|Year : 2017 | Volume
| Issue : 3 | Page : 107-110
Infections in transplant “Bugs which bug transplantation in India”
Department of Nephrology, Osmania Medical College and General Hospital, Hyderabad, Telangana, India
|Date of Web Publication||20-Dec-2017|
Dr. Manisha Sahay
Department of Nephrology, Osmania Medical College and General Hospital, Afzal Gunj, Hyderabad - 500 012, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sahay M. Infections in transplant “Bugs which bug transplantation in India”. Indian J Transplant 2017;11:107-10
Renal transplantation is the best option for patients with end-stage renal disease. The number of transplants is increasing worldwide. Currently, approximately 7500 kidney transplantations are performed at 250 kidney transplant centers in India. Of these, 90% come from living donors and 10% from deceased donors. The data are not as accurate as would be desirable due to the absence of a national transplant registry.
The number of deceased donor transplants has also increased in India over the past few years. The organs transplanted include kidneys, liver, heart, lungs, pancreas, and bone marrow. Multiorgan transplantations such as kidney-pancreas in type 1 diabetic with end-stage kidney disease and liver-kidney pancreas in patients with end-stage renal disease due to oxalosis are also being performed in many centers across India.
The most common immunosuppression protocol includes calcineurin inhibitors (CNI) such as tacrolimus or cyclosporine, mycophenolate mofetil (MMF), and steroids. Induction with antithymocyte globulin (ATG) is used in high-risk transplants, i.e., second transplant, deceased donor transplants, ABO incompatible transplants, etc., interleukin-2 receptor (IL2R) blocker basiliximab is used in some centers in place of ATG.
On the one hand, the use of potent immunosuppression has improved the graft survival and the episodes of rejection have come down, on the other hand, the infections have become one of the major causes of morbidity and mortality posttransplant. Infections also increase the risk of new-onset diabetes after transplantation, cardiovascular events, posttransplant lymphoproliferative disorders (PTLDs), and adversely affect allograft outcomes.
The major factors responsible for breach in immunity are immunosuppressive drug-induced anti-proliferative activity leading to mucosal erosions, transient cytopenias, uremia, hyperglycemia, malnutrition, use of invasive devices (leading to trauma, colonization, and infection), and abnormalities in tissue perfusion (vascular or surgery-related etiologies) which predispose the transplant recipient to myriad of infections. Cytomegalovirus (CMV) infection, Epstein–Barr virus (EBV) infection and HIV infection may themselves cause immunomodulation and predispose to other infections. Immunosuppressive drugs play a major role in compromising the host defense mechanisms. The state of overall immunosuppression is important rather than any individual drug. ATG increases the risk for CMV infection, BK virus (BKV) viremia and nephropathy, pneumocystis species, and other invasive fungal pathogens. Basiliximab has a lesser risk of infections as compared to ATG, but the latter is more potent. CNIs reduce IL2 production while steroids depress many aspects of cellular and humoral immunity. Azathioprine and mycophenolate are anti-proliferative agents and are involved with impaired lymphocyte proliferation. Extremes of recipient age, female gender, deceased donor source, older donor age, CMV +ve donor, longer time on dialysis, and systemic lupus erythematosus as the cause of kidney disease increased the infection risk.,
Infections can be bacterial, viral, fungal, parasitic, and also infections with unusual organisms. They may be derived from the donor or may be acquired from the environment. Travel and pet exposure may also contribute to unique infections in recipients. Some recipients may harbor infections before transplant.
According to Rubin's calendar, the infections occurring in first posttransplant month are due to healthcare-related causes, i.e., central lines, urinary stents, catheters, etc. and are bacterial in nature. Clostridium difficile also be seen in 1st month. Infections from 1st month to 6th month are due to opportunistic organisms which include CMV, BKV, varicella zoster virus (VZV), EBV, herpes simplex virus (HSV), and fungal infections such as pneumocystis carinii and Aspergillus, while after 6 months infections are mostly community-acquired infections like those seen in the general population. However, studies by Indian authors have shown that the timetable of infections is changing due to changes in drugs and chemoprophylaxis regiments and transplant infections may occur beyond 6 months after chemoprophylaxis is over.,
In a study in this issue from South India by Sriperumbuduri et al. the authors found that the most common site of infections was bacterial infections of urinary tract (34.5%) followed by bloodstream infection (sepsis) in 15.2%. The overall etiology of infections was viral (31.2%), mycobacterial (9.7%) fungal (6.2%), and others. Parasitic infections (giardiasis and Strongyloides hyperinfection syndrome) were seen in 2 (1.4%) patients. CMV accounted for 14.5% and BKV for 5.5% of total infections. Majority (77.1%) of the infection episodes occurred in the first 6 months of transplantation.
Some common infections seen in Indian transplant recipients and highlighted in this issue are discussed below.
| Viral Infections|| |
CMV is one of the most common viral infections posttransplant and may present with cytopenias, gastrointestinal complaints and renal dysfunction. CMV prophylaxis in high-risk cases (those receiving ATG or for those where recipients are seronegative but receive organs from seropositive donors) has reduced posttransplant CMV to a large extent, but late infections may occur. CMV was demonstrated in 14.5% in the study by Sriperumbuduri et al. Ganciclovir and valganciclovir are effective. Foscarnet, cidofovir, and intravenous immunoglobulin (IVIg) are used for resistant cases. Maribavir, brincidofovir, and letermovir are some of the new drugs for CMV.
Parvovirus presents with pure red cell aplasia in transplant patients. IVIg is used for treatment.
BKV manifests with allograft dysfunction and ureteral strictures. BKV was seen in 5.5% in the study from South India. Reduction of immunosuppression, withdrawal of MMF, leflunomide, cidofovir, and IVIg can be used for treatment.
EBV may manifest with PTLD characterized by unexplained weight loss. In a study from India by Janani et al. EBV was demonstrated in 51.4%. However, no cases were reported in Sriperumbuduri series.
Hepatitis C virus (HCV) can get activated posttransplant or may be derived from the donor. More and more transplants are being done for HCV positive patients and recipients should undergo genotype and viral load and should preferably receive anti – HCV treatment before transplant. Interferon was earlier used for treatment. It has now been largely replaced by directly acting antivirals. Elbasvir and grazoprevir are safe in CKD. Treatment for HCV can be done posttransplant as well if the waiting time till transplant is less. Pangenotype drugs such as Velpatasvir and sofosbuvir have simplified treatment. Hepatitis B (HB) can be treated with lamivudine or entecavir. Blood polymerase chain reaction (PCR) was positive in 100% with raised serum glutamic pyruvic transaminase (>40 U/L) in Sriperumbuduri et al. study  however, the etiology was not mentioned.
HSV can present posttransplant with varied manifestations. High index of suspicion is required to diagnose HSV. Treatment improves graft and patient survival. In a case report by Ayyappa et al. in this issue, the authors have described posttransplant HSV and its management.
Human immunodeficiency virus was earlier considered to be a contraindication for transplantation. However, patients with HIV are no longer excluded from transplant lists provided the recipient is stable, viral load is undetectable, CD4 counts is >200/ul for at least 6 months, and the recipient is free of malignancies and opportunistic infections. A large study done from Africa has demonstrated that outcome of transplants in HIV-positive recipients is not different from HIV-negative recipients. The rate of graft survival at 1 year was 93% (95% confidence interval, 74–98), decreasing to 84% at 3 years and 5 years in this study.
In a paper in this issue by Kavalam et al. successful renal transplant was carried out in a patient with retroviral infection complicated by Kaposi's sarcoma where they have highlighted problems with immunosuppression in HIV recipients. There are three unique issues related to drug use after transplantation in HIV. The immunosuppressive drugs used after transplantation do not cause HIV viral proliferation though azathioprine may be an exception. One of the major issues is the interaction of antiviral drugs with the immunosuppressant drugs. Commonly used anti-retroviral drugs such as lamivudine (nucleoside analog reverse-transcriptase inhibitor [NRTI]), abacavir (NRTI) along with protease inhibitors like ritonavir can have significant interactions with CNIs producing very high serum levels and hence toxicity as they inhibit cytochromeP450 which metabolizes tacrolimus while nonnucleoside reverse transcriptase inhibitors such as efavirenz and nevirapine may increase the metabolism of CNIs with resultant inadequate levels and lead to rejection. Hence, frequent monitoring of drug levels is needed. Furthermore, the drugs can cause nephrotoxicity especially may lead to the formation of urine crystals, for example, in indinavir.
Varicella-zoster may present with involvement of multiple dermatomes and was seen in 7.6% in a study from South India. Sahay have reported a case of severe posttransplant varicella. Acyclovir is used for treatment. This highlights the importance of pretransplant screening and vaccination.
Tuberculosis is common in our population and recipients should be evaluated for latent tuberculosis. A purified protein derivative (PPD)/Mantoux test of >5 mm needs to be evaluated. As PPD may be positive in bacillus Calmette–Guérin (BCG) vaccinated individuals interferon-gamma release assay (IGRA) (Quantiferon gold) should be done which distinguishes between BCG, nontuberculosis mycobacteria and pathogenic TB and is based on interferon production by lymphocytes. Elispot which measures the lymphocyte numbers may also be used for latent TB. If latent TB is detected the recipient should be treated before transplant. Treatment of latent TB may include isonicotinylhydrazide (INH) monotherapy for 9 months or rifampicin and INH for 6 months. For active TB newer tests like fluorescence microscopy/LED microscopy are more sensitive than conventional Ziehl Neelsen ZN or Auramine. For TB culture conventional methods which took 4–8 weeks have been replaced by liquid culture - 15 days, i.e., mycobacterial growth indicator tube and radiometric BACTEC methods which give faster results. Molecular methods (PCR, real-time PCR, transcription mediated amplification, loop amplification, and ligase method) have increased detection but should be done with microscopy and culture as molecular methods may be positive even after treatment as nonviable organisms are also detected. For drug sensitivity testing microscopic observed drug susceptibility rapid culture using Middlebrook medium, line probe assay (LPA) and gene Xpert/cartridge-based nucleic acid amplification testing (CBNAAT) testing is used. Newer LPA for extensively drug-resistant (XDR) TB is available. Rapid PCR (nucleic acid amplification) based test for multidrug-resistance (MDR) and XDR TB is available known as gene Xpert/CBNAAT which detects MTB directly from sputum/other specimens and also tests for Rifampicin resistance in 3 h. Gene Xpert can be used as first test instead of microscopy and culture in MDR, HIV TB, or CSF TB may be used as first line in all patients and also for follow-up for smear negative patients.
Posttransplant management of TB is complicated by drug interaction of immunosuppressive drugs with rifampicin. Rifampicin is an enzyme inducer and decreases the levels of tacrolimus, cyclosporine, everolimus, sirolimus, etc. European kidney transplantation guidelines recommend 2 months of isoniazid, rifampicin, and pyrazinamide therapy (with the addition of ethambutol when there is >4% isoniazid resistance), followed by isoniazid and rifampicin for an additional 4 months. Immunosuppressive drug levels should be monitored. Some protocols described nonrifampicin regimes which include INH and Ethambutol and pyrazinamide or levofloxacin for 2 months, followed by a two-drug regimen of INH plus ethambutol or pyrazinamide for 12–18 months
If both INH and rifampicin cannot be given, then the combination of 4–6 drugs along with at least one injectable is given. In this issue, Kirushnan et al. have described two cases of TB one in the esophagus while in the other lymphocele showed tubercle bacilli. Oesophageal TB was diagnosed by histology and Quantiferon gold assay while AFB was demonstrated in lymphocele fluid.
Nocardia may be seen rarely. Fungal infections are common posttransplant and are an important cause of morbidity and mortality. Fungal infections were documented in 6.2% recipients in the study from South India. Many centers use fluconazole for antifungal prophylaxis. Candida, aspergillus, and pneumocystis jeroveci are the most common infections posttransplant in India. Aspergillus is common in and around construction sites and saprophytic fungi are acquired from gardening. Azoles, fungins, and amphotericin can be used for treatment depending on the type of fungal infection. Amphotericin is nephrotoxic and liposomal amphotericin may be used. It covers most fungal infections except Aspergillus niger. Intravenous voriconazole is relatively contraindicated as the vehicle is nephrotoxic. In this issue, Fernandes et al. have reported eumycetoma by an unusual fungus.
Other sources of infections are Cryptosporidium from well water and Salmonella More Details and listeria from uncooked meat or dairy products, and leptospirosis in field workers. Parasitic infestations, for example, giardia and strongyloides may be seen.
| Diagnosis|| |
Smears, cultures for bacteria and multiplex PCR aid in diagnosis. Serology may not be accurate and PCR often provides evidence of viral infections (HCV, HBV, HIV, CMV, EBV, BKV, VZV, HSV, etc.). Bone marrow examination may show pure red cell aplasia and may point toward parvovirus. Erythroblasts may show intranuclear inclusions in parvovirus infections or basophilic owl-eyed inclusions in CMV. Haufen are icosahedral aggregates of polyomavirus particles and Tamm–Horsfall protein that can be detected in the urine of kidney transplant patients with BKV nephropathy using negative-staining electron microscopy. Immunohistochemistry and tissue PCR may sometimes aid in the diagnosis of CMV or parvovirus, BKV, and other viral infections.
Gram stain, stains for fungus (potassium hydroxide mount, lactophenol, Gomori methanamine stain) cultures (on solid, liquid, and Sabouraud's medium and special media), serology, and PCR for quantitative and qualitative analysis are helpful for diagnosis of fungal infections. Galactomannan may be useful for diagnosis of Aspergillus. Pan fungal detection of b–glucan may be useful.
IGRA (Qf Gold)/Elispot for latent TB and PCR/gene Xpert for active TB (as discussed above) is used for diagnosis and detection of resistance to drugs.
Early and aggressive use of imaging techniques such as ultrasound, computed tomography scans or magnetic resonance imaging, and invasive procedures such as bronchoalveolar lavage, imaging-guided aspiration, and/or biopsies for obtaining specimens for histological and/or microbiological examination are essential for accurate diagnosis.
| Prevention Is Better Than Cure|| |
Prevention of infections includes recipient and donor screening, minimizing the use of blood and blood products, leukocyte filtersk and vaccinations pretransplant. Guidelines for screening of donors and recipients have been published by kidney disease improving global outcomes and endorsed by other societies.,,,
Donor candidates should be assessed for factors associated with an increased likelihood of endemic or unexpected infections, including geographic, seasonal, occupational, animal and environmental exposures. Donor candidates should complete a urinalysis and testing for HIV, HBV, HCV, CMV, EBV, and Treponema pallidum yphilis). PPD or IGRA should be done for the donor if indicated by regional epidemiology or individual history. Avoid donors with meningitis, encephalitis, history of animal bites, and severe acute respiratory syndrome. Transplant programs should develop protocols to screen donor candidates for emerging infections in consultation with local public health specialists. In general, donor infection risk factor and microbiological assessments should be performed or updated as close in time to donation as possible. For HIV, HBV, and HCV, screening should be current within 28 days of donation. Pretransplant screening for recipient includes HCV, HB surface antigen (HBsAg), HIV, CMV, EBV, VZV, BKV, HSV, VDRL for syphilis, PPD, screening for strongyloidoses and others as needed according to the geographical area.,,,
Pretransplant vaccinations include HB, varicella, pneumococcal, flu vaccine, Tdap, and MMR if boosters not given. Live vaccines should be given 4 weeks before transplant. Most live vaccines are contraindicated posttransplant.
Posttransplant chemoprophylaxis includes cotrimoxazole for preventing urinary tract infections, pneumocystis, nocardia; valganciclovir for CMV-related complications in at-risk recipients; and lamivudine for prevention of progressive liver disease in HBsAg positive recipients. Viral load monitoring and preemptive treatment are used for BKV infection. BKV should be monitored by nucleic acid amplification technologies at frequent intervals posttransplant and immunosuppression decreased if titres >107 copies/ml. Antifungal prophylaxis with oral azole can be used but drug levels should be monitored.
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