Epidemiology and Management of Infections in Liver Transplant Recipients

Abstract

Background:

Improvements in liver transplant (LT) outcomes are attributed to advances in surgical techniques, use of potent immunosuppressants, and rigorous pre-LT testing. Despite these improvements, post-LT infections remain the most common complication in this population. Bacteria constitute the most common infectious agents, while fungal and viral infections are also frequently encountered. Multi-drug–resistant bacterial infections develop because of polymicrobial overuse and prolonged hospital stays. Immediate post-LT infections are commonly caused by viruses.

Conclusions:

Appropriate vaccination, screening of both donor and recipients before LT and antiviral prophylaxis in high-risk individuals are recommended. Antimicrobial drug resistance is common in high-risk LT and associated with poor outcomes; epidemiology and management of these cases is discussed. Additionally, we also discuss the effect of coronavirus disease 2019 (COVID-19) infection and monkeypox in the LT population.

The most promising treatment for liver disease that is considered end-stage is deemed to be liver transplant (LT). In United States the LT numbers increased from 2010 (6,009 deceased donor and 282 live donor) to 2021 (8,925 deceased donor and 603 live donors).¹ Because of utilization of potent immunosuppressive agents, the LT outcomes have improved in the last 30 years. Although fatalities resulting from infections have declined, post-LT infections remain the primary contributor to mortality.² Almost 50% of the deaths within one year of LT are secondary to infections.^2,3 Another study showed that 45% of LT recipients developed infections within six months post-LT.⁴ A study using autopsy data showed that infections were the most common cause of immediate post LT deaths. These included 48% bacterial, 22% fungal and 12% viral infections.⁵ Other factors that are associated with incidence of infections in liver recipients are Model for End Stage Liver Disease-Sodium (MELD-Na) score higher than 30 prior to transplant, post-transplant renal replacement therapy, re-transplantation and longer intensive care unit (ICU) care.⁶

The inflammatory response may be suppressed with the use of anti-rejection medications, so typical symptoms present late or are often mild and these cases are diagnosed at the advanced stages associated with complications.⁷ The course of the infections in this population may be rapidly progressive and early diagnosis can improve the outcomes.⁸ Over years, microbiologic diagnostic tests have improved and clinicians are able to identify infectious agents that were previously unknown. American Association for the Study of Liver Disease (AASLD) recommends pre-transplant testing of common infections including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), tuberculosis (TB), syphilis, and endemic mycoses. Furthermore, appropriate pre-LT treatment of infections, vaccination, and post-transplant prophylaxis are emphasized. Administration of pre-LT measles mumps rubella (MMR) and conventional varicella (live vaccines) are recommended to limit post-LT infections caused by immunocompromised state (Table 1).⁹

Table 1.

American Association for the Study of Liver Disease Guidelines for Preventing Post-Liver Transplant Infections⁹

Pre-transplant vaccination	Pneumococcus, influenza, diphtheria, pertusis, tetanus (DPT), hepatitis A and B, HPV, measles, mumps, rubella (MMR), COVID-19
Pre-transplant recipient screening	HIV, hepatitis A, B and C, CMV, syphilis, EBV, tuberculosis. Strongyloides and endemic mycosis in selective cases. Dental examination for infection.
Pre-transplant donor evaluation	HIV, HCV, HBV

COVID-19 = coronavirus disease 2019; HIV = human immunodeficiency virus; CMV = cytomegalovirus; EBV = Epstein = Barr virus; HCV = hepatitis C virus; HBV = hepatitis B virus.

It is crucial to identify patterns of post-LT infections and ongoing risk factors to tailor the immunosuppression accordingly, as well as to initiate appropriate antibiotic prophylaxis. In this review we present epidemiology, management, and prevention of post-LT infections in the United States.

Risk Factors

The risk factors for post-LT infections include prolonged immunosuppression, antimicrobial use in the peri-transplant period, neutropenia (drug or inflammation induced), immunodeficiency due to certain infections including HIV, pre-transplant chronic CMV, and the use of acid suppressant medications.¹⁰ The literature also reports pre-transplant ICU stay longer than 48 hours, MELD score greater than 30, intra-operative transfusions, re-transplantation, and peri-transplant dialysis as risk factors of post-transplant infections.⁶ Environmental derived factors including prolonged hospital stay, recurrent hospitalizations, and travel to endemic regions are also associated with post-LT infections. Donors can be seropositive for viral infections and can serve as source of post-LT infections.^6,10 Hospital-acquired infections as Clostridioides difficile infection (CDI), hospital-acquired pneumonia (HAP) caused by Staphylococcus aureus, and gram-negative bacteria can be seen in the post-LT period.¹¹ The catheter and drains can also contribute as source of infections in these patients (Fig. 1).¹²

FIG. 1.

Risk factors of post-LT infections. LT = lung transplant; HIV = human immunodeficiency virus; CMV = cytomegalovirus; ICU = intensive care unit; MELD = Model for End Stage Liver Disease-Sodium.

Acute on chronic live failure (ACLF) and acute liver failure (ALF) cases requiring LT have most of the above risk factors. Infections can predispose ACLF in compensated cirrhosis, whereas some ALF cases are caused by infections including hepatitis A and B.^13,14 The post-LT infection spectrum data in ALF are deficient. Commonly observed infections in these patients irrespective of LT status are bacterial infections (gram-negative, gram-positive, and anaerobes), and fungal infections (predominantly Candida).¹⁴ Hence surveillance of these organisms and broad-spectrum antibiotic agents with coverage of these organisms should be considered while waiting for culture results.¹⁵ Post-LT infections are more common in ACLF with organ failure (≥1 grade).¹⁶ Among these infections, multi-drug–resistant bacterial infections and invasive fungal infections have higher incidence.^17,18 Bacterial infections are more common in ACLF awaiting LT and these cases have higher post-LT new bacterial and fungal infections despite successful pre-LT treatment.¹³

Viral Infections

Viral infections including HBV and HCV are the leading etiology of the chronic liver disease and ACLF requiring LT.^19,20 Individuals who have undergone LT are at risk of developing new viral infections, such as HBV, HCV, CMV, EBV, and herpes simplex virus (HSV). Additionally, these patients can develop reactivation of infection after LT. Development of affective antiviral treatments have improved the outcome in this population.²¹ Epidemiology and treatment of drug-resistant infection is shown in Table 2.

Table 2.

Adverse Events Associated With Antimicrobial Use in LT Recipients

Antimicrobial agents	Adverse effects and interaction with immunosuppressants
Antiviral agents
Foscarnet and cidofovir^{22,35,104,207}	Nephrotoxicity, neutropenia, drug interaction with CSA and TAC
Brincidofovir¹⁰⁴	GI symptoms (diarrhea, nausea, vomiting, and abdominal pain)
Gancyclovir and valganciclovir²²	Neutropenia, drug interaction with SRL, EVR, MMF and AZA.
Maribavir⁴⁰	Gastrointestinal toxicity
Letermovir^41,207	Increases cyclosporine levels
Acyclovir (intravenous)^{53, 207}	Nephrotoxicity, interaction with TAC.
Remdesivir^208,209	Hepatotoxicity, gastrointestinal side effects (nausea, gastroparesis)
Paxlovid (nirmatrelvir/ritonavir)⁹⁶	Dysgeusia, diarrhea, drug interaction with common antirejection medications (increase levels of SRL, EVR, TAC, CSA)
Tecorivimat¹⁰⁴	Headache, nausea, abdominal pain
Antibacterial
Isoniazid¹¹⁹	Hepatotoxicity
Rifamycin¹¹⁸	Interaction with CSA, EVR, SRL, MMF, TAC and reduce their levels.
Clofazimine¹¹⁹	Hyperpigmentation, prolonged QTc interval.
Delamanid¹¹⁹	Prolonged QTc, neurotoxicity when used with isoniazid
Azithromycin^{196, 207}	Increase drug levels of SRL and TAC
Linezolid^{119, 207}	Hepatotoxicity, peripheral neuropathy, myelosuppression, interaction with MMF, AZA, SRL, EVR.
Bedaquiline¹¹⁹	QT prolongation,
Vancomycin^124,132	Nephrotoxicity, allergic reaction
Carbapenem²¹⁰	Neurotoxicity more with imipenem, nephrotoxicity, and immunomodulation.
Aminoglycosides²⁰⁷	Nephrotoxicity which is enhanced in presence of TAC
Piperacillin-tazobactam²¹¹	CDI, allergic reaction
Trimethoprim-sulfamethoxazole²⁰⁷	Allergy, myelosuppression with use of EVR, SRL, MMF, AZA
Antifungal agents
Azole^{168, 207}	Increase SRL, EVR, CSA, TAC levels
Ecchinocandins^168,207,212	Allergic reaction, phlebitis, hemolysis, reduce tacrolimus levels.
Flucytosine^{178, 207}	Myelosuppression
Amphotericin^178,207	Nephrotoxicity
Antiparasites
Benznidazole¹⁹⁶	Rash, peripheral neuropathy
Nifurtimox¹⁹⁶	Nausea, anorexia, irritability, tremors.

GI = gastrointestinal; SRL = sirolimus; TAC = tacrolimus; EVR = everolimus; MMF = mycophenolate mofetil; AZA = azathioprine.

Cytomegalovirus

Cytomegalovirus (CMV) stands as the predominant opportunistic viral infection that manifests in post-LT patients. It directly impacts patient mortality and graft survival in these patients.²² The global seroprevalence e of CMV is 83% with a lower prevalence in Europe and a higher seroprevalence in low socioeconomic regions.^23,24 In LT patients, CMV infections ranges from 18.9% to 32% in the absence of preventative measures, this incidence is higher in seronegative recipients with seropositive donors.^25,26 Higher incidence of CMV infection in LT recipients is linked to factors such as donor serostatus, history of hepatocellular cancer, and Hispanic ethnicity.²⁵ Primary CMV infection is the occurrence of viral disease in a seronegative recipient. CMV reactivation occurs in patients with evidence of active CMV replication who are seropositive. CMV disease includes “CMV syndrome” and “tissue invasive disease.” Cytomegalovirus syndrome is defined as positive CMV serology in the presence of two or more of the following features: fever higher than 38°C for 48 hours, two separate measurements of leukopenia or neutropenia, thrombocytopenia, elevated aminotransferases, new or worsening fatigue and malaise, and 5% atypical lymphocytes, whereas tissue invasive disease is determined based on a histologic involvement.^27,28

Primary CMV infections occur early on in life, usually in the first two decades. The route of primary infection is through mucosal tissue. Thereafter, the virus spreads throughout the body via CD14+ monocytes and eventually reaches lymphoid and myeloid cells where it remains latent; in most immunocompetent individuals this disease remains latent for most of life. Those patients who are maintained on high immunosuppressive therapy after LT, may experience a reactivation of the disease.²⁹ In patients who have undergone LT and are not receiving prophylactic medication, CMV infections develops within the first three months post-LT (Fig. 2). Once reactivated, CMV begins replicating in lymphoid tissues and disseminates throughout the body via the blood.³⁰ Cytomegalovirus has an affinity for specifically impacting the transplanted liver compared with other organs of the body. It is unclear why the transplanted organ is more susceptible; however it has been hypothesized that this is because the liver graft may serve as a reservoir for latent CMV.³¹

FIG. 2.

Timeline of post-LT infections. LT = liver transplant; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HPV = human papilloma virus; HSV = herpes simplex virus; HBV = hepatitis B virus; HCV = hepatitis C virus; VZV = varicella zoster virus; HHV = human herpes viruses; PTLD = post-transplant lymphoproliferative disease; COVID-19 = coronavirus disease 2019; CDI = Clostridioides difficile infection; PCP = pneumocystis pneumonia.

The viral infection can present as hepatitis, signs of bone marrow suppression, gastrointestinal symptoms (colitis is most common), mononucleosis-like syndrome with viral symptoms as fever, fatigue, and myalgias.^22,32 Cytomegalovirus can pose adverse effects on the graft by developing alloantigens that can predispose to chronic graft rejection. Cytomegalovirus may also cause immunosuppression because of its effects on CD4 T-cells, macrophages, and various cytokines.²² Bone marrow suppression caused by CMV also leads to leukopenia. This results in patients having increased susceptibility to fungemia, viremia, and bacteremia.^22,27 In particular, post-LT patients with CMV are at an increased susceptibility to developing EBV associated post-transplant lymphoproliferative disease, as well as co-infections such as human herpes viruses (HHV).³³

Prophylactic therapy involves giving anti-CMV medication (e.g., valganciclovir) to LT recipients who are at an increased risk of CMV reactivation, whereas pre-emptive therapy involves treating only those patients who have CMV viremia (without symptoms). Both prevention strategies have shown to have similar effectiveness in preventing post-transplant CMV infection. A randomized control trial had shown that pre-emptive treatment of CMV-seronegative recipients with a seropositive donor had a reduced incidence of CMV in 12 months of follow-up compared with conventional post-LT CMV prophylaxis.³⁴ The antiviral prophylaxis has the added benefit of having activity against other common viruses from the herpes family including VZV, HSV, and EBV. It is recommended to give least three months post-transplant viral prophylaxis to cases who are at increased risk of CMV reactivation, and three to six months of pre-emptive therapy in those with early viremia.^27,35 Treatment of CMV infection in post-LT patients includes oral valganciclovir or intravenous (IV) ganciclovir. In severe cases the preferred therapeutic agent is IV ganciclovir. Treatment is given for at least two weeks and should be discontinued based upon symptom resolution and serum clearance of the virus. Foscarnet and cidofovir are avoided because of their nephrotoxic effects and are considered second-line agents reserved for refractory cases of CMV infection (Table 2).^22,27,35

Resistance to CMV treatment is commonly observed (5%%–14.5%).^36,37,38 Mutation in UL97 gene is the leading cause of CMV resistance. The product of UL97 is viral protein kinase which phosphorylates ganciclovir (Table 3).³⁹ Mutation UL54 DNA polymerase gene appears late and has demonstrated cross-resistance to cidofovir and foscarnet. Risk factors for resistance are prolonged antiviral exposure, strong immunosuppression, subtherapeutic antiviral drug levels, and inadequate delivery of drug.³⁸ Treatment of resistant CMV cases include reduction of immunosuppression, increased dose of ganciclovir, change in drug delivery method, change antiviral to foscarnet or cidofovir, and adjunctive treatment with CMV-specific cytotoxic T-lymphocyte infusions. Cidofovir and foscarnet are associated with nephrotoxicity. Experimental drugs including maribavir, brincidofovir, and letermovir are also options when CMV is resistant to all available agents.^38,40,41

Table 3.

Bacterial and Viral Drug Resistance and Appropriate Treatment

Infections	Epidemiology	Mechanism	Treatment
Viral infections
CMV^36,37, ^39, ^38,40,41	Ganciclovir resistance seen in 10 to 5% to 14.5% cases	UL97 protein kinase mutation, UL54 DNA polymerase mutation	Reducing immunosuppression, increased dose of ganciclovir, change mode of drug delivery, Use of foscarnet or cidofovir, CMV specific cytotoxic T-cell infusion. Novel options include maribavir, brincidofovir, and letermovir.
HSV, VZV^53,57, ^61, ⁶³	Acyclovir resistance is rare in LT	Mutation of gene encoding viral thymidine kinase	For resistant HSV, reduction of immunosuppression, foscarnet, and intravenous cidofovir are recommended. Resistant VZV was treated in past with change acyclovir to IV or foscarnet.
HHV-6⁷⁵	Resistance to ganciclovir and/or cidofovir (uncommon)	Mutation of genes encoding for phosphotransferase, DNA polymerase, and R798I	Cidofovir used for ganciclovir cases. Foscarnet is recommended if virus is resistant to both cidofovir and foscarnet
Adenovirus⁷⁸	Resistance to cidofovir (uncommon)	Mutation of DNA polymerase	Foscarnet
Bacterial infections
Tuberculosis.^119, ^213, ²¹⁴	20% resistant to single drug and 10% resistant to multiple drugs.	Efflux pump activation at bacterial surface, drug target alteration and that can affect drug activation.	Long-term treatment up to 24 months. Utilization of newer agents including newer agents including bedaquiline, linezolid, clofazimine, and delamanid.
MRSA¹³⁰	9.4% colonization post-transplant	β-lactam resistance	Daptomycin, linezolid
VRE^130, ¹³⁴	16.2 colonization post-transplant	Change of terminal peptide of peptidoglycan precursors which reduces the binding affinity of vancomycin to bacteria.	Linezolid is used against most species, Ampicillin against Enterococcus faecalis.
ESBL Enterobacteriaceae^125,137	5.5% to 7%	β-lactam resistance	Carbapenems, cefepime or piperacillin-tazobactam
MDR Pseudomonas aeruginosa^142,143	12% of Pseudomonas blood stream infections in 10-y period.	Loss of outer membrane protein and target mutations	Polymyxins, combination drugs as cefepime-tobramycin/aztreonam, ceftolozane-tazobactam and ceftazidime-avibactam
Carbapenemase-producing Enterobacteriaceae^215-148	3% to 10%	Carbapenamase enzyme production, porins and efflux pump mutations.	Simple UTI—nitrofurantoinCystitis—aminoglycosides, trimethoprim-sulfamethoxazoleExtra urinary infections: imipenem-cilastatin-relebactam, ceftazidime-avibactam, and meropenem-vaborbactamHigh-resistance regions: ceftazidime-avibactam plus aztreonam, or cefiderocolCR Klebsiella pneumoniae: imipenem-cilastatin-relebactam, ceftazidime-avibactam and meropenem-vaborbactam.CR Acinatobacter: ampicillin-sulbactam, colistin with meropenem or rifampin or tigecycline.

LT = liver transplant; IV = intravenous; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HHV-6 = human herpes virus-6; HSV = herpes simplex virus; MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant Enterococcus; ESBL = extended spectrum β-lactamase; MDR = multi-drug–resistant.

Epstein-Barr virus

Epstein-Barr virus is the most common cause of post-transplant lymphoproliferative disease (PTLD), a grave complication in LT recipients.^42,43 More than of 80% individuals in the United States are seropositive for EBV by age 19.⁴⁴ Primary EBV infection presents with oropharynx disease and in most immunocompetent patients the disease clears and remains latent with infected B-lymphocytes. Epstein-Barr virus reactivation is suppressed by EBV-specific cytotoxic T lymphocytes (CTLs) under normal circumstances. However, in post-transplant cases who are being maintained on immunosuppressive therapy these EBV-specific CTLs are decreased in number and functionally impaired allowing latent EBV in B-lymphocytes to reactivate.^45,46 Recipients who are seronegative for EBV and receive organs from donors who are seropositive for EBV are at an increased risk of developing EBV-associated PTLD.⁴⁶ The clinical features of EBV infected post-transplant patients (not specifically LT) include classic infectious mononucleosis like symptoms including cervical lymphadenopathy, fever, pharyngitis, hepatosplenomegaly and atypical lymphocytosis on blood tests. These patients may also experience hepatitis, pneumonitis, gastrointestinal (GI) symptoms, leukopenia, thrombocytopenia, or hemolytic anemia.^47,48 The disease may also spread to sites outside of the allograft and presents with classic lymphoma symptoms such as fever, weight loss, lymphadenopathy, and splenomegaly.^49,46

Because one of the common primary causes of post-transplant EBV infection is the degree of immunosuppression being utilized, reduction in immunosuppression is a major strategy used in prevention and treatment.⁴⁶ Reduction in immunosuppression allows EBV-specific CTLs to proliferate and deal with EBV-induced B-lymphocyte proliferation. Studies have illustrated significant reduction in EBV viral load with reduction in immunosuppression in solid organ transplant (SOT) including LT recipients. However, this strategy must be weighed against graft rejection risk in the setting of decreased immunosuppression.^49,46,50 Strategy in treating established EBV-associated PTLD begins with reduction in immunosuppression to allow EBV-specific CTLs to control EBV-induced B-lymphocyte proliferation. The treatment of PTLD is not specific to LT but it includes monoclonal antibody (MAB) Rituximab, San Francisco, CA, which is an effective treatment because of its activity against CD20 located on B-lymphocytes in PTLD.⁵⁰ In cases of CD20-positive PTLD, remission rates are as high as 44% to 65% with Rituximab therapy. Other treatment modalities include chemotherapy, surgical resection, and radiotherapy. ^46,51

Herpes simplex virus

The reported incidence of herpes viral infection (HSV and herpes zoster virus) is 8% in the first month of LT, 10% of in the first six months, and 16% after six months post-LT (Fig. 2).⁵² These patients manifest severe HSV disease that responds slower to treatment as compared with immunocompetent counterparts.^52,53 Infection typically occurs approximately 20 days (±12 days) post-transplantation. The majority of cases are caused by reactivation of latent virus, however de novo infection (usually donor derived) may also occur.^52,54,55 The typical clinical manifestations are non-specific and encompass signs and symptoms such as fever, elevations in liver enzymes, discomfort in the upper right abdomen, and leukopenia. In less than one-third of LT patients, mucocutaneous lesions can be seen as well. Approximately 85% of these mucocutaneous lesions are oral lesions followed by anogenital involvement. These lesions are typically painful vesicular or ulcerative. In more severe cases, HSV esophagitis and pneumonitis have also been reported in this patient population.^52,54 The American Society of Transplantation (AST) recommends three months of prophylactic valacyclovir in seropositive LT recipients who are not considered for CMV prophylaxis.⁵⁶ For LT patients with established HSV, acyclovir is the medication of choice. Foscarnet and cidofovir can be utilized in refractory cases.^55,56 Resistance to HSV treatment is less common and need to be considered in the cases which are not responding to appropriate doses of acyclovir. These cases are treated with reduction in immunosuppression, foscarnet, IV or topical cidofovir, or topical trifluridine (Table 3).^53,57

Varicella zoster virus

Varicella zoster virus (VZV) primary infection targets epithelial cells, T lymphocytes, and ganglia and causes chickenpox. When cellular immunity decreases in advanced age, or individual is immunosuppressed, the virus can cause herpes zoster (HZ, shingles).⁵⁸ Herpes zoster commonly presents with cutaneous vesicular lesions in dermatomal distribution. Complications of HZ can include hepatitis, pancreatitis, ocular (keratitis and retinopathy), and neurologic disorders (chronic pain, encephalitis, and never palsies).⁵⁸ The incidence of HZ ranges from 7% to 9% in the five-year post-LT period.

Advanced age and exposure to mycophenolate were associated with higher risk in these patients.⁵⁹ The clinical presentation is helpful to make diagnosis but confirmatory laboratory testing is recommended for transplant recipients. Polymerase chain reaction of serum, vesicle, CSF, or involved tissue is diagnostic method of choice.⁶⁰ Acyclovir is the first-line treatment and it can be given orally to non-complicated skin disease and intravenous to severe disease (CNS involvement, HZ ophthalmicus). Post-transplant primary varicella infection should be treated with IV acyclovir, because this population is at high risk of developing complications.⁶⁰ Short duration prophylaxis with acyclovir or valacyclovir is recommended if LT recipient is VZV or HSV seropositive and not receiving CMV prophylaxis.⁶⁰ Resistance to acyclovir can develop because of gene mutation in viral thymidine kinase, which phosphorylates acyclovir to active form.⁶¹ The literature is limited for therapeutic options for VZV-resistant cases in LT recipients.⁶² One case series in patients with HIV reported possible treatment options including change in formulation to IV, or foscarnet or sorivudine.⁶³

The Advisory Committee on Immunization Practices (ACIP) recommends recombinant zoster vaccine (RZV) for chronic medical conditions spaced two to six months apart after age 50.⁶⁴ Recently the Food and Drug Administration (FDA) and ACIP expanded the use of RZV in younger adults. It is recommended to give this vaccine to immunosuppressed patients 19 or more years old.⁶⁵ Although data in LT recipients are lacking, clinical trials showed that RZV is safe and demonstrated robust immune response in renal transplant and stem cell transplant populations.^66,67 If vaccination is not completed before transplant, then it is recommended to give RZV six to 12 months post-transplant.⁶⁵ The RZV vaccines should also be offered to eligible caregivers and close contacts.⁶⁰

Human papilloma virus

The prevalence of HPV is approximately 18% within the first three weeks after LT.⁶⁸ Human papilloma virus-infected patients may present with pre-malignant lesions or warts of the anal canal, penis, scrotum, vulva, and cervix. Screening is very important because these lesions are mostly asymptomatic and delayed detection may allow them to become malignant.⁶⁹ Current guidelines recommend vaccination against HPV in all SOT recipients based on its efficacy in the general population. As with non-transplant patients, there is no treatment for HPV infection in itself, making prevention extremely important. The infection generally clears on its own and therapeutics are targeted toward the resultant lesions.^69,70

Human herpes virus

As much as 95% of the population are seropositive for HHV6, with most infections occurring during childhood. Because this pathogen usually infects humans in early childhood, pediatric LT patients are at greater risk because they have a higher risk of being exposed to HHV6.⁷¹ Primary infection with HHV6 mostly occurs during childhood and can be asymptomatic or present as high fevers followed by maculopapular rash (Roseola infantum).⁷² In LT patients, the majority of the infections are due to reactivation of the latent infection, however, in a small fraction of HHV6-naive patients infection arises from a seropositive donor.⁷¹ The vast majority of LT recipients who develop HHV6 infection are asymptomatic; mild cases can present as febrile illness and maculopapular rash. However in rare cases complications such as hepatitis, encephalitis, pneumonitis, myelosuppression, and allograft rejection may occur.^71–73 HHV6 also plays an immunomodulating role in LT patients and can lead to a higher chance of reactivation of other infectious etiologies such as CMV and hepatitis viruses.⁷¹ Treatment is not specific to LT patients. In symptomatic cases of HHV6 antiviral therapy such as ganciclovir is the main treatment modality; cidofovir and foscarnet have also been used. It is currently not recommended for these patients to undergo routine screening, pre-emptive therapy, or prophylactic therapy in transplant recipients.⁷⁴ Sporadic cases of resistance to ganciclovir and cidofovir have been reported. Pathogenesis includes mutation of genes encoding for DNA polymerase, phosphotransferase, and R798I. Foscarnet is recommended for cases resistant to both ganciclovir and cidofovir.⁷⁵

Adenovirus

Some studies showed an incidence of 5.8% in LT patients with 64% of them being symptomatic and 36% being asymptomatic.⁷⁶ The mean time to first detection of virus in LT patients in one study was 2.2 months (Fig. 2).^76,77 Patients commonly experienced hepatitis and in some cases colitis, pneumonitis, and urinary symptoms.⁷⁶ There are limited LT-specific data for treatment, reduction in immunosuppression and supportive therapy are the main treatment modalities with some studies showing complete resolution of infection in SOT recipients. In terms of pharmacotherapy, IV cidofovir has been shown to have good outcomes in these patients.^76,77 Mutation of DNA polymerase can lead to cidofovir resistance and like other post-LT viral infections, foscarnet can use used for treatment, which has added side effects including nephrotoxicity (Table 3).⁷⁸

Parvovirus B19

Parvovirus B19 (PB19) is a common childhood illness with some studies suggesting that half the population is seropositive for this pathogen by age 15.⁷⁹ Transmission typically occurs via respiratory droplets and occurs during childhood. Some studies show that transmission may also occur at the time of SOT.⁸⁰ Clinical features of this disease in LT patients may differ from the childhood disease.⁷⁹ PB19 in LT recipients commonly presents with anemia, fever, arthralgia, and rash.^81,80 The rarity of this entity, with symptomatic cases being even rarer, also makes the case for routine screening being unnecessary in LT recipients. Additionally, the reliability of serology in establishing the diagnosis is questionable. Standard isolation and droplet precautions are the only currently recommended prevention guidelines.^79,80 There are currently no antiviral pharmacologic therapies for PB19, however, studies have shown efficacy of IV immunoglobulin in these patients. Reduction in immunotherapy has also shown to be an effective strategy.⁸⁰

Corona virus disease 2019

LT recipients have a higher risk of acquiring corona virus disease 2019 (COVID-19) infection because of chronic immunocompromised state. In these patients, higher incidence is observed in older age and male population.^82,83 The COVID-19 infection in LT recipients can compromise both graft and patients health due to thrombosis, myocardial damage, respiratory and renal failure. Corona virus disease 2019 can also present as acute hepatitis, which can be challenging to differentiate from rejection, and other causes of hepatitis. Those with persistent or worsening liver enzymes need histologic diagnosis.^84,85 Severe disease is observed in those on high-dose mycophenolate.⁸² Another study showed that COVID-19 in LT patients with steroid and mycofenolate use had higher hospitalization.⁸⁶ Hence immunosuppression transition to calcineurin inhibitors in hospitalized LT patients may have benefits.⁸² Vaccination in LT recipients show lower immune responses and administration of boosters is recommended.^87,88 mRNA vaccine booster is recommended in patients who had received adenovirus vector vaccine initially (Table 4).^89,90

Table 4.

American Association for the Study of Liver Disease Recommendation for Use of COVID-19 Vaccination in LT Recipients

Vaccine schedule	mRNA vaccine	Adenovirus vector vaccine	Novovax adjuvanated
Primary series	Three doses for pediatric and adult.	One dose followed by mRNA vaccine in adults.	Two doses for age ≥12.
Booster	Monovalent ≥3 mo or bivalent ≥2 mo after primary series	Bivalent ≥2 mo after primary series	Bivalent ≥2 mo after primary series
Adverse events	Anaphylactic reaction, myocarditis	GBS, thrombosis and thrombocytopenia	Allergic reaction
Management	• Antihistamine, epinephrine, steroids, and hospitalization• Supportive care	• IVIG or plasmapheresis for GBS based on severity.• Anti-P4 Ab and avoid heparin	Supportive care

GBS = Guillain-Barré Syndrome; IVIG = intravenous immunoglobulin.

Detailed treatment guidelines are discussed by the National Institutes of Health (NIH).^91–93 Briefly, supportive measures including antipyretics and analgesics have generally been used for symptom control.⁸³ Remdesivir is a nucleoside analog and the only FDA-approved treatment recommended for hospitalized patients requiring oxygen supplementation. Dexamethasone 6 mg daily or equivalent corticosteroid should be given to hospitalized patients who have moderate to severe disease.⁹⁴ Tocilizumab (interleukin-6 inhibitor) or baricitinib in addition to dexamethasone are recommended for critically ill patients who have progressive increase in oxygen requirement.⁹⁵ Use of dexamethasone or tocilizumab can potentially increase the risk of HBV reactivation; hence HBV prophylaxis should be considered in those who are hepatitis B surface antigen-positive.⁸⁹ The AST recommends outpatient remdesivir or monoclonal antibody to prevent the severe disease. Nirmatrelvir/ritonavir is associated with anti-rejection medication drug interaction. Hence it is challenging to use nirmatrelvir/ritonavir because it is difficult to monitor drug levels in outpatient setting. Molnupiravir had shown lower efficacy in transplant recipients. It is recommended when preferred treatments including nirmatrelvir/ritonavir and remdesivir are not available (Table 2).^92,96

Monkeypox virus

The World Health Organization (WHO) declared monkeypox virus as a health care emergency in July 2022.⁹⁷ This disease spreads from infected animals and humans via cutaneous contact, respiratory droplet and sexual transmission. The presentation is non-specific with fever, myalgia, lethargy, headache, and lymphadenopathy.⁹⁸ Outcomes of monkeypox can be more severe in LT recipients and the U.S. Centers for Disease Control and Prevention (CDC) recommend treating these patients with antivirals.⁹⁹ Disease prevention strategies are similar to smallpox. which include preventive measures to limit infection spread, vaccination, and post-exposure immunoglobulin. Because of limited data, efficacy of the vaccination in LT recipients is unknown. Replication-deficient live virus vaccine (JYNNEOS) is preferred post-exposure in transplant recipients whereas replication- competent live virus vaccine (ACAM2000) is contraindicated. Vaccination is recommended within four days of exposure, it is also shown effective in four to 14 days and should be offered; there is no clear recommendation to unexposed individuals.^100,101

Those who have a history of side effects to vaccines and are severely immunocompromised are candidate for immunoglobulin post-exposure prophylaxis.¹⁰² The CDC recommends use of the antiviral agents that were used for smallpox.¹⁰³ Tecovirimat (envelope-wrapping protein inhibitor) is a commonly used antiviral agent followed by cidofovir and brincidofovir (viral DNA polymerase inhibitors); the latter agents are associated with drug discontinuation due to side effects.¹⁰⁴ The literature shows successful treatment of a post-LT case with tecovirimat for 14 days, and lowering immunosuppression. The patient received two doses of JYNNEOS vaccination post treatment because of future risk of exposure.¹⁰⁵

Bacterial Infections

The nature of bacterial infections differs based on timing from the LT. In the first month post-LT, nosocomial infections including urine tract infections, healthcare-acquired pneumonia, CDI, intra-abdominal (surgery related infections), bacteremia, and catheter-related infections are more common.^8,106 Antibiotic resistance is associated with poor outcome (Table 3). Use of potent immunosuppression, environmental exposure, increasing antibiotic resistance, and prolonged hospital stay are risk factors for bacterial infections. Another observational study has shown diabetes mellitus and low albumin levels as risk factors for post-LT bacteremia.¹⁰⁷ Use of antibiotic agents in LT recipients can be associated significant drug interaction and side effects (Table 2).

Community-acquired organisms

Infections that occur after six months of LT are usually environment-related. The common infections seen in late-stage post-LT are pneumonia (community-acquired), infections of the urinary tract, intra-abdominal infections, and sepsis of unknown origin. Reactivation of TB in those with latent infection, development of listeriosis and Nocardia infection can be seen two to six months post-LT (Fig. 2).¹⁰⁸ Although uncommon, community-acquired multi-drug–resistant (MDR) bacteria including methicillin-resistant Staphylococcus aureus (MRSA) can be seen in this population and are associated with poor outcomes.^109,110

Tuberculosis

The global burden of TB increased during the COVID-19 pandemic with 10.6 million new cases in 2021, which was a 4.5% increase from 2020, including a 3% increase in drug-resistant TB cases.¹¹¹ A review based on retrospective case series reported an 18-fold increase in risk of active TB in LT recipients with four times higher mortality than in the general population. Additionally post-LT TB was associated with extrapulmonary and multiorgan involvement.¹¹² It is crucial to diagnose and treat the latent TB as active TB can increase spread to healthy individuals.^113,114 Mean time of diagnosis of active TB post-LT was four weeks.¹¹² In LT recipients, diagnosis of latent TB can be diagnosed with tuberculin skin test or interferon-γ release assay (IGRA) test (Quantiferon or T-SPOT). The test sensitivity is low in both cases; hence, radiologic data and history are important.¹¹⁵ It is recommended that all LT candidates should be tested for latent TB.⁹

Investigators have reported that treatment of latent TB cases prior to LT can reduce TB reactivation.¹¹⁶ Holy et al.¹¹² reported that 44% of post-LT active TB had latent TB in the latent period. The treatment of latent TB should be continued after LT in patients who had incomplete treatment at the time of LT. Isoniazid is the preferred therapy for latent TB in pre- and post-LT patients and rifamycin is an alternative option.¹¹⁷ Rifamycin may interact with the immunosuppressive agents.¹¹⁸ The treatment of active TB in LT recipients and the general population is similar.¹¹⁸ Single and MDR TB, especially to isoniazid and rifampicin, are challenging to treat in transplant recipients. Resistance to second-line agents as fluroquinolones further increases complexity and these infections are considered extended-resistant TB (Table 3). Almost 20% global cases are resistant to single drugs and 10% cases are MDR.¹¹⁹ These individuals require longer duration of treatment, and combination of anti-TB drugs that increases the risk of toxicities. Studies have shown few SOT cases of anti-TB drug resistance which were treated with combination of newer agents including bedaquiline, linezolid, clofazimine, and delamanid.¹¹⁹

Hospital-acquired organisms

These infections mostly affect the LT recipients in the early post-LT period.¹²⁰ Catheter-associated infections, infections associated with surgical sites, deep intra-abdominal infections, and ventilator-associated pneumonia are common hospital-acquired infections. The predominant bacteria causing surgical site infections are Staphylococcus aureus, Enterococcus species, and Escherichia coli.¹²¹ Surgical complications including biliary stricture and hepatic artery stenosis are associated with increased incidence of infections.¹⁰⁷

Multi-drug–resistant bacterial infections

The complex post-operative course of LT involves use of invasive devices and long-term utilization of empiric broad-spectrum antibiotic agents that can lead to an increase in the number of incidences of MDR bacterial infections (Table 3).^122–124 The pre-transplant colonization of the recipient with MDR bacteria can also lead to higher post-LT MDR infections.¹²⁵ Post-LT MDR infections are associated with high mortality and recurrence rate.^126–128 Severity of the infection, the state of immunosuppression, and high rate of treatment failure make management of these cases challenging. Methicillin resistant Staphylococcus aureus, MDR Pseudomonas aeruginosa, extended spectrum β-lactamase-producing (ESBL) Enterobacteriaceae, carbapenem-producing Enterobacteriaceae, vancomycin-resistant Enterococcus species (VRE), and carbapenem-resistant Acinetobacter baumannii are common MDR organism that can infect LT recipients in the early post-LT period.¹²⁴

Methicillin-resistant Staphylococcus aureus

The common sources of MRSA are catheter associated, open wounds, intra-abdominal, and lung infections.¹²⁹ Post-LT colonization prevalence is 9.4%.¹³⁰ The treatment for LT cases is same as general population. Vancomycin is commonly used for the treatment of this infection, teicoplanin had shown similar efficacy but not commonly used.^131,132 Daptomycin is bactericidal and can be used for most cases, but it is not effective against lung infections. Linezolid is a bacteriostatic antibiotic which can be used for skin and lung infections.¹³³

Enterococcus species

Colonization with VRE is seen in 16.2% of LT cases.¹³⁰ Infection with VRE commonly presents within two months post-LT and can grow in urine, blood, or bile (Fig. 2).¹²⁸ The possible mechanism is the alteration of peptide moiety of peptidoglycan precursor that reduces affinity of vancomycin to bind to bacterial walls.¹³⁴ The treatment is not different in LT patients than general population. Ampicillin is commonly used against Enterococcus faecalis but its efficacy against Enterococcus faecium is not known. Linezolid has bacteriostatic activity for both Enterococcus species.¹²⁴ Linezolid-resistant Enterococcus has been observed in post-transplant patients.¹³⁵ A recent multicenter study had shown that 22% of Enterococcus spp. in post-LT population are daptomycin-resistant (DRE) and DRE had higher associated mortality rates.¹³⁶

Extended spectrum β-lactamase

Commonly seen Enterobacteriaceae are Escherichia coli and Klebsiella pneumoniae. The infection incidence is 5.5% to 7% in LT recipients.^125,137 The presentation and treatment is not specific for LT patients. These infections are frequently isolated from the urine. Carbapenems are commonly utilized for the treatment of these cases.¹³⁸ However, ertapenem resistance is observed in this group.¹³⁹ Cefepime and piperacillin-tazobactam are alternatives and can used in severe cases.¹²⁴ Multi-drug–resistant Pseudomonas aeruginosa causes post-LT pneumonia and blood stream infections.^140,141 A single center organ transplant recipients (52% LT) 10-year experience showed 29.6% Pseudomonas aeruginosa cases and 43% of them were MDR. These cases were associated with higher mortality.¹⁴² The treatment for LT cases is same as general population. Polymyxins can be considered for these cases although the therapeutic window is small. The combination antibiotic agents including cefepime-tobramycin, cefepime-aztreonam, ceftolozane-tazobactam, and ceftazidime-avibactam are available options.¹⁴³

Carbapenemase-producing Enterobacteriaceae (CRE) are more common in colonized recipients and those with high pre-transplant MELD scores.¹²⁶ The incidence in CRE post-LT ranges from 10.3% to 15.7% in early post-LT period.^144,145 Surgical site infection was reported the most common manifestation in these patients.¹⁴⁴ The treatment is not specific for LT cases. The aminoglycosides and trimethoprim-sulfamethoxazole (TMP-SMX) can be used for cystitis and pyelonephritis with CRE whereas nitrofurantoin can be considered in uncomplicated urine tract infections.¹⁴⁶ In addition to urinary tract infections, imipenem-cilastatin-relebactam, ceftazidime-avibactam, and meropenem-vaborbactam can be used if the carbapenamase results are not available. In high-drug–resistant regions, the combination of ceftazidime-avibactam with aztreonam, or cefiderocol as single agents are options. Imipenem-cilastatin-relebactam, ceftazidime-avibactam and meropenem-vaborbactam can be used for Klebsiella pneumonia carbapenamase bacteria.¹⁴⁶ Carbapenem-resistant Acinetobacter baumannii (CR-Ab) in LT recipients is associated with high mortality.¹⁴⁷ Monotherapy with ampicillin-sulbactam or combination therapy of colistin with meropenem or rifampin or tigecycline are treatment options.¹⁴⁸

Clostridioides difficile infection

Clostridioides difficile is one of the most common nosocomial infections that typically grows in the colon.¹⁴⁹ The incidence of CDI post-LT ranges from 9% to 18.9%.^150–152 The increased incidence of CDI in LT recipients can be explained by prolonged hospital stay, immunosuppressed state, altered GI anatomy, and frequent use of antibiotic agents.^153,154 Clostridioides difficile infection is commonly seen immediately post-LT; late infection is also seen when the immunosuppression dose is increased or post-transplant course is complicated.^151,152 The severe form of infection is associated with renal failure, colectomy, fulminant colitis, graft loss, mortality, high 30-day hospital re-admission, and increased resources utilization.^153,155,156

Recurrence is common and the most common reason for re-admission in these patients was identified as the CDI (recurrent or persistent disease).¹⁵⁷ The Infectious Diseases Society of America (IDSA) guidelines recommend use of fidaxomicin as first-line agent and vancomycin as an alternative. The fidaxomicin treatment (standard or extended) or pulsed vancomycin dose are recommended for the recurrent CDI. In cases with multiple recurrences, extended fidaxomicin, pulsed vancomycin or vancomycin followed by rifaximin are suggested regimens. Fecal microbiota transplantation (FMT) has also shown promising response in recurrent CDI, and it is recommended treatment. The use of bezlotoxumab with primary treatment is also suggested in recurrent cases.¹⁵⁸ There are no specific guidelines for the FMT in post-LT patients, but safety had been shown in the literature.¹⁵⁹

Fungal Infections

The incidence of invasive fungal infections (IFI) post-LT ranges from 1.8% to 7% and these infections are associated with increased morbidity and mortality.^160,161 Candidiasis causes 60% to 80% of IFI whereas aspergillosis and other mold infections account for 1% to 8%.^162,163 The risk factors in LT recipients include re-transplantation, intensive care unit stay, surgical treatment, transfusion of blood products, CMV infection, respiratory failure, metabolic dysfunction, pre-transplant use of antibiotic agents, fulminant hepatic failure, and longer transplant surgery. Hence, antifungal prophylaxis should be given in these high-risk patients.^{8,160,164,165} Because most fungal infections are seen in the first four to six weeks post-LT, antifungal prophylaxis is suggested for this period.¹⁶⁶

Candida albicans is the most common fungal infection in post-LT period.¹⁶⁰ Candida glabrata and Candida tropicalis are other common post-transplant infections. Common invasive Candida infections are candidemia and abdominal infections.¹⁶⁷ Similar to the general population, the azoles are recommended for initial treatment of candidiasis in LT recipients. The azoles are associated with drug interactions with immunosuppressants. The echinocandins are considered as preferred treatment for severe Candida infection and those with history of azole resistance.^168,169 Amphotericin B and voriconazole are alternatives in severe infection but have greater toxicity (Table 2). The recommended duration of treatment is two weeks after negative blood culture or tissue culture or resolution of symptoms. Most of the candiduria patients do not require treatment and removal of the urinary catheter is recommended. Candida in urine with neutropenia, and presence of symptoms should be treated as invasive candidiasis.¹⁷⁰ Candida auris is an MDR nosocomial infection recently observed in immunocompromised individuals with long hospital stay. The CDC recommend combination of antifungal or investigational drugs for pan-resistant cases. It should be on higher on differential list in centers that have reported Candida auris cases in recent past.^171,172

Invasive Aspergillus infection is seen in the early post-transplant period in up to 8% of LT recipients.^163,173 Presence of other post-LT infections including CMV, renal failure, and re-transplantation are common risk factors of invasive Aspergillus infection in LT recipients.¹⁷⁴ Serum galactomannan and beta-D-glucan are tested for the diagnosis. Early treatment should be initiated in suspected cases. Treatment is not specific to LT patients and is derived from data in immunosuppressed patients. Voriconazole is the first-line treatment and liposomal amphotericin B is an alternative. The combination of voriconazole with echinocandins can be used in selective cases. The echinocandins are used as salvage treatment and not utilized as primary monotherapy.^118,175 The common duration of these antifungal agents is 12 weeks, but it is usually prescribed based on clinical response and level of immunosuppression. Lowering immunosuppression can be utilized as adjunctive therapy to control invasive aspergillosis.¹⁷⁶ The individuals with successful treatment should be considered for secondary prophylaxis.¹⁷⁵ The IDSA also recommends surgical treatment for localized cases as cutaneous disease, CNS focal infection, osteomyelitis, or endocarditis.¹⁷⁵

Cryptococcus infection can present as pneumonia, isolated meningitis, and disseminated infection. Liver transplant recipients who have received alemtuzumab or anti-thymocyte antibody have higher incidence of Cryptococcus.¹⁷⁷ Treatment is similar in LT recipients as in other SOT. Liposomal amphotericin B and flucytosine combination for two weeks is the preferred treatment; an alternative option is liposomal amphotericin B monotherapy for four to six weeks. This initial therapy is followed by eight weeks of consolidation and six to 12 months of fluconazole maintenance therapy. Fluconazole monotherapy can be considered for mild cases (isolated pulmonary disease) for six to 12 months.¹⁷⁸ The AST does not recommend prophylaxis against Cryptococcus in LT recipients.¹⁷⁸

Mucormycosis or zygomycosis is an uncommon fungal infection observed in LT patients and associated with high mortality. Rhino-orbital and pulmonary syndrome are common manifestations.¹⁷⁹ It is reported in less than 1% of SOT recipients and risk factors associated with this infection are diabetes mellitus, renal transplant, and renal failure.^180,181 Liver-transplant–specific data are lacking. Almyroudis et al.¹⁸² reviewed literature from 1970 to 2022 and identified 106 SOT cases with mucormycosis. Of these 40% cases were given augmented immunosuppression to prevent post-transplant rejection. The authors also observed high mortality in mucormycosis after SOT (49%).¹⁸² Rino-sino-orbital disease had better prognosis whereas disseminated disease and rhinocerebral involvement was associated with higher mortality.¹⁸² A case control study showed that this infection manifested earlier in LT recipients (median months: 0.8 vs. 5.7, p < 0.001) and had higher association with disseminated disease as compared to other SOT.¹⁸¹

Mucormycosis is diagnosed based on clinical presentation, supported with CT brain, sinus, and chest with or without bronchoscopy. Culture of secretions or blood are often negative or contaminated and diagnosis is confirmed on histopathology. Although not commercially available, Mucorales PCR had shown higher detection rate in culture-negative mucormycosis. Mucorales PCR of tissue sample showed high positivity in histologically proved cases (22/27).¹⁸³ The recommended treatment for LT is same as general population. Treatment of mucormycosis include combination of surgical debridement and antifungal treatment.¹⁸⁴ Lipid formulation of amphotericin B is a first-line therapy and associated with improved outcomes. Delay in diagnosis and treatment with amphotericin B (>5 days) had shown a two times increase in mortality.^182,185 Posaconazole or isavuconazole are considered for step down therapy or salvage treatment in cases who cannot tolerate amphotericin B.¹⁸⁶ Treatment of underlying risk factors including hyperglycemia, renal failure, and high immunosuppression can also improve the outcome. Duration of treatment varies from case-to-case basis. The antifungal treatment is continued until resolution of symptoms and radiologic signs.¹⁸⁷ The outcomes with combination of amphotericin and echinocandins as compared to amphotericin B only are heterogenous.¹⁸⁶

Pneumocystis pneumonia (PCP) is a severe pulmonary infection caused by an opportunistic organism Pneumocystis jirovecii. Pneumocystis pneumonia is commonly seen in immunocompromised individuals. A study has shown that incidence of non-HIV PCP in LT recipients was more than 20 in 100,000.^188,189 Sputum analysis with PCP stains or PCR testing are recommended in suspected cases. This helps in diagnosing concomitant fungal, bacterial, and viral infections. Bronchoalveolar lavage is more sensitive test than sputum analysis; other diagnostic modalities are lung biopsy and plasma beta-D-glucan levels.¹⁹⁰ Liver transplant recipients who are given high immunosuppression in the setting of acute rejection are recommended to receive PCP prophylaxis with TMP-SMX.^191,192 A consensus summary suggests use of PCP prophylaxis in patient who are receiving high-dose steroids.

Duration of the chemoprophylaxis varies. Commonly recommended duration of prophylaxis is 21 days but it could be up to 12 months in some situations (previously PCP-treated cases). Those with ongoing treatment of graft versus host disease may require indefinite prophylaxis.¹⁹³ The treatment is not specific to LT, the treatment of choice is TMP-SMX, with alternatives being atovaquone, inhalational pentamidine, macrolide and SMX, trimetrexate with folinic acid, dapsone with TMP, or combination of clindamycin with primaquine.¹⁹⁰

Endemic mycoses are relatively rare in LT recipients but are associated with poor outcomes. These include histoplasmosis, coccidiomycosis, and blastomycosis; the clinical presentation of these infections ranges from pulmonary to disseminated disease. These are difficult to differentiate from typical pulmonary infections. Those patients with non-response to treatment and who reside in endemic area or have a history of exposure should have directed testing.¹⁹⁴ The risk of endemic mycosis extends years after the transplant.¹⁹⁴ Mild cases are treated with prolonged use of azoles, and severe and CNS cases are treated with amphotericin followed by prolonged azole use.¹⁹⁵

Parasitic Infections

Risk factors for parasitic infections are increased post-LT in endemic areas, transplantation among immigrants, use of immunosuppressive agents in those with latent infections, and after travel to endemic area after the organ transplant.¹⁹⁶

Toxoplasmosis gondii infection is more commonly seen in endemic areas (hot, humid climate and low altitude); the seropositivity rates in the United States (11%) are lower than endemic areas.^197,198 Possible sources of the transmission are contaminated soil, undercooked meat, contact with feline feces and maternofetal transmission.¹⁹⁹ There are few cases of toxoplasmosis in LT that presented as pneumonia, meningitis, encephalitis, and disseminated disease.^200,201 Mortality is high in these reported cases.²⁰⁰ The AST has no current recommendations for pretransplant testing for Toxoplasmosis gondii in noncardiac transplants. Recommended treatments include pyrimethamine, sulfadiazine and leucovorin induction followed by maintenance therapy for active Toxoplasmosis gondii. Because these patients are on long-term immunosuppression, alternative maintenance therapy with TMP-SMX have shown reduced toxicity.¹⁹⁶

Trypanosoma cruzii is endemic in Latin America and all organ transplant donors and recipients should be screened for Trypanosoma cruzii in these countries.¹⁹⁶ Chagas cardiomyopathy has been reported post-LT.²⁰² Liver transplantation using seropositive donors should have post-LT monitoring. The AST recommends benznidazole as preferred treatment and nifurtimox as an alternative agent.¹⁹⁶

Leishmania donovani causes visceral disease and the other Leishmania species cause mucocutaneous disease; these diseases present similarly to non-transplant patients. Asymptomatic individuals require regular monitoring.²⁰³ Pre-transplant screening with serology test is suggested in individuals who have potential exposure or spent time endemic areas. Post-LT cases can be diagnosed based on serology, bone marrow, or skin biopsy based on presentation. The AST recommends treatment of post-transplant visceral leishmaniasis with liposomal amphotericin B and the mucocutaneous disease with pentavalent antimony.¹⁹⁶

Malaria remains one of the major infections in developing countries. Liver transplant recipients traveling to high-risk areas should receive chemoprophylaxis and early diagnosis and treatment with anti-plasmodial agents in active disease improves outcomes.¹⁹⁶

Babesiosis microti is a tick-borne infection seen in the northeastern United States transmitted by the Ixodes scapularis. The same tick can lead to transmission of Lyme disease (Borrelia burgdorferi) and anaplasmosis (Anaplasma phagocytophilum).²⁰⁴ Parasitemia in LT recipients can be life threatening. Relapse of these infections is commonly observed and the AST recommends longer treatment.¹⁹⁶

The intestinal protozoal infections seen in SOT patients include Cryptosporidium, Cyclospora, Blastocystis hominis, Microsporidia, Cystoisospora belli, Giardia and Entamoeba histolytica, and intestinal nematodes.¹⁹⁶ Mycophenolate mofetil is a common cause of diarrhea in LT recipients, chronic diarrhea should raise concerns of the intestinal protozoal infections. These infections can be identified by stool ova and parasite, and immunofluorescence study. The LT recipients should use treated water and avoid fresh untreated water. The chlorination of water does not eliminate Cryptosporidium infection, although microfiltration can be utilized to reduce spead.¹⁹⁶ Treatment includes electrolyte and water replacement; there are several anti-parasite medication options with the most recommended treatments being a combination of nitaxoxanide and paromomycin or macrolides.²⁰⁵ The BioFire FilmArray GI Panel has better diagnostic yield for diarrhea cases than traditional stool PCR testing and cultures. It had shown reduced diagnostic turnaround time, days of antibiotic use, and isolation.²⁰⁶ These benefits may add to improvement of post-LT outcomes.

In summary, infections are the most common post-LT–related complications. They are associated with transplant failure, increased morbidity, and mortality. The potent immunosuppression, prolonged hospital stays, and prolonged use of broad-spectrum antibiotic agents are associated with higher risk of developing post-LT infections. Use of infection screening, vaccination, appropriate antibiotic prophylaxis, and antibiotic stewardship can prevent and control most of infections. The development of drug resistance, late presentations and invasive fungal infections can be challenging to treat. Early diagnosis and treatment of these infections are associated with improved outcomes.

Footnotes

Authors' Contributions

Response to reviewers: Amjad. Literature review: Rahman. Conceptualization: Schiano, Jafri. Supervision: Schiano, Jafri. Critical revision: Schiano. Finalizing response to reviewers: Schiano. Outline: Jafri. Writing—original draft: Amjad, Rahman. Writing—reviewing and editing: Jafri.

Funding Information

No funding was received.

Author Disclosure Statement

No competing financial interests exist.

References

Transplants by Donor Type Page 1 of 1 U.S. Transplants Performed: January 1, 1988–April 30, 2022. National data-OPTN (hrsa.gov). Available from: https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/ [Last assessed: April 30, 2022].

Singh

, Limaye

. Infections in solid-organ transplant recipients. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 1998:3440–3452. Published online 2015; doi: 10.1016/B978-1-4557-4801-3.00313-1

Limaye

, Bakthavatsalam

, Kim

, et al. Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis. Transplantation, 2006; 81(12):1645-1652; doi: 10.1097/01.tp.0000226071.12562.1a

Leibovici-Weissman

, Anchel

, Nesher

, et al. Early post-liver transplantation infections and their effect on long-term survival. Transpl Infect Dis, 2021; 23(4):13673; doi: 10.1111/tid.13673

Torbenson

, Wang

, Nichols

, et al. Causes of death in autopsied liver transplantation patients. Mod Pathol, 1998; 11(1):37–46.

Sun

H-Y

, Cacciarelli T

, Singh

. Identifying a targeted population at high risk for infections after liver transplantation in the MELD era. Clin Transplant, 2011; 25(3):420–425; doi: 10.1111/j.1399-0012.2010.01262.x

Pène

, Pickkers

, Hotchkiss

. Is this critically ill patient immunocompromised?. Intensive Care Med, 2016; 42(6):1051–1054; doi: 10.1007/s00134-015-4161-y

Fishman

JA.

Infection in solid-organ transplant recipients. N Engl J Med, 2007; 357(25):2601–2614; doi: 10.1056/NEJMra064928

Martin

, DiMartini

, Feng

, et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology, 2014; 59(3):1144–1165; doi: 10.1002/hep.26972

10.

Fishman

, Rubin

. Infection in organ-transplant recipients. N Engl J Med, 1998; 338(24):1741–1751; doi: 10.1056/NEJM199806113382407

11.

Fischer

, Lu

. Screening of donor and recipient in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):9–21; doi: 10.1111/ajt.12094

12.

Fishman

, Issa

. Infection in organ transplantation: Risk factors and evolving patterns of infection. Infect Dis Clin North Am, 2010; 24(2):273–283; doi: 10.1016/j.idc.2010.01.005

13.

Levesque

, Winter

, Noorah

, et al. Impact of acute-on-chronic liver failure on 90-day mortality following a first liver transplantation. Liver Int, 2017; 37(5):684–693; doi: 10.1111/liv.13355

14.

Stravitz

, Lee

. Acute liver failure. Lancet, 2019; 394(10201):869–881; doi: 10.1016/S0140-6736(19)31894-X

15.

Rolando

, Gimson

, Wade

, et al. Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology, 1993; 17(2):196–201; doi: 10.1002/hep.1840170206

16.

Sundaram

, Mahmud

, Perricone

, et al. Longterm outcomes of patients undergoing liver transplantation for acute-on-chronic liver failure. Liver Transplant, 2020; 26(12):1594–1602; doi: 10.1002/lt.25831

17.

Goosmann

, Buchholz

, Bangert

, et al. Liver transplantation for acute-on-chronic liver failure predicts post-transplant mortality and impaired long-term quality of life. Liver Int, 2021; 41(3):574–584; doi: 10.1111/liv.14756

18.

Logre

, Bert

, Khoy-Ear

, et al. Risk factors and impact of perioperative prophylaxis on the risk of extended-spectrum β-lactamase-producing Enterobacteriaceae-related infection among carriers following liver transplantation. Transplantation, 2021; 105(2):338–345; doi: 10.1097/TP.0000000000003231

19.

Lavanchy

Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat, 2004; 11(2):97–107; doi: 10.1046/j.1365-2893.2003.00487.x

20.

Thein

H-H

, Yi

, Dore

, Krahn

. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: A meta-analysis and meta-regression. Hepatology, 2008; 48(2):418–431; doi: 10.1002/hep.22375

21.

Jothimani

, Venugopal

, Vij

, Rela

. Post liver transplant recurrent and de novo viral infections. Best Pract Res Clin Gastroenterol, 2020; 46–47:101689; doi: 10.1016/j.bpg.2020.101689

22.

Lizaola-Mayo

, Rodriguez

. Cytomegalovirus infection after liver transplantation. World J Transplant, 2020; 10(7):183–190; doi: 10.5500/wjt.v10.i7.183

23.

Zuhair

, Smit

GSA

, Wallis

, et al. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev Med Virol, 2019; 29(3):2034; doi: 10.1002/rmv.2034

24.

Cannon

, Schmid

, Hyde

. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol, 2010; 20(4):202–213; doi: 10.1002/rmv.655

25.

Singh

, Wannstedt

, Keyes

, et al. Who among cytomegalovirus-seropositive liver transplant recipients is at risk for cytomegalovirus infection?. Liver Transplant, 2005; 11(6):700–704; doi: 10.1002/lt.20417

26.

Gane

, Saliba

, Valdecasas

, et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The Oral Ganciclovir International Transplantation Study Group [corrected]. Lancet, 1997; 350(9093):1729–1733; doi: 10.1016/s0140-6736(97)05535-9

27.

Yadav

, Saigal

, Choudhary

, et al. Cytomegalovirus infection in liver transplant recipients: Current approach to diagnosis and management. J Clin Exp Hepatol, 2017; 7(2):144–151; doi: 10.1016/j.jceh.2017.05.011

28.

Ljungman

, Boeckh

, Hirsch

, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis, 2017; 64(1):87–91; doi: 10.1093/cid/ciw668

29.

Collins-McMillen

, Buehler

, Peppenelli

, Goodrum

. Molecular determinants and the regulation of human cytomegalovirus latency and reactivation. Viruses, 2018; 10(8):444; doi: 10.3390/v10080444

30.

Razonable

, Paya C

, Smith

. Role of the laboratory in diagnosis and management of cytomegalovirus infection in hematopoietic stem cell and solid-organ transplant recipients. J Clin Microbiol, 2002; 40(3):746–752; doi: 10.1128/JCM.40.3.746-752.2002

31.

Humar

, Snydman

. Cytomegalovirus in solid organ transplant recipients. Am J Transplant, 2009; 9(Suppl 4):S78–86; doi: 10.1111/j.1600-6143.2009.02897.x

32.

You

, Johnson

. Cytomegalovirus infection and the gastrointestinal tract. Curr Gastroenterol Rep, 2012; 14(4):334–342; doi: 10.1007/s11894-012-0266-4

33.

Razonable

, Humar

. Cytomegalovirus in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):93–106; doi: 10.1111/ajt.12103

34.

Singh

, Winston

, Razonable

, et al. Effect of preemptive therapy vs antiviral prophylaxis on cytomegalovirus disease in seronegative liver transplant recipients with seropositive donors: A randomized clinical trial. JAMA, 2020; 323(14):1378–1387; doi: 10.1001/jama.2020.3138

35.

Kotton

CN.

CMV: Prevention, diagnosis and therapy. Am J Transplant, 2013; 13(Suppl 3):24–40; doi: 10.1111/ajt.12006

36.

Shmueli

, Or

, Shapira

, et al. High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. J Infect Dis, 2014; 209(4):557–561; doi: 10.1093/infdis/jit475

37.

Hantz

, Garnier-Geoffroy

, Mazeron

M-C

, et al. Drug-resistant cytomegalovirus in transplant recipients: A French cohort study. J Antimicrob Chemother, 2010; 65(12):2628–2640; doi: 10.1093/jac/dkq368

38.

Kotton

, Kumar

, Caliendo

, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation, 2018; 102(6):900–931; doi: 10.1097/TP.0000000000002191

39.

Gilbert

, Boivin

. Human cytomegalovirus resistance to antiviral drugs. Antimicrob Agents Chemother, 2005; 49(3):873–883; doi: 10.1128/AAC.49.3.873-883.2005

40.

El Chaer

, Shah

, Chemaly

. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood, 2016; 128(23):2624–2636; doi: 10.1182/blood-2016-06-688432

41.

Sassine

, Khawaja

, Shigle

, et al. Refractory and resistant cytomegalovirus after hematopoietic cell transplant in the letermovir primary prophylaxis era. Clin Infect Dis, 2021; 73(8):1346–1354; doi: 10.1093/cid/ciab298

42.

Cohen

JI.

Epstein-Barr virus infection. N Engl J Med, 2000; 343(7):481–492; doi: 10.1056/NEJM200008173430707

43.

Tajima

, Hata

, Haga

, et al. Post-transplant lymphoproliferative disorders after liver transplantation: A retrospective cohort study including 1954 transplants. Liver Transplant, 2021; 27(8):1165–1180; doi: 10.1002/lt.26034

44.

Dowd

, Palermo

, Brite

, McDade

, Aiello

. Seroprevalence of Epstein-Barr virus infection in U.S. children ages 6–19, 2003–2010. PLoS One, 2013; 8(5):e64921; doi: 10.1371/journal.pone.0064921

45.

Thorley-Lawson

, Gross

. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med, 2004; 350(13):1328–1337; doi: 10.1056/NEJMra032015

46.

Kamdar

, Rooney

, Heslop

. Posttransplant lymphoproliferative disease following liver transplantation. Curr Opin Organ Transplant, 2011; 16(3):274–280; doi: 10.1097/MOT.0b013e3283465715

47.

Allen

, Preiksaitis

. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):107–120; doi: 10.1111/ajt.12104

48.

Nourse

, Jones

, Gandhi

. Epstein-Barr Virus-related post-transplant lymphoproliferative disorders: Pathogenetic insights for targeted therapy. Am J Transplant, 2011; 11(5):888–895; doi: 10.1111/j.1600-6143.2011.03499.x

49.

Nijland

, Kersten

, Pals

, et al. Epstein-Barr Virus-Positive posttransplant lymphoproliferative disease after solid organ transplantation: pathogenesis, clinical manifestations, diagnosis, and management. Transplant Direct, 2016; 2(1):48; doi: 10.1097/TXD.0000000000000557

50.

Choquet

, Varnous

, Deback

, et al. Adapted treatment of Epstein-Barr virus infection to prevent posttransplant lymphoproliferative disorder after heart transplantation. Am J Transplant, 2014; 14(4):857–866; doi: 10.1111/ajt.12640

51.

Evens

, David

, Helenowski

, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: Outcomes and prognostic factors in the modern era. J Clin Oncol, 2010; 28(6):1038–1046; doi: 10.1200/JCO.2009.25.4961

52.

San Juan

, Aguado

, Lumbreras

, et al. Incidence, clinical characteristics and risk factors of late infection in solid organ transplant recipients: Data from the RESITRA study group. Am J Transplant, 2007; 7(4):964–971; doi: 10.1111/j.1600-6143.2006.01694.x

53.

Lee

, Zuckerman

. Herpes simplex virus infections in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 2019; 33(9):13526; doi: 10.1111/ctr.13526

54.

Riediger

, Sauer

, Matevossian

, et al. Herpes simplex virus sepsis and acute liver failure. Clin Transplant, 2009; 23(Suppl 21):37–41; doi: 10.1111/j.1399-0012.2009.01108.x

55.

Arana

, Cofan

, Ruiz

, et al. Primary herpes simplex virus type 1 infection with acute liver failure in solid organ transplantation: Report of three cases and review. IDCases, 2022; 28:01485; doi: 10.1016/j.idcr.2022.e01485

56.

Côté-Daigneault

, Carrier

, Toledano

, et al. Herpes simplex hepatitis after liver transplantation: Case report and literature review. Transpl Infect Dis, 2014; 16(1):130–134; doi: 10.1111/tid.12178

57.

Piret

, Boivin

. Antiviral resistance in herpes simplex virus and varicella-zoster virus infections: Diagnosis and management. Curr Opin Infect Dis, 2016; 29(6):654–662; doi: 10.1097/QCO.0000000000000288

58.

Gershon

, Gershon

. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clin Microbiol Rev, 2013; 26(4):728–743; doi: 10.1128/CMR.00052-13

59.

Hamaguchi

, Mori

, Uemura

, et al. Incidence and risk factors for herpes zoster in patients undergoing liver transplantation. Transpl Infect Dis, 2015; 17(5):671–678; doi: 10.1111/tid.12425

60.

Pergam

, Limaye

. Varicella zoster virus in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 2019; 33(9):13622; doi: 10.1111/ctr.13622

61.

Talarico

, Phelps

, Biron

. Analysis of the thymidine kinase genes from acyclovir-resistant mutants of varicella-zoster virus isolated from patients with AIDS. J Virol, 1993; 67(2):1024–1033; doi: 10.1128/JVI.67.2.1024-1033.1993

62.

Zuckerman

, Limaye

. Varicella zoster virus (VZV) and herpes simplex virus (HSV) in solid organ transplant patients. Am J Trasnplant, 2013; 13(Suppl 3):55–66; doi: 10.1111/ajt.12003

63.

Saint-Léger

, Caumes

, Breton

, et al. Clinical and virologic characterization of acyclovir-resistant varicella-zoster viruses isolated from 11 patients with acquired immunodeficiency syndrome. Clin Infect Dis, 2001; 33(12):2061–2067; doi: 10.1086/324503

64.

Dooling

, Guo

, Patel

, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly Rep, 2018; 67(3):103–108; doi: 10.15585/mmwr.mm6703a5

65.

Shingles (Herpes Zoster) Clinical Considerations for Use of Recombinant Zoster Vaccine (RZV, Shingrix) in Immunocompromised Adults Aged ≥19 Years. 2022. Clinical Considerations for Use of Recombinant Zoster Vaccine (RZV, Shingrix) in Immunocompromised Adults Aged ≥19 Years | CDC. Available from: https://www.cdc.gov/shingles/vaccination/immunocompromised-adults.html [Last assessed: February 27, 2024].

66.

Vink

, Ramon Torrell

, Sanchez Fructuoso

, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in chronically immunosuppressed adults following renal transplant: A phase 3, randomized clinical trial. Clin Infect Dis, 2020; 70(2):181–190; doi: 10.1093/cid/ciz177

67.

Bastidas

, de la Serna

, El Idrissi

, et al. Effect of recombinant zoster vaccine on incidence of Herpes zoster After autologous stem cell transplantation: A randomized clinical trial. JAMA, 2019; 322(2):123–133; doi: 10.1001/jama.2019.9053

68.

Albuquerque

, Pessegueiro Miranda

, Lopes

, et al. Liver transplant recipients have a higher prevalence of anal squamous intraepithelial lesions. Br J Cancer, 2017; 117(12):1761–1767; doi: 10.1038/bjc.2017.370

69.

Chin-Hong

P V

, Reid

. Human papillomavirus infection in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019; 33(9):13590; doi: 10.1111/ctr.13590

70.

Human Papillomavirus (HPV) Infection. 2021. Human Papillomavirus (HPV) Infection-STI Treatment Guidelines (cdc.gov). Available from: https://www.cdc.gov/std/treatment-guidelines/hpv.htm [Last assessed: September 7, 2022].

71.

Abdel Massih

, Razonable

. Human herpesvirus 6 infections after liver transplantation. World J Gastroenterol, 2009; 15(21):2561–2569; doi: 10.3748/wjg.15.2561

72.

Yamanishi

, Okuno

, Shiraki

, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet, 1988; 1(8594):1065–1067; doi: 10.1016/s0140-6736(88)91893-4

73.

Lautenschlager

, Höckerstedt

, Linnavuori

, Taskinen

. Human herpesvirus-6 infection after liver transplantation. Clin Infect Dis, 1998; 26(3):702–707; doi: 10.1086/514592

74.

Pellett Madan

, Hand

. Human herpesvirus 6, 7, and 8 in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 2019; 33(9):13518; doi: 10.1111/ctr.13518

75.

Phan

, Lautenschlager

, Razonable

, Munoz

. HHV-6 in liver transplantation: A literature review. Liver Int, 2018; 38(2):210–223; doi: 10.1111/liv.13506

76.

Florescu

, Hoffman

. Adenovirus in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):206–211; doi: 10.1111/ajt.12112

77.

Florescu

, Schaenman

. Adenovirus in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 2019; 33(9):13527; doi: 10.1111/ctr.13527

78.

Lindemans

, Leen

, Boelens

. How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood, 2010; 116(25):5476–5485; doi: 10.1182/blood-2010-04-259291

79.

Eid

, Ardura

. Human parvovirus B19 in solid organ transplantation: Guidelines from the American Sciety of Transplantation Infectious Diseases community of practice. Clin Transplant, 2019; 33(9):13535; doi: 10.1111/ctr.13535

80.

Eid

, Chen

. Human parvovirus B19 in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):201–205; doi: 10.1111/ajt.12111

81.

Cheng

, Jian

, Fu

, Ma

. Parvovirus B19-associated severe anemia in adult liver transplant recipients: A case series and review of the literature. Surg Infect, 2022; 23(9):848–856; doi: 10.1089/sur.2022.186

82.

Colmenero

, Rodríguez-Perálvarez

, Salcedo

, et al. Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients. J Hepatol, 2021; 74(1):148–155; doi: 10.1016/j.jhep.2020.07.040

83.

Guarino

, Cossiga

, Loperto

, et al. COVID-19 in liver transplant recipients: Incidence, hospitalization and outcome in an Italian prospective double-centre study. Sci Rep, 2022; 12(1):4831; doi: 10.1038/s41598-022-08947-x

84.

Whitsett

, Ortiz

, Weinberg

. CON: Liver transplantation in the times of COVID-19: Patients with COVID-19 infection should not undergo liver transplantation. Clin Liver Dis, 2021; 18(5):233–236; doi: 10.1002/cld.1136

85.

Fix

, Hameed

, Fontana

, et al. Clinical best practice advice for hepatology and liver transplant providers during the COVID-19 pandemic: AASLD Expert Panel Consensus Statement. Hepatology, 2020; 72(1):287–304; doi: 10.1002/hep.31281

86.

Kolla

, Weill

, Zaidan

, et al. COVID-19 Hospitalization in solid organ transplant recipients on immunosuppressive therapy. JAMA Netw Open, 2023; 6(11):2342006; doi: 10.1001/jamanetworkopen.2023.42006

87.

Webb

, Marjot

, Cook

, et al. Outcomes following SARS-CoV-2 infection in liver transplant recipients: An international registry study. Lancet Gastroenterol Hepatol, 2020; 5(11):1008–1016; doi: 10.1016/S2468-1253(20)30271-5

88.

Thuluvath

, Robarts

, Chauhan

. Analysis of antibody responses after COVID-19 vaccination in liver transplant recipients and those with chronic liver diseases. J Hepatol, 2021; 75(6):1434–1439; doi: 10.1016/j.jhep.2021.08.008

89.

AASLD Expert Panel Consensus Statement: COVID-19 Clinical Best Practice Advice for Hepatology and Evaluation of COVID-19 Patients with Elevated Liver Biochemistries AASLD COVID-19 Task Force Clinical Oversight and Education Subcommittee. Published online 2022. AASLD COVID-19 Guidance Document. 10.06.2022F.pdf Available from: https://www.aasld.org/sites/default/files/2022-10/AASLD%20COVID-19%20Guidance%20Document%2010.06.2022F.pdf [Last assessed: March 29, 2023].

90.

Marjot

, Webb

, Barritt

, et al. SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question. Lancet Gastroenterol Hepatol, 2021; 6(3):156–158; doi: 10.1016/S2468-1253(21)00008-X

91.

General Management of Nonhospitalized Adults With Acute COVID-19. 2022. Nonhospitalized Adults: General Management | COVID-19 Treatment Guidelines (nih.gov). Available from: https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-adults/nonhospitalized-adults-general-management [Last assessed: February 26, 2024].

92.

Therapeutic Management of Nonhospitalized Adults With COVID-19. 2023. Nonhospitalized Adults: Therapeutic Management | COVID-19 Treatment Guidelines (nih.gov). Available from: https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-adults/nonhospitalized-adults--therapeutic-management [Last assessed: February 26, 2024].

93.

Therapeutic Management of Hospitalized Adults With COVID-19 Hospitalized but Does Not Require Supplemental Oxygen. 2023. Hospitalized Adults: Therapeutic Management | COVID-19 Treatment Guidelines (nih.gov). Available from: https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-adults/hospitalized-adults--therapeutic-management/ [Last assessed: February 26, 2024].

94.

Piedade

, Pereira

. COVID-19 in liver transplant recipients. J Liver Transplant, 2021; 3:100026; doi: 10.1016/j.liver.2021.100026

95.

Yamani

, Alraddadi

, Almaghrabi

, et al. Early use of tocilizumab in solid organ transplant recipients with COVID-19: A retrospective cohort study in Saudi Arabia. Immunity Inflamm Dis, 2022; 10(3):587; doi: 10.1002/iid3.587

96.

AST statement on oral antiviral therapy for covid-19 for organ transplant recipients. November 2022. AST Statement on Oral Antiviral Therapy for COVID Jan 4 (2).pdf (myast.org). vailable from: https://www.myast.org/sites/default/files/AST%20Statement%20on%20Oral%20Antiviral%20Therapy%20for%20COVID%20Jan%204%20%282%29.pdf [Last assessed: April 19, 2023].

97.

WHO Director-General's Statement at the Press Conference Following IHR Emergency Committee Regarding the Multi-Country Outbreak of Monkeypox. July 2022. WHO Director-General's statement at the press conference following IHR Emergency Committee regarding the multi-country outbreak of monkeypox-23 July 2022. Available from: https://www.who.int/news-room/speeches/item/who-director-general-s-statement-on-the-press-conference-following-IHR-emergency-committee-regarding-the-multi--country-outbreak-of-monkeypox--23-july-2022 [Last assessed: March 19, 2023].

98.

Thornhill

, Barkati

, Walmsley

, et al. Monkeypox virus infection in humans across 16 countries: April–June 2022. N Engl J Med, 2022; 387(8):679–691; doi: 10.1056/NEJMoa2207323

99.

Mpox Treatment Information for Healthcare Professionals Interim Clinical Guidance for the Treatment of Mpox Medical Countermeasures Available for the Treatment of Mpox. 2023. Treatment Information for Healthcare Professionals | Mpox | Poxvirus | CDC. Available from: https://www.cdc.gov/poxvirus/mpox/clinicians/treatment.html [Last assessed: February 11, 2024].

100.

Interim Clinical Considerations for Use of JYNNEOS and ACAM2000 Vaccines during the 2022 U.S. Mpox Outbreak. 2022. Interim Clinical Considerations for Use of JYNNEOS and ACAM2000 Vaccines during the 2022 U.S. Mpox Outbreak | Mpox | Poxvirus | CDC. Available from: https://www.cdc.gov/poxvirus/mpox/clinicians/vaccines/vaccine-considerations.html [Last assessed: March 16, 2023].

101.

Components of the U.S. National Mpox Vaccination Strategy. 2023. Vaccination | Mpox | Poxvirus | CDC. Available from: https://www.cdc.gov/poxvirus/mpox/interim-considerations/overview.html [Last assessed: March 16, 2023].

102.

Al Jurdi

, Kotton

. Monkeypox in transplant recipients: No breaks between outbreaks. Transplantation, 2022; 106(11):512–513; doi: 10.1097/TP.0000000000004337

103.

Treatment Information for Healthcare Professionals. 2023. Treatment Informatio for Healthcare Professionals | Mpox | Poxvirus | CDC. Available from: https://www.cdc.gov/poxvirus/mpox/clinicians/treatment.html [Last assessed: March 29, 2023].

104.

Shamim

, Padhi

, Satapathy

, et al. The use of antivirals in the treatment of human monkeypox outbreaks: A systematic review. Int J Infect Dis, 2023; 127:150–161; doi: 10.1016/j.ijid.2022.11.040

105.

Jung

, Bhaimia

, Reau

. Use of tecovirimat for mpox infection followed by JYNNEOS vaccination postinfection in a liver transplant recipient. Transpl Infect Dis, 2023; 25(3):14030; doi: 10.1111/tid.14030

106.

Blair

, Kusne

. Bacterial, mycobacterial, and protozoal infections after liver transplantation—Part I. Liver Transplant, 2005; 11(12):1452–1459; doi: 10.1002/lt.20624

107.

Singh

, Paterson

, Gayowski

, Wagener

, Marino

. Predicting bacteremia and bacteremic mortality in liver transplant recipients. Liver Transplant, 2000; 6(1):54–61; doi: 10.1002/lt.500060112

108.

Kim S Il. Bacterial infection after liver transplantation. World J Gastroenterol, 2014; 20(20):6211–6220; doi: 10.3748/wjg.v20.i20.6211

109.

Shbaklo

, Tandoi

, Lupia

, et al. Bacterial and viral infections in liver transplantation: New Insights from clinical and surgical perspectives. biomedicines. 2022; 10(7):1561; doi: 10.3390/biomedicines10071561

110.

Merli

, Lucidi

, Di Gregorio

, et al. The spread of multi drug resistant infections is leading to an increase in the empirical antibiotic treatment failure in cirrhosis: A prospective survey. PLoS One, 2015; 10(5):0127448; doi: 10.1371/journal.pone.0127448

111.

Tuberculosis Deaths and Disease Increase during the COVID-19 Pandemic. Elsevier. 2022. Tuberculosis deaths and disease increase during the COVID-19 pandemic - PAHO/WHO | Pan American Health Organization. Available from: https://www.paho.org/en/news/27-10-2022-tuberculosis-deaths-and-disease-increase-during-covid-19-pandemic [Last assessed: April 19, 2023].

112.

Holty

J-EC

, Gould

, Meinke

, et al. Tuberculosis in liver transplant recipients: a systematic review and meta-analysis of individual patient data. Liver Transplant, 2009; 15(8):894–906; doi: 10.1002/lt.21709

113.

Reichler

, Reves

, Bur

, et al. Evaluation of investigations conducted to detect and prevent transmission of tuberculosis. JAMA, 2002; 287(8):991–995; doi: 10.1001/jama.287.8.991

114.

Kline

, Hedemark

, Davies

. Outbreak of tuberculosis among regular patrons of a neighborhood bar. N Engl J Med, 1995; 333(4):222–227; doi: 10.1056/NEJM199507273330404

115.

Yehia

, Blumberg

. Mycobacterium tuberculosis infection in liver transplantation. Liver Transplant, 2010; 16(10):1129–1135; doi: 10.1002/lt.22133

116.

Aguado

, Herrero

, Gavaldá

, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplantation, 1997; 63(9):1278–1286; doi: 10.1097/00007890-199705150-00015

117.

Mycobacterium tuberculosis. Am J Transplant, 2004; 4(Suppl 10):37–41; doi: 10.1111/j.1600-6135.2004.00724.x

118.

Hernandez

MDP

, Martin

, Simkins

. Infectious complications after liver transplantation. Gastroenterol Hepatol (NY), 2015; 11(11):741–753.

119.

Dheda

, Gumbo

, Maartens

, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med, 2017; 5(4):291–306 doi: 10.1016/S2213-2600(17)30079-6

120.

Paya

, Hermans

, Washington

JA 2nd

, et al. Incidence, distribution, and outcome of episodes of infection in 100 orthotopic liver transplantations. Mayo Clin Proc, 1989; 64(5):555–564; doi: 10.1016/s0025-6196(12)65561-x

121.

Asensio

, Ramos

, Cuervas-Mons

, et al. Effect of antibiotic prophylaxis on the risk of surgical site infection in orthotopic liver transplant. Liver Transplant, 2008; 14(6):799–805; doi: 10.1002/lt.21435

122.

Bodro

, Sabé

, Tubau

, et al. Risk factors and outcomes of bacteremia caused by drug-resistant ESKAPE pathogens in solid-organ transplant recipients. Transplantation, 2013; 96(9):843–849; doi: 10.1097/TP.0b013e3182a049fd

123.

Papanicolaou

, Meyers

, et al. Nosocomial infections with vancomycin-resistant Enterococcus faecium in liver transplant recipients: Risk factors for acquisition and mortality. Clin Infect Dis, 1996; 23(4):760–766; doi: 10.1093/clinids/23.4.760

124.

Santoro-Lopes

, de Gouvêa

. Multidrug-resistant bacterial infections after liver transplantation: An ever-growing challenge. World J Gastroenterol, 2014; 20(20):6201–6210; doi: 10.3748/wjg.v20.i20.6201

125.

Bert

, Larroque

, Paugam-Burtz

, et al. Pretransplant fecal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae and infection after liver transplant, France. Emerg Infect Dis, 2012; 18(6):908–916; doi: 10.3201/eid1806.110139

126.

Kalpoe

, Sonnenberg

, Factor

, et al. Mortality associated with carbapenem-resistant Klebsiella pneumoniae infections in liver transplant recipients. Liver Transplant, 2012; 18(4):468–474; doi: 10.1002/lt.23374

127.

Shields

, Clancy

, Gillis

, et al. Epidemiology, clinical characteristics and outcomes of extensively drug-resistant Acinetobacter baumannii infections among solid organ transplant recipients. PLoS One, 2012; 7(12):52349; doi: 10.1371/journal.pone.0052349

128.

Gearhart

, Martin

, Rudich

, et al. Consequences of vancomycin-resistant Enterococcus in liver transplant recipients: A matched control study. Clin Transplant, 2005; 19(6):711–716; doi: 10.1111/j.1399-0012.2005.00362.x

129.

Singh

, Paterson

, Chang

, et al. Methicillin-resistant Staphylococcus aureus: The other emerging resistant gram-positive coccus among liver transplant recipients. Clin Infect Dis, 2000; 30(2):322–327; doi: 10.1086/313658

130.

Ziakas

, Pliakos

, Zervou

, Knoll

, Rice

, Mylonakis

. MRSA and VRE colonization in solid organ transplantation: A meta-analysis of published studies. Am J Transplant, 2014; 14(8):1887–1894; doi: 10.1111/ajt.12784

131.

Liu

, Bayer

, Cosgrove

, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: Executive summary. Clin Infect Dis, 2011; 52(3):285–292; doi: 10.1093/cid/cir034

132.

Svetitsky

, Leibovici

, Paul

. Comparative efficacy and safety of vancomycin versus teicoplanin: Systematic review and meta-analysis. Antimicrob Agents Chemother, 2009; 53(10):4069–4079; doi: 10.1128/AAC.00341-09

133.

Hassoun

, Linden

, Friedman

. Incidence, prevalence, and management of MRSA bacteremia across patient populations: A review of recent developments in MRSA management and treatment. Crit Care, 2017; 21(1):211; doi: 10.1186/s13054-017-1801-3

134.

Miller

, Munita

, Arias

. Mechanisms of antibiotic resistance in enterococci. Expert Rev Anti Infect Ther, 2014; 12(10):1221–1236; doi: 10.1586/14787210.2014.956092

135.

Pogue

, Paterson

, Pasculle

, Potoski

. Determination of risk factors associated with isolation of linezolid-resistant strains of vancomycin-resistant Enterococcus. Infect Control Hosp Epidemiol, 2007; 28(12):1382–1388; doi: 10.1086/523276

136.

Lee

, Goldman

, Haidar

, et al. Daptomycin-resistant enterococcus bacteremia is associated with prior daptomycin use and increased mortality after liver transplantation. Open Forum Infect Dis, 2022; 9(3):659; doi: 10.1093/ofid/ofab659

137.

Linares

, Cervera

, Hoyo

, et al. Klebsiella pneumoniae infection in solid organ transplant recipients: Epidemiology and antibiotic resistance. Transplant Proc, 2010; 42(8):2941–2943; doi: 10.1016/j.transproceed.2010.07.080

138.

Paterson

, Ko

W-C

, Von Gottberg

, et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: Implications of production of extended-spectrum beta-lactamases. Clin Infect Dis, 2004; 39(1):31–37; doi: 10.1086/420816

139.

Lee

N-Y

, Lee

C-C

, Huang

W-H

, et al. Carbapenem therapy for bacteremia due to extended-spectrum-β-lactamase-producing Escherichia coli or Klebsiella pneumoniae: Implications of ertapenem susceptibility. Antimicrob Agents Chemother, 2012; 56(6):2888–2893; doi: 10.1128/AAC.06301-11

140.

Cervera

, Agustí

, Angeles Marcos

, et al. Microbiologic features and outcome of pneumonia in transplanted patients. Diagn Microbiol Infect Dis, 2006; 55(1):47–54; doi: 10.1016/j.diagmicrobio.2005.10.014

141.

Zhong

, Men

T-Y

, Li

, et al. Multidrug-resistant gram-negative bacterial infections after liver transplantation: Spectrum and risk factors. J Infect, 2012; 64(3):299–310; doi: 10.1016/j.jinf.2011.12.005

142.

Johnson

, D'Agata

EMC

, Paterson

, et al. Pseudomonas aeruginosa bacteremia over a 10-year period: Multidrug resistance and outcomes in transplant recipients. Transpl Infect Dis, 2009; 11(3):227–234; doi: 10.1111/j.1399-3062.2009.00380.x

143.

Horcajada

, Montero

, Oliver

, et al. Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections. Clin Microbiol Rev, 2019; 32(4); doi: 10.1128/CMR.00031-19

144.

Freire

, Oshiro

ICVS

, Pierrotti

, et al. Carbapenem-Resistant enterobacteriaceae acquired before liver transplantation: Impact on recipient outcomes. Transplantation, 2017; 101(4):811–820; doi: 10.1097/TP.0000000000001620

145.

Giannella

, Bartoletti

, Campoli

, et al. The impact of carbapenemase-producing Enterobacteriaceae colonization on infection risk after liver transplantation: A prospective observational cohort study. Clin Microbiol Infect, 2019; 25(12):1525–1531; doi: 10.1016/j.cmi.2019.04.014

146.

Clancy

. Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended- Spectrum β -lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE). 2022. Available from: IDSA 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections (idsociety.org). [Last assessed: July 18, 2022].

147.

Kim

, Kim

, Lee

, et al. Carbapenem-resistant Acinetobacter baumannii bacteremia in liver transplant recipients. Transplant Proc, 2018; 50(4):1132–1135; doi: 10.1016/j.transproceed.2018.01.043

148.

Tamma

, Aitken

, Bonomo

, et al. Infectious Diseases Society of America Guidance on the Treatment of AmpC β-lactamase-producing enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections. Clin Infect Dis, 2022; 74(12):2089–2114; doi: 10.1093/cid/ciab1013

149.

Leffler

, Lamont

. Clostridium difficile infection. N Engl J Med, 2015; 372(16):1539–1548; doi: 10.1056/NEJMra1403772

150.

Paudel

, Zacharioudakis

, Zervou

, et al. Prevalence of Clostridium difficile infection among solid organ transplant recipients: A meta-analysis of published studies. PLoS One, 2015; 10(4):0124483; doi: 10.1371/journal.pone.0124483

151.

Albright

, Bonatti

, Mendez

, et al. Early and late onset Clostridium difficile-associated colitis following liver transplantation. Transpl Int, 2007; 20(10):856–866; doi: 10.1111/j.1432-2277.2007.00530.x

152.

Mittal

, Hassan

, Arshad

, et al. Clostridium difficile infection in liver transplant recipients: A retrospective study of rates, risk factors and outcomes. Am J Transplant, 2014; 14(8):1901–1907; doi: 10.1111/ajt.12798

153.

Boutros

, Al-Shaibi

, Chan

, et al. Clostridium difficile colitis: increasing incidence, risk factors, and outcomes in solid organ transplant recipients. Transplantation, 2012; 93(10):1051–1057; doi: 10.1097/TP.0b013e31824d34de

154.

Len

, Rodríguez-Pardo

, Gavaldà

, et al. Outcome of Clostridium difficile-associated disease in solid organ transplant recipients: A prospective and multicentre cohort study. Transpl Int, 2012; 25(12):1275–1281; doi: 10.1111/j.1432-2277.2012.01568.x

155.

Dubberke

, Reske

, Olsen

, et al. Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients. Transpl Infect Dis, 2018; 20(2):12855; doi: 10.1111/tid.12855

156.

Rochon

, Kardashian

, Mahadevappa

, et al. Liver graft failure and hyperbilirubinemia in liver transplantation recipients after Clostridium difficile infection. Transplant Proc, 2011; 43(10):3819–3823; doi: 10.1016/j.transproceed.2011.08.098

157.

Amjad

, Qureshi

, Malik

, et al. The outcomes of Clostridioides difficile infection in inpatient liver transplant population. Transpl Infect Dis, 2022; 24(1):13750; doi: 10.1111/tid.13750

158.

Johnson

, Lavergne

, Skinner

, et al. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis, 2021; 73(5):1029–1044; doi: 10.1093/cid/ciab549

159.

Cheng

Y-W

, Phelps

, Ganapini

, et al. Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience. Am J Transplant, 2019; 19(2):501–511; doi: 10.1111/ajt.15058

160.

Rabkin

, Oroloff

, Corless

, et al. Association of fungal infection and increased mortality in liver transplant recipients. Am J Surg, 2000; 179(5):426–430; doi: 10.1016/s0002-9610(00)00366-4

161.

Eschenauer

, Kwak

, Humar

, et al. Targeted versus universal antifungal prophylaxis among liver transplant recipients. Am J Transplant, 2015; 15(1):180–189; doi: 10.1111/ajt.12993

162.

Singh

Fungal infections in the recipients of solid organ transplantation. Infect Dis Clin North Am, 2003; 17(1):113–134, viii; doi: 10.1016/s0891-5520(02)00067-3

163.

Singh

, Paterson

. Aspergillus infections in transplant recipients. Clin Microbiol Rev, 2005; 18(1):44–69; doi: 10.1128/CMR.18.1.44-69.2005

164.

Karchmer

, Samore

, Hadley

, et al. Fungal infections complicating orthotopic liver transplantation. Trans Am Clin Climatol Assoc, 1995; 106:38.

165.

Pappas

, Andes

, Schuster

, et al. Invasive fungal infections in low-risk liver transplant recipients: A multi-center prospective observational study. Am J Transplant, 2006; 6(2):386–391; doi: 10.1111/j.1600-6143.2005.01176.x

166.

Eschenauer

, Lam

, Carver

. Antifungal prophylaxis in liver transplant recipients. Liver Transplant, 2009; 15(8):842–858; doi: 10.1002/lt.21826

167.

Neofytos

, Fishman

, Horn

, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis, 2010; 12(3):220–229; doi: 10.1111/j.1399-3062.2010.00492.x

168.

Pappas

, Kauffman

, Andes

, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis, 2009; 48(5):503–535; doi: 10.1086/596757

169.

Silveira

, Kusne

. Candida infections in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):220–227; doi: 10.1111/ajt.12114

170.

Shoham

, Marr

. Invasive fungal infections in solid organ transplant recipients. Future Microbiol, 2012; 7(5):639–655; doi: 10.2217/fmb.12.28

171.

Theodoropoulos

, Bolstorff

, Bozorgzadeh

, et al. Candida auris outbreak involving liver transplant recipients in a surgical intensive care unit. Am J Transplant, 2020; 20(12):3673–3679; doi: 10.1111/ajt.16144

172.

Candida Auris. 2018. About Candida auris (C. auris) | Candida auris | Fungal Diseases | CDC. Available from: https://www.cdc.gov/fungal/candida-auris/candida-auris-qanda.html [Last assessed: October 28, 2023]

173.

Barchiesi

, Mazzocato

, Mazzanti

, et al. Invasive aspergillosis in liver transplant recipients: Epidemiology, clinical characteristics, treatment, and outcomes in 116 cases. Liver Transplant, 2015; 21(2):204–212; doi: 10.1002/lt.24032

174.

Fortún

, Martín-Dávila

, Moreno

, et al. Risk factors for invasive aspergillosis in liver transplant recipients. Liver Transplant, 2002; 8(11):1065–1070; doi: 10.1053/jlts.2002.36239

175.

Patterson

, Thompson

GR 3rd

, Denning

, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis, 2016; 63(4):1–60; doi: 10.1093/cid/ciw326

176.

Singh

, Husain

. Aspergillosis in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):228–241; doi: 10.1111/ajt.12115

177.

Silveira

, Husain

, Kwak

, et al. Cryptococcosis in liver and kidney transplant recipients receiving anti-thymocyte globulin or alemtuzumab. Transpl Infect Dis, 2007; 9(1):22–27; doi: 10.1111/j.1399-3062.2006.00149.x

178.

Baddley

, Forrest

. Cryptococcosis in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):242–249; doi: 10.1111/ajt.12116

179.

Kauffman

, Malani

. Zygomycosis: An emerging fungal infection with new options for management. Curr Infect Dis Rep, 2007; 9(6):435–440; doi: 10.1007/s11908-007-0066-4

180.

Park

, Pappas

, Wannemuehler

, et al. Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001–2006. Emerg Infect Dis, 2011; 17(10):1855–1864; doi: 10.3201/eid1710.110087

181.

Singh

, Aguado

, Bonatti

, et al. Zygomycosis in solid organ transplant recipients: A prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis, 2009; 200(6):1002–1011; doi: 10.1086/605445

182.

Almyroudis

, Sutton

, Linden

, et al. Zygomycosis in solid organ transplant recipients in a tertiary transplant center and review of the literature. Am J Transplant, 2006; 6(10):2365–2374; doi: 10.1111/j.1600-6143.2006.01496.x

183.

Hammond

, Bialek

, Milner

, et al. Molecular methods to improve diagnosis and identification of mucormycosis. J Clin Microbiol, 2011; 49(6):2151–2153; doi: 10.1128/JCM.00256-11

184.

Farmakiotis

, Kontoyiannis

. Mucormycoses. Infect Dis Clin North Am, 2016; 30(1):143–163; doi: 10.1016/j.idc.2015.10.011

185.

Chamilos

, Lewis

, Kontoyiannis

. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis, 2008; 47(4):503–509; doi: 10.1086/590004

186.

Reserved

. Mucormycosis (zygomycosis). 2023. Mucormycosis (zygomycosis) - UpToDate. Available from: https://www.uptodate.com/contents/mucormycosis-zygomycosis [Last assessed: July 30, 2023].

187.

Kontoyiannis

, Lewis

. How I treat mucormycosis. Blood, 2011; 118(5):1216–1224; doi: 10.1182/blood-2011-03-316430

188.

Fillatre

, Decaux

, Jouneau

, et al. Incidence of Pneumocystis jiroveci pneumonia among groups at risk in HIV-negative patients. Am J Med, 2014; 127(12):1242; doi: 10.1016/j.amjmed.2014.07.010

189.

Fishman

, Gans

. Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 2019; 33(9):e13587; doi: 10.1111/ctr.13587

190.

Martin

, Fishman

. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):272–279; doi: 10.1111/ajt.12119

191.

Stauffer

, Ahn

. Pneumocystis jiroveci pneumonia prophylaxis in patients with autoimmune hepatitis. Clin Liver Dis, 2022; 20(3):86–89; doi: https://doi.org/10.1002/cld.1233

192.

Fortea

, Cuadrado

, Puente Á, et al. Is routine prophylaxis against Pneumocystis jirovecii needed in liver transplantation? A retrospective single-centre experience and current prophylaxis strategies in Spain. J Clin Med, 2020; 9(11):3573; doi: 10.3390/jcm9113573

193.

Cooley

, Dendle

, Wolf

, et al. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J, 2014; 44(12b):1350–1363; doi: 10.1111/imj.12599

194.

Kauffman

, Freifeld

, Andes

, et al. Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET). Transpl Infect Dis, 2014; 16(2):213–224; doi: 10.1111/tid.12186

195.

Nel

, Bartelt

, van Duin

, et al. Endemic mycoses in solid organ transplant recipients. Infect Dis Clin North Am, 2018; 32(3):667–685; doi: 10.1016/j.idc.2018.04.007

196.

Schwartz

, Mawhorter

. Parasitic infections in solid organ transplantation. Am J Transplant, 2013; 13(Suppl 4):280–303; doi: 10.1111/ajt.12120

197.

Toxoplasmosis-Epidemiology & Risk Factors. September 2018. CDC - Toxoplasmosis - Epidemiology & Risk Factors. Available from: https://www.cdc.gov/parasites/toxoplasmosis/epi.html [Last assessed: February 11, 2024].

198.

McCall

, Rothfeldt

, Giesbrecht

, et al. Public Health surveillance and reporting for human toxoplasmosis: Six states, 2021. MMWR Morb Mortal Wkly Rep, 2022; 71(28):889–893; doi: 10.15585/mmwr.mm7128a1

199.

Jones

, Kruszon-Moran

, Rivera

, et al. Toxoplasma gondii seroprevalence in the United States 2009–2010 and comparison with the past two decades. Am J Trop Med Hyg, 2014; 90(6):1135–1139; doi: 10.4269/ajtmh.14-0013

200.

Assi

, Rosenblatt

, Marshall

. Donor-transmitted toxoplasmosis in liver transplant recipients: A case report and literature review. Transpl Infect Dis, 2007; 9(2):132–136; doi: 10.1111/j.1399-3062.2006.00187.x

201.

Botterel

, Ichai

, Feray

, et al. Disseminated toxoplasmosis, resulting from infection of allograft, after orthotopic liver transplantation: Usefulness of quantitative PCR. J Clin Microbiol, 2002; 40(5):1648–1650; doi: 10.1128/JCM.40.5.1648-1650.2002

202.

Souza

, Castro-E-Silva

, Marin Neto

, et al. Acute chagasic myocardiopathy after orthotopic liver transplantation with donor and recipient serologically negative for Trypanosoma cruzi: A case report. Transplant Proc, 2008; 40(3):875–878; doi: 10.1016/j.transproceed.2008.02.032

203.

Clemente

, Rabello

, Faria

, et al. High prevalence of asymptomatic Leishmania spp. infection among liver transplant recipients and donors from an endemic area of Brazil. Am J Transplant, 2014; 14(1):96–101; doi: 10.1111/ajt.12521

204.

Eisen

, Eisen

. The blacklegged tick, Ixodes scapularis: An increasing public health concern. Trends Parasitol, 2018; 34(4):295–309; doi: 10.1016/j.pt.2017.12.006

205.

Florescu

, Sandkovsky

. Cryptosporidium infection in solid organ transplantation. World J Transplant, 2016; 6(3):460–471; doi: 10.5500/wjt.v6.i3.460

206.

Machiels

, Cremers

AJH

, van Bergen-Verkuyten

MCGT

, et al. Impact of the BioFire FilmArray gastrointestinal panel on patient care and infection control. PLoS One, 2020; 15(2):0228596; doi: 10.1371/journal.pone.0228596

207.

Sparkes

, Lemonovich

. Interactions between anti-infective agents and immunosuppressants: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 2019; 33(9):13510; doi: 10.1111/ctr.13510

208.

Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement. 2021. AASLD COVID-19 Expert Panel Consensus Statement Update 11.02.2021 (1).pdf. Available from: https://www.aasld.org/sites/default/files/2022-04/AASLD%20COVID-19%20Expert%20Panel%20Consensus%20Statement%20Update%2011.02.2021%20%281%29.pdf [Last assessed: March 29, 2023].

209.

Fan

, Zhang

, Ma

, Zhang

. Safety profile of the antiviral drug remdesivir: An update. Biomed Pharmacother, 2020; 130:110532; doi: 10.1016/j.biopha.2020.110532

210.

Papp-Wallace

, Endimiani

, Taracila

, Bonomo

. Carbapenems: past, present, and future. Antimicrob Agents Chemother, 2011; 55(11):4943–4960; doi: 10.1128/AAC.00296-11

211.

Philpott-Howard

, Burroughs

, Fisher

, et al. Piperacillin-tazobactam versus ciprofloxacin plus amoxicillin in the treatment of infective episodes after liver transplantation. J Antimicrob Chemother, 2003; 52(6):993–1000; doi: 10.1093/jac/dkg463

212.

Denning

DW.

Echinocandin antifungal drugs. Lancet, 2003; 362(9390):1142–1151; doi: 10.1016/S0140-6736(03)14472-8

213.

Jang

, Chung

. Diagnosis and treatment of multidrug-resistant tuberculosis. Yeungnam Univ J Med, 2020; 37(4):277–285; doi: 10.12701/yujm.2020.00626

214.

Babar

, Nasim

, Kumar

, et al. A case series of multidrug-resistant tuberculosis in renal transplant recipients: Challenges in management from a TB endemic country. Transpl Infect Dis, 2021; 23(4):13659; doi: 10.1111/tid.13659

215.

Pouch

, Patel

. Multidrug-resistant gram-negative bacterial infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 2019; 33(9):13594; doi: 10.1111/ctr.13594