A systematic review of outbreaks of bloodborne infections (hepatitis B and C, HIV) transmitted from patient to patient in healthcare settings

Healthcare facilities have always played an important role in transmission of bloodborne infections. Procedures involving blood and blood fluids pose a risk of transmitting hepatitis B, hepatitis C and HIV not only to healthcare workers, but also to patients. To assess the role of healthcare facilities in transmission of bloodborne infections and to identify risk groups among patients as well as transmission factors, a total of 75 outbreaks of hepatitis B, hepatitis C and HIV have been analyzed with reference to the data published in different countries in 2008–2020. The comparative analysis was conducted for the outbreaks in the United States during 1992–2008 and 2008–2019. Most of the outbreaks of bloodborne infections at healthcare facilities were caused by non-adherence to standard precautions among healthcare workers: Reusing disposable items; improper handwashing; reusing gloves; non-disinfecting surfaces, reusable equipment and devices; non-sterilizing reusable instruments. In terms of bloodborne infections, high-risk facilities include hemodialysis centers, oncohematology clinics, outpatient clinics, nursing homes, residential care facilities, and diabetes treatment centers. High-risk groups include patients undergoing hemodialysis, oncohematological patients, and patients with diabetes. high-risk patients, inves ti- gation of outbreaks, adoption of rules and procedures combined with training and compliance control of healthcare workers contribute to solution of the problem associated with nosocomial transmission of bloodborne infections. study Author contribution. Аll authors made a substantial contribution


Introduction
Bloodborne infections have always had a high potential of transmission in healthcare facilities, both among healthcare workers and among patients. Bloodborne infections are characterized by a long incubation period (up to 6 months), absence of symptoms or presence of mild, non-specific clinical manifestations. Infections may linger undetected for years, while patients may have multiple medical care encounters, becoming a source of nosocomial infection.
Prior to the 1990s, unsafe blood transfusions accounted for most of the healthcare-associated outbreaks; however, the adoption of effective measures aimed at safety of blood components made it possible to achieve considerable success in preventing transmission of bloodborne infections during blood transfusions [1]. The employment of highly sensitive diagnostic systems, quarantine of plasma and screening of blood donors helped reduce significantly the contribution of blood transfusions to transmission of bloodborne infections over the past few decades. Yet, in low-income countries, the problem still persists due to the lack of possibility to perform fullscale screening of all donors. According to the WHO Report, in high-income countries, 99.6% of donations were screened compared to 66% in low-income countries 1 . In the United States, the last blood-transfusion-associated outbreak of hepatitis B was recorded in 1997. In 1995, the United States reported the outbreak of hepatitis B during transplantation of autologous hematopoietic stem cells; the infection resulted from contamination of the liquid nitrogen from the damaged container of infected cells long before the infection event [2].
While the safety of blood transfusions receded into the background, the problem of bloodborne infections in healthcare facilities remained unsolved; furthermore, the role of unsafe injections and manipulations was uncovered. The Global Burden of Disease Study conducted in 2000 revealed that in 10 out of the 14 most affected regions, 39% injections were given with reused unsterile injection equipment. The researchers modelled a real situation of infection during injections, considering injection-associated risks, the proportion of unsafe injections, the total incidence, immunity, etc. The modelling made it possible to assume that in 2000, unsafe injections caused an estimated 21 million HBV infections, 2 million HCV infections and 260,000 HIV ЖУРНАЛ МИКРОБИОЛОГИИ, ЭПИДЕМИОЛОГИИ И ИММУНОБИОЛОГИИ. 2021; 98(3) DOI: https://doi.org/10.36233/0372-9311-112 ОБЗОРЫ infections, accounting for 32%, 40%, and 5%, respectively, of new infections [3]. Since 2000, substantial efforts have been made by WHO, under the leadership of the Safe Injection Global Network, to reduce the risks associated with unsafe injections. Over the 2000-2010 decade, the number of unsafe injections decreased in 81% of countries; the proportion of re-use of injection devices dropped from 39.8% to 5.5%. In 2015, safe injections accounted for 97% [4]. The implementation of hepatitis B vaccination strongly contributed to resolving the problem of nosocomial transmission of hepatitis B, though nosocomial outbreaks of hepatitis B are still being reported due to the low vaccination coverage in developing countries and due to existing unvaccinated people among elderly groups in developed countries [2].
Hemodialysis centers have been historically associated with high risk of bloodborne infections both among patients and among healthcare workers [5].
Over the past few decades, some progress has been made in this sector: The incidence of hepatitis B and C has decreased [6][7][8]. As there is no possibility to vaccinate patients on hemodialysis against hepatitis B, the vaccination coverage of this group of population in the United States is as low as 56%. The prevalence during the post-vaccination period was 1% [9]. The hepatitis C prevalence among hemodialysis patients is 8% and exceeds the prevalence in the population approximately 5 times. The prevalence among patients and persisting outbreaks in the healthcare facilities demonstrate the significance of hemodialysis in transmission of bloodborne infections [10].
Oncohematological patients have always been seen as a high-risk group in terms of bloodborne infections associated with multiple blood transfusions and bone-marrow transplantation [11]. Before screening when donors were not examined, the prevalence of hepatitis B among patients in Poland before 1992 reached 62%, while the hepatitis C prevalence before 2000 was 54.3%. In 1999-2000, when screening of donors started, the hepatitis B prevalence among patients went down to 1.9% and the hepatitis C prevalence decreased to 2.8% [12]. The seroprevalence among oncohematological patients depends on the screening coverage of donors and on the prevalence in the population. For example, in Egypt, the seroprevalence of anti-HCV among children with hematological disorders is 81.6%, among children with oncologic diseases -17.6%, HBV-DNA -38% [13]. In Brazil, the HBV seroprevalence among oncological patients accounted for 13.97% [14]. In Turkey, the seroprevalence of HBsAg among oncological patients was 4.2%, anti-HCV -0.7% [15]. In the United States, the HBV seroprevalence is 6.5%, while the seroprevalence of HCV and HIV is 2.4% and 1.1%, respectively [16]. In addition, oncohematological patients have higher mortality when infected with viral hepatitis as compared to the overall population, since chemotherapy enhances viral replication and contributes to the development of fulminant hepatitis [2].
Transplantation-related transmission of bloodborne infections is rarely mentioned in literature. The United States reported 2 outbreaks of hepatitis C, which were associated with transplantation [17].
Healthcare-associated transmission of each infection has different significance. Being the infection controlled by specific immunoprophylaxis, hepatitis B is of significance among unvaccinated groups. Hepatitis C, on the contrary, due to the absence of specific immunoprophylaxis is of high significance among all the groups of population, and the problem of nosocomial transmission remains unsolved even in developed countries. Heterogeneous spread of hepatitis C among regions and within a region signifies active artificial transmission in healthcare facilities and intravenous drug abuse 2 . The role of the artificial mode of HCV transmission during medical manipulations may strongly vary in different countries and depends on the prevalence in the population. The higher the prevalence in the population, the higher the significance of artificial transmission. The dominance of senior-age people and people of all ages in the hepatitis C prevalence structure is indicative of an active artificial mode of transmission during medical manipulations [18,19].
Despite the achieved success, healthcare facilities still pose a risk of bloodborne infections; in some areas the risk tends to increase due to growing numbers of invasive interventions as well as due to hepatitis C and HIV prevalence in population.
The purpose of the systemic review is to evaluate the significance of healthcare facilities in transmission of bloodborne infections, to identify risk groups among patients and causes of infection with hepatitis B, C, and HIV.
We analyzed publications about nosocomial outbreaks of bloodborne infections (hepatitis B, hepatitis C, and HIV) from the following information resources: PubMed, Outbreak Database, ClinicalKey, NCBI, EB-SCOhost, Web of Science, Cambridge University Press, ResearchGate, and eLibrary. Outbreaks in the United States were analyzed with reference to the report from the Centers for Disease Control and Prevention [20].

Data about outbreaks of bloodborne infections in the world
For the analysis, we selected publications about outbreaks recorded in different countries, with the onset of outbreaks falling on the period from 2008 to November 2020. The analysis included the outbreaks with patient-to patient transmission of infection, represented by 2 or more cases, characterized by epidemiological and genetic association. Outbreaks in hemodialysis centers, oncohematology clinics, and patients' long-term care facilities were analyzed separately, representing highest-risk facilities. Tables 1-3 show the list of outbreaks, the causes and factors of their occurrence.
Since the data on outbreaks are best presented in the United States, we compared the analysis results for outbreaks of two periods, which were recorded in the United States, namely, the data obtained in this review (2008-2020) and the analysis data for outbreaks in 1998-2008 [21]. The comparison was based on outbreaks in non-hospital facilities, as in 2008-2020, there were no recorded outbreaks associated with patient-to-patient transmission in U.S. in-patient facilities (hospitals).
A total of 75 outbreaks (1,100 cases of infection) meeting the selection criteria were analyzed ( Table  2). The report about outbreaks in the United States

Data about outbreaks of bloodborne infections in Russia
In Russia, no descriptions of outbreaks meeting the criteria were found. However, the problem of nosocomial transmission of bloodborne infections remains currently central in Russia. In 2019, the retrospective investigation of the cluster revealed multiple hepatitis C cases in the hematology department of the healthcare facility in the Amur Region 3 . Although there were no data on nosocomial outbreaks, departments of the Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing report a large percentage of hepatitis C cases (54.7%) associated with unidentified transmission modes in Russian regions from 2010 to 2019, thus implying that the clusters were not properly investigated. According to the data from the Federal Scientific and Methodological Center for the Prevention and Control of AIDS, from 1987 through 2019, in Russia there were recorded 463 confirmed cases of healthcare-associated HIV infection among patients in healthcare facilities, including 103 cases of infection during transfusion of blood and its components as well as 3 cases of HIV transmission during transplantation. In 2019, 9 cases with suspected infection in healthcare facilities when using unsterilized medical instruments were reported; 1 case was reported when the recipient was infected during the platelet transfusion from a blood donor. 3  Among the analyzed outbreaks, the largest number (25) is recorded in other facilities with the highest percentage of outpatient clinics (17 outbreaks). Hemodialysis centers reported 24 outbreaks. A total of 21 outbreaks were recorded in long-term care facilities including assisted-living facilities, residential care facilities, and nursing homes. A total of 5 outbreaks were recorded in oncohematology clinics.
The largest number of infection cases was recorded in other facilities -596 cases, in long-term care facilities -184, in hemodialysis centers -173, and in oncohematology clinics -147 cases.

Other facilities (including outpatient clinics)
The outbreaks in other facilities were mainly caused by contaminated medication vials (12 outbreaks). Vials can become contaminated when medicine is withdrawn with a used syringe. Vials with the following agents were the cause of outbreaks: a saline solution, contrast medium, agents for procedural sedation and anesthesia (propofol, ketamine, marcaine, lidocaine, etc.) in 12 outbreaks. Multiple uses of single-dose vials were reported in 5 outbreaks. The outbreaks in Pakistan and India were caused by injections (2 outbreaks), namely, by reuse of syringes and needles. In Pakistan, blood transfusion also caused an outbreak. The HIV outbreak in China was caused by a line for lymphocyte collection and processing used during lymphocyte immunization therapy for infertility treatment. Hong Kong reported an outbreak caused by a contaminated holder of vacutainer tubes for blood collection.

Hemodialysis centers
The most frequent causes of bloodborne infections in hemodialysis centers are the absence of disinfection of surfaces (in 14 outbreaks): working surfaces, armchairs and arm-rests, the hemodialysis apparatus and surrounding surfaces. In 10 outbreaks, there were reported hand hygiene-related violations: hand-washing and using of gloves. In 4 outbreaks, the causes included non-delineated areas for preparation of infusions (the "clean" area), for work with blood samples (the "dirty" area) and for work with a patient (the "treatment" area); 4 outbreaks were caused by the improper intravenous catheter care that included routine flushing and dressing change. The outbreak in Pakistan was caused by the absence of personnel, absence of differentiation of equipment for infected and non-infected patients as well as patients' purchasing of blood components from unauthorized laboratories and banks.

Long-term care facilities
The occurrence of outbreaks in long-term care facilities (assisted-living facilities, nursing homes, residential care facilities) and their causes in Germany and the United States depend on the groups of patients in

Main transmission factor
Reuse of lancet Contaminated glucometers these facilities. The most common cause is glucose measuring, i.e. contamination of glucometers, which were not personal and were not disinfected between uses by multiple patients (12 outbreaks). The multiple use of a lancet for skin piercing during capillary blood tests, including blood glucose measuring was a contributing factor in 7 outbreaks. The application of unsterilized instruments for podiatric diabetic foot care contributed to 4 outbreaks. Hand hygiene-related violations were mentioned in 4 outbreaks.

Oncohematology clinics
The causes of outbreaks in oncohematology clinics included multiple violations related to standard precautions: delineation of "clean" and "dirty" areas, reuse of plugs and stoppers, violations related to hand hygiene, waste mismanagement, contaminated vials with saline solution for flushing of an intravenous catheter, multiple uses of single-dose vials. In South Africa, the outbreak occurred due to absent vaccination of children and multiple violations of standard precautions.

Comparison of the review data on outbreaks in the United States
The profile of outbreaks in the United States during two periods: 1998-2008 and 2008-2019 is shown in Table 4.
When comparing the two periods, we can note that the number of outbreaks increased, though the number of infection cases remained unchanged.
Although in outpatient clinics, the number of hepatitis C transmission cases decreased, the impact of contaminated vials is still a challenging issue. The high impact of outpatient clinics on spread of infections in the United States is explained by the fact that most of the medical services are provided in such facilities, including services to oncohematological patients and hemodialysis patients.
The number of bloodborne infection transmission cases increased significantly in hemodialysis centers. At the same time, in 2008-2019, contaminated vials being the main factor in 1992-2008 were of no importance. In the later period, contaminated surfaces and poor adherence to hand hygiene came to the fore.
The number of infections increased in long-term care facilities; the problem of capillary blood collection and blood glucose measurement remain of high significance.
Thus, the factors that used to be significant during the previous decades continue to contribute to nosocomial spread of bloodborne infections, while the significance of some of them is increasing.

Findings
The heterogeneity of outbreaks of bloodborne infections in different healthcare facilities is connected with nosology of main diseases of patients. Most of the outbreaks occur in the healthcare facilities for patients with a weak immune system, end-stage renal disease, diabetes, cancer disease [2].
Oncohematological patients, patients, on hemodialysis and patients in long-term care facilities (assisted-living facilities, residential care facilities, and nursing homes) represent groups of high risk of healthcare-associated bloodborne infections. Oncohematological patients and hemodialysis patients, in addition to immunosuppression, have another risk factor -a venous catheter. Manipulations involving a venous catheter tend to produce small drops of blood. Studies show that the hepatitis B virus can be found on visually clean surfaces in the setting of a patient with hepatitis B infection after manipulations with the catheter or after the hemodialysis procedure [38,39]. The significance of prevention of bloodborne infections among patients of long-term care facilities is increasing with the growing number of senior and elderly people in developed countries. Furthermore, outbreaks of hepatitis B in these facilities are frequently accompanied by fatal outcomes [21].
At present, the main factors of transmission of HIV, hepatitis B and C are healthcare workers' non-adherence to standard precautions: reuse of disposable items, low commitment to hand hygiene and using of gloves, absent disinfection of surfaces, reusable devices and equipment, absent sterilization of reusable instruments. Outbreaks caused by such manipulations as endoscopic surgery [40], myocardial perfusion imaging [41], computer tomography [30,31,42], endomyocardial biopsy [43] were also associated with non-adherence to the main preventive measures.
In hemodialysis clinics, the main contributor to infection transmission is absent disinfection of surfaces in the patient's setting; in oncohematology centers, the main contributor is multiple violations of standard precautions. In long-term care facilities, especially for patients with diabetes, the emphasis should be put on immunoprophylaxis of hepatitis B and using of personal devices for blood glucose measuring.
Today, blood transfusions involved in transmission of bloodborne infections are of significance only in low-income countries.
HIV is reported rarely as a nosocomial infection; however, the outbreak in Pakistan demonstrates the significance of the artificial mode of transmission of this infection in low-income countries as well as insufficient attention to this problem.

Conclusion
Bloodborne infections are characterized by a multiple number of latent forms, thus creating a threat of infection spread when standard precautions, which play a major part in nosocomial transmission, are not complied with. The regular screening of donors and patients from the high-risk group is of critical importance. To prevent transmission of bloodborne infections, it is important to investigate the outbreaks and to adopt rules and procedures (standard operating procedures) with the emphasis on adherence to standard precautions. The above measures require regular training of personnel, motivation and monitoring of the commitment to compliance. In the above outbreaks, where the causes and factors were not identified, the implementation of standard precautions, along with training and compliance control, had a critical role in prevention of the further spread of infections. Adherence to standard precautions is important for all healthcare facilities; however, the adherence to preventive measures is of most significance in high-risk facilities such as hemodialysis centers, oncohematology and outpatient clinics, nursing homes, assisted-living facilities, and in diabetes treatment centers.
Hepatitis B vaccination is of importance for immunocompromised patients and older adults; in low-income countries, it is the mainstay of prevention of nosocomially transmitted hepatitis B among all the groups of population.