could help prevent transfusion-transmitted malaria in blood banks.[19]  

The prevalence of inconclusive serology in blood banks and the absence of a universally accepted gold standard test for Chagas disease prompted an investigation into the effectiveness of the blood culture and various commercial tests, including enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence, and hemagglutination assay. These methods proved valuable in detecting anti-Trypanosoma cruzi antibodies. When employed collectively, they exhibited a 100% probability of accurately predicting the absence of infection.[37] The US uses ELISA-based testing, and endemic countries use serologic testing and deferral of positive donors.

Treatment / Management

Donation centers and hospitals are responsible for collecting blood products using proper sterile techniques, participating in lookback programs, implementing suitable pathogen inactivation methods, and deferring donors who may pose a potential risk to the blood supply's safety. Additionally, regular training and education of staff regarding blood safety protocols are crucial for maintaining the integrity of the blood supply.

Bacterial Contamination

Donors must be healthy, without active infection or antibiotic usage. Phlebotomy procedures should include timed cleansing with chlorhexidine to prevent skin flora transfer. To minimize the risk of introducing skin flora, the initial 15 to 30 mL of blood undergoes testing for blood bank and infectious diseases.[4] 

Distinguishing between septic and other transfusion reactions can be challenging. If a patient develops symptoms, clinicians should stop the transfusion and send the blood product for a Gram stain and culture. Additionally, they should repeat the type and cross-match and collect blood for the patient's Coombs test and bacterial culture. Initiation of empiric antibiotics and any other necessary treatments like fluid resuscitation should be promptly undertaken.

Lookback Programs

Lookback programs are designed to alert recipients who have received blood products from a donor who initially tested negative for an infectious agent but has since tested positive. The primary goal of these programs is to halt the potential spread of the infectious agent and offer affected recipients an opportunity to seek medical evaluation and care.

For instance, confirmatory testing is conducted at the donation center if a donor's blood tests positive for HCV. If confirmed positive, the center discards the blood product and informs the hospital where the donor previously donated blood. The hospital is responsible for identifying any patients who may have received blood from that donor in the past. Subsequently, the donation center notifies the recipient's current healthcare provider or the clinician who initially requested the blood product. It is then the clinician's responsibility to inform the patient and arrange for the recommended testing.

Pathogen Inactivation

Pathogen inactivation serves to inactivate most clinically relevant viruses, bacteria, and protozoa, which helps to eliminate the residual risk of infection during the window period when donor screening tests cannot detect transfusion-relevant pathogens.[38] Additionally, pathogen inactivation techniques enhance the safety and efficacy of blood transfusion practices.

Solvent-Detergent method

This method disrupts membranes of lipid-enveloped viruses like HIV, HTLV, EBV, HBV, and HCV. The solvent-detergent method is not effective against HAV, parvovirus, or prions. In the US, clinicians tend to avoid this method because it causes the loss of protein S, antitrypsin, and antiplasmin during the removal of the solvent-detergent, leading to some fatalities. Nevertheless, certain regions of Europe still utilize this technique.[39]

Methylene blue

Methylene blue, used in Europe to eliminate viruses, attaches to cellular elements and, when exposed to light, becomes active and destroys the wall where it has attached. Methylene blue is not effective against intracellular organisms or prions.[39]

Synthetic Psoralen

Synthetic psoralen stops the multiplication of nearly all currently screened for pathogens. After exposure to ultraviolet (UV) light, synthetic psoralen forms cross-links in the nucleic acid chains. Synthetic psoralen does decrease platelet activity, requiring more frequent platelet transfusions. [39]

Riboflavin

In addition to UV light, riboflavin can inactivate pathogens in platelets and plasma without affecting the coagulant and anticoagulant properties. Because riboflavin is a natural product, it does not require removal at the end of the process.[39] 

Leukodepletion

Given the high prevalence of CMV-positive donors in the general population, CMV-negative blood products may be challenging to find. CMV resides within the white blood cells, and donation centers filter leukocytes from the RBCs to prevent CMV transmission to immunocompromised patients and infants. The data is unclear if filtering leukocytes from RBCs is as effective as transfusing CMV-negative blood products.[39]  

Heat pasteurization

Heat pasteurization entails treating therapeutic plasma proteins such as human albumin, coagulation factors, immunoglobulins, and enzyme inhibitors at 60 °C for 10 hours to deactivate blood-borne viruses. This method effectively reduces the risk of TTDs while preserving the therapeutic properties of the plasma proteins.

Nanofiltration

Nanofiltration involves filtering protein solutions through membranes featuring nanometric-sized pores. These membranes serve to retain a variety of viruses.

Deferral of Donation

"Donation centers permanently defer donors with a history of HIV, AIDS, hepatitis, Creutzfeldt-Jakob Disease (CJD), a dura mater transplant, Chagas Disease, or leishmaniasis. For individuals receiving medication to prevent HIV infection, the deferral period is 2 years after the last injection. Donors detained or incarcerated in a facility for more than 72 hours must wait 12 months before donating."

The waiting period for donation is 3 months after receiving a blood transfusion from another donor, engaging in sexual contact with a person who has hepatitis, experiencing a nonsterile needle stick, exposure to someone else's blood, last intravenous drug use or the last dose of any oral medications taken to prevent HIV infection. Donors with a history of malaria or residents of endemic countries may not donate for 3 years. Travelers to endemic areas may not donate for 1 year from return.[40]

Differential Diagnosis

The primary challenge with TTD is distinguishing TTBI from other transfusion reactions. Several other transfusion reactions begin with fever and chills. The following list includes the differential diagnoses of TTD: 

• Febrile nonhemolytic transfusion reaction: Noted fever and chills without additional systemic symptoms. Because the development of additional systemic symptoms is unknown at the onset of the fever, febrile nonhemolytic transfusion reaction is a diagnosis of exclusion.

• Acute hemolytic transfusion reaction: Involves the acute intravascular hemolysis of transfused red blood cells, often due to ABO incompatibility. The classic symptoms are fever, chills, flank pain, and oozing from intravenous sites.

• Transfusion-related acute lung injury: Presents with Fever, chills, and respiratory distress due to anti-HLA or anti-neutrophil antibodies from the donor blood activating the recipient's neutrophils.

• Hypotensive transfusion reactions: Present as a decrease in systolic blood pressure of 30 mm Hg or more without any other identifiable cause. The patient's blood pressure returns to normal on discontinuation of the transfusion. 

• Preexisting infection

• Transfusion-associated graft versus host disease

Prognosis

The prognosis of TTD depends on the specific pathogen, the availability and quality of healthcare in the recipient's country, and the recipient's immune status. Deaths due to TTBI are more likely with gram-negative organisms. Recent data reveals 2 to 3 deaths per year in the US due to TTBI.

Between 12% and 20% of patients with chronic HBV progress to cirrhosis. Among those who develop cirrhosis, approximately 20% experience hepatic decompensation, and 6% to 15% develop hepatocellular carcinoma. Patients with compensated cirrhosis have a survival rate of 85% at 5 years. Those with decompensated cirrhosis have a 14% to 35% survival at 5 years.[41]

Between 50% to 85% of patients infected with HCV develop chronic infection. Over the following 20 to 30 years, 5%  to 30% progress to cirrhosis. The estimated annual death toll from HCV in the US is 8000 to 13,000.

Without antiretroviral therapy, the average life expectancy after HIV infection is 12 to 18 months. Initiation of antiretroviral therapy can lead to a near-normal lifespan.

Serious adverse outcomes associated with WNV occur primarily in patients who develop neuroinvasive disease. The estimated mortality rates are 2% in patients with meningitis, 14% in patients with encephalitis, and 13% in those with acute flaccid paralysis.[42] Malaria infection carries a favorable prognosis if appropriately treated. Nonetheless, over 600,000 people die from malaria each year, with most being children under the age of 5 in Africa. 

Survival rates for adult T-cell leukemia-lymphoma vary based on the form. The acute form has a median survival rate of approximately 6 months. On the other hand, the chronic form has a median survival of 2 years, and the smoldering form extends up to 5 years.

Mortality associated with chronic Chagas disease is almost exclusively related to cardiovascular involvement. The annual all-cause mortality rate is 7.9%, and the yearly cardiovascular death rate is 6.3%.  

Complications

Complications of TTD are specific to the transmitted pathogen. These are broken down as follows:

West Nile Virus

• Chorioretinitis
• Retinal hemorrhages
• Vitreitis
• Rhabdomyolysis
• Fatal hemorrhagic fever with multiple organ failure and palpable purpura 
• Hepatitis and pancreatitis
• Central diabetes insipidus
• Myocarditis
• Myositis
• Orchitis
• Brachial plexopathy
• Demyelinating neuropathy
• Motor axonopathy
• Axonal polyneuropathy
• Myasthenia gravis
• Acute transverse myelitis
• Symptoms similar to Guillain-Barré syndrome [43][44][45]

HIV 

• Opportunistic infections  
• Malignancy
• Progression to AIDS
• Death

Hepatitis B and C

• Chronic hepatitis  
• Liver failure   
• Cirrhosis    
• Hepatocellular carcinoma
• Variceal hemorrhage
• Encephalopathy
• Death

Cytomegalovirus

• Congenital CMV
• Rejection of transplanted organs
• Enteritis
• Colitis
• Hepatitis
• Nephritis
• Pneumonitis
• Meningitis
• Encephalitis
• Retinitis

Syphilis

• Aortitis
• Gummatous disease
• General paresis
• Tabes dorsalis
• Meningitis

Zika Virus

• Guillain-Barré syndrome
• Encephalitis
• Transverse myelitis
• Encephalomyelitis
• Meningoencephalitis
• Chronic inflammatory demyelinating polyneuropathy
• Brain ischemia
• Neuropsychiatric and cognitive symptoms [46][47][48]

Chagas disease

• Muscle atrophy
• Heart failure 
• Megaesophagus
• Megacolon
• Arrhythmias
• Thromboembolism
• Left ventricular wall motion abnormalities
• Aspiration
• Esophageal fistulas
• Esophageal ulcerations
• Esophageal perforation
• Esophageal bleeding
• Hypertrophy of the salivary glands [49]

Malaria

• Acute respiratory distress syndrome
• Seizures
• Coma
• Severe anemia
• Coagulopathies
• Hypoglycemia
• Pulmonary edema  
• Multiple organ failure 
• Anemia
• Death [50]

Babesiosis

• Acute respiratory distress syndrome
• Congestive heart failure
• Severe anemia
• Renal failure
• Coma
• Splenic rupture
• Death
• Disseminated intravascular coagulation

Deterrence and Patient Education

While the US blood supply is currently regarded as highly safe, there remains a potential risk of transmitting blood-borne pathogens during transfusion. TTDs can be caused by various organisms, including bacteria, viruses, prions, and parasites. Rigorous measures, such as standard donor screening questionnaires and laboratory tests, are implemented to minimize this risk. Furthermore, using Pathogen Reduction Technology following blood collection provides additional protection against transfusion-transmitted diseases. 

Parasitic infections transmitted through transfusion are rare but include diseases such as babesiosis, Chagas Disease, leishmaniasis, and malaria. Donation centers question donors about recent travel to assess the risk of transmitting specific infections. Viral diseases, including HAV, HBV, HCV, HIV, HTLV, WNV, and Zika Virus, can be transmitted through transfusion. However, the risk of transfusion-transmitted viral diseases is extremely low due to rigorous blood supply testing. Prion diseases, such as vCJD, are rare neurodegenerative disorders also transmitted by blood transfusion. The risk of acquiring vCJD from transfusion is uncertain, and preventative measures are in place to monitor and mitigate potential risks.

Patients should be informed about the risks associated with blood transfusion, participate in screening processes, and adhere to guidelines provided by healthcare professionals. Blood donors are subject to strict eligibility criteria and deferral periods to prevent potential transmission of infectious agents. A complete list of donor eligibility criteria is available on the Red Cross' website at https://www.redcrossblood.org/donate-blood/how-to-donate/eligibility-requirements/eligibility-criteria-alphabetical.html. 

Pearls and Other Issues

 Key facts to keep in mind about TTDs are as follows:

• Transfusion-transmitted leishmaniasis is a concern in endemic regions. Donors should be tested for leishmaniasis using an immunofluorescent antibody, PCR, ELISA, and rapid test. Blood banks should be aware of the threat that imposes leishmania-contaminated blood and should routinely include a test to diagnose this infection.[51]

• Anaplasma phagocytophilum and Ehrlichia bacteria, resulting in human granulocytic anaplasmosis (HGA) and Ehrlichiosis, respectively, are tick-borne illnesses and present with fever, chills, myalgias, and headache symptoms. Patients with HGA will have polymorphonuclear leukocytes containing morulae in the peripheral smear. Samples from the recipient may test positive by PCR for Anaplasma phagocytophilum.[52] 

• Zika virus exposure during pregnancy can cause congenital microcephaly. Pregnant women should avoid travel to areas of Zika transmission below 6500 ft. 

• Transfusion of blood products may also transmit yellow fever and dengue fever. Mosquitos transmit both infections. Nearly 400 million people a year become infected with dengue fever annually in the tropics and subtropics of Africa and South America. Affected patients may experience mild illness or progress to severe liver disease with bleeding and jaundice. A vaccine for yellow fever exists.

• Chikungunya virus transmission may also occur. Chikungunya spreads typically via mosquito bites throughout Africa, Asia, Europe, the Indian and Pacific Oceans, and the Caribbean. Typical symptoms are fever and joint pain.

• Prompt diagnosis and management are essential if a TTD is suspected, which may involve discontinuing the transfusion, performing relevant diagnostic tests, and providing appropriate supportive care. 

   

   

   

   

   

   

   

   

   

Enhancing Healthcare Team Outcomes

Blood transfusions, crucial in medical interventions, can potentially transmit various blood-borne pathogens. Almost 5 million Americans undergo blood transfusions yearly for various medical requirements. Despite the minimal risk, TTDs persist due to donations made during the window period and the potential contamination of blood products.

Bacterial infections, particularly in platelet transfusions, pose a higher risk than viral infections. Common viral organisms transmitted include HIV, HCV, HBV, WNV, CMV, and others. Ongoing advancements in screening, donor vigilance, and pathogen inactivation enhance blood supply safety. Rigorous donor evaluation and comprehensive testing protocols, encompassing bacterial, viral, and parasitic screenings, help ensure the safety of the blood supply. Vigilance programs, lookback initiatives, and pathogen inactivation techniques further contribute to comprehensive transfusion safety.

Healthcare professionals must discuss skills, strategy, interprofessional communication, and care coordination by physicians, advanced practitioners, nurses, pharmacists, and other health professionals to enhance patient-centered care, outcomes, patient safety, and team performance related to TTDs