Transfusion-Transmitted Diseases

Hepatitis B

HBV is a deoxyribonucleic acid (DNA) virus in the family Hepadnaviridae . The infectious virion is occasionally referred to as the Dane particle and has surface and core components, surface antigen (HBsAg) and core antigen (HBcAg), respectively. Epitopes on the viral surface provide a basis for epidemiologic studies and consist of the HBsAg “a,” d/y, and w/r determinants. However, this approach is being replaced by genotyping and DNA sequencing methods. Recombinant vaccines containing the “a” determinant confer protective immunity to a high proportion of vaccinees and are dramatically altering the incidence and prevalence of HBV infection in the general population where they are in wide use and consequently also impact the frequency of HBV infection in the donor population.

The average incubation period (the time from infection to liver enzyme elevation and symptomatic hepatitis) is 59 days (range, 5 to 12 weeks) but may be as long as 6 months. Symptoms, which occur in 30% to 50% of infected persons aged 5 years and older, include fatigue, anorexia, nausea, vomiting, jaundice, dark urine, light stools, arthralgias, rashes, vasculitis, and glomerulonephritis. The risk for progression to chronic infection is inversely related to age at infection. HBV infection becomes chronic in more than 90% of infants, 25% to 50% of children 1 to 5 years of age, and fewer than 5% of older children and adults. Approximately 5% of the US population has serologic evidence of prior HBV infection (antibodies against HBcAg [anti-HBc] reactive). From the mid-1980s with increasing immunization in early childhood, the incidence of acute HBV infection has decreased. In 2017, 46 states reported over 3400 cases of acute HBV to the US Centers for Disease Control and Prevention (CDC), or 1.1 case per 100,000 population. Due to underreporting and asymptomatic cases that are not diagnosed and reported, estimates of the actual number of acute cases in 2017 is over 22,000. An additional 13,300 cases of chronic HBV cases were reported and approximately 862,000 people are estimated to be living with chronic HBV infection. Approximately 1700 deaths occurred in 2017 resulting from hepatitis B and its complications.

Based largely on data from parenteral exposures of health care workers, HBV is 100 times more infectious than human immunodeficiency virus (HIV) and 10 times more infectious than HCV. The predominant mode of transmission to adults and adolescents is through sexual contact. Forty percent have infected partners, 15% are males having sex with other males, injecting drug users account for 14% of cases, and one-third have no identifiable risk. A recent study of risk factors in blood donors found to be infected with HBV found that of 292 infected donors surveyed, the characteristics most frequently associated with infection were living abroad or having immigrated to the United States (51% vs. controls at 6%), a family member infected with hepatitis (15% vs. 2%), having been in a jail or detention for 3 nights or more (19% vs. 5%), and having taken illegal drugs (20% vs. 12%).

HBsAg is detectable in blood approximately 4 weeks (30 to 60 days) after infection. Subsequently, immunoglobulin M (IgM) anti-HBc antibodies appear coincident with symptom onset. High viral titers present at that time decline subsequently. HBsAg persists transiently in acute infections for up to 4 months (average 63 days). More recent data using extremely sensitive HBsAg assays for blood donation screening show the mean period of HBsAg duration to be 43 days. Antibodies against HBsAg (anti-HBs) develop subsequently and are generally thought to protect against reinfection although recent studies on blood donors have identified a few breakthrough cases of infection. These cases were mainly caused by HBV genotypes differing from that of the vaccine strain and were mild and self-limited. Such donations were not detected by HBsAg blood donation screening but required more sensitive HBV DNA screening.

Some anti-HBc–positive and HBsAg-negative individuals have circulating HBV DNA, and this pattern defines so-called occult HBV infection (OBI). In rare cases, OBI may be accompanied by anti-HBs, usually at levels below 200 mIU per mL. Donors with OBI may transmit HBV via blood transfusion, but the frequency of such infection is low, and seems to be absent if anti-HBs are present. Although anti-HBs usually confers immunity to reinfection, sufficient virus remains in the liver to transmit HBV following liver transplant from anti-HBs–positive donors through reactivation under intense immunosuppression.

It should be noted that the FDA has eliminated the requirement to ask blood donors about a history of viral hepatitis, effective May 2016. The detection of HBV DNA is performed by nucleic acid testing (NAT) in minipools of 6 to 16 donations each as now required per Food and Drug Administration (FDA) Guidance, Use of Nucleic Acid Tests on Pooled and Individual Samples from Donors of Whole Blood and Blood Components, including Source Plasma, to Reduce the Risk of Transmission of Hepatitis B Virus ( www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm , October 2013) and made final in updates to the Code of Federal Regulations. The risk for HBV transmission per unit in the United States has recently decreased substantially as a result of very sensitive HBsAg testing, the implementation of NAT, and a recent decline in the incidence of HBV infections among donors undoubtedly because of universal vaccination ( Table 118.1 ). Before NAT implementation, most contemporary HBV transfusion-transmitted infections were attributable to blood donations from asymptomatic donors during acute infection preceding the development of detectable HBsAg. Early in infection, HBV replicates relatively slowly with a doubling time of approximately 2.6 days. The current window period between infection and the detection of HBV DNA by NAT ranges from 30 to 38 days depending on the infectious dose, which, early in infection, is estimated to be between 1 and 10 copies per mL. Since the implementation of HBV NAT in the United States, there have been no documented cases of breakthrough HBV transfusion transmissions. The per unit residual risk for donations to the American Red Cross was estimated to be 1 per 843,000 to 1 per 1,208,000 in 2013 and 1 per 1,529,000 in 2015 to 2016 using an 18.5 day window period and weighted for all donors (first-time and repeat). Residual risks of 1 per million using the same methods are documented from large multicenter national studies for 2018 to 2019.

There is evidence that some HBsAg assays will not detect all HBsAg and HBc genetic variants of HBV. Because all blood donations are screened by HBV NAT, HBsAg, and anti-HBc, it is unlikely that any mutant strain of HBV would go undetected in the United States. Among 12.8 million blood donors to the American Red Cross during 2009 to 2011, 1 per 9337 were infected with HBV. Of these, 1090 were positive for HBsAg, with or without HBV DNA (1 per 11,736), and only 5 were identified solely by NAT in minipools (1 per 2.55 million). However, more recent data, also from the American Red Cross, demonstrate the HBV DNA detection rate of seronegative donations by NAT to be 1 per 770,000 donations. NAT on individual donation aliquots has the potential to reduce the risk for transfusion-transmitted HBV further by detecting newly infected donors slightly earlier than either minipool-NAT or HBsAg tests licensed for blood donor screening, but the additional cost of individual donation-NAT in the United States would be high with very little to no demonstrable clinical benefit.

Hepatitis D

Hepatitis D virus (HDV) was originally called the delta agent. It is a defective ribonucleic acid (RNA)–containing passenger virus that requires active synthesis of HBsAg to act as a “helper” for assembly of HDV virions. As many as 10% of HBV infections are accompanied by HDV worldwide. Its prevalence is very low in the United States but higher in intravenous drug users. HDV superinfection of chronic HBV carriers is associated with worsened chronic sequelae and with fulminant hepatitis. Screening for HBV acts synergistically to prevent transfusion-associated HDV cases by identifying donors that are co-infected with HBV and HDV. There has never been an HBV-HDV–related transfusion transmission reported.

Hepatitis C

HCV is an RNA virus in the family Flaviviridae , genus Hepacivirus . There are six genotypes that share similar epidemiology, pathogenesis, and natural histories. In the United States, genotype 1 causes 75% of infections, genotypes 2 or 3 causing 15% to 20% of infections, and genotypes 4, 5, and 6 causing less than 5% of infections. Genotype 1 responds relatively poorly to traditional treatment regimens using pegylated interferon combined with oral doses of ribavirin compared with genotypes 2 and 3; the overall cure rate for all genotypes using this regimen was no better than 40% to 50%. HCV protease inhibitors (direct acting antivirals) are materially improving these rates. Two oral regimens of Harvoni and Viekira Pak are now the standard of care in the United States, and result in a sustained virologic response of greater than 90% ( https://www.cdc.gov/hepatitis/statistics/2017surveillance/index.htm#hepatitisB , Viral Hepatitis–2017 Surveillance).

HCV is distinguished by a low rate of recognized acute infection and by a high rate of chronic infection, with substantial morbidity and mortality over long periods of observation as a result. The CDC estimates that there were 2.4 million people living with chronic HCV infections in 2017.

The most common source of HCV acquisition is intravenous drug use. The prevalence of HCV in US adults (20 to 59 years old) with any history of illegal intravenous drug use is greater than 45%. Other risks include blood transfusion before donor serologic screening began in 1990, exposure in health care settings, including through dialysis, among infants born to HCV-infected mothers, and tattoos in unregulated settings. In a large series, 15% to 30% of patients report no risk factors. Vertical transmission occurs in 3% to 7% of infants of mothers with active infections. In contrast to HBV, sexual transmission is an inefficient route of infection and much less often reported but was found to be the most likely mode of transmission of HCV among HIV-infected men who have sex with men (MSM) in New York City. In 2012 the CDC recommended that individuals born during 1945 to 1965 have one-time HCV screening since among all persons living with HCV infection, about 75% were born during this time. Such individuals have a 3% prevalence, which is five times higher than the prevalence seen in adults born in other years. Among blood donors, 0.03% have confirmed-positive HCV test results. There have been studies on risk factors among HCV-infected blood donors, and despite policies requiring deferral of injection drug users, such use is the most common risk factor. Of 316 blood donors followed who were HCV-confirmed positive, risks identified via a retrospective questionnaire revealed risks versus control donors of illegal drug use (37% vs. <1% for controls), followed by jail or detention (57% vs. 5%), history of a blood transfusion before screening (18% vs. 7%), and living in a household with someone having hepatitis (15% vs. 2%).

At most 20% to 30% of newly infected persons develop recognizable symptoms during acute HCV infection. Some 20% of infected individuals clear their infection over a relatively short initial period, remaining antibody-positive but RNA-negative. Chronic infection develops in 75% to 85% of persons infected after 45 years of age and in 50% to 60% of those infected as children or young adults. Chronic HCV infection progresses to cirrhosis in 15% to 30% over 30 years of observation. Hepatocellular carcinoma occurs in 1% to 4% per year in those with cirrhosis. HCV is among the most prevalent causes of chronic hepatitis, cirrhosis, and primary liver cancer in the developed world and is the most common indication for liver transplantation in the United States, resulting in around 2400 procedures annually.

A single positive anti-HCV result cannot distinguish between acute and chronic HCV infection or between current or cleared infection. In 2012 laboratory criteria for the confirmation of anti-HCV reactivity were modified to add one specific assay including RNA detection, using a supplemental anti-HCV assay (as available) or a single value above a specific threshold on the screening test. The risk for posttransfusion HCV infection declined progressively with the introduction of surrogate markers for non-A, non-B hepatitis in the 1980s (alanine aminotransferase [ALT] and anti-HBc) and of serologic testing for HCV antibodies in May 1990, followed sequentially by improved serologic testing and NAT. The seronegative-window period for the first-generation HCV antibody test extended to 6 months from infection but was reduced to 82 and 70 days with second- and third-generation assays, respectively. NAT further reduced the window period to approximately 7 days. The risk per unit declined from an estimated 1 per 276,000 units to 1 per 2,600,000 units from 2007 to 2016 and in 2018 to 2019 in larger multicenter national studies to 1 per 2 million weighted for all donations from both first-time and repeat donors.

Like HBV, in the United States, testing for HCV RNA has used NAT in small minipools combining aliquots from 16 to 24 donations (currently 6 to 16). Loss of test sensitivity because of sample pooling was tolerable given the rapid increase or burst of HCV viremia before antibody seroconversion (estimated doubling time of 10.8 hours in that period during the 40- to 50-day window period) and the high titer of viremia that remains preceding antibody seroconversion. However, the rest of the world (except the United States, Canada, the United Kingdom, and most of Germany) has implemented NAT for screening individual donation samples intended for transfusion. The HCV RNA yield by NAT in seronegative donations using data from the American Red Cross is 1 per 270,000 donations.

As an alternative to NAT assays, enzyme immunoassays (EIAs) have been developed that detect HCV HBcAg in serum or plasma, either as an individual analyte in parallel with antibody assays or as HCV antigen-antibody combination assays. These tests reduce the pre-seroconversion window period and were adopted in some developing countries. They are less sensitive than HCV NAT, are not approved for blood donor screening in the United States, and use has decreased significantly. Since the implementation of NAT, reports of transfusion-transmitted HCV are very infrequent.

The high seroprevalence of HCV at the onset of serology screening in the early 1990s, the prolonged interval between infection and clinical manifestations, and the relatively high rate of HCV clinical sequelae prompted blood collection facilities and hospitals to conduct “look-back” notification of previous recipients of blood given by donors found on subsequent donations to be HCV infected. Look-back was subsequently made mandatory in companion rules from FDA and the Centers for Medicare and Medicaid Services. In general, HCV look-back programs found half or fewer of targeted transfused individuals alive but were able to find both seropositive and RNA-positive recipients who were unaware of their status. This population has benefited significantly from identification and subsequent treatment with the advent of curative direct-acting antivirals.

Hepatitis A

The hepatitis A virus (HAV), a nonenveloped picornavirus, genus Hepatovirus , is transmitted predominantly by the fecal-oral route, with an average incubation period of 28 days (range, 15 to 50 days) with signs or symptoms persisting for less than 2 months. The incidence of HAV infection in the United States fell by 76% between 1997 and 2003 after the recommendation for targeted immunization of members in high-risk communities. Populations at risk include those in areas where extended community outbreaks occur and children living in states that have high and intermediate rates of disease, staff and residents of closed communities, close personal contacts of cases, the staff and parents of children in daycare centers, and those with common-source exposure to infected food or water. For many sporadic cases there is no recognized source. HAV is self-limited with no chronic carrier state, but approximately 10% to 15% of infected individuals develop a more prolonged or relapsing illness. It is the most frequent cause of hepatitis among children under 11 years of age.

Transfusion-related transmission, although rare, is caused by a blood donation from a recently infected, asymptomatic, viremic individual. The peak viremia occurs 2 weeks before onset of jaundice or elevation of hepatocellular enzymes and persists for a median period of 42 days (range, up to 59 days). The virus is quite resistant to many inactivation procedures, including the pathogen-reduction procedures being developed for cellular blood components (e.g., licensed psoralens or investigational riboflavin, both with ultraviolet [UV] irradiation) and fresh-frozen plasma (solvent/detergent and methylene blue). Transmission by clotting-factor concentrates treated with the solvent/detergent pathogen-reduction process occurred in the 1990s, but not thereafter. Plasma for further manufacture is routinely screened for HAV RNA by pooled NAT.

A 120-day deferral is recommended after exposure to HAV during community outbreaks to prevent transfusion transmission. Screening for HAV is not done for donations of blood for transfusion.

While the average number of annual HAV infections reported to CDC in recent years has declined substantially compared to 2000, fluctuations have occurred in the last 20 years due to large outbreaks. After a long downward trend, the first increase between 2012 and 2013 (1562 and 1781 reported cases, respectively) was due to a large multi-state outbreak associated with pomegranate arils imported from Turkey. Between 2015 and 2016, the reported cases again increased by 44.4% from 1390 in 2015 to 2007 cases in 2016. The 2016 increase was due to two hepatitis A outbreaks, each of which was linked to imported foods. Substantial increases in incident cases of hepatitis A occurred in 2017 and 2018 (3366 and 12,474 reported cases, respectively) due to ongoing outbreaks reported to CDC among people who use drugs and people experiencing homelessness as well as outbreaks among MSM.

Hepatitis E

The hepatitis E virus (HEV) is a small, nonenveloped single-stranded RNA virus in the Hepeviridae family. HEV was first recognized in the 1980s in Afghanistan among soldiers with unexplained hepatitis. There is a single serotype but at least four genotypes with differing geographic distributions and epidemiologic patterns. Genotypes 1 and 2 are generally associated with large, water-borne (fecal-orally transmitted) outbreaks in less developed tropical countries. Illness is usually self-limited but can be lethal in pregnant women, their fetuses, and patients with chronic liver disease. Genotypes 3 and 4 appear to be animal viruses that result in zoonotic infection of humans, most often through consumption of inadequately cooked pork products. Genotype 3 seems to be widely distributed and is present in developed countries, whereas genotype 4 seems to be more common in certain Asian countries. Transfusion-related transmission, mostly of serotype 3, has been well-documented in Japan, France, England, the Netherlands, and Spain.

Recent studies suggest a wide range of seroprevalence rates, but some of the variability may be attributable to the differences in performance characteristics of the tests used and some to dietary habits. Most studies indicate a cohort effect, with prevalence rates increasing with age. Transfusion infectivity is logically associated with the presence of detectable viral RNA in the plasma and the frequency of this finding varies between 1 in 1000 to 1 in 10,000 donations.

In a large study in England, 225,000 donations were tested and 79, or 1 in 2848, were found to be positive when tested for HEV RNA. For 43 of these, recipient tracing was possible and 18 (42%) showed evidence of transfusion-transmitted infection. A North American study screened 101,489 donations from Canada and the United States for HEV RNA and reported 14 positive donors, or 1 in 7300, all with low viral loads (ranging from 20 to 3080 copies/mL) consistent with a prior US study finding 7.7% of donors anti-HEV positive but only two of approximately 19,000 that were RNA positive. Although the Canadian prevalence was fourfold higher than in the United States, quantitative and risk-based analysis found testing to not be cost effective. A current broader concern is the finding that highly immunosuppressed patients (such as solid-organ transplant recipients) do develop chronic HEV infections with long-term clinical sequelae, although these have not been specifically linked to infection via transfusion. While testing is standard in some European countries and Japan, where incidence rates are higher and transfusion transmissions well documented, in the United States and Canada routine testing is currently not recommended due to the absence of recognized transfusion transmission.

Non–A-E Hepatitis

Cases of posttransfusion hepatitis only rarely if ever occur but there remains speculation that undiscovered hepatitis agents exist. A small but consistent percentage of community-acquired hepatitis cases test negative for known hepatitis viruses, some cirrhosis is classified as “cryptogenic,” an etiologic agent for hepatitis-associated aplastic anemia ( Chapter 31 ) eludes description, and the cause of some cases of acute liver failure remains elusive. Several candidate agents have been proposed as non–A-E hepatitis viruses. None of these agents have been shown to be pathogenic and are instead likely commensal and nonpathogenic.

GBV-C (initially called hepatitis G virus) is a flavivirus with no confirmed disease association that is transmitted parenterally, including frequently by transfusion. Of interest, GBV-C infection may delay progression of disease in those co-infected with HIV, which has led to studies of the interactions between these viruses.

From 1% to 4% of US blood donors are viremic compared with 15% to 20% of intravenous drug users who have detectable GBV-C RNA. Infection occurs frequently among those infected with HCV and HIV. More people have antibodies against the E2 envelope protein, in the absence of RNA, suggesting viral clearance. GBV-C has not been shown to cause liver disease or other morbidities, and hence there is no consideration of donor screening at this time. GBV-C is now referred to as a human pegivirus. A second human pegivirus has recently been described associated with HCV likely as a result of an acute parenteral co-infection event, but again, has not been associated with hepatitis or any pathology. This virus was identified by next generation sequencing. Likely other such commensal agents will continue to be identified by the use of sophisticated molecular techniques ( Chapter 3 ).

The torque teno virus (TTV) complex is a genetically diverse group of nonenveloped DNA viruses in the family Circoviridae , which was discovered in 1997. They cause viremia, and they are transmitted by transfusion, but they cause no recognized liver disease or other clinical illness.

SEN virus (SENV), another member of the Circoviridae , was described using degenerate polymerase chain reaction (PCR) primers while working with TTV. After an initial report associating SENV variants in two patients with transfusion-associated non–A-E hepatitis, subsequent epidemiologic studies have failed to link SENV with clinical hepatitis.