Indian Journal of Transplantation

REVIEW ARTICLE
Year
: 2022  |  Volume : 16  |  Issue : 5  |  Page : 2--14

Preparing for transplant - Screening and prophylaxis of donor and recipients before solid organ transplantation: Expert group opinion from South Asia


Shyam Bihari Bansal1, Vijay Kher1, Venkatasubramanian Ramsubramanian2, Narendra S Choudhary3, Camille Nelson Kotton4,  
1 Department of Nephrology and Renal Transplant Medicine, Medanta Kidney and Urology Institute, Medanta Medicity, Hospital, Gurgaon, Haryana, India
2 Infectious Diseases and Tropical Medicine, Apollo Hospitals; Infectious Diseases - Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
3 Department of Hepatology and Liver Transplant, Medanta, The Medicity Hospital, Gurgaon, Haryana, India
4 Infectious Diseases Division, Massachusetts General Hospital and Harward Medical School Boston, Massachusetts, USA

Correspondence Address:
Dr. Shyam Bihari Bansal
Department of Nephrology and Renal Transplant medicine, Medanta Kidney and Urology Institute, Medanta Medicity, Sector 38, Gurgaon, Haryana
India

Abstract

Infections are major cause of morbidity and mortality after transplantation. Although many infections are common worldwide, there are differences in various geographic locations. South Asia and India, in particular, has a very active transplant program for kidney and liver transplantation, however, there are no guidelines as how to screen and provide prophylaxis to solid organ transplant (SOT) recipients and donors for both specific infections prevalent in this region along with usual infections. Keeping this in mind, a working group was created comprising transplant physicians, surgeons, and infectious disease specialists from South Asia as well as experts from other countries. This working group developed guidelines based on published evidence, unpublished data from large centers in this region, along with expert opinion. This section of the guidelines deals with pretransplant screening of donors and recipients, which should be useful in dealing with transplants performed in this region for patients belonging to these countries, for those coming for transplantation from other countries, and for programs outside of South Asia who are screening donors and recipients from this region or who have spent significant time in this region.



How to cite this article:
Bansal SB, Kher V, Ramsubramanian V, Choudhary NS, Kotton CN. Preparing for transplant - Screening and prophylaxis of donor and recipients before solid organ transplantation: Expert group opinion from South Asia.Indian J Transplant 2022;16:2-14


How to cite this URL:
Bansal SB, Kher V, Ramsubramanian V, Choudhary NS, Kotton CN. Preparing for transplant - Screening and prophylaxis of donor and recipients before solid organ transplantation: Expert group opinion from South Asia. Indian J Transplant [serial online] 2022 [cited 2022 Dec 8 ];16:2-14
Available from: https://www.ijtonline.in/text.asp?2022/16/5/2/358656


Full Text



 Introduction



Transplantation is often lifesaving surgery for patients with organ failure and the best treatment for most patients with kidney failure. Infections remain an important cause of morbidity and mortality in transplant recipients.[1]

Rates of transplantation are increasing in developing countries like India and other South Asian countries (India, Pakistan, Bangladesh, Nepal, and Sri Lanka). India is a major health-care destination and performs transplant procedures for patients coming from many countries in the Middle East, Africa, Myanmar, Afghanistan, Bhutan and the former Soviet Union countries such as Uzbekistan, Turkmenistan, Tajikistan and Kirgizstan, etc., According to Indian transplant data in Global Observatory on Donation and Transplantation, an estimated 13,700 solid organ transplants (SOTs) were performed in South East Asian region in year 2019, of which 12,666 were done in India alone.[2] Out of 13,700 transplants, approximately 10,635 (80%) were kidney transplants, 2708 were liver transplants, 218 heart transplants, 114 lung transplants, and 25 pancreas transplants were performed.[2] About 83% of kidney transplants involved living donors, while 66% of liver transplants utilized living donors, which puts India as the country with the highest numbers of living donors for SOTs and second after the USA in the total number of SOTs. Sometimes patients from this region also travel outside the region to undergo transplantation. Travel to and from this region for tourism and work is also very common.

The pretransplant screening and evaluation of prospective donors and recipients for infections is important for many reasons: To rule out any active infection and/or treat them adequately before transplant, to recognize the risk of infection and make strategies to reduce the risk of posttransplant infections, and to prevent certain infections by adequate immunization of recipients.[3],[4] Many guidelines are available for the screening of donors and recipients in various regions including the American Society of Transplantation guidelines, Latin American, Australian, and New Zealand guidelines;[5],[6],[7] however, there are no such guidelines for South Asia, even though there are many endemic infections which are specific to this region and have not been a focus of these guidelines whereas other infections might not be as relevant.

These guidelines address various infections which are prevalent in this region and covered in further detail in other chapters of these guidelines. This chapter addresses the pretransplant screening and evaluation of both donors and recipients for infections [Table 1] and [Table 2] along with guidelines for pre- and post-transplant prophylaxis in this region. As there is the paucity of published literature pertaining to this region, these guidelines comprise a combination of literature review, expert opinion, and unpublished data from leading transplant centers in this region. These guidelines will aid the transplant specialists who are seeing transplant patients both in this region and also transplant recipients traveling to or from these countries. These guidelines would also help to standardize transplant management in this region.{Table 1}{Table 2}

While routine general screening for major pathogens is the same worldwide, additional pre transplant screening in various regions is recommended based on differing disease epidemiology.[8] In this chapter, we will discuss optimal screening for various infections in donors and recipients before transplant in the region of South Asia.

 Donor Screening



Routine screening of donors is required for certain infections before accepting them for donation. Despite pretransplant screening, donor-derived infection remains a major concern both in South Asia and throughout the world. A thorough history is mandatory; history of prior exposures should be obtained carefully including the history of prior infections, vaccinations, places of travel and residence, occupations, hobbies, and history of contact with people with infections and animals.[9],[10] High-risk behaviors including sexual exposures and intravenous drug abuse should be obtained directly from the donor, or close contacts of deceased donors.[9],[10] The history should also include infections in the family, for example, tuberculosis (TB). There are endemic infections such as TB, strongyloidiasis, toxoplasmosis, leishmaniasis, malaria, dengue, chikungunya, and others which can be both locally endemic and may result from exposures during travel and interaction with other people [Table 3].{Table 3}

History should be supplemented by a complete physical examination, laboratory studies, and radiological evaluation of the donor. In living donors, routine tests such as chest X-ray, abdominal ultrasound, blood tests, and urine culture are indicated. Deceased donors should also have blood cultures to rule out bacteremia. Routine screening for infections such as hepatitis B virus (HBV), cytomegalovirus (CMV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Epstein–Barr virus (EBV), and syphilis is mandatory in prospective donors of SOT.[6],[11] Serology for Toxoplasma gondii should be done before heart transplant, as this is not common in other organ transplants. In the South Asian region, where TB is endemic, screening for TB should be done actively in all donors. Deceased donors admitted with altered mental status should be thoroughly evaluated for central nervous system (CNS) infection as donors with certain CNS infections (especially viral meningoencephalitis of unknown causes) should not be accepted as donors[8],[9],[10] [Table 2]. In regions of South Asia, where Leishmania is endemic (i.e., Bihar in India, Nepal) serology for Leishmania might be considered, however routine screening is not recommended.[6],[12],[13] Malarial antigen or peripheral smear for malaria should be done in all symptomatic donors at the time of donation.[14],[15] Strongyloides infection is endemic throughout South Asia so serologic screening should be done (versus empiric treatment of the donor before transplant).[16],[17],[18] Screening for Trypanosoma cruzi is not required unless there is a history of prolonged travel to an endemic region (Central or South America). The routine screening for the South Asia region is shown in [Table 1].

For living donors, the screening should be done (or repeated, if necessary) within four weeks prior to surgery and preferably as close to the transplant as possible.[4],[5] To decrease the risk of disease transmission, HBV, HIV, and HCV viral loads should be repeated within a week of transplant, however, for deceased donors such screening should be performed within hours (12–18 h) before transplant.[4],[9],[17],[18]

 Donor Screening for Bacterial Infections



Screening for bacterial infections should be done in all living and deceased donors.[5],[17],[18],[19] The evaluation should include the history of exposure, symptoms, physical examination, and radiological investigations as required. Living donors with such infections should be fully treated before transplantation.[18] For deceased donors, as time is limited, blood and urine cultures should be obtained. Donors with serious infections such as Pseudomonas aeruginosa or Staphylococcus aureus should receive a minimum of 48 h of appropriate antibiotics before donation and recipients should be treated for a full course of 2 weeks or more after transplant, depending on the infection, as inadequate treatment might lead to incomplete resolution of infection and mycotic aneurysm at the site of vascular anastomoses.[19],[20],[21],[22],[23] Patients who receive organs from donors infected with less virulent organisms should be given at least one week of empiric therapy.[21],[22] It is important for donors to receive at least 48 hours of effective antibiotics before donation, with subsequent negative culture results (i.e., clearance of bacteremia).[7],[22],[24] Organs from donors with meningitis can be used after adequate treatment for at least 48 h with clearance of bacteremia and therapy is continued in the recipient afterward.[25],[26] If multidrug-resistant organisms are identified, then the donation may be considered after careful evaluation with close follow-up of the recipient. The donation should be avoided if the donor has persistently bacteremia and/or there is positive culture from the organ to be transplanted, unless there is a clear plan for appropriate and available antibiotic management, as per above.[22],[23],[24]

Donors with meningitis of unknown origin or meningitis with highly virulent organisms or Mycobacterium TB (MTB) which suggest disseminated infection should be rejected as donors[25],[26],[27],[28],[29],[30] [Table 2].

Lung transplantation patients have unique issues as the lungs are in contact with the external environment, and colonization with multiple organisms is common. Before accepting lung grafts, bronchoscopy and bronchial lavage of the donor should be done and the donor and recipient should be given appropriate coverage for the organisms grown from these cultures.[1],[5],[31]

Syphilis is rarely transmitted through transplant, however routine testing for syphilis is recommended in all donors in Western guidelines.[5],[6],[32] The testing recommended by the US Centers for Disease Control is as follows: an initial enzyme immunoassay treponemal test (TP) is performed, with a positive result confirmed by a nontreponemal test such as the rapid plasma reagin (RPR) test. If the RPR test is negative, a second TP test should be performed such as the Treponema pallidum particle agglutination test. If this second TP test is negative, then a third TP test should be performed, such as the fluorescent TP antibody absorption. If either the second or third antibody tests are positive then a diagnosis of syphilis is made.[33] The presence of syphilis is not a contraindication to either a living or deceased donation, however in living donation the donor should receive full treatment with benzyl penicillin and in deceased donation, the recipient should receive treatment after transplant.[34] In the South Asian region, the incidence of syphilis has reduced considerably, so most centers do not perform routine screening for syphilis; however, it should be performed in the endemic region.

Leptospira is a spirochete infection and one of the most common zoonosis affecting rodents, cats, dogs, livestock, and wild mammals. It is endemic in some parts of South Asia. In India, Kerala, Tamil Nadu, and Andaman are endemic and cases are also reported in other parts.[35] There is a significant association with occupation (farmers, veterinarians, sewage workers, and animal handlers) and environmental exposure. Humans acquire infection by penetration of the bacteria via abraded skin or mucous membrane on direct contact with an animal or indirect contact with urine or blood of an infected animal. Donor screening is not routinely recommended for Leptospira, however, in febrile patients with myalgia, Leptospira serology (IgM) should be done to rule out active infection. Microscopic agglutination test, with rise in four-fold titer in the paired sample, can also be done to diagnose. Deferral period for 3 months is advised after recovery from acute infection in living donors.[7],[36]

Typhoid fever is cause by Salmonella enterica, serovar typhi via ingestion of contaminated food and water and it is endemic in certain regions of South Asia.[37] There is no role for donor screening for typhoid.

Melioidosis is an infectious disease caused by Burkholderia pseudomallei, which is a Gram-negative aerobic bacillus found in soil and surface water. Melioidosis is endemic in South-East Asia and cases are mainly seen in the rainy season.[38] Melioidosis in transplant recipients can be due to reactivation or primary infection and presents as febrile syndrome with pneumonia after transplant which can be fatal if not treated on time.[39],[40] There are no recommendations for pretransplant screening for melioidosis.

Mycobacterium tuberculosis

MTB can be transmitted via organ grafts and is among the more common donor-derived infections in this region, so it is important to evaluate thoroughly for this infection before donation.[41] A detailed history is mandatory which includes symptoms of active disease, history of TB, and history of TB in close contacts.[42] If a living donor is asymptomatic with a normal physical examination, usually only a chest X-ray is done. If the chest X-ray is suspicious for active disease, then a computed tomography (CT) scan of the chest should be done to rule out any parenchymal lesion or lymphadenopathy. Living donors who are symptomatic (pulmonary or extra-pulmonary) should be evaluated for active TB. Sputum for AFB should be routinely performed in all symptomatic donors who are producing sputum, if not then a bronchoscopy and bronchoalveolar lavage (BAL) should be done and fluid examination for Gene Xpert MTB or other rapid tests should be performed.[42] In the case of hilar/mediastinal lymphadenopathy, fine needle aspiration cytology (FNAC) is done. If urinalysis reveals sterile pyuria, urine AFB stain and culture should be done daily for 3 days. A tuberculin skin test (TST) test or interferon-gamma release assays (IGRA) like Quantiferon TB Gold or ELISPOT TB are not helpful to diagnose active TB and should not be used for it.[43],[44] These tests, can be both false positive and false negative in patients with miliary and disseminated TB.

The western guidelines recommend completing the treatment of a donor before accepting for transplantation,[4],[5] however in India and other South Asian countries, the donor is accepted after completion of the intensive phase along with clinical and radiological resolution (Expert Opinion). For donors with latent TB either 6-month prophylaxis with isoniazid (INH) or 4 month prophylaxis with rifampicin (R-CIN) or 3 months of weekly prophylaxis with INH and RCIN may be given. However, most transplant centers in South Asia do not do TST or IGRA for screening of latent TB in living donors as chances of false positive/negative results are high due to the poor sensitivity and specificity of these tests (Expert opinion). However, some centres might continue to do these tests routinely. TST or IGRA can be done if there is a history of TB in close contacts or if there is a history of inadequate treatment of TB.

Screening of deceased donors for latent TB remains challenging as TST is not possible given time constraints and IGRA is not validated in deceased donors.[43] Deceased donors with known or suspected active TB are not usually accepted as donors. Further detailed discussion is provided in the TB section of these guidelines.

 Donor Screening for Viral Infections



Viral infections are an important cause of morbidity and mortality in SOT recipients, so adequate screening in donors is of paramount importance to prevent (or evaluate the risk for) the transmission of infections to the recipient. The results of both the donor and recipient should be interpreted and compared to estimate the risk of transmission.

Cytomegalovirus

CMV was considered the most common viral infection in SOT recipients before the COVID pandemic. All donors and recipients should be tested for CMV serology (IgG). IgM testing is not recommended as it is not useful, and can be false positive.[45] If the recipient is seronegative pretransplant then repeat testing should be done just before transplant as it has important posttransplant management implications.[46] The risk of transmission depends upon the donor and recipient serological status, however donor seropositivity is not a contraindication for transplant. The risk for transmission is highest in D + R-category, intermediate in D + R+, and lowest in D-R-category and accordingly posttransplant prophylaxis is planned.[46],[47]

Hepatitis B virus

HBV infection is still common in this region, as vaccination for hepatitis B is not universal and is mostly done in high-risk cases and children. All potential donors should be screened for hepatitis B surface antigen (HBsAg) and core antibody (both IgM and IgG Anti-HBc).[48],[49] Donors with HBsAg and IgM anti-HBc positivity have acute hepatitis and are excluded from donation, similarly, donors who are HBsAg negative and IgM Anti-HBc positive might be in the window period and donation should be avoided.[48],[50],[51] Donors who are HBsAg negative and Anti HBc positive might be false positive, recovered from HBV infection or chronic carriers (occult hepatitis B with detectable HBV DNA. In these donors, quantitative HBV nucleic acid testing (NAT) should be done and if it is negative then nonliver organs can be used in recipients who are fully vaccinated with protective Anti HBs-Ab titres of >100 IU/ml or who were previously infected with HBV.[49] HBsAg positive donors can be accepted for HBsAg negative recipients only in exceptional circumstances and with full informed consent as well as plans for long term antiviral prophylaxis.[48],[51] The chances of transmission of infection from HBsAg negative/Anti HBc positive liver donors to anti HBs/anti HBc negative or alone anti HBs or anti HBc positive recipients are significant (in absence of prophylaxis) and these recipients require posttransplant prophylaxis (antivirals against HBV). If a recipient is positive for both anti HBc and anti HBs, then chances of de novo hepatitis B infection from antiHBc positive donor are minimal and a prophylaxis may not be considered.[49],[52] In case of nonliver grafts, the chances of de novo HBV infection from antiHBc donor are low and these donors can be accepted with plans for posttransplant monitoring and/or prophylaxis.[52],[53] Living donors should be evaluated for hepatitis B as close to transplant as possible. Further detailed discussion is provided in the Hepatitis section of these guidelines.

Hepatitis C virus

HCV infection is endemic in some countries in South Asia. India has significant burden of HCV due to its large population.[54] HCV antibody screening is mandatory in all donors. For living donor kidney transplant, if testing for HCV antibody is negative then NAT testing is not recommended.[4],[5] In deceased donor transplant, HCV NAT testing should be done as infection might be in the window period and seroconversion takes more than a month.[5],[8] Anti-HCV antibody positivity implies either a treated infection, or active infection or a false positive result, in which case a quantitative NAT testing is performed; and if the HCV NAT is negative then the donor can be accepted.[5],[8] For liver transplant, NAT testing is performed in all donors. Current guidelines recommend that organs from HCV positive donors can be taken for HCV positive recipients.[5],[55] With the availability of very effective directly acting antiviral (DAA) for the treatment of HCV infections, some centres accept positive donors for HCV negative recipients in kidney, lung and heart transplant recipients and subsequently treat the recipients after transplant.[56],[57],[58] Recent studies have shown excellent treatment outcomes of HCV after liver transplantation from seropositive or viremic donors to hepatitis C negative recipients.[56],[57]

Human immunodeficiency virus

Screening for HIV-1 and HIV-2 is integral part of donor screening. The fourth generation immunoassay test detects both HIV-1 andHIV-2antibodies with very good sensitivity and specificity, and it also detects p 24 antigen.[5],[59] The fourth generation test becomes positive as early as 2 weeks as compared to third generation ELISA which takes a longer time to become positive. HIV NAT is not routinely required except in the case of high-risk donors and in deceased donors where there is uncertainty about history or recent exposure. The acceptance of organs from HIV-positive donors for HIV-positive recipients is only performed in experimental/research settings at this time.[5]

Epstein–Barr virus

Screening for EBV is routinely performed in all donors, as it is an important cause of posttransplant lymphoproliferative disorder (PTLD).[4],[5] There are higher chances of EBV-related PTLD in D+R-cases, especially in children. PTLD can also be seen in seropositive patients when induction with potent induction agents like anti-thymocyte globulin (ATG) or Belatacept is used.[5] The incidence of PTLD is low in South Asia with approximately 1-2% incidence which is much less as compared to that in developed countries.[60]

Hepatitis E virus

Hepatitis E virus (HEV) is highly endemic in South Asian countries and is the most common cause of acute hepatitis in South Asia. HEV spreads via the fecal-oral route and is responsible for significant morbidity, mortality, and acute liver failure in this region.[61] In donors with raised liver enzymes, screening for HEV is recommended in this region by serology testing of HEV IgM, and a donor with acute infection is not accepted, however, those with remote infections (e.g., HEV IgG positive) can be accepted as donors.[62]

Hepatitis A virus

Hepatitis A Virus (HAV) infection is highly endemic in many South Asian countries. HAV infection occurs through ingestion of contaminated food or water and by 18 years of age, 90% of the population is seropositive for HAV.[61],[63] There are no reports of the donor to recipient transmission of HAV in organ transplantation. Donors who have resolved hepatitis related to acute HAV can be accepted and these recipients do not need special treatment in the peri-operative period.

Arboviruses

Arboviral infections like dengue, chikungunya, and zika virus are endemic in South Asia; however, routine screening for these infections is not recommended in asymptomatic donors and those with active infection are often symptomatic.[64],[65] As disease transmission is periodic/seasonal, donor screening for dengue (NS1Ag) should be done during periods of high transmission as a person might be in incubation periods.[65] If donor is confirmed to have any of these arboviral infections, then donor deferral for 30 days is recommended for dengue and chikungunya and 120 days for Zika virus. In patients with a recent history of fever or new sexual contact, it is prudent to wait for two weeks and reassess before proceeding with the evaluation. The initial screening should be done by polymerase chain reaction (PCR) or antigen testing and after 7 days with IgM antibodies against the specific virus.[5]

Other viruses

Japanese encephalitis virus (JEV) is a flavivirus and is spread by mosquitoes. JEV is the major cause of viral encephalitis in many countries of South Asia.[66] No donor-derived cases of JEV have been reported, so routine screening of donors for JEV is not recommended; but organ harvesting from a person suffering from unknown encephalitis, particularly for which treatment does not exist, is contraindicated.[26]

Rabies is very common in the South Asia region, the virus can be acquired through the bite of an infected animal and rarely through organ transplant.[67] It causes encephalitis but the process may take weeks to months and it continues to be largely fatal. As such, donor-derived rabies is uncommon, so testing for rabies in a case of encephalitis should be done after common causes have been ruled out. The demonstration of antibodies in the serum or in cerebrospinal fluid (CSF), in the absence of a history of vaccination for rabies is indirect evidence of rabies infection. The negative serological tests do not rule out rabies. Demonstration of virus antigen through fluorescent antibody test in brain biopsy specimen (which are largely obtained postmortem) is the gold standard.[68] There is no specific anti-viral agent effective against rabies. As the disease is mostly fatal and the incubation period ranging from few days to few years, it is advised not to procure organs from a donor with unspecified encephalitis or with significant rabies exposure risk.[69]

Influenza is a major cause of significant morbidity and mortality in transplant recipients. Donor-derived influenza transmission is very rare; there have been few reports of both influenza A and B getting transmitted through donor in lung transplant recipients.[70] Deceased donors suspected to have influenza should be screened using NAT and organs from these donors may be used with caution along with treatment with oseltamivir for 5-10 days, except for lung and small bowel where donation is contraindicated.[71],[72]

Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic is currently ongoing and is responsible for high morbidity and mortality in transplant recipients. All potential SOT donor should be assessed for signs and symptoms that are associated with COVID-19. All prospective donors should undergo diagnostic molecular testing for SARS-CoV-2 within 24–48 before donation, If SARS-CoV-2 is detected, the donation should be deferred.[73] Transplant should be deferred in prospective donors with signs or symptoms suggestive of COVID despite negative test for COVID, similarly donation should be deferred if there is the history of exposure to COVID-19 patient in previous 2 weeks.[73] For living donors nasopharyngeal sample is sufficient, however for deceased donor, it is recommended to take a sample from the lower respiratory tract as there are reports of transmission of COVID from a deceased donor with negative upper tract samples.[74] The optimal duration of the waiting period for donation is not known, but it is suggested to wait for at least 4 weeks after resolution or 14 weeks from acquiring an infection.[73],[74],[75]

Various other viruses

Routine donor screening for herpes simplex 1 or 2 is not required as effective prophylaxis is available; cases of acute infection without adequate treatment should be deferred until better.[5],[8] West Nile virus, human herpes virus-8 (HHV-8, Kaposi sarcoma virus), and HTLV-1/2 are not common in this region so routine screening is not recommended.

 Donor Screening for Fungal Infections



There is a significant burden of fungal infections, especially invasive fungal infections (IFI) in organ transplant recipients in South Asia due to certain geographical and demographic features.[76] We will discuss the screening of relevant invasive and other endemic fungal infections in SOT donors.

Candidiasis

The incidence of candidemia is high in Asia and up to 50% of the global cases of candidemia have been reported from Asia.[77] Infections associated with Cândida species may occur in the setting of positive preservation fluid cultures or possibly due to contamination at the time of organ procurement. Bowel perforation in the deceased donor is another common source of Cândida contamination of the allograft.[5] Infections with Candida species without systemic spread are not a contraindication for transplantation, with the exception of the involvement of the infected organ.[4],[5]

Cryptococcosis

Routine screening of transplant donors is not recommended in South Asia. Cryptococcosis should be considered in donors with undiagnosed meningoencephalitis and isolated pulmonary nodules in the presence of receipt of corticosteroids, immunosuppressants, sarcoidosis, end-stage liver or renal disease, and rheumatologic disorders. Serum cryptococcal antigen should be performed in donors with meningoencephalitis and in those with unexplained pulmonary lesions or fever of undetermined origin if they have underlying medical conditions predisposing to cryptococcosis.[78] CSF analysis for donors with meningoencephalitis of undetermined etiology and biopsy with histopathology for focal lesions are suggested.[78] Use of organs from untreated donors with documented systemic or CNS cryptococcosis is not recommended. If donor disease is detected posttransplant, the recipient must be treated preemptively.[79]

Aspergillosis

Donors with active invasive mold infections are not suitable for organ procurement. Contaminated preservation fluid, infected donors, or breaches in aseptic techniques during organ procurement, transport or implantation has been shown or suspected to be the mode of transmission of aspergillosis.[79] Donors with suspected pulmonary Aspergillus infection should be screened with BAL, culture and tissue diagnosis before accepting for transplant.[80]

Mucormycosis

In India, mucormycosis is an endemic infection and a review of several Indian studies has revealed a prevalence rate of 0.14 cases/1000 population, which is 70 times the worldwide rate.[81] There are no guidelines to screen donors for mucormycosis.

Endemic mycoses

Endemic mycoses are a frequent problem in the Asia-Pacific region but, there is limited data in SOT recipients. Histoplasmosis caused by Histoplasma capsulatum, sporotrichosis (Sporothrix) caused by Sporothrix schenckii and penicillosis caused by Penicillium (talaromyces) marneffei are endemic fungal infections seen in several countries of South Asia.[82]

Histoplasmosis, penicillosis, and sporothrix are endemic in South East Asia and North-eastern India, where they are seen in HIV and other immunocompromised patients including transplant recipients.[82],[83] Routine screening for these infections is not indicated pretransplant. If there is a nodule on chest imaging then further evaluation with sputum, BAL and imaging with CT should be done to rule out these. If there is lymphadenopathy, hepatosplenomegaly or skin lesion then FNAC should be performed to confirm the diagnosis, given that other endemic infections (such as TB) could mimic these infections.[83] Donors with active histoplasmosis are excluded from donating organs. Living donors may be reconsidered for donation after adequate treatment for at least 3–6 months with the resolution of signs and symptoms of active disease and clearance of Histoplasma antigen.[84] Radiographic sequelae of old histoplasmosis are not considered a contraindication for transplant. Primary prophylaxis for these infections in endemic areas is not recommended before organ transplant.

 Donor Screening for Parasitic Infections



Some of the endemic parasitic infections in South Asia are: toxoplasmosis, strongyloidiasis, malaria, and leishmaniasis.

Toxoplasma, a protozoan parasite has a prevalence of 4.7%–37.3% in the general population in India. Toxoplasma gondii is an opportunistic infection seen in immunocompromised individuals including SOT recipients, particularly in heart transplant recipients, however, occasionally transmission in other organs can also occur.[5],[6] Toxoplasmosis occurring in the first 3 months posttransplant is well recognized and is mostly donor derived. Infections occurring >3–6 months is mainly due to reactivation of latent disease or de novo infection due to immunosuppression.[4],[5] The majority of Toxoplasma infections occur by ingestion of cysts in infected meat, soil, or water infected with cat feces which contains oocytes. The prevalence depends upon the seropositivity of the donor and recipient and the use of chemoprophylaxis. In the donor positive, recipient negative (D+/R−) situation, transmission is highest with heart transplantation (50%–75%) without prophylaxis, however a recent review of cases has shown it be common in other organ transplant recipients also.[85] Screening is done by serology for Toxoplasma (IgG) in donor and recipient and if donor is seropositive and the recipient is negative then prophylaxis should be given.[86] Prophylaxis is similar to Pneumocystis jiroveci, i.e., trimethoprim/sulfamethoxazole or if there is an allergy to sulpha then atovaquone with or without pyrimethamine/leucovorin can be used.[3] Toxoplasma IgM serology or NAT testing is done if the donor is suspected to have an acute infection.

Strongyloides stercoralisis an endemic infection in this South Asia and transmission of infection from donor to recipient (s) or reactivation of latent infection in the recipients at the time of transplant can lead to acute infection and hyperinfection syndrome.[16],[87] Primary infection occurs through contact of skin with soil infected with human feces containing filariform larva. ELISA IgG is the preferred method of screening, as stool examination is poorly sensitive.[5] Donors with eosinophilia should be evaluated for Strongyloides by serology. Infected donor as well as recipients of organs from infected donors should be treated with ivermectin as the mortality with disseminated Strongyloides is close to 80%.[87],[88] Empiric treatment with stat dose of Ivermectin can be carried out in all transplant recipients when access to investigations is limited.

Malaria is endemic in South Asia and can be transmitted from the parasitized RBCs in the donor organ or reactivation of hypnozoites from donor liver. Symptomatic donors should be screened with thick smear and rapid antigen tests.[6],[85] Molecular diagnostics like real time PCR have a much more higher sensitivity (detecting 0.35 parasites per microlitre) and can be used to detect asymptomatic parasitemia missed by smear examination to prevent donor-derived infections in highly endemic areas. All donors with active infection are deferred until treated adequately.[6] Posttreatment deferral period depends upon regional recommendations and it should be kept for 3 months in this region. Permanent deferral for Plasmodium malariae infection is recommended. The details of prophylaxis and treatment are covered in other parts of these guidelines.

Visceral leishmaniasis (VL) is a caused by the protozoan Leishmania and is transmitted by the sand fly.[89] VL is common in the eastern part of India and Nepal. Routine screening of donors is not recommended due to the asymptomatic nature of infection and no clear proof of transmission from donor to recipient. Screening should be done if suspecting leishmaniasis in endemic region.[90] Donors with active disease should not be taken and disease should be fully treated before organ donation is done. Positive serology without evidence of active infection may suggest previous exposure, is not a contraindication to donation.

Trypanosoma cruzi is not endemic to this part of the world, so screening is only indicted if the donor has resided in an endemic region (Central or South America) or donor was born to a mother from that region. Donors infected with Trypanosoma cruzi are not usually taken for heart transplant, however other organs can be used with careful posttransplant monitoring by PCR and microscopy and treatment with benznidazole.[91]

Filariae are a group of tissue-based nematodes that can grow in the subcutaneous tissue and lymphatic vessels. Filariasis is endemic in some pockets in North India.[92] The disease spectrum can range from asymptomatic patients to episodes of lymphangitis, orchitis, funiculitis, or epididymitis. Long-standing obstruction of lymphatic vessels may lead to hydrocele, chyluria or lymphatic varices Screening of donor should be done if there is a high index of suspicion.[93] The diagnosis is established by detection of circulating filarial antigen (for W. bancrofti infection only), demonstration of microfilariae or filarial DNA in the blood, or of adult worms in the lymphatics. Donors with the active disease must be treated fully before organ donation with either two-drug regimens of diethylcarbamazine plus albendazole or ivermectin and albendazole.[93]

 Screening of the Transplant Recipient



Adequate screening is of vital importance in prospective transplant recipients as infections are common in these patients and lead to significant morbidity and mortality. In kidney transplant recipients, urine culture and chest X-ray is routinely done to rule out any obvious infection. In symptomatic patients with fever, blood cultures and culture of other body fluids are performed. In patients with a history of severe vesicoureteral reflux with recurrent infections or autosomal polycystic kidney disease with recurrent UTI, nephrectomy might be required before transplant.[4],[5] In patients with suspicious chest lesions, CT scan and bronchoscopy may be needed to evaluate for active infection (or malignancy). Kidney transplant recipients with vascular catheters as a mode of dialysis have higher chances of infections as compared to patients with AV fistulae. In patients with central venous catheters and line sepsis, it is better to remove the line and treat with antibiotics for at least one week after removal, before accepting them for transplant.[3],[4],[5] The knowledge of local microbiological patterns and susceptibility is very important when developing empirical antibiotic therapy and perioperative antibiotic prophylaxis.[3],[6]

Liver transplant recipients are at high risk of sepsis due to poor nutrition, ascites, and indwelling lines. Spontaneous bacterial peritonitis is common in these patients and adequate treatment is crucial before taking them for transplant. Patients with biliary tree abnormalities are predisposed to cholangitis so adequate screening is important before transplant.[3],[4],[5]

Patients for pancreatic transplants may be at high risk of various infections due to poorly or uncontrolled diabetes. Adequate treatment of diabetic foot infections and osteomyelitis is mandatory before accepting them for transplant.[3],[4],[5]

Candidates awaiting heart transplant have a higher risk of infections due to intravascular catheters and the presence of ventricular assist device (VAD) in some. If infection is not eradicated but only controlled with antibiotic therapy then removal of VAD at the time of transplant with appropriate antibiotic therapy often cures the infection.[5],[94]

Lung transplants recipients may have frequent colonization with more resistant organisms so knowledge of local flora with susceptibility, as well as the results of donor BAL cultures should be available to provide optimal prophylaxis.[5],[95]

Typhoid fever is endemic in certain regions of South Asia.[37] It is advisable to vaccinate prospective recipients in the endemic region against typhoid. Two vaccines are licensed for use, Ty21a (live attenuated oral) and an injectable purified Vi capsular polysaccharide vaccine.[96] A typhoid conjugate vaccine, Typbar-TCV has recently been prequalified for use in several countries

Recipient screening for mycobacterial infection

TB is endemic in South Asian countries, and the incidence of TB in SOT recipients living in South Asia is between 5.7% to 12.3%.[41] All transplant candidates are screened with chest X-rays to exclude active/healed pulmonary TB. All patients in whom there is suspicion of active TB clinically, on chest X-ray or routine abdominal ultrasound, are further evaluated by imaging with CT scan and either sputum or bronchoscopy and BAL for AFB stain and culture. Patients with lymphadenopathy should have FNAC or biopsy to confirm the diagnosis. Patients with pleural effusion or ascites should have fluid testing and appropriate tests including ADA and Gene Xpert (or other rapid tests) should be done to exclude TB.[97] TST or IGRA although recommended by WHO but is not routinely done in asymptomatic patients with normal physical examination, X-ray chest and USG as TB is endemic in South Asia and we are primarily screening for active disease. A tuberculin skin test (TST) test or interferon-gamma release assays (IGRA) like Quantiferon TB Gold or ELISPOT TB can be done in patients with h/o close contacts with TB or inadequately treated TB. Some centres might continue to these tests to screen for latent TB. Routine prophylaxis with isoniazid monotherapy is not practised by most centers as the risk of hepatotoxicity is significant and there is no effect on all-cause mortality.[98]

Patients with active MTB infection should ideally complete the treatment before being taken for transplantation, however practically it is difficult to wait due to poor quality of dialysis, and risk of other infections during this time, so most centers in India and South Asia accept the recipients after completion of intensive phase (2–3 months) with 4 drugs including R-CIN and later on continue with 3 drugs excluding R-CIN for 1 year to complete the treatment (Expert Opinion).

Recipient screening for fungal infections

IFI are common in SOT recipients in this region. In a recent study in KTRs from India, invasive candidiasis was the most common IFI followed by mucormycosis, invasive aspergillosis, and cryptococcosis.[99]

For Candida infection, recipients who receive organs from bacteremic or fungaemic donors (often either at least partially treated or recognized in hindsight) should receive targeted antimicrobial therapy for at least 14 days. Echinocandins are the drug of choice followed by fluconazole.[3],[79]

Cryptococcal disease in SOT recipients is considered to represent reactivation of quiescent infection in the majority of patients. Among SOTs, lung transplant recipients are at the highest risk for cryptococcosis. Routine screening of transplant recipients is not recommended.[78] Donor-derived cryptococcosis should be considered in the following scenarios: unexplained early meningitis within 30 days after transplantation; Cryptococcus demonstrated microbiologically or histologically at the surgical or graft site; cryptococcosis documented at any site in the first 30 days after transplant, particularly at atypical sites outside the lungs and CNS; or cryptococcal disease diagnosed in another recipient from the same donor.[5],[78]

Invasive Aspergillosis (IA) is an important cause of morbidity and mortality in SOT patients in Asia. The hot and humid climatic conditions in most Asian countries as well as construction activities lead to very high environmental fungal colony counts. Pretransplant fungal screening for Aspergillus and other molds by sputum culture, imaging, and BAL is required in lung transplant recipients. Patients with colonization may need prophylaxis with antifungals.[3] Patients who are symptomatic would require adequate treatment to achieve complete resolution of the radiological picture along with clinical and microbiological resolution before accepting them for transplant.[80] Some cases may benefit from additional treatment or prophylaxis after transplant, at the discretion of the treating team. IFI are less common in candidates for kidney and liver transplant, except those with previously failed transplant on some immunosuppressive medications, so screening and treatment is not usually necessary before transplant.

Routine screening for endemic fungal infections like histoplasmosis, penicillosis, and sporothrix is not usually necessary in transplant recipients.[93] Transplantation should be avoided during active disease until the treatment is completed. Primary prophylaxis for histoplasmosis in endemic areas is not recommended before organ transplant. Recipient with pretransplant histoplasmosis needs to be monitored clinically. Histoplasma infection can have a similar presentation to TB and an FNAC or biopsy of lymph nodes is indicated for suspicious lesions.[82] Screening of penicillosis and sporothrix should be done in the endemic region in the presence of characteristic skin or subcutaneous lesions.[4],[5]

Recipient screening for parasitic infections

Screening for Strongyloides is recommended in transplant candidates in South Asia. As stool examination is not very sensitive, serology should be done in recipients and positive patients should be treated with ivermectin (preferred) or thiabendazole before transplant.[3],[5] Infection in recipients may be precipitated by pulse doses of corticosteroids.[87]

Screening for Toxoplasma (IgG) must be done in all patients for heart transplant. Thowever.[5] A recent review showed that it is not uncommon in other organ transplants.[85] Prophylaxis with TMP-SMX for pneumocystis done for 6 months in all transplant recipients, also covers Toxoplasma. If there is allergy to sulpha then atovaquone with or without pyrimethamine/leucovorin can be used.[3]

Other parasitic infections like malaria are acute infections and screening is indicated only in febrile patients. Leishmania screening is not routinely recommended before transplant.[89]

Routine screening for Trypanosoma cruzi is not recommended in this region unless there are exposures in Central or South America.

Recipient screening for viral infections

Routine screening for HBV, HCV, HIV, CMV, varicella-zoster virus (VZV), and EBV should be performed in all transplant recipients [Table 1]. In kidney and other SOT transplant recipients except for liver, HBsAg and core antibody testing are sufficient (IgG and IgM) for hepatitis B screening, however for liver transplant candidates, HBV DNA PCR is also done routinely.[5],[100] Vaccination for HBV and testing for Anti-HBs should be performed in all transplant recipients and if titers are inadequate, these patients should be revaccinated or booster doses should be given as required as the serological response is poor posttransplant. As HCV infection is common in dialysis units in India and South Asia, and antibody testing may not be sufficient, it is advisable to do HCV NAT qualitative in all patients before kidney transplant. In liver transplant recipients, HCV NAT is done as a part of routine evaluation.[4],[5] Patients who are HBV or HCV positive before transplant should be treated and once the viral load is undetectable or sufficiently low, they can be considered for transplant with the continuation of treatment posttransplant. As South Asia is endemic for HAV and HEV virus, all liver transplant recipients should undergo serology for these (IgM Anti-HAV and IgM Anti-HEV) before transplant.

There are standard guidelines for HIV patients before taking them for transplant. Patient should have HIV RNA <50 copies/ml and CD4+ T-cell count of >200 cells for at least 4 months and should not be having any opportunistic infection within this period.[5],[101]

Universal screening for CMV is recommended for all SOT recipients by IgG. Patients who are seronegative for CMV with seropositive donors (D + R-) should be kept on prophylaxis with valganciclovir for 6 months in kidney and lung transplant recipients and 3-6 months for other organs.[5],[46] For all other serostatus (D + R + and D + R−), prophylaxis for 3 months is sufficient. The dose of prophylactic valganciclovir is 900 mg daily, which should be adjusted according to GFR. In the South Asian region, many centers do not give routine prophylaxis to D+R + and D-R+ except those who receive ATG induction (Expert Opinion).

Serology for EBV (IgG) is recommended for all transplant candidates. EBV negative recipients with EBV positive donors should not get induction with ATG or belatacept.[5] In patients with D+/R-serology, close monitoring for signs/symptoms and EBV load monitoring by PCR should be done periodically usually in the first year after transplant and if EBV load is increasing or persistently elevated, reduction of immunosuppression is recommended as chances of posttransplant lymphoproliferative disease is high.[102]

Serology for varicella-zoster (VZ) should be done in all transplant candidates and patients with negative serology for VZV should receive pretransplant vaccination as primary VZV infection can be fatal in transplant recipients.[103] This is a live viral vaccine that is not usually given after transplant.

Acute viral infections like dengue and chikungunya are endemic in this region, and patients who have fever in the previous 2 weeks should be screened for these viruses. As dengue virus is a seasonal virus, screening by rapid antigen test or IgM should be considered in hyperendemic areas in the peak season. Additionally, the Zika virus is endemic or active in some parts of India (Kerala), where routine screening should be considered.

Screening for other viruses like HTLV-1, HHV 6, 7, 8, herpes simplex virus is not routinely required in this region. Vaccination for measles, mumps, and rubella should be completed before transplantation as it is a live vaccine and cannot be given after transplant.[103]

COVID-19 screening and vaccination

Screening for COVID-19 is mandatory before transplantation in all recipients. PCR testing from nasopharyngeal swab should be conducted 24-48 hours before transplantation.[75] Recipients with the history of COVID-19 should be deferred for transplantation for 4-12 weeks after complete recovery of infection, and demonstration of 2 negative reports of Reverse transcription-PCR testing 1 week apart. A noncontrast CT scan should also be done in previously positive patients before transplant to know the residual lung damage.[104]

SOT candidates should receive SARS-CoV-2 vaccines while they are awaiting transplant. In general, vaccination should be completed at least 2 weeks before SOT for best response or started at least 1 or more months after SOT. It is recommended to take at least one dose of vaccine 2 weeks before proceeding for any SOT.[105] Vaccination of household members, close contacts, and health-care providers who provide care for immunocompromised patients is imperative to protect immunocompromised patients from infection.[104],[105] If possible the recipient should undergo anti-COVID antibody testing to assess the response of vaccination, with thought to giving additional doses of vaccine if needed.

 Conclusions



Pretransplant screening of prospective donors and recipients is of paramount importance to assess the feasibility and safety of transplantation. It also provides an opportunity to detect potential infections which could be transmitted and need to be adequately treated. Pretransplant assessment is required to decide about optimal pre-emptive and prophylactic strategies for each transplant recipient, and vaccination as required. There are specific infections that are clinically important in various regions so it is imperative to have regionwide guidelines to help transplant specialists.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest

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